Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus.

PubMed

Lu, P; Fleischmann, R; Curtis, C; Ignatenko, S; Clarke, S H; Desai, M; Wong, S L; Grebe, K M; Black, K; Zeng, J; Stolzenbach, J; Medema, J K

2018-02-01

Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.

The maximum single dose of resistant maltodextrin that does not cause diarrhea in humans.

PubMed

Kishimoto, Yuka; Kanahori, Sumiko; Sakano, Katsuhisa; Ebihara, Shukuko

2013-01-01

The objective of the present study was to determine the maximum dose of resistant maltodextrin (Fibersol)-2, a non-viscous water-soluble dietary fiber), that does not induce transitory diarrhea. Ten healthy adult subjects (5 men and 5 women) ingested Fibersol-2 at increasing dose levels of 0.7, 0.8, 0.9, 1.0, and 1.1 g/kg body weight (bw). Each administration was separated from the previous dose by an interval of 1 wk. The highest dose level that did not cause diarrhea in any subject was regarded as the maximum non-effective level for a single dose. The results showed that no subject of either sex experienced diarrhea at dose levels of 0.7, 0.8, 0.9, or 1.0 g/kg bw. At the highest dose level of 1.1 g/kg bw, no female subject experienced diarrhea, whereas 1 male subject developed diarrhea with muddy stools 2 h after ingestion of the test substance. Consequently, the maximum non-effective level for a single dose of the resistant maltodextrin Fibersol-2 is 1.0 g/kg bw for men and >1.1 g/kg bw for women. Gastrointestinal symptoms were gurgling sounds in 4 subjects (7 events) and flatus in 5 subjects (9 events), although no association with dose level was observed. These symptoms were mild and transient and resolved without treatment.

Single-dose lubiprostone along with split-dose PEG solution without dietary restrictions for bowel cleansing prior to colonoscopy: a randomized, double-blind, placebo-controlled trial.

PubMed

Stengel, Joel Z; Jones, David P

2008-09-01

Proper colonic cleansing prior to colonoscopy is paramount to ensuring complete mucosal visualization and polyp identification. In a double-blind fashion, we compared single-dose lubiprostone (24 microg) versus placebo pretreatment prior to a split-dose polyethylene glycol electrolyte (PEG-E) bowel preparation without dietary restriction to determine the efficacy, safety, and patient tolerability. Two hundred patients referred for outpatient colorectal cancer screening were randomized to receive a single-dose of unlabeled lubiprostone (24 microg) or placebo prior to a split-dose PEG-E bowel preparation without dietary restriction. The patients were surveyed prior to the colonoscopy on the tolerability of the bowel preparation, and any adverse events were recorded. The cleanliness of the colon was graded by the endoscopist during the procedure utilizing the Ottawa bowel preparation scale. One hundred ninety-one patients completed the study (95%). Split-dose PEG-E with lubiprostone pretreatment was found to be more effective at bowel cleansing in each segment of the colon when compared with split-dose PEG-E with placebo (P < 0.001). Patients enrolled in the lubiprostone treatment arm rated the overall experience as more tolerable (P 0.003) and complained of less abdominal bloating (P 0.049). No differences were observed between the groups for treatment-emergent side effects or adverse events (P > 0.05). Single-dose lubiprostone prior to split-dose PEG-E without dietary restriction significantly improves colonic mucosa visualization during colonoscopy and is well tolerated by patients.

Single dose oral paracetamol (acetaminophen) for postoperative pain in adults

PubMed Central

Toms, Laurence; McQuay, Henry J; Derry, Sheena; Moore, R Andrew

2014-01-01

Background This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on ‘Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain’. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way. Objectives To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain. Search methods We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Area under the “pain relief versus time” curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected. Main results Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 500 mg NNT 3.5 (2.7 to 4.8); 600 to 650 mg NNT 4.6 (3.9 to 5.5); 975 to 1000 mg NNT 3.6 (3.4 to 4.0). There was no dose response. Sensitivity analysis showed no significant effect of trial size or quality on this outcome. About half of participants needed additional analgesia over four to six hours, compared with about 70% with placebo. Five people would need to be treated with 1000 mg paracetamol, the most commonly used dose, to prevent one needing rescue medication over four to six hours, who would have needed it with placebo. Adverse event reporting was inconsistent and often incomplete. Reported adverse events were mainly mild and transient, and occurred at similar rates with 1000 mg paracetamol and placebo. No serious adverse events were reported. Withdrawals due to adverse events were uncommon and occurred in both paracetamol and placebo treatment arms. Authors’ conclusions A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events. PMID:18843665

Safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole sodium injections after single and multiple intravenous doses in healthy Chinese subjects.

PubMed

Jiao, Hui-Wen; Sun, Lu-Ning; Li, Yue-Qi; Yu, Lei; Zhang, Hong-Wen; Wang, Mei-Feng; Yu, Li-Yuan; Yuan, Zi-Qing-Yun; Xie, Li-Jun; Chen, Juan; Meng, Ling; Zhang, Xue-Hui; Wang, Yong-Qing

2018-03-01

The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole (PPZ) sodium injections following single and multiple intravenous doses in healthy Chinese subjects. The dosage groups were set as followed: 20 mg of single and multiple intravenous administration of S-(-)-PPZ, 40 mg of single and multiple intravenous administration of S-(-)-PPZ or pantoprazole, and 80 mg of single dosage group of S-(-)-PPZ. Subjects were sampled for pharmacokinetic analysis and were monitored for 24-h intragastric pH prior to and 48-h intragastric pH after administration for the pharmacodynamic study. The pharmacokinetic and pharmacodynamic parameters were compared between S-(-)-PPZ and PPZ. Safety was evaluated on the basis of adverse events, vital signs, laboratory tests, and physical examination. All adverse events were mild and of limited duration. Maximum plasma concentration and area under the concentration-time curve for S-(-)-PPZ were dose proportional over the range of 20-80 mg following a single intravenous administration. Elimination rate constant and half-life observed statistical difference from a single dose to multiple doses in 40 mg of S-(-)-PPZ groups. After administration of a single dose, the mean 24-h intragastric pH value was observed higher in 80-mg group than in 40- and 20-mg groups. Slightly increase of intragastric pH was found after a single dose of 40 mg S-(-)-PPZ than 40 mg PPZ; however, the differences were not statistically significant. Twice daily of 40 mg S-(-)-PPZ sodium injections is effective in achieving satisfying acid inhibition. Compared with plasma R-(+)-PPZ levels, most subjects presented more potent and prolonged suppression of gastric acid of S-(-)-PPZ, while a few subjects showed faster metabolic rate of S-(-)-PPZ in vivo.

Inactivated yellow fever 17D vaccine: development and nonclinical safety, immunogenicity and protective activity.

PubMed

Monath, Thomas P; Lee, Cynthia K; Julander, Justin G; Brown, Alicja; Beasley, David W; Watts, Douglas M; Hayman, Edward; Guertin, Patrick; Makowiecki, Joseph; Crowell, Joseph; Levesque, Philip; Bowick, Gavin C; Morin, Merribeth; Fowler, Elizabeth; Trent, Dennis W

2010-05-14

In the last 10 years new concerns have arisen about safety of the live, attenuated yellow fever (YF) 17D vaccine, in particular viscerotropic adverse events, which have a case-fatality rate of 64%. A non-replicating cell culture-based vaccine would not cause these adverse events, and potentially could be used in persons with precautions or contraindications to use of the live vaccine, including age <9 months and >60 years, egg allergy, immune suppression, and pregnancy. We developed a whole virion vaccine from the 17D strain inactivated with beta-propiolactone, and adsorbed to aluminum hydroxide. The inactivated vaccine was highly immunogenic in mice, hamsters, and cynomolgus macaques. After a single dose in hamsters and macaques, neutralizing antibody titers were similar to those elicited by the live 17D vaccine (YF-VAX, Sanofi Pasteur). After two doses of inactivated vaccine, neutralizing antibody titers in hamsters were significantly higher than after a single dose of YF-VAX [geometric mean titer (GMT) 20,480 vs. 1940, respectively (P<0.001, ANOVA)]. Hamsters given a single dose or two doses of inactivated vaccine or a single dose of YF-VAX were fully protected against hepatitis, viremia, weight loss and death after challenge with YF virus (Jimenez strain). A clinical trial of the inactivated vaccine (XRX-001) has been initiated. Copyright 2010 Elsevier Ltd. All rights reserved.

Single dose oral diclofenac for acute postoperative pain in adults

PubMed Central

Derry, Philip; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

2014-01-01

Background Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), available as a potassium salt (immediate-release) or sodium salt (delayed-release). This review updates an earlier review published in The Cochrane Database of Systematic Reviews (Issue 2, 2004) on ‘Single dose oral diclofenac for postoperative pain’. Objectives To assess single dose oral diclofenac for the treatment of acute postoperative pain. Search methods Cochrane CENTRAL, MEDLINE, EMBASE, Biological Abstracts, the Oxford Pain Relief Database, and reference lists of articles were searched; last search December 2008. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of single dose, oral diclofenac (sodium or potassium) for acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed studies for inclusion and quality, and extracted data. The area under the pain relief versus time curve was used to derive the proportion of participants with at least 50% pain relief over 4 to 6 hours, using validated equations. Relative benefit (risk) and number needed to treat to benefit (NNT) were calculated. Information on adverse events, time to remedication, and participants needing additional analgesia was also collected. Main results Fifteen studies (eight additional studies) with 1512 participants more than doubled the information available at each dose. Overall 50% to 60% of participants experienced at least 50% pain relief over 4 to 6 hours at any dose with diclofenac, compared to 10 to 20% with placebo, giving NNTs of about 2.5 for doses of 25 mg to 100 mg (similar to earlier review); no dose response was demonstrated. At 50 mg and 100 mg, NNTs for diclofenac potassium (2.1 (1.8 to 2.4) and 1.9 (1.7 to 2.2)) were significantly lower (better) than for diclofenac sodium (6.7 (4.2 to 17) and 4.5 (3.2 to 7.7)). The median time to use of rescue medication was 2 hours for placebo, 4.3 hours for diclofenac 50 mg and 4.9 hours for diclofenac 100 mg. Adverse events were reported at a similar rate to placebo, with no serious events. Authors’ conclusions Oral diclofenac is an effective single-dose treatment for moderate to severe postoperative pain. Significantly more participants experienced at least 50% pain relief over 4 to 6 hours with diclofenac potassium than with diclofenac sodium. There was no significant difference between diclofenac and placebo in the incidence of adverse events. PMID:19370609

The risk of solar proton events to space missions

NASA Technical Reports Server (NTRS)

Burrell, M. O.

1972-01-01

The total dose in rads-tissue from solar protons was tabulated for weekly time intervals, and the number of weeks which gave a dose above 25 rads behind 10 g/sq cm of aluminum for the active 6 years of the 19th cycle were called dangerous or large event weeks. The number of such event weeks was found to be only 3 weeks for the past 20 years. Even though the chance for smaller events is examined, it was found that for any reasonable, high confidence level (95%), the smaller events could be ignored. Consequently, the total particle flux for the 19th cycle was divided by a factor of 3 and determined a single large event week. Using this spectrum, the tissue dose in rads is calculated at the center of an aluminum spherical shell.

Current Single Event Effects and Radiation Damage Results for Candidate Spacecraft Electronics

NASA Technical Reports Server (NTRS)

OBryan, Martha V.; LaBel, Kenneth A.; Reed, Robert A.; Ladbury, Ray L.; Howard, James W., Jr.; Kniffin, Scott D.; Poivey, Christian; Buchner, Stephen P.; Bings, John P.; Titus, Jeff L.

2002-01-01

We present data on the vulnerability of a variety of candidate spacecraft electronics to proton and heavy ion induced single event effects, total ionizing dose and proton-induced damage. Devices tested include optoelectronics, digital, analog, linear bipolar, hybrid devices, Analog-to-Digital Converters (ADCs), Digital-to-Analog Converters (DACs), and DC-DC converters, among others.

Investigation of the Semicoa SCF9550 and the International Rectifier IRHM57260SE for Single-Event Gate Rapture and Single-Event Burnout : NASA Electronic Parts and Packaging (NEPP) Program Office of Safety and Mission Assurance

NASA Technical Reports Server (NTRS)

Scheick, Leif

2011-01-01

Single-event-effect test results for hi-rel total-dose-hardened power MOSFETs are presented in this report. TheSCF9550 from Semicoa and the IRHM57260SE from International Rectifier were tested to NASA test condition/standards and requirements.The IRHM57260SE performed much better when compared to previous testing. These initial results confirm that parts from the Temecula line are marginally comparable to the El Segundo line. The SCF9550 from Semicoa was also tested and represents the initial parts offering from this vendor. Both parts experienced single-event gate rupture (SEGR) and single-event burnout (SEB). All of the SEGR was from gate to drain.

Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes.

PubMed

Hatorp, V; Huang, W C; Strange, P

1999-04-01

Pharmacokinetic profiles of single- and multiple-dose regimens of repaglinide were evaluated in 12 elderly subjects with type 2 diabetes. On day 1, following a 10-hour fast, subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, each subject received a 2-mg dose of repaglinide 15 minutes before each of the three main meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve (AUC), log(AUC), maximal concentration (Cmax), log(Cmax), time to maximal concentration (Tmax), and half-life (T(1/2)), were determined at completion of the single- and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7. The mean log(AUC) values after multiple dosing were significantly higher than the values obtained after a single dose. The mean values for log(Cmax), and Tmax were comparable after each dosing regimen. The T(1/2) of repaglinide after multiple dosing was 1.7 hours. The trough values for repaglinide were low. No hypoglycemic events were reported. The pharmacokinetic profiles of repaglinide after single- and multiple-dose regimens were similar, and repaglinide was well tolerated by elderly subjects with type 2 diabetes.

The effects of recombinant activated factor VII dose on the incidence of thromboembolic events in patients with coagulopathic bleeding.

PubMed

Bucklin, Mason H; Acquisto, Nicole M; Nelson, Catherine

2014-05-01

Previous studies have suggested the used of off-label recombinant factor VII (rFVIIa) increases the risk of thromboembolic events, but the effect of the dose of rFVIIa is not well described in the literature. All adult patients that received off-label rFVIIa from 2005-2012 were included in this single-center, retrospective cohort study. The primary endpoint was the incidence of a thromboembolic event in the low dose (<50 mcg/kg) compared to the high dose (≥50 mcg/kg) cohort. Secondary endpoints compared time to thromboembolic event, incidence of arterial compared to venous events, and mortality. There were 152 patients that received rFVIIa during the study period with 66 in the low dose cohort and 86 in the high dose cohort. Mean total dose of rFVIIa was 30.2 mcg/kg (SD ± 9.5 mcg/kg) in the low dose and 99.8 mcg/kg (SD ± 64.7 mcg/kg) in the high dose cohort (p=0.0001). The overall incidence of thromboembolic events was 12.5%. There were 12 (14%) events in the low dose cohort and seven (10.6%) in the high dose cohort, RR=0.76 (95% CI 0.31-1.82). There were no differences in any of the secondary outcomes. A higher incidence of thromboembolic events in cardiothoracic surgery (20.8%) and penetrating trauma patients (21.4%) was seen compared to the remaining cohort (6.7%). No significant difference in the incidence of thromboembolic events was seen between low dose versus high dose rFVIIa over a seven year period at our institution. However, due to the relatively low overall incidence and a small sample size, type II error may be present. Copyright © 2014 Elsevier Ltd. All rights reserved.

A 0.18 micrometer CMOS Thermopile Readout ASIC Immune to 50 MRAD Total Ionizing Dose (SI) and Single Event Latchup to 174MeV-cm(exp 2)/mg

NASA Technical Reports Server (NTRS)

Quilligan, Gerard T.; Aslam, Shahid; Lakew, Brook; DuMonthier, Jeffery J.; Katz, Richard B.; Kleyner, Igor

2014-01-01

Radiation hardened by design (RHBD) techniques allow commercial CMOS circuits to operate in high total ionizing dose and particle fluence environments. Our radiation hard multi-channel digitizer (MCD) ASIC (Figure 1) is a versatile analog system on a chip (SoC) fabricated in 180nm CMOS. It provides 18 chopper stabilized amplifier channels, a 16- bit sigma-delta analog-digital converter (SDADC) and an on-chip controller. The MCD was evaluated at Goddard Space Flight Center and Texas A&M University's radiation effects facilities and found to be immune to single event latchup (SEL) and total ionizing dose (TID) at 174 MeV-cm(exp 2)/mg and 50 Mrad (Si) respectively.

Single Event Effects and Total Dose Testing of the Intersil ISL 70003SEH Integrated Point of Load Converter

NASA Astrophysics Data System (ADS)

van Vonno, N. W.; White, J. D.; Pearce, L. G.; Thomson, E. J.; Gill, J. S.; Mansilla, O. E.

2014-08-01

Single-event transient (SET) phenomena in power management applications has evolved into a key issue, particularly in point of load (POL) buck regulators, as the loads driven by these devices are sensitive to even short-term overvoltage conditions. We preface this paper by a discussion of earlier destructive and nondestructive SEE testing of Intersil integrated point of load regulators, with emphasis on SET phenomena and some of the lessons learned in this work. We then report recent results of SET and destructive SEE testing of the ISL70003SEH POL converter, together with a brief discussion of the part's electrical and radiation hardness specifications. We conclude with a brief overview of low and high dose rate total dose testing of the part.

Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects.

PubMed

Shin, Dongseong; Lee, SeungHwan; Yi, Sojeong; Yoon, Seo Hyun; Cho, Joo-Youn; Bahng, Mi Young; Jang, In-Jin; Yu, Kyung-Sang

2017-01-01

DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects. A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated. After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2-3 h and was eliminated with terminal elimination half-life of 17.9-28.7 h. The mean renal clearance was 3.7-5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20-80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized C max and AUC 0- t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported. In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20-80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less.

Treatment of Human Scabies with Oral Ivermectin. Eczematous Eruptions as a New Non-Reported Adverse Event.

PubMed

Sanz-Navarro, J; Feal, C; Dauden, E

2017-09-01

Oral ivermectin is an alternative therapy for human scabies infection due to its ease of administration and good safety profile. However, there is no definitive consensus on the optimal dosing regimen. To describe the treatment of human scabies with different dosages of oral ivermectin and the possible adverse events. 23 patients with human scabies were treated with oral ivermectin: 10 patients received a single oral dose of 200μg/kg and 13 a dose of 400μg/kg. A second, or even a third dose, was administered in cases of treatment failure. A complete clinical response was achieved by all of the patients. The first ten patients required at least two (80%) or three (20%) doses of ivermectin for complete resolution of the infection. The remaining cases resolved with a single 400μg/kg oral dose. Within the first 72h after the administration of oral ivermectin, new cutaneous lesions were observed in eleven patients (47.8%). Cutaneous biopsies showed signs of subacute eczema. The eruption was treated with topical corticosteroids and emollient therapy. There was no other new drug administration or a history of irritants. There was no history of atopic diathesis except for one patient. Oral ivermectin is an effective therapy for the treatment of human scabies. A single 400μg/kg oral dose demonstrated high efficacy and good tolerance. However, the appearance of eczematous cutaneous lesions induced by oral ivermectin has not previously been reported in the literature. Dermatologists should be aware of this possible adverse event. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Rad-Hard/HI-REL FPGA

NASA Technical Reports Server (NTRS)

Wang, Jih-Jong; Cronquist, Brian E.; McGowan, John E.; Katz, Richard B.

1997-01-01

The goals for a radiation hardened (RAD-HARD) and high reliability (HI-REL) field programmable gate array (FPGA) are described. The first qualified manufacturer list (QML) radiation hardened RH1280 and RH1020 were developed. The total radiation dose and single event effects observed on the antifuse FPGA RH1280 are reported on. Tradeoffs and the limitations in the single event upset hardening are discussed.

Radiation Tests on 2Gb NAND Flash Memories

NASA Technical Reports Server (NTRS)

Nguyen, Duc N.; Guertin, Steven M.; Patterson, J. D.

2006-01-01

We report on SEE and TID tests of highly scaled Samsung 2Gbits flash memories. Both in-situ and biased interval irradiations were used to characterize the response of the total accumulated dose failures. The radiation-induced failures can be categorized as followings: single event upset (SEU) read errors in biased and unbiased modes, write errors, and single-event-functional-interrupt (SEFI) failures.

Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women
.

PubMed

Schultze-Mosgau, Marcus-Hillert; Schuett, Barbara; Hafner, Frank-Thorsten; Zollmann, Frank; Kaiser, Andreas; Hoechel, Joachim; Rohde, Beate

2017-01-01

Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids. In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and - after a wash-out period - daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28). Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 - 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 µg/L (1 mg) to 68.6 µg/L (30 mg) and 58.5 µg×h/L to 1,590 µg×h/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0-24)md/AUC(0-24)sd ratios: 1.9 to 3.2). The ratio AUC(0-24)md/AUCsd increased with dose from ~ 1 (1 mg) to 1.5 (30 mg). Exposure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t1/2, indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range.
.

Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects.

PubMed

Harrell, Robert E; Karim, Aziz; Zhang, Wencan; Dudkowski, Caroline

2016-05-01

Azilsartan medoxomil (AZL-M) is an angiotensin II receptor blocker approved to treat hypertension. After oral dosing, AZL-M is quickly hydrolyzed to azilsartan (AZL). The aims of this study were to assess the effects of age, sex, and race on the pharmacokinetics of AZL-M in healthy subjects, as well as safety and tolerability. Sixty-one healthy adults were enrolled in this phase I, single-blind, randomized placebo-controlled study (placebo control was for assessment of safety/tolerability only). Subjects were stratified by age (18-45 vs. 65-85 years), sex, and race (black vs. white) and given oral AZL-M 60 mg (3 × 20 mg capsules) or placebo as a single dose (Day 1) and consecutive daily doses (Days 4-8) (6:2 ratio for AZL-M:placebo per group). Pharmacokinetics were evaluated (AZL-M patients only) on Days 1-3 and 8-9 and safety/tolerability was monitored. Age, sex, and race had no clinically meaningful effect on AZL exposures after single or multiple dosing. Pharmacokinetic parameters remained similar between Days 1 and 8 for each age, sex, and race subgroup. The frequency of adverse events was similar for AZL-M (32%) and placebo (29%). No discontinuations or serious adverse events occurred. Based on these pharmacokinetic and safety/tolerability findings, no AZL-M dose adjustments are required based on age, sex, or race (black/white).

Pharmacokinetic Properties and Tolerability of Cycloserine Following Oral Administration in Healthy Chinese Volunteers: A Randomized, Open-Label, Single- and Multiple-Dose 3-Way Crossover Study.

PubMed

Zhou, Huili; Wu, Guolan; Hu, Xingjiang; Zhu, Meixiang; Zhai, You; Liu, Jian; Shentu, Jianzhong; Wu, Lihua

2015-06-01

A new generic formulation of cycloserine has been developed in China but the pharmacokinetic properties of cycloserine in the Chinese population have not been reported. The aim of our study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of cycloserine capsules in healthy Chinese volunteers. This open-label, single- and multiple-dose 3-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of cycloserine (250, 500, or 1000 mg) in separate trial periods, with a 1-week washout between periods. Those allocated to the 250-mg dose continued into the multiple-dose phase, in which they received 250 mg BID for 5 consecutive days. During the single-dose phase, blood samples were collected at regular intervals from 0 to 72 hours after drug administration and the concentrations of cycloserine were determined using LC-MS/MS. During the multiple-dose phase, blood samples were obtained before drug administration on Days 4, 5, and 6 to determine the Cmin at steady state. On Day 6, blood samples were also collected from 0 to 72 hours after drug administration. Pharmacokinetic parameters were estimated using noncompartmental methods. Tolerability was determined using clinical evaluation and monitoring of adverse events. The study enrolled 12 healthy Chinese volunteers (6 men: mean [SD] age = 23.0 [2.6] years, weight = 60.2 [6.2] kg, height = 170.0 [3.0] cm, and body mass index = 20.7 [1.7]; 6 women: mean [SD] age = 25.3 [1.4] years, weight = 51.5 [3.3] kg, height = 160.0 [4.0] cm, and body mass index = 20.1 [0.9]). After administration of a single dose, cycloserine was rapidly absorbed, reaching peak plasma concentrations approximately 0.84 hours after oral administration, and t½ in plasma was about 13.0 hours. The geometric mean (SD) Cmax value increased in proportion to cycloserine dose, from 19.42 (5.89) to 84.76 (21.74) mg/L, and the geometric mean (SD) AUC0-72h value increased from 264.16 (133.37) to 1153.87 (522.16) mg·h/L in the range of a 250- to 1000-mg dose. After administration of multiple doses of cycloserine 250 mg BID, the mean (SD) t½ was 13.56 (4.38) hours, the apparent total clearance of the drug from plasma after oral administration was 1.02 (0.42) L/h, and the apparent volume of distribution was 18.22 (5.25) L, which were comparable with those after single dosing. The accumulation index was 2.19 (0.51), and the fluctuation was 1.05 (0.35). Results of the t tests of Cmax and AUC found no significant differences between the male and female groups. No serious adverse events were reported, and there were no discontinuations due to adverse events. The pharmacokinetic properties of cycloserine were linear at doses from 250 mg to 1000 mg. After multiple doses, the pharmacokinetic properties of cycloserine were consistent with those after single doses. At the doses studied, cycloserine appears to be well tolerated in these healthy volunteers. Chinese Clinical Trials registration: ChiCTR-TTRCC-13003982. Copyright © 2015. Published by Elsevier Inc.

Safety and immunogenicity of ricin vaccine, RVEc™, in a Phase 1 clinical trial.

PubMed

Pittman, Phillip R; Reisler, Ronald B; Lindsey, Changhong Y; Güereña, Fernando; Rivard, Robert; Clizbe, Denise P; Chambers, Matthew; Norris, Sarah; Smith, Leonard A

2015-12-16

Ricin is a potent toxin and potential bioterrorism weapon for which no specific licensed countermeasures are available. We report the safety and immunogenicity of the ricin vaccine RVEc™ in a Phase 1 (N=30) multiple-dose, open-label, non-placebo-controlled, dose-escalating (20, 50, and 100μg), single-center study. Each subject in the 20- and 50-μg dose groups (n=10 for each group) received three injections at 4-week intervals and was observed carefully for untoward effects of the vaccine; blood was drawn at predetermined intervals after each dose for up to 1 year. RVEc™ was safe and well tolerated at the 20- and 50-μg doses. The most common adverse events were pain at the injection site and headache. Of the 10 subjects who received a single 100-μg dose, two developed elevated creatine phosphokinase levels, which resolved without sequelae. No additional doses were administered to subjects in the 100-μg group. Immunogenicity of the vaccine was evaluated by measuring antibody response using the well standardized enzyme-linked immunosorbent assay (ELISA) and toxin neutralization assay (TNA). Of the subjects in the 20- and 50-μg dose groups, 100% achieved ELISA anti-ricin IgG titers of 1:500 to 1:121,500 and 50% produced neutralizing anti-ricin antibodies measurable by TNA. Four subjects in the 50-μg group received a single booster dose of RVEc™ 20-21 months after the initial dose. The single booster was safe and well tolerated, resulting in no serious adverse events, and significantly enhanced immunogenicity of the vaccine in human subjects. Each booster recipient developed a robust anamnestic response with ELISA anti-ricin IgG titers of 1:13,500 to 1:121,500 and neutralizing antibody titers of 1:400 to 1:3200. Future studies will attempt to optimize dose, scheduling, and route of administration. This study is registered at clinicaltrials.gov (NCT01317667 and NCT01846104). Published by Elsevier Ltd.

Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects.

PubMed

Anderson, Matt S; Gilmartin, Jocelyn; Cilissen, Caroline; De Lepeleire, Inge; Van Bortel, Luc; Dockendorf, Marissa F; Tetteh, Ernestina; Ancona, June K; Liu, Rachael; Guo, Ying; Wagner, John A; Butterton, Joan R

2015-01-01

Doravirine is a novel non-nucleoside inhibitor of HIV-1 reverse transcriptase with potent activity against wild-type virus (95% inhibitory concentration 19 nM, 50% human serum). Doravirine has low potential to cause drug-drug interactions since it is primarily eliminated by oxidative metabolism and does not inhibit or significantly induce drug-metabolizing enzymes. The pharmacokinetics and safety of doravirine were investigated in two double-blind, dose-escalation studies in healthy males. Thirty-two subjects received single doses of doravirine (6-1,200 mg) or matching placebo tablets; 40 subjects received doravirine (30-750 mg) or matching placebo tablets once daily for 10 days. In addition, the effect of doravirine (120 mg for 14 days) on single-dose pharmacokinetics of the CYP3A substrate midazolam was evaluated (10 subjects). The maximum plasma concentration (Cmax) of doravirine was achieved within 1-5 h with an apparent terminal half-life of 12-21 h. Consistent with single-dose pharmacokinetics, steady state was achieved after approximately 7 days of once daily administration, with accumulation ratios (day 10/day 1) of 1.1-1.5 in the area under the plasma concentration-time curve during the dosing interval (AUC0-24 h), Cmax and trough plasma concentration (C24 h). All dose levels produced C24 h>19 nM. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC time zero to infinity (AUC0-∞) and C24 h with no change in Cmax. Midazolam AUC0-∞ was slightly reduced by coadministration of doravirine (geometric mean ratio 0.82, 90% CI 0.70, 0.97). There was no apparent relationship between adverse event frequency or intensity and doravirine dose. No rash or significant central nervous system events other than headache were reported. Doravirine is generally well tolerated in single doses up to 1,200 mg and multiple doses up to 750 mg once daily for up to 10 days, with a pharmacokinetic profile supportive of once-daily dosing. Doravirine at steady state slightly reduced the exposure of coadministered midazolam, to a clinically unimportant extent.

Single fixed-dose oral dexketoprofen plus tramadol for acute postoperative pain in adults.

PubMed

Derry, Sheena; Cooper, Tess E; Phillips, Tudor

2016-09-22

Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. A new combination of dexketoprofen (a nonsteroidal anti-inflammatory drug) plus tramadol (an opioid) has been tested in acute postoperative pain conditions. It is not yet licensed for use. This review is one of a series on oral analgesics for acute postoperative pain. Individual reviews have been brought together in two overviews to provide information about the relative efficacy and harm of the different interventions. To assess the analgesic efficacy and adverse effects of a single fixed-dose of oral dexketoprofen plus tramadol, compared with placebo, for moderate to severe postoperative pain in adults, using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. A secondary objective was to compare the combination with the individual analgesics alone. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via CRSO, MEDLINE via Ovid, and Embase via Ovid from inception to 31 May 2016. We also searched the reference lists of retrieved studies and reviews, and two online clinical trial registries. Randomised, double-blind trials of oral dexketoprofen plus tramadol administered as a single oral dose, for the relief of acute postoperative pain in adults, and compared to placebo. Two review authors independently considered trials for inclusion in the review, examined issues of study quality and potential bias, and extracted data. For dichotomous outcomes, we calculated risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) for dexketoprofen plus tramadol, compared with placebo with 95% confidence intervals (CI). We collected information on the number of participants with at least 50% of the maximum possible pain relief over six hours, the median time to use of rescue medication, and the proportion of participants requiring rescue medication. We also collected information on adverse events and withdrawals. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table.We also collected information on the number of participants with at least 50% of the maximum possible pain relief over six hours for dexketoprofen alone and tramadol alone. We included three studies with 1853 participants who had undergone surgical removal of impacted wisdom teeth, hip replacement, or hysterectomy. The overall risk of bias across the three included studies was low, with unclear risk of bias in relation to the size of the three studies. Two studies did not report all our prespecified outcomes, which limited the analyses we could do.The proportion of participants achieving at least 50% pain relief over six hours with dexketoprofen 25 mg plus tramadol 75 mg was 66%, compared to 32% with placebo, giving an NNT of 3.0 (95% CI 2.5 to 3.7) (RR 2.1 (95% CI 1.7 to 2.4); 748 participants; 3 studies) (moderate quality evidence). The response rate with dexketoprofen 25 mg alone was 53% (RR 1.3 (95% CI 1.1 to 1.4); 744 participants; 3 studies) and with tramadol alone was 45% (RR 1.5 (95% CI 1.3 to 1.7); 741 participants; 3 studies) (moderate quality evidence). We downgraded the evidence because of some inconsistency in the results.The median time to use of rescue medication could not be estimated exactly, but was probably eight hours or more, indicating a long duration of effect (moderate quality evidence). We downgraded the evidence because it was not possible to estimate the effect exactly in the two multiple dose studies, resulting in imprecision. Fewer participants used rescue medication with higher doses of active treatment (summary statistic not calculated; 123 participants; 1 study) (very low quality evidence). We downgraded the evidence because the data came from a single study with few participants and events.Adverse events and serious adverse events were not reported consistently for the single dose phase of the studies. In the single dose study, 11% of participants experienced adverse events with dexketoprofen 25 mg plus tramadol 75 mg, which were mostly mild or moderate nausea, vomiting, or dizziness, and typical with these medicines. Rates were lower with placebo and lower doses (very low quality evidence). We downgraded the evidence because the data came from a single study with few participants and events. Information on multiple dosing over three and five days supported a low event rate with the combination. Overall, rates were generally low in all treatment arms, as they were for withdrawals for adverse events or other reasons. A single oral dose of dexketoprofen 25 mg plus tramadol 75 mg provided good levels of pain relief with long duration of action to more people than placebo or the same dose of dexketoprofen or tramadol alone. The magnitude of the effect was similar to other good analgesics. Adverse event rates were low.There is modest uncertainty about the precision of the point estimate for efficacy, but the NNT of 3 is consistent with other analgesics considered effective and commonly used.

Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.

PubMed

Rosario, Maria; Wyant, Timothy; Leach, Timothy; Sankoh, Serap; Scholz, Catherine; Parikh, Asit; Fox, Irving; Feagan, Brian G

2016-11-01

Vedolizumab, a humanized monoclonal antibody against the α 4 β 7 integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers. Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α 4 β 7 saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored. Vedolizumab maximum observed serum concentration (C max ) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC 0-inf ) and shorter terminal elimination half-life (t 1/2 ) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α 4 β 7 was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent. Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α 4 β 7 saturation was observed at all doses. A single intravenous infusion of vedolizumab was well tolerated by healthy volunteers.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

PubMed

Alistar, Angela; Morris, Bonny B; Desnoyer, Rodwige; Klepin, Heidi D; Hosseinzadeh, Keyanoosh; Clark, Clancy; Cameron, Amy; Leyendecker, John; D'Agostino, Ralph; Topaloglu, Umit; Boteju, Lakmal W; Boteju, Asela R; Shorr, Rob; Zachar, Zuzana; Bingham, Paul M; Ahmed, Tamjeed; Crane, Sandrine; Shah, Riddhishkumar; Migliano, John J; Pardee, Timothy S; Miller, Lance; Hawkins, Gregory; Jin, Guangxu; Zhang, Wei; Pasche, Boris

2017-06-01

Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Comprehensive Cancer Center of Wake Forest Baptist Medical Center. Copyright © 2017 Elsevier Ltd. All rights reserved.

Compendium of Current Total Ionizing Dose and Displacement Damage Results from NASA Goddard Space Flight Center and NASA Electronic Parts and Packaging Program

NASA Technical Reports Server (NTRS)

Topper, Alyson D.; Campola, Michael J.; Chen, Dakai; Casey, Megan C.; Yau, Ka-Yen; Cochran, Donna J.; Label, Kenneth A.; Ladbury, Raymond L.; Mondy, Timothy K.; O'Bryan, Martha V.;

Clinical and Immune Responses to Inactivated Influenza A(H1N1)pdm09 Vaccine in Children

PubMed Central

Kotloff, Karen L.; Halasa, Natasha B.; Harrison, Christopher J.; Englund, Janet A.; Walter, Emmanuel B.; King, James C.; Creech, C. Buddy; Healy, Sara A.; Dolor, Rowena J.; Stephens, Ina; Edwards, Kathryn M.; Noah, Diana L.; Hill, Heather; Wolff, Mark

2014-01-01

Background As the influenza AH1N1 pandemic emerged in 2009, children were found to experience high morbidity and mortality and were prioritized for vaccination. This multicenter, randomized, double-blind, age-stratified trial assessed the safety and immunogenicity of inactivated influenza A(H1N1)pdm09 vaccine in healthy children aged 6 months to 17 years. Methods Children received two doses of approximately 15 μg or 30 μg hemagglutin antigen 21 days apart. Reactogenicity was assessed for 8 days after each dose, adverse events through day 42, and serious adverse events or new-onset chronic illnesses through day 201. Serum hemagglutination inhibition (HAI) titers were measured on days 0 (pre-vaccination), 8, 21, 29, and 42. Results A total of 583 children received the first dose and 571 received the second dose of vaccine. Vaccinations were generally well-tolerated and no related serious adverse events were observed. The 15 μg dosage elicited a seroprotective HAI (≥1:40) in 20%, 47%, and 93% of children in the 6-35 month, 3-9 year, and 10-17 year age strata 21 days after dose 1 and in 78%, 82%, and 98% of children 21 days after dose 2, respectively. The 30 μg vaccine dosage induced similar responses. Conclusions The inactivated influenza A(H1N1)pdm09 vaccine exhibited a favorable safety profile at both dosage levels. While a single 15 or 30 μg dose induced seroprotective antibody responses in most 10-17 year olds, younger children required 2 doses, even when receiving dosages 4-6 fold higher than recommended. Well-tolerated vaccines are needed that induce immunity after a single dose for use in young children during influenza pandemics. PMID:25222307

A Phase I clinical trial of lodenafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, in healthy male volunteers.

PubMed

Mendes, Gustavo D; dos Santos Filho, Hilton Oliveira; dos Santos Pereira, Alberto; Mendes, Fabiana D; Ilha, Jaime O; Alkharfy, Khalid M; De Nucci, Gilberto

2012-12-01

Lodenafil carbonate is a new phosphodiesterase Type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 - 100 mg) single oral doses to healthy male volunteers (n = 33). The study was an open label, dose-escalation, Phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg - 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16, 20 and 24 h post-dosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements, clinical and laboratory exams and ECG revealed no significant changes even at higher doses. Lodenafil carbonate was not detected in any samples, indicating that it acts as a prodrug. The mean lodenafil pharmacokinetic parameters for tmax and t1/2 were 1.6 ( ± 0.4) h and 3.3 ( ± 1.1) h, respectively. This study demonstrated that lodenafil carbonate was well tolerated and showed a good safety profile in healthy male volunteers.

Repaglinide pharmacokinetics in healthy young adult and elderly subjects.

PubMed

Hatorp, V; Huang, W C; Strange, P

1999-04-01

In this open-label, single-center, pharmacokinetic study of repaglinide, 12 healthy volunteers (6 men, 6 women) were enrolled in each of 2 groups (total, 24 volunteers). One group consisted of young adult subjects (18 to 40 years), and the other group consisted of elderly subjects (> or = 65 years). On day 1, after a 10-hour fast, all 24 subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, subjects received a 2-mg dose of repaglinide 15 minutes before each of 3 meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve, maximum concentration (Cmax), time to Cmax, and half-life, were determined at completion of the single-dose and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7 to assess steady state. The single-dose and multiple-dose pharmacokinetic variables of serum repaglinide were not significantly different between young adult and elderly subjects. Repaglinide was well tolerated in both groups. Hypoglycemic events occurred in 5 young adult and 5 elderly subjects. This study demonstrates that the pharmacokinetics of repaglinide are similar in healthy young adult and elderly subjects.

Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses.

PubMed

Wach, Achim; Dembowsky, Klaus; Dale, Glenn E

2018-04-01

Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified. Copyright © 2018 American Society for Microbiology.

Current Status and Future Challenges in Risk-Based Radiation Engineering

NASA Technical Reports Server (NTRS)

Pellish, Jonathan A.

2017-01-01

This presentation covers the basis and challenges for radiation effects in electronic systems. The three main types of radiation effects in electronics are: 1) total ionizing dose (TID), 2) total non-ionizing dose (TNID) / displacement damage dose (DDD), and 3) single-event effect (SEE). Some content on relevant examples of effects, current concerns, and possible environmental model-driven solutions are also included.

A Long-Acting Human Growth Hormone With Delayed Clearance (VRS-317): Results of a Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Growth Hormone–Deficient Adults

PubMed Central

Yuen, Kevin C. J.; Conway, Gerard S.; Popovic, Vera; Merriam, George R.; Bailey, Timothy; Hamrahian, Amir H.; Biller, Beverly M. K.; Kipnes, Mark; Moore, Jerome A.; Humphriss, Eric; Cleland, Jeffrey L.

2013-01-01

Background: Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes. Objectives: This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317. Design: This was a randomized, double-blind, placebo-controlled, single ascending dose study. Patients: Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo). Setting: The study was conducted in 17 adult endocrinology centers in North America and Europe. Main Outcome Measures: Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed. Results: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3–5.0 μg/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between −1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed. Conclusions: The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing. PMID:23585663

Two Phase 1, Open-Label, Single-Dose, Randomized, Crossover Studies to Assess the Pharmacokinetics, Safety, and Tolerability of Orally Administered Granules of Secnidazole (2 g) in Healthy Female Volunteers Under Different Administration Conditions.

PubMed

Pentikis, Helen S; Adetoro, Nikki

2017-11-10

Bacterial vaginosis (BV) is the most common vaginal infection in reproductive-age women and a significant risk factor for sexually transmitted diseases and pregnancy complications. Standard 5- to 7-day antimicrobial treatments for BV are associated with high rates of recurrence and adverse events. SYM-1219 is a novel granule formulation containing 2 g of secnidazole, developed as an oral, single-dose BV treatment. Two phase 1, open-label, single-center, randomized, crossover trials (studies 102 and 103) assessed the pharmacokinetics and safety of SYM-1219 single doses (≥7-day washout between doses) in healthy, nonpregnant women aged 18 to 65 years inclusive. Study 102 compared SYM-1219 in applesauce in fasted vs fed states. Study 103 compared SYM-1219 (fasted) in pudding and yogurt vs applesauce. Studies 102 and 103 each dosed 24 subjects (mean [standard deviation] ages, 36 [1.8] and 40 [11.6] years, respectively). In both studies the 90% confidence intervals for all treatment comparisons of maximum plasma concentration, area under the concentration-time curve from 0 to last measurable concentration and to infinity, geometric mean ratios were within 80% to 125%, demonstrating bioequivalence. In both studies median fasted time to maximum plasma concentration was 4 hours (6 hours fed in study 102), and mean half-life ranged from 17 to 19 hours. Treatment-emergent adverse events occurred in 70.8% and 83.3% subjects in studies 102 and 103, respectively, most commonly headache (41.7% and 50.0%) and gastrointestinal treatment-emergent adverse events. The pharmacokinetics of SYM-1219 were similar in fed and fasted states and when administered in different foods. © 2017 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning.

PubMed

Heard, K; Rumack, B H; Green, J L; Bucher-Bartelson, B; Heard, S; Bronstein, A C; Dart, R C

2014-06-01

Acetylcysteine prevents hepatic injury when administered soon after acetaminophen overdose. The most commonly used treatment protocols are a 72-hour oral and a 21-hour intravenous (IV) protocol. Between 1984 and 1994, 409 patients were enrolled in a study to describe the outcomes of patients who were treated using a 48-hour IV protocol. In 1991, an interim analysis reported the first 223 patients. The objective of this manuscript is to report the rates of hepatotoxicity and adverse events occurring during a 48-hour IV acetylcysteine protocol in the entire 409 patient cohort. This was a multicenter, single-arm, open-label clinical trial enrolling patients who presented with a toxic serum acetaminophen concentration within 24 h of acute acetaminophen ingestion. Patients were treated with 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses. Serum aminotransferase activities were measured every 8 h during the protocol, and adverse events were recorded. The primary outcome was the percentage of subjects who developed hepatotoxicity defined as a peak serum aminotransferase greater than 1000 IU/L. Four hundred and nine patients were enrolled, and 309 met inclusion for the outcome analysis. The overall percentage of patients developing hepatotoxicity was 18.1%, and 3.4% of patients treated within 10 h developed hepatotoxicity. One acetaminophen-related death occurred in a patient treated at 22 h. Adverse events occurred in 28.9% of enrolled subjects; the most common adverse events were nausea, vomiting, and flushing, and no events were rated as serious by the investigator. Acetaminophen-overdosed patients treated with IV acetylcysteine administered as 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses had a low rate of hepatotoxicity and few adverse events. This protocol delivers a higher dose of acetylcysteine which may be useful in selected cases involving very large overdoses.

Evaluation of commercial ADC radiation tolerance for accelerator experiments

DOE PAGES

Chen, K.; Chen, H.; Kierstead, J.; ...

2015-08-17

Electronic components used in high energy physics experiments are subjected to a radiation background composed of high energy hadrons, mesons and photons. These particles can induce permanent and transient effects that affect the normal device operation. Ionizing dose and displacement damage can cause chronic damage which disable the device permanently. Transient effects or single event effects are in general recoverable with time intervals that depend on the nature of the failure. The magnitude of these effects is technology dependent with feature size being one of the key parameters. Analog to digital converters are components that are frequently used in detectormore » front end electronics, generally placed as close as possible to the sensing elements to maximize signal fidelity. We report on radiation effects tests conducted on 17 commercially available analog to digital converters and extensive single event effect measurements on specific twelve and fourteen bit ADCs that presented high tolerance to ionizing dose. We discuss mitigation strategies for single event effects (SEE) for their use in the large hadron collider environment.« less

Single-dose pharmacokinetics and safety of azilsartan medoxomil in children and adolescents with hypertension as compared to healthy adults.

PubMed

Webb, Nicholas J A; Wells, Thomas; Tsai, Max; Zhao, Zhen; Juhasz, Attila; Dudkowski, Caroline

2016-04-01

This open-label, multicenter, single-dose study characterized the pharmacokinetics and short-term safety of azilsartan medoxomil (AZL-M) in hypertensive pediatric subjects (12-16 years [cohort 1a; n = 9]; 6-11 years [cohort 2; n = 8]; 4-5 years [cohort 3; n = 3]). Model-based simulations were performed to guide dosing, especially in 1-5-year olds, who were difficult to enroll. AZL-M was dosed according to body weight (20-60-mg tablet, cohorts 1a and 2; 0.66 mg/kg granule suspension, cohort 3). In cohort 1, gender-matched healthy adults (cohort 1b; n = 9) received AZL-M 80 mg. Exposure to AZL (active moiety of AZL-M), measured by dose-/body weight-normalized C max and AUC0-∞, was ∼15-30 % lower in pediatric subjects versus adults. In simulations, exposure with 0.66 mg/kg AZL-M in pediatric subjects weighing 8-25 kg approximated to AZL-M 40 mg (typical starting dose) in adults. The simulations suggest that 25-50-kg subjects require half the adult dose (10-40 mg), whereas 50-100-kg subjects can use the same dosing as adults. Adverse events were mild in intensity, apart from one moderate event (migraine). This dosing strategy should be safe in pediatric patients, as AZL exposure would not exceed that seen in adults with the highest approved AZL-M dose (80 mg).

Multiple Rising Doses of Oral BI 425809, a GlyT1 Inhibitor, in Young and Elderly Healthy Volunteers: A Randomised, Double-Blind, Phase I Study Investigating Safety and Pharmacokinetics.

PubMed

Moschetti, Viktoria; Schlecker, Christina; Wind, Sven; Goetz, Sophia; Schmitt, Holger; Schultz, Armin; Liesenfeld, Karl-Heinz; Wunderlich, Glen; Desch, Michael

2018-05-30

Schizophrenia and Alzheimer's disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-D-aspartate receptor hypofunction. Glycine is an N-methyl-D-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-D-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers. Part 1 evaluated BI 425809 10, 25, 50 or 75 mg once daily or 75 mg twice daily in young subjects, and 25 mg or 50 mg once daily in elderly subjects. Each dose group comprised 12 subjects who received BI 425809 (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; days 4-14: multiple dosing). Part 2 compared pharmacokinetic profiles in 12 subjects who received a single dose of BI 425809 25 mg in the morning and evening. Pharmacokinetic profiles were similarly shaped for all dose groups. Median time to maximum plasma concentration was 3.0-4.5 h with steady state being reached between days 6 and 10. Pharmacokinetic parameters demonstrated dose linearity at the predicted therapeutic exposure range of BI 425809 ≤ 25 mg once daily, but increased less than dose proportionally for ≥ 50 mg once daily. All reported adverse events were of mild-to-moderate intensity, 51/84 (61%; part 1) subjects had one or more treatment-related adverse event, no serious adverse events occurred and no dose dependency was observed. Pharmacokinetic properties support both morning and evening dosing. BI 425809 was generally well tolerated at all tested doses. CLINICALTRIALS. NCT02337283.

Radiation induced leakage due to stochastic charge trapping in isolation layers of nanoscale MOSFETs

NASA Astrophysics Data System (ADS)

Zebrev, G. I.; Gorbunov, M. S.; Pershenkov, V. S.

2008-03-01

The sensitivity of sub-100 nm devices to microdose effects, which can be considered as intermediate case between cumulative total dose and single event errors, is investigated. A detailed study of radiation-induced leakage due to stochastic charge trapping in irradiated planar and nonplanar devices is developed. The influence of High-K insulators on nanoscale ICs reliability is discussed. Low critical values of trapped charge demonstrate a high sensitivity to single event effect.

Titrated propofol induction vs. continuous infusion in children undergoing magnetic resonance imaging.

PubMed

Cho, J E; Kim, W O; Chang, D J; Choi, E M; Oh, S Y; Kil, H K

2010-04-01

Propofol is the popular intravenous (i.v.) anaesthetic for paediatric sedation because of its rapid onset and recovery. We compared the efficacy and safety of a single dose and conventional infusion of propofol for sedation in children who underwent magnetic resonance imaging (MRI). This was a double-blind, randomized-controlled study. One hundred and sixty children were assigned to group I (single dose) or II (infusion). Sedation was induced with i.v. propofol 2 mg/kg, and supplemental doses of propofol 0.5 mg/kg were administered until adequate sedation was achieved. After the induction of sedation, we treated patients with a continuous infusion of normal saline at a rate of 0.3 ml/kg/h in group I and the same volume of propofol in group II. In case of inadequate sedation, additional propofol 0.5 mg/kg was administered and the infusion rate was increased by 0.05 ml/kg/h. Induction time, sedation time, recovery time, additional sedation and adverse events were recorded. Recovery time was significantly shorter in group I compared with group II [0 (0-3) vs. 1 (0-3), respectively, P<0.001]. Group I (single dose) had significantly more patients with recovery time 0 compared with group II (infusion) (65/80 vs. 36/80, respectively, P<0.001). Induction and sedation times were not significantly different between groups. There was no significant difference in the frequency of additional sedation and adverse events between groups. A single dose of propofol without a continuous infusion can provide appropriate sedation in children undergoing MRI for <30 min.

Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors.

PubMed

Doi, Toshihiko; Hewes, Becker; Kakizume, Tomoyuki; Tajima, Takeshi; Ishikawa, Norifumi; Yamada, Yasuhide

2018-01-01

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single-agent ribociclib on a 3-weeks-on/1-week-off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose-escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose-limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3-weeks-on/1-week-off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Safety and pharmacokinetics of Bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers.

PubMed

Martin, David E; Blum, Robert; Wilton, John; Doto, Judy; Galbraith, Hal; Burgess, Gina L; Smith, Philip C; Ballow, Charles

2007-09-01

Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV) maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (n = 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (n = 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters. BVM was well absorbed after oral administration, with peak plasma concentrations being achieved 1 to 3 h after dosing. The half-life was 60 to 80 h. The exposure assessed by determination of the peak concentration and the area under the concentration-time curve was dose proportional. Single oral doses of BVM were well tolerated: there were no dose-limiting toxicities, and no serious adverse events were reported. These findings suggest that that BVM offers a favorable pharmacokinetic profile, with predictable pharmacokinetics following the oral administration of single doses. The long half-life of BVM may facilitate once-daily dosing.

Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects.

PubMed

Togawa, Michinori; Yamaya, Hidetoshi; Rodríguez, Mónica; Nagashima, Hirotaka

2016-12-01

Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). After single oral doses, maximum plasma concentrations (C max ) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies.

Towards tracer dose reduction in PET studies: Simulation of dose reduction by retrospective randomized undersampling of list-mode data.

PubMed

Gatidis, Sergios; Würslin, Christian; Seith, Ferdinand; Schäfer, Jürgen F; la Fougère, Christian; Nikolaou, Konstantin; Schwenzer, Nina F; Schmidt, Holger

2016-01-01

Optimization of tracer dose regimes in positron emission tomography (PET) imaging is a trade-off between diagnostic image quality and radiation exposure. The challenge lies in defining minimal tracer doses that still result in sufficient diagnostic image quality. In order to find such minimal doses, it would be useful to simulate tracer dose reduction as this would enable to study the effects of tracer dose reduction on image quality in single patients without repeated injections of different amounts of tracer. The aim of our study was to introduce and validate a method for simulation of low-dose PET images enabling direct comparison of different tracer doses in single patients and under constant influencing factors. (18)F-fluoride PET data were acquired on a combined PET/magnetic resonance imaging (MRI) scanner. PET data were stored together with the temporal information of the occurrence of single events (list-mode format). A predefined proportion of PET events were then randomly deleted resulting in undersampled PET data. These data sets were subsequently reconstructed resulting in simulated low-dose PET images (retrospective undersampling of list-mode data). This approach was validated in phantom experiments by visual inspection and by comparison of PET quality metrics contrast recovery coefficient (CRC), background-variability (BV) and signal-to-noise ratio (SNR) of measured and simulated PET images for different activity concentrations. In addition, reduced-dose PET images of a clinical (18)F-FDG PET dataset were simulated using the proposed approach. (18)F-PET image quality degraded with decreasing activity concentrations with comparable visual image characteristics in measured and in corresponding simulated PET images. This result was confirmed by quantification of image quality metrics. CRC, SNR and BV showed concordant behavior with decreasing activity concentrations for measured and for corresponding simulated PET images. Simulation of dose-reduced datasets based on clinical (18)F-FDG PET data demonstrated the clinical applicability of the proposed data. Simulation of PET tracer dose reduction is possible with retrospective undersampling of list-mode data. Resulting simulated low-dose images have equivalent characteristics with PET images actually measured at lower doses and can be used to derive optimal tracer dose regimes.

Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings.

PubMed

Keyserling, Constance H; Barbaras, Ronald; Benghozi, Renee; Dasseux, Jean-Louis

2017-05-01

CER-001 comprises recombinant human apolipoprotein A-I complexed with phospholipids that mimics natural, nascent, pre-β high-density lipoprotein (HDL). We present animal model data showing dose-dependent increases in cholesterol efflux with CER-001 and its subsequent elimination by reverse lipid transport, together with inhibition of atherosclerotic plaque progression. We report the first phase I study results with CER-001 in humans, starting at 0.25 mg/kg, which is 1/80th of the safe dose (20 mg/kg) established in 4-week multiple-dose animal studies dosed every second day. Healthy volunteers, 18-55 years old with a low-density lipoprotein-cholesterol:HDL-cholesterol ratio greater than 3.0, received single intravenous escalating doses of CER-001 (0.25-45.0 mg/kg) and placebo in a double-blind randomised cross-over fashion. Subjects were followed up for 3 weeks post-dose. Assessments included adverse event monitoring, blood sampling, and clinical laboratory measurements. Thirty-two subjects were enrolled. All CER-001 doses (0.25-45 mg/kg) were safe and well tolerated, with an adverse event profile similar to placebo. Effects on clinical chemistry, haematology and coagulation parameters were comparable to placebo. No adverse effects of CER-001 on electrocardiograms were observed. No antibodies to apolipoprotein A-I were detected following single-dose administration of CER-001. Plasma apolipoprotein A-I levels increased in a dose-related manner and returned to baseline by 24 h post-dose for doses up to 10 mg/kg but remained in circulation for >72 h post-dose for doses >10 mg/kg. CER-001 caused elevations in plasma cholesterol and total and unesterified cholesterol in the HDL fraction. Mobilisation of unesterified cholesterol in the HDL fraction was seen with CER-001 at doses as low as 2 mg/kg. CER-001 is well tolerated when administered to humans as single doses up to 45 mg/kg and mobilises and eliminates cholesterol via reverse lipid transport.

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

PubMed Central

Cui, Yimin; Song, Yan; Wang, Jessie; Yu, Zhigang; Schuster, Alan; Barrett, Yu Chen; Frost, Charles

2013-01-01

Background The pharmacokinetics (PK), pharmacodynamics (PD), and safety of apixaban were assessed in healthy Chinese subjects in this randomized, placebo-controlled, double-blind, single-sequence, single- and multiple-dose study. Subjects and methods Eighteen subjects 18–45 years of age were randomly assigned (2:1 ratio) to receive apixaban or matched placebo. Subjects received a single 10 mg dose of apixaban or placebo on day 1, followed by 10 mg apixaban or placebo twice daily for 6 days (days 4–9). The PK and PD of apixaban were assessed by collecting plasma samples for 72 hours following the dose on day 1 and the morning dose on day 9, and measuring apixaban concentration and anti-Xa activity. Safety was assessed via physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory evaluations. Results PK analysis showed similar characteristics of apixaban after single and multiple doses, including a median time to maximum concentration of ~3 hours, mean elimination half-life of ~11 hours, and renal clearance of ~1.2 L/hour. The accumulation index was 1.7, consistent with twice-daily dosing and the observed elimination half-life. Single-dose data predict multiple-dose PK, therefore apixaban PK are time-independent. The relationship between anti-Xa activity and plasma apixaban concentrations appears to be linear. Apixaban was safe and well tolerated, with no bleeding-related adverse events reported. Conclusion Apixaban was safe and well tolerated in healthy Chinese subjects. Apixaban PK and PD were predictable and consistent with findings from previous studies in Asian and non-Asian subjects. The administration of apixaban does not require any dose modification based on race. PMID:24353445

Adverse events associated with pediatric exposures to dextromethorphan.

PubMed

Paul, Ian M; Reynolds, Kate M; Kauffman, Ralph E; Banner, William; Bond, G Randall; Palmer, Robert B; Burnham, Randy I; Green, Jody L

2017-01-01

Dextromethorphan is the most common over-the-counter (OTC) antitussive medication. We sought to characterize adverse events associated with dextromethorphan in children <12 years old from a surveillance program of OTC cough/cold medication exposures. This is a retrospective case series of oral exposures to dextromethorphan with ≥1 adverse event from multiple U.S. sources (National Poison Data System, FDA Adverse Event Reporting System, manufacturer safety reports, news/media, medical literature) reported between 2008 and 2014. An expert panel determined the relationship between exposure and adverse events, estimated dose ingested, intent of exposure, and identified contributing factors to exposure. 1716 cases contained ≥1 adverse event deemed at least potentially related to dextromethorphan; 1417 were single product exposures. 773/1417 (55%) involved only one single-ingredient dextromethorphan product (dextromethorphan-only). Among dextromethorphan-only cases, 3% followed ingestion of a therapeutic dose; 78% followed an overdose. 69% involved unsupervised self-administration and 60% occurred in children <4 years old. No deaths or pathologic dysrhythmias occurred. Central nervous system [e.g., ataxia (N = 420)] and autonomic symptoms [e.g., tachycardia (N = 224)] were the most common adverse events. Flushing and/or urticarial rash occurred in 18.1% of patients. Dystonia occurred in 5.4%. No fatalities were identified in this multifaceted surveillance program following a dextromethorphan-only ingestion. Adverse events were predominantly associated with overdose, most commonly affecting the central nervous and autonomic systems.

Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn's disease.

PubMed

Sandborn, W J; Elliott, D E; Weinstock, J; Summers, R W; Landry-Wheeler, A; Silver, N; Harnett, M D; Hanauer, S B

2013-08-01

Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461. © 2013 John Wiley & Sons Ltd.

Analyses of risks associated with radiation exposure from past major solar particle events

NASA Technical Reports Server (NTRS)

Weyland, Mark D.; Atwell, William; Cucinotta, Francis A.; Wilson, John W.; Hardy, Alva C.

1991-01-01

Radiation exposures and cancer induction/mortality risks were investigated for several major solar particle events (SPE's). The SPE's included are: February 1956, November 1960, August 1972, October 1989, and the September, August, and October 1989 events combined. The three 1989 events were treated as one since all three could affect a single lunar or Mars mission. A baryon transport code was used to propagate particles through aluminum and tissue shield materials. A free space environment was utilized for all calculations. Results show the 30-day blood forming organs (BFO) limit of 25 rem was surpassed by all five events using 10 g/sq cm of shielding. The BFO limit is based on a depth dose of 5 cm of tissue, while a more detailed shield distribution of the BFO's was utilized. A comparison between the 5 cm depth dose and the dose found using the BFO shield distribution shows that the 5 cm depth value slightly higher than the BFO dose. The annual limit of 50 rem was exceeded by the August 1972, October 1989, and the three combined 1989 events with 5 g/sq cm of shielding. Cancer mortality risks ranged from 1.5 to 17 percent at 1 g/sq cm and 0.5 to 1.1 percent behind 10 g/sq cm of shielding for five events. These ranges correspond to those for a 45 year old male. It is shown that secondary particles comprise about 1/3 of the total risk at 10 g/sq cm of shielding. Utilizing a computerized Space Shuttle shielding model to represent a typical spacecraft configuration in free space at the August 1972 SPE, average crew doses exceeded the BFO dose limit.

A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-05-01

A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects. Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a minimum of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatography-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated. Δ(9)-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concentration (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concentration (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported. The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.

Randomized Crossover Comparison of the Short-Term Efficacy and Safety of Single Half-Dose Silodosin and Tamsulosin Hydrochoride in Men With Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia.

PubMed

Takeshita, Hideki; Moriyama, Shingo; Arai, Yoshiaki; Washino, Satoshi; Saito, Kimitoshi; Chiba, Koji; Horiuchi, Susumu; Noro, Akira

2016-01-01

To compare the efficacy and safety of single half-dose silodosin and single full-dose tamsulosin in Japanese men with lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). Japanese men aged ≥50 years with LUTS/BPH and an International Prostate Symptom Score (IPSS) of ≥8 were enrolled in the randomized crossover study and divided into silodosin-preceding (S-T) and tamsulosin-preceding (T-S) groups. The S-T group received 4 mg silodosin once daily for 4 weeks followed by 0.2 mg tamsulosin once daily for 4 weeks. The T-S group received the reverse treatment sequence. A washout period prior to drug crossover was not included. Subjective and objective efficacy parameters including IPSS, quality of life (QOL) index, uroflowmetry, and safety were compared between the two groups. Thirty of 34 men (S-T group n = 16; T-S group n = 14) completed the study. Both drugs significantly improved all IPSS items and QOL index in the first treatment period. Subjective improvement in nocturia by silodosin was observed in both the first and crossover treatment periods. Objective improvement in maximum flow rate by silodosin was only observed in the first treatment period. Adverse events occurred more frequently with silodosin than with tamsulosin; however, none of the adverse events required treatment discontinuation. Ejaculation disorders occurred in three participants (10%) and were associated with silodosin use. Single half-dose silodosin has a similar efficacy to full-dose tamsulosin in Japanese men with LUTS/BPH and thus, may represent an effective, safe, and affordable treatment option. © 2015 Wiley Publishing Asia Pty Ltd.

A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation.

PubMed

Stevens, R B; Wrenshall, L E; Miles, C D; Farney, A C; Jie, T; Sandoz, J P; Rigley, T H; Osama Gaber, A

2016-06-01

A previous nonblinded, randomized, single-center renal transplantation trial of single-dose rabbit anti-thymocyte globulin induction (SD-rATG) showed improved efficacy compared with conventional divided-dose (DD-rATG) administration. The present multicenter, double-blind/double-dummy STAT trial (Single dose vs. Traditional Administration of Thymoglobulin) evaluated SD-rATG versus DD-rATG induction for noninferiority in early (7-day) safety and tolerability. Ninety-five patients (randomized 1:1) received 6 mg/kg SD-rATG or 1.5 mg/kg/dose DD-rATG, with tacrolimus-mycophenolate maintenance immunosuppression. The primary end point was a composite of fever, hypoxia, hypotension, cardiac complications, and delayed graft function. Secondary end points included 12-month patient survival, graft survival, and rejection. Target enrollment was 165 patients with an interim analysis scheduled after 80 patients. Interim analysis showed primary end point noninferiority of SD-rATG induction (p = 0.6), and a conditional probability of <1.73% of continued enrollment producing a significant difference (futility analysis), leading to early trial termination. Final analysis (95 patients) showed no differences in occurrence of primary end point events (p = 0.58) or patients with no, one, or more than one event (p = 0.81), or rejection, graft, or patient survival (p = 0.78, 0.47, and 0.35, respectively). In this rigorously blinded trial in adult renal transplantation, we have shown SD-rATG induction to be noninferior to DD-rATG induction in early tolerability and equivalent in 12-month safety. (Clinical Trials.gov #NCT00906204.). © Copyright 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of the American Society of Transplantation and the American Society of Transplant Surgeons.

Pharmacokinetics and safety of eszopiclone in healthy Chinese volunteers.

PubMed

Wu, F; Zhao, X L; Wei, M J; Wang, S M; Zhou, H; Guo, S J; Zhang, P

2012-12-01

The main objective of this study was to investigate the pharmacokinetic characters of eszopiclone (CAS: 138729-47-2) after single and multiple-dose oral administration in healthy adult Chinese volunteers.In single-dose study, 12 subjects were given oral administrations of 1.5, 3 and 6 mg eszopiclone in an open-label, randomized, crossover fashion. In multiple-dose study, 8 subjects were given 3 mg eszopiclone once daily consecutively for 7 days. Blood samples were collected over 24 h and plasma eszopiclone were determined using a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay. The safety and tolerability of eszopiclone was evaluated by adverse events recording, physical examination, laboratory testing, vital signs, and 12-lead ECG findings.The main pharmacokinetic parameters of eszopiclone after single-dose administration were as follows: doses of 1.5, 3 and 6 mg; Cmax of 18.08±4.65, 38.29±15.41 and 76.38±23.34 ng/ml; Tmax of 0.94±0.39, 1.04±0.63 and 1.08±0.51 h; AUC0-24 of 110.90±23.06, 227.36±62.41 and 504.10±140.13 ng*h/ml; elimination half-lives of 5.84±1.03, 5.53±1.91 and 6.17±1.23 h. After multiple-dose administration, the steady-state levels of eszopiclone were achieved by the 4th day, and the main pharmacokinetic parameters were Css_max at 33.43±5.63 ng/ml and AUCss (0-24) at 263.30±51.21 ng*h/ml. The most common adverse event was bitter or abnormal taste. All the adverse events were judged as mild to moderate and resolved without any medication.The pharmacokinetic character of eszopiclone is linear and dose-proportional over the range of 1.5-6 mg. The systemic exposure does not accumulate with once-daily administrations. Eszopiclone appears to have good safety and is well tolerated. © Georg Thieme Verlag KG Stuttgart · New York.

Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers.

PubMed

Jung, J A; Kim, N; Yang, J-S; Kim, T-e; Kim, J-R; Song, G-S; Kim, H; Ko, J W; Huh, W

2014-12-01

Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea.An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods.A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 μg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 μg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · μg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively.A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated. © Georg Thieme Verlag KG Stuttgart · New York.

Comparison of the Efficacy and Safety of 2 Acetaminophen Dosing Regimens in Febrile Infants and Children: A Report on 3 Legacy Studies.

PubMed

Temple, Anthony R; Zimmerman, Brenda; Gelotte, Cathy; Kuffner, Edwin K

2017-01-01

Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to ≤ 11 years from 3 double-blind, randomized, single or multiple dose studies. Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study. A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses. Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours.

Pharmacokinetics of pregabalin controlled-release in healthy volunteers: effect of food in five single-dose, randomized, clinical pharmacology studies.

PubMed

Chew, Marci L; Plotka, Anna; Alvey, Christine W; Pitman, Verne W; Alebic-Kolbah, Tanja; Scavone, Joseph M; Bockbrader, Howard N

2014-09-01

The pharmacokinetic properties of the immediate-release (IR) and the recently developed controlled-release (CR) formulation of pregabalin are dose proportional. Pregabalin IR can be taken with or without food. This analysis characterizes the effect of food on pregabalin CR. The objectives of this analysis were: (1) to evaluate the effect of administration time and fat or caloric content of an accompanying meal on the pharmacokinetic properties of a single dose of pregabalin CR (330 mg) relative to a single dose of pregabalin IR (300 mg); (2) to evaluate the pharmacokinetic properties of a single dose of pregabalin CR administered fasted relative to a single dose of pregabalin CR administered immediately after food; and (3) to determine the safety and tolerability of single-dose administration of pregabalin CR and IR with and without food. The effect of food on the pharmacokinetic properties of pregabalin CR was determined in five phase I, open-label, single-dose, crossover studies (24-28 participants/study). Caloric and fat content of meals were varied and treatments were administered in the morning, at midday, or in the evening. Blood samples were collected up to 48 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. One hundred and twenty-eight healthy participants (19-54 years of age) received pregabalin. Peak plasma concentrations (C max) were lower for CR than the respective pregabalin IR doses, and time to C max occurred later. When pregabalin CR was administered with food at midday or in the evening, total exposures [area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC∞)] were equivalent for pregabalin CR and IR formulations regardless of fat or caloric content. When pregabalin CR was administered with an 800-1,000 calorie medium-fat breakfast, AUC∞ was equivalent for pregabalin CR and IR. Bioequivalence criteria for comparison of pregabalin CR after a low- or medium-calorie breakfast relative to pregabalin IR were not met; however, bioavailability of the pregabalin CR vs. IR formulation was relatively high (75-86 %). When pregabalin CR was administered fasted, the AUC∞ was 70-78 % of the AUC∞ of pregabalin CR administered with food and bioequivalence criteria were not met. Additionally, the AUC∞ of the pregabalin CR formulation administered fasted was 62-69 % of that of pregabalin IR administered fasted and bioequivalence criteria were not met. Single-dose pregabalin CR and IR were well tolerated in all studies, with no serious or severe adverse events reported. Time of day of administration and the fat and caloric content of the accompanying meal had minimal overall effect on the pharmacokinetic properties and bioavailability of the pregabalin CR formulation.

Evaluation of the new electron-transport algorithm in MCNP6.1 for the simulation of dose point kernel in water

NASA Astrophysics Data System (ADS)

Antoni, Rodolphe; Bourgois, Laurent

2017-12-01

In this work, the calculation of specific dose distribution in water is evaluated in MCNP6.1 with the regular condensed history algorithm the "detailed electron energy-loss straggling logic" and the new electrons transport algorithm proposed the "single event algorithm". Dose Point Kernel (DPK) is calculated with monoenergetic electrons of 50, 100, 500, 1000 and 3000 keV for different scoring cells dimensions. A comparison between MCNP6 results and well-validated codes for electron-dosimetry, i.e., EGSnrc or Penelope, is performed. When the detailed electron energy-loss straggling logic is used with default setting (down to the cut-off energy 1 keV), we infer that the depth of the dose peak increases with decreasing thickness of the scoring cell, largely due to combined step-size and boundary crossing artifacts. This finding is less prominent for 500 keV, 1 MeV and 3 MeV dose profile. With an appropriate number of sub-steps (ESTEP value in MCNP6), the dose-peak shift is almost complete absent to 50 keV and 100 keV electrons. However, the dose-peak is more prominent compared to EGSnrc and the absorbed dose tends to be underestimated at greater depths, meaning that boundaries crossing artifact are still occurring while step-size artifacts are greatly reduced. When the single-event mode is used for the whole transport, we observe the good agreement of reference and calculated profile for 50 and 100 keV electrons. Remaining artifacts are fully vanished, showing a possible transport treatment for energies less than a hundred of keV and accordance with reference for whatever scoring cell dimension, even if the single event method initially intended to support electron transport at energies below 1 keV. Conversely, results for 500 keV, 1 MeV and 3 MeV undergo a dramatic discrepancy with reference curves. These poor results and so the current unreliability of the method is for a part due to inappropriate elastic cross section treatment from the ENDF/B-VI.8 library in those energy ranges. Accordingly, special care has to be taken in setting choice for calculating electron dose distribution with MCNP6, in particular with regards to dosimetry or nuclear medicine applications.

Pharmacokinetic properties and safety profile of histamine dihydrochloride injection in Chinese healthy volunteers: a phase I, single-center, open-label, randomized study.

PubMed

Li, Jiapeng; Huang, Xiaojun; Wang, Qian; Jing, Shan; Jiang, Hao; Wei, Zhongna; Zang, Yannan; Liu, Yang; Zhao, Libo; Fang, Yi; Feng, Wanyu

2015-10-01

Histamine dihydrochloride (HDC) injection has been approved in Europe for the treatment of adults with acute myeloid leukemia, used in combination therapy with the T-cell-derived cytokine interleukin-2. Despite years of clinical applications of HDC in Europe, no data are available on its tolerability and pharmacokinetic properties in Chinese patients. The objective of this study was to determine the safety profile and pharmacokinetic properties of HDC in Chinese healthy volunteers (HVs). In this Phase I, single-center, open-label, randomized study, 20 Chinese HVs were randomized to receive a single dose of 0.5 or 1.0 mg HDC via a 10-minute subcutaneous injection. Whole-blood and urine samples were collected at designated time points after dosing. Plasma and urine concentrations of histamine and metabolite N-methyl histamine were measured using a validated HPLC-MS/MS method. Pharmacokinetic parameters were estimated through noncompartmental procedures based on concentration-time data. Adverse events and evaluation of clinical laboratory tests were used to assess the safety profile. The pharmacokinetic profile for a single-dose of 1.0 mg HDC in Chinese HVs was compared with that in Western HVs. No severe adverse events occurred in this study, and the severity of all adverse events was grade I according to the Common Terminology Criteria for Adverse Events, version 4.0. For the pharmacokinetic parameters of histamine at the 0.5-mg and 1.0-mg dose levels, t½ was 0.50 and 1.02 hours; Tmax was 0.15 and 0.14 hours; mean Cmax was 26.59 and 71.01 nmol/L; AUC0-t was 8.35 and 20.43 nmol/h/L; AUC0-∞ was 9.61 and 22.69 nmol/h/L; accumulated amount excreted in urine within 24 hours was 125.93 and 145.52 nmol; and maximum urine excretion rates were 21.85 and 38.94 nmol/h, respectively. For N-methyl histamine at the 0.5-mg and 1.0-mg dose levels, t½ was 0.58 and 0.66 hours; Tmax was 0.28 and 0.26 hours; mean Cmax was 17.01 and 23.54 nmol/L; AUC0-t was 7.72 and 17.08 nmol/h/L; AUC0-∞ was 9.01 and 19.62 nmol/h/L; accumulated amount excreted in urine within 24 hours was 331.7 and 583.21 nmol; and maximum urine excretion rates were 53.29 and 133.53 nmol/h, respectively. Both single-dose 0.5 mg and 1.0 mg HDC were well tolerated in Chinese HVs, and the pharmacokinetic profile of HDC in Chinese HVs was characterized in this study. A single dose of 1.0 mg HDC had a more rapid but similar extent of absorption, a wider distribution, and a little more rapid elimination in Chinese HVs compared with Western HVs. Findings from this study support additional clinical trials for HDC using in Chinese patients. Chinese Clinical Trial Registry identifier: ChiCTR-ONC-13003954. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Fixed-dose combination therapy for the prevention of cardiovascular disease

PubMed Central

de Cates, Angharad N; Farr, Matthew RB; Wright, Nicola; Jarvis, Morag C; Rees, Karen; Ebrahim, Shah; Huffman, Mark D

2014-01-01

Background Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, yet CVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure and cholesterol lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of CVD by up to 80% given its potential for better adherence and lower costs. Objectives To determine the effectiveness of fixed-dose combination therapy on reducing fatal and non-fatal CVD events and on improving blood pressure and lipid CVD risk factors for both primary and secondary prevention of CVD. We also aimed to determine discontinuation rates, adverse events, health-related quality of life, and costs of fixed-dose combination therapy. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library(2013, Issue 6), MEDLINE Ovid (1946 to week 2 July 2013), EMBASE Ovid (1980 to Week 28 2013), ISI Web of Science (1970 to 19 July 2013), and the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), and Health Economics Evaluations Database (HEED) (2011, Issue 4) in The Cochrane Library. We used no language restrictions. Selection criteria We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure lowering and one lipid lowering component versus usual care, placebo, or a single drug active component for any treatment duration in adults ≥ 18 years old with no restrictions on presence or absence of pre-existing cardiovascular disease. Data collection and analysis Three review authors independently selected studies for inclusion and extracted the data. We evaluated risk of bias using the Cochrane risk of bias assessment tool. We sought to include outcome data on all-cause mortality, fatal and non-fatal CVD events, adverse events, changes in systolic and diastolic blood pressure, total and low density lipoprotein (LDL) cholesterol concentrations, discontinuation rates, quality of life, and costs. We calculated risk ratios (RR) for dichotomous data and weighted mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I2 < 50%) and random-effects models when heterogeneity was high (I2 > 50%). Main results We found nine randomised controlled trials with a total of 7047 participants. Seven of the nine trials evaluated the effects of fixed-dose combination therapy on primary CVD prevention, and the trial length ranged from six weeks to 15 months. We found a moderate to high risk of bias in the domains of selection, performance, detection, attrition, and other types of bias in five of the nine trials. Compared with the comparator groups, the effects of the fixed-dose combination treatment on mortality (1.2% versus 1.0%, RR 1.26, 95% CI 0.67 to 2.38, N = 3465) and cardiovascular events (4.0% versus 2.9%, RR 1.38, 95% CI 0.91 to 2.10, N = 2479) were uncertain (low quality evidence). The low event rates for these outcomes, limited availability of data as only two out of nine trials reported on these outcomes, and a high risk of bias in at least one domain suggest that these results should not be viewed with confidence. Adverse events were common in both the intervention (30%) and comparator (24%) groups, with participants randomised to fixed-dose combination therapy being 20% (95% CI 9% to 30%) more likely to report an adverse event. Notably, no serious adverse events were reported. Compared with placebo, the rate of discontinuation among participants randomised to fixed-dose combination was higher (14% versus 11%, RR 1.26 95% CI 1.02 to 1.55). The weighted mean differences in systolic and diastolic blood pressure between the intervention and control arms were -7.05 mmHg (95% CI -10.18 to -3.87) and -3.65 mmHg (95% CI -5.44 to -1.85), respectively. The weighted mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.75 mmol/L (95% CI -1.05 to -0.46) and -0.81 mmol/L (95% CI -1.09 to -0.53), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 70% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multi-drug strategy by 33% (26% to 41%) compared with usual care, but this comparison was reported in only one study. The effects of fixed-dose combination therapy on quality of life are uncertain, though these results were reported in only one trial. No trials reported costs. Authors' conclusions Compared with placebo, single drug active component, or usual care, the effects of fixed-dose combination therapy on all-cause mortality or CVD events are uncertain; only few trials report these outcomes and the included trials were primarily designed to observe changes in CVD risk factor levels rather than clinical events. Reductions in blood pressure and lipid parameters are generally lower than those previously projected, though substantial heterogeneity of results exists. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, single drug active component, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing trials of fixed-dose combination therapy will likely inform key outcomes. PMID:24737108

Fosfomycin trometamol: a review of its use as a single-dose oral treatment for patients with acute lower urinary tract infections and pregnant women with asymptomatic bacteriuria.

PubMed

Keating, Gillian M

2013-11-01

Fosfomycin trometamol (fosfomycin tromethamine) [Monuril(®), Monurol(®), Monural(®)] is approved in numerous countries worldwide, mainly for the treatment of uncomplicated urinary tract infections (UTIs). Fosfomycin has good in vitro activity against common uropathogens, such as Escherichia coli (including extended-spectrum β-lactamase-producing E. coli), Proteus mirabilis, Klebsiella pneumoniae and Staphylococcus saprophyticus, and the susceptibility of uropathogens to fosfomycin has remained relatively stable over time. A single oral dose of fosfomycin trometamol 3 g (the approved dosage) achieves high concentrations in urine. Results of recent randomized trials indicate that single-dose fosfomycin trometamol had similar clinical and/or bacteriological efficacy to 3- to 7-day regimens of ciprofloxacin, norfloxacin, cotrimoxazole or nitrofurantoin in women with uncomplicated lower UTIs. In addition, single-dose fosfomycin trometamol had similar bacteriological efficacy to a 5-day course of cefuroxime axetil or a 7-day course of amoxicillin/clavulanic acid in pregnant women with asymptomatic bacteriuria, and similar clinical and/or bacteriological efficacy to a 5-day course of cefuroxime axetil or amoxicillin/clavulanic acid or a 3-day course of ceftibuten in pregnant women with a lower UTI. Single-dose fosfomycin trometamol was generally well tolerated, with gastrointestinal adverse events (e.g. diarrhoea, nausea) reported most commonly. In conclusion, single-dose fosfomycin trometamol is an important option for the first-line empirical treatment of uncomplicated lower UTIs.

Pharmacodynamics and pharmacokinetics of single doses of subcutaneous pegylated human G-CSF mutant (Ro 25-8315) in healthy volunteers: comparison with single and multiple daily doses of filgrastim.

PubMed

van Der Auwera, P; Platzer, E; Xu, Z X; Schulz, R; Feugeas, O; Capdeville, R; Edwards, D J

2001-04-01

Ro 25-8315 is produced by conjugation of rhG-CSF mutant with polyethylene glycol (PEG). The purpose of this study was to examine the pharmacodynamics and pharmacokinetics of Ro 25-8315 in comparison with Filgrastim (rhG-CSF). Subjects received single subcutaneous doses of Ro 25-8315 ranging from 10 to 150 microg/kg using a double-blind, randomized, placebo-controlled design. Filgrastim was administered as a single dose (5 or 10 microg/kg) and, following a 14-day washout period, daily for 7 days. Ro 25-8315 increased absolute neutrophil count (ANC) by 6- to 8-fold and CD34+ cell count more than 30-fold at the highest doses tested. Single doses (60-150 microg/kg) of Ro 25-8315 and multiple doses of Filgrastim had similar effects on ANC and CD34+, although Ro 25-8315 had a greater effect on CFU-GM. The pharmacokinetics of Ro 25-8315 were dose-dependent, with peak concentrations and area under the serum concentration-time curve (AUC) increasing 100-fold over the range of doses studied. Time to reach peak concentration (T(max)) and half-life of Ro 25-8315 averaged 20-30 hr at all doses, approximately three times longer than with Filgrastim. Adverse events were not serious and occurred with similar frequency with both products. Pegylation of rhG-CSF mutant results in more desirable pharmacokinetic properties and a longer duration of action with effective increases in ANC and measures of peripheral blood progenitor cell mobilization for at least 1 week. Copyright 2001 Wiley-Liss, Inc.

Effects of cosmic rays on single event upsets

NASA Technical Reports Server (NTRS)

Venable, D. D.; Zajic, V.; Lowe, C. W.; Olidapupo, A.; Fogarty, T. N.

1989-01-01

Assistance was provided to the Brookhaven Single Event Upset (SEU) Test Facility. Computer codes were developed for fragmentation and secondary radiation affecting Very Large Scale Integration (VLSI) in space. A computer controlled CV (HP4192) test was developed for Terman analysis. Also developed were high speed parametric tests which are independent of operator judgment and a charge pumping technique for measurement of D(sub it) (E). The X-ray secondary effects, and parametric degradation as a function of dose rate were simulated. The SPICE simulation of static RAMs with various resistor filters was tested.

Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.

PubMed

Scherz, Michael W; Brossard, Patrick; D'Ambrosio, Daniele; Ipek, Murat; Dingemanse, Jasper

2015-06-01

Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval. © 2015, The American College of Clinical Pharmacology.

Trial Evaluating Ambulatory Therapy of Travelers' Diarrhea (TrEAT TD) Study: A Randomized Controlled Trial Comparing 3 Single-Dose Antibiotic Regimens With Loperamide.

PubMed

Riddle, Mark S; Connor, Patrick; Fraser, Jamie; Porter, Chad K; Swierczewski, Brett; Hutley, Emma J; Danboise, Brook; Simons, Mark P; Hulseberg, Christine; Lalani, Tahaniyat; Gutierrez, Ramiro L; Tribble, David R

2017-11-29

Recommended treatment for travelers' diarrhea includes the combination of an antibiotic, usually a fluoroquinolone or azithromycin, and loperamide for rapid resolution of symptoms. However, adverse events, postdose nausea with high-dose azithromycin, effectiveness of single-dose rifaximin, and emerging resistance to front-line agents are evidence gaps underlying current recommendations. A randomized, double-blind trial was conducted in 4 countries (Afghanistan, Djibouti, Kenya, and Honduras) between September 2012 and July 2015. US and UK service members with acute watery diarrhea were randomized and received single-dose azithromycin (500 mg; 106 persons), levofloxacin (500 mg; 111 persons), or rifaximin (1650 mg; 107 persons), in combination with loperamide (labeled dosing). The efficacy outcomes included clinical cure at 24 hours and time to last unformed stool. Clinical cure at 24 hours occurred in 81.4%, 78.3%, and 74.8% of the levofloxacin, azithromycin, and rifaximin arms, respectively. Compared with levofloxacin, azithromycin was not inferior (P = .01). Noninferiority could not be shown with rifaximin (P = .07). At 48 and 72 hours, efficacy among regimens was equivalent (approximately 91% at 48 and 96% at 72 hours). The median time to last unformed stool did not differ between treatment arms (azithromycin, 3.8 hours; levofloxacin, 6.4 hours; rifaximin, 5.6 hours). Treatment failures were uncommon (3.8%, 4.4%, and 1.9% in azithromycin, levofloxacin, and rifaximin arms, respectively) (P = .55). There were no differences between treatment arms with postdose nausea, vomiting, or other adverse events. Single-dose azithromycin, levofloxacin, and rifaximin with loperamide were comparable for treatment of acute watery diarrhea. NCT01618591. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Current Radiation Issues for Programmable Elements and Devices

NASA Technical Reports Server (NTRS)

Katz, Richard; LaBel, K.; Reed, R.; Wang, J. J.; Cronquist, B.; McCollum, J.; Paolini, W.; Sin, B.; Koga, R.a; Crain, S.;

Recent Radiation Test Results for Power MOSFETs

NASA Technical Reports Server (NTRS)

Lauenstein, Jean-Marie; Topper, Alyson D.; Casey, Megan C.; Wilcox, Edward P.; Phan, Anthony M.; Kim, Hak S.; LaBel, Kenneth A.

2013-01-01

Single-event effect (SEE) and total ionizing dose (TID) test results are presented for various hardened and commercial power metal-oxide-semiconductor field effect transistors (MOSFETs), including vertical planar, trench, superjunction, and lateral process designs.

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers

PubMed Central

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-01-01

Aim The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Methods Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. Results ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Conclusions Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. PMID:23016924

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.

PubMed

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-05-01

The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. © 2012 Abbott Laboratories. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial ▿

PubMed Central

Dunbar, Lala M.; Milata, Joe; McClure, Ty; Wasilewski, Margaret M.

2011-01-01

Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA. PMID:21537018

The Nuclear Weapons Effects National Enterprise

DTIC Science & Technology

2010-06-01

dependent on computers and electrical circuitry for effectiveness. The danger from radiation induced upset or burnout of improperly or unshielded...for Unmanned Systems Radiation Effect Thermal mechanical shock - X-ray Prompt X-ray/gamma dose rate - Rail-span collapse - Photoionization burnout ...event upset (SEU) or even single-event burnout . SEU results when enough ionization charge is deposited by a high-energy particle (natural or man

Single Low Dose Primaquine (0.25 mg/kg) Does Not Cause Clinically Significant Haemolysis in G6PD Deficient Subjects.

PubMed

Bancone, Germana; Chowwiwat, Nongnud; Somsakchaicharoen, Raweewan; Poodpanya, Lalita; Moo, Paw Khu; Gornsawun, Gornpan; Kajeechiwa, Ladda; Thwin, May Myo; Rakthinthong, Santisuk; Nosten, Suphak; Thinraow, Suradet; Nyo, Slight Naw; Ling, Clare L; Wiladphaingern, Jacher; Kiricharoen, Naw Lily; Moore, Kerryn A; White, Nicholas J; Nosten, Francois

2016-01-01

Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum. The transmission blocking dose of primaquine previously recommended was 0.75 mg/kg (adult dose 45 mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15-20%) in populations living in malarious areas. To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25 mg/kg (adult dose 15 mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing. Direct evidence of the safety of this low dose is lacking. Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%. The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects. Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration. G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females. Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models. No adverse events related to primaquine were reported during the trial. Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant. Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic. The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency. The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria. ClinicalTrials.gov NCT01872702.

A Detailed Dosimetric Analysis of Spinal Cord Tolerance in High-Dose Spine Radiosurgery.

PubMed

Katsoulakis, Evangelia; Jackson, Andrew; Cox, Brett; Lovelock, Michael; Yamada, Yoshiya

2017-11-01

Dose-volume tolerance of the spinal cord (SC) in spinal stereotactic radiosurgery (SRS) is difficult to define because radiation myelitis rates are low, and published reports document cases of myelopathy but do not account for the total number of patients treated at given dose-volume combinations who do not have myelitis. This study reports SC toxicity from single-fraction spinal SRS and presents a comprehensive atlas of the incidence of adverse events to examine dose-volume predictors. A prospective database of all patients undergoing single-fraction spinal SRS at our institution between 2004 and 2011 was reviewed. SC toxicity was defined by clinical myelitis with accompanying magnetic resonance imaging (MRI) signal changes that were not attributable to tumor progression. Dose-volume histogram (DVH) atlases were created for these endpoints. Rates of adverse events with 95% confidence limits and probabilities that rates of adverse events were <2% and <5% for myelitis were determined as functions of dose and absolute volume. Information about DVH and myelitis was available for 228 patients treated at 259 sites. The median follow-up time was 14.6 months (range, 0.1-138.3 months). The median prescribed dose to the planning treatment volume was 24 Gy (range, 18-24 Gy). There were 2 cases of radiation myelitis (rate r=0.7%) with accompanying MRI signal changes. Myelitis occurred in 2 patients, with Dmax >13.33 Gy, and minimum doses to the hottest 0.1, 0.2, 0.5, and 1 cc were >10.66, 10.9, and 8 Gy, respectively; however, both myelitis cases occurred below the 34th percentile for Dmax and there were 194 DVHs in total with Dmax >13.33 Gy. A median SC Dmax of 13.85 Gy is safe and supports that a Dmax limit of 14 Gy carries a low <1% rate of myelopathy. No dose-volume thresholds or relationships between SC dose and myelitis were apparent. This is the largest study examining dosimetric data and radiation-induced myelitis in de novo spine SRS. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy of Single-dose and 2-dose Intravenous Administration of Ramosetron in Preventing Postoperative Nausea and Vomiting After Laparoscopic Gynecologic Operation: A Randomized, Double-blind, Placebo-controlled, Phase 2 Trial.

PubMed

Lee, Banghyun; Kim, Kidong; Suh, Dong Hoon; Shin, Hyun-Jung; No, Jae Hong; Lee, Jung Ryeol; Jee, Byung Chul; Hwang, Jung Won; Do, Sang Hwan; Kim, Yong Beom

2017-06-01

This randomized trial investigated whether a 2-dose administration of intravenous ramosetron (5-hydroxytryptamine type 3 receptor antagonist) is more effective than a single-dose administration in preventing postoperative nausea and vomiting (PONV) in 89 patients who were scheduled to undergo laparoscopic operation for benign gynecologic diseases and to receive intravenous patient-controlled analgesia for relief of postoperative pain. After assignment at a ratio of 1:1, intravenous ramosetron (0.3 mg) was initially administered at the end of skin closure in all patients. Thereafter, ramosetron (0.3 mg) and placebo were administered to the study and control groups, respectively, at 4 hours after the operation. The baseline and operative characteristics were similar between the groups. The incidence of PONV during the 24-hour period after operation which was assessed as the primary endpoint did not differ between the groups. No serious adverse events occurred in either group. A 2-dose administration of intravenous ramosetron may not be superior to a single-dose administration in preventing PONV in patients undergoing laparoscopic operation for benign gynecologic diseases.

Total Dose Effects on Error Rates in Linear Bipolar Systems

NASA Technical Reports Server (NTRS)

Buchner, Stephen; McMorrow, Dale; Bernard, Muriel; Roche, Nicholas; Dusseau, Laurent

2007-01-01

The shapes of single event transients in linear bipolar circuits are distorted by exposure to total ionizing dose radiation. Some transients become broader and others become narrower. Such distortions may affect SET system error rates in a radiation environment. If the transients are broadened by TID, the error rate could increase during the course of a mission, a possibility that has implications for hardness assurance.

Attention benefits after a single dose of metadoxine extended release in adults with predominantly inattentive ADHD.

PubMed

Manor, Iris; Rubin, Jonathan; Daniely, Yaron; Adler, Lenard A

2014-09-01

To assess the first-dose effectiveness and tolerability of metadoxine extended release (MDX) in adults with predominantly inattentive attention-deficit/hyperactivity disorder (ADHD-PI). In this double-blind, placebo-controlled, crossover study, adults with ADHD-PI were randomized 1:1:1 to receive a single dose of MDX 1400 mg, MDX 700 mg, and placebo (ClinicalTrials.gov identifier: NCT01685281). The primary efficacy end point was the mean change in the Test of Variables of Attention (TOVA) ADHD score from baseline to 3 to 5 hours after drug administration. Secondary assessments included TOVA subscores, TOVA response rates (defined as an increase of 0.8 points in the TOVA ADHD score), and the Cambridge Neuropsychological Automated Test Battery. Safety assessments included adverse events and vital signs. The intention-to-treat population included 36 patients (52.8% men; mean age, 32 years). The efficacy of MDX 1400 mg was demonstrated by a statistically significant difference in the mean (± SD) change in the TOVA ADHD score at baseline to 3 to 5 hours after drug administration compared with placebo (2.0 [4.2]; P = 0.009). The TOVA response time variability subscore was significantly different between MDX 1400 mg and placebo (mean difference, 7.9 [19.2] points; P = 0.022). Significantly more adults responded to single-dose MDX 1400 mg versus placebo (97.1% vs 71.4%, P = 0.006). There were no statistically significant differences between MDX 700 mg and placebo on any measures. Exploratory analyses of the Cambridge Neuropsychological Automated Test Battery did not yield significant findings. Fatigue and headache were the 2 most frequently reported adverse events. There were no clinically significant abnormalities in laboratory values, vital signs measurements, Columbia-Suicide Severity Rating Scale scores, or electrocardiographic parameters. Single-dose MDX 1400 mg significantly improved sustained and selective attention in adults with ADHD-PI as measured by the TOVA ADHD score 3 to 5 hours after drug administration. Single doses of MDX 700 and 1400 mg were well tolerated.

Comparison of CREME (cosmic-ray effects on microelectronics) model LET (linear energy transfer) spaceflight dosimetry data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Letaw, J.R.; Adams, J.H.

The galactic cosmic radiation (GCR) component of space radiation is the dominant cause of single-event phenomena in microelectronic circuits when Earth's magnetic shielding is low. Spaceflights outside the magnetosphere and in high inclination orbits are examples of such circumstances. In high-inclination orbits, low-energy (high LET) particles are transmitted through the field only at extreme latitudes, but can dominate the orbit-averaged dose. GCR is an important part of the radiation dose to astronauts under the same conditions. As a test of the CREME environmental model and particle transport codes used to estimate single event upsets, we have compiled existing measurements ofmore » HZE doses were compiled where GCR is expected to be important: Apollo 16 and 17, Skylab, Apollo Soyuz Test Project, and Kosmos 782. The LET spectra, due to direct ionization from GCR, for each of these missions has been estimated. The resulting comparisons with data validate the CREME model predictions of high-LET galactic cosmic-ray fluxes to within a factor of two. Some systematic differences between the model and data are identified.« less

Using Aminocaproic Acid to Reduce Blood Loss After Primary Unilateral Total Knee Arthroplasty.

PubMed

Churchill, Jessica L; Toney, Victor A; Truchan, Susan; Anderson, Michael J

2016-01-01

xtensive blood loss after total knee arthroplasty (TKA) is common, and affected patients often require blood transfusions. Studies suggest that antifibrinolytic agents such as aminocaproic acid (ACA) reduce blood loss and blood transfusion rates in patients undergoing TKA. We conducted a study to evaluate whether a single intravenous 10-g dose of ACA given during primary unilateral TKA would decrease perioperative blood loss, raise postoperative hemoglobin levels, and reduce postoperative blood transfusion rates. We retrospectively reviewed the charts of 50 comparable cemented primary unilateral TKAs. Twenty-five patients had been given a single intraoperative 10-g dose of ACA (antifibrinolytic group), and the other 25 had not been given ACA (control group). Postoperative drain output was decreased significantly (P < .0001) in the antifibrinolytic group (155 mL) compared with the control group (410 mL), as was the number of units of blood transfused after surgery (antifibrinolytic group, 0 units; control group, 10 units; P < .002). There were no adverse events in the antifibrinolytic group. In TKA, perioperative blood loss and blood transfusion rates were reduced significantly in patients given a single intraoperative intravenous 10-g dose of ACA compared with patients not given antifibrinolytics. The positive effects of ACA were obtained without adverse events or complications.

Safety, tolerability, and pharmacokinetics of sumatriptan suppositories following single and multiple doses in healthy volunteers.

PubMed

Kunka, R L; Hussey, E K; Shaw, S; Warner, P; Aubert, B; Richard, I; Fowler, P A; Pakes, G E

1997-06-01

A suppository formulation of the 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single doses (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3-14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not dose-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to dose from 25 to 100 mg; area under the plasma concentration-time curve (AUC infinity) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5 h, and the t1/2 was approximately 2 h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t 1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite concentrations were two to three-fold higher than corresponding sumatriptan concentrations. No clinically significant accumulation of sumatriptan or its metabolite occurred. Overall, these studies show that sumatriptan administration via a suppository formulation is well tolerated, allows rapid absorption of sumatriptan, results in sumatriptan Cmax values that are proportional to dose from 25 to 100 mg, and is not associated with accumulation of sumatriptan or its metabolite.

A Compendium of Recent Optocoupler Radiation Test Data

NASA Technical Reports Server (NTRS)

Label, K. A.; Kniffin, S. D.; Reed, R. A.; Kim, H. S.; Wert, J. L.; Oberg, D. L.; Normand, E.; Johnston, A. H.; Lum, G. K.; Koga, R.;

Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population.

PubMed

Li, Xueqing; Wang, Rutao; Liu, Yang; Liu, Yun; Zheng, Heng; Feng, Yabo; Zhao, Na; Geng, Hongbin; Zhang, Wanzhi; Wen, Aidong

2017-11-16

Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C max showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t max of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed. Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The t max of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).

A single dose of erythropoietin reduces perioperative transfusions in cardiac surgery: results of a prospective single-blind randomized controlled trial.

PubMed

Weltert, Luca; Rondinelli, Beatrice; Bello, Ricardo; Falco, Mauro; Bellisario, Alessandro; Maselli, Daniele; Turani, Franco; De Paulis, Ruggero; Pierelli, Luca

2015-07-01

We conducted a prospective single-blind randomized study to assess whether a single 80,000 IU dose of human recombinant erythropoietin (HRE), given just 2 days before cardiac surgery, could be effective in reducing perioperative allogeneic red blood cell transfusion (aRBCt). Six-hundred patients presenting with preoperative hemoglobin (Hb) level of not more than 14.5 g/dL were randomly assigned to either HRE or control. The primary endpoint was the incidence of perioperative aRBCt. The secondary endpoints were mortality and the incidence of adverse events in the first 45 days after surgery, Hb level on Postoperative Day 4, and number of units of RBC transfusions in the first 4 days after surgery. A total of 17% (HRE) versus 39% (control) required transfusion (relative risk, 0.436; p<0.0005). After baseline Hb was controlled for, there was no difference in the incidence of aRBCt between HRE (0%) and control (3.5%) among the patients with baseline Hb of 13.0 g/dL or more, which included the nonanemic fraction of the study population. The mean (range) Hb level on Postoperative Day 4 was 10.2 (9.9-10.6) g/dL (HRE) versus 8.7 (8.5-9.2) g/dL (control; p<0.0005). The distribution of number of units transfused was shifted toward fewer units in HRE (p<0.0005). The all-cause mortality at 45 days was 3.00% (HRE) versus 3.33% (control). The 45-day adverse event rate was 4.33% (HRE) versus 5.67% (control; both p=NS). In anemic patients (Hb<13 g/dL), a single high dose of HRE administered 2 days before cardiac surgery is effective in reducing the incidence of aRBCt without increasing adverse events. © 2015 AABB.

Alternative methods for CYP2D6 phenotyping: comparison of dextromethorphan metabolic ratios from AUC, single point plasma, and urine.

PubMed

Chen, Rui; Wang, Haotian; Shi, Jun; Hu, Pei

2016-05-01

CYP2D6 is a high polymorphic enzyme. Determining its phenotype before CYP2D6 substrate treatment can avoid dose-dependent adverse events or therapeutic failures. Alternative phenotyping methods of CYP2D6 were compared to aluate the appropriate and precise time points for phenotyping after single-dose and ultiple-dose of 30-mg controlled-release (CR) dextromethorphan (DM) and to explore the antimodes for potential sampling methods. This was an open-label, single and multiple-dose study. 21 subjects were assigned to receive a single dose of CR DM 30 mg orally, followed by a 3-day washout period prior to oral administration of CR DM 30 mg every 12 hours for 6 days. Metabolic ratios (MRs) from AUC∞ after single dosing and from AUC0-12h at steady state were taken as the gold standard. The correlations of metabolic ratios of DM to dextrorphan (MRDM/DX) values based on different phenotyping methods were assessed. Linear regression formulas were derived to calculate the antimodes for potential sample methods. In the single-dose part of the study statistically significant correlations were found between MRDM/DX from AUC∞ and from serial plasma points from 1 to 30 hours or from urine (all p-values < 0.001). In the multiple-dose part, statistically significant correlations were found between MRDM/DX from AUC0-12h on day 6 and MRDM/DX from serial plasma points from 0 to 36 hours after the last dosing (all p-values < 0.001). Based on reported urinary antimode and linear regression analysis, the antimodes of AUC and plasma points were derived to profile the trend of antimodes as the drug concentrations changed. MRDM/DX from plasma points had good correlations with MRDM/DX from AUC. Plasma points from 1 to 30 hours after single dose of 30-mg CR DM and any plasma point at steady state after multiple doses of CR DM could potentially be used for phenotyping of CYP2D6.

CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study.

PubMed

Seto, Takashi; Kiura, Katsuyuki; Nishio, Makoto; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yamamoto, Nobuyuki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Takeuchi, Kengo; Shimada, Tadashi; Tanaka, Tomohiro; Tamura, Tomohide

2013-06-01

Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93.5%, 95% CI 82.1-98.6) including two complete responses (4.3%, 0.5-14.8) and 41 partial responses (89.1%, 76.4-96.4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC. Chugai Pharmaceutical Co, Ltd. Copyright © 2013 Elsevier Ltd. All rights reserved.

SEE induced in SRAM operating in a superconducting electron linear accelerator environment

NASA Astrophysics Data System (ADS)

Makowski, D.; Mukherjee, Bhaskar; Grecki, M.; Simrock, Stefan

2005-02-01

Strong fields of bremsstrahlung photons and photoneutrons are produced during the operation of high-energy electron linacs. Therefore, a mixed gamma and neutron radiation field dominates the accelerators environment. The gamma radiation induced Total Ionizing Dose (TID) effect manifests the long-term deterioration of the electronic devices operating in accelerator environment. On the other hand, the neutron radiation is responsible for Single Event Effects (SEE) and may cause a temporal loss of functionality of electronic systems. This phenomenon is known as Single Event Upset (SEU). The neutron dose (KERMA) was used to scale the neutron induced SEU in the SRAM chips. Hence, in order to estimate the neutron KERMA conversion factor for Silicon (Si), dedicated calibration experiments using an Americium-Beryllium (241Am/Be) neutron standard source was carried out. Single Event Upset (SEU) influences the short-term operation of SRAM compared to the gamma induced TID effect. We are at present investigating the feasibility of an SRAM based real-time beam-loss monitor for high-energy accelerators utilizing the SEU caused by fast neutrons. This paper highlights the effects of gamma and neutron radiations on Static Random Access Memory (SRAM), placed at selected locations near the Superconducting Linear Accelerator driving the Vacuum UV Free Electron Laser (VUVFEL) of DESY.

Immunogenicity and safety of a live attenuated shingles (herpes zoster) vaccine (Zostavax®) in individuals aged ≥ 70 years: a randomized study of a single dose vs. two different two-dose schedules.

PubMed

Vesikari, Timo; Hardt, Roland; Rümke, Hans C; Icardi, Giancarlo; Montero, Jordi; Thomas, Stéphane; Sadorge, Christine; Fiquet, Anne

2013-04-01

Disease protection provided by herpes zoster (HZ) vaccination tends to reduce as age increases. This study was designed to ascertain whether a second dose of the HZ vaccine, Zostavax(®), would increase varicella zoster virus (VZV)-specific immune response among individuals aged ≥ 70 y. Individuals aged ≥ 70 y were randomized to receive HZ vaccine in one of three schedules: a single dose (0.65 mL), two doses at 0 and 1 mo, or two doses at 0 and 3 mo. VZV antibody titers were measured at baseline, 4 weeks after each vaccine dose, and 12 mo after the last dose. In total, 759 participants (mean age 76.1 y) were randomized to receive vaccination. Antibody responses were similar after a single dose or two doses of HZ vaccine [post-dose 2/post-dose 1 geometric mean titer (GMT) ratios for the 1-mo or 3-mo schedules were 1.11, 95% confidence interval (CI) 1.02-1.22 and 0.78, 95% CI 0.73-0.85], respectively). The 12-mo post-dose 2/12-mo post-dose 1 GMT ratio was similar for the 1-mo schedule and for the 3-mo schedule (1.06, 95% CI 0.96-1.17 and 1.08, 95% CI 0.98-1.19, respectively). Similar immune responses were observed in participants aged 70-79 y and those aged ≥ 80 y. HZ vaccine was generally well tolerated, with no evidence of increased adverse event incidence after the second dose with either schedule. Compared with a single-dose regimen, two-dose vaccination did not increase VZV antibody responses among individuals aged ≥ 70 y. Antibody persistence after 12 mo was similar with all three schedules.

Prospective memory deficits in illicit polydrug users are associated with the average long-term typical dose of ecstasy typically consumed in a single session.

PubMed

Gallagher, Denis T; Hadjiefthyvoulou, Florentia; Fisk, John E; Montgomery, Catharine; Robinson, Sarita J; Judge, Jeannie

2014-01-01

Neuroimaging evidence suggests that ecstasy-related reductions in SERT densities relate more closely to the number of tablets typically consumed per session rather than estimated total lifetime use. To better understand the basis of drug related deficits in prospective memory (p.m.) we explored the association between p.m. and average long-term typical dose and long-term frequency of use. Study 1: Sixty-five ecstasy/polydrug users and 85 nonecstasy users completed an event-based, a short-term and a long-term time-based p.m. task. Study 2: Study 1 data were merged with outcomes on the same p.m. measures from a previous study creating a combined sample of 103 ecstasy/polydrug users, 38 cannabis-only users, and 65 nonusers of illicit drugs. Study 1: Ecstasy/polydrug users had significant impairments on all p.m. outcomes compared with nonecstasy users. Study 2: Ecstasy/polydrug users were impaired in event-based p.m. compared with both other groups and in long-term time-based p.m. compared with nonillicit drug users. Both drug using groups did worse on the short-term time-based p.m. task compared with nonusers. Higher long-term average typical dose of ecstasy was associated with poorer performance on the event and short-term time-based p.m. tasks and accounted for unique variance in the two p.m. measures over and above the variance associated with cannabis and cocaine use. The typical ecstasy dose consumed in a single session is an important predictor of p.m. impairments with higher doses reflecting increasing tolerance giving rise to greater p.m. impairment.

Safety and immunogenicity of the killed bivalent (O1 and O139) whole-cell cholera vaccine in the Philippines.

PubMed

Capeding, Maria Rosario Z; Gonzales, Maria Liza Antoinette M; Dhingra, Mandeep Singh; D'Cor, Naveena Aloysia; Midde, Venkat Jayanth; Patnaik, Badri Narayan; Thollot, Yaël; Desauziers, Eric

2017-10-03

The killed bivalent (O1 and O139) whole cell oral cholera vaccine (OCV) (Shanchol™) was first licensed in India in 2009 and World Health Organization pre-qualified in 2011. We assessed the safety and immunogenicity of this OCV in the Philippines. This was a phase IV, single-arm, descriptive, open-label study. We recruited 336 participants from 2 centers: 112 participants in each age group (1-4, 5-14 and ≥ 15 years). Participants received 2 OCV doses 14 d apart. Safety was monitored throughout the trial. Blood samples were collected at baseline (pre-vaccination) and 14 d after each dose. Serum vibriocidal antibody titers to V. cholerae O1 (El Tor Inaba and El Tor Ogawa) and O139 strains were assessed, with seroconversion defined as ≥ 4-fold increase from baseline in titers. No immediate unsolicited systemic adverse events/reactions were observed. Unsolicited systemic adverse events were mostly grade 1 intensity. One serious adverse event occurred after the first dose, but was unrelated to vaccination. High seroconversion rates (range 69-92%) were achieved against the O1 serotypes with a trend toward higher rates in the 1-4 y (86-92%) and 5-14 y (86-88%) age groups than the ≥ 15 y age group (69-83%). Lower seroconversion rates were achieved against the O139 serotype (35-70%), particularly in those aged ≥ 15 y (35-42%). The 2-dose regimen of the killed bivalent whole cell OCV was well-tolerated in this study conducted in the Philippines, a cholera-endemic country. Robust immune responses were observed even after a single-dose.

Radiation 101: Effects on Hardware and Robotic Systems

NASA Technical Reports Server (NTRS)

Pellish, Jonathan A.

2015-01-01

We present basic information on different types of radiation effects, including total ionizing dose, displacement damage, and single-event effects. The content is designed to educate space weather professionals, space operations professionals, and other science and engineering stakeholders.

Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study.

PubMed

Miner, Philip B; Silberg, Debra G; Ruth, Magnus; Miller, Frank; Pandolfino, John

2014-11-18

The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose-response effect of lesogaberan on reflux episodes in partial responders. In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan. Each dose was given twice (12 h apart) during a 24-h period, during which impedance-pH measurements were taken. Twenty-five patients were included in the efficacy analysis and 27 in the safety analysis. The effect of lesogaberan on the mean number of reflux episodes was dose-dependent, and all doses significantly reduced the mean number of reflux episodes relative to placebo. Lesogaberan also dose-dependently reduced the mean number of acid reflux episodes (except the 30 mg dose) and weakly acid reflux episodes (all doses) significantly, relative to placebo. Regardless of dose, lesogaberan had a similar effect on the percentage of time with esophageal pH < 4 [mean reduction: 68.5% (30 mg), 54.2% (90 mg), 65.9% (120 mg), 72.1% (240 mg); p < 0.05 except 90 mg dose]. No adverse events led to discontinuation and no serious adverse events occurred during active treatment. Lesogaberan inhibited reflux in a dose-dependent manner in partial responders taking optimised PPI therapy, and these effects were significant versus placebo. All lesogaberan doses were well tolerated and were not associated with clinically relevant adverse events. ClinicalTrials.gov identifier: NCT01043185.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects.

PubMed

Li, Xiaojiao; Liu, Chang; Wu, Min; Zhang, Hong; Sun, Yanfu; Cheng, Longmei; Chen, Hong; Liu, Chengjiao; Yang, Lizhi; Zhang, Qi; Cao, Yuchen; Gu, Jingkai; Ding, Yanhua

2016-08-01

Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.

Steady-state pharmacokinetics of fluvastatin in healthy subjects following a new extended release fluvastatin tablet, Lescol XL.

PubMed

Barilla, Denise; Prasad, Pratapa; Hubert, Martine; Gumbhir-Shah, Kavita

2004-03-01

This was an open-label, randomized, three-period, three-treatment, multiple dose, crossover study in 12 healthy male and female subjects. This study evaluated single dose and steady-state pharmacokinetics of fluvastatin following single and multiple dose administrations of a new extended release fluvastatin 8 h matrix tablet, Lescol XL 80 mg and 160 mg doses once a day. The study also included a twice a day administration of an immediate release (IR) form of fluvastatin capsule, Lescol, for comparative purposes. All doses were administered for 7 days. The safety and tolerability were also assessed. The pharmacokinetics of fluvastatin were evaluated on days 1 and 7 following each treatment. Fluvastatin systemic exposure was 50% less when administered as Lescol XL 80 mg qd compared with Lescol IR 40 mg bid. Conversely, fluvastatin systemic exposure was 22% higher when administered as Lescol XL 160 mg qd compared with Lescol IR 40 mg bid. Single doses of Lescol XL 80 mg and 160 mg were dose proportional but, deviation (30%) from dose proportionality was observed for the Lescol XL 160 mg at steady-state. There appeared to be moderate (20%-40%) accumulation of serum fluvastatin maximal concentrations and exposure after multiple doses of Lescol XL tablets. Both Lescol XL 80 mg and 160 mg showed delayed absorption and longer apparent elimination half-life compared with fluvastatin IR capsule. Single and multiple doses of fluvastatin were generally well tolerated in this healthy volunteer population. Adverse event profiles were consistent with the published safety profile of the marketed formulations. Aside from one incidence of creatine phosphokinase (CPK) elevation (following Lescol XL 160 mg qd treatment), there were no safety concerns with any of the treatments when administered acutely (7 days). Copyright 2004 John Wiley & Sons, Ltd.

Efficacy of Praziquantel against Schistosoma mekongi and Opisthorchis viverrini: A Randomized, Single-Blinded Dose-Comparison Trial

PubMed Central

Phongluxa, Khampheng; Ayé Soukhathammavong, Phonepasong; Vonghachack, Youthanavanh; Keiser, Jennifer; Vounatsou, Penelope; Tanner, Marcel; Hatz, Christoph; Utzinger, Jürg; Odermatt, Peter; Akkhavong, Kongsap

2012-01-01

Background Schistosomiasis and opisthorchiasis are of public health importance in Southeast Asia. Praziquantel (PZQ) is the drug of choice for morbidity control but few dose comparisons have been made. Methodology Ninety-three schoolchildren were enrolled in an area of Lao PDR where Schistosoma mekongi and Opisthorchis viverrini coexist for a PZQ dose-comparison trial. Prevalence and intensity of infections were determined by a rigorous diagnostic effort (3 stool specimens, each examined with triplicate Kato-Katz) before and 28–30 days after treatment. Ninety children with full baseline data were randomized to receive PZQ: the 40 mg/kg standard single dose (n = 45) or a 75 mg/kg total dose (50 mg/kg+25 mg/kg, 4 hours apart; n = 45). Adverse events were assessed at 3 and 24 hours posttreatment. Principal Findings Baseline infection prevalence of S. mekongi and O. viverrini were 87.8% and 98.9%, respectively. S. mekongi cure rates were 75.0% (95% confidence interval (CI): 56.6–88.5%) and 80.8% (95% CI: 60.6–93.4%) for 40 mg/kg and 75 mg/kg PZQ, respectively (P = 0.60). O. viverrini cure rates were significantly different at 71.4% (95% CI: 53.4–84.4%) and 96.6% (95% CI: not defined), respectively (P = 0.009). Egg reduction rates (ERRs) against O. viverrini were very high for both doses (>99%), but slightly lower for S. mekongi at 40 mg/kg (96.4% vs. 98.1%) and not influenced by increasing diagnostic effort. O. viverrini cure rates would have been overestimated and no statistical difference between doses found if efficacy was based on a minimum sampling effort (single Kato-Katz before and after treatment). Adverse events were common (96%), mainly mild with no significant differences between the two treatment groups. Conclusions/Significance Cure rate from the 75 mg/kg PZQ dose was more efficacious than 40 mg/kg against O. viverrini but not against S. mekongi infections, while ERRs were similar for both doses. Trial Registration Controlled-Trials.com ISRCTN57714676 PMID:22848766

Evaluation of Recent Technologies of Nonvolatile RAM

NASA Astrophysics Data System (ADS)

Nuns, Thierry; Duzellier, Sophie; Bertrand, Jean; Hubert, Guillaume; Pouget, Vincent; Darracq, FrÉdÉric; David, Jean-Pierre; Soonckindt, Sabine

2008-08-01

Two types of recent nonvolatile random access memories (NVRAM) were evaluated for radiation effects: total dose and single event upset and latch-up under heavy ions and protons. Complementary irradiation with a laser beam provides information on sensitive areas of the devices.

CREME: The 2011 Revision of the Cosmic Ray Effects on Micro-Electronics Code

NASA Technical Reports Server (NTRS)

Adams, James H., Jr.; Barghouty, Abdulnasser F.; Reed, Robert A.; Sierawski, Brian D.; Watts, John W., Jr.

2012-01-01

We describe a tool suite, CREME, which combines existing capabilities of CREME96 and CREME86 with new radiation environment models and new Monte Carlo computational capabilities for single event effects and total ionizing dose.

Microdose Induced Drain Leakage Effects in Power Trench MOSFETs: Experiment and Modeling

NASA Astrophysics Data System (ADS)

Zebrev, Gennady I.; Vatuev, Alexander S.; Useinov, Rustem G.; Emeliyanov, Vladimir V.; Anashin, Vasily S.; Gorbunov, Maxim S.; Turin, Valentin O.; Yesenkov, Kirill A.

2014-08-01

We study experimentally and theoretically the micro-dose induced drain-source leakage current in the trench power MOSFETs under irradiation with high-LET heavy ions. We found experimentally that cumulative increase of leakage current occurs by means of stochastic spikes corresponding to a strike of single heavy ion into the MOSFET gate oxide. We simulate this effect with the proposed analytic model allowing to describe (including Monte Carlo methods) both the deterministic (cumulative dose) and stochastic (single event) aspects of the problem. Based on this model the survival probability assessment in space heavy ion environment with high LETs was proposed.

Single Low Dose Primaquine (0.25mg/kg) Does Not Cause Clinically Significant Haemolysis in G6PD Deficient Subjects

PubMed Central

Bancone, Germana; Chowwiwat, Nongnud; Somsakchaicharoen, Raweewan; Poodpanya, Lalita; Moo, Paw Khu; Gornsawun, Gornpan; Kajeechiwa, Ladda; Thwin, May Myo; Rakthinthong, Santisuk; Nosten, Suphak; Thinraow, Suradet; Nyo, Slight Naw; Ling, Clare L.; Wiladphaingern, Jacher; Kiricharoen, Naw Lily; Moore, Kerryn A.; White, Nicholas J.; Nosten, Francois

2016-01-01

Background Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum. The transmission blocking dose of primaquine previously recommended was 0.75mg/kg (adult dose 45mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15–20%) in populations living in malarious areas. To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25mg/kg (adult dose 15mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing. Direct evidence of the safety of this low dose is lacking. Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%. Methods and Findings The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects. Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration. G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females. Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models. No adverse events related to primaquine were reported during the trial. Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant. Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic. Conclusions The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency. The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria. Trial Registration ClinicalTrials.gov NCT01872702 PMID:27010542

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.

PubMed

Boettcher, Michael-Friedrich; Heinig, Roland; Schmeck, Carsten; Kohlsdorfer, Christian; Ludwig, Matthias; Schaefer, Anja; Gelfert-Peukert, Sabine; Wensing, Georg; Weber, Olaf

2012-02-01

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

The SATRAM Timepix spacecraft payload in open space on board the Proba-V satellite for wide range radiation monitoring in LEO orbit

NASA Astrophysics Data System (ADS)

Granja, Carlos; Polansky, Stepan; Vykydal, Zdenek; Pospisil, Stanislav; Owens, Alan; Kozacek, Zdenek; Mellab, Karim; Simcak, Marek

2016-06-01

The Space Application of Timepix based Radiation Monitor (SATRAM) is a spacecraft platform radiation monitor on board the Proba-V satellite launched in an 820 km altitude low Earth orbit in 2013. The is a technology demonstration payload is based on the Timepix chip equipped with a 300 μm silicon sensor with signal threshold of 8 keV/pixel to low-energy X-rays and all charged particles including minimum ionizing particles. For X-rays the energy working range is 10-30 keV. Event count rates can be up to 106 cnt/(cm2 s) for detailed event-by-event analysis or over 1011 cnt/(cm2 s) for particle-counting only measurements. The single quantum sensitivity (zero-dark current noise level) combined with per-pixel spectrometry and micro-scale pattern recognition analysis of single particle tracks enables the composition (particle type) and spectral characterization (energy loss) of mixed radiation fields to be determined. Timepix's pixel granularity and particle tracking capability also provides directional sensitivity for energetic charged particles. The payload detector response operates in wide dynamic range in terms of absorbed dose starting from single particle doses in the pGy level, particle count rate up to 106-10 /cm2/s and particle energy loss (threshold at 150 eV/μm). The flight model in orbit was successfully commissioned in 2013 and has been sampling the space radiation field in the satellite environment along its orbit at a rate of several frames per minute of varying exposure time. This article describes the design and operation of SATRAM together with an overview of the response and resolving power to the mixed radiation field including summary of the principal data products (dose rate, equivalent dose rate, particle-type count rate). The preliminary evaluation of response of the embedded Timepix detector to space radiation in the satellite environment is presented together with first results in the form of a detailed visualization of the mixed radiation field at the position of the payload and resulting spatial- and time-correlated radiation maps of cumulative dose rate along the satellite orbit.

Radiation Performance of 1 Gbit DDR SDRAMs Fabricated in the 90 nm CMOS Technology Node

NASA Technical Reports Server (NTRS)

Ladbury, Raymond L.; Gorelick, Jerry L.; Berg, M. D.; Kim, H.; LaBel, K.; Friendlich, M.; Koga, R.; George, J.; Crain, S.; Yu, P.;

Single dose oral aspirin for acute postoperative pain in adults.

PubMed

Derry, Sheena; Moore, R Andrew

2012-04-18

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews on 'Single dose oral aspirin for acute pain'. Aspirin has been known for many years to be an effective analgesic for many different pain conditions. Although its use as an analgesic is now limited in developed countries, it is widely available, inexpensive, and remains commonly used throughout the world. To assess the analgesic efficacy and associated adverse events of single dose oral aspirin in acute postoperative pain. For the earlier review, we identified randomised trials by searching CENTRAL (The Cochrane Library) (1998, Issue 1), MEDLINE (1966 to March 1998), EMBASE (1980 to January 1998), and the Oxford Pain Relief Database (1950 to 1994). We updated searches of CENTRAL, MEDLINE, and EMBASE to January 2012. Single oral dose, randomised, double-blind, placebo-controlled trials of aspirin for relief of established moderate to severe postoperative pain in adults. We assessed studies for methodological quality and two review authors extracted the data independently. We used summed total pain relief (TOTPAR) over four to six hours to calculate the number of participants achieving at least 50% pain relief. We used these derived results to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over four to six hours. We sought numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, as additional measures of efficacy. We collected information on adverse events and withdrawals. We included 68 studies in which aspirin was used at doses from 300 mg to 1200 mg, but the vast majority of participants received either 600/650 mg (2409 participants, 64 studies) or 990/1000 mg (380 participants, eight studies). There was only one new study.Studies were overwhelmingly of adequate or good methodological quality. NNTs for at least 50% pain relief over four to six hours were 4.2 (3.9 to 4.8), 3.8 (3.0 to 5.1), and 2.7 (2.0 to 3.8) for 600/650 mg, 900/1000 mg, and 1200 mg respectively, compared with placebo. Type of pain model had no significant impact on the results. Lower doses were not significantly different from placebo. These results do not differ from those of the earlier review.Fewer participants required rescue medication with aspirin than with placebo over four to eight hours postdose, but by 12 hours there was no difference. The number of participants experiencing adverse events was not significantly different from placebo for 600/650 mg aspirin, but for 900/1000 mg the number needed to treat to harm was 7.5 (4.8 to 17). The most commonly reported events were dizziness, drowsiness, gastric irritation, nausea, and vomiting, nearly all of which were of mild to moderate severity. Aspirin is an effective analgesic for acute pain of moderate to severe intensity. High doses are more effective, but are associated with increased adverse events, including drowsiness and gastric irritation. The pain relief achieved with aspirin was very similar milligram for milligram to that seen with paracetamol. There was no change to the conclusions in this update.

A single high dose of dexamethasone affects the phosphorylation state of glutamate AMPA receptors in the human limbic system

PubMed Central

Lopes, M W; Leal, R B; Guarnieri, R; Schwarzbold, M L; Hoeller, A; Diaz, A P; Boos, G L; Lin, K; Linhares, M N; Nunes, J C; Quevedo, J; Bortolotto, Z A; Markowitsch, H J; Lightman, S L; Walz, R

2016-01-01

Glucocorticoids (GC) released during stress response exert feedforward effects in the whole brain, but particularly in the limbic circuits that modulates cognition, emotion and behavior. GC are the most commonly prescribed anti-inflammatory and immunosuppressant medication worldwide and pharmacological GC treatment has been paralleled by the high incidence of acute and chronic neuropsychiatric side effects, which reinforces the brain sensitivity for GC. Synapses can be bi-directionally modifiable via potentiation (long-term potentiation, LTP) or depotentiation (long-term depression, LTD) of synaptic transmission efficacy, and the phosphorylation state of Ser831 and Ser845 sites, in the GluA1 subunit of the glutamate AMPA receptors, are a critical event for these synaptic neuroplasticity events. Through a quasi-randomized controlled study, we show that a single high dexamethasone dose significantly reduces in a dose-dependent manner the levels of GluA1-Ser831 phosphorylation in the amygdala resected during surgery for temporal lobe epilepsy. This is the first report demonstrating GC effects on key markers of synaptic neuroplasticity in the human limbic system. The results contribute to understanding how GC affects the human brain under physiologic and pharmacologic conditions. PMID:27959333

Efficacy and Safety of Single and Double Doses of Ivermectin versus 7-Day High Dose Albendazole for Chronic Strongyloidiasis

PubMed Central

Suputtamongkol, Yupin; Premasathian, Nalinee; Bhumimuang, Kid; Waywa, Duangdao; Nilganuwong, Surasak; Karuphong, Ekkapun; Anekthananon, Thanomsak; Wanachiwanawin, Darawan; Silpasakorn, Saowaluk

2011-01-01

Background Strongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. It remains an important health problem due to autoinfection, which may result in hyperinfection and disseminated infection in immunosuppressed patients, especially patients receiving chemotherapy or corticosteroid treatment. Ivermectin and albendazole are effective against strongyloidiasis. However, the efficacy and the most effective dosing regimen are to be determined. Methods A prospective, randomized, open study was conducted in which a 7-day course of oral albendazole 800 mg daily was compared with a single dose (200 microgram/kilogram body weight), or double doses, given 2 weeks apart, of ivermectin in Thai patients with chronic strongyloidiasis. Patients were followed-up with 2 weeks after initiation of treatment, then 1 month, 3 months, 6 months, 9 months, and 1 year after treatment. Combination of direct microscopic examination of fecal smear, formol-ether concentration method, and modified Koga agar plate culture were used to detect strongyloides larvae in two consecutive fecal samples in each follow-up visit. The primary endpoint was clearance of strongyloides larvae from feces after treatment and at one year follow-up. Results Ninety patients were included in the analysis (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). All except one patient in this study had at least one concomitant disease. Diabetes mellitus, systemic lupus erythrematosus, nephrotic syndrome, hematologic malignancy, solid tumor and human immunodeficiency virus infection were common concomitant diseases in these patients. The median (range) duration of follow-up were 19 (2–76) weeks in albendazole group, 39 (2–74) weeks in single dose ivermectin group, and 26 (2–74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin, and double doses of oral ivermectin respectively (P = 0.006) in modified intention to treat analysis. No serious adverse event associated with treatment was found in any of the groups. Conclusion/Significance This study confirms that both a single, and a double dose of oral ivermectin taken two weeks apart, is more effective than a 7-day course of high dose albendazole for patients with chronic infection due to S. stercoralis. Double dose of ivermectin, taken two weeks apart, might be more effective than a single dose in patients with concomitant illness. Trial Registration ClinicalTrials.gov NCT00765024 PMID:21572981

Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases.

PubMed

Frey, Benjamin; Hehlgans, Stephanie; Rödel, Franz; Gaipl, Udo S

2015-11-28

Inflammation is a homeostatic mechanism aiming to maintain tissue integrity. The underlying immunological mechanisms and the interrelationship between ionizing radiation and inflammation are complex and multifactorial on cellular and chemical levels. On the one hand, radiation with single doses exceeding 1 Gy might initiate inflammatory reactions and thereby impact on tumor development. On the other hand, radiation is capable of attenuating an established inflammatory process, which is clinically used for the treatment of inflammatory and degenerative diseases with low-dose radiotherapy (single dose <1 Gy). At higher doses, ionizing radiation, especially in combination with additional immune stimulation, fosters the induction of immunogenic forms of tumor cell death and shifts the tumor microenvironment as well as the infiltration of immune cells from an anti- to a pro-inflammatory state. Distinct tumor infiltrating immune cells predict the response to radiochemotherapy in a multitude of tumor entities. While a high tumor infiltration of these adaptive immune cells mostly predicts a favorable disease outcome, a high infiltration of tumor-associated macrophages predicts an unfavorable response. Pro-inflammatory events should dominate over anti-inflammatory ones in this scenario. This review focuses on how ionizing radiation modulates inflammatory events in benign inflammatory and in malign diseases. A special focus is set on the role of tumor infiltrating lymphocytes and macrophages as biomarkers to predict treatment response and anti-tumor immunity and on mechanisms implicated in the anti-inflammatory effects of low-dose radiation therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic

PubMed Central

Buda, Jeffrey J; Carroll, F I; Kosten, Thomas R; Swearingen, Dennis; Walters, Bradford B

2015-01-01

Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator (WSF)); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard instrument was administered predose and daily postdose Days 1–6. At 1 mg, 2 of the 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests that NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine whether a significant JDTic human cardiac effect indeed exists, and if so, whether it is specific to JDTic or represents a KORAn class effect. PMID:25628006

Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects.

PubMed

Sarashina, Akiko; Koiwai, Kazuki; Seman, Leo J; Yamamura, Norio; Taniguchi, Atsushi; Negishi, Takahiro; Sesoko, Shogo; Woerle, Hans J; Dugi, Klaus A

2013-01-01

This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.

Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers

PubMed Central

Chiesa, Joseph; Lückermann, Mark; Fischer, Carsten; Dalhoff, Axel; Fuhr, Uwe

2017-01-01

ABSTRACT Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.) PMID:28784673

The Lack of Effect of Food on the Pharmacokinetics of ZX008 (Fenfluramine Oral Solution): Results of a Single-dose, Two-period Crossover Study.

PubMed

Gammaitoni, Arnold; Smith, Steven; Boyd, Brooks

2018-06-22

Fenfluramine is being developed as a low-dose adjunctive treatment for seizures in patients with Dravet syndrome and other epileptic encephalopathies, including Lennox-Gastaut syndrome. Most patients with Dravet syndrome receive multiple antiepileptic drugs, making it challenging for caregivers to track correct administration times. The present Phase I study was conducted to determine the effect of food on the pharmacokinetic properties of fenfluramine. Healthy nonsmoking subjects aged 18 to 50years were enrolled in an open-label, crossover, Phase I pharmacokinetic and safety profile study and received 2 single 0.8-mg/kg doses of ZX008 (fenfluramine hydrochloride oral solution), 1 after a 10-hour overnight fast and the other 30 minutes after the start of consumption of a high-fat breakfast, in a randomly assigned order. A washout period of at least 9days separated the 2 treatment periods. Venous blood samples were taken before each dose and periodically for 72hours after each dose for determination of concentrations of fenfluramine and its active metabolite norfenfluramine. Plasma pharmacokinetic parameters were estimated for each subject by noncompartmental analysis. In the 13 subjects completing both treatment periods, food had no effect on the rate or extent of absorption and bioavailability of fenfluramine as assessed by fed vs fasted adjusted geometric mean observed plasma C max (59.1vs 56.7 ng/mL; NS) and AUC 0-∞ (1640vs 1600 ng · h/mL; NS). Additionally, there was no impact of food on systemic exposure of norfenfluramine. Seven subjects reported at least 1 treatment-emergent adverse event; all treatment-emergent adverse events were mild in severity. The bioequivalence and tolerability of single 0.8-mg/kg oral doses of ZX008 in the fed and fasted states support ZX008 administration without regard to meals. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

The protective effects of ascorbic acid, cimetidine, and nifedipine on diethyldithiocarbamate-induced hepatic toxicity in albino rats.

PubMed

Gaafa, Khadiga Mohammed; Badawy, Mohammed M; Hamza, Alaaeldin A

2011-10-01

The aim of the present work was to clarify the involvement of free radicals, cytochrome P450 toxic metabolites, and deregulation of calcium homeostasis in the mechanism of diethyldithiocarbamate (DDC) hepatotoxicity. This was elucidated through the preadministration of ascorbic acid (a free radical scavenger), cimetidine (an inhibitor of cytochrome P450 enzymes), or nifedipine (a calcium-blocking agent) before DDC treatment to male albino rats. DDC was administered either as a single dose [800 mg/kg body weight (b.w.), subcutaneously, s.c.] or daily repeated doses for 30 days (400 mg/kg b.w., s.c.). Oxidative stress indicators [e.g., malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase enzyme (SOD)] showed that single or repeated DDC doses induce an increase in MDA level and a decrease in SOD activity in the liver, whereas it causes depletion in hepatic GSH after a single dose and an elevation in its value after repeated doses. Severe histopathological changes were also observed in the livers of rats treated with single or repeated DDC doses. Ascorbic acid, cimetidine, and nifedipine pretreatments were found to induce highly protective effects against the evinced DDC hepatotoxicity, manifesting that free radical, cytochrome P450, and calcium-dependent processes contribute to DDC liver toxicity. Finally, although multiple mechanisms may be involved in the hepatotoxic changes induced by DDC, calcium disarrangement and free radical formation play a more critical role than cytochrome P450 in metabolic events leading to toxic effects of DDC.

A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management.

PubMed

Holdcroft, Anita; Maze, Mervyn; Doré, Caroline; Tebbs, Susan; Thompson, Simon

2006-05-01

Cannabinoids have dose-related antinociceptive effects in animals. This clinical study aimed to investigate whether a single oral dose of cannabis plant extract (Cannador; Institute for Clinical Research, IKF, Berlin, Germany) could provide pain relief with minimal side effects for postoperative pain. Patients (aged 18-75 yr) were recruited and consented before surgery if patient-controlled analgesia was planned for provision of postoperative pain relief. Each patient received a single dose of 5, 10, or 15 mg Cannador if he or she had at least moderate pain after stopping patient-controlled analgesia. Starting with 5 mg, dose escalation was based on the number of patients requesting rescue analgesia and adverse effects. Pain relief, pain intensity, and side effects were recorded over 6 h and analyzed using tests for trend with dose. Rescue analgesia was requested by all 11 patients (100%) receiving 5 mg, 15 of 30 patient (50%) receiving 10 mg, and 6 of 24 patients (25%) receiving 15 mg Cannador (log rank test for trend in time to rescue analgesia with dose P < 0.001). There were also significant trends across the escalating dose groups for decreasing pain intensity at rest (P = 0.01), increasing sedation (P = 0.03), and more adverse events (P = 0.002). The number needed to treat to prevent one rescue analgesia request for the 10-mg and 15-mg doses, relative to 5 mg, were 2.0 (95% confidence interval, 1.5-3.1) and 1.3 (95% confidence interval, 1.1-1.7), respectively. The study was terminated because of a serious vasovagal adverse event in a patient receiving 15 mg. These significant dose-related improvements in rescue analgesia requirements in the 10 mg and 15 mg groups provide a number needed to treat that is equivalent to many routinely used analgesics without frequent adverse effects.

An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

PubMed

Liu, Hongzhong; Wu, Runhui; Hu, Pei; Sun, Feifei; Xu, Lihong; Liang, Yali; Nepal, Sunil; Qu, Peng Roger; Huard, Francois; Korth-Bradley, Joan M

2017-07-01

Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C <1%) and a history of at least 150 exposure-days to any FVIII-containing product. Eligible patients received a single dose of moroctocog alfa (AF-CC) 50 IU/kg IV within 10 minutes. Blood samples were collected within 2 hours before administration and through 72 hours after dosing. Pharmacokinetic parameters were assessed based on FVIII:C and were analyzed by age groups: ages 6 to <12 years (n = 3) and ≥12 years (n = 10). The mean plasma concentration-time profile for FVIII:C activity was consistently lower in patients aged 6 to <12 years compared with those aged ≥12 years. Geometric AUC 0-∞ and C max were approximately 57% and 28% lower in the younger patients relative to the older patients, respectively. A total of 4 adverse events occurred in 4 patients. Low-titer, transient FVIII inhibitors were observed in 2 patients and were considered serious adverse events. Neither case resulted in clinical manifestations nor required treatment. This is the first report of the pharmacokinetic parameters of FVIII:C after moroctocog alfa (AF-CC) in an all-Chinese population of males with hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported with recombinant FVIII products in studies with a predominantly white population; younger patients had reduced exposure to FVIII:C. The single doses of moroctocog alfa (AF-CC) were well tolerated; 2 cases of transient, low-titer FVIII inhibitor development were observed. ClinicalTrials.gov identifier: NCT02461992. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Assessment of the cardiac safety between cetuximab and panitumumab as single therapy in Chinese chemotherapy-refractory mCRC.

PubMed

Tang, Xue-Miao; Chen, Hao; Li, Qing; Song, Yiling; Zhang, Shuping; Xu, Xiao-Shuan; Xu, Yiwei; Chen, Shulin

2018-01-01

The cardiac safety of cetuximab and panitumumab, particularly as single agents, has not been investigated extensively. This trial was designed to specifically evaluate the cardiac safety of cetuximab and panitumumab as single therapy in Chinese chemotherapy-refractory metastatic colorectal cancer (mCRC) patients. Sixty-one patients received cetuximab at an initial dose of 400 mg/m 2 intravenously over 120 minutes on day 1 (week 1), followed by a maintenance dose of 250 mg/m 2 intravenously over 60 minutes on day 1 of each 7-day cycle. Forty-three patients received panitumumab at a dose of 6 mg/kg intravenously every 14 days. Routine laboratory tests and electrocardiogram (ECG) were performed at baseline, during therapy and after the treatment (4th and 10th months). The incidence of elevation of troponin I ultra (TNI Ultra), abnormal ECGs, cardiac events and noncardiac adverse events (AEs) were recorded and analyzed. The incidence of elevation of TNI Ultra between the two groups had no significance ( p =0.681), and TNI Ultra+ was observed more frequently in patients with metastases to more than three organs and they received fourth or above lines of chemotherapy. The most frequent abnormal ECG manifestations were nonspecific ST changes and QTc prolongation in the two groups. At 10 months after treatment, most of the abnormal ECG manifestations were reversed. The most common cardiac AEs of cetuximab and panitumumab included palpitations, dyspnea, chest pain and arrhythmias requiring treatment. Most of the events were mild and transient. The incidence of cardiac AEs had no significant difference between the two groups. Rash was still the most common noncardiac AE in both groups. Cetuximab and panitumumab showed favorable cardiac safety as single agents for Chinese chemotherapy-refractory mCRC patients. But monitoring for cardiac AEs is still necessary throughout the entire treatment process.

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease

PubMed Central

Jia, Jing-ying; Zhao, Qian-hua; Liu, Yun; Gui, Yu-zhou; Liu, Gang-yi; Zhu, Da-yuan; Yu, Chen; Hong, Zhen

2013-01-01

Aim: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. Methods: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0–72 h and AUC0–∞ were calculated. Tolerance assessments were conducted throughout the study. Results: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76–0.82 h; the AUC0–72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. Conclusion: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers. PMID:23624756

A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception.

PubMed

Shohel, Mohammad; Rahman, Mohammad Mahfuzur; Zaman, Asif; Uddin, Mir Muhammad Nasir; Al-Amin, Md Mamun; Reza, Hasan Mahmud

2014-04-04

Unintended pregnancy is a complex phenomenon which raise to take an emergency decision. Low contraceptive prevalence and high user failure rates are the leading causes of this unexpected situation. High user failure rates suggest the vital role of emergency contraception to prevent unplanned pregnancy. Levonorgestrel - a commonly used progestin for emergency contraception. However, little is known about its pharmacokinetics and optimal dose for use. Hence, there is a need to conduct a systematic review of the available evidences. Randomized, double-blind trials were sought, evaluating healthy women with regular menstrual cycles, who requested emergency contraception within 72 h of unprotected coitus, to one of three regimens: 1.5 mg single dose levonorgestrel, two doses of 0.75 mg levonorgestrel given 12 h apart or two doses of 0.75 mg levonorgestrel given 24 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. Every trial under consideration successfully established the contraceptive effectiveness of levonorgestrel for preventing unintended pregnancy. Moreover, a single dose of levonorgestrel 1.5 mg for emergency contraception supports its safety and efficacy profile. If two doses of levonorgestrel 0.75 mg are intended for administration, the second dose can positively be taken 12-24 h after the first dose without compromising its contraceptive efficacy. The main side effect was frequent menstrual irregularities. No serious adverse events were reported. The review shows that, emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen. All the regimens studied were very efficacious for emergency contraception and prevented a high proportion of pregnancies if taken within 72 h of unprotected coitus. Single levonorgestrel dose (1.5 mg) can substitute two 0.75 mg doses 12 or 24 h apart. With either regimen, the earlier the treatment is given, the more effective it seems to be.

A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception

PubMed Central

2014-01-01

Background Unintended pregnancy is a complex phenomenon which raise to take an emergency decision. Low contraceptive prevalence and high user failure rates are the leading causes of this unexpected situation. High user failure rates suggest the vital role of emergency contraception to prevent unplanned pregnancy. Levonorgestrel - a commonly used progestin for emergency contraception. However, little is known about its pharmacokinetics and optimal dose for use. Hence, there is a need to conduct a systematic review of the available evidences. Methods Randomized, double-blind trials were sought, evaluating healthy women with regular menstrual cycles, who requested emergency contraception within 72 h of unprotected coitus, to one of three regimens: 1.5 mg single dose levonorgestrel, two doses of 0.75 mg levonorgestrel given 12 h apart or two doses of 0.75 mg levonorgestrel given 24 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. Results Every trial under consideration successfully established the contraceptive effectiveness of levonorgestrel for preventing unintended pregnancy. Moreover, a single dose of levonorgestrel 1.5 mg for emergency contraception supports its safety and efficacy profile. If two doses of levonorgestrel 0.75 mg are intended for administration, the second dose can positively be taken 12–24 h after the first dose without compromising its contraceptive efficacy. The main side effect was frequent menstrual irregularities. No serious adverse events were reported. Conclusions The review shows that, emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen. All the regimens studied were very efficacious for emergency contraception and prevented a high proportion of pregnancies if taken within 72 h of unprotected coitus. Single levonorgestrel dose (1.5 mg) can substitute two 0.75 mg doses 12 or 24 h apart. With either regimen, the earlier the treatment is given, the more effective it seems to be. PMID:24708837

Evaluation of the gastrointestinal tolerability of corn starch fiber, a novel dietary fiber, in two independent randomized, double-blind, crossover studies in healthy men and women.

PubMed

Crincoli, Christine M; Garcia-Campayo, Vicenta; Rihner, Marisa O; Nikiforov, Andrey I; Liska, DeAnn; van de Ligt, Jennifer L G

2016-11-01

Two independent clinical studies were conducted to compare the gastrointestinal (GI) tolerability of corn starch fiber, a novel dietary fiber, at up to 50 g/day (single-dose study) or 90 g/day (multiple-serving study) with a negative control (no fiber) and a positive control (50 or 90 g polydextrose, for single- and multiple-serving studies, respectively) in generally healthy study volunteers. Flatulence and borborygmus were the primary symptoms reported at the higher doses of corn starch fiber and for the positive control interventions. Bowel movements were increased over 48 h with corn starch fiber at 90 g. Thresholds for mild GI effects were established at 30 g as a single dose and 60 g as multiple servings spread over the day. Other than moderate abdominal pain and mild increased appetite in one subject at 90-g corn starch fiber, no test article-related adverse events were reported.

UVPROM dosimetry, microdosimetry and applications to SEU and extreme value theory

NASA Astrophysics Data System (ADS)

Scheick, Leif Zebediah

A new method is described for characterizing a device in terms of the statistical distribution of first failures. The method is based on the erasure of a commercial Ultra- Violet erasable Programmable Read Only Memory (UVPROM). The method of readout would be used on a spacecraft or in other restrictive radiation environments. The measurement of the charge remaining on the floating gate is used to determine absorbed dose. The method of determining dose does not require the detector to be destroyed or erased nor does it effect the ability for taking further measurements. This is compared to extreme value theory applied to the statistical distributions that apply to this device. This technique predicts the threshold of Single Event Effects (SEE), like anomalous changes in erasure time in programmable devices due to high microdose energy-deposition events. This technique also allows for advanced non-destructive, screening of a single microelectronic devices for predictable response in a stressful, i.e. radiation, environments.

Pharmacokinetic Profile and Tolerability of Liposomal Bupivacaine Following a Repeated Dose via Local Subcutaneous Infiltration in Healthy Volunteers.

PubMed

Rice, David; Heil, Justin W; Biernat, Lukasz

2017-03-01

Liposomal bupivacaine is indicated for administration into the surgical site to produce post-surgical analgesia. The objectives of this study were to characterize the pharmacokinetic and safety profiles of liposomal bupivacaine following a repeated dose in healthy volunteers. Healthy adults were assigned to receive liposomal bupivacaine via subcutaneous infiltration in a single 266 mg dose (cohort 1) or in two 266 mg doses, with the second dose given immediately, 24, 48, or 72 h after the first dose (cohorts 2-5). Pharmacokinetic parameters were estimated from blood samples collected up to day 14. Subjects were monitored for adverse events and assessed for neurologic function, cardiac function, and infiltration area abnormalities. Twelve subjects were assigned to each cohort. The mean ± standard deviation maximum observed plasma concentration (C max ) of bupivacaine after a single dose was 129 ± 47 ng/mL. The mean C max after the second dose was higher, but always less than double the C max for cohort 1. The highest individual C max (589 ng/mL) was observed in a subject who received the second dose 24 h after the first dose (cohort 4), but was well below the reported thresholds for neurotoxicity and cardiac toxicity (2000 and 4000 ng/mL, respectively). A single and repeated dose were well-tolerated, and there were no clinically meaningful findings regarding neurologic examinations and electrocardiography. The mean C max following a repeated dose of liposomal bupivacaine remained well below accepted values for central nervous system and cardiac toxicity. Liposomal bupivacaine was well-tolerated and revealed no clinically important safety signals. CLINICALTRIALS. NCT02210247.

Single Dose and Repeat Once-Daily Dose Safety, Tolerability and Pharmacokinetics of Valbenazine in Healthy Male Subjects.

PubMed

Luo, Rosa; Bozigian, Haig; Jimenez, Roland; Loewen, Gordon; O'Brien, Christopher F

2017-08-01

Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI-98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 C max and AUC increased dose-proportionally from 50 to 150 mg and more than dose-proportionally from 1 to 50 mg. QD VBZ and NBI-98782 C max and AUC parameters were also dose-proportional between the 50 and 100 mg doses. Steady-state for both analytes appeared to be achieved by Day 8. The accumulation index was ~1.5 for VBZ and ~2.5 for NBI-98782. Peak to trough fluctuation was approximately 250% for VBZ and 70% for NBI-98782. Across both studies, NBI-98782 exposure was approximately 20%-30% that of VBZ based on molar ratios. In the first study, the maximum-tolerated dose was not achieved; headache (2 events) was the only treatment-emergent adverse event (TEAE) reported by more than one subject. In the second study, fatigue (4 events) was the only TEAE reported by more than one subject following SD VBZ. Following QD VBZ, the TEAEs of fatigue, insomnia, disturbance in attention, and nervousness were dose-dependent; the latter three TEAEs were considered dose-limiting. Subject withdrawals due to TEAEs were 1 each for PBO and 50 mg VBZ QD, and 3 for 100 mg VBZ QD. Clinically relevant effects on laboratory parameters, vital signs or ECGs were limited to increased CPK (SD: 1 each for 5 mg VBZ and PBO), ALT (QD: 1 each for 50 and 100 mg VBZ and PBO), and triglycerides (QD: 1 each for 50 mg VBZ and PBO). VBZ has an acceptable safety profile and predictable pharmacokinetics that result in stable concentrations of active compounds with low peak-to-trough fluctuation following once-daily dosing.

Single Dose and Repeat Once-Daily Dose Safety, Tolerability and Pharmacokinetics of Valbenazine in Healthy Male Subjects

PubMed Central

Luo, Rosa; Bozigian, Haig; Jimenez, Roland; Loewen, Gordon; O’Brien, Christopher F.

2017-01-01

Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI-98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 Cmax and AUC increased dose-proportionally from 50 to 150 mg and more than dose-proportionally from 1 to 50 mg. QD VBZ and NBI-98782 Cmax and AUC parameters were also dose-proportional between the 50 and 100 mg doses. Steady-state for both analytes appeared to be achieved by Day 8. The accumulation index was ~1.5 for VBZ and ~2.5 for NBI-98782. Peak to trough fluctuation was approximately 250% for VBZ and 70% for NBI-98782. Across both studies, NBI-98782 exposure was approximately 20%–30% that of VBZ based on molar ratios. In the first study, the maximum-tolerated dose was not achieved; headache (2 events) was the only treatment-emergent adverse event (TEAE) reported by more than one subject. In the second study, fatigue (4 events) was the only TEAE reported by more than one subject following SD VBZ. Following QD VBZ, the TEAEs of fatigue, insomnia, disturbance in attention, and nervousness were dose-dependent; the latter three TEAEs were considered dose-limiting. Subject withdrawals due to TEAEs were 1 each for PBO and 50 mg VBZ QD, and 3 for 100 mg VBZ QD. Clinically relevant effects on laboratory parameters, vital signs or ECGs were limited to increased CPK (SD: 1 each for 5 mg VBZ and PBO), ALT (QD: 1 each for 50 and 100 mg VBZ and PBO), and triglycerides (QD: 1 each for 50 mg VBZ and PBO). VBZ has an acceptable safety profile and predictable pharmacokinetics that result in stable concentrations of active compounds with low peak-to-trough fluctuation following once-daily dosing. PMID:28839339

Alpha-decay-induced fracturing in zircon - The transition from the crystalline to the metamict state

NASA Technical Reports Server (NTRS)

Chakoumakos, Bryan C.; Murakami, Takashi; Lumpkin, Gregory R.; Ewing, Rodney C.

1987-01-01

Zonation due to alpha-decay damage in a natural single crystal of zircon from Sri Lanka is discussed. The zones vary in thickness on a scale from one to hundreds of microns. The uranium and thorium concentrations vary from zone to zone such that the alpha decay dose is between 0.2 x 10 to the 16th and 0.8 x 10 to the 16th alpha-events per milligram. The transition from the crystalline to the aperiodic metamict state occurs over this dose range. At doses greater than 0.8 x 10 to the 16th alpha events/mg there is no evidence for long-range order. This type of damage will accumulate in actinide-bearing, ceramic nuclear waste forms. The systematic pattern of fractures would occur in crystalline phases that are zoned with respect to actinide radionuclides.

Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis

PubMed Central

Gallardo, Carmen R; Rigau Comas, David; Valderrama Rodríguez, Angélica; Roqué i Figuls, Marta; Parker, Lucy Anne; Caylà, Joan; Bonfill Cosp, Xavier

2016-01-01

Background People who are newly diagnosed with pulmonary tuberculosis (TB) typically receive a standard first-line treatment regimen that consists of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by four months of isoniazid and rifampicin. Fixed-dose combinations (FDCs) of these drugs are widely recommended. Objectives To compare the efficacy, safety, and acceptability of anti-tuberculosis regimens given as fixed-dose combinations compared to single-drug formulations for treating people with newly diagnosed pulmonary tuberculosis. Search methods We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library, Issue 11 2015); MEDLINE (1966 to 20 November 2015); EMBASE (1980 to 20 November 2015); LILACS (1982 to 20 November 2015); the metaRegister of Controlled Trials; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), without language restrictions, up to 20 November 2015. Selection criteria Randomized controlled trials that compared the use of FDCs with single-drug formulations in adults (aged 15 years or more) newly diagnosed with pulmonary TB. Data collection and analysis Two review authors independently assessed studies for inclusion, and assessed the risk of bias and extracted data from the included trials. We used risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with 95% confidence intervals (CIs). We attempted to assess the effect of treatment for time-to-event measures with hazard ratios and their 95% CIs. We used the Cochrane 'Risk of bias' assessment tool to determine the risk of bias in included trials. We used the fixed-effect model when there was little heterogeneity and the random-effects model with moderate heterogeneity. We used an I² statistic value of 75% or greater to denote significant heterogeneity, in which case we did not perform a meta-analysis. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results We included 13 randomized controlled trials (RCTs) in the review, which enrolled 5824 participants. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants. Overall there is little or no difference detected between FDCs and single-drug formulations for most outcomes reported. We did not detect a difference in treatment failure between FDCs compared with single-drug formulations (RR 1.28, 95% CI 0.82 to 2.00; 3606 participants, seven trials, moderate quality evidence). Relapse may be more frequent in people treated with FDCs compared to single-drug formulations, although the confidence interval (CI) includes no difference (RR 1.28, 95% CI 1.00 to 1.64; 3621 participants, 10 trials, low quality evidence). We did not detect any difference in death between fixed-dose and single-drug formulation groups (RR 0.96, 95% CI 0.67 to 1.39; 4800 participants, 11 trials, moderate quality evidence). When we compared FDCs with single-drug formulations we found little or no difference for sputum smear or culture conversion at the end of treatment (RR 0.99, 95% CI 0.96 to 1.02; 2319 participants, seven trials, high quality evidence), for serious adverse events (RR 1.45, 95% CI 0.90 to 2.33; 3388 participants, six trials, moderate quality evidence), and for adverse events that led to discontinuation of therapy (RR 0.96, 95% CI 0.56 to 1.66; 5530 participants, 13 trials, low quality evidence). We conducted a sensitivity analysis excluding studies at high risk of bias and this did not alter the review findings. Authors' conclusions Fixed-dose combinations and single-drug formulations probably have similar effects for treating people with newly diagnosed pulmonary TB. PLAIN LANGUAGE SUMMARY Fixed-dose combinations for treating pulmonary tuberculosis What are fixed-dose combinations and how might they improve care of people with tuberculosis Tuberculosis (TB) is an important health problem, especially in developing countries. The treatment for pulmonary TB in new patients includes four oral medicines taken for six months, sometimes as fixed-dose combinations (FDCs) that are combined in one tablet, or taken separately as single-drug formulations. The World Health Organization recommends prescribers use fixed-dose combinations to reduce the number of tablets that people take. On the supply side, this might reduce prescribing errors and improve drug supply efficiency; on the patient's side, FDCS simplify treatment and improve adherence. We conducted a review to assess the efficacy, safety, and acceptability of FDCs compared with single-drug formulations for treating people with newly diagnosed pulmonary TB. What the research says We searched for relevant trials up to 20 November 2015, and included 13 randomized controlled trials that enrolled 5824 people. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants. There is probably little or no difference in FDCs compared to single-drug formulations for treatment failure (moderate quality evidence); relapse may be more frequent (low quality evidence); and the number of deaths were similar (moderate quality evidence). There is little or no difference in sputum smear or culture conversion (high quality evidence), and no difference was shown for serious adverse events (moderate quality evidence) or adverse events that led to discontinuation of therapy (low quality evidence). Authors' conclusions We concluded that fixed-dose combinations have similar efficacy to single-drug formulations for treating people with newly diagnosed pulmonary TB. PMID:27186634

ULTRAFINE PARTICULATE MATTER EXPOSURE ATTENUATES MOUSE AORTIC RELAXATIONS

EPA Science Inventory

Particulate air pollution (PM) contributes to adverse cardiovascular events by yet unknown mechanisms. We tested the hypothesis that PM exposure altered endothelial regulation of systemic vascular tone. 6-10 week old male ICR mice were exposed to a single dose of 10, 30 or 100 'g...

Randomized, Placebo-Controlled, Single-Ascending-Dose Study of BMS-791325, a Hepatitis C Virus (HCV) NS5B Polymerase Inhibitor, in HCV Genotype 1 Infection

PubMed Central

Lemm, Julie; Eley, Timothy; Liu, Menping; Berglind, Anna; Sherman, Diane; Lawitz, Eric; Vutikullird, Apinya B.; Tebas, Pablo; Gao, Min; Pasquinelli, Claudio; Grasela, Dennis M.

2014-01-01

BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC50], 3 nM) and 1b (EC50, 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.) PMID:24733462

Efficacy and safety of valsartan/amlodipine single-pill combination in patients with essential hypertension (PEAK LOW).

PubMed

Kızılırmak, Pınar; Ar, Idilhan; Ilerigelen, Barış

2014-06-01

This study evaluated the efficacy as well as the safety and tolerability profile of low-dose valsartan/amlodipine (Val/Amlo) single-pill combination (SPC) (160/5 mg) in patients with essential hypertension in Turkey. Adult patients with essential hypertension [systolic blood pressure (SBP)>140 mmHg and/or diastolic blood pressure (DBP)>90 mmHg], who were on low dose Val/Amlo (160/5 mg) SPC before enrollment and gave informed consent, were accepted for this multi-centric observational study performed at 30 sites. The absolute changes in SBP and DBP from baseline were the primary efficacy outcomes. Safety assessments consisted of recording all adverse events. Of 381 patients enrolled, 327 completed the study; 39% were females. The mean age was 57.3±11.8 years. Median duration of hypertension was 38 months. Both SBP and DBP values showed reductions from 162.6±16.6 mmHg and 94.0±13.2 mmHg to 137.6±14.2 mmHg and 81.9±9.0 mmHg at 4th week and to 131.6±11.5 mmHg and 79.7±7.6 mmHg at 12th week, respectively. The control and response rates at the end of the study were 82.0% and 92.6%, respectively. Twelve patients (3.2%) experienced a total of 12 adverse events; there were no serious adverse events. The most common adverse event was edema (1.3%). Patient compliance was approximately 99%. Low-dose (160/5 mg) Val/Amlo SPC is efficacous and has a good tolerability and safety profile for the management of essential hypertension in Turkey.

Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

PubMed

Krishnaswami, Sriram; Boy, Mary; Chow, Vincent; Chan, Gary

2015-03-01

Tofacitinib is an oral Janus kinase inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs. © 2014, The American College of Clinical Pharmacology.

Evaluation of the Pharmacokinetics of Single- and Multiple-dose Buprenorphine Buccal Film in Healthy Volunteers.

PubMed

Bai, Stephen A; Xiang, Qinfang; Finn, Andrew

2016-02-01

Buprenorphine, a partial μ-receptor agonist, is approved for the management of moderate to severe pain, but it has low oral bioavailability. Two open-label studies were performed to determine the pharmacokinetic profile of buprenorphine from buccal film formulations of buprenorphine. Both studies enrolled healthy volunteers, aged 18 to 55 years, who received concurrent oral naltrexone to reduce adverse events (AEs); subjects with a history or evidence of substance abuse or current use of any product affecting cytochrome P450 3A4 activity were excluded. The first study (n = 25) was a 5-period crossover trial with 4 single doses (75 and 300 and 300 and 1200 μg) of 2 formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-μg intravenous dose of buprenorphine with a 7-day washout between periods. In the second study, each subject (n = 10) received 6 doses of 4 BBUP strengths (60, 120, 180, and 240 μg BID) in a dose-escalation design. Plasma concentrations of buprenorphine and norbuprenorphine were assayed, and pharmacokinetics were summarized with descriptive statistics and analyzed by using a linear mixed effects model (single-dose study). AEs were recorded. In the single-dose study, the 2 formulations exhibited comparable bioavailability of 46% to 51% that was independent of dose, with a single buprenorphine peak concentration from each BBUP dose occurring at 2.5 to 3 hours. The mean buprenorphine Cmax across the doses ranged from 0.17 ng/mL for the 75-µg dose to 1.43 ng/mL for the 1200-µg dose. AUC0-∞, AUC0-last, and Cmax were proportional to the dose of BBUP administered. Cmax of norbuprenorphine after BBUP administration was approximately one tenth that of buprenorphine Cmax. In the multiple-dose study, steady state was reached within 3 days of BID dosing. There was a linear increase in exposure across the dose range from 60 to 240 μg BID. Treatment-emergent AEs in both studies were consistent with those reported with opiate administration to healthy volunteers. The absolute bioavailability of BBUP was 46% to 51% across a 16-fold dose range, with dose-proportional increases in systemic exposure. Apparent steady-state conditions occurred within 3 days of dosing. These pharmacokinetic results suggest that therapeutic buprenorphine plasma concentrations can be obtained with BBUP across a wide dose range in a shorter time than other (eg, transdermal) dosage forms. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Hierarchical CAD Tools for Radiation Hardened Mixed Signal Electronic Circuits

DTIC Science & Technology

2005-01-28

11 Figure 3: Schematic of Analog and Digital Components 12 Figure 4: Dose Rate Syntax 14 Figure 5: Single Event Effects (SEE) Syntax 15 Figure 6...Harmony-AMS simulation of a Digital Phase Locked Loop 19 Figure 10: SEE results from DPLL Simulation 20 Figure 11: Published results used for validation...analog and digital circuitry. Combining the analog and digital elements onto a single chip has several advantages, but also creates unique challenges

Tranexamic acid use during total hip arthroplasty: A single center retrospective analysis.

PubMed

Stoicea, Nicoleta; Moran, Kenneth; Mahmoud, Abdel-Rasoul; Glassman, Andrew; Ellis, Thomas; Ryan, John; Granger, Jeffrey; Joseph, Nicholas; Salon, Nathan; Ackermann, Wiebke; Rogers, Barbara; Niermeyer, Weston; Bergese, Sergio D

2018-05-01

Tranexamic acid (TXA) is an antifibrinolytic agent that has shown promise in reducing blood loss during total hip arthroplasty (THA). Several studies have reported side effects of high-dose TXA administration, including myocardial infarction (MI), thromboembolic events, and seizures. These possible side effects have prevented the widespread adoption of TXA in the surgical community. We conducted a retrospective chart review of 564 primary and revision THAs performed at a single academic center. Surgical patients received either no TXA or 1 g IV TXA at the beginning of surgery followed by a second bolus just before the surgical wound closure, at the surgeon's discretion. We analyzed differences in hemoglobin (Hb), hematocrit (Hct), estimated blood loss (EBL), and adverse events in patients receiving TXA versus patients not receiving TXA up to 2 days following surgery. Significantly higher Hb and Hct values were found across all time points among patients undergoing primary posterior or revision THA who had received TXA. In addition, transfusion rates were significantly decreased in both primary posterior THAs and revision THAs when TXA was administered. Patients who received TXA experienced significantly fewer adverse events than those who did not for all surgery types. Administration of low-dose intravenous (IV) and intra-articular (IA) TXA does not appear to increase rates of adverse events and may be effective in minimizing blood loss, as reflected by Hb and Hct values following THA.

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

PubMed

Palanca-Wessels, Maria Corinna A; Czuczman, Myron; Salles, Gilles; Assouline, Sarit; Sehn, Laurie H; Flinn, Ian; Patel, Manish R; Sangha, Randeep; Hagenbeek, Anton; Advani, Ranjana; Tilly, Herve; Casasnovas, Olivier; Press, Oliver W; Yalamanchili, Sreeni; Kahn, Robert; Dere, Randall C; Lu, Dan; Jones, Surai; Jones, Cheryl; Chu, Yu-Waye; Morschhauser, Franck

2015-06-01

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Genentech. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Phase I Study to Investigate the Absorption, Pharmacokinetics, and Excretion of [(14)C]Prucalopride After a Single Oral Dose in Healthy Volunteers.

PubMed

Flach, Stephen; Scarfe, Graeme; Dragone, Jeffrey; Ding, Jie; Seymour, Mark; Pennick, Mike; Pankratz, Todd; Troy, Steven; Getsy, Jay

2016-09-01

Chronic constipation is a prevalent gastrointestinal disorder globally. It is often treated with medications such as laxatives. Newer therapies to improve gastric motility include the selective 5-hydroxytryptamine receptor-4 agonist prucalopride, which is licensed for the treatment of chronic constipation in adults. The aim of this study was to investigate the pharmacokinetic properties and excretion of prucalopride in healthy individuals, using a microtracer approach with (14)C radioactivity detection using liquid scintillation counting and accelerator mass spectrometry. This was a single-period, open-label, nonrandomized absorption, metabolism, and excretion study of [(14)C]prucalopride. Participants were 6 healthy men aged 18 to 50 years. After screening, participants were administered a single dose of [(14)C]prucalopride succinate 2 mg (~200 nCi). Postadministration, urine, feces, and blood samples were collected over a 10-day period. Safety and adverse event data were also collected. Almost 100% of the administered dose of radioactivity was recovered, with a mean (SD) of 84.2% (8.88%) recovered in urine and 13.3% (1.73%) recovered in feces. The mean blood-to-plasma concentration ratio of 1.9 indicated uptake of prucalopride into blood cells. The renal clearance of prucalopride was 17.0 (2.5) L/h, which is higher than the glomerular filtration rate in healthy individuals, suggesting active renal transport of prucalopride. Prucalopride was well tolerated, with no serious adverse events reported. Prucalopride was well absorbed and excreted mainly by the kidneys, including both passive and active transporter mechanisms. Quantitative recovery of the radioactive dose was achieved. Consistent with previous studies, prucalopride was generally well tolerated. ClinicalTrials.gov identifier: NCT01807000. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor

PubMed Central

Yang, Lucy; Boardley, Rebecca L.; Goyal, Navin S.; Robertson, Jonathan; Baldwin, Sandra J.; Newby, David E.; Wilkinson, Ian B.; Tal‐Singer, Ruth; Mayer, Ruth J.; Cheriyan, Joseph

2016-01-01

Aims Endothelial‐derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that was tested in two phase I studies. Methods Single escalating doses of GSK2256294 2–20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected. Results GSK2256294 was well‐tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half‐life averaging 25–43 h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose‐dependent, from an average of 41.9% on 2 mg (95% confidence interval [CI] –51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. There were no significant changes in serum VEGF or plasma fibrinogen. Conclusions GSK2256294 was well‐tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD. PMID:26620151

Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects.

PubMed

Hausner, Helene; Derving Karsbøl, Julie; Holst, Anders G; Jacobsen, Jacob B; Wagner, Frank-Dietrich; Golor, Georg; Anderson, Thomas W

2017-11-01

Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects. Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25). Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related. No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.

A Multicenter, Randomized, Open-Label, Pharmacokinetics and Safety Study of Pantoprazole Tablets in Children and Adolescents Aged 6 Through 16 Years With GERD

PubMed Central

Ward, Robert M.; Kearns, Gregory L.; Tammara, Brinda; Bishop, Phyllis; O’Gorman, Molly A.; James, Laura P.; Katz, Mitchell H.; Maguire, Mary K.; Rath, Natalie; Meng, Xu; Comer, Gail M.

2011-01-01

SUMMARY Children with GERD may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drug’s kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed-release tablets in pediatric patients with GERD aged ≥6 through 11 years (study 1) and 12 through 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose, and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar toPK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug-associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults. PMID:20852004

The Effects of Low Dose-Rate Ionizing Radiation on the Shapes of Transients in the LM124 Operational Amplifier

NASA Technical Reports Server (NTRS)

Buchner, Stephen; McMorrow, Dale; Roche, Nicholas; Dusseau, Laurent; Pease, Ron L.

2008-01-01

Shapes of single event transients (SETs) in a linear bipolar circuit (LM124) change with exposure to total ionizing dose (TID) radiation. SETs shape changes are a direct consequence of TID-induced degradation of bipolar transistor gain. A reduction in transistor gain causes a reduction in the drive current of the current sources in the circuit, and it is the lower drive current that most affects the shapes of large amplitude SETs.

Repaglinide plus single-dose insulin glargine: a safe regimen for low-risk type 2 diabetic patients who insist on fasting in Ramadan.

PubMed

Bakiner, Okan; Ertorer, Melek E; Bozkirli, Emre; Tutuncu, Neslihan B; Demirag, Nilgun G

2009-03-01

Aim of this prospective study is to evaluate the effect of repaglinide t.i.d. (three times a day) plus single-dose insulin glargine regimen in low-risk type 2 diabetic patients during Ramadan fasting. Participants had been taking the regimen for at least 3 months. Patients with a history of diabetic coma, severe hypoglycemic crisis or repeating attacks of hypoglycemia were excluded. Hypoglycemic unawareness, kidney or liver disease or HbA1c over 8% were also accepted as exclusion criteria. Eleven patients who insisted on this worship and eight non-fasting cases were involved. All were told to make home-glucose-monitorisation weekly and report any hypoglycemic event throughout Ramadan. Fasting blood glucose (FBG), post-prandial blood glucose (PBG) and fructosamine levels, body weights and blood pressures were recorded just before and after Ramadan. Seven patients in each group concluded the follow-up. Any significant change was detected in the parameters in either groups (P>0.05). Glucose control remained unchanged; fructosamine 318.14+/-65.38 versus 317.28+/-52.80 mmol/L in fasting group, 290.71+/-38.48 versus 290+/-38.56 mmol/L in non-fasting group. None of them exhibited either a major or a minor hypoglycemic event. The results of this pilot study indicated that repaglinide t.i.d. plus single-dose insulin glargine regimen was safe for low-risk type 2 diabetic patients who insisted on fasting during Ramadan.

Metabolism, distribution and elimination of lisdexamfetamine dimesylate: open-label, single-centre, phase I study in healthy adult volunteers.

PubMed

Krishnan, Suma M; Pennick, Michael; Stark, Jeffrey G

2008-01-01

Attention-deficit/hyperactivity disorder (ADHD) in children often persists into adulthood and is potentially associated with significant social and occupational impairments. It is important to understand the effects of pharmacological treatments of ADHD in adults. This study aimed to assess the absorption, metabolism and elimination of lisdexamfetamine dimesylate in normal, healthy adult subjects following a single oral dose. A secondary objective was to assess the safety and tolerability of treatment. In an open-label, single-centre study, six healthy adult volunteers aged 22-52 years received a single oral 70 mg dose of (14)C-radiolabelled lisdexamfetamine dimesylate in solution following a 10-hour fast. Blood samples drawn pre-dose and at time points up to 120 hours post-dose were used for plasma pharmacokinetic analysis of the active d-amphetamine and the intact parent compound lisdexamfetamine dimesylate. Recovery of radioactivity was determined by liquid scintillation counting of blood samples (whole blood and plasma), urine samples and faecal samples collected pre-dose and at designated time points up to 120 hours post-dose. Urine samples were also analysed for the presence of amphetamine-derived metabolites. Safety was assessed by adverse event reporting, changes in physical findings, vital sign measurements, ECG measurements, and clinical laboratory test results. For intact lisdexamfetamine dimesylate, the median time to reach maximum plasma drug concentration (t(max)) was 1.00 hour, and the mean maximum plasma drug concentration (C(max)) was 58.2 +/- 28.1 ng/mL. Intact lisdexamfetamine dimesylate exhibited modest systemic exposure (area under the drug concentration-time curve from time 0 to infinity [AUC(infinity)] 67.04 +/- 18.94 ng . h/mL), and rapid elimination (mean apparent terminal elimination half-life [t((1/2)beta)] 0.47 hours). For d-amphetamine, the median t(max) was 3.00 hours, and the mean C(max) was 80.3 +/- 11.8 ng/mL. The AUC(infinity) of d-amphetamine was 1342 +/- 216.9 ng . h/mL, and elimination occurred as a first-order process. The t((1/2)beta) of d-amphetamine was 10.39 hours. Peaks consistent with amphetamine and hippuric acid were identified in urine samples by high-performance liquid chromatography radioactive profiling. Relative to dose administered, 41.5% was recovered in urine as d-amphetamine, 24.8% as hippuric acid and 2.2% as intact lisdexamfetamine dimesylate. Less than 0.3% of the administered dose was recovered in the faeces. During the 0- to 48-hour urine samples, no unexpected adverse events or clinically significant laboratory, ECG or physical examination findings related to the study medication were observed. Following a single 70 mg oral dose, lisdexamfetamine dimesylate was quickly absorbed, extensively metabolized to d-amphetamine and its derivatives, and rapidly eliminated. Systemic exposure to d-amphetamine was approximately 20-fold higher than systemic exposure to intact lisdexamfetamine dimesylate in healthy adults. Lisdexamfetamine dimesylate, administered as a single 70 mg dose, was generally well tolerated in this study.

AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

PubMed

Rangarajan, Savita; Walsh, Liron; Lester, Will; Perry, David; Madan, Bella; Laffan, Michael; Yu, Hua; Vettermann, Christian; Pierce, Glenn F; Wong, Wing Y; Pasi, K John

2017-12-28

Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected. The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with stabilization of hemostasis and a profound reduction in factor VIII use in all seven participants. In this small study, no safety events were noted, but no safety conclusions can be drawn. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795 ; EudraCT number, 2014-003880-38 .).

High-dose, single-bolus eptifibatide: a safe and cost-effective alternative to conventional glycoprotein IIb/IIIa inhibitor use for elective coronary interventions.

PubMed

Fischell, Tim A; Attia, Tamer; Rane, Santosh; Salman, Waddah

2006-10-01

Adjunctive pharmacotherapy with eptifibatide, a glycoprotein (GP) IIb/IIIa inhibitor, as an intravenous bolus followed by infusion has been shown to improve outcomes in elective coronary interventions (PCI). However, bleeding complications and costs have limited the routine adoption of this regimen. The goal of this study was to examine the safety, efficacy and cost-effectiveness of high-dose, single-bolus eptifibatide, without post-intervention infusion, in "real-world" patients undergoing elective PCI. We studied 401 patients with stable and unstable angina who were treated with a high-dose (20 mg), single bolus of eptifibatide plus heparin prior to the start of elective PCI. Exclusion criteria included recent MI, stenting of bypass graft(s), rotational atherectomy and/or brachytherapy. The primary study endpoints were major adverse clinical events (MACE), defined as the in-hospital and 30-day incidence of death from any cause, Q-wave or non-Q-wave MI, repeat target vessel revascularization and/or major bleeding complications. Relevant demographic and procedural characteristics included mean age: 66.4 +/- 11.2; male gender: 242/401 (61%); number of vessels treated per patient: 1.46 +/- 0.42; and number of stents deployed per patient: 1.82 +/- 0.65. In-hospital non-Q-wave MI (CPK and/or CPK-MB > 3 times the upper limit of normal) occurred in 7/401 patients (1.75%) and MACE was 2.25%. Major bleeding complications were seen in 2/401 patients (0.49%). There were 4 additional MACE events at 30-day follow up (total MACE and bleeding = 3.25%). The average anticoagulation cost was 66 dollars/patient. Intravenous eptifibatide, administered as a high-dose (20 mg) single-vial bolus, is a safe, effective and highly cost-effective alternative to the conventional regimens of bolus plus prolonged intravenous GP IIb/IIIa inhibitor infusion for patients undergoing elective PCI.

Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers.

PubMed

Macha, Sreeraj; Sennewald, Regina; Rose, Peter; Schoene, Katja; Pinnetti, Sabine; Woerle, Hans J; Broedl, Uli C

2013-03-01

Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. The goal of this study was to investigate potential drug-drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. The potential drug-drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5. Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0-∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87-107.20; Cmax: GMR, 92.39%; 90% CI, 85.38-99.97) or ramipril (AUC over a uniform dosing interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05-100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65-111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% CI 100.51-116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73-119.64) or its active metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00-101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67-104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0-∞ (GMR, 106.11%; 90% CI, 96.71-116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33-130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation in any of the studies. No dose adjustment of empagliflozin is required when coadministered with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril). Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.

Single dose dipyrone for acute postoperative pain

PubMed Central

Derry, Sheena; Faura, Clara; Edwards, Jayne; McQuay, Henry J; Moore, R Andrew

2014-01-01

Background Dipyrone (metamizole) is a non-steroidal anti-inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in others because of an association with life-threatening blood agranulocytosis. This review updates a 2001 Cochrane review, and no relevant new studies were identified, but additional outcomes were sought. Objectives To assess the efficacy and adverse events of single dose dipyrone in acute postoperative pain. Search methods The earlier review searched CENTRAL, MEDLINE, EMBASE, LILACS and the Oxford Pain Relief Database to December 1999. For the update we searched CENTRAL, MEDLINE,EMBASE and LILACS to February 2010. Selection criteria Single dose, randomised, double-blind, placebo or active controlled trials of dipyrone for relief of established moderate to severe postoperative pain in adults. We included oral, rectal, intramuscular or intravenous administration of study drugs. Data collection and analysis Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR) was used to calculate the number of participants achieving at least 50% pain relief. Derived results were used to calculate, with 95% confidence intervals, relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Use and time to use of rescue medication were additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Fifteen studies tested mainly 500 mg oral dipyrone (173 participants), 2.5 g intravenous dipyrone (101), 2.5 g intramuscular dipyrone (99); fewer than 60 participants received any other dose. All studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen, dexketoprofen, ketorolac, pethidine, tramadol, suprofen); eight used placebo controls. Over 70% of participants experienced at least 50% pain relief over 4 to 6 hours with oral dipyrone 500 mg compared to 30% with placebo in five studies (288 participants; NNT 2.4 (1.9 to 3.2)). Fewer participants needed rescue medication with dipyrone (7%) than with placebo (34%; four studies, 248 participants). There was no difference in participants experiencing at least 50% pain relief with 2.5 g intravenous dipyrone and 100 mg intravenous tramadol (70% vs 65%; two studies, 200 participants). No serious adverse events were reported. Authors’ conclusions Based on very limited information, single dose dipyrone 500 mg provides good pain relief to 70% of patients. For every five individuals given dipyrone 500 mg, two would experience this level of pain relief who would not have done with placebo, and fewer would need rescue medication, over 4 to 6 hours. PMID:20824835

Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose.

PubMed

Viscardi, Rose M; Othman, Ahmed A; Hassan, Hazem E; Eddington, Natalie D; Abebe, Elias; Terrin, Michael L; Kaufman, David A; Waites, Ken B

2013-05-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.

Azithromycin To Prevent Bronchopulmonary Dysplasia in Ureaplasma-Infected Preterm Infants: Pharmacokinetics, Safety, Microbial Response, and Clinical Outcomes with a 20-Milligram-per-Kilogram Single Intravenous Dose

PubMed Central

Othman, Ahmed A.; Hassan, Hazem E.; Eddington, Natalie D.; Abebe, Elias; Terrin, Michael L.; Kaufman, David A.; Waites, Ken B.

2013-01-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)0.75 [WT(kg)0.75 indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)0.75; central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined. PMID:23439637

Experience with custom processors in space flight applications

NASA Technical Reports Server (NTRS)

Fraeman, M. E.; Hayes, J. R.; Lohr, D. A.; Ballard, B. W.; Williams, R. L.; Henshaw, R. M.

1991-01-01

The Applied Physics Laboratory (APL) has developed a magnetometer instrument for a swedish satellite named Freja with launch scheduled for August 1992 on a Chinese Long March rocket. The magnetometer controller utilized a custom microprocessor designed at APL with the Genesil silicon compiler. The processor evolved from our experience with an older bit-slice design and two prior single chip efforts. The architecture of our microprocessor greatly lowered software development costs because it was optimized to provide an interactive and extensible programming environment hosted by the target hardware. Radiation tolerance of the microprocessor was also tested and was adequate for Freja's mission -- 20 kRad(Si) total dose and very infrequent latch-up and single event upset events.

Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency.

PubMed

Wasserstein, Melissa P; Jones, Simon A; Soran, Handrean; Diaz, George A; Lippa, Natalie; Thurberg, Beth L; Culm-Merdek, Kerry; Shamiyeh, Elias; Inguilizian, Haig; Cox, Gerald F; Puga, Ana Cristina

2015-01-01

Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy. Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks. All patients successfully reached 3.0mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4h across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed. This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD. Copyright © 2015. Published by Elsevier Inc.

Investigation of the Semicoa 2N7616 and 2N7425 and the Microsemi 2N7480 for Single-Event Gate Rupture and Single-Event Burnout

NASA Technical Reports Server (NTRS)

Scheick, Leif

2014-01-01

Single-event-effect test results for hi-rel total-dose-hardened power MOSFETs are presented in this report. The 2N7616 and the 2N7425 from Semicoa and the 2N7480 from International Rectifier were tested to NASA test condition standards and requirements. The 2N7480 performed well and the data agree with the manufacture's data. The 2N7616 and 2N7425 were entry parts from Semicoa using a new device architecture. Unfortunately, the device performed poorly and Semicoa is withdrawing power MOSFETs from it line due to these data. Vertical metal-oxide-semiconductor field-effect transistors (MOSFETs) are the most commonly used power transistor. MOSFETs are typically employed in power supplies and high current switching applications. Due to the inherent high electric fields in the device, power MOSFETs are sensitive to heavy ion irradiation and can fail catastrophically as a result of single-event gate rupture (SEGR) or single-event burnout (SEB). Manufacturers have designed radiation-hardened power MOSFETs for space applications. See [1] through [5] for more information. The objective of this effort was to investigate the SEGR and SEB responses of two power MOSFETs recently produced. These tests will serve as a limited verification of these parts. It is acknowledged that further testing on the respective parts may be needed for some mission profiles.

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects.

PubMed

Iitsuka, Hiromi; van Gelderen, Marcel; Katashima, Masataka; Takusagawa, Shin; Sawamoto, Taiji

2015-05-01

The objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects. In total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring. After administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0-∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects. Our studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Effect of a single intraoperative high-dose ATG-Fresenius on delayed graft function in donation after cardiac-death donor renal allograft recipients: a randomized study.

PubMed

van den Hoogen, Martijn W F; Kho, Marcia M L; Abrahams, Alferso C; van Zuilen, Arjan D; Sanders, Jan-Stephan; van Dijk, Marja; Hilbrands, Luuk B; Weimar, Willem; Hoitsma, Andries J

2013-04-01

Reducing the incidence of delayed graft function after transplant with donation after cardiac death donor renal allografts would facilitate managing recipients during their first weeks after a transplant. To reduce this incidence, in most studies, induction therapy with depleting anti-T-lymphocyte antibodies is coupled with a reduction of the dosage of the calcineurin inhibitor. The separate effect of anti-T-cell therapy on the incidence and duration of delayed graft function is therefore difficult to assess. We performed a randomized study to evaluate the effect of a single intraoperative high-dose of anti-T-lymphocyte immunoglobulin (ATG)-Fresenius (9 mg/kg body weight) on the incidence of delayed graft function. Eligible adult recipients of a first donation after cardiac death donor renal allograft were randomly assigned to ATG-Fresenius or no induction therapy. Maintenance immunosuppression consisted of tacrolimus, in an unadjusted dose, mycophenolate mofetil, and steroids. The study was prematurely terminated because of a lower-than-anticipated inclusion rate. Baseline characteristics were comparable in the ATG-Fresenius group (n=28) and the control group (n=24). Twenty-two patients in the ATG-Fresenius group (79%) had delayed graft function, compared with 13 in the control group (54%; P = .06). Allograft and patient survival were comparable in both groups. Serious adverse events occurred more frequently in the ATG-Fresenius group than they did in the control group (57% vs 29%; P < .05). Intraoperative administration of a single high-dose of ATG-Fresenius in donation after cardiac death donor renal allograft recipients, followed by triple immunosuppression with an unadjusted tacrolimus dose, seems ineffective to reduce the incidence of delayed graft function. Moreover, this was associated with a higher rate of serious adverse events (EudraCT-number, 2007-000210-36.).

Effects of TD-5108 on Gastrointestinal Transit and Bowel Function in Health and Pharmacokinetics in Health and Constipation

PubMed Central

Manini, Mhd Louai; Camilleri, Michael; Goldberg, Michael; Sweetser, Seth; McKinzie, Sanna; Burton, Duane; Wong, Shekman; Kitt, Michael M.; Li, Yu-Ping; Zinsmeister, Alan R.

2010-01-01

Background TD-5108 is a potent, selective high intrinsic activity serotonin 5-HT4 receptor agonist. Aim To assess effects of TD-5108 on gastrointestinal transit and compare its pharmacokinetics (PK) in healthy volunteers (HV) and chronic constipation (CC) patients. Methods 60 HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg TD-5108 (single and 6-day dosing). Primary endpoints were colonic transit (geometric center at 24 hours, GC24) and ascending colon emptying (ACE) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Results Single dose TD-5108 significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50°mg TD-5108 accelerated all 3 endpoints. With multiple doses, TD-5108 30 mg accelerated GC24, and overall accelerated GE T1/2 at 15–50 mg. PK studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of TD-5108. Stimulation of bowel function after15 mg TD-5108 were similar in CC and controls. There were no serious adverse events; notable adverse were the predictable GI effects such as diarrhea or altered bowel movements. Conclusions TD-5108 significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted. PMID:19691492

Safe single-dose administration of propofol in patients with established Brugada syndrome: a retrospective database analysis.

PubMed

Flamée, Panagiotis; De Asmundis, Carlo; Bhutia, Jigme T; Conte, Giulio; Beckers, Stefan; Umbrain, Vincent; Verborgh, Christian; Chierchia, Gian-Battista; Van Malderen, Sophie; Casado-Arroyo, Rubén; Sarkozy, Andrea; Brugada, Pedro; Poelaert, Jan

2013-12-01

Propofol is an anesthetic drug with a very attractive pharmacokinetic profile, which makes it the induction agent of choice, especially in day-case surgery. Data on its potential proarrhythmic effects in patients with Brugada syndrome (BS) patients are still lacking. The aim of our study was to investigate whether a single dose of propofol triggered any adverse events in consecutive high-risk patients with BS. All consecutive patients with BS having undergone an implantable cardiac defibrillator implantation under general anesthesia were eligible for this study. The anesthetic chart of each patient was reviewed, and the occurrence of malignant arrhythmic events as well as the need for defibrillation during induction and maintenance of anesthesia was investigated. Further monitoring of the patient comprised five-lead electrocardiogram (ECG), pulse oxymetry, and continuous carbon dioxide monitoring through side sampling from the ventilator tubes. Anesthesia was induced with propofol and sufentanyl. Injection of propofol occurred in a single-shot bolus-as often performed by most anesthetists-over a few seconds. Anesthesia was maintained with volatile anesthetics (sevoflurane or desflurane) in an oxygen-air mixture. From 1996 to 2011, 57 high-risk patients with BS (35 males; mean age: 43 ± 16 years) underwent an automated implantable cardioverter defibrillator implantation at our center using propofol as induction drug of general anesthesia. Three patients had a history of spontaneous type I ECG, three had aborted sudden death, and 51 had a history of recurrent or unexplained syncope. The induction dose ranged between 0.8 mg/kg and 5.0 mg/kg (2.2 ± 0.7 mg/kg). Only one case received propofol to maintain anesthesia. The surgical procedure involved an anesthetic period of 75 ± 25 minutes. No patient developed a malignant rhythm during induction and maintenance of anesthesia. All patients were then safely discharged from the postanesthetic care unit after 1 hour. No adverse events were noticed during the recovery phase. In our study, administration of a single-dose propofol in patients with BS was safe. Nevertheless, extreme caution is still recommended when conducting general anesthesia in patients with BS, especially if BS patients are sedated with propofol for longer periods. ©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.

Potential impact of single-risk-factor versus total risk management for the prevention of cardiovascular events in Seychelles.

PubMed

Ndindjock, Roger; Gedeon, Jude; Mendis, Shanthi; Paccaud, Fred; Bovet, Pascal

2011-04-01

To assess the prevalence of cardiovascular (CV) risk factors in Seychelles, a middle-income African country, and compare the cost-effectiveness of single-risk-factor management (treating individuals with arterial blood pressure ≥ 140/90 mmHg and/or total serum cholesterol ≥ 6.2 mmol/l) with that of management based on total CV risk (treating individuals with a total CV risk ≥ 10% or ≥ 20%). CV risk factor prevalence and a CV risk prediction chart for Africa were used to estimate the 10-year risk of suffering a fatal or non-fatal CV event among individuals aged 40-64 years. These figures were used to compare single-risk-factor management with total risk management in terms of the number of people requiring treatment to avert one CV event and the number of events potentially averted over 10 years. Treatment for patients with high total CV risk (≥ 20%) was assumed to consist of a fixed-dose combination of several drugs (polypill). Cost analyses were limited to medication. A total CV risk of ≥ 10% and ≥ 20% was found among 10.8% and 5.1% of individuals, respectively. With single-risk-factor management, 60% of adults would need to be treated and 157 cardiovascular events per 100000 population would be averted per year, as opposed to 5% of adults and 92 events with total CV risk management. Management based on high total CV risk optimizes the balance between the number requiring treatment and the number of CV events averted. Total CV risk management is much more cost-effective than single-risk-factor management. These findings are relevant for all countries, but especially for those economically and demographically similar to Seychelles.

Single photon detection and signal analysis for high sensitivity dosimetry based on optically stimulated luminescence with beryllium oxide

NASA Astrophysics Data System (ADS)

Radtke, J.; Sponner, J.; Jakobi, C.; Schneider, J.; Sommer, M.; Teichmann, T.; Ullrich, W.; Henniger, J.; Kormoll, T.

2018-01-01

Single photon detection applied to optically stimulated luminescence (OSL) dosimetry is a promising approach due to the low level of luminescence light and the known statistical behavior of single photon events. Time resolved detection allows to apply a variety of different and independent data analysis methods. Furthermore, using amplitude modulated stimulation impresses time- and frequency information into the OSL light and therefore allows for additional means of analysis. Considering the impressed frequency information, data analysis by using Fourier transform algorithms or other digital filters can be used for separating the OSL signal from unwanted light or events generated by other phenomena. This potentially lowers the detection limits of low dose measurements and might improve the reproducibility and stability of obtained data. In this work, an OSL system based on a single photon detector, a fast and accurate stimulation unit and an FPGA is presented. Different analysis algorithms which are applied to the single photon data are discussed.

Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study.

PubMed

Morain, P; Robin, J L; De Nanteuil, G; Jochemsen, R; Heidet, V; Guez, D

2000-10-01

The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers. This was a double-blind, randomized, placebo-controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection. PEP activity in plasma was dose-dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5-2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half-life (t(1/2)) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose. S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once-daily dosing without any serious adverse events.

Single dose regorafenib-induced hypertensive crisis.

PubMed

Yilmaz, B; Kemal, Y; Teker, F; Kut, E; Demirag, G; Yucel, I

2014-06-01

Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common drug-related adverse events with regorafenib are hypertension, hand-foot skin reactions, and diarrhea. Grade IV hypertensive side effect has never been reported after a single dose. In this report, we present a case of Grade IV hypertensive side effect (hypertensive crisis and seizure) after a single dose of regorafenib. A 54-year-old male normotensive GIST patient was admitted to the emergency department with seizure and encephalopathy after the first dosage of regorafenib. His blood pressure was 240/140 mmHg upon admission. After intensive treatment with nitrate and nitroprusside, his blood pressure returned to normal levels in five days. Regorafenib was discontinued, and he did not experience hypertension again. This paper reports the first case of Grade IV hypertension after the first dosage of regorafenib. We can suggest that hypertension is an idiosyncratic side effect unrelated to the dosage.

Randomized trial of single-dose versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim report.

PubMed

Stevens, R Brian; Mercer, David F; Grant, Wendy J; Freifeld, Alison G; Lane, James T; Groggel, Gerald C; Rigley, Theodore H; Nielsen, Kathleen J; Henning, Megan E; Skorupa, Jill Y; Skorupa, Anna J; Christensen, Kecia A; Sandoz, John P; Kellogg, Anna M; Langnas, Alan N; Wrenshall, Lucile E

2008-05-27

The optimal dosing protocol for rabbit anti-thymocyte globulin (rATG) induction in renal transplantation has not been determined, but evidence exists that rATG infusion before renal allograft reperfusion improves early graft function. Infusing a large rATG dose over a short interval has not previously been evaluated for its effect on renal function and allograft nephropathy in a prospective, randomized comparison against conventional rATG induction. Between April 20, 2004 and December 26, 2007 we enrolled renal transplant patients into a prospective, randomized, nonblinded trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment=160) followed after 6 months by calcineurin-inhibitor withdrawal. Primary endpoints are renal function by calculated glomerular filtration rate (GFR) and chronic allograft nephropathy at protocol biopsy. We now present the early GFR data of all 160 patients and safety and efficacy data of the first 142 patients with 6 months follow up and before calcineurin inhibitor withdrawal (average follow up=23.3+/-11.6 months). There were no differences between groups in rATG-related adverse events, patient and graft survival, acute rejection, or chronic allograft nephropathy rate at 6 months. Calculated DeltaGFR (POD 1-4) was significantly better in the single-dose group (P=0.02), with a trend toward improved renal function from months 2 to 6 in recipients of deceased donor kidneys (P=0.08). This study demonstrates that administering 6 mg/kg of rATG over 24 hr is safe and is associated with improved early renal function compared with administering rATG in alternate-day doses.

Efficacy of a Single-Dose, Inactivated Oral Cholera Vaccine in Bangladesh.

PubMed

Qadri, Firdausi; Wierzba, Thomas F; Ali, Mohammad; Chowdhury, Fahima; Khan, Ashraful I; Saha, Amit; Khan, Iqbal A; Asaduzzaman, Muhammad; Akter, Afroza; Khan, Arifuzzaman; Begum, Yasmin A; Bhuiyan, Taufiqur R; Khanam, Farhana; Chowdhury, Mohiul I; Islam, Taufiqul; Chowdhury, Atique I; Rahman, Anisur; Siddique, Shah A; You, Young A; Kim, Deok R; Siddik, Ashraf U; Saha, Nirod C; Kabir, Alamgir; Cravioto, Alejandro; Desai, Sachin N; Singh, Ajit P; Clemens, John D

2016-05-05

A single-dose regimen of the current killed oral cholera vaccines that have been prequalified by the World Health Organization would make them more attractive for use against endemic and epidemic cholera. We conducted an efficacy trial of a single dose of the killed oral cholera vaccine Shanchol, which is currently given in a two-dose schedule, in an urban area in which cholera is highly endemic. Nonpregnant residents of Dhaka, Bangladesh, who were 1 year of age or older were randomly assigned to receive a single dose of oral cholera vaccine or oral placebo. The primary outcome was vaccine protective efficacy against culture-confirmed cholera occurring 7 to 180 days after dosing. Prespecified secondary outcomes included protective efficacy against severely dehydrating culture-confirmed cholera during the same interval, against cholera and severe cholera occurring 7 to 90 versus 91 to 180 days after dosing, and against cholera and severe cholera according to age at baseline. A total of 101 episodes of cholera, 37 associated with severe dehydration, were detected among the 204,700 persons who received one dose of vaccine or placebo. The vaccine protective efficacy was 40% (95% confidence interval [CI], 11 to 60%; 0.37 cases per 1000 vaccine recipients vs. 0.62 cases per 1000 placebo recipients) against all cholera episodes, 63% (95% CI, 24 to 82%; 0.10 vs. 0.26 cases per 1000 recipients) against severely dehydrating cholera episodes, and 63% (95% CI, -39 to 90%), 56% (95% CI, 16 to 77%), and 16% (95% CI, -49% to 53%) against all cholera episodes among persons vaccinated at the age of 5 to 14 years, 15 or more years, and 1 to 4 years, respectively, although the differences according to age were not significant (P=0.25). Adverse events occurred at similar frequencies in the two groups. A single dose of the oral cholera vaccine was efficacious in older children (≥5 years of age) and in adults in a setting with a high level of cholera endemicity. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02027207.).

Pharmacokinetics and Bioavailability of Plant Lignan 7-Hydroxymatairesinol and Effects on Serum Enterolactone and Clinical Symptoms in Postmenopausal Women: A Single-Blinded, Parallel, Dose-Comparison Study

PubMed Central

Udani, Jay K.; Brown, Donald J.; Tan, Maria Olivia C.; Hardy, Mary

2013-01-01

Objective 7-Hydroxymaitairesinol (7-HMR) is a naturally occurring plant lignan found in whole grains and the Norway spruce (Piciea abies). The purpose of this study was to evaluate the bioavailability of a proprietary 7-HMR product (HMRlignan, Linnea SA, Locarno, Switzerland) through measurement of lignan metabolites and metabolic precursors. Methods A single-blind, parallel, pharmacokinetic and dose-comparison study was conducted on 22 post-menopausal females not receiving hormone replacement therapy. Subjects were enrolled in either a 36 mg/d (low-dose) or 72 mg/d dose (high-dose) regimen for 8 weeks. Primary measured outcomes included plasma levels of 7-HMR and enterolactone (ENL), and single-dose pharmacokinetic analysis was performed on a subset of subjects in the low-dose group. Safety data and adverse event reports were collected as well as data on hot flash frequency and severity. Results Pharmacokinetic studies demonstrated 7-HMR Cmax = 757.08 ng/ml at 1 hour and ENL Cmax = 4.8 ng/ml at 24 hours. From baseline to week 8, plasma 7-HMR levels increased by 191% in the low-dose group (p < 0.01) and by 1238% in the high-dose group (p < 0.05). Plasma ENL levels consistently increased as much as 157% from baseline in the low-dose group and 137% in the high-dose group. Additionally, the mean number of weekly hot flashes decreased by 50%, from 28.0/week to 14.3/week (p < 0.05) in the high-dose group. No significant safety issues were identified in this study. Conclusion The results demonstrate that HMRlignan is quickly absorbed into the plasma and is metabolized to ENL in healthy postmenopausal women. Clinically, the data demonstrate a statistically significant improvement in hot flash frequency. Doses up to 72 mg/d HMRlignan for 8 weeks were safe and well tolerated in this population. PMID:24606716

Pharmacokinetics and bioavailability of plant lignan 7-hydroxymatairesinol and effects on serum enterolactone and clinical symptoms in postmenopausal women: a single-blinded, parallel, dose-comparison study.

PubMed

Udani, Jay K; Brown, Donald J; Tan, Maria Olivia C; Hardy, Mary

2013-01-01

7-Hydroxymaitairesinol (7-HMR) is a naturally occurring plant lignan found in whole grains and the Norway spruce (Piciea abies). The purpose of this study was to evaluate the bioavailability of a proprietary 7-HMR product (HMRlignan, Linnea SA, Locarno, Switzerland) through measurement of lignan metabolites and metabolic precursors. A single-blind, parallel, pharmacokinetic and dose-comparison study was conducted on 22 postmenopausal females not receiving hormone replacement therapy. Subjects were enrolled in either a 36 mg/d (low-dose) or 72 mg/d dose (high-dose) regimen for 8 weeks. Primary measured outcomes included plasma levels of 7-HMR and enterolactone (ENL), and single-dose pharmacokinetic analysis was performed on a subset of subjects in the low-dose group. Safety data and adverse event reports were collected as well as data on hot flash frequency and severity. Pharmacokinetic studies demonstrated 7-HMR C max = 757.08 ng/ml at 1 hour and ENL C max = 4.8 ng/ml at 24 hours. From baseline to week 8, plasma 7-HMR levels increased by 191% in the low-dose group (p < 0.01) and by 1238% in the high-dose group (p < 0.05). Plasma ENL levels consistently increased as much as 157% from baseline in the low-dose group and 137% in the high-dose group. Additionally, the mean number of weekly hot flashes decreased by 50%, from 28.0/week to 14.3/week (p < 0.05) in the high-dose group. No significant safety issues were identified in this study. The results demonstrate that HMRlignan is quickly absorbed into the plasma and is metabolized to ENL in healthy postmenopausal women. Clinically, the data demonstrate a statistically significant improvement in hot flash frequency. Doses up to 72 mg/d HMRlignan for 8 weeks were safe and well tolerated in this population.

Practical Applications for Single Pill Combinations in the Cardiovascular Continuum

PubMed Central

Iellamo, Ferdinando; Werdan, Karl; Narkiewicz, Krzysztof; Rosano, Giuseppe

2017-01-01

Despite the availability of new drugs and devices, the treatment of cardiovascular disease remains suboptimal. Single-pill combination therapy offers a number of potential advantages. It can combine different classes of drugs to increase efficacy while mitigating the risks of treatment-related adverse events, reduce pill burden, lower medical cost, and improve patient adherence. Furthermore, in hypertension, single pill combinations include standard to lower doses of each drug than would be necessary to achieve goals with monotherapy, which may explain their better tolerability compared with higher dose monotherapy. Combination therapy is now established in the treatment of hypertension. In ischaemic heart disease, the concept of a preventative polypill has been studied, but its benefits have not been established conclusively. However, the combination of ivabradine and beta-blockers has proven efficacy in patients with stable angina pectoris. This combination has also demonstrated benefits in patients with chronic heart failure. PMID:28785474

High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group.

PubMed

Takahashi, Hiroyuki; Watanabe, Tomoyuki; Kinoshita, Akitoshi; Yuza, Yuki; Moritake, Hiroshi; Terui, Kiminori; Iwamoto, Shotaro; Nakayama, Hideki; Shimada, Akira; Kudo, Kazuko; Taki, Tomohiko; Yabe, Miharu; Matsushita, Hiromichi; Yamashita, Yuka; Koike, Kazutoshi; Ogawa, Atsushi; Kosaka, Yoshiyuki; Tomizawa, Daisuke; Taga, Takashi; Saito, Akiko M; Horibe, Keizo; Nakahata, Tatsutoshi; Miyachi, Hayato; Tawa, Akio; Adachi, Souichi

2016-08-01

We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered. © 2016 John Wiley & Sons Ltd.

Single dose oral flurbiprofen for acute postoperative pain in adults

PubMed Central

Sultan, Asquad; McQuay, Henry J; Moore, R Andrew; Derry, Sheena

2014-01-01

Background Flurbiprofen is a non-selective non-steroidal anti-inflammatory drug (NSAID), related to ibuprofen and naproxen, used to treat acute and chronic painful conditions. There is no systematic review of its use in acute postoperative pain. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral flurbiprofen in acute postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to January 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered flurbiprofen in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk (RR) and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Eleven studies compared flurbiprofen (699 participants) with placebo (362 participants) in studies lasting 6 to 12 hours. Studies were of adequate reporting quality, and most participants had pain following dental extractions. The dose of flurbiprofen used was 25 mg to 100 mg, with most information for 50 mg and 100 mg. The NNT for at least 50% pain relief over 4 to 6 hours for flurbiprofen 50 mg compared with placebo (692 participants) was 2.7 (2.3 to 3.3) and for 100 mg (416 participants) it was 2.5 (2.0 to 3.1). With flurbiprofen 50 mg and 100 mg 65% to 70% of participants experienced at least 50% pain relief, compared with 25% to 30% with placebo. Rescue medication was used by 25% and 16% of participants with flurbiprofen 50 mg and 100 mg over 6 hours, compared with almost 70% with placebo. Adverse events were uncommon, and not significantly different from placebo. Authors’ conclusions Flurbiprofen at doses of 50 mg and 100 mg is an effective analgesic in moderate to severe acute postoperative pain. The NNT for at least 50% pain relief is similar to that of commonly used NSAIDs such as ibuprofen and naproxen at usual doses. Use of rescue medication indicates a duration of action exceeding 6 hours. PMID:19588427

Pharmacokinetics and tolerability of intravenous ibuprofen injection in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose study
.

PubMed

Zhou, Huili; Xu, Wei; Wu, Guolan; Wu, Lihua; Shentu, Jianzhong; Pan, Zhengfei; Hu, Shuai; Liu, Yang

2016-11-01

Recently a formulation of intravenous (IV) ibuprofen was developed in China for management of mild to moderate pain in patients who could not take oral medications or where intravenous administration was preferable. The aim of this study was to evaluate the pharmacokinetic properties and tolerability of single and multiple doses of ibuprofen injection in healthy Chinese volunteers. This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. In the single-dose phase, subjects were randomized to receive a single dose of ibuprofen injection 0.2, 0.4, or 0.8 g administered as a 30-minute IV infusion with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 12.5 hours after drug administration and were analyzed using a validated LC-MS/MS method. In the multiple-dose phase, subjects received 0.4 g ibuprofen every 6 hours for 9 doses. Blood samples were obtained before the 7^th, 8^th, and 9^th administration to determine the C_min at steady state; on the 9^th intravenous administration, blood samples were also collected for 12.5 hours after drug administration. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). A total of 12 healthy male (n = 6) and female (n = 6) Chinese volunteers were enrolled and completed the trial. After IV administration of single dose, the mean (SD) C_max value increased from 35.77 (6.98) to 117.12 (19.78) µg/mL, and the mean (SD) AUC_0-t value increased from 67.63 (10.30) to 230.50 (33.55) µg×h/mL in the range of 0.2-g to 0.8-g dose. The terminal half-life in plasma was ~ 2.0 hours. After IV administration of 9 doses of ibuprofen 400 mg every 6 hours, the mean (SD) C_max was 66.49 (8.49) µg/mL, the AUC_0-t was 135.65 (26.91) µg×h/mL, the t_1/2 was 2.14 (0.34) hours, the Cl/F was 3.34 (0.68) L/h, and the Vz/F was 10.32 (2.69) L, which were comparable with those after single dosing. The accumulation index was 1.17 (0.06), and the fluctuation was 304.0 (57.7) %. Results of the t-tests of C_max and AUC found no significant differences between the male and female groups. No serious AEs were reported, and there were no discontinuations due to AEs. The pharmacokinetics of ibuprofen exhibited dose-related kinetics from the 0.2- to the 0.8-g dose. After multiple doses, the pharmacokinetic parameters of ibuprofen were consistent with those after single doses. There was no accumulation in ibuprofen exposure in healthy Chinese between multiple doses and single dose. At the doses studied, ibuprofen appeared to be well tolerated in these healthy volunteers.
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Monitoring Space Radiation Hazards with the Responsive Environmental Assessment Commercially Hosted (REACH) Project

NASA Astrophysics Data System (ADS)

Mazur, J. E.; Guild, T. B.; Crain, W.; Crain, S.; Holker, D.; Quintana, S.; O'Brien, T. P., III; Kelly, M. A.; Barnes, R. J.; Sotirelis, T.

2017-12-01

The Responsive Environmental Assessment Commercial Hosting (REACH) project uses radiation dosimeters on a commercial satellite constellation in low Earth orbit to provide unprecedented spatial and time sampling of space weather radiation hazards. The spatial and time scales of natural space radiation environments coupled with constraints for the hosting accommodation drove the instrumentation requirements and the plan for the final orbital constellation. The project has delivered a total of thirty two radiation dosimeter instruments for launch with each instrument containing two dosimeters with different passive shielding and electronic thresholds to address proton-induced single-event effects, vehicle charging, and total ionizing dose. There are two REACH instruments currently operating with four more planned for launch by the time of the 2017 meeting. Our aim is to field a long-lived system of highly-capable radiation detectors to monitor the hazards of single-event effects, total ionizing dose, and spacecraft charging with maximized spatial coverage and with minimal time latency. We combined a robust detection technology with a commercial satellite hosting to produce a new demonstration for satellite situational awareness and for other engineering and science applications.

Single-event Effect Report for EPC Series eGaN FETs: Proton Testing for SEE and TNID Effects

NASA Technical Reports Server (NTRS)

Scheick, Leif

2014-01-01

Previous testing of the Enhanced Power Conversion (EPC) eGaN FETs showed sensitivity to destructive single-event effects (SEE) effects to heavy ions. The presence of tungsten plugs in the gate area raises concerns that the device may be vulnerable to SEE from protons. Irradiation of biased and unbiased devices with heavy ion has results in some damage suspected of being due to total non-ionizing dose (TNID). Proton irradiation is a better radiation type to study this effect. This study presents the results of testing device with protons for SEE and TNID. No SEE in the EPC2012 device, the most sensitive device to SEE, were seen with 53 MeV protons at several angles. The devices continued to function after 1.5 Mrad (Si) of proton dose with only a slight shift in parameters. These results suggest that gross TNID will not be a factor in using these devices nor suffer from SEE due to protons. However, the device should be tested at with 500 MeV protons to guarantee to immunity proton SEE.

Pupillography as a sensitive, noninvasive biomarker in healthy volunteers: first-in-man study of BAY 63-9044, a new 5-HT1A-receptor agonist with dopamine agonistic properties.

PubMed

Wensing, Georg; Haase, Claus; Brendel, Erich; Böttcher, Michael Friedrich

2007-12-01

BAY 63-9044 is a new full 5-HT(1A)-agonist with functional dopamine agonist properties aimed for the treatment of Parkinson's disease. This first-in-man study investigated the pharmacodynamics, safety and tolerability as well as the pharmacokinetics of BAY 63-9044 in a randomized, single-blind, placebo-controlled group-comparison dose escalation study. 45 healthy men received BAY 63-9044 as an oral solution in single doses of 0.25 mg, 0.5 mg, 1.2 mg, 2.5 mg and 5.0 mg. Pupil reaction (baseline pupil diameter (DIAM), constriction amplitude (CA)), body temperature, electroencephalography (EEG) and prolactin, cortisol and adrenocorticotrophic hormone (ACTH) served as pharmacodynamic measures and were monitored up to 24 h after drug intake. Safety, tolerability and plasma samples for determination of BAY 63-9044 were followed up to 72 h. Up to a dose of 2.5 mg, BAY 63-9044 was safe and well tolerated. Dose-limiting adverse events (nausea, vomiting, and dizziness) occurred in 5 out of 6 volunteers at the 5 mg dose. Adverse events resolved spontaneously in all but one volunteers who was treated with an antihistaminergic for vomiting. Dose-dependent changes of DIAM and CA were observed at doses higher than 0.5 mg and 1.2 mg, respectively. Body temperature showed a trend for reduction starting at C(max) in the highest two doses only. No clear effect was found on prolactin, cortisol and ACTH levels. The pharmacokinetics of BAY 63-9044 showed a dose-dependent increase with maximum plasma concentrations reached within 1 h. Plasma concentrations declined in a bi-phased manner with an apparent terminal half-life of 5.2-8.1 h. Up to the maximum tolerated dose (MTD) of 2.5 mg BAY 63-9044 was safe and well tolerated and showed predictable linear pharmacokinetics. Pupil reaction may serve as a non-invasive biomarker for pharmacodynamic effects of 5-HT(1A)-compounds with DIAM being the most sensitive parameter.

Adverse Events During a Randomized Trial of Ketamine Versus Co-Administration of Ketamine and Propofol for Procedural Sedation in a Pediatric Emergency Department.

PubMed

Weisz, Keith; Bajaj, Lalit; Deakyne, Sara J; Brou, Lina; Brent, Alison; Wathen, Joseph; Roosevelt, Genie E

2017-07-01

The co-administration of ketamine and propofol (CoKP) is thought to maximize the beneficial profile of each medication, while minimizing the respective adverse effects of each medication. Our objective was to compare adverse events between ketamine monotherapy (KM) and CoKP for procedural sedation and analgesia (PSA) in a pediatric emergency department (ED). This was a prospective, randomized, single-blinded, controlled trial of KM vs. CoKP in patients between 3 and 21 years of age. The attending physician administered either ketamine 1 mg/kg i.v. or ketamine 0.5 mg/kg and propofol 0.5 mg/kg i.v. The physician could administer up to three additional doses of ketamine (0.5 mg/kg/dose) or ketamine/propofol (0.25 mg/kg/dose of each). Adverse events (e.g., respiratory events, cardiovascular events, unpleasant emergence reactions) were recorded. Secondary outcomes included efficacy, recovery time, and satisfaction scores. Ninety-six patients were randomized to KM and 87 patients were randomized to CoKP. There was no difference in adverse events or type of adverse event, except nausea was more common in the KM group. Efficacy of PSA was higher in the KM group (99%) compared to the CoKP group (90%). Median recovery time was the same. Satisfaction scores by providers, including nurses, were higher for KM, although parents were equally satisfied with both sedation regimens. We found no significant differences in adverse events between the KM and CoKP groups. While CoKP is a reasonable choice for pediatric PSA, our study did not demonstrate an advantage of this combination over KM. Copyright © 2017 Elsevier Inc. All rights reserved.

Systemic effects of low-dose dopamine during administration of cytarabine.

PubMed

Connelly, James; Benani, Dina J; Newman, Matthew; Burton, Bradley; Crow, Jessica; Levis, Mark

2017-09-01

Purpose Low-dose dopamine has been utilized to improve renal blood flow, urine output, and reduce drug-induced nephrotoxicity. The purpose of this study was to assess changes in renal function, cardiovascular adverse events, and neurologic toxicity in patients receiving cytarabine with or without low-dose dopamine. Methods A retrospective, single-center, cohort study of patients receiving cytarabine at 667 mg/m 2 /dose or greater, with or without dopamine at ≤5 mcg/kg/min. Cohorts were based upon initiation or absence of low-dose dopamine; cytarabine only, cytarabine + pre- and day of low-dose dopamine, and cytarabine + post-low-dose dopamine. Renal outcomes (urine output, serum creatinine, and creatinine clearance) were compared with baseline and between cohorts. Safety endpoints (arrhythmias, tachycardia, and neurotoxicity) were compared between cohorts based on low-dose dopamine exposure. Results There was no difference in urine output from baseline in all cohorts. Comparing cytarabine only and pre- and day of low-dose dopamine cohorts, there was no difference in urine output. In those receiving low-dose dopamine, there was no difference in serum creatinine and creatinine clearance from baseline. No arrhythmias were documented during the study period, and there was no difference in the incidence of tachycardia between groups (P = 0.66). Neurotoxicity was reported in three patients who were on low-dose dopamine. Conclusion Though variation existed in individual patients administered low-dose dopamine, the use of low-dose dopamine did not significantly impact renal function in this small sample at a single institution. In addition, low-dose dopamine did not negatively impact cardiovascular function.

Efficacy and safety of a single oral 150 mg dose of fluconazole for the treatment of vulvovaginal candidiasis in Japan.

PubMed

Mikamo, Hiroshige; Matsumizu, Miyako; Nakazuru, Yoshiomi; Okayama, Akifumi; Nagashima, Masahito

2015-07-01

Vulvovaginal candidiasis is the second most common cause of vaginal infections following bacterial vaginosis. For the treatment of vulvovaginal candidiasis, antifungal agents are used either as topical (vaginal tablets and cream) or oral formulations. A single oral 150 mg dose of fluconazole has been recommended as the standard therapy for uncomplicated, acute vulvovaginal candidiasis in global guidelines; however, in Japan oral fluconazole therapy has not been approved. We conducted a phase 3 study to evaluate the efficacy and safety of a single oral 150 mg dose of fluconazole in Japanese subjects with vulvovaginal candidiasis for regulatory submission. A total of 157 subjects received a single oral 150 mg dose of fluconazole. Candida species (104 strains) were identified by fungal culture from 102 subjects at baseline, including Candida albicans (100 strains). The efficacy rate for the therapeutic outcome (assessed based on a comprehensive evaluation of the clinical and mycological efficacy in each subject) was 74.7% (74/99) on Day 28 in the modified Intent-To-Treat (m-ITT) population. Concerning the clinical and mycological efficacy on Day 28 in the m-ITT population, the cure, cure or improvement, and eradication rates were 81.6%, 95.9%, and 85.9%, respectively. The most common treatment-related adverse events were diarrhea and nausea (1.9% for each). No clinically significant safety issues were reported. A single oral 150 mg dose of fluconazole demonstrated excellent therapeutic efficacy and was well tolerated in Japanese subjects with vulvovaginal candidiasis. NCT01806623. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers.

PubMed

Stevens, Misty W; Henry, Ralph L; Owens, S Michael; Schutz, Ralph; Gentry, W Brooks

2014-01-01

This first-in-human study examined the safety and pharmacokinetics of ch-mAb7F9, an anti-methamphetamine monoclonal antibody, in healthy volunteers. Single, escalating doses of ch-mAb7F9 over the range of 0.2 to 20 mg/kg were administered to 42 subjects who were followed for 147 d. Safety was measured by physical examinations, adverse events, vital signs, electrocardiograms, and clinical laboratory testing. Serum ch-mAb7F9 concentration and immunogenicity analyses were performed. There were no serious adverse reactions or discontinuations from the study due to adverse events. No trends emerged in the frequency, relatedness, or severity of adverse events with increased dose or between active and placebo treated subjects. Ch-mAb7F9 displayed expected IgG pharmacokinetic parameters, including a half-life of 17-19 d in the 3 highest dose groups and volume of distribution of 5-6 L, suggesting the antibody is confined primarily to the vascular compartment. Four (12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study; however, this response did not appear to be dose related. Overall, no apparent safety or tolerability concerns were identified; a maximum tolerated dose was not reached in this Phase 1 study. Ch-mAb7F9 therefore appears safe for human administration.

Pharmacokinetics and bioequivalence of a rosuvastatin/ezetimibe fixed-dose combination tablet versus single agents in healthy male subjects
.

PubMed

Kang, Woo Youl; Seong, Sook Jin; Ohk, Boram; Gwon, Mi-Ri; Kim, Bo Kyung; Na, Sookie; Kim, Hyun-Ju; Yoon, Young-Ran; Lee, Hae Won

2018-01-01

The pharmacokinetic profiles and bioequivalence of a new rosuvastatin/ezetimibe fixed-dose combination (FDC; NVP-1205) vs. rosuvastatin and ezetimibe concomitantly administered as single agents were evaluated. In this open-label, single-dose, crossover study (NCT02029625), eligible subjects were randomly assigned in a 1 : 1 ratio to receive a single dose of rosuvastatin (10 mg) with ezetimibe (10 mg) as either a FDC or as single agents concomitantly administered under fasted conditions, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected predose and up to 96 hours postdose in each period for determination of plasma rosuvastatin and ezetimibe concentrations by liquid-chromatography tandem mass spectroscopy and calculation of pharmacokinetic parameters. The mean C_max and AUC_0-t values of rosuvastatin were 12.5 ng/mL and 115.6 ng×h/mL for the FDC, and 12.2 ng/mL and 115.1 ng×h/mL for the single agents concomitantly administered, respectively. The mean C_max and AUC_0-t values of ezetimibe were 4.7 ng/mL and 67.3 ng×h/mL for the FDC, and 4.5 ng/mL and 68.2 ng×h/mL for the single agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the rosuvastatin C_max and AUC_0-t were 106.20 (96.62 - 116.74) and 102.88 (96.32 - 109.90), respectively. The GMR and 90% CI for the ezetimibe C_max and AUC_0-t were 108.96 (98.56 - 120.51) and 98.13 (92.01 - 104.66), respectively. All treatments were well tolerated during this study, with no serious adverse events reported. The rosuvastatin/ezetimibe (10/10 mg) FDC was bioequivalent to single agents concomitantly administered. A single dose of rosuvastatin/ezetimibe as the FDC or as single agents was well tolerated.
.

Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

PubMed

Glue, Paul; Cape, Gavin; Tunnicliff, Donna; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, C Tak; Harland, Sarah; Devane, Jane; Crockett, R S; Howes, John; Darpo, Borje; Zhou, Meijian; Weis, Holger; Friedhoff, Lawrence

2016-11-01

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and C max and was slowly eliminated (mean t 1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues. © 2016, The American College of Clinical Pharmacology.

Interplanetary Particle Environment. Proceedings of a Conference

NASA Technical Reports Server (NTRS)

Feynman, Joan (Editor); Gabriel, Stephen (Editor)

1988-01-01

A workshop entitled the Interplanetary Charged Particle Environment was held at the Jet Propulsion Laboratory (JPL) on March 16 and 17, 1987. The purpose of the Workshop was to define the environment that will be seen by spacecraft operating in the 1990s. It focused on those particles that are involved in single event upset, latch-up, total dose and displacement damage in spacecraft microelectronic parts. Several problems specific to Magellan were also discussed because of the sensitivity of some electronic parts to single-event phenomena. Scientists and engineers representing over a dozen institutions took part in the meeting. The workshop consisted of two major activities, reviews of the current state of knowledge and the formation of working groups and the drafting of their reports.

Single-dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection With Vibrio cholerae O1 El Tor.

PubMed

Chen, Wilbur H; Cohen, Mitchell B; Kirkpatrick, Beth D; Brady, Rebecca C; Galloway, David; Gurwith, Marc; Hall, Robert H; Kessler, Robert A; Lock, Michael; Haney, Douglas; Lyon, Caroline E; Pasetti, Marcela F; Simon, Jakub K; Szabo, Flora; Tennant, Sharon; Levine, Myron M

2016-06-01

No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance.PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model. Consenting healthy adult volunteers, 18-45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 × 10(8) colony-forming units [CFU]) or placebo in double-blind fashion. Volunteers ingested approximately 1 × 10(5) CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration. The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (≥3.0 L) to severe (≥5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P < .0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P < .0001). The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine. NCT01895855. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

The Impact on Space Radiation Requirements and Effects on ASIMS

NASA Technical Reports Server (NTRS)

Barnes, C.; Johnston, A.; Swift, G.

1995-01-01

The evolution of highly miniaturized electronic and mechanical systems will be accompanied by new problems and issues regarding the radiation response of these systems in the space environment. In this paper we discuss some of the more prominent radiation problems brought about by miniaturization. For example, autonomous micro-spacecraft will require large amounts of high density memory, most likely in the form of stacked, multichip modules of DRAM's, that must tolerate the radiation environment. However, advanced DRAM's (16 to 256 Mbit) are quite susceptible to radiation, particularly single event effects, and even exhibit new radiation phenomena that were not a problem for older, less dense memory chips. Another important trend in micro-spacecraft electronics is toward the use of low-voltage microelectronic systems that consume less power. However, the reduction in operating voltage also caries with it an increased susceptibility to radiation. In the case of application specific integrated microcircuits (ASIM's), advanced devices of this type, such as high density field programmable gate arrays (FPGA's) exhibit new single event effects (SEE), such as single particle reprogramming of anti-fuse links. New advanced bipolar circuits have been shown recently to degrade more rapidly in the low dose rate space environment than in the typical laboratory total dose radiation test used to qualify such devices. Thus total dose testing of these parts is no longer an appropriately conservative measure to be used for hardness assurance. We also note that the functionality of micromechanical Si-based devices may be altered due to the radiation-induced deposition of charge in the oxide passivation layers.

Effect of aspirin on acute changes in peripheral arterial stiffness and endothelial function following exertional heat stress in firefighters: The factorial group results of the Enhanced Firefighter Rehab Trial.

PubMed

Olafiranye, Oladipupo; Hostler, David; Winger, Daniel G; Wang, Li; Reis, Steven E

2015-06-01

Peripheral arterial stiffness and endothelial function, which are independent predictors of cardiac events, are abnormal in firefighters. We examined the effects of aspirin on peripheral arterial stiffness and endothelial function in firefighters. Fifty-two firefighters were randomized to receive daily 81 mg aspirin or placebo for 14 days before treadmill exercise in thermal protection clothing, and a single dose of 325 mg aspirin or placebo immediately following exertion. Peripheral arterial augmentation index adjusted for a heart rate of 75 (AI75) and reactive hyperemia index (RHI) were determined immediately before, and 30, 60, and 90 minutes after exertion. Low-dose aspirin was associated with lower AI75 (-15.25±9.25 vs -8.08±10.70, p=0.014) but not RHI. On repeated measures analysis, treatment with low-dose aspirin before, but not single-dose aspirin after exertion, was associated with lower AI75 following exertional heat stress (p=0.018). Low-dose aspirin improved peripheral arterial stiffness and wave reflection but not endothelial function in firefighters. © The Author(s) 2015.

Electrocardiographic effects of hawthorn (Crataegus oxyacantha) in healthy volunteers: A randomized controlled trial.

PubMed

Trexler, Stephanie E; Nguyen, Elaine; Gromek, Samantha M; Balunas, Marcy J; Baker, William L

2018-04-19

The objective of this study was to evaluate the electrocardiographic effects of hawthorn in healthy adult volunteers. It was double-blind cross-over trial randomized 20 healthy adult volunteers to receive either a single oral 160-mg dose of hawthorn or matching placebo. Triplicate 12-lead electrocardiograms were taken before treatment and at 1-, 2-, 4-, and 6-hr post-dose. Following at least a 7-day washout period, participants were crossed over to the opposing treatment arm and had the measurements repeated. The primary endpoint was the change in corrected (Fridericia) QT intervals (QT c I) at 4 and 6 hr. Maximum post-dose QT c I and changes in PR and QRS intervals were measured. No significant differences in 4- or 6-hr QT c I were seen between hawthorn and placebo. Maximum post-dose QT c I in the hawthorn and placebo groups were similar (346 ± 35 vs 346 ± 40 ms; p = .979). No significant adverse events were seen. In conclusion, a single dose of oral hawthorn had no effect on electrocardiographic parameters in healthy volunteers. Copyright © 2018 John Wiley & Sons, Ltd.

Safety of fluralaner, a novel systemic antiparasitic drug, in MDR1(-/-) Collies after oral administration

PubMed Central

2014-01-01

Background Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. This study investigated the safety of oral administration of fluralaner at 3 times the highest expected clinical dose to Multi Drug Resistance Protein 1 (MDR1(-/-)) gene defect Collies. Methods Sixteen Collies homozygous for the MDR1 deletion mutation were included in the study. Eight Collies received fluralaner chewable tablets once at a dose of 168 mg/kg; eight sham dosed Collies served as controls. All Collies were clinically observed until 28 days following treatment. Results No adverse events were observed subsequent to fluralaner treatment of MDR1(-/-) Collies at three times the highest expected clinical dose. Conclusions Fluralaner chewable tablets are well tolerated in MDR1(-/-) Collies following oral administration. PMID:24602342

Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers.

PubMed

de Bono, Johann; Ramanathan, Ramesh K; Mina, Lida; Chugh, Rashmi; Glaspy, John; Rafii, Saeed; Kaye, Stan; Sachdev, Jasgit; Heymach, John; Smith, David C; Henshaw, Joshua W; Herriott, Ashleigh; Patterson, Miranda; Curtin, Nicola J; Byers, Lauren Averett; Wainberg, Zev A

2017-06-01

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2 -mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation-associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day. Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation-associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620-9. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

Multiple-dose pharmacokinetics and safety of an ibuprofen-pseudoephedrine cold suspension in children.

PubMed

Gelotte, Cathy K; Prior, Mary Jane; Pendley, Charles; Zimmerman, Brenda; Lavins, Bernard J

2010-07-01

Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 + or - 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 + or - 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 + or - 2.2 mL/kg/min and Vd/F was 2.52 + or - 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.

[Influence of dose regimen on gentamycin nephrotoxicity in rats].

PubMed

Oliveira, V C; Tejos, C R; Hosaka, E M; Andrade, S C; Araújo, M; Vattimo, M F

2001-06-01

The acute renal failure (ARF), that still presents a right mortality rate (50%) can be defined as an abrupt decline of the glomerular filtration, resultant of ischemic or toxicity event. The drugs nephrotoxicity is one of the most frequent cause (27%) of ARF and it is suggested that the interval of administration of the drug can interfere in this side effect, however the best administration regimen is not very well established. This study evaluated the renal function of rats that received gentamicin (100 mg/kg) in one dose or in two doses (2 x 50 mg/kg), by intraperitoneal infusion. The results obtained in this research, indicated that the single infusion of gentamicin determined smaller nephrotoxicity by the reduction of serum concentration of this drug in 24 hours, decreasing the intracellular accumulation of this gentamicin, which is one of the main cellular mechanisms of this renal injury. The single dose treatment regime, otherwise, shows advantages not only related to the nephrotoxicity effect, but also it is relevant to the cost and safety, which can be rationable factors in the administration of this drug.

Prediction of error rates in dose-imprinted memories on board CRRES by two different methods. [Combined Release and Radiation Effects Satellite

NASA Technical Reports Server (NTRS)

Brucker, G. J.; Stassinopoulos, E. G.

1991-01-01

An analysis of the expected space radiation effects on the single event upset (SEU) properties of CMOS/bulk memories onboard the Combined Release and Radiation Effects Satellite (CRRES) is presented. Dose-imprint data from ground test irradiations of identical devices are applied to the predictions of cosmic-ray-induced space upset rates in the memories onboard the spacecraft. The calculations take into account the effect of total dose on the SEU sensitivity of the devices as the dose accumulates in orbit. Estimates of error rates, which involved an arbitrary selection of a single pair of threshold linear energy transfer (LET) and asymptotic cross-section values, were compared to the results of an integration over the cross-section curves versus LET. The integration gave lower upset rates than the use of the selected values of the SEU parameters. Since the integration approach is more accurate and eliminates the need for an arbitrary definition of threshold LET and asymptotic cross section, it is recommended for all error rate predictions where experimental sigma-versus-LET curves are available.

Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers.

PubMed

Chien, S C; Wong, F A; Fowler, C L; Callery-D'Amico, S V; Williams, R R; Nayak, R; Chow, A T

1998-04-01

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0-24) following a single 750-mg dose were 7.1 microg/ml and 71.3 microg x h/ml, respectively, compared to 8.6 microg/ml and 90.7 microg x h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0-24 values were 8.9 microg/ml and 95.4 microg x h/ml, respectively; corresponding values at steady state were 11.8 microg/ml and 118 microg x h/ml. These Cmax and AUC0-24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CL[R]) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CL(R) following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.

Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers

PubMed Central

Chien, Shu-Chean; Wong, Frank A.; Fowler, Cynthia L.; Callery-D’Amico, Susan V.; Williams, R. Rex; Nayak, Ramchandra; Chow, Andrew T.

1998-01-01

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These Cmax and AUC0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CLR) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CLR following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache. PMID:9559801

Low-dose CT for the diagnosis of appendicitis in adolescents and young adults (LOCAT): a pragmatic, multicentre, randomised controlled non-inferiority trial.

PubMed

2017-11-01

CT radiation is arguably carcinogenic. Results from single-centre studies, mostly retrospective, have advocated lowering the CT radiation dose for the diagnosis of appendicitis. However, adoption of low-dose CT has been slow. We aimed to assess the effectiveness of low-dose CT compared with standard-dose CT in the diagnosis of appendicitis in adolescents and young adults. We did this pragmatic, multicentre, randomised controlled non-inferiority trial at 20 South Korean teaching hospitals with little experience with low-dose CT. Patients aged 15-44 years with suspected appendicitis were randomly assigned (1:1), via computer-generated random assignments (permuted block sizes of two, four, six, and eight) concealed in sequentially numbered envelopes, to receive low-dose CT (2 mSv) or standard-dose CT (≤8 mSv). Randomisation was stratified by site. Group allocation was concealed from patients, outcome assessors, and adverse event adjudicators; care providers, site pathologists, and data collectors were aware of allocation. The primary endpoint was the negative (unnecessary) appendectomy rate among all appendectomies, with a non-interiority margin of 4·5% for low-dose versus standard-dose CT. Primary analysis was by modified intention to treat, which included all patients who received an appendectomy in the group to which they were assigned. This trial is registered with ClinicalTrials.gov, number NCT01925014. Between Dec 4, 2013, and Aug 18, 2016, we assigned 1535 patients to the low-dose CT group and 1539 patients to the standard-dose CT group. 22 (3·9%) of 559 patients had a negative appendectomy in the low-dose group versus 16 (2·7%) of 601 patients in the standard-dose group (difference 1·3%, 95% CI -0·8 to 3·3; p=0·0022 for the non-inferiority test). We recorded 43 adverse events in 43 (2·8%) of 1535 patients in the low-dose group and 41 adverse events in 40 (2·6%) of 1539 patients in the standard-dose group. One life-threatening adverse event of anaphylaxis caused by an iodinated contrast material occurred in the low-dose group. Radiation dose of appendiceal CT for adolescents and young adults can be reduced to 2 mSv without impairing clinical outcomes. In view of the vast number of appendiceal CT examinations done worldwide, use of low-dose CT could prevent a sizeable number of radiation-associated cancers in the future. Korea Health Industry Development Institute, Seoul National University Bundang Hospital, Dasol Life Science, and Bracco Imaging Korea. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety and immunogenicity of an MF59-adjuvanted A/H1N1 pandemic influenza vaccine in children from three to seventeen years of age.

PubMed

Knuf, Markus; Leroux-Roels, Geert; Rümke, Hans C; Abarca, Katia; Rivera, Luis; Lattanzi, Maria; Pedotti, Paola; Arora, Ashwani; Kieninger-Baum, Dorothee; Della Cioppa, Giovanni

2015-01-01

This study was designed to identify the optimal dose of an MF59-adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects. Subjects aged 3-8 years (n=194) and 9-17 years (n=160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 μg antigen with half a standard dose of MF59 adjuvant, 7.5 μg antigen with a full dose of MF59, or (children 3-8 years only), a non-adjuvanted 15 μg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months). A single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres ≥1:40>70%; seroconversion>40%; and GMR>2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres ≥1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non-adjuvanted group. HI titres ≥1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event. An MF59-adjuvanted influenza vaccine containing 3.75 μg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the European licensure criteria after a single dose in healthy children 3-17 years old. Copyright © 2014 Elsevier Ltd. All rights reserved.

SU-F-T-185: Study of the Robustness of a Proton Arc Technique Based On PBS Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Z; Zheng, Y

Purpose: One potential technique to realize proton arc is through using PBS beams from many directions to form overlaid Bragg peak (OBP) spots and placing these OBP spots throughout the target volume to achieve desired dose distribution. In this study, we analyzed the robustness of this proton arc technique. Methods: We used a cylindrical water phantom of 20 cm in radius in our robustness analysis. To study the range uncertainty effect, we changed the density of the phantom by ±3%. To study the setup uncertainty effect, we shifted the phantom by 3 & 5 mm. We also combined the rangemore » and setup uncertainties (3mm/±3%). For each test plan, we performed dose calculation for the nominal and 6 disturbed scenarios. Two test plans were used, one with single OBP spot and the other consisting of 121 OBP spots covering a 10×10cm{sup 2} area. We compared the dose profiles between the nominal and disturbed scenarios to estimate the impact of the uncertainties. Dose calculation was performed with Gate/GEANT based Monte Carlo software in cloud computing environment. Results: For each of the 7 scenarios, we simulated 100k & 10M events for plans consisting of single OBP spot and 121 OBP spots respectively. For single OBP spot, the setup uncertainty had minimum impact on the spot’s dose profile while range uncertainty had significant impact on the dose profile. For plan consisting of 121 OBP spots, similar effect was observed but the extent of disturbance was much less compared to single OBP spot. Conclusion: For PBS arc technique, range uncertainty has significantly more impact than setup uncertainty. Although single OBP spot can be severely disturbed by the range uncertainty, the overall effect is much less when a large number of OBP spots are used. Robustness optimization for PBS arc technique should consider range uncertainty with priority.« less

Bioequivalence study of a new sildenafil 100 mg orodispersible film compared to the conventional film-coated 100 mg tablet administered to healthy male volunteers.

PubMed

Radicioni, Milko; Castiglioni, Chiara; Giori, Andrea; Cupone, Irma; Frangione, Valeria; Rovati, Stefano

2017-01-01

A new orodispersible film formulation of the phosphodiesterase type 5 inhibitor, sildenafil, has been developed to examine the advantages of an orally disintegrating film formulation and provide an alternative to the current marketed products for the treatment of erectile dysfunction. The pharmacokinetics of the sildenafil 100 mg orodispersible film (IBSA) was compared to that of the conventional marketed 100 mg film-coated tablet (Viagra ® ) after single-dose administration to 53 healthy male volunteers (aged 18-51 years) in a randomized, open, two-way crossover bioequivalence study. Each subject received a single oral dose of 100 mg of sildenafil as test or reference formulation administered under fasting conditions at each of the two study periods according to a randomized crossover design. There was a washout interval of ≥7 days between the two administrations of the investigational medicinal products. Blood samples for pharmacokinetic analysis were collected up to 24 h post-dosing. The primary objective was to compare the rate (peak plasma concentration; C max ) and extent (area under the curve [AUC] from administration to last observed concentration time; AUC 0-t ) of sildenafil absorption after single-dose administration of test and reference. Secondary endpoints were observed to describe the plasma pharmacokinetic profiles of sildenafil and its metabolite N-desmethyl-sildenafil relative bioavailability and safety profile after single-dose administration. The mean sildenafil and N-desmethyl-sildenafil plasma concentration-time profiles up to 24 h after single-dose administration of sildenafil 100 mg orodispersible film and film-coated tablet were nearly superimposable. The bioequivalence test was fully satisfied for sildenafil and N-desmethyl-sildenafil in terms of rate and extent of bioavailability. Adverse events occurred at similar rates for the two formulations and were of mild-to-moderate severity. The results suggest that the new orodispersible film formulation can be used interchangeably with the conventional film-coated formulation.

Bioequivalence study of a new sildenafil 100 mg orodispersible film compared to the conventional film-coated 100 mg tablet administered to healthy male volunteers

PubMed Central

Radicioni, Milko; Castiglioni, Chiara; Giori, Andrea; Cupone, Irma; Frangione, Valeria; Rovati, Stefano

2017-01-01

A new orodispersible film formulation of the phosphodiesterase type 5 inhibitor, sildenafil, has been developed to examine the advantages of an orally disintegrating film formulation and provide an alternative to the current marketed products for the treatment of erectile dysfunction. The pharmacokinetics of the sildenafil 100 mg orodispersible film (IBSA) was compared to that of the conventional marketed 100 mg film-coated tablet (Viagra®) after single-dose administration to 53 healthy male volunteers (aged 18–51 years) in a randomized, open, two-way crossover bioequivalence study. Each subject received a single oral dose of 100 mg of sildenafil as test or reference formulation administered under fasting conditions at each of the two study periods according to a randomized crossover design. There was a washout interval of ≥7 days between the two administrations of the investigational medicinal products. Blood samples for pharmacokinetic analysis were collected up to 24 h post-dosing. The primary objective was to compare the rate (peak plasma concentration; Cmax) and extent (area under the curve [AUC] from administration to last observed concentration time; AUC0–t) of sildenafil absorption after single-dose administration of test and reference. Secondary endpoints were observed to describe the plasma pharmacokinetic profiles of sildenafil and its metabolite N-desmethyl-sildenafil relative bioavailability and safety profile after single-dose administration. The mean sildenafil and N-desmethyl-sildenafil plasma concentration–time profiles up to 24 h after single-dose administration of sildenafil 100 mg orodispersible film and film-coated tablet were nearly superimposable. The bioequivalence test was fully satisfied for sildenafil and N-desmethyl-sildenafil in terms of rate and extent of bioavailability. Adverse events occurred at similar rates for the two formulations and were of mild-to-moderate severity. The results suggest that the new orodispersible film formulation can be used interchangeably with the conventional film-coated formulation. PMID:28442892

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies.

PubMed

Kusawake, Tomohiro; Keirns, James J; Kowalski, Donna; den Adel, Martin; Groenendaal-van de Meent, Dorien; Takada, Akitsugu; Ohtsu, Yoshiaki; Katashima, Masataka

2017-12-01

Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella-zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants. Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5-2400 mg) or daily (300 or 600 mg/day) for 7 days. Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUC inf ) and C max . After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUC inf increased by about 90%. In the bioavailability study, AUC inf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported. Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUC inf almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated. Astellas Pharma. ClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003).

Heavy Ion and Proton Tests for Subsystem Upset.

DTIC Science & Technology

1988-03-21

R. Kennerud, P. Measel , and K. Wahlin, "Transient And Total Dose Radiation Properties Of The CMOS/SOS EPIC Chip Set", IEEE Trans. on Nucl. Sci., Vol...NS-30, No. 6, Dec. 1983 .(3) T. L. Criswell, P. R. Measel , and K. L. Wahlin, "Single Event Upset P Testing With Relativistic Heavy Ions", IEEE Trans

Microcircuit radiation effects databank

NASA Technical Reports Server (NTRS)

1983-01-01

Radiation test data submitted by many testers is collated to serve as a reference for engineers who are concerned with and have some knowledge of the effects of the natural radiation environment on microcircuits. Total dose damage information and single event upset cross sections, i.e., the probability of a soft error (bit flip) or of a hard error (latchup) are presented.

Capture of complexity of specialty care in pediatric cardiology by work RVU measures.

PubMed

Bergersen, Lisa; Gauvreau, Kimberlee; McElhinney, Doff; Fenwick, Sandra; Kirshner, David; Harding, Julie; Hickey, Patricia; Mayer, John; Marshall, Audrey

2013-02-01

We sought to determine the relationship between relative value units (RVUs) and intended measures of work in catheterization for congenital heart disease. RVU was determined by matching RVU values to Current Procedural Terminology codes generated for cases performed at a single institution. Differences in median case duration, radiation exposure, adverse events, and RVU values by risk category and cases were assessed. Interventional case types were ranked from lowest to highest median RVU value, and correlations with case duration, radiation dose, and a cases-predicted probability of an adverse event were quantified with the Spearman rank correlation coefficient. Between January 2008 and December 2010, 3557 of 4011 cases were identified with an RVU and risk category designation, of which 2982 were assigned a case type. Median RVU values, radiation dose, and case duration increased with procedure risk category. Although all diagnostic cases had similar RVU values (median 10), adverse event rates ranged from 6% to 21% by age group (P < .001). Median RVU values ranged from 9 to 54 with the lowest in diagnostic and biopsy cases and increasing with isolated and then multiple interventions. Among interventional cases, no correlation existed between ranked RVU value and case duration, radiation dose, or adverse event probability (P = .13, P = .62, and P = .43, respectively). Time, skill, and stress inherent to performing catheterization procedures for congenital heart disease are not captured by measurement of RVU alone.

Pre-clinical and Clinical Safety Studies of CMX-2043: A Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury

PubMed Central

Kates, Steven A; Lader, Alan S; Casale, Ralph; Beeuwkes, Reinier

2014-01-01

CMX-2043 is an α-lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia–reperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre-clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX-2043 did not bind to a wide range of receptors and specific targets at approximately 4 μg/mL (10 μM). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14-day repeat intravenous doses and in dogs (single intravenous dose) with a 2-week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10 mg/kg, respectively. No serious adverse events were reported in a placebo-controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre-clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX-2043 in a human efficacy trial. PMID:24751172

Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study

PubMed Central

Morain, P; Robin, J L; De Nanteuil, G; Jochemsen, R; Heidet, V; Guez, D

2000-01-01

Aims The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers. Methods This was a double-blind, randomized, placebo-controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection. Results PEP activity in plasma was dose-dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5–2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half-life (t½) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose. Conclusions S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once-daily dosing without any serious adverse events. PMID:11012558

Treatment discontinuation and tolerability as a function of dose and titration of duloxetine in the treatment of major depressive disorder.

PubMed

Harada, Eiji; Shirakawa, Osamu; Satoi, Yoichi; Marangell, Lauren B; Escobar, Rodrigo

2016-01-01

We sought to better understand how dose and titration with duloxetine treatment may impact tolerability and treatment discontinuation in patients with major depressive disorder. We investigated Phase III duloxetine trials. Group 1 was a single placebo-controlled study with a 20 mg initial dose and a slow titration to 40 and 60 mg. Group 2 was a single study with a 40 mg initial dose and final "active" doses of 40 and 60 mg (5 mg control group), with 1-week titration. Group 3 consisted of eight placebo-controlled studies with starting doses of 40, 60, and 80 mg/day with minimal titration (final dose 40-120 mg/day). Tolerability was measured by rate of discontinuation due to adverse events (DCAE). The DCAE in Group 1 were 3.6% in the 60 mg group, 3.3% in the 40 mg group, and 3.2% in the placebo group. In Group 2, the DCAE were 15.0% in the 60 mg group, 8.1% in the 40 mg group, and 4.9% in the 5 mg group. In Group 3, the DCAE were 9.7% and 4.2% in the duloxetine and placebo groups, respectively. This study suggests that starting dose and titration may have impacted tolerability and treatment discontinuation. A lower starting dose of duloxetine and slower titration may contribute to improving treatment tolerability for patients with major depressive disorder.

A strategy to reduce cardiovascular disease by more than 80%

PubMed Central

Wald, N J; Law, M R

2003-01-01

Objectives To determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels. Design We quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta-analysis of 15 trials of low dose (50-125 mg/day) aspirin. Outcome measures Proportional reduction in ischaemic heart disease (IHD) events and strokes; life years gained; and prevalence of adverse effects. Results The formulation which met our objectives was: a statin (for example, atorvastatin (daily dose 10 mg) or simvastatin (40 mg)); three blood pressure lowering drugs (for example, a thiazide, a β blocker, and an angiotensin converting enzyme inhibitor), each at half standard dose; folic acid (0.8 mg); and aspirin (75 mg). We estimate that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%). One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke. Summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation). Conclusion The Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention. PMID:12829553

Urinary symptoms following external beam radiotherapy of the prostate: Dose-symptom correlates with multiple-event and event-count models.

PubMed

Yahya, Noorazrul; Ebert, Martin A; Bulsara, Max; House, Michael J; Kennedy, Angel; Joseph, David J; Denham, James W

2015-11-01

This study aimed to compare urinary dose-symptom correlates after external beam radiotherapy of the prostate using commonly utilised peak-symptom models to multiple-event and event-count models which account for repeated events. Urinary symptoms (dysuria, haematuria, incontinence and frequency) from 754 participants from TROG 03.04-RADAR trial were analysed. Relative (R1-R75 Gy) and absolute (A60-A75Gy) bladder dose-surface area receiving more than a threshold dose and equivalent uniform dose using exponent a (range: a ∈[1 … 100]) were derived. The dose-symptom correlates were analysed using; peak-symptom (logistic), multiple-event (generalised estimating equation) and event-count (negative binomial regression) models. Stronger dose-symptom correlates were found for incontinence and frequency using multiple-event and/or event-count models. For dysuria and haematuria, similar or better relationships were found using peak-symptom models. Dysuria, haematuria and high grade (⩾ 2) incontinence were associated to high dose (R61-R71 Gy). Frequency and low grade (⩾ 1) incontinence were associated to low and intermediate dose-surface parameters (R13-R41Gy). Frequency showed a parallel behaviour (a=1) while dysuria, haematuria and incontinence showed a more serial behaviour (a=4 to a ⩾ 100). Relative dose-surface showed stronger dose-symptom associations. For certain endpoints, the multiple-event and event-count models provide stronger correlates over peak-symptom models. Accounting for multiple events may be advantageous for a more complete understanding of urinary dose-symptom relationships. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects.

PubMed

Liu, Dongyang; Jiang, Ji; Zhang, Li; Tan, Fenlai; Wang, Yingxiang; Zhang, Don; Hu, Pei

2014-04-01

Icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, has proved effectiveness in xenografted nude mice. Purpose of the present studies was to investigate tolerability and pharmacokinetics of Icotinib in healthy subjects for the first time, including dose proportionality, food effect, and tolerability. Two studies were conducted in total of 22 healthy subjects: a randomized, two-Latin-square crossover, dose proportional study (n = 12) and a randomized two-way crossover food-effect study (n = 10). Plasma concentration of Icotinib reached peak at a median Tmax of 0.75-3.5 h after single dose and then declined with a mean t1/2β of 6.02-7.83 h. Over the dose range of 100-600 mg, AUC values were proportional to dose and Cmax showed a slight saturation when dose increases. Only 0.2 % of the dose was excreted through kidney in unchanged Icotinib. After dosing 400 mg of Icotinib with high-fat and high-calorie meal, mean Cmax and AUC were significantly increased by 59 and 79 %, respectively. Three subjects experienced four adverse events (rash, increase in AST and ALT, and external injury). Rash and increased levels of AST and ALT were considered as drug-related. No serious adverse events were reported. The current work demonstrated that Icotinib was well tolerated in healthy male subjects (n = 22) over the dose range of 100-600 mg with or without food. Icotinib exposure, expressed in AUC, was proportionally increased with dose over the above dose range. Food intake significantly increased the absorption and exposure of Icotinib in healthy subjects.

Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial.

PubMed

Dicko, Alassane; Brown, Joelle M; Diawara, Halimatou; Baber, Ibrahima; Mahamar, Almahamoudou; Soumare, Harouna M; Sanogo, Koualy; Koita, Fanta; Keita, Sekouba; Traore, Sekou F; Chen, Ingrid; Poirot, Eugenie; Hwang, Jimee; McCulloch, Charles; Lanke, Kjerstin; Pett, Helmi; Niemi, Mikko; Nosten, François; Bousema, Teun; Gosling, Roly

2016-06-01

Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali. In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification. In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0·125 mg/kg, and 0·5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0·25 mg/kg primaquine or 0·0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin-piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane-feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov, number NCT01743820. Between Jan 2, 2013, and Nov 27, 2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0·25 mg/kg primaquine dose group (n=15) and 0·5 mg/kg primaquine dose group (n=14) had significantly lower mean within-person reductions in infectivity at day 2-92·6% (95% CI 78·3-100; p=0·0014) for the 0·25 mg/kg group; and 75·0% (45·7-100; p=0·014) for the 0·5 mg/kg primaquine group-compared with those in the control group (n=14; 11·3% [-27·4 to 50·0]). Reductions were not significantly different from control for participants assigned to the 0·0625 mg/kg dose group (n=16; 41·9% [1·4-82·5]; p=0·16) and the 0·125 mg/kg dose group (n=12; 54·9% [13·4-96·3]; p=0·096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups. A single dose of 0·25 mg/kg primaquine, given alongside dihydroartemisinin-piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine. Bill & Melinda Gates Foundation. Copyright © 2016 Elsevier Ltd. All rights reserved.

First-in-human trial of the safety, pharmacokinetics and immunogenicity of a PEGylated anti-CD40L antibody fragment (CDP7657) in healthy individuals and patients with systemic lupus erythematosus.

PubMed

Tocoian, A; Buchan, P; Kirby, H; Soranson, J; Zamacona, M; Walley, R; Mitchell, N; Esfandiari, E; Wagner, F; Oliver, R

2015-09-01

The objective of this paper is to investigate the safety, pharmacokinetics (PK) and immunogenicity of CDP7657, a PEGylated anti-CD40L antibody fragment, in healthy individuals and patients with systemic lupus erythematosus (SLE). This randomized, double-blind, single-dose, dose-escalation phase I study consisted of two parts. In part 1, 28 healthy individuals received CDP7657 IV (0.004-5 mg/kg) or placebo. In part 2, 17 patients with SLE received CDP7657 IV (5-60 mg/kg) or placebo. The CDP7657:placebo ratio was 3:1. Adverse events (AEs) were reported by 76% of healthy individuals and 100% of patients with SLE treated with CDP7657; most were mild or moderate in intensity. Two healthy individuals reported serious AEs (SAEs), one of which was considered treatment related (infusion-related reaction; 5 mg/kg cohort). One patient with SLE (60 mg/kg cohort) experienced three SAEs, one of which was considered treatment related (herpes zoster infection). No thromboembolic events were reported. CPD7657 exposure increased in a dose-proportional manner. Low anti-CDP7657 antibody titres were detected in the majority of CDP7657-treated participants with no apparent impact on the PK of CDP7657. Single doses of CDP7657 showed predictable PK in healthy individuals and patients with SLE and were well tolerated, with no safety signals of concern. These findings support further investigation of CDP7657 as a therapy for SLE. © The Author(s) 2015.

Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey

PubMed Central

Hunt, Patricia A.; Lawson, Crystal; Gieske, Mary; Murdoch, Brenda; Smith, Helen; Marre, Alyssa; Hassold, Terry; VandeVoort, Catherine A.

2012-01-01

Widespread use of the endocrine disrupting chemical bisphenol A (BPA) in consumer products has resulted in nearly continuous human exposure. In rodents, low-dose exposures have been reported to adversely affect two distinct stages of oogenesis in the developing ovary: the events of prophase at the onset of meiosis in the fetal ovary and the formation of follicles in the perinatal ovary. Because these effects could influence the reproductive longevity and success of the exposed individual, we conducted studies in the rhesus monkey to determine whether BPA induces similar disturbances in the developing primate ovary. The routes and levels of human exposure are unclear; hence, two different exposure protocols were used: single daily oral doses and continuous exposure via subdermal implant. Our analyses of second trimester fetuses exposed at the time of meiotic onset suggest that, as in mice, BPA induces subtle disturbances in the prophase events that set the stage for chromosome segregation at the first meiotic division. Our analyses of third-trimester fetuses exposed to single daily oral doses during the time of follicle formation revealed an increase in multioocyte follicles analogous to that reported in rodents. However, two unique phenotypes were evident in continuously exposed animals: persistent unenclosed oocytes in the medullary region and small, nongrowing oocytes in secondary and antral follicles. Because effects on both stages of oogenesis were elicited using doses that yield circulating levels of BPA analogous to those reported in humans, these findings raise concerns for human reproductive health. PMID:23012422

A randomized phase II trial evaluating different schedules of zoledronic acid on bone mineral density in patients with prostate cancer beginning androgen deprivation therapy.

PubMed

Lang, Joshua M; Wallace, Marianne; Becker, Jordan T; Eickhoff, Jens C; Buehring, Bjoern; Binkley, Neil; Staab, Mary Jane; Wilding, George; Liu, Glenn; Malkovsky, Miroslav; McNeel, Douglas G

2013-12-01

To assess the effects of timing and schedule of zoledronic acid (ZA) administration on bone mineral density (BMD) in patients beginning androgen deprivation therapy (ADT) for the treatment of recurrent prostate cancer. In this randomized, 3-arm trial, we evaluated changes in BMD after 3 different ZA administration schedules in men with recurrent prostate cancer who were beginning ADT. Forty-four patients were enrolled and randomized to receive a single dose of ZA given 1 week before beginning ADT (arm 1), a single dose of ZA given 6 months after beginning ADT (arm 2), or monthly administration of ZA starting 6 months after beginning ADT, for a total of 6 doses (arm 3). Patients who received ZA before ADT had a significant improvement in BMD at the total proximal femur and trochanter after 6 months compared with the other groups. In addition, only patients in the arm that received multiple doses improved lumbar spine BMD while on ADT, with these findings persisting to 24 months. However, this group also experienced more grade 1 adverse events. Analysis of these data suggests that ZA administration before initiation of ADT was superior to treatment 6 months after starting ADT in maintaining BMD. In addition, monthly ZA administration can increase BMD above baseline but is associated with more adverse events. Further study is needed to examine whether the timing and frequency of ZA therapy in patients on ADT can reduce fracture risk. Copyright © 2013 Elsevier Inc. All rights reserved.

A single subcutaneous dose of tramadol for mild to moderate musculoskeletal trauma in the emergency department

PubMed Central

Cardozo, Alejandro; Silva, Carlos; Dominguez, Luis; Botero, Beatriz; Zambrano, Paulo; Bareno, Jose

2014-01-01

BACKGROUND: Mild to moderate musculoskeletal trauma is a common cause for an emergency room visit, and frequent pain is one of the cardinal symptoms of consultation. The objective of this study is to assess the perception of a single subcutaneous dose of 50 mg tramadol for pain management in patients with mild to moderate musculoskeletal trauma, likewise to appraise the perception of pain by subcutaneous injection. METHODS: A total of 77 patients, who met inclusion criteria, received a single subcutaneous dose of tramadol. Pain control was evaluated based on the verbal numerical pain scale (0–10) at baseline, 20 and 60 minutes; similarly, pain perception was evaluated secondary to subcutaneous injection of the analgesic. RESULTS: On admission, the average pain perceived by patients was 8; twenty minutes later, 89% of the patients reported five or less, and after sixty minutes, 94% had three or less on the verbal numerical pain scale. Of the patients, 88% reported pain perception by verbal numeric scale of 3 or less by injection of the drug, and 6.5% required a second analgesic for pain control. Two events with drug administration (soft tissue infection and mild abdominal rectus injection) were reported. CONCLUSION: We conclude that a single subcutaneous dose of tramadol is a safe and effective option for the management of patients with mild to moderate pain and musculoskeletal disease in the emergency department. PMID:25548601

Optimizing a readout protocol for low dose retrospective OSL-dosimetry using household salt.

PubMed

Christiansson, Maria; Mattsson, Sören; Bernhardsson, Christian; Rääf, Christopher L

2012-06-01

The authors' aim has been to find a single aliquot regenerative dose (SAR) protocol that accurately recovers an unknown absorbed dose in the region between 1-250 mGy in household salt. The main investigation has been conducted on a specific mine salt (>98.5% NaCl) intended for household use, using optical stimulation by blue LED (λ = 462 nm). The most accurate dose recovery for this brand of salt is found to be achieved when using Peak Signal Summing (PSS) of the OSL-decay and a preheat temperature of 200°C after the test dose. A SAR protocol for the household salt with preset values of regenerative doses (R1--R5) and a test dose (TED) of 17 mGy is also suggested here. Under laboratory conditions, the suggested protocol recovers unknown absorbed doses in this particular brand within 5% (2 SD) in the dose range between 1-250 mGy. This is a very promising result for low dose applications of household salt as a retrospective dosimeter after a nuclear or radiological event.

Tafenoquine for preventing relapse in people with Plasmodium vivax malaria.

PubMed

Rajapakse, Senaka; Rodrigo, Chaturaka; Fernando, Sumadhya Deepika

2015-04-29

Plasmodium vivax malaria is widespread, and the persistent liver stage causes relapse of the disease which contributes to continued P. vivax transmission. Primaquine is currently the only drug that cures the parasite liver stage, but requires 14 days to be effective and can cause haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, there is some evidence of parasite resistance to the drug. Tafenoquine is a new alternative with a longer half-life. To assess the effects of tafenoquine in people with P. vivax infection. We searched the following databases up to 13 April 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; CINAHL; SCOPUS; and LILACS. We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials using "tafenoquine" and "malaria" as search terms up to 13 April 2015. Randomized controlled trials (RCTs) in people with P. vivax malaria. Adverse effects of tafenoquine are assessed in populations where people with G6PD deficiency have been excluded, and in populations without screening for G6PD deficiency. All review authors independently extracted data and assessed trial quality. Meta-analysis was carried out where appropriate, and estimates given as relative risk with 95% confidence intervals. We assessed the quality of the evidence using the GRADE approach. Three RCTs met our inclusion criteria, with the asexual infection in both the tafenoquine and comparator arm treated with chloroquine, and in all trials G6PD deficiency patients were excluded. Tafenoquine dose comparisonsThree of the included trials compared eight different dosing regimens. Tafenoquine doses of 300 mg and above resulted in fewer relapses than no hypnozoite treatment over six months follow-up in adults (300 mg single dose: RR 0.19, 95% CI 0.08 to 0.41, one trial, 110 participants, moderate quality evidence; 500 to 600 mg single dose: RR 0.14, 95%CI 0.06 to 0.34, two trials, 122 participants, moderate quality evidence; 1800 mg to 3000 mg in divided doses: RR 0.05, 95% CI 0.01 to 0.23, two trials, 63 participants, low quality evidence).In people with normal G6PD status, there may be little or no difference in serious adverse events (three trials, 358 participants, low quality evidence); or any adverse event (one trial, 272 participants, low quality evidence). Tafenoquine versus primaquine Two of the included trials compared four different dosing regimens of tafenoquine against the standard primaquine regimen of 15 mg/day for 14 days. A single tafenoquine dose of 600 mg may be more effective than primaquine in relation to relapses at six months follow-up (RR 0.29, 95% CI 0.10 to 0.84, two trials, 98 participants, low quality evidence)In people with normal G6PD status, there may be little or no difference for serious adverse events (two trials, 323 participants, low quality evidence) or any adverse event (two trials, 323 participants, low quality evidence) between tafenoquine and primaquine. Tafenoquine prevents relapses after clinically and parasitologically confirmed P. vivax malaria. The drug is untested in pregnancy, children and in G6PD-deficient people. The shorter treatment course is an important practical advantage in people who do not have G6PD deficiency, but the longer half-life may have more substantive consequences if given inadvertently to people with G6PD deficiency.

Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study.

PubMed

Sankaranarayanan, Rengaswamy; Joshi, Smita; Muwonge, Richard; Esmy, Pulikottil Okkuru; Basu, Partha; Prabhu, Priya; Bhatla, Neerja; Nene, Bhagwan M; Shaw, Janmesh; Poli, Usha Rani Reddy; Verma, Yogesh; Zomawia, Eric; Pimple, Sharmila; Tommasino, Massimo; Pawlita, Michael; Gheit, Tarik; Waterboer, Tim; Sehr, Peter; Pillai, Madhavan Radhakrishna

2018-03-15

Human papillomavirus (HPV) vaccination is a major strategy for preventing cervical and other ano-genital cancers. Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to 'no vaccination'. In a multi-centre cluster randomized trial of two vs three doses of quadrivalent HPV vaccination (Gardasil™) in India, suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10-18 year old girls leading to four study groups, two by design and two by default. They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity for the vaccine-targeted HPV types and HPV infections. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. Of the 17,729 vaccinated girls, 4348 (25%) received three doses on days 1, 60, 180 or later, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses on days 1 and 60, and 4950 (28%) received one dose. One dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18, albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period. The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients. The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women. Our results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules, although the study suffer from some limitations. Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented. Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current standard of care for cervical cancer prevention is 'no intervention'. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Plitidepsin Has a Safe Cardiac Profile: A Comprehensive Analysis

PubMed Central

Soto-Matos, Arturo; Szyldergemajn, Sergio; Extremera, Sonia; Miguel-Lillo, Bernardo; Alfaro, Vicente; Coronado, Cinthya; Lardelli, Pilar; Roy, Elena; Corrado, Claudia Silvia; Kahatt, Carmen

2011-01-01

Plitidepsin is a cyclic depsipeptide of marine origin in clinical development in cancer patients. Previously, some depsipeptides have been linked to increased cardiac toxicity. Clinical databases were searched for cardiac adverse events (CAEs) that occurred in clinical trials with the single-agent plitidepsin. Demographic, clinical and pharmacological variables were explored by univariate and multivariate logistic regression analysis. Forty-six of 578 treated patients (8.0%) had at least one CAE (11 patients (1.9%) with plitidepsin-related CAEs), none with fatal outcome as a direct consequence. The more frequent CAEs were rhythm abnormalities (n = 31; 5.4%), mostly atrial fibrillation/flutter (n = 15; 2.6%). Of note, life-threatening ventricular arrhythmias did not occur. Myocardial injury events (n = 17; 3.0%) included possible ischemic-related and non-ischemic events. Other events (miscellaneous, n = 6; 1.0%) were not related to plitidepsin. Significant associations were found with prostate or pancreas cancer primary diagnosis (p = 0.0017), known baseline cardiac risk factors (p = 0.0072), myalgia present at baseline (p = 0.0140), hemoglobin levels lower than 10 g/dL (p = 0.0208) and grade ≥2 hypokalemia (p = 0.0095). Treatment-related variables (plitidepsin dose, number of cycles, schedule and/or total cumulative dose) were not associated. Electrocardiograms performed before and after plitidepsin administration (n = 136) detected no relevant effect on QTc interval. None of the pharmacokinetic parameters analyzed had a significant impact on the probability of developing a CAE. In conclusion, the most frequent CAE type was atrial fibrillation/atrial flutter, although its frequency was not different to that reported in the age-matched healthy population, while other CAEs types were rare. No dose-cumulative pattern was observed, and no treatment-related variables were associated with CAEs. Relevant risk factors identified were related to the patient’s condition and/or to disease-related characteristics rather than to drug exposure. Therefore, the current analysis supports a safe cardiac risk profile for single-agent plitidepsin in cancer patients. PMID:21747745

Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites.

PubMed

Mahipal, Amit; Klapman, Jason; Vignesh, Shivakumar; Yang, Chung S; Neuger, Anthony; Chen, Dung-Tsa; Malafa, Mokenge P

2016-07-01

Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects. Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC. No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4-9.3 and 4.7-7.3 h, maximum concentration of 795.6-3742.6 and 493.3-3746 ng/mL, half-life of 1.7-5.9 and 2.3-6.9 h, and 0-12 h area under the curve of 4518.7-20,781.4 and 1987.7-22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30-60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed. Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.

Methylphenidate, cognition, and epilepsy: A double-blind, placebo-controlled, single-dose study.

PubMed

Adams, Jesse; Alipio-Jocson, Valerie; Inoyama, Katherine; Bartlett, Victoria; Sandhu, Saira; Oso, Jemima; Barry, John J; Loring, David W; Meador, Kimford

2017-01-31

To evaluate the potential efficacy of immediate-release methylphenidate (MPH) for treating cognitive deficits in epilepsy. This was a double-blind, randomized, single-dose, 3-period crossover study in patients with epilepsy and chronic cognitive complaints comparing the effects of placebo and MPH 10 and 20 mg given 1 week apart. Cognitive outcome was evaluated on the basis of an omnibus z score calculated from performance on the Conners Continuous Performance Test 3 (ability to discriminate between target and nontarget stimuli [d'] and hit reaction time standard deviation), Symbol-Digit Modalities Test, and Medical College of Georgia Paragraph Memory Test. Adverse events and seizure frequency were monitored. An open-label follow-up is reported elsewhere. Thirty-five adult patients with epilepsy participated, of whom 31 finished. Demographics included the following: mean age = 35.3 years (range 20-62 years), 13 men and 18 women, and baseline seizure frequency of 2.8 per month. Epilepsy types were focal (n = 24), generalized (n = 6), or unclassified (n = 1). Mean epilepsy duration was 12.5 years. A statistically significant performance benefit was present at both 10-mg (p = 0.030) and 20-mg (p = 0.034) MPH doses. No seizures were associated with either MPH dose. Adverse effects leading to withdrawal included cognitive "fogginess" (n = 1 on 20 mg), anxiety/agitation (n = 1 on 10 mg), and tachycardia (n = 1). One participant was lost to follow-up after one 20-mg dose without side effect. This single-dose study suggests that MPH may be effective in ameliorating some cognitive deficits in patients with epilepsy. Additional studies are required. NCT02178995. This study provides Class II evidence that single doses of MPH improve cognitive performance on some measures of attention and processing speed in patients with epilepsy and cognitive complaints. © 2016 American Academy of Neurology.

Safety, Tolerability and Pharmacokinetics of Single Doses of Oxytocin Administered via an Inhaled Route in Healthy Females: Randomized, Single-blind, Phase 1 Study.

PubMed

Fernando, Disala; Siederer, Sarah; Singh, Sunita; Schneider, Ian; Gupta, Ashutosh; Powell, Marcy; Richards, Duncan; McIntosh, Michelle P; Lambert, Peter; Fowles, Susan

2017-08-01

The utility of intramuscular (IM) oxytocin for the prevention of postpartum hemorrhage in resource-poor settings is limited by the requirement for temperature-controlled storage and skilled staff to administer the injection. We evaluated the safety, tolerability and pharmacokinetics (PK) of a heat-stable, inhaled (IH) oxytocin formulation. This phase 1, randomized, single-center, single-blind, dose-escalation, fixed-sequence study (NCT02542813) was conducted in healthy, premenopausal, non-pregnant, non-lactating women aged 18-45years. Subjects initially received IM oxytocin 10 international units (IU) on day 1, IH placebo on day 2, and IH oxytocin 50μg on day 3. Subjects were then randomized 4:1 using validated GSK internal software to IH placebo or ascending doses of IH oxytocin (200, 400, 600μg). PK was assessed by comparing systemic exposure (maximum observed plasma concentration, area under the concentration-time curve, and plasma concentrations at 10 and 30min post dose) for IH versus IM oxytocin. Adverse events (AEs), spirometry, laboratory tests, vital signs, electrocardiograms, physical examinations, and cardiac telemetry were assessed. Subjects were recruited between September 14, 2015 and October 12, 2015. Of the 16 subjects randomized following initial dosing, 15 (IH placebo n=3; IH oxytocin n=12) completed the study. IH (all doses) and IM oxytocin PK profiles were comparable in shape. However, systemic exposure with IH oxytocin 400μg most closely matched IM oxytocin 10IU. Systemic exposure was approximately dose proportional for IH oxytocin. No serious AEs were reported. No clinically significant findings were observed for any safety parameters. These data suggest that similar oxytocin systemic exposure can be achieved with IM and IH administration routes, and no safety concerns were identified with either route. The inhalation route may offer the opportunity to increase access to oxytocin for women giving birth in resource-poor settings. Copyright © 2017. Published by Elsevier B.V.

Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Digoxin in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy.

PubMed

Zhang, Weijiang; McIntyre, Christine; Kuhn, Melissa; Forbes, Harper; Kim, Tae Min; Lee, Jeeyun; Demidov, Lev; Colburn, Dawn

2018-04-12

The primary objective of this phase 1, open-label, multicenter, 3-period, fixed-sequence study was to evaluate the effect of multiple doses of vemurafenib on the pharmacokinetics of a single dose of digoxin, a probe P-glycoprotein (P-gp) substrate, in patients with BRAF V600 mutation-positive metastatic malignancy. Following a 28-day screening period, patients received a single oral dose of digoxin 0.25 mg on day 1 in period A, oral vemurafenib 960 mg twice daily for 21 days in period B (days 8-28), and a single oral dose of digoxin 0.25 mg on day 29 and vemurafenib 960 mg twice a day for 7 days (days 29-35) in period C. Log-transformed area under the concentration-time curve and peak concentration values for digoxin were compared between periods A (digoxin alone) and C (digoxin + vemurafenib) using an analysis of variance model. Twenty-six patients were evaluated for the primary pharmacokinetic analysis. The geometric mean ratio (period C/period A) of area under the curve to the last measurable concentration for digoxin was 1.82 (90%CI 1.63 to 2.02), and the geometric mean ratio of peak concentrations was 1.47 (90%CI 1.30 to 1.65); the 90%CIs were outside of the equivalence limits of 0.82 to 1.22, indicating an effect of vemurafenib on digoxin. Multiple oral doses of vemurafenib were generally well tolerated, with an adverse event profile similar to that previously seen in phase 2 and 3 studies of vemurafenib monotherapy. This study confirmed vemurafenib as an inhibitor of P-gp in vivo with a statistically significant drug-drug interaction with digoxin. Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates. © 2018, The American College of Clinical Pharmacology.

Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

PubMed

Han, Yi; Ayalasomayajula, Surya; Pan, Wei; Yang, Fan; Yuan, Yaozong; Langenickel, Thomas; Hinder, Markus; Kalluri, Sampath; Pal, Parasar; Sunkara, Gangadhar

2017-02-01

Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max ) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2 ) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC 0-last ), and maximum plasma concentration (C max ) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy

PubMed Central

Ricotti, Valeria; Spinty, Stefan; Roper, Helen; Hughes, Imelda; Tejura, Bina; Robinson, Neil; Layton, Gary; Davies, Kay

2016-01-01

Purpose SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration ClinicalTrials.gov NCT02383511 PMID:27055247

Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.

PubMed

Ito, Yoshinori; Suenaga, Mitsukuni; Hatake, Kiyohiko; Takahashi, Shunji; Yokoyama, Masahiro; Onozawa, Yusuke; Yamazaki, Kentaro; Hironaka, Shuichi; Hashigami, Kiyoshi; Hasegawa, Hirotaka; Takenaka, Nobuko; Boku, Narikazu

2012-04-01

Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors. Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses. Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose. The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.

Oral and Inactivated Poliovirus Vaccines in the Newborn: A review

PubMed Central

Mateen, Farrah J.; Shinohara, Russell T.; Sutter, Roland W.

2015-01-01

Background Oral poliovirus vaccine (OPV) remains the vaccine-of-choice for routine immunization and supplemental immunization activities (SIAs) to eradicate poliomyelitis globally. Recent data from India suggested lowerthanexpected immunogenicity of an OPV birth dose, prompting a review of the immunogenicity of OPV or inactivated poliovirus vaccine (IPV) when administered at birth. Methods We evaluated the seroconversion and reported adverse events among infants given a single birth dose (given ≤7 days of life) of OPV or IPV through a systematic review of published articles and conference abstracts from 1959-2011 in any language found on PubMed, Google Scholar, or reference lists of selected articles. Results 25 articles from 13 countries published between1959 and 2011 documented seroconversion rates in newborns following an OPV dose given within the first seven days of life. There were 10 studies that measured seroconversion rates between 4 and 8 weeks of a single birth dose of TOPV, using an umbilical cord blood draw at the time of birth to establish baseline antibody levels. The percentage of newborns who seroconverted at 8 weeks range 6-42% for poliovirus type 1, 2-63% for type 2, and 1-35% for type 3). For mOPV type 1, seroconversion ranged from 10-76%; mOPV type 3, the range was 12-58%; and for the one study reporting bOPV, it was 20% for type 1 and 7% for type 3. There were four studies of IPV in newborns with a seroconversion rate of 8-100% for serotype 1, 15-100% for serotype 2, and 15-94% for serotype 3, measured at 4-6 weeks of life. No serious adverse events related to newborn OPV or IPV dosing were reported, including no cases of acute flaccid paralysis. Conclusions There is great variability of the immunogenicity of a birth dose of OPV for reasons largely unknown. Our review confirms the utility of a birth dose of OPV, particularly in countries where early induction of polio immunity is imperative. IPV has higher seroconversion rates in newborns and may be a superior choice in countries which can afford IPV, but there have been studies of an IPV dose for newborns. PMID:22728224

PDSOI and Radiation Effects: An Overview

NASA Technical Reports Server (NTRS)

Forgione, Joshua B.

2005-01-01

Bulk silicon substrates are a common characteristic of nearly all commercial, Complementary Metal-Oxide-Semiconductor (CMOS), integrated circuits. These devices operate well on Earth, but are not so well received in the space environment. An alternative to bulk CMOS is the Silicon-On-Insulator (SOI), in which a &electric isolates the device layer from the substrate. SO1 behavior in the space environment has certain inherent advantages over bulk, a primary factor in its long-time appeal to space-flight IC designers. The discussion will investigate the behavior of the Partially-Depleted SO1 (PDSOI) device with respect to some of the more common space radiation effects: Total Ionized Dose (TID), Single-Event Upsets (SEUs), and Single-Event Latchup (SEL). Test and simulation results from the literature, bulk and epitaxial comparisons facilitate reinforcement of PDSOI radiation characteristics.

Potential impact of single-risk-factor versus total risk management for the prevention of cardiovascular events in Seychelles

PubMed Central

Ndindjock, Roger; Gedeon, Jude; Mendis, Shanthi; Paccaud, Fred

2011-01-01

Abstract Objective To assess the prevalence of cardiovascular (CV) risk factors in Seychelles, a middle-income African country, and compare the cost-effectiveness of single-risk-factor management (treating individuals with arterial blood pressure ≥ 140/90 mmHg and/or total serum cholesterol ≥ 6.2 mmol/l) with that of management based on total CV risk (treating individuals with a total CV risk ≥ 10% or ≥ 20%). Methods CV risk factor prevalence and a CV risk prediction chart for Africa were used to estimate the 10-year risk of suffering a fatal or non-fatal CV event among individuals aged 40–64 years. These figures were used to compare single-risk-factor management with total risk management in terms of the number of people requiring treatment to avert one CV event and the number of events potentially averted over 10 years. Treatment for patients with high total CV risk (≥ 20%) was assumed to consist of a fixed-dose combination of several drugs (polypill). Cost analyses were limited to medication. Findings A total CV risk of ≥ 10% and ≥ 20% was found among 10.8% and 5.1% of individuals, respectively. With single-risk-factor management, 60% of adults would need to be treated and 157 cardiovascular events per 100 000 population would be averted per year, as opposed to 5% of adults and 92 events with total CV risk management. Management based on high total CV risk optimizes the balance between the number requiring treatment and the number of CV events averted. Conclusion Total CV risk management is much more cost-effective than single-risk-factor management. These findings are relevant for all countries, but especially for those economically and demographically similar to Seychelles. PMID:21479093

First-In-Human, Double-Blind, Placebo-Controlled, Randomized, Dose-Escalation Study of BG00010, a Glial Cell Line-Derived Neurotrophic Factor Family Member, in Subjects with Unilateral Sciatica.

PubMed

Rolan, Paul E; O'Neill, Gilmore; Versage, Eve; Rana, Jitesh; Tang, Yongqiang; Galluppi, Gerald; Aycardi, Ernesto

2015-01-01

To evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica. This was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier NCT00961766; funded by Biogen Idec). Adults with unilateral sciatica were enrolled at The Royal Adelaide Hospital, Australia. Four subjects were assigned to each of eleven cohorts (intravenous BG00010 0.3, 1, 3, 10, 25, 50, 100, 200, 400, or 800 μg/kg, or subcutaneous BG00010 50 μg/kg) and were randomized 3:1 to receive a single dose of BG00010 or placebo. The primary safety and tolerability assessments were: adverse events; clinical laboratory parameters and vital signs; pain as measured by a Likert rating scale; intra-epidermal nerve fiber density; and longitudinal assessment of quantitative sensory test parameters. Blood, serum, and plasma samples were collected for pharmacokinetic and pharmacodynamic assessments. Subjects were blinded to treatment assignment throughout the study. The investigator was blinded to treatment assignment until the Data Safety Review Committee review of unblinded data, which occurred after day 28. Beyond the planned enrollment of 44 subjects, four additional subjects were enrolled into to the intravenous BG00010 200 μg/kg cohort after one original subject experienced mild generalized pruritus. Therefore, a total of 48 subjects were enrolled between August 2009 and December 2011; all were included in the safety analyses. BG00010 was generally well tolerated: in primary analyses, the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache; no trends were observed in clinical laboratory parameters, vital signs, intra-epidermal nerve fiber density, or quantitative sensory testing. BG00010 was not associated with any clear, dose-dependent trends in Likert pain scores. BG00010 was rapidly distributed, with a prolonged terminal elimination phase. These data support the development of BG00010 for the treatment of neuropathic pain. ClinicalTrials.gov NCT00961766.

Differential and Dose-Dependent Inflammatory Responses in a Mouse Model of Respirable Instillation of Environmental Diesel, Emission-Source Diesel , Emmission-Source Diesel and Ambient Air Pollution Particles In Vivo.

EPA Science Inventory

Rationale: Previously, we found that ambient particulate matter (APM) activates pulmonary dendritic cells in vitro. We hypothesized that single acute exposures to PM would promote inflammatory activation of the lung in vivo and provide information on early immunological events of...

Radiation Environment Effects on Spacecraft

NASA Technical Reports Server (NTRS)

Ladbury, Ray.

2017-01-01

Space poses a variety of radiation hazards. These hazards pose different risks for different missions depending on the mission environment, duration and requirements. This presentation presents a brief look at several radiation related hazards, including destructive and nondestructive Single-Event Effect, Total Ionizing Dose, Displacement Damage and Spacecraft Charging. The temporal and spatial characteristics for the environments of concern for each are considered.

Total Ionizing Dose Influence on the Single-Event Upset Sensitivity of 130-nm PD SOI SRAMs

NASA Astrophysics Data System (ADS)

Zheng, Qiwen; Cui, Jiangwei; Liu, Mengxin; Zhou, Hang; Liu, Mohan; Wei, Ying; Su, Dandan; Ma, Teng; Lu, Wu; Yu, Xuefeng; Guo, Qi; He, Chengfa

2017-07-01

Effect of total ionizing dose (TID) on single-event upset (SEU) hardness of 130 nm partially depleted (PD) silicon-on-insulator (SOI) static random access memories (SRAMs) is investigated in this paper. The measurable synergistic effect of TID on SEU sensitivity of 130-nm PD SOI SRAM was observed in our experiment, even though that is far less than micrometer and submicrometer devices. Moreover, SEU cross section after TID irradiation has no dependence on the data pattern that was applied during TID exposure: SEU cross sections are characterized by TID data pattern and its complement data pattern are decreased consistently rather than a preferred state and a nonpreferred state as micrometer and sub-micrometer SRAMs. The memory cell test structure allowing direct measurement of static noise margin (SNM) under standby operation was designed using identical memory cell layout of SRAM. Direct measurement of the memory cell SNM shows that both data sides' SNM is decreased by TID, indicating that SEU cross section of 130-nm PD SOI SRAM will be increased by TID. And, the decreased SNM is caused by threshold shift in memory cell transistors induced by “radiation-induced narrow channel effect”.

Pharmacokinetics and physiologic effects of alprazolam after a single oral dose in healthy mares.

PubMed

Wong, D M; Davis, J L; Alcott, C J; Hepworth-Warren, K L; Galow-Kersh, N L; Rice, S; Coetzee, J F

2015-06-01

The objective of this study was to evaluate the pharmacokinetic properties and physiologic effects of a single oral dose of alprazolam in horses. Seven adult female horses received an oral administration of alprazolam at a dosage of 0.04 mg/kg body weight. Blood samples were collected at various time points and assayed for alprazolam and its metabolite, α-hydroxyalprazolam, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of alprazolam was analyzed by a one-compartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single-dose administration of alprazolam were as follows: Cmax 14.76 ± 3.72 ng/mL and area under the curve (AUC0-∞ ) 358.77 ± 76.26 ng·h/mL. Median (range) Tmax was 3 h (1-12 h). Alpha-hydroxyalprazolam concentrations were detected in each horse, although concentrations were low (Cmax 1.36 ± 0.28 ng/mL). Repeat physical examinations and assessment of the degree of sedation and ataxia were performed every 12 h to evaluate for adverse effects. Oral alprazolam tablets were absorbed in adult horses and no clinically relevant adverse events were observed. Further evaluation of repeated dosing and safety of administration of alprazolam to horses is warranted. © 2014 John Wiley & Sons Ltd.

Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D6*10 allele.

PubMed

Cui, Yi M; Teng, Choo H; Pan, Alan X; Yuen, Eunice; Yeo, Kwee P; Zhou, Ying; Zhao, Xia; Long, Amanda J; Bangs, Mark E; Wise, Stephen D

2007-10-01

To characterize atomoxetine pharmacokinetics, explore the effect of the homozygous CYP2D6*10 genotype on atomoxetine pharmacokinetics and evaluate the tolerability of atomoxetine, in healthy Chinese subjects. Twenty-four subjects, all CYP2D6 extensive metabolizers (EM), were randomized to receive atomoxetine (40 mg qd for 3 days, then 80 mg qd for 7 days) or matching placebo (2 : 1 ratio) in a double-blind fashion. Atomoxetine serum concentrations were measured following single (40 mg) and multiple (80 mg) doses. Adverse events, clinical safety laboratory data and vital signs were assessed during the study. Atomoxetine was rapidly absorbed with median time to maximum serum concentrations of approximately 1.5 h after single and multiple doses. Atomoxetine concentrations appeared to decrease monoexponentially with a mean apparent terminal half-life (t(1/2)) of approximately 4 h. The apparent clearance, apparent volume of distribution and t(1/2) following single and multiple doses were similar, suggesting linear pharmacokinetics with respect to time. Homozygous CYP2D6*10 subjects had 50% lower clearances compared with other EM subjects, resulting in twofold higher mean exposures. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. The pharmacokinetics of atomoxetine in healthy Chinese subjects appears comparable to other ethnic populations. Multiple dosing of 80 mg qd atomoxetine was well tolerated in this study.

Adverse effects of mefloquine for the treatment of uncomplicated malaria in Thailand: A pooled analysis of 19, 850 individual patients.

PubMed

Lee, Sue J; Ter Kuile, Feiko O; Price, Ric N; Luxemburger, Christine; Nosten, François

2017-01-01

Mefloquine (MQ) has been used for the treatment of malaria since the mid-1980s, first as monotherapy or as fixed combination with sulfadoxine-pyrimethamine (MSP) and since the mid-1990s in combination with artesunate. There is a renewed interested in MQ as part of a triple therapy for the treatment of multi-drug resistance P. falciparum malaria. The widespread use of MQ beyond south-East Asia has been constrained by reports of poor tolerability. Here we present the side effect profile of MQ for the treatment of uncomplicated malaria on the Thai-Myanmar/Cambodia borders. In total 19,850 patients received seven different regimens containing either 15 or 24-25 mg/kg of MQ, the latter given either as a single dose, or split over two or three days. The analysis focused on (predominantly) gastrointestinal and neuropsychiatric events as compared to the new fixed dose combination of MQ plus artesunate given as equal doses of 8 mg/kg MQ per day over three days. Gastrointestinal side effects were dose-dependent and associated with the severity of malaria symptoms. Serious neuropsychiatric side effects associated with MQ use were rare: for a single 25 mg/kg dose it was 11.9 per 10,000 treatments (95% confidence interval, CI, 4-285) vs. 7.8 (3-15) for the 15 mg/kg dose. The risk with 25 mg/kg was much higher when it was given as repeat dosing in patients who had failed treatment with 15 mg/kg MQ in the preceding month; (RR 6.57 (95% CI 1.33 to 32.4), p = 0.0077). MQ was best tolerated as 15 mg/kg or as 24 mg/kg when given over three days in combination with artesunate. We conclude that the tolerance of a single dose of MQ in the treatment of uncomplicated malaria is moderate, but can be improved by administering it as a split dose over three days.

Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial.

PubMed

Battelino, Tadej; Rasmussen, Michael Højby; De Schepper, Jean; Zuckerman-Levin, Nehama; Gucev, Zoran; Sävendahl, Lars

2017-10-01

To evaluate the safety, local tolerability, pharmacodynamics and pharmacokinetics of escalating single doses of once-weekly somapacitan, a reversible, albumin-binding GH derivative, vs once-daily GH in children with GH deficiency (GHD). Phase 1, randomized, open-label, active-controlled, dose-escalation trial (NCT01973244). Thirty-two prepubertal GH-treated children with GHD were sequentially randomized 3:1 within each of four cohorts to a single dose of somapacitan (0.02, 0.04, 0.08 and 0.16 mg/kg; n=6 each), or once-daily Norditropin ® SimpleXx ® (0.03 mg/kg; n=2 each) for 7 days. Pharmacokinetic and pharmacodynamic profiles were assessed. Adverse events were all mild, and there were no apparent treatment-dependent patterns in type or frequency. Four mild transient injection site reactions were reported in three of 24 children treated with somapacitan. No antisomapacitan/anti-human growth hormone (hGH) antibodies were detected. Mean serum concentrations of somapacitan increased in a dose-dependent but nonlinear manner: maximum concentration ranged from 21.8 ng/mL (0.02 mg/kg dose) to 458.4 ng/mL (0.16 mg/kg dose). IGF-I and IGFBP-3, and change from baseline in IGF-I standard deviation score (SDS) and IGFBP-3 SDS, increased dose dependently; greatest changes in SDS values were seen for 0.16 mg/kg. IGF-I SDS values were between -2 and +2 SDS, except for peak IGF-I SDS with 0.08 mg/kg somapacitan. Postdosing, IGF-I SDS remained above baseline levels for at least 1 week. Single doses of once-weekly somapacitan (0.02-0.16 mg/kg) were well tolerated in children with GHD, with IGF-I profiles supporting a once-weekly treatment profile. No clinically significant safety/tolerability signals or immunogenicity concerns were identified. © 2017 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.

A clinical trial of malaria prophylaxis using a single dose of chloroquine at different intervals in an endemic malarious area.

PubMed

Karunakaran, C S

1980-10-01

A controlled trial of chloroquine prophylaxis was carried out to find whether this drug could be administered at intervals longer than the conventional ones recommended, in endemic malarious areas. Statistically significant results obtained show that chloroquine at suitable doses could be used successfully at intervals of 3 months. The possibility of chloroquine and acquired immunity acting together synergistically is discussed. The author is of the opinion that with this dose regime, the community would still be able to build up substantial immunity, so that in the event of the drug being discontinued, the community would not be faced with the problem of overwhelming malarial infections. The various advantages in using this regime are also considered.

Pharmacokinetics, Safety, and Tolerability of a Single 500-mg or 1000-mg Intravenous Dose of Dalbavancin in Healthy Japanese Subjects.

PubMed

Scoble, Patrick J; Owens, Robert C; Puttagunta, Sailaja; Yen, Mark; Dunne, Michael W

2015-12-01

Dalbavancin is a novel, once-weekly glycopeptide antibiotic approved for treatment of acute bacterial skin infections. Given the importance of understanding any pharmacokinetic variability across different patient populations, a double-blind, placebo-controlled study was conducted to evaluate the pharmacokinetics, safety, and tolerability of a single 500-mg and a single 1000-mg intravenous dose of dalbavancin in healthy Japanese subjects. Ten subjects received intravenous dalbavancin 1000 mg, five subjects received intravenous dalbavancin 500 mg, and three subjects received intravenous placebo. After a single infusion of dalbavancin, the maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC) increased in a proportional manner from 500 mg to 1000 mg (C max: 157 μg/ml and 299 μg/ml; AUClast: 10,850 μg·h/ml and 22,679 μg·h/ml, on the 500-mg and 1000-mg regimens, respectively) with low inter-subject variability. The mean terminal phase half-life (t 1/2) was 204 and 193 h after the 500-mg and 1000-mg dose, respectively. Clearance and volume of distribution were similar for the two dose concentrations. Treatment-emergent adverse events reported were considered to be of mild intensity. There were no relevant changes in laboratory values or vital signs over time in subjects in either treatment group. Overall, dalbavancin 500 mg and dalbavancin 1000 mg, administered as a single 30-min infusion, was well tolerated in this population and resulted in plasma exposures similar to those in non-Asians.

Nasal decongestants in monotherapy for the common cold.

PubMed

Deckx, Laura; De Sutter, An Im; Guo, Linda; Mir, Nabiel A; van Driel, Mieke L

2016-10-17

Many treatments for the common cold exist and are sold over-the-counter. Nevertheless, evidence on the effectiveness and safety of nasal decongestants is limited. To assess the efficacy, and short- and long-term safety, of nasal decongestants used in monotherapy to alleviate symptoms of the common cold in adults and children. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 6, June 2016), which contains the Cochrane Acute Respiratory Infections (ARI) Specialised Register, MEDLINE (1946 to July 2016), Embase (2010 to 15 July 2016), CINAHL (1981 to 15 July 2016), LILACS (1982 to July 2016), Web of Science (1955 to July 2016) and clinical trials registers. Randomised controlled trials (RCTs) and cluster-RCTs investigating the effectiveness and adverse effects of nasal decongestants compared with placebo for treating the common cold in adults and children. We excluded quasi-RCTs. Three review authors independently extracted and summarised data on subjective measures of nasal congestion, overall patient well-being score, objective measures of nasal airway resistance, adverse effects and general recovery. One review author acted as arbiter in cases of disagreement. We categorised trials as single and multi-dose and analysed data both separately and together. We also analysed studies using an oral or topical nasal decongestant separately and together. We included 15 trials with 1838 participants. Fourteen studies included adult participants only (aged 18 years and over). In six studies the intervention was a single dose and in nine studies multiple doses were used. Nine studies used pseudoephedrine and three studies used oxymetazoline. Other decongestants included phenylpropanolamine, norephedrine and xylometazoline. Phenylpropanolamine (or norephedrine) is no longer available on the market therefore we did not include the results of these studies in the meta-analyses. Eleven studies used oral decongestants; four studies used topical decongestants.Participants were included after contracting the common cold. The duration of symptoms differed among studies; in 10 studies participants had symptoms for less than three days, in three studies symptoms were present for less than five days, one study counted the number of colds over one year, and one study experimentally induced the common cold. In the single-dose studies, the effectiveness of a nasal decongestant was measured on the same day, whereas the follow-up in multi-dose studies ranged between one and 10 days.Most studies were conducted in university settings (N = eight), six at a specific university common cold centre. Three studies were conducted at a university in collaboration with a hospital and two in a hospital only setting. In two studies the setting was unclear.There were large differences in the reporting of outcomes and the reporting of methods in most studies was limited. Therefore, we judged most studies to be at low or unclear risk of bias. Pooling was possible for a limited number of studies only; measures of effect are expressed as standardised mean differences (SMDs). A positive SMD represents an improvement in congestion. There is no defined minimal clinically important difference for measures of subjective improvement in nasal congestion, therefore we used the SMDs as a guide to assess whether an effect was small (0.2 to 0.49), moderate (0.5 to 0.79) or large (≥ 0.8).Single-dose decongestant versus placebo: 10 studies compared a single dose of nasal decongestant with placebo and their effectiveness was tested between 15 minutes and 10 hours after dosing. Seven of 10 studies reported subjective symptom scores for nasal congestion; none reported overall patient well-being. However, pooling was not possible due to the large diversity in the measurement and reporting of symptoms of congestion. Two studies recorded adverse events. Both studies used an oral decongestant and each of them showed that there was no statistical difference between the number of adverse events in the treatment group versus the placebo group.Multi-dose decongestant versus placebo: nine studies compared multiple doses of nasal decongestants with placebo, but only five reported on the primary outcome, subjective symptom scores for nasal congestion. Only one study used a topical decongestant; none reported overall patient well-being. Subjective measures of congestion were significantly better for the treatment group compared with placebo approximately three hours after the last dose (SMD 0.49, 95% confidence interval (CI) 0.07 to 0.92; P = 0.02; GRADE: low-quality evidence). However, the SMD of 0.49 only indicates a small clinical effect. Pooling was based on two studies, one oral and one topical, therefore we were unable to assess the effects of oral and topical decongestants separately. Seven studies reported adverse events (six oral and one topical decongestant); meta-analysis showed that there was no statistical difference between the number of adverse events in the treatment group (125 per 1000) compared to the placebo group (126 per 1000). The odds ratio (OR) for adverse events in the treatment group was 0.98 (95% CI 0.68 to 1.40; P = 0.90; GRADE: low-quality evidence). The results remained the same when we only considered studies using an oral decongestant (OR 0.95, 95% CI 0.65 to 1.39; P = 0.80; GRADE: low-quality evidence). We were unable to draw conclusions on the effectiveness of single-dose nasal decongestants due to the limited evidence available. For multiple doses of nasal decongestants, the current evidence suggests that these may have a small positive effect on subjective measures of nasal congestion in adults with the common cold. However, the clinical relevance of this small effect is unknown and there is insufficient good-quality evidence to draw any firm conclusions. Due to the small number of studies that used a topical nasal decongestant, we were also unable to draw conclusions on the effectiveness of oral versus topical decongestants. Nasal decongestants do not seem to increase the risk of adverse events in adults in the short term. The effectiveness and safety of nasal decongestants in children and the clinical relevance of their small effect in adults is yet to be determined.

Anithrombotic prevention in vascular disease: bases for a new strategy in antithrombotic therapy

PubMed Central

Altman, Raul

2007-01-01

A tendency toward bleeding often undercuts the beneficial preventive effect of higher doses of a single antithrombotic drug or combined antithrombotic therapy. Although high doses of antithrombotic drugs may be necessary for optimal prevention, such therapy can also elicit more frequent bleeding. Although major bleeding could be a reversible event is likely to lead clinicians to discontinue antithrombotic therapy which in turn could increase the risk of myocardial infarction, stroke, and cardiovascular death. Thus, to prevent thrombotic events without frequent bleeding complications, the preferred approach might be to use anti-inflammatory drugs in addition to the first-line antithrombotic drugs to reduce inflammation and thrombin formation in atheroma. Although some preliminary data have been already published, to confirm the potential benefit of anti-inflammatory drugs in acute coronary syndromes large prospective double-bind randomized trials are necessary. PMID:17727726

Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights.

PubMed

Bell, D; Pediconi, C; Jacobs, A

2014-03-01

The application of α-adrenoceptor agonists can improve faecal incontinence symptoms. The aim of this study was to investigate the pharmacokinetic and systemic effects of NRL001 administered as different strengths in 1 or 2 g suppositories. This randomised, double-blind, placebo controlled study included 48 healthy subjects. Group 1 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 5, 7.5 or 10 mg NRL001, or matching placebo. Group 2 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 10, 12.5 or 15 mg NRL001, or matching placebo. Doses were given in an escalating manner with placebo at a random position within the sequence. Tmax was at ~4.5 h post-dose for all NRL001 doses. Median AUC0-tz , AUC0-∞ and Cmax increased with increasing dose for both suppository sizes. The estimate of ratios of geometric means comparing 2 g with 1 g suppository, and regression analysis for dose proportionality, was close to 1 for the variables AUC0-tz , AUC0-∞ and Cmax (P > 0.05). For both suppository sizes, 20-min mean pulse rate was significantly decreased compared with placebo with all doses (P < 0.05). Blood pressure decreased overall. There were 144 adverse events (AEs) and no serious AEs reported during the study. All AEs were mild in severity. The regression analysis concluded that the doses were dose proportional. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

Albendazole and Praziquantel: Review and Safety Monitoring in Korea

PubMed Central

2018-01-01

Albendazole (ADZ) and praziquantel (PZQT) have been used as anthelmintics for over 30 years. Worldwide, hundreds of millions tablets are administered to people and livestock every year. ADZ is poorly orally absorbed (<5%), and its uptake is enhanced by high-fat meals, while PZQT is well absorbed (>75%) and uptake is enhanced by carbohydrate-rich meals. Both ADZ and PZQT are safe, but not recommended for children <2 years or for women in the first trimester of pregnancy. Serious adverse events occur following high dose and prolonged administration of these drugs for treatment of echinococcosis or neurocysticercosis, especially in patients with poor liver function. The adverse events may be induced by the drugs, or by the dead worms themselves. The Korea Institute of Drug Safety & Risk Management monitors drug-related adverse events in Korea, and its database included 256 probable or possible ADZ-associated events and 108 PZQT-associated events between 2006 and 2015. Such low incidence rates in Korea are due to the low single dose treatments of ADZ, and the short-term use of PZQT. The number of serious adverse events due to drug interaction induced by ADZ and PZQT were six and two, respectively. We conclude that ADZ and PZQT are generally safe drugs, but they must be used with caution in people with poor liver function or those being comedicated for gastroesophageal reflux disease. PMID:29637747

Effect of pirfenidone on gastric emptying in a rat model.

PubMed

Pan, Lin; Gelzleichter, Thomas; Chen, Yuan; Burg, Cindy; Limb, Susan L; Nguyen, Linda

2018-06-23

Gastrointestinal (GI) adverse events (AEs) are commonly reported in patients with idiopathic pulmonary fibrosis who are treated with pirfenidone. Taking pirfenidone with a substantial amount of food or dividing the dose over the course of a meal has been reported to reduce the frequency of GI AEs in clinical practice. In humans, the maximum plasma concentration (C max ) of pirfenidone was reduced when the drug was taken with food compared with the fasting state, and the lower C max was associated with a reduction in GI AE rates. In this study, the effects of the divided-dose approach and timing of pirfenidone administration relative to meal intake on gastric emptying were assessed using a rat model. The aim of this study was to investigate whether modification of dosing regimens could minimize pirfenidone's effect on inhibition of gastric emptying. Gastric emptying was assessed in male Sprague-Dawley rats after administration of a test meal by weighing stomach contents at various time points up to 120 min after the meal. Pirfenidone was administered via oral gavage either as a single-bolus dose of 30 mg/kg or as divided doses of 3 × 10 mg/kg at intervals ranging from 10 to 30 min for a total duration of 30-90 min. In addition, the test meal was given either at 30 min before, coincident with, or 30 min following pirfenidone oral administration. Administration of an oral 30-mg/kg single-bolus dose of pirfenidone with a meal resulted in a statistically significant decrease in gastric emptying in a rat model. The effect of pirfenidone on decreasing gastric emptying was lessened when the same total dose (i.e., 30 mg/kg) was administered as 3 divided doses (i.e., 3 × 10 mg/kg) over intervals up to 30 min in between each divided dose. Pharmacokinetic simulation suggested that a divided dosing regimen would decrease pirfenidone C max relative to single-bolus administration. When the same single-bolus dose of 30 mg/kg was administered 30 min following a meal rather than coincident with a meal, pirfenidone's effect on decreasing gastric emptying was reduced to the same extent as when the dose was divided as 3 × 10 mg/kg over a 90-min period. Administration of pirfenidone 30 min after a meal as a single-bolus dose or a divided dose over a 90-min period blunted pirfenidone's effect on inhibition of gastric emptying in rats compared with pirfenidone administration as a single-bolus dose coincident with a meal. Decreased gastric emptying, which is associated with pirfenidone administration, may be one of the contributing factors leading to GI tolerability issues associated with pirfenidone use in humans. Modification of the dosing regimen diminished this impact and may provide insight into possible mitigation strategies to minimize GI-related toxicities in the clinic. Copyright © 2018. Published by Elsevier Ltd.

Potential impact of clinical use of noninvasive FFRCT on radiation dose exposure and downstream clinical event rate.

PubMed

Bilbey, Nicolas; Blanke, Philipp; Naoum, Christopher; Arepalli, Chesnel Dey; Norgaard, Bjarne Linde; Leipsic, Jonathon

2016-01-01

This study aims to determine the potential impact of introducing noninvasive fractional flow reserve based on coronary computed tomography angiography (CTA) into clinical practice, with respect to radiation dose exposure and downstream event rate. We modeled a population of 1000 stable, symptomatic patients with suspected coronary artery disease, using the disease prevalence from the CONFIRM registry to estimate the pretest likelihood. Four potential clinical pathways were modeled based on the first noninvasive diagnostic test performed: (1) dobutamine echo; (2) single-photon emission computerized tomography (SPECT); (3) coronary CTA; and (4) CTA+FFRCT and leading to possible invasive coronary angiography. The posttest likelihood of testing positive/negative by each test was based on the presenting disease burden and diagnostic accuracy of each test. The dobutamine echo pathway resulted in the lowest radiation dose of 5.4 mSv, with 4.0 mSv from angiography and 1.4 mSv from percutaneous coronary intervention (PCI). The highest dose was with SPECT, with 26.5 mSv. The coronary computed tomography angiography (cCTA) pathway demonstrated a dose of 14.2 mSv, 3.7 mSv from cCTA, 7.7 mSv from angiography, and 2.8 mSv from PCI. The CTA+FFRCT pathway exhibited a radiation dose of 9.7 mSv, 3.7 mSv for cCTA, 4.2 mSv for angiography, and 1.8 mSv for PCI. Radiation dose exposure for CTA+FFRCT was lower than for SPECT (P<.001). The CTA+FFRCT pathway resulted in the lowest projected death/myocardial infarction rate at 1 year (2.44%) while the dobutamine stress pathway had the highest 1-year event rate (2.84%). Our analysis suggests that integrating FFRCT into the CTA clinical pathway may result in reduced cumulative radiation exposure, while promoting favorable clinical outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Antibody responses to natural influenza A/H1N1/09 disease or following immunization with adjuvanted vaccines, in immunocompetent and immunocompromised children.

PubMed

Meier, Sara; Bel, Michael; L'huillier, Arnaud; Crisinel, Pierre-Alex; Combescure, Christophe; Kaiser, Laurent; Grillet, Stéphane; Pósfay-Barbe, Klara; Siegrist, Claire-Anne

2011-04-27

To compare antibody responses elicited by influenza A/H1N1/09 disease and immunization with adjuvanted vaccines, in immunocompetent or immunocompromised children. Prospective parallel cohort field study enrolling children with confirmed influenza A/H1N1/09 disease or immunized with 1 (immunocompetent) or 2 (immunocompromised) doses of influenza A/H1N1/09 squalene-based AS03- or MF59-adjuvanted vaccines. Antibody geometric mean titers (GMT) were measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays 4-6 weeks after vaccination/disease. Vaccine adverse events were self-recorded in a 7-day diary. Antibody titers were as high in 48 immunocompetent children after a single immunization (HAI and MN seroprotection rates: 98%; HAI-GMT: 395, MN-GMT: 370) as in 51 convalescent children (seroprotection rates: 98% (HAI) and 92% (MN); GMT: 350 (HAI) and 212 (MN). Twenty-seven immunocompromised children reached slightly lower seroprotection rates (HAI: 89%, MN: 85%) but similar antibody titers (HAI-GMT: 306, MN-GMT: 225) after 2 immunizations. Adverse events increased with age (P=0.01) and were more frequent with Pandemrix® than Focetria® (P=0.03). Similarly high seroresponses may be expected in immunocompetent children after a single dose of adjuvanted vaccines as responses of convalescent children. Two vaccine doses were sufficient for most immunocompromised children. NCT0102293 and NCT01022905. Copyright © 2011 Elsevier Ltd. All rights reserved.

Radiation Effects on DC-DC Converters

NASA Technical Reports Server (NTRS)

Zhang, De-Xin; AbdulMazid, M. D.; Attia, John O.; Kankam, Mark D. (Technical Monitor)

2001-01-01

In this work, several DC-DC converters were designed and built. The converters are Buck Buck-Boost, Cuk, Flyback, and full-bridge zero-voltage switched. The total ionizing dose radiation and single event effects on the converters were investigated. The experimental results for the TID effects tests show that the voltages of the Buck Buck-Boost, Cuk, and Flyback converters increase as total dose increased when using power MOSFET IRF250 as a switching transistor. The change in output voltage with total dose is highest for the Buck converter and the lowest for Flyback converter. The trend of increase in output voltages with total dose in the present work agrees with those of the literature. The trends of the experimental results also agree with those obtained from PSPICE simulation. For the full-bridge zero-voltage switch converter, it was observed that the dc-dc converter with IRF250 power MOSFET did not show a significant change of output voltage with total dose. In addition, for the dc-dc converter with FSF254R4 radiation-hardened power MOSFET, the output voltage did not change significantly with total dose. The experimental results were confirmed by PSPICE simulation that showed that FB-ZVS converter with IRF250 power MOSFET's was not affected with the increase in total ionizing dose. Single Event Effects (SEE) radiation tests were performed on FB-ZVS converters. It was observed that the FB-ZVS converter with the IRF250 power MOSFET, when the device was irradiated with Krypton ion with ion-energy of 150 MeV and LET of 41.3 MeV-square cm/mg, the output voltage increased with the increase in fluence. However, for Krypton with ion-energy of 600 MeV and LET of 33.65 MeV-square cm/mg, and two out of four transistors of the converter were permanently damaged. The dc-dc converter with FSF254R4 radiation hardened power MOSFET's did not show significant change at the output voltage with fluence while being irradiated by Krypton with ion energy of 1.20 GeV and LET of 25.97 MeV-square cm/mg. This might be due to fact that the device is radiation hardened.

Safety and immunogenicity of an intramuscular quadrivalent influenza vaccine in children 3 to 8 y of age: A phase III randomized controlled study.

PubMed

Pepin, Stephanie; Szymanski, Henryk; Rochín Kobashi, Ilya Angélica; Villagomez Martinez, Sandra; González Zamora, José Francisco; Brzostek, Jerzy; Huang, Li-Min; Chiu, Cheng-Hsun; Chen, Po-Yen; Ahonen, Anitta; Forstén, Aino; Seppä, Ilkka; Quiroz, René Farfán; Korhonen, Tiina; Rivas, Enrique; Monfredo, Celine; Hutagalung, Yanee; Menezes, Josemund; Vesikari, Timo

2016-12-01

A quadrivalent, inactivated, split-virion influenza vaccine containing a strain from both B lineages (IIV4) has been developed, but its safety and immunogenicity in young children has not been described. This was a phase III, randomized, double-blind, active-controlled, multi-center study to examine the immunogenicity and safety of IIV4 in children 3-8 y of age (EudraCT no. 2011-005374-33). Participants were randomized 5:1:1 to receive the 2013/2014 Northern Hemisphere formulation of IIV4, an investigational trivalent comparator (IIV3) containing the B/Victoria lineage strain, or the licensed Northern Hemisphere IIV3 containing the B/Yamagata lineage strain. Participants who had not previously received a full influenza vaccination schedule received 2 doses of vaccine 28 d apart; all others received a single dose. 1242 children were included. For all 4 strains, IIV4 induced geometric mean haemagglutination inhibition titres non-inferior to those induced by the IIV3 comparators. For both B strains, geometric mean antibody titres induced by IIV4 were superior to those induced by the IIV3 with the alternative lineage strain. Similar proportions of participants vaccinated with IIV4 and IIV3 reported solicited injection-site reactions, solicited systemic reactions, and vaccine-related adverse events. A single vaccine-related serious adverse event, thrombocytopenia, was reported 9 d after vaccination with IIV4 and resolved without sequelae. In conclusion, in children aged 3-8 y who received one dose or 2 doses 28 d apart, IIV4 had an acceptable safety profile, was as immunogenic as IIV3 for the shared strains, and had superior immunogenicity for the additional B strain.

High-dose tranexamic acid reduces intraoperative and postoperative blood loss in posterior lumbar interbody fusion.

PubMed

Kushioka, Junichi; Yamashita, Tomoya; Okuda, Shinya; Maeno, Takafumi; Matsumoto, Tomiya; Yamasaki, Ryoji; Iwasaki, Motoki

2017-03-01

OBJECTIVE Tranexamic acid (TXA), a synthetic antifibrinolytic drug, has been reported to reduce blood loss in orthopedic surgery, but there have been few reports of its use in spine surgery. Previous studies included limitations in terms of different TXA dose regimens, different levels and numbers of fused segments, and different surgical techniques. Therefore, the authors decided to strictly limit TXA dose regimens, surgical techniques, and fused segments in this study. There have been no reports of using TXA for prevention of intraoperative and postoperative blood loss in posterior lumbar interbody fusion (PLIF). The purpose of the study was to evaluate the efficacy of high-dose TXA in reducing blood loss and its safety during single-level PLIF. METHODS The study was a nonrandomized, case-controlled trial. Sixty consecutive patients underwent single-level PLIF at a single institution. The first 30 patients did not receive TXA. The next 30 patients received 2000 mg of intravenous TXA 15 minutes before the skin incision was performed and received the same dose again 16 hours after the surgery. Intra- and postoperative blood loss was compared between the groups. RESULTS There were no statistically significant differences in preoperative parameters of age, sex, body mass index, preoperative diagnosis, or operating time. The TXA group experienced significantly less intraoperative blood loss (mean 253 ml) compared with the control group (mean 415 ml; p < 0.01). The TXA group also had significantly less postoperative blood loss over 40 hours (mean 321 ml) compared with the control group (mean 668 ml; p < 0.01). Total blood loss in the TXA group (mean 574 ml) was significantly lower than in the control group (mean 1080 ml; p < 0.01). From 2 hours to 40 hours, postoperative blood loss in the TXA group was consistently significantly lower. There were no perioperative complications, including thromboembolic events. CONCLUSIONS High-dose TXA significantly reduced both intra- and postoperative blood loss without causing any complications during or after single-level PLIF.

Safety of Single-Dose Primaquine in G6PD-Deficient and G6PD-Normal Males in Mali Without Malaria: An Open-Label, Phase 1, Dose-Adjustment Trial.

PubMed

Chen, Ingrid; Diawara, Halimatou; Mahamar, Almahamoudou; Sanogo, Koualy; Keita, Sekouba; Kone, Daouda; Diarra, Kalifa; Djimde, Moussa; Keita, Mohamed; Brown, Joelle; Roh, Michelle E; Hwang, Jimee; Pett, Helmi; Murphy, Maxwell; Niemi, Mikko; Greenhouse, Bryan; Bousema, Teun; Gosling, Roly; Dicko, Alassane

2018-03-28

The World Health Organization recommendation on the use of a single low dose of primaquine (SLD-PQ) to reduce Plasmodium falciparum malaria transmission requires more safety data. We conducted an open-label, nonrandomized, dose-adjustment trial of the safety of 3 single doses of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient adult males in Mali, followed by an assessment of safety in G6PD-deficient boys aged 11-17 years and those aged 5-10 years, including G6PD-normal control groups. The primary outcome was the greatest within-person percentage drop in hemoglobin concentration within 10 days after treatment. Fifty-one participants were included in analysis. G6PD-deficient adult males received 0.40, 0.45, or 0.50 mg/kg of SLD-PQ. G6PD-deficient boys received 0.40 mg/kg of SLD-PQ. There was no evidence of symptomatic hemolysis, and adverse events considered related to study drug (n = 4) were mild. The mean largest within-person percentage change in hemoglobin level between days 0 and 10 was -9.7% (95% confidence interval [CI], -13.5% to -5.90%) in G6PD-deficient adults receiving 0.50 mg/kg of SLD-PQ, -11.5% (95% CI, -16.1% to -6.96%) in G6PD-deficient boys aged 11-17 years, and -9.61% (95% CI, -7.59% to -13.9%) in G6PD-deficient boys aged 5-10 years. The lowest hemoglobin concentration at any point during the study was 92 g/L. SLD-PQ doses between 0.40 and 0.50 mg/kg were well tolerated in G6PD-deficient males in Mali. NCT02535767.

Safety and pharmacokinetics of NXN-188 after single and multiple doses in five phase I, randomized, double-blind, parallel studies in healthy adult volunteers.

PubMed

Vaughan, David; Speed, Joanne; Medve, Robert; Andrews, John S

2010-01-01

NXN-188 is a dual-action oral therapeutic being developed for the treatment of acute migraine. The mechanism of action of NXN-188 involves inhibition of both the neuronal nitric oxide synthase enzyme isoform and affinity for serotonin (5-hydroxytryptamine1B/D) receptors. The aims of the initial Phase I clinical studies were to compare the pharmacokinetic (PK) properties of NXN-188 administered as a single dose or multiple twice-daily doses to healthy adult volunteers and to determine the tolerability of NXN-188 in these individuals. Healthy adult male and female subjects were enrolled in 5 Phase I, randomized, double-blind studies, all of which (except for a fed/fasted trial) were placebo controlled. In the 4 single-dose studies, which differed with respect to feeding status and the formulation used (capsules or solution), subjects received NXN-188 at doses of 2 to 800 mg (0.027-11.2 mg/kg). In the repeat-dose study, subjects received 50-mg (0.71 mg/kg) doses twice daily for 4 days. Serum samples were analyzed for NXN-188 using validated HPLC-MS/MS methods. Standard clinical laboratory analyses (chemistry, hematology, and urinalysis) and measurements of serum creatine kinase and myoglobin levels were conducted at screening, admission, discharge, and follow-up. Baseline and postexposure values were compared to assess tolerability. Electrocardiography and physical examination were conducted at screening and at discharge and follow-up if any negative change occurred from the previous findings. Vital signs (heart rate, blood pressure, respiration), including assessment for orthostatic changes, were measured at screening, check-in, and follow-up visits (1 hour before dosing, every 30 minutes for the first 4 hours, then every hour for the next 4 hours, then every 4 hours for the remainder of the 24-hour study). Adverse events were recorded, reviewed, and monitored throughout the study. Two hundred three subjects (102 women, 101 men) 18 to 50 years of age were enrolled in the 5 studies; 168 subjects received NXN-188 and 35 received placebo. Most (91%) of the subjects were white; weight ranged from 69.3 to 71.8 kg (body mass index, 24.5-25.8 kg/m(2)). The initial absorption phase of orally administered NXN-188 peaked at approximately 1 hour, followed by a second absorption phase with a T(max) of approximately 4 to 5 hours. Exposure (C(max) and AUC) increased in a slightly greater than dose-proportional manner across a dose range of 2 to 800 mg (0.027-11.2 mg/kg). Elimination was multiexponential, with an initial rapid plasma drug elimination (plasma concentrations decreased approximately 70%-90% from Cmax within 24 hours after dosing), followed by a prolonged clearance phase of very low NXN-188 concentrations ( approximately 1%-5% of Cmax) that persisted for several weeks. Clearance ranged from 70 to 130 L/h, and the NXN-188 halflife ranged from 11 to 178 hours. Neither food nor gender had any measurable effect on the PK properties of NXN-188. Overall, dizziness was reported more often in the NXN-188 groups than in the placebo groups (6.3% vs 2.9%, respectively). Frequently reported adverse events that occurred more often in the placebo groups than in the NXN-188 groups were somnolence (11.4% vs 6.3%, respectively), and headache (8.6% vs 6.9%). Incidences of orthostatic hypotension (6.3% vs 5.7%) and postural (orthostatic) tachycardia syndrome (6.3% vs 5.7%) were comparable in the NXN-188 and placebo groups, respectively. No serious adverse events were reported at any dose of NXN-188 up to the current maximum dose (800 mg or 11.2 mg/kg). NXN-188 exhibited linear pharmaco-kinetics over the dose range studied and appeared to be well tolerated in these healthy volunteers.

Tolerance of the High Energy X-ray Imaging Technology ASIC to potentially destructive radiation processes in Earth-orbit-equivalent environments

NASA Astrophysics Data System (ADS)

Ryan, D. F.; Baumgartner, W. H.; Wilson, M.; Benmoussa, A.; Campola, M.; Christe, S. D.; Gissot, S.; Jones, L.; Newport, J.; Prydderch, M.; Richards, S.; Seller, P.; Shih, A. Y.; Thomas, S.

2018-02-01

The High Energy X-ray Imaging Technology (HEXITEC) ASIC is designed on a 0.35 μm CMOS process to read out CdTe or CZT detectors and hence provide fine-pixellated spectroscopic imaging in the range 2-200 keV. In this paper, we examine the tolerance of HEXITEC to both potentially destructive cumulative and single event radiation effects. Bare ASICs are irradiated with X-rays up to a total ionising dose (TID) of 1 Mrad (SiO2) and bombarded with heavy ions with linear energy transfer (LET) up to 88.3 MeV mg-1 cm-2. HEXITEC is shown to operate reliably below a TID of 150 krad, have immunity to fatal single event latchup (SEL) and have high tolerance to non-fatal SEL up to LETs of at least 88.3 MeV mg-1 cm-2. The results are compared to predictions of TID and SELs for various Earth-orbits and aluminium shielding thicknesses. It is found that HEXITEC's radiation tolerance to both potentially destructive cumulative and single event effects is sufficient to reliably operate in these environments with moderate shielding.

Phase I clinical studies of the advanced glycation end-product (AGE)-breaker TRC4186: safety, tolerability and pharmacokinetics in healthy subjects.

PubMed

Chandra, Kumar P; Shiwalkar, Ajay; Kotecha, Jignesh; Thakkar, Purav; Srivastava, Ambrish; Chauthaiwale, Vijay; Sharma, Sanjay K; Cross, Maurice R; Dutt, Chaitanya

2009-01-01

Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic complications through a variety of mechanisms including endothelial dysfunction and structural abnormalities in the vasculature and myocardium. Reducing the AGEs burden and their ensuing pro-inflammatory, pro-oxidative and pro-coagulant effect with associated dysfunctional proteins in various target tissues may retard the progression of and even reverse diabetic macro- and microvascular complications. Pyridinium, 3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]-chloride (TRC4186) has demonstrated AGE-breaking activities in in vitro experiments and improvement in the endothelial and myocardial function in animal models of diabetes mellitus with reduction of AGEs accumulation in tissues over time. The safety of TRC4186 has been established in in vitro and in vivo preclinical studies. Thus, this drug is being developed for the treatment of complications associated with diabetes. This investigation set out to evaluate the safety, tolerability and pharmacokinetics of TRC4186 in healthy human subjects after single and multiple ascending doses, fixed doses in elderly male and female subjects, and with food and different formulations of the compound. Four studies were conducted during phase I clinical development of TRC4186. These were: (i) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in healthy male subjects with doses of TRC4186 ranging from 250 to 2500 mg administered as an oral solution (total six doses); (ii) a randomized, double-blind, placebo-controlled, multiple-dose, dose-ascending study in healthy male subjects with three doses of TRC4186 ranging from 500 to 2000 mg twice daily for 6 days with a final single dose on day 7; (iii) a randomized, open-label, three-way crossover study to assess the effect of food (fasted vs fed) and formulation (solution vs tablet) with TRC4186 500 mg; (iv) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in elderly male and female subjects at a dose of TRC4186 500 mg followed by TRC4186 1000 mg after a 7-day washout period. The safety and tolerability of TRC4186 were assessed by considering adverse events (AEs), ECG findings, vital signs and laboratory investigation results. TRC4186 was rapidly absorbed, with maximum plasma concentrations (C(max)) attained within 1-4 hours. C(max) and area under the plasma concentration-time curve (AUC) were dose proportional over the range 250-2500 mg for a single dose and 500-2000 mg for multiple doses with twice-daily administration. Steady-state conditions were attained within 6 days at different dose levels. C(max) and AUC were not affected by age, sex, race or type of formulation. The tablet formulation of TRC4186 was bioequivalent with the solution form of the drug under fasting conditions and systemic availability of the tablet formulation was reduced by 40% when administered under fed conditions. Terminal elimination and renal clearance in the elderly male (age 69.1 +/- 6.0 years) were not significantly different compared with younger subjects (age 31 +/- 8.6 years). TRC4186 was safe and well tolerated when administered orally with either a single or multiple doses across the different ages, sexes, races and formulations studied. A dose-proportional increase in plasma TRC4186 concentration was seen, with steady state being achieved within 6 days.

The Radiation Environment for the LISA/Laser Interferometry Space Antenna

NASA Technical Reports Server (NTRS)

Barth, Janet L.; Xapsos, Michael; Poivey, Christian

2005-01-01

The purpose of this document is to define the radiation environment for the evaluation of degradation due to total ionizing and non-ionizing dose and of single event effects (SEES) for the Laser Interferometry Space Antenna (LISA) instruments and spacecraft. The analysis took into account the radiation exposure for the nominal five-year mission at 20 degrees behind Earth's orbit of the sun, at 1 AU (astronomical unit) and assumes a launch date in 2014. The transfer trajectory out to final orbit has not yet been defined, therefore, this evaluation does not include the impact of passing through the Van Allen belts. Generally, transfer trajectories do not contribute significantly to degradation effects; however, single event effects and deep dielectric charging effects must be taken into consideration especially if critical maneuvers are planned during the van Allen belt passes.

Methylene blue MMX® tablets for chromoendoscopy. Bioavailability, colon staining and safety in healthy volunteers undergoing a full colonoscopy.

PubMed

Di Stefano, A F D; Radicioni, M M; Vaccani, A; Fransioli, A; Longo, L; Moro, L; Repici, A

2018-06-01

Methylene blue-MMX® tablets are proposed as an aid for detection and visualisation of adenomas and carcinomas in patients undergoing colonoscopy, by improving their detection rate and highlighting the presence of the intestinal dysplastic lesions. Single total doses of 100 and 200 mg were administered to healthy volunteers undergoing a bowel cleansing preparation and a full colonoscopy to investigate the colonic staining. The pharmacokinetics of methylene blue and the safety after exposure to the tablets were also investigated. With 200 mg, the best staining, assessed as the sum of acceptable and good staining, was achieved in the ascending colon and rectosigmoid (75% subjects each), the transverse and the descending colon (approximately 63% each). Absence of staining or overstaining were reported for no colonic region of interest in any subject. Similar results were observed in the 100 mg dose group. Methylene blue blood concentrations reached a peak (C max ) in a median time (T max ) of 12 h with 100 mg and 16 h with 200 mg. AUC 0-t was 10.7 ± 6.7 μg/mLxh after 100 mg and 25.2 ± 7.4 μg/mLxh after 200 mg. Half-life ranged between 9 and 22 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative excretion was about 28% after 100 mg and about 39% after 200 mg. The overall frequency of adverse events was 39%, but only one was related to the product: abnormal transaminases. The most frequent adverse event was a transient polyuria (17%). One serious adverse event (gastrointestinal haemorrhage) led the subject to study discontinuation and hospitalisation and another subject withdrew the study due to one adverse event (haematemesis). Either event was not related to methylene blue. Copyright © 2017. Published by Elsevier Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walton, B.T.; Ho, C.H.; Ma, C.Y.

Morphological abnormalities including extra compound eyes, extra heads, and distally duplicated legs were generated in cricket embryos by treating eggs with single doses of either benz(g)isoquinoline-5,10-dione or benzo(h)quinoline-5,6-dione. Slight structural modifications of the molecules resulted in a loss of teratogenic activity, although embryotoxicity occurred. These potent insect teratogens can be used for analysis of developmental events during embryogenesis. 13 references, 4 figures, 1 table.

Anaphylaxis following intravenous ranitidine: a rare adverse reaction of a common drug.

PubMed

Chopra, Deepti; Arora, Pooja; Khan, Shamimullah; Dwivedi, Shridhar

2014-01-01

Ranitidine hydrochloride is a widely used drug that is generally well-tolerated. Anaphylaxis is rarely observed with ranitidine. We report a case who developed severe anaphylaxis following single dose of intravenous ranitidine. The article highlights the importance of recognition of this serious adverse event and re-emphasizes the need for cautious use of drugs, especially in those with known history of allergy.

A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload.

PubMed

Neufeld, Ellis J; Galanello, Renzo; Viprakasit, Vip; Aydinok, Yesim; Piga, Antonio; Harmatz, Paul; Forni, Gian Luca; Shah, Farrukh T; Grace, Rachael F; Porter, John B; Wood, John C; Peppe, Jennifer; Jones, Amber; Rienhoff, Hugh Young

2012-04-05

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.

Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies

PubMed Central

Gomes, Melba; Ribeiro, Isabela; Warsame, Marian; Karunajeewa, Harin; Petzold, Max

2008-01-01

Background Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria. Methods Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success. Results Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether. Conclusion Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy. PMID:18373841

Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine.

PubMed

Tfelt-Hansen, Peer; Ågesen, Frederik Nybye; Pavbro, Agniezka; Tfelt-Hansen, Jacob

2017-05-01

In this review, we evaluate the variability in the pharmacokinetics of 11 drugs with established prophylactic effects in migraine to facilitate 'personalized medicine' with these drugs. PubMed was searched for 'single-dose' and 'steady-state' pharmacokinetic studies of these 11 drugs. The maximum plasma concentration was reported in 248 single-dose and 115 steady-state pharmacokinetic studies, and the area under the plasma concentration-time curve was reported in 299 single-dose studies and 112 steady-state pharmacokinetic studies. For each study, the coefficient of variation was calculated for maximum plasma concentration and area under the plasma concentration-time curve, and we divided the drug variability into two categories; high variability, coefficient of variation >40%, or low or moderate variability, coefficient of variation <40%. Based on the area under the plasma concentration-time curve in steady-state studies, the following drugs have high pharmacokinetic variability: propranolol in 92% (33/36), metoprolol in 85% (33/39), and amitriptyline in 60% (3/5) of studies. The following drugs have low or moderate variability: atenolol in 100% (2/2), valproate in 100% (15/15), topiramate in 88% (7/8), and naproxen and candesartan in 100% (2/2) of studies. For drugs with low or moderate pharmacokinetic variability, treatment can start without initial titration of doses, whereas titration is used to possibly enhance tolerability of topiramate and amitriptyline. The very high pharmacokinetic variability of metoprolol and propranolol can result in very high plasma concentrations in a small minority of patients, and those drugs should therefore be titrated up from a low initial dose, depending mainly on the occurrence of adverse events.

A randomized phase I study of methanesulfonyl fluoride, an irreversible cholinesterase inhibitor, for the treatment of Alzheimer's disease

PubMed Central

Moss, Donald E; Fariello, Ruggero G; Sahlmann, Jörg; Sumaya, Isabel; Pericle, Federica; Braglia, Enrico

2013-01-01

Aims To ascertain the tolerability profile of single and repeated oral doses of methanesulfonyl fluoride (MSF, SNX-001) in healthy aged subjects, and to determine the degree of erythrocyte acetylcholinesterase (AChE) inhibition induced by MSF after single and repeated oral doses. Methods To calculate properly the kinetics and the duration of AChE inhibition, the effects of MSF were also studied in rodents. These experiments suggested that MSF administered three times per week should provide safe and efficacious AChE inhibition. In a randomized placebo-controlled phase I study, 3.6 mg, 7.2 mg or 10.8 mg MSF were then orally administered to 27 consenting healthy volunteers (aged 50 to 72 years). After a single dose phase and a 1 week wash-out period, the subjects received the same doses three times per week for 2 weeks. Results Twenty-two out of the 27 subjects completed the study. Four patients withdrew due to adverse events (AEs) and one for non-compliance. Erythrocyte AChE was inhibited by a total of 33%, 46%, and 62% after 2 weeks of 3.6 mg, 7.2 mg and 10.8 mg MSF, respectively. No serious AEs occurred. The most frequent AEs were headache (27%), nausea (11%) and diarrhoea (8%). Conclusions MSF proved to be well tolerated even with repeated oral dosing. It is estimated that MSF provided a degree of AChE inhibition that should effectively enhance memory. This molecule deserves to be tested for efficacy in a pilot randomized controlled study in patients with Alzheimer's disease. PMID:23116458

The safety and effectiveness of a long-acting transdermal fentanyl solution compared with oxymorphone for the control of postoperative pain in dogs: a randomized, multicentered clinical study

PubMed Central

Martinez, S A; Wilson, M G; Linton, D D; Newbound, G C; Freise, K J; Lin, T-L; Clark, T P

2014-01-01

A prospective, double-blinded, positive-controlled, multicenter, noninferiority study was conducted to evaluate the safety and effectiveness of transdermal fentanyl solution (TFS) compared with oxymorphone for the control of postoperative pain in dogs. Five hundred and two (502) client-owned dogs were assigned to a single dose of TFS (2.7 mg/kg) applied 2–4 h prior to surgery or oxymorphone hydrochloride (0.22 mg/kg) administered subcutaneously 2–4 h prior to surgery and q6h through 90 h. Pain was evaluated over 4 days by blinded observers using a modified Glasgow composite pain scale, and the a priori criteria for treatment failure was a pain score ≥8 or adverse event necessitating withdrawal. Four TFS- and eight oxymorphone-treated dogs were withdrawn due to lack of pain control. Eighteen oxymorphone-treated, but no TFS-treated dogs were withdrawn due to severe adverse events. The one-sided upper 95% confidence interval of the difference between TFS and oxymorphone treatment failure rates was −5.3%. Adverse events associated with oxymorphone were greater in number and severity compared with TFS. It was concluded that a single administration of TFS was safe and noninferior to repeated injections of oxymorphone for the control of postoperative pain over 4 days at the dose rates of both formulations used in this study. PMID:24344787

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma.

PubMed

Davids, Matthew S; Roberts, Andrew W; Seymour, John F; Pagel, John M; Kahl, Brad S; Wierda, William G; Puvvada, Soham; Kipps, Thomas J; Anderson, Mary Ann; Salem, Ahmed Hamed; Dunbar, Martin; Zhu, Ming; Peale, Franklin; Ross, Jeremy A; Gressick, Lori; Desai, Monali; Kim, Su Young; Verdugo, Maria; Humerickhouse, Rod A; Gordon, Gary B; Gerecitano, John F

2017-03-10

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

PubMed Central

Roberts, Andrew W.; Seymour, John F.; Pagel, John M.; Kahl, Brad S.; Wierda, William G.; Puvvada, Soham; Kipps, Thomas J.; Anderson, Mary Ann; Salem, Ahmed Hamed; Dunbar, Martin; Zhu, Ming; Peale, Franklin; Ross, Jeremy A.; Gressick, Lori; Desai, Monali; Kim, Su Young; Verdugo, Maria; Humerickhouse, Rod A.; Gordon, Gary B.; Gerecitano, John F.

2017-01-01

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing. PMID:28095146

High-dose levofloxacin in community-acquired pneumonia: a randomized, open-label study.

PubMed

Lee, Jin Hwa; Kim, Seo Woo; Kim, Ji Hye; Ryu, Yon Ju; Chang, Jung Hyun

2012-09-01

The conventional treatment for community-acquired pneumonia (CAP) involves combination therapy consisting of a β-lactam penicillin or a cephalosporin with a macrolide. Alternatively, high-dose levofloxacin treatment has been used as single-agent therapy for treating CAP, covering atypical pathogens. This study compared the clinical efficacy and safety of high-dose levofloxacin with combined ceftriaxone and azithromycin for the treatment of CAP. This phase IV, prospective, randomized, open-label trial enrolled patients admitted to a tertiary referral hospital for CAP treatment from 2010 to 2011. Hospital admission was decided based on clinical judgement and the pneumonia severity index. Forty subjects were enrolled and assigned to two treatment arms using a random numbers table. The 20 subjects in the experimental group were given levofloxacin 750 mg intravenously once daily, followed by the same dose of oral levofloxacin at discharge when clinically improved and the 20 subjects in the control group were given ceftriaxone 2.0 g intravenously once daily plus oral azithromycin 500 mg for 3 consecutive days, followed by oral cefpodoxime 200 mg per day at discharge after clinical improvement. The primary outcome was the clinical success rate. Secondary outcomes were the microbiological success rate and adverse events during the study. Of the 40 subjects enrolled, 36 completed the study: 17 in the experimental group and 19 in the control group. The groups did not differ in terms of demographic factors or clinical findings at baseline. The clinical success rate (cured + improved) was 94% in the experimental (levofloxacin) group and 84% in the control group (p > 0.05). The microbiological success rate and overall adverse events were also similar in both groups. Single-agent, high-dose levofloxacin treatment exhibited excellent clinical and microbiological efficacy with a safety profile comparable to that of ceftriaxone plus azithromycin therapy. Large-scale clinical trials are required to verify these results. WHO International Clinical Trials Registry: KCT0000374; Daiichi-Sankyo Korea study code: T11-13-V1.

The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study.

PubMed

Eisenberg, Elon; Ogintz, Miri; Almog, Shlomo

2014-09-01

Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a "main stream" pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC₀→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs.

Comparative Proteomic Analysis of Liver Steatosis and Fibrosis after Oral Hepatotoxicant Administration in Sprague-Dawley Rats.

PubMed

McDyre, B Claire; AbdulHameed, Mohamed Diwan M; Permenter, Matthew G; Dennis, William E; Baer, Christine E; Koontz, Jason M; Boyle, Molly H; Wallqvist, Anders; Lewis, John A; Ippolito, Danielle L

2018-02-01

The past decade has seen an increase in the development and clinical use of biomarkers associated with histological features of liver disease. Here, we conduct a comparative histological and global proteomics analysis to identify coregulated modules of proteins in the progression of hepatic steatosis or fibrosis. We orally administered the reference chemicals bromobenzene (BB) or 4,4'-methylenedianiline (4,4'-MDA) to male Sprague-Dawley rats for either 1 single administration or 5 consecutive daily doses. Livers were preserved for histopathology and global proteomics assessment. Analysis of liver sections confirmed a dose- and time-dependent increase in frequency and severity of histopathological features indicative of lipid accumulation after BB or fibrosis after 4,4'-MDA. BB administration resulted in a dose-dependent increase in the frequency and severity of inflammation and vacuolation. 4,4'-MDA administration resulted in a dose-dependent increase in the frequency and severity of periportal collagen accumulation and inflammation. Pathway analysis identified a time-dependent enrichment of biological processes associated with steatogenic or fibrogenic initiating events, cellular functions, and toxicological states. Differentially expressed protein modules were consistent with the observed histology, placing physiologically linked protein networks into context of the disease process. This study demonstrates the potential for protein modules to provide mechanistic links between initiating events and histopathological outcomes.

High-Resolution Genome-Wide Analysis of Irradiated (UV and γ-Rays) Diploid Yeast Cells Reveals a High Frequency of Genomic Loss of Heterozygosity (LOH) Events

PubMed Central

St. Charles, Jordan; Hazkani-Covo, Einat; Yin, Yi; Andersen, Sabrina L.; Dietrich, Fred S.; Greenwell, Patricia W.; Malc, Ewa; Mieczkowski, Piotr; Petes, Thomas D.

2012-01-01

In diploid eukaryotes, repair of double-stranded DNA breaks by homologous recombination often leads to loss of heterozygosity (LOH). Most previous studies of mitotic recombination in Saccharomyces cerevisiae have focused on a single chromosome or a single region of one chromosome at which LOH events can be selected. In this study, we used two techniques (single-nucleotide polymorphism microarrays and high-throughput DNA sequencing) to examine genome-wide LOH in a diploid yeast strain at a resolution averaging 1 kb. We examined both selected LOH events on chromosome V and unselected events throughout the genome in untreated cells and in cells treated with either γ-radiation or ultraviolet (UV) radiation. Our analysis shows the following: (1) spontaneous and damage-induced mitotic gene conversion tracts are more than three times larger than meiotic conversion tracts, and conversion tracts associated with crossovers are usually longer and more complex than those unassociated with crossovers; (2) most of the crossovers and conversions reflect the repair of two sister chromatids broken at the same position; and (3) both UV and γ-radiation efficiently induce LOH at doses of radiation that cause no significant loss of viability. Using high-throughput DNA sequencing, we also detected new mutations induced by γ-rays and UV. To our knowledge, our study represents the first high-resolution genome-wide analysis of DNA damage-induced LOH events performed in any eukaryote. PMID:22267500

Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study.

PubMed

Rosenson, Jonathan; Clements, Carter; Simon, Barry; Vieaux, Jules; Graffman, Sarah; Vahidnia, Farnaz; Cisse, Bitou; Lam, Joseph; Alter, Harrison

2013-03-01

Acute alcohol withdrawal syndrome (AAWS) is encountered in patients presenting acutely to the Emergency Department (ED) and often requires pharmacologic management. We investigated whether a single dose of intravenous (i.v.) phenobarbital combined with a standardized lorazepam-based alcohol withdrawal protocol decreases intensive care unit (ICU) admission in ED patients with acute alcohol withdrawal. This was a prospective, randomized, double-blind, placebo-controlled study. Patients were randomized to receive either a single dose of i.v. phenobarbital (10 mg/kg in 100 mL normal saline) or placebo (100 mL normal saline). All patients were placed on the institutional symptom-guided lorazepam-based alcohol withdrawal protocol. The primary outcome was initial level of hospital admission (ICU vs. telemetry vs. floor ward). There were 198 patients enrolled in the study, and 102 met inclusion criteria for analysis. Fifty-one patients received phenobarbital and 51 received placebo. Baseline characteristics and severity were similar in both groups. Patients that received phenobarbital had fewer ICU admissions (8% vs. 25%, 95% confidence interval 4-32). There were no differences in adverse events. A single dose of i.v. phenobarbital combined with a symptom-guided lorazepam-based alcohol withdrawal protocol resulted in decreased ICU admission and did not cause increased adverse outcomes. Copyright © 2013 Elsevier Inc. All rights reserved.

Methylphenidate bioavailability in adults when an extended-release multiparticulate formulation is administered sprinkled on food or as an intact capsule.

PubMed

Pentikis, Helen S; Simmons, Roy D; Benedict, Michael F; Hatch, Simon J

2002-04-01

To determine the single-dose bioavailability of 20-mg Metadate CD (methylphenidate HCI, USP) Extended-Release Capsules sprinkled onto 1 level tablespoon (15 mL) of applesauce relative to an intact capsule under fasted conditions in healthy adults. This was a single-center, open-label, single-dose, randomized, two-way crossover study with a 6-day washout period between doses, in healthy male and female subjects (N= 26), aged 21-40 years. Plasma concentration-time data for methylphenidate were used to calculate the pharmacokinetic parameters for each treatment. The pharmacokinetic profile for Metadate CD exhibited biphasic release characteristics with a sharp initial slope and a second rising portion. For Cmax (maximum observed concentration), AUC(0-infinity) (area under the plasma concentration curve from time 0 to infinity) and AUC(0-infinity) (area under the plasma concentration curve from time 0 to the last measurable time point), the geometric least squares mean ratios and 90% confidence intervals were within the 80% to 125% confidence interval for bioequivalence. Adverse events were similar to those reported for methylphenidate. The bioavailability of methylphenidate was not altered when Metadate CD capsules were administered by sprinkling their contents onto a small amount of applesauce.

Design and qualification of the SEU/TD Radiation Monitor chip

NASA Technical Reports Server (NTRS)

Buehler, Martin G.; Blaes, Brent R.; Soli, George A.; Zamani, Nasser; Hicks, Kenneth A.

1992-01-01

This report describes the design, fabrication, and testing of the Single-Event Upset/Total Dose (SEU/TD) Radiation Monitor chip. The Radiation Monitor is scheduled to fly on the Mid-Course Space Experiment Satellite (MSX). The Radiation Monitor chip consists of a custom-designed 4-bit SRAM for heavy ion detection and three MOSFET's for monitoring total dose. In addition the Radiation Monitor chip was tested along with three diagnostic chips: the processor monitor and the reliability and fault chips. These chips revealed the quality of the CMOS fabrication process. The SEU/TD Radiation Monitor chip had an initial functional yield of 94.6 percent. Forty-three (43) SEU SRAM's and 14 Total Dose MOSFET's passed the hermeticity and final electrical tests and were delivered to LL.

Biological Response to SPE Exposures

NASA Technical Reports Server (NTRS)

Wilson, J. W.; Cucinotta, F. A.; Kim, M.; Shinn, J. L.; Jones, T. D.; Chang, C. K.

2004-01-01

It has long been recognized that a single solar particle event (SPE) can produce, over a short period of time, exposures on the order of LD50 for humans under normal physiological conditions. It is further recognized that recovery from injury over the period of exposure would greatly increase the chances of survival (dose rate effects) although such effects were left unquantified. In the present report we use the bioresponse model derived from a broad range of animal and human exposure data for evaluation of troop readiness in tactical nuclear warfare to evaluate the biological risk posed by the solar event of 4 August 1972. The astronaut blood forming organ (BFO) exposure in deep space would have been 2.2 Sv (1.6 Gy) in a space suit, 1.8 Sv (1.3 Gy) in an aluminum pressure vessel, and 0.7 Sv (0.5 Gy) in an equipment room compared to an X-ray mortality threshold of 1.5 Gy (assuming high dose rate). We find BFO dose rate effectiveness factors for this SPE on the order of 3 to 4, greatly reducing the mortality risks for this event. There is an approximate 3 percent chance that an even larger event may occur for which exposures could be 2-4 times higher. Assured survival of the astronaut requires added shelter shielding and a warning system for this event. The required mass of the shelter shield can be greatly reduced by using hydrogenous materials such as polymers, water, food, and other biological materials in its construction. Limitations of the current bioresponse model arise from the exposures taking place in the microgravity environment wherein the immune system is already challenged and the effective mortality threshold may be reduced by a factor of two. Such microgravity effects could greatly affect astronaut risks.

Dosimetric Predictors of Symptomatic Cardiac Events after Conventional-Dose Chemoradiation Therapy for Inoperable Non-Small Cell Lung Cancer.

PubMed

Yegya-Raman, Nikhil; Wang, Kyle; Kim, Sinae; Reyhan, Meral; Deek, Matthew P; Sayan, Mutlay; Li, Diana; Patel, Malini; Malhotra, Jyoti; Aisner, Joseph; Marks, Lawrence B; Jabbour, Salma K

2018-06-05

We hypothesized that higher cardiac doses correlates with clinically significant cardiotoxicity after standard-dose chemoradiation therapy (CRT) (∼60 Gy) for inoperable non-small cell lung cancer (NSCLC). We retrospectively reviewed the records of 140 patients with inoperable NSCLC treated with concurrent CRT from 2007-2015. Extracted data included baseline cardiac status, dosimetric parameters to the whole heart (WH) and cardiac substructures, and the development of post-CRT symptomatic cardiac events (acute coronary syndrome [ACS], arrhythmia, pericardial effusion, pericarditis, and congestive heart failure [CHF]). Competing risks analysis was used to estimate time to cardiac events. Median follow-up was 47.4 months. Median radiation therapy dose was 61.2 Gy (interquartile range, 60-66 Gy). Forty patients (28.6%) developed 47 symptomatic cardiac events at a median of 15.3 months to first event. On multivariate analysis, higher WH doses and baseline cardiac status were associated with an increased risk of symptomatic cardiac events. The 4-year cumulative incidence of symptomatic cardiac events was 48.6% versus 18.5% for mean WH dose ≥ 20 Gy versus < 20 Gy, respectively (p = 0.0002). Doses to the WH, ventricles, and left anterior descending artery were associated with ACS/CHF, whereas doses to the WH and atria were not associated with supraventricular arrhythmias. Symptomatic cardiac events (p = 0.0001) were independently associated with death. Incidental cardiac irradiation was associated with subsequent symptomatic cardiac events, particularly ACS/CHF, and symptomatic cardiac events were associated with inferior survival. These results support the minimization of cardiac doses among patients with inoperable NSCLC receiving standard-dose CRT. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery

PubMed Central

Hill, Kevin D.; Tunks, Robert D.; Barker, Piers C. A.; Benjamin, Daniel K.; Cohen-Wolkowiez, Michael; Fleming, Gregory A.; Laughon, Matthew; Li, Jennifer S.

2013-01-01

Objective To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery. Design Prospective, dose escalation trial. Setting Single-center, pediatric catheterization laboratory. Patients 12 children post stage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range: 0.8, 4.0), weight 11 kg (8, 13), 9 females, and 10 with a single right ventricle. Interventions Catheterization and echocardiography performed before and immediately after single-dose intravenous sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 minutes). Measurements Peak sildenafil and des-methyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance. Main Results Maximum sildenafil concentrations ranged from 92–775 ng/ml and were above the in vitro threshold needed for 77% phosphodiesterase type-5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index (PVRI) in all 12 subjects (median PVRI 2.2 [range: 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU x m2; p<0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p=0.04) and saturations (+2% [0, 16], p=0.04) in those with baseline PVRI ≥2 WU x m2 (n=7). Change in saturations correlated inversely with change in PVRI (r2 = 0.74 p<0.01). Sildenafil also lowered mean blood pressure (−12% [−20, +10]; p=0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events. Conclusions Sildenafil demonstrated non-linear exposure with high inter-individual variability but was well tolerated and effectively lowered PVRI in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index. PMID:23823195

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

PubMed

Pasi, K John; Rangarajan, Savita; Georgiev, Pencho; Mant, Tim; Creagh, Michael D; Lissitchkov, Toshko; Bevan, David; Austin, Steve; Hay, Charles R; Hegemann, Inga; Kazmi, Rashid; Chowdary, Pratima; Gercheva-Kyuchukova, Liana; Mamonov, Vasily; Timofeeva, Margarita; Soh, Chang-Heok; Garg, Pushkal; Vaishnaw, Akshay; Akinc, Akin; Sørensen, Benny; Ragni, Margaret V

2017-08-31

Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Psychological characteristics, stressful life events and deliberate self-harm: findings from the Child & Adolescent Self-harm in Europe (CASE) Study.

PubMed

Madge, Nicola; Hawton, Keith; McMahon, Elaine M; Corcoran, Paul; De Leo, Diego; de Wilde, Erik Jan; Fekete, Sandor; van Heeringen, Kees; Ystgaard, Mette; Arensman, Ella

2011-10-01

There is evidence to suggest that both psychological characteristics and stressful life events are contributory factors in deliberate self-harm among young people. These links, and the possibility of a dose-response relationship between self-harm and both psychological health and life events, were investigated in the context of a seven-country school-based study. Over 30,000, mainly 15 and 16 year olds, completed anonymous questionnaires at secondary schools in Belgium, England, Hungary, Ireland, the Netherlands, Norway and Australia. Pupils were asked to report on thoughts and episodes of self-harm, complete scales on depression and anxiety symptoms, impulsivity and self-esteem and indicate stressful events in their lives. Level and frequency of self-harm was judged according to whether they had thought about harming themselves or reported single or multiple self-harm episodes. Multinomial logistic regression assessed the extent to which psychological characteristics and stressful life events distinguished between adolescents with different self-harm histories. Increased severity of self-harm history was associated with greater depression, anxiety and impulsivity and lower self-esteem and an increased prevalence of all ten life event categories. Female gender, higher impulsivity and experiencing the suicide or self-harm of others, physical or sexual abuse and worries about sexual orientation independently differentiated single-episode self-harmers from adolescents with self-harm thoughts only. Female gender, higher depression, lower self-esteem, experiencing the suicide or self-harm of others, and trouble with the police independently distinguished multiple- from single-episode self-harmers. The findings reinforce the importance of psychological characteristics and stressful life events in adolescent self-harm but nonetheless suggest that some factors are more likely than others to be implicated.

Effects of an injectable trace mineral supplement on first-service conception rate of dairy cows.

PubMed

Vanegas, J A; Reynolds, J; Atwill, E R

2004-11-01

A total of 825 dairy cows from a commercial dairy farm in central California were used to evaluate effects of one or 2 doses of an injectable trace mineral supplement containing 20 mg/mL of zinc, 20 mg/mL of manganese, 5 mg/mL of selenium, and 10 mg/mL of copper on first-service conception rate. Cows were randomly allocated into treatment or control group to either a single dose (experiment 1) or a double dose (experiment 2) of injected supplement. Allocation was based on days in lactation for experiment 1 and the length of gestation periods for experiment 2. In experiment 1, cows 38 to 45 d in lactation (n = 190) received a single dose of 5 mL of injected supplement. Similar cows were used as controls (n = 227). In experiment 2, cows and pregnant heifers received an initial injection of 5 mL of the mineral supplement from 2 to 3 wk precalving (n = 186). An equal dose was repeated 38 to 45 d in lactation. A similar group of cows and pregnant heifers served as controls for experiment 2 (n = 222). Health and reproductive events postcalving were recorded. In experiment 1, the odds of first-service conception were not significantly different for cows receiving a one-dose regimen of minerals compared with untreated control cows; conception rates were 26.8 and 27.5% for experiment 1 treatment and control groups, respectively. In experiment 1, the odds of first-service conception were significantly lower (odds ratio = 0.66) for cows and heifers given the 2-dose regimen of minerals compared with untreated controls; overall conception rates were 21.5 and 31.5% for experiment 2 treatment and control groups, respectively. In this intensively managed dairy herd, a single dose of injected trace minerals before breeding had no beneficial effects on first-service conception rate. However, dairy cows receiving a dose of trace minerals before calving and another dose before breeding had lower conception at first service.

Bioavailability of oral carisoprodol 250 and 350 mg and metabolism to meprobamate: A single-dose crossover study

PubMed Central

Simon, Steve; D’Andrea, Carrie; Wheeler, William J.; Sacks, Harry

2010-01-01

Background: Carisoprodol is a skeletal muscle relaxant indicated for use in the treatment of acute, painful musculoskeletal conditions. Two randomized, controlled clinical trials have reported that carisoprodol 250 mg QID was equally effective as and better tolerated than carisoprodol 350 mg QID. Objectives: The primary objective of the current study was to determine the relative bioavailability of carisoprodol and its metabolite, meprobamate, with singledose administration of 250- and 350-mg tablets. A secondary objective of the study was to determine whether lowering the carisoprodol dose would decrease plasma meprobamate concentrations. Methods: This single-dose, randomized, open-label, crossover study enrolled healthy volunteers. Each dose was administered with water in the morning; after a 7-day washout, subjects received the alternate dose. Blood samples were drawn at prespecified times over a 48-hour period. For tolerability assessment, subjects underwent a physical examination, including 12-lead ECG. Results: A total of 24 subjects were enrolled (12 men, 12 women; mean age, 22.8 years). The dose-adjusted AUC0−∞ values for carisoprodol were 5.29 μg/mL/h with the 250-mg tablet and 5.75 μg/mL/h with the 350-mg tablet (relative bioavailability, 92%). The mean (SD) Cmax values of carisoprodol and meprobamate after administration of the 250-mg carisoprodol tablet were 1.24 (0.49) and 1.84 (0.31) μg/mL, respectively, compared with 1.78 (0.97) and 2.46 (0.47) μg/mL with the 350-mg tablet. AUC0−∞ was dose proportional, and the apparent t1/2 values at the terminal phase were 1.74 hours with the 250-mg tablet and 1.96 hours with the 350-mg tablet. There were 3 mild adverse events considered possibly treatment related (weakness, dizziness, and drowsiness); these were reported in 2 subjects with 350-mg carisoprodol. Conclusions: In this small study in healthy fasting subjects, the exposure to carisoprodol and meprobamate was dose proportional between the single 250- and 350-mg doses. Both doses were generally well tolerated. PMID:24683250

Comparison of a four-drug fixed-dose combination regimen with a single tablet regimen in smear-positive pulmonary tuberculosis.

PubMed

Bartacek, A; Schütt, D; Panosch, B; Borek, M

2009-06-01

To compare the efficacy, safety and acceptability of two short-course regimens of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) given either as fixed-dose combination (4-FDC) tablets or as single tablets (ST) in patients with newly diagnosed pulmonary tuberculosis (PTB). This randomised, open, multicentre, multinational study was conducted in 26 centres and included 1159 patients with smear-positive PTB. 4-FDC daily for 2 months then H+R for 4 months, or single preparations of H, R, Z and E for 2 months followed by H and R for 4 months were administered daily. Sputum smear conversion rates at 2, 4 and 6 months (end of treatment [EOT], primary endpoint) and at 9 and 12 months (follow-up) were measured, together with adverse events and the acceptability of the formulations. Smear conversion rates for 4-FDC and ST at EOT were 80.4% (468/582 patients) vs. 82.7% (477/577) in the intent-to-treat (ITT) population, and 98.1% (404/412) vs. 98.6% (416/422) in the per-protocol (PP) subgroup. Non-inferiority of 4-FDC was demonstrated at month 2, EOT and follow-up in both the ITT and the PP populations. Overall numbers of adverse events were not significantly different between the groups. The efficacy of the 4-FDC regimen was non-inferior to that of the ST regimens, but patient acceptability significantly improved with 4-FDC.

Effective treatment of laparoscopic cholecystectomy pain with intravenous followed by oral COX-2 specific inhibitor.

PubMed

Joshi, Girish P; Viscusi, Eugene R; Gan, Tong J; Minkowitz, Harold; Cippolle, Mark; Schuller, Rienhard; Cheung, Raymond Y; Fort, John G

2004-02-01

In this multicenter, double-blinded, randomized, placebo-controlled study we evaluated the analgesic and opioid-sparing efficacy of a preoperative dose of i.v. parecoxib followed by oral valdecoxib in treating pain associated with elective laparoscopic cholecystectomy. Patients were randomized to receive a single i.v. dose of parecoxib 40 mg (n = 134) or placebo (n = 129) 30-45 min before induction of anesthesia. Six to 12 h after the i.v. dose, the parecoxib group received a single oral dose of valdecoxib 40 mg, followed by valdecoxib 40 mg qd on postoperative days 1-4, then 40 mg qd prn days 5-7. The placebo i.v. group received oral placebo on an identical schedule. All patients were allowed supplemental i.v. fentanyl as needed during the first 4 h postoperatively (T0-240 min) followed by hydrocodone 5 mg/acetaminophen 500 mg (Vicodin(R); 1-2 tablets orally every 4-6 h as needed). Patients taking parecoxib used 21% less fentanyl than those receiving placebo (P = 0.011). The mean area under the curve of pain intensity (PI) scores over time from T0-240 min was 55.2 for parecoxib and 61.2 for placebo (P = 0.083). At T180 and T240 min, mean PI score was 7.0 and 7.6 points lower in the parecoxib group, respectively (P < 0.02). Fewer patients on valdecoxib required supplemental analgesics (P < 0.05) after discharge. At T240 min and at day 7, Patient's and Physician's/Nurse's Global Evaluations were significantly better in the parecoxib/valdecoxib group (P < 0.05). Incidences of adverse events, adverse events causing withdrawal, and serious adverse events were less for parecoxib/valdecoxib than for placebo. The authors conclude that preoperative parecoxib is a valuable opioid-sparing adjunct to the standard of care for treating pain after laparoscopic cholecystectomy, and subsequent treatment with oral valdecoxib extends this clinical benefit. Parecoxib 40 mg i.v., 30-45 min preoperatively followed by oral valdecoxib 40 mg qd reduced opioid requirements and provided superior pain relief as well as improved patient global evaluation after laparoscopic cholecystectomy.

Bioavailability in healthy adults of efavirenz capsule contents mixed with a small amount of food.

PubMed

Kaul, Sanjeev; Ji, Ping; Lu, Michael; Nguyen, Kim L; Shangguan, Tong; Grasela, Dennis

2010-02-01

The effect of mixing the contents of efavirenz capsules (sprinkles) with a small amount of food on the bioavailability and pharmacokinetics of efavirenz in healthy adults was evaluated. In a randomized, three-period, crossover study, 24 healthy adult subjects were divided equally into two groups. Group I received treatments A, B, and C, and those in group II received treatments A, D, and E. Treatment A was three efavirenz 200-mg intact capsules under fasting conditions. Treatments B, C, D, and E were three efavirenz 200-mg capsule contents mixed with two teaspoons of applesauce, grape jelly, yogurt, or infant formula, respectively. A single dose was given on days 1, 21, and 41. The steady-state mean maximum observed concentration, time of maximum observed concentration, area under the concentration-time curve (AUC) half-life, taste, and safety were assessed. The AUC after administration of a single 600-mg dose of efavirenz sprinkles mixed with two teaspoons of any of the food vehicles to healthy adults was bioequivalent to a 600-mg efavirenz dose given as intact capsules under fasting conditions. Subjects rated efavirenz mixed with grape jelly as the most palatable. Adverse events and laboratory abnormalities were similar for all treatments. The AUC of efavirenz 600 mg administered as capsule sprinkles with two teaspoons of applesauce, grape jelly, yogurt, or infant formula was bioequivalent to a single dose of efavirenz 600 mg given as intact capsules under fasting conditions in healthy adults.

Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization.

PubMed

Langenickel, Thomas H; Jordaan, Pierre; Petruck, Jesika; Kode, Kiran; Pal, Parasar; Vaidya, Soniya; Chandra, Priya; Rajman, Iris

2016-08-01

Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction. This study was aimed to evaluate the effect of single oral therapeutic (400 mg) and supratherapeutic (1200 mg) doses of LCZ696 on cardiac repolarization. This randomized double-blind crossover study in healthy male subjects compared the effect of therapeutic and supratherapeutic doses of LCZ696 with placebo and moxifloxacin 400 mg (open-label treatment) as positive control. The primary assessment was mean baseline- and placebo-corrected QTcF (∆∆QTcF; Fridericia correction). Additional assessments included the ∆∆QTcB (Bazett's correction), PR interval, QRS duration, heart rate (HR), LCZ696 pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and safety. Of the 84 subjects enrolled, 81 completed the study. The maximum upper bound of the two-sided 90 % confidence interval for ∆∆QTcF for LCZ696 400 mg and 1200 mg were <10 ms, and assay sensitivity was confirmed with moxifloxacin. No relevant treatment-emergent changes were observed in any of the ECG-derived parameters with LCZ696 or placebo, and the incidence of adverse events was comparable among the treatment groups. Single therapeutic and supratherapeutic doses of LCZ696 did not affect cardiac repolarization as defined by the E14 ICH guidelines.

Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model

NASA Astrophysics Data System (ADS)

Cekanova, Maria; Uddin, Md. Jashim; Legendre, Alfred M.; Galyon, Gina; Bartges, Joseph W.; Callens, Amanda; Martin-Jimenez, Tomas; Marnett, Lawrence J.

2012-11-01

We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1 mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1 mg/kg showed a peak of fluorocoxib A (92±28 ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.

Changes in HbA1c, insulin dose and incidence of hypoglycemia in patients with type 1 diabetes after switching to insulin degludec in an outpatient setting: an observational study.

PubMed

Landstedt-Hallin, Lena

2015-08-01

Insulin degludec, a basal insulin with an ultra-long duration of action, became available in Sweden from July 2013. The diabetes team at Danderyd Hospital decided to perform a clinical follow-up of patients with type 1 diabetes switching to insulin degludec to evaluate its clinical performance, using a simple form and available measures, thereby indirectly assessing cost-effectiveness. This was a prospective, open-label, single-arm, observational, clinical follow-up from August 2013 to February 2015 of consecutive patients who switched to insulin degludec according to predefined indications (i.e., currently administering basal insulin twice daily, unacceptable HbA1c, repeated hypoglycemic events and/or unstable glucose, difficulty with fixed-time administration) in conjunction with professional judgment and patient wishes. Information about HbA1c, insulin dose and frequency of hypoglycemia (self-reported by patient recall) was collected at baseline and repeated after 4-6 months. In February 2015, data were available on 357 patients. Median time to follow-up was 20 weeks. Mean (SD) HbA1c decreased from 68.9 (15.7) to 65.8 (14.3) mmol/mol, p < 0.0001, and this improvement was achieved despite less insulin. Median reduction of the total insulin dose (basal + prandial) was 12% (interquartile range [IQR] -20% to -3%). The mean (SD) number of self-reported hypoglycemic events in the previous 4 weeks decreased from 8.2 (8.9) to 6.4 (7.6) events, p < 0.0001, and nocturnal hypoglycemic events were reduced from 1.6 (2.9) to 0.7 (2.0) events, p < 0.0001. Due to improvement in glycemic control, reduction of hypoglycemic events and reduction of insulin dose, we concluded that insulin degludec was clinically useful and economically justifiable for our patients with type 1 diabetes. Not every patient may benefit to the same degree after switching to insulin degludec. Controlled studies are needed to confirm these benefits in a larger sample of real-world patients.

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

PubMed

Stein, Eytan M; Garcia-Manero, Guillermo; Rizzieri, David A; Tibes, Raoul; Berdeja, Jesus G; Savona, Michael R; Jongen-Lavrenic, Mojca; Altman, Jessica K; Thomson, Blythe; Blakemore, Stephen J; Daigle, Scott R; Waters, Nigel J; Suttle, A Benjamin; Clawson, Alicia; Pollock, Roy; Krivtsov, Andrei; Armstrong, Scott A; DiMartino, Jorge; Hedrick, Eric; Löwenberg, Bob; Tallman, Martin S

2018-05-03

Pinometostat (EPZ-5676) is a first-in-class, small-molecule inhibitor of the histone methyltransferase DOT1L. In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving MLL rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose escalation cohorts (n=26) and 2 expansion cohorts (n=25) at pinometostat doses of 54 and 90 mg/m 2 /day by continuous intravenous infusion in 28-day cycles. As a maximum tolerated dose was not established in the dose escalation phase, the expansion doses were selected based upon safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remissions at 54 mg/m 2 /day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as no. NCT01684150. Copyright © 2018 American Society of Hematology.

Open-Label Single-Sequence Crossover Study Evaluating Pharmacokinetics, Efficacy, and Safety of Once-Daily Dosing of Nitisinone in Patients with Hereditary Tyrosinemia Type 1.

PubMed

Guffon, Nathalie; Bröijersén, Anders; Palmgren, Ingrid; Rudebeck, Mattias; Olsson, Birgitta

2018-01-01

Although nitisinone is successfully used to treat hereditary tyrosinemia type 1 (HT-1) with the recommended twice-daily dosing, data describing a long half-life motivate less frequent dosing. Therefore, in agreement with the Pharmacovigilance Risk Assessment Committee at the European Medicines Agency, this study was performed to investigate the switch to once-daily dosing. This open-label, non-randomized, single-sequence crossover study evaluated the pharmacokinetics, efficacy, and safety of once-daily compared to twice-daily dosing of nitisinone in patients with HT-1 (NCT02323529). Well-controlled patients of <2, 2 to <12, 12 to <18, and ≥18 years of age who were on twice-daily dosing were eligible for participation. Nitisinone and succinylacetone levels were determined from dry blood spots by tandem mass spectrometry. The primary endpoint was C min of nitisinone after ≥4 weeks of treatment on each dosing regimen. Secondary objectives were evaluation of efficacy and safety during each dosing regimen. In total, 19 patients were enrolled and 17 included in the per-protocol analysis set. The mean (SD) nitisinone C min decreased by 23%, from 26.4 (10.2) to 21.2 (9.9) μmol/L in dry blood spot samples (not equivalent to plasma concentrations), when patients switched from twice- to once-daily dosing. There was no apparent age- or bodyweight-related trend in the degree of C min decrease. No patient had quantifiable succinylacetone levels during the once-daily treatment period, indicating efficacious treatment. All adverse events were mild or moderate and judged unrelated to nitisinone. The switch to once-daily treatment with nitisinone appeared efficacious and safe in the treatment of patients with HT-1.

The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.

PubMed

Simon, Ted W; Simons, S Stoney; Preston, R Julian; Boobis, Alan R; Cohen, Samuel M; Doerrer, Nancy G; Fenner-Crisp, Penelope A; McMullin, Tami S; McQueen, Charlene A; Rowlands, J Craig

2014-08-01

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs.

Anaphylaxis following intravenous ranitidine: A rare adverse reaction of a common drug

PubMed Central

Chopra, Deepti; Arora, Pooja; Khan, Shamimullah; Dwivedi, Shridhar

2014-01-01

Ranitidine hydrochloride is a widely used drug that is generally well-tolerated. Anaphylaxis is rarely observed with ranitidine. We report a case who developed severe anaphylaxis following single dose of intravenous ranitidine. The article highlights the importance of recognition of this serious adverse event and re-emphasizes the need for cautious use of drugs, especially in those with known history of allergy. PMID:24741203

TID and SEE Response of an Advanced Samsung 4G NAND Flash Memory

NASA Technical Reports Server (NTRS)

Oldham, Timothy R.; Friendlich, M.; Howard, J. W.; Berg, M. D.; Kim, H. S.; Irwin, T. L.; LaBel, K. A.

2007-01-01

Initial total ionizing dose (TID) and single event heavy ion test results are presented for an unhardened commercial flash memory, fabricated with 63 nm technology. Results are that the parts survive to a TID of nearly 200 krad (SiO2), with a tractable soft error rate of about 10(exp -l2) errors/bit-day, for the Adams Ten Percent Worst Case Environment.

Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study

PubMed Central

Schlesinger, Naomi; Mysler, Eduardo; Lin, Hsiao-Yi; De Meulemeester, Marc; Rovensky, Jozef; Arulmani, Udayasankar; Balfour, Alison; Krammer, Gerhard; Sallstig, Peter; So, Alexander

2011-01-01

Objective This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1β monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment. Methods In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4×4-weekly doses of canakinumab (50+50+25+25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks. Results A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses ≥50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28–0.38, p≤0.0083), and the percentage of patients experiencing ≥1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing ≥1 flare for canakinumab doses ≥50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28–0.36, p≤0.05). The incidence of adverse events was similar across treatment groups. Conclusions Single canakinumab doses ≥50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg. PMID:21540198

A phase 1 trial of 2 dose schedules of ABT-510, an antiangiogenic, thrombospondin-1-mimetic peptide, in patients with advanced cancer.

PubMed

Gordon, Michael S; Mendelson, David; Carr, Robert; Knight, Raymond A; Humerickhouse, Rod A; Iannone, Maria; Stopeck, Alison T

2008-12-15

ABT-510 is a substituted nonapeptide that mimics the antiangiogenic activity of the endogenous protein thrombospondin-1 (TSP-1). The current study was designed to establish the safety of ABT-510 in the treatment of patients with advanced malignancies on a once-daily (QD) and twice-daily dosing schedule. Patients were randomly assigned to 1 of 6 dosing regimens: 20 mg, 50 mg, or 100 mg QD or 10 mg, 25 mg, or 50 mg twice daily. ABT-510 was administered by subcutaneous bolus injection in cycles of 28 days. Tumor response and disease progression were monitored at 8-week intervals by computed tomography scan or magnetic resonance imaging. Thirty-six patients were randomly assigned in equal numbers to the 6 study regimens, with an additional 13 patients randomized to the 10-mg-twice-daily and 50-mg-twice-daily ABT-510 regimens. The expected pharmacokinetic target was achieved at all dose levels tested. The majority of adverse events were grade 1 or 2 (according to National Cancer Institute Common Toxicity Criteria [version 2]) and were not found to be dose related. The most frequently reported adverse events that were possibly related to ABT-510 included injection site reactions, asthenia, headache, and nausea. Grade 3 events considered to possibly be related included nausea, dyspnea, bone pain, constipation, vomiting, asthenia, and chills and tremors. One partial response was observed in a patient with carcinosarcoma who received 20 mg QD. The 6-month progression-free survival rate was 6%. Approximately 42% of patients (21 of 50 patients) had stable disease for > or =3 months. ABT-510 can be administered at doses of 20 mg/day to 100 mg/day without significant toxicity. In the current study, minimal antitumor activity was observed, which was similar to observations in other single-agent antiangiogenic trials.

A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors.

PubMed

Aghajanian, Carol; Bell-McGuinn, Katherine M; Burris, Howard A; Siu, Lillian L; Stayner, Lee-Ann; Wheler, Jennifer J; Hong, David S; Kurkjian, Carla; Pant, Shubham; Santiago-Walker, Ademi; Gauvin, Jennifer L; Antal, Joyce M; Opalinska, Joanna B; Morris, Shannon R; Infante, Jeffrey R

2018-04-03

Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257.

The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study

PubMed Central

2013-01-01

Background Empagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment. This QT interval study assessed potential effects of empagliflozin on ventricular repolarisation and other electrocardiogram (ECG) parameters. Methods A randomised, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design to reduce sample size, while maintaining full statistical power. Treatments: single empagliflozin doses of 25 mg (therapeutic) and 200 mg (supratherapeutic), matching placebo and open-label moxifloxacin 400 mg (positive control). Triplicate 12-lead ECGs of 10 second duration were recorded at baseline and during the first 24 hours after dosing. The primary endpoint was mean change from baseline (MCfB) in the population heart rate-corrected QT interval (QTcN) between 1–4 hours after dosing. Results Thirty volunteers (16 male, 14 female, mean [range] age: 34.5 [18–52] years) were randomised. The placebo-corrected MCfB in QTcN 1–4 hours after dosing was 0.6 (90% CI: -0.7, 1.9) ms and -0.2 (-1.4, 0.9) ms for empagliflozin 25 mg and 200 mg, respectively, below the ICH E14 defined threshold of regulatory concern 10 ms. Assay sensitivity was confirmed by a placebo-corrected MCfB in QTcN 2–4 hours post-dose of 12.4 (10.7, 14.1) ms with moxifloxacin 400 mg. Empagliflozin tolerability was good for all volunteers; 23.3% experienced adverse events (AEs) with empagliflozin and 27.6% with placebo. The most frequent AE was nasopharyngitis. Conclusions/interpretation Single doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers. Trial registration ClinicalTrials.gov: NCT01195675 PMID:23617452

Pharmacokinetic characteristics of telaprevir in healthy Korean male subjects and comparisons with Japanese.

PubMed

Choi, Yewon; Yoon, Seonghae; Matsumoto, Kyoko; Ohta, Yoshiyasu; Lee, SeungHwan; Yu, Kyung-Sang; Jang, In-Jin

2018-01-01

Telaprevir, a reversible selective inhibitor of viral protease and a potential blocker of viral replication, is indicated for the treatment of hepatitis C virus genotype 1 infection. In this study, the pharmacokinetic profile, safety, and tolerability of telaprevir and the effect of food on telaprevir exposure were evaluated in healthy Korean subjects, and compared with data from a previous study in Japanese male subjects. The single ascending dose study was conducted in 3 dose-based groups (500, 750, and 1,250 mg, six subjects each) in a fasted state. In the multiple dose study, eight subjects in the fed state received 750 mg of telaprevir once on Day 1 and every 8 hours from Day 2 until the morning of Day 6. Serial blood samples for pharmacokinetic analysis were collected for up to 24 hours in the single ascending dose study and for 6 days in the multiple dose study. Individual pharmacokinetic parameters were calculated using a non-compartmental analysis method. Safety and tolerability profiles were evaluated throughout the study. Following multiple administrations of telaprevir, maximum plasma concentrations (C max ), area under the concentration-time curve (AUC 0-8 ), and C trough (concentration at 8 h after drug administration) increased by ~2.41-fold. Compared to fasted state values, mean C max and AUC 0-24 increased by 4.92- and 4.81-fold, respectively, after food intake. The C max and AUC inf of Korean subjects were 26%-34% higher than those of Japanese subjects; however, these differences were not clinically significant. All observed adverse events were mild and there was no discontinuation due to AEs. In conclusion, the telaprevir's pharmacokinetic characteristics were similar in Korean and Japanese subjects. Telaprevir was well tolerated in a single dose of up to 1,250 mg and in multiple doses of 750 mg.

Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206.

PubMed

Adra, N; Einhorn, L H; Althouse, S K; Ammakkanavar, N R; Musapatika, D; Albany, C; Vaughn, D; Hanna, N H

2018-01-01

Despite remarkable results with salvage standard-dose or high-dose chemotherapy ∼15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT. Single arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized. Twelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1-32, 760) and hCG 4 (range 0.6-37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1-8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining. This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. NCT02499952. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Relative bioavailability of generic and branded 250-mg and 500-mg oral chlorphenesin carbamate tablets in healthy Korean volunteers: a single-dose, randomized-sequence, open-label, two-period crossover trial.

PubMed

Yu, Ji-young; Song, Hyun Ho; Kim, Bo Gyeom; Park, Hyeon Ju; Choi, Kwang Sik; Kwon, Young Ee

2009-11-01

Chlorphenesin carbamate is a skeletal muscle relaxant approved in Korea for use in the treatment of pain and discomfort related to skeletal muscle trauma and inflammation. The aim of this study was to assess the bioequivalence of a generic formulation of chlorphenesin carbamate at doses of 250 and 500 mg and 2 branded formulations of the same doses in healthy Korean adults. This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Korean male and female volunteers. Subjects were assigned to receive, in a randomized sequence, a single dose of the generic (test) and branded (reference) formulations of chlorphenesin carbamate at a dose of 250 or 500 mg. Blood samples were drawn at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, and 15 hours after administration. Pharmacokinetic properties (C(max), T(max), AUC(0-t) AUC(0-infinity), t(1/2), and ke) were determined using HPLC. The formulations were to be considered bioequivalent if the 90% CIs of the treatment ratios of the geometric means of C(max) and AUC(0-t) were within a predetermined range of log 0.80 to log 1.25 based on regulatory criteria. Tolerability was assessed by monitoring for adverse events (AEs) on physical examination and/or e-mail and personal interview at the beginning and end of each study period. Twenty-eight subjects (22 men, 6 women) received chlorphenesin carbamate at the 250-mg dose, and 24 male subjects received the 500-mg dose. The mean (SD) ages of the subjects were 24.0 (2.6) and 24.0 (1.9) years in the 250- and 500-mg groups, respectively. No significant differences were found between the test and reference formulations (90% CIs: C(max), 1.0048-1.1153 with the 250-mg dose and 0.9630-1.1189 with the 500-mg dose; AUC(0-t), 0.9882-1.0546 and 0.9842-1.0578, respectively). No clinically significant AEs (upper gastric pain, abdominal bloating, pyrexia, edema, nausea, heartburn, constipation, headache, dizziness, drowsiness, or fatigue) were reported throughout the study. In this single-dose study in these healthy Korean subjects, the generic and branded formulations of chlorphenesin carbamate 250 and 500 mg met the regulatory criteria for bioequivalence. All formulations were well tolerated. Copyright 2009 Excerpta Medica Inc. All rights reserved.

Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor.

PubMed

Herman, Ann E; Chinn, Leslie W; Kotwal, Shweta G; Murray, Elaine R; Zhao, Rui; Florero, Marilyn; Lin, Alyse; Moein, Anita; Wang, Rena; Bremer, Meire; Kokubu, Serika; Serone, Adrian P; Hanze, Eva L; Viberg, Anders; Morimoto, Alyssa M; Winter, Helen R; Katsumoto, Tamiko R

2018-06-01

GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications. © 2018 American Society for Clinical Pharmacology and Therapeutics.

Oxantel pamoate-albendazole for Trichuris trichiura infection.

PubMed

Speich, Benjamin; Ame, Shaali M; Ali, Said M; Alles, Rainer; Huwyler, Jörg; Hattendorf, Jan; Utzinger, Jürg; Albonico, Marco; Keiser, Jennifer

2014-02-13

Infections with soil-transmitted helminths (Ascaris lumbricoides, hookworm, and Trichuris trichiura) are widespread and often occur concomitantly. These parasitic-worm infections are typically treated with albendazole or mebendazole, but both drugs show low efficacy against T. trichiura. Albendazole is the drug of choice against hookworm. In this double-blind trial conducted on Pemba Island, Tanzania, we randomly assigned children, 6 to 14 years of age, to receive one of four treatments: oxantel pamoate at a dose of 20 mg per kilogram of body weight, plus 400 mg of albendazole, administered on consecutive days; oxantel pamoate at a single dose of 20 mg per kilogram; albendazole at a single dose of 400 mg; or mebendazole at a single dose of 500 mg. We assessed the efficacy and safety profile of oxantel pamoate-albendazole when used in the treatment of T. trichiura infection (primary outcome) and concomitant soil-transmitted helminth infection (secondary outcome). Efficacy was determined by means of assessment of the cure rate and egg-reduction rate. Adverse events were assessed four times after treatment. Complete data were available for 458 children, of whom 450 were infected with T. trichiura, 443 with hookworm, and 293 with A. lumbricoides. The cure rate of T. trichiura infection was significantly higher with oxantel pamoate-albendazole than with mebendazole (31.2% vs. 11.8%, P=0.001), as was the egg-reduction rate (96.0% [95% confidence interval {CI}, 93.5 to 97.6] vs. 75.0% [95% CI, 64.2 to 82.0]). The cure rate with albendazole (2.6%) and the egg-reduction rate with albendazole (45.0%; 95% CI, 32.0 to 56.4) were significantly lower than the rates with mebendazole (P=0.02 for the comparison of cure rates). Oxantel pamoate had low efficacy against hookworm and A. lumbricoides. Adverse events (mainly mild) were reported by 30.9% of all children. Treatment with oxantel pamoate-albendazole resulted in higher cure and egg-reduction rates for T. trichiura infection than the rates with standard therapy. (Funded by the Medicor Foundation and the Swiss National Science Foundation; Current Controlled Trials number, ISRCTN54577342.).

Toxicogenomics and cancer risk assessment: a framework for key event analysis and dose-response assessment for nongenotoxic carcinogens.

PubMed

Bercu, Joel P; Jolly, Robert A; Flagella, Kelly M; Baker, Thomas K; Romero, Pedro; Stevens, James L

2010-12-01

In order to determine a threshold for nongenotoxic carcinogens, the traditional risk assessment approach has been to identify a mode of action (MOA) with a nonlinear dose-response. The dose-response for one or more key event(s) linked to the MOA for carcinogenicity allows a point of departure (POD) to be selected from the most sensitive effect dose or no-effect dose. However, this can be challenging because multiple MOAs and key events may exist for carcinogenicity and oftentimes extensive research is required to elucidate the MOA. In the present study, a microarray analysis was conducted to determine if a POD could be identified following short-term oral rat exposure with two nongenotoxic rodent carcinogens, fenofibrate and methapyrilene, using a benchmark dose analysis of genes aggregated in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) biological processes, which likely encompass key event(s) for carcinogenicity. The gene expression response for fenofibrate given to rats for 2days was consistent with its MOA and known key events linked to PPARα activation. The temporal response from daily dosing with methapyrilene demonstrated biological complexity with waves of pathways/biological processes occurring over 1, 3, and 7days; nonetheless, the benchmark dose values were consistent over time. When comparing the dose-response of toxicogenomic data to tumorigenesis or precursor events, the toxicogenomics POD was slightly below any effect level. Our results suggest that toxicogenomic analysis using short-term studies can be used to identify a threshold for nongenotoxic carcinogens based on evaluation of potential key event(s) which then can be used within a risk assessment framework. Copyright © 2010 Elsevier Inc. All rights reserved.

Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study.

PubMed

Llanos-Cuentas, Alejandro; Lacerda, Marcus V; Rueangweerayut, Ronnatrai; Krudsood, Srivicha; Gupta, Sandeep K; Kochar, Sanjay K; Arthur, Preetam; Chuenchom, Nuttagarn; Möhrle, Jörg J; Duparc, Stephan; Ugwuegbulam, Cletus; Kleim, Jörg-Peter; Carter, Nick; Green, Justin A; Kellam, Lynda

2014-03-22

Clinical effectiveness of previous regimens to treat Plasmodium vivax infection have been hampered by compliance. We aimed to assess the dose-response, safety, and tolerability of single-dose tafenoquine plus 3-day chloroquine for P vivax malaria radical cure. In this double-blind, randomised, dose-ranging phase 2b study, men and women (aged ≥16 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to <100,000 per μL blood) were enrolled from community health centres and hospitals across seven sites in Brazil, Peru, India, and Thailand. Patients with glucose-6-phosphate dehydrogenase enzyme activity of less than 70% were excluded. Eligible patients received chloroquine (days 1-3) and were randomly assigned (1:1:1:1:1:1) by a computer-generated randomisation schedule to receive single-dose tafenoquine 50 mg, 100 mg, 300 mg, or 600 mg, primaquine 15 mg for 14 days, or chloroquine alone. Randomisation was stratified by baseline parasite count (≤7500 and >7500 per μL blood). The primary efficacy endpoint was relapse-free efficacy at 6 months from initial dose (ie, clearance of initial infection without subsequent microscopically confirmed infection), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01376167. Between Sept 19, 2011, and March 25, 2013, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or to chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 57·7% (95% CI 43-70) with tafenoquine 50 mg, 54·1% (40-66) with tafenoquine 100 mg, 89·2% (77-95) with tafenoquine 300 mg, 91·9% (80-97) with tafenoquine 600 mg, 77·3% (63-87) with primaquine, and 37·5% (23-52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51·7% [95% CI 35-69], p<0·0001, with tafenoquine 300 mg and 54·5% [38-71], p<0·0001, with tafenoquine 600 mg), as did primaquine (treatment difference 39·9% [21-59], p=0·0004). Adverse events were similar between treatments. 29 serious adverse events occurred in 26 (8%) of 329 patients; QT prolongation was the most common serious adverse event (11 [3%] of 329), occurring in five (2%) of 225 patients receiving tafenoquine, four (8%) of 50 patients receiving primaquine, and two (4%) of 54 patients receiving chloroquine alone, with no evidence of an additional effect on QT of chloroquine plus tafenoquine coadministration. Single-dose tafenoquine 300 mg coadministered with chloroquine for P vivax malaria relapse prevention was more efficacious than chloroquine alone, with a similar safety profile. As a result, it has been selected for further clinical assessment in phase 3. GlaxoSmithKline, Medicines for Malaria Venture. Copyright © 2014 Elsevier Ltd. All rights reserved.

Oral availability of bilastine.

PubMed

Sádaba, B; Gómez-Guiu, A; Azanza, J R; Ortega, I; Valiente, R

2013-05-01

Bilastine (Bilaxten™) is a novel non-sedating H1 receptor antagonist (antihistamine) developed in the dosage form of oral tablets and indicated for the treatment of allergic rhinitis (seasonal and perennial) and urticaria. Several clinical trials have been performed in order to determine the efficacy and safety of bilastine. The aim of this trial was to study the absolute oral bioavailability of bilastine in humans. Twelve male and female adults were recruited into a single centre for a randomized, single-dose, open-label, controlled two-arm crossover study with a minimum 14-day washout period between the two single doses. Two single doses of bilastine were administered: a 20-mg oral tablet and a 10-mg intravenous formulation. Blood and urine samples were collected between 0 and 72 h post each administration. The clinical trial was carried out under quality assurance and quality control systems with standard operating procedures to ensure that the study was conducted and data generated in compliance with the protocol, Good Clinical Practice standards, International Conference on Harmonisation and other applicable regulations. Oral bioavailability of bilastine was 60.67 % with a 90 % parametric confidence interval of 53.79-67.56. The maximum bilastine concentration was measured 1.31 h after oral administration. Pharmacokinetic parameters were similar to those observed in previous studies. Tolerance to treatment was good, with no adverse events related to study medication. The absorption of bilastine after oral administration to healthy subjects was rapid. The absolute oral bioavailability was moderate.

Total Dose Effects on Single Event Transients in Linear Bipolar Systems

NASA Technical Reports Server (NTRS)

Buchner, Stephen; McMorrow, Dale; Bernard, Muriel; Roche, Nicholas; Dusseau, Laurent

2008-01-01

Single Event Transients (SETs) originating in linear bipolar integrated circuits are known to undermine the reliability of electronic systems operating in the radiation environment of space. Ionizing particle radiation produces a variety of SETs in linear bipolar circuits. The extent to which these SETs threaten system reliability depends on both their shapes (amplitude and width) and their threshold energies. In general, SETs with large amplitudes and widths are the most likely to propagate from a bipolar circuit's output through a subsystem. The danger these SET pose is that, if they become latched in a follow-on circuit, they could cause an erroneous system response. Long-term exposure of linear bipolar circuits to particle radiation produces total ionizing dose (TID) and/or displacement damage dose (DDD) effects that are characterized by a gradual degradation in some of the circuit's electrical parameters. For example, an operational amplifier's gain-bandwidth product is reduced by exposure to ionizing radiation, and it is this reduction that contributes to the distortion of the SET shapes. In this paper, we compare SETs produced in a pristine LM124 operational amplifier with those produced in one exposed to ionizing radiation for three different operating configurations - voltage follower (VF), inverter with gain (IWG), and non-inverter with gain (NIWG). Each configuration produces a unique set of transient shapes that change following exposure to ionizing radiation. An important finding is that the changes depend on operating configuration; some SETs decrease in amplitude, some remain relatively unchanged, some become narrower and some become broader.

Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Bapineuzumab: A Single-Ascending-Dose Study in Patients With Mild to Moderate Alzheimer Disease.

PubMed

Lu, Ming; Brashear, H Robert

2018-06-19

This study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending subcutaneous doses of bapineuzumab in patients with mild to moderate Alzheimer disease. Forty patients were randomized across 5 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 80 mg; 8 patients each [bapineuzumab 6; placebo 2]). The incidence of treatment-emergent adverse events (TEAEs) was higher in pooled bapineuzumab cohorts (83%) than in the pooled placebo group (27.7%). Most common TEAEs in the bapineuzumab group were gastrointestinal disorders and musculoskeletal and connective tissue disorders (bapineuzumab 17% each; placebo 0%). Serious TEAEs were observed in 7% of bapineuzumab-treated patients without any deaths or adverse event-related discontinuation. The median times to reach peak measurable concentration (C max ) of bapineuzumab were 14 days for 5-, 10-, and 20-mg cohorts, 11 days for 40-mg, and 7 days for 80-mg cohorts. The apparent volume of distribution of bapineuzumab was 134.29 to 204.68 mL/kg. The total body clearance was consistent at 10 to 80 mg. The average terminal half-life ranged from 26 to 46 days (5- to 80-mg groups). Exposure to bapineuzumab increased dose-proportionally from 10 to 80 mg. There was a positive correlation between C max and area under the concentration-time curve to the last measurable concentration (AUC last ) of plasma amyloid-β, and between the C max and AUC last of serum bapineuzumab. © 2018, The American College of Clinical Pharmacology.

Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial.

PubMed

Pernas, Sonia; Martin, Miguel; Kaufman, Peter A; Gil-Martin, Marta; Gomez Pardo, Patricia; Lopez-Tarruella, Sara; Manso, Luis; Ciruelos, Eva; Perez-Fidalgo, Jose Alejandro; Hernando, Cristina; Ademuyiwa, Foluso O; Weilbaecher, Katherine; Mayer, Ingrid; Pluard, Timothy J; Martinez Garcia, Maria; Vahdat, Linda; Perez-Garcia, Jose; Wach, Achim; Barker, Debra; Fung, Samson; Romagnoli, Barbara; Cortes, Javier

2018-04-26

The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m 2 on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m 2 on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. Polyphor. Copyright © 2018 Elsevier Ltd. All rights reserved.

Single dose oral analgesics for acute postoperative pain in adults

PubMed Central

Moore, R Andrew; Derry, Sheena; McQuay, Henry J; Wiffen, Philip J

2014-01-01

Background Thirty-five Cochrane Reviews of randomised trials testing the analgesic efficacy of individual drug interventions in acute postoperative pain have been published. This overview brings together the results of all those reviews and assesses the reliability of available data. Objectives To summarise data from all Cochrane Reviews that have assessed the effects of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery, who have been given a single dose of oral analgesic taken alone. Methods We identified systematic reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single Review Group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews we extracted the number needed to treat (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, the percentage of participants remedicating by 6, 8, 12, or 24 hours, and results for participants experiencing at least one adverse event. Main results The overview included 35 separate Cochrane Reviews with 38 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 45,000 participants studied in approximately 350 individual studies. The individual reviews included only high-quality trials of standardised design and outcome reporting. The reviews used standardised methods and reporting for both efficacy and harm. Event rates with placebo were consistent in larger data sets. No statistical comparison was undertaken. There were reviews but no trial data were available for acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for dexibuprofen, dextropropoxyphene 130 mg, diflunisal 125 mg, etoricoxib 60 mg, fenbufen, and indometacin. Where there was adequate information for drug/dose combinations (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. Reliable results were obtained for 46 drug/dose combinations in all painful postsurgical conditions; 45 in dental pain and 14 in other painful conditions. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours in the same pain condition. Participants reporting at least one adverse event were few and generally no different between active drug and placebo, with a few exceptions, principally for aspirin and opioids. Drug/dose combinations with good (low) NNTs were ibuprofen 400 mg (2.5; 95% confidence interval (CI) 2.4 to 2.6), diclofenac 50 mg (2.7; 95% CI 2.4 to 3.0), etoricoxib 120 mg (1.9; 95% CI 1.7 to 2.1), codeine 60 mg + paracetamol 1000 mg (2.2; 95% CI 1.8 to 2.9), celecoxib 400 mg (2.5; 95% CI 2.2 to 2.9), and naproxen 500/550 mg (2.7; 95% CI 2.3 to 3.3). Long duration of action (8 hours) was found for etoricoxib 120 mg, diflunisal 500 mg, oxycodone 10 mg + paracetamol 650 mg, naproxen 500/550 mg, and celecoxib 400 mg. Not all participants had good pain relief and for many drug/dose combinations 50% or more did not achieve at last 50% maximum pain relief over four to six hours. Authors’ conclusions There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers. PMID:21901726

A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-04-01

To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, when administered to healthy male subjects. Twelve subjects took part in this fed-fasted cross-over study and received a single dose of THC/CBD spray (4 sprays = 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time-points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC). Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80-14.91 ng/ml) and lower in 5 subjects (2.81-3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97-9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0-t), AUC(0-inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2-2.5 h. Only mild adverse events were reported. The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.

A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition.

PubMed

Cuvier, V; Lorch, U; Witte, S; Olivier, A; Gibot, S; Delor, I; Garaud, J J; Derive, M; Magguilli-Salcedo, M

2018-06-08

The peptide nangibotide is the first clinical-stage agent targeting the immunoreceptor TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) and is being investigated as a novel therapy for acute inflammatory disorders such as septic shock. This first-in-man, randomised, double-blind, ascending dose, placebo-controlled Phase I study evaluated the safety, tolerability, and pharmacokinetics of nangibotide. 27 healthy subjects (aged 18-45 years) were randomised into eight groups. Nangibotide was administered as a single continuous intravenous infusion. The first two groups received a single I.V. dose of 1 and 10 mg, respectively, over 15 min. Subsequent groups were randomised in a product: placebo 3:1 ratio at doses ranging from 0.03 to 6 mg/kg/h over 7 h 45 min, preceded by a 15-minute loading dose of up to 5 mg/kg. Nangibotide was safe and well tolerated up to the highest dose tested. There were only few adverse events and they were mild in severity and considered unrelated to treatment. Nangibotide displayed dose-proportional PK properties, with a clearance of 6.6 L/kg/h for a subject of 70 kg and a 3 min effective half-life, which are compatible with extensive enzymatic metabolism in blood. Central and peripheral volumes of distribution were 16.7 L and 15.9 L respectively, indicating limited distribution of the drug mainly in blood and interstitial fluid. No circulating anti-drug antibodies were detectable up to 28 days after administration. The novel immunomodulator nangibotide displayed favourable safety and PK profiles at all doses, including expected pharmacologically active doses, and warrants further clinical development. This article is protected by copyright. All rights reserved.

Absolute bioavailability and safety of a novel rivastigmine nasal spray in healthy elderly individuals.

PubMed

Morgan, Timothy M; Soh, Bob

2017-03-01

To test the feasibility of a novel rivastigmine nasal spray as prospective treatment for dementia. A single dose, crossover absolute bioavailability and safety study was conducted with rivastigmine intravenous solution (1 mg) and nasal spray (3.126 mg) in eight healthy elderly individuals, aged 58-75 years. Absolute bioavailability (F) of the nasal spray was significant at 0.62 (0.15) for F > 0 (P < 0.001, n = 8). The systemic dose absorbed was 2.0 (0.6) mg, time to maximum plasma concentration was 1.1 (0.5) h and maximum plasma concentration was 6.9 (2.0) ng ml -1 . The NAP226-90 to rivastigmine AUC 0-∞ ratio was 0.78 (0.19). The single dose safety was good with two of five mild adverse events related to the nasal spray. Nasal and throat irritation were perceived as mild and transient, and both had resolved at 20 min post-nasal dose. An estimated dose of two or three sprays twice-daily with nasal spray would deliver comparable rivastigmine exposure and efficacy as a 6-9.7 mg day -1 oral dose and a 10 cm 2 transdermal patch, respectively. The rivastigmine nasal spray had superior absolute bioavailability compared to historical values for oral capsule and transdermal patch determined by other researchers. It had rapid onset of action, low NAP226-90 to rivastigmine exposure ratio and a favourable safety and tolerability profile. The ability to achieve adjustable, individual, twice-daily dosing during waking hours has good potential to minimise undesirable cholinergic burden and sleep disturbances whilst delivering an effective dose for the treatment of dementia associated with Alzheimer's and Parkinson's disease. © 2016 The British Pharmacological Society.

A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload

PubMed Central

Neufeld, Ellis J.; Galanello, Renzo; Viprakasit, Vip; Aydinok, Yesim; Piga, Antonio; Harmatz, Paul; Forni, Gian Luca; Shah, Farrukh T.; Grace, Rachael F.; Porter, John B.; Wood, John C.; Peppe, Jennifer; Jones, Amber

2012-01-01

This was a 24-week, multicenter phase- 2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was −0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators. This trial was registered at www.clinicaltrials.gov as NCT01186419. PMID:22251482

Balanced propofol sedation administered by nonanesthesiologists: The first Italian experience

PubMed Central

Repici, Alessandro; Pagano, Nico; Hassan, Cesare; Carlino, Alessandra; Rando, Giacomo; Strangio, Giuseppe; Romeo, Fabio; Zullo, Angelo; Ferrara, Elisa; Vitetta, Eva; Ferreira, Daniel de Paula Pessoa; Danese, Silvio; Arosio, Massimo; Malesci, Alberto

2011-01-01

AIM: To assess the efficacy and safety of a balanced approach using midazolam in combination with propofol, administered by non-anesthesiologists, in a large series of diagnostic colonoscopies. METHODS: Consecutive patients undergoing diagnostic colonoscopy were sedated with a single dose of midazolam (0.05 mg/kg) and low-dose propofol (starter bolus of 0.5 mg/kg and repeated boluses of 10 to 20 mg). Induction time and deepest level of sedation, adverse and serious adverse events, as well as recovery times, were prospectively assessed. Cecal intubation and adenoma detection rates were also collected. RESULTS: Overall, 1593 eligible patients were included. The median dose of propofol administered was 70 mg (range: 40-120 mg), and the median dose of midazolam was 2.3 mg (range: 2-4 mg). Median induction time of sedation was 3 min (range: 1-4 min), and median recovery time was 23 min (range: 10-40 min). A moderate level of sedation was achieved in 1561 (98%) patients, whilst a deep sedation occurred in 32 (2%) cases. Transient oxygen desaturation requiring further oxygen supplementation occurred in 8 (0.46%; 95% CI: 0.2%-0.8%) patients. No serious adverse event was observed. Cecal intubation and adenoma detection rates were 93.5% and 23.4% (27.8% for male and 18.5% for female, subjects), respectively. CONCLUSION: A balanced sedation protocol provided a minimalization of the dose of propofol needed to target a moderate sedation for colonoscopy, resulting in a high safety profile for non-anesthesiologist propofol sedation. PMID:21987624

Intraoperative Use of Low-Dose Recombinant Activated Factor VII During Thoracic Aortic Operations

PubMed Central

Andersen, Nicholas D.; Bhattacharya, Syamal D.; Williams, Judson B.; Fosbol, Emil L.; Lockhart, Evelyn L.; Patel, Mayur B.; Gaca, Jeffrey G.; Welsby, Ian J.; Hughes, G. Chad

2013-01-01

Background Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. Methods Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. Results Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16–43 μg/kg) rFVIIa given 51 minutes (42–67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p = 0.05; international normalized ratio, 0.8 versus 1.2; p < 0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p = 0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. Conclusions Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach. PMID:22551846

Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations.

PubMed

Andersen, Nicholas D; Bhattacharya, Syamal D; Williams, Judson B; Fosbol, Emil L; Lockhart, Evelyn L; Patel, Mayur B; Gaca, Jeffrey G; Welsby, Ian J; Hughes, G Chad

2012-06-01

Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16-43 μg/kg) rFVIIa given 51 minutes (42-67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p=0.05; international normalized ratio, 0.8 versus 1.2; p<0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p=0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach. Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Direct measurement of the 3-dimensional DNA lesion distribution induced by energetic charged particles in a mouse model tissue

PubMed Central

Mirsch, Johanna; Tommasino, Francesco; Frohns, Antonia; Conrad, Sandro; Durante, Marco; Scholz, Michael; Friedrich, Thomas; Löbrich, Markus

2015-01-01

Charged particles are increasingly used in cancer radiotherapy and contribute significantly to the natural radiation risk. The difference in the biological effects of high-energy charged particles compared with X-rays or γ-rays is determined largely by the spatial distribution of their energy deposition events. Part of the energy is deposited in a densely ionizing manner in the inner part of the track, with the remainder spread out more sparsely over the outer track region. Our knowledge about the dose distribution is derived solely from modeling approaches and physical measurements in inorganic material. Here we exploited the exceptional sensitivity of γH2AX foci technology and quantified the spatial distribution of DNA lesions induced by charged particles in a mouse model tissue. We observed that charged particles damage tissue nonhomogenously, with single cells receiving high doses and many other cells exposed to isolated damage resulting from high-energy secondary electrons. Using calibration experiments, we transformed the 3D lesion distribution into a dose distribution and compared it with predictions from modeling approaches. We obtained a radial dose distribution with sub-micrometer resolution that decreased with increasing distance to the particle path following a 1/r2 dependency. The analysis further revealed the existence of a background dose at larger distances from the particle path arising from overlapping dose deposition events from independent particles. Our study provides, to our knowledge, the first quantification of the spatial dose distribution of charged particles in biologically relevant material, and will serve as a benchmark for biophysical models that predict the biological effects of these particles. PMID:26392532

Safety and pharmacokinetics of ramucirumab in combination with docetaxel in Japanese patients with locally advanced or metastatic breast cancer: a Phase Ib study.

PubMed

Masuda, Norikazu; Iwata, Hiroji; Aogi, Kenjiro; Xu, Yihuan; Ibrahim, Ayman; Gao, Ling; Dalal, Rita; Yoshikawa, Reigetsu; Sasaki, Yasutsuna

2016-12-01

The primary objective of this study was to investigate the safety and tolerability and to confirm the recommended dose of the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab in combination with docetaxel in Japanese patients with metastatic/locally advanced breast cancer. In this multicenter, single-arm, Phase Ib trial, eligibility criteria included: 20 years or older, Eastern Cooperative Oncology Group performance status of 0/1 and confirmed diagnosis of human epidermal growth factor receptor 2-negative metastatic/locally recurrent inoperable breast adenocarcinoma. Patients received docetaxel (75 mg/m 2 ) followed by ramucirumab (10 mg/kg) on Day 1 of 21-day cycles. Recommended dose was defined as <33% dose-limiting toxicities in dose-limiting toxicity-evaluable patients in Cycle 1. The safety, pharmacokinetics, immunogenicity and antitumor activity were examined. Seven patients were treated. Most adverse events were mild to moderate. Two patients during Cycle 1 experienced a dose-limiting toxicity; one patient each experienced Grade 3 febrile neutropenia and Grade 3 gingivitis. Both dose-limiting toxicities subsequently resolved. No patients discontinued study therapies during Cycle 1. Four serious adverse events were possibly related to ramucirumab in combination with docetaxel. Anti-ramucirumab antibodies were not detected. Pharmacokinetic analysis revealed low total body clearance and long apparent terminal elimination half-life (~7-12 days). Partial response was reported in four patients. The combination of ramucirumab and docetaxel was tolerable in female Japanese patients with breast cancer. Ramucirumab 10 mg/kg in combination with docetaxel (75 mg/m 2 ) was confirmed as the recommended dose among Japanese patients, supporting its use in future studies. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A new fully human recombinant FSH (follitropin epsilon): two phase I randomized placebo and comparator-controlled pharmacokinetic and pharmacodynamic trials.

PubMed

Abd-Elaziz, Khalid; Duijkers, Ingrid; Stöckl, Lars; Dietrich, Bruno; Klipping, Christine; Eckert, Kelvin; Goletz, Steffen

2017-08-01

What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters. Recombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule. Both studies were randomized, placebo- and comparator-controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing. In the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or 150 IU once daily [QD], or 150 IU every other day [QAD], 10 subjects each) and 27 subjects received 150 IU Gonal-f, 150 IU Bravelle, or placebo for 7 days (11/10/6 subjects). Blood samples for measuring PK as well as PD parameters were collected systematically before, during and after dosing. Adverse events (AEs) and other relevant safety parameters were recorded. Data were summarized using descriptive statistics. The single- and multiple-dose PK parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) increased in a linear fashion with increasing dose levels of follitropin epsilon. Follitropin epsilon showed PK characteristics comparable to the comparators indicating that well established treatment schemes could be applied. There was a dose-response effect of single and multiple doses of follitropin epsilon on follicular growth, which was shown for the biomarker inhibin B as well as for the mean number and size of follicles. Multiple doses of 75 IU follitropin epsilon given daily, as well as 150 IU follitropin epsilon every second day, showed a follicle growth comparable with 150 IU Gonal-f given daily, while in case of daily administration of 150 IU Bravelle only weak follicle stimulation was observed. Multiple doses of 150 IU follitropin epsilon induced a much higher follicle growth compared to the same dose of Gonal-f. All single and multiple follitropin epsilon doses tested were safe and well tolerated, and overall there were no relevant differences between follitropin epsilon and the comparators in terms of safety. The average number of AEs increased with increasing dose levels. No clinically relevant abnormalities were reported for any of the other safety parameters assessed. No follitropin epsilon anti-drug antibodies were observed. The studies were conducted as a single-blind design. Hormone levels or other parameters assessed in serum are generally not considered as being subject to bias. Other assessments directly performed by the investigators, such as transvaginal ultrasound assessments, may have been subject to personal bias. No prospective calculations of statistical power had been made, as is common practice for first in human and early phase I studies in healthy volunteers. These early development studies showed that follitropin epsilon exhibits comparable PK characteristics, as well as inducing stronger PD effects in terms of follicle growth and serum inhibin B, than the comparators. Follitropin epsilon induced a dose-dependent increase in follicular growth. The results warrant further studies with this new fully human recombinant FSH. The studies were sponsored by GLYCOTOPE GmbH, Berlin, Germany. K.A-E. is an employee of QPS-Netherlands, B.V., which received funding for the studies from Glycotope GmbH; I.D. and C.K. are employees of Dinox B.V., which received funding for the studies from Glycotope GmbH; L.S. and S.G. are employees and shareholders of Glycotope GmbH; B.D. and K.E. are employees of Glycotope GmbH. www.clinicaltrials.gov: NCT01354886 (single-dose); NCT01477073 (multiple-dose). The single-dose trial was registered on 11 May 2011 while the multiple-dose trial was registered on 09 November 2011. First subject was enroled in the single-dose trial in 27 April 2011 and in the multiple-dose trial in 02 October 2011. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Prognostic value of high-dose dobutamine stress magnetic resonance imaging in 1,493 consecutive patients: assessment of myocardial wall motion and perfusion.

PubMed

Korosoglou, Grigorios; Elhmidi, Yacine; Steen, Henning; Schellberg, Dieter; Riedle, Nina; Ahrens, Johannes; Lehrke, Stephanie; Merten, Constanze; Lossnitzer, Dirk; Radeleff, Jannis; Zugck, Christian; Giannitsis, Evangelos; Katus, Hugo A

2010-10-05

This study sought to determine the prognostic value of wall motion and perfusion assessment during high-dose dobutamine stress (DS) cardiac magnetic resonance imaging (MRI) in a large patient cohort. DS-MRI offers the possibility to integrate myocardial perfusion and wall motion analysis in a single examination for the detection of coronary artery disease (CAD). A total of 1,493 consecutive patients with suspected or known CAD underwent DS-MRI, using a standard protocol in a 1.5-T magnetic resonance scanner. Wall motion and perfusion were assessed at baseline and during stress, and outcome data including cardiac death, nonfatal myocardial infarction ("hard events"), and "late" revascularization performed >90 days after the MR scans were collected during a 2 ± 1 year follow-up period. Fifty-three hard events, including 14 cardiac deaths and 39 nonfatal infarctions, occurred during the follow-up period, whereas 85 patients underwent "late" revascularization. Using multivariable regression analysis, an abnormal result for wall motion or perfusion during stress yielded the strongest independent prognostic value for both hard events and late revascularization, clearly surpassing that of clinical and baseline magnetic resonance parameters (for wall motion: adjusted hazard ratio [HR] of 5.9 [95% confidence interval (CI): 2.5 to 13.6] for hard events and of 3.1 [95% CI: 1.7 to 5.6] for late revascularization, and for perfusion: adjusted HR of 5.4 [95% CI: 2.3 to 12.9] for hard events and of 6.2 [95% CI: 3.3 to 11.3] for late revascularization, p < 0.001 for all). DS-MRI can accurately identify patients who are at increased risk for cardiac death and myocardial infarction, separating them from those with normal findings, who have very low risk for future cardiac events. (Prognostic Value of High Dose Dobutamine Stress Magnetic Resonance Imaging; NCT00837005). Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

What Reliability Engineers Should Know about Space Radiation Effects

NASA Technical Reports Server (NTRS)

DiBari, Rebecca

2013-01-01

Space radiation in space systems present unique failure modes and considerations for reliability engineers. Radiation effects is not a one size fits all field. Threat conditions that must be addressed for a given mission depend on the mission orbital profile, the technologies of parts used in critical functions and on application considerations, such as supply voltages, temperature, duty cycle, and redundancy. In general, the threats that must be addressed are of two types-the cumulative degradation mechanisms of total ionizing dose (TID) and displacement damage (DD). and the prompt responses of components to ionizing particles (protons and heavy ions) falling under the heading of single-event effects. Generally degradation mechanisms behave like wear-out mechanisms on any active components in a system: Total Ionizing Dose (TID) and Displacement Damage: (1) TID affects all active devices over time. Devices can fail either because of parametric shifts that prevent the device from fulfilling its application or due to device failures where the device stops functioning altogether. Since this failure mode varies from part to part and lot to lot, lot qualification testing with sufficient statistics is vital. Displacement damage failures are caused by the displacement of semiconductor atoms from their lattice positions. As with TID, failures can be either parametric or catastrophic, although parametric degradation is more common for displacement damage. Lot testing is critical not just to assure proper device fi.mctionality throughout the mission. It can also suggest remediation strategies when a device fails. This paper will look at these effects on a variety of devices in a variety of applications. This paper will look at these effects on a variety of devices in a variety of applications. (2) On the NEAR mission a functional failure was traced to a PIN diode failure caused by TID induced high leakage currents. NEAR was able to recover from the failure by reversing the current of a nearby Thermal Electric Cooler (turning the TEC into a heater). The elevated temperature caused the PIN diode to anneal and the device to recover. It was by lot qualification testing that NEAR knew the diode would recover when annealed. This paper will look at these effects on a variety of devices in a variety of applications. Single Event Effects (SEE): (1) In contrast to TID and displacement damage, Single Event Effects (SEE) resemble random failures. SEE modes can range from changes in device logic (single-event upset, or SEU). temporary disturbances (single-event transient) to catastrophic effects such as the destructive SEE modes, single-event latchup (SEL). single-event gate rupture (SEGR) and single-event burnout (SEB) (2) The consequences of nondestructive SEE modes such as SEU and SET depend critically on their application--and may range from trivial nuisance errors to catastrophic loss of mission. It is critical not just to ensure that potentially susceptible devices are well characterized for their susceptibility, but also to work with design engineers to understand the implications of each error mode. -For destructive SEE, the predominant risk mitigation strategy is to avoid susceptible parts, or if that is not possible. to avoid conditions under which the part may be susceptible. Destructive SEE mechanisms are often not well understood, and testing is slow and expensive, making rate prediction very challenging. (3) Because the consequences of radiation failure and degradation modes depend so critically on the application as well as the component technology, it is essential that radiation, component. design and system engineers work togetherpreferably starting early in the program to ensure critical applications are addressed in time to optimize the probability of mission success.

Single low-dose rHuIL-12 safely triggers multilineage hematopoietic and immune-mediated effects

PubMed Central

2014-01-01

Background Recombinant human interleukin 12 (rHuIL-12) regulates hematopoiesis and cell-mediated immunity. Based on these hematopoietic and immunomodulatory activities, a recombinant human IL-12 (rHuIL-12) is now under development to address the unmet need for a medical countermeasure against the hematopoietic syndrome of the acute radiation syndrome (HSARS) that occurs in individuals exposed to lethal radiation, and also to serve as adjuvant therapy that could provide dual hematopoietic and immunotherapeutic benefits in patients with cancer receiving chemotherapy. We sought to demonstrate in healthy subjects the safety of rHuIL-12 at single, low doses that are appropriate for use as a medical countermeasure for humans exposed to lethal radiation and as an immunomodulatory anti-cancer agent. Methods Two placebo-controlled, double-blinded studies assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of rHuIL-12. The first-in-human (FIH) dose-escalation study randomized subjects to single subcutaneous injections of placebo or rHuIL-12 at 2, 5, 10, and 20 μg doses. Due to toxicity, dose was reduced to 15 μg and then to 12 μg. The phase 1b expansion study randomized subjects to the highest safe and well tolerated dose of 12 μg. Results Thirty-two subjects were enrolled in the FIH study: 4 active and 2 placebo at rHuIL-12 doses of 2, 5, 10, 12, and 15 μg; 1 active and 1 placebo at 20 μg. Sixty subjects were enrolled in the expansion study: 48 active and 12 placebo at 12 μg dose of rHuIL-12. In both studies, the most common adverse events (AEs) related to rHuIL-12 were headache, dizziness, and chills. No immunogenicity was observed. Elimination of rHuIL-12 was biphasic, suggesting significant distribution into extravascular spaces. rHuIL-12 triggered transient changes in neutrophils, platelets, reticulocytes, lymphocytes, natural killer cells, and CD34+ hematopoietic progenitor cells, and induced increases in interferon-γ and C-X-C motif chemokine 10. Conclusion A single low dose of rHuIl-12 administered subcutaneously can elicit hematological and immune-mediated effects without undue toxicity. The safety and the potent multilineage hematopoietic/immunologic effects triggered by low-dose rHuIL-12 support the development of rHuIL-12 both as a radiation medical countermeasure and as adjuvant immunotherapy for cancer. Trial registration ClinicalTrials.gov: NCT01742221 PMID:24725395

Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.

PubMed

Vogel, Charles L; Cobleigh, Melody A; Tripathy, Debu; Gutheil, John C; Harris, Lyndsay N; Fehrenbacher, Louis; Slamon, Dennis J; Murphy, Maureen; Novotny, William F; Burchmore, Michael; Shak, Steven; Stewart, Stanford J; Press, Michael

2002-02-01

To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

Pharmacokinetics and tolerability of febuxostat after oral administration in healthy Chinese volunteers: a randomized, open-label, singleand multiple-dose three-way crossover study.

PubMed

Zhou, Huili; Zheng, Yunliang; Wu, Guolan; Hu, Xingjiang; Zhai, You; Iv, Duo; Liu, Jian; Wu, Lihua; Shentu, Jianzhong

2016-02-01

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase indicated for the chronic management of hyperuricemia in patients with gout. The aim of the present study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of febuxostat capsules in healthy Chinese volunteers. This openlabel, single- and multiple-dose three-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of febuxostat 40, 80, or 120 mg in separate trial periods, with a 1-week washout between periods. Those allocated to the 40 mg and 80 mg dose continued into the multiple-dose phase, in which they received 40 mg or 80 mg once daily for 6 consecutive days. During the course of the study, blood samples were collected and the concentrations of febuxostat were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). 12 healthy Chinese volunteers were enrolled and completed 3 treatment periods. After oral administration of single doses of 40, 80, and 120 mg of febuxostat, the mean (SD) Cmax was 2,835.43 (1,136.41), 5,356.75 (1,711.33), and 7,718.21 (2,446.34) ng/mL, respectively; the AUC0-48h was 8,821.10 (3,018.35), 17,854.46 (5,113.28), and 30,832.05 (10,992.20) ng×h/ mL; the AUC0-∞ was 8,990.33 (3,046.14), 18,193.58 (5,160.80), and 31,466.93 (1,1074.74) ng×h/mL; the t1/2 was 5.95 (2.71), 9.41 (7.47), and 12.34 (10.34) hours; the Cl/F was 4.81 (1.18), 4.70 (1.21), and 4.18(1.19) L/h; and the Vz/F was 39.66 (16.69), 62.72 (51.41), and 73.41 (64.84) L. After administration of multiple doses of 40 and 80 mg febuxostat, the mean (SD) Cmax,ss was 2,762.38 (1,331.96) and 5,047.27 (1,456.57) ng/mL; the Cmin,ss was 124.10 (6.32) and 46.93 (15.86) ng/mL; the AUCss,0-τ was 8,525.49 (2,160.64) and 16,757.12 (4,223.17) ng×h /mL; the steadystate plasma concentration (Css) was 355.23 (90.03) and 698.21 (175.97) ng/mL; the t1/2 was 7.68 (3.30) and 11.33 (6.94) hours; the Cl/F was 4.99 (1.30) and 5.05 (1.22) L/h; and the Vz/F was 54.10 (24.10) and 85.51 (65.99) L. No serious AEs were reported, and there were no discontinuations due to AEs. The PK of febuxostat exhibited dose proportional kinetics from 40 to 120 mg dose. After multiple doses, the pharmacokinetic parameters of febuxostat were consistent with those after single doses. There was no accumulation in febuxostat exposure in healthy Chinese between multiple doses and single dose. At the doses studied, febuxostat appeared to be well tolerated in these healthy volunteers.

A single-item self-report medication adherence question predicts hospitalisation and death in patients with heart failure.

PubMed

Wu, Jia-Rong; DeWalt, Darren A; Baker, David W; Schillinger, Dean; Ruo, Bernice; Bibbins-Domingo, Kristen; Macabasco-O'Connell, Aurelia; Holmes, George M; Broucksou, Kimberly A; Erman, Brian; Hawk, Victoria; Cene, Crystal W; Jones, Christine DeLong; Pignone, Michael

2014-09-01

To determine whether a single-item self-report medication adherence question predicts hospitalisation and death in patients with heart failure. Poor medication adherence is associated with increased morbidity and mortality. Having a simple means of identifying suboptimal medication adherence could help identify at-risk patients for interventions. We performed a prospective cohort study in 592 participants with heart failure within a four-site randomised trial. Self-report medication adherence was assessed at baseline using a single-item question: 'Over the past seven days, how many times did you miss a dose of any of your heart medication?' Participants who reported no missing doses were defined as fully adherent, and those missing more than one dose were considered less than fully adherent. The primary outcome was combined all-cause hospitalisation or death over one year and the secondary endpoint was heart failure hospitalisation. Outcomes were assessed with blinded chart reviews, and heart failure outcomes were determined by a blinded adjudication committee. We used negative binomial regression to examine the relationship between medication adherence and outcomes. Fifty-two percent of participants were 52% male, mean age was 61 years, and 31% were of New York Heart Association class III/IV at enrolment; 72% of participants reported full adherence to their heart medicine at baseline. Participants with full medication adherence had a lower rate of all-cause hospitalisation and death (0·71 events/year) compared with those with any nonadherence (0·86 events/year): adjusted-for-site incidence rate ratio was 0·83, fully adjusted incidence rate ratio 0·68. Incidence rate ratios were similar for heart failure hospitalisations. A single medication adherence question at baseline predicts hospitalisation and death over one year in heart failure patients. Medication adherence is associated with all-cause and heart failure-related hospitalisation and death in heart failure. It is important for clinicians to assess patients' medication adherence on a regular basis at their clinical follow-ups. © 2013 John Wiley & Sons Ltd.

Meningococcal quadrivalent (serogroups A, C, W135 and Y) tetanus toxoid conjugate vaccine (Nimenrix™).

PubMed

Croxtall, Jamie D; Dhillon, Sohita

2012-12-24

Nimenrix™ (MenACWY-TT) is a quadrivalent meningococcal conjugate vaccine, comprising the polysaccharide serogroups A, C, W135 and Y, and tetanus toxoid (TT) as carrier protein. It is the first quadrivalent vaccine (administered as a single dose) to be approved in Europe for active immunization of individuals aged ≥ 12 months against invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W135 and Y. Administration of a single dose of Nimenrix™ elicited a strong immune response against all four vaccine serogroups in healthy toddlers aged 12-23 months, children and adolescents aged 2-17 years and adults aged 18-55 years in randomized, multicentre, phase III trials. In toddlers, Nimenrix™ was noninferior to Meningitec® in terms of seroresponse rates against meningococcal serogroup C 42 days post-vaccination. In children, adolescents and adults, Nimenrix™ was noninferior to Mencevax™ in terms of vaccination response rates against all four serogroups 1 month post-vaccination. Furthermore, several phase II studies and a phase III trial showed that the immune response elicited by Nimenrix™ in all age groups persisted for 7-42 months after the primary vaccination (when evaluated by rabbit serum bactericidal activity), with the vaccine also inducing immune memory in toddlers. In addition, several randomized, multicentre, phase III, noninferiority trials showed that when coadministered with other childhood vaccines or a seasonal flu vaccine, the immunogenicity of Nimenrix™ or that of the coadministered vaccine was generally not altered. Nimenrix® was generally well tolerated in all age groups whether administered as a single vaccine or coadministered with other routine vaccines. The incidence of grade 3 local or systemic solicited adverse events during the first 4 days following vaccination and of serious adverse events over an extended follow-up period of up to 6 months was low (<4.5%). Although protective effectiveness and longer-term persistence studies are required, current evidence suggests that Nimenrix™, administered as a single dose, provides a valuable vaccination option for the prevention of meningococcal disease across a broad age group, including children as young as 12 months.

Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator.

PubMed

Tran, Jonathan Q; Hartung, Jeffrey P; Peach, Robert J; Boehm, Marcus F; Rosen, Hugh; Smith, Heather; Brooks, Jennifer L; Timony, Gregg A; Olson, Allan D; Gujrathi, Sheila; Frohna, Paul A

2017-08-01

The sphingosine-1-phosphate 1 receptor (S1P 1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P 1R and S1P 5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose-limiting toxicities. The most common ozanimod-related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady-state volume of distribution (73-101 L/kg), moderate oral clearance (204-227 L/h), and an elimination half-life of approximately 17 to 21 hours. Ozanimod produced a robust dose-dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose-dependent negative chronotropic effect was observed following the first dose, with the dose-escalation regimen attenuating the first-dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once-daily regimens under clinical investigation. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Tutorial: Radiation Effects in Electronic Systems

NASA Technical Reports Server (NTRS)

Pellish, Jonathan A.

2017-01-01

This tutorial presentation will give an overview of radiation effects in electrical, electronic, and electromechanical (EEE) components as it applies to civilian space systems of varying size and complexity. The natural space environment presents many unique threats to electronic systems regardless of where the systems operate from low-Earth orbit to interplanetary space. The presentation will cover several topics, including: an overview and introduction to the applicable space radiation environments common to a broad range of mission designs; definitions and impacts of effects due to impinging particles in the space environment e.g., total ionizing dose (TID), total non-ionizing dose (TNID), and single-event effects (SEE); and, testing for and evaluation of TID, TNID, and SEE in EEE components.

Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

PubMed

van den Eertwegh, Alfons J M; Versluis, Jurjen; van den Berg, H Pieter; Santegoets, Saskia J A M; van Moorselaar, R Jeroen A; van der Sluis, Tim M; Gall, Helen E; Harding, Thomas C; Jooss, Karin; Lowy, Israel; Pinedo, Herbert M; Scheper, Rik J; Stam, Anita G M; von Blomberg, B Mary E; de Gruijl, Tanja D; Hege, Kristen; Sacks, Natalie; Gerritsen, Winald R

2012-05-01

The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam. Copyright © 2012 Elsevier Ltd. All rights reserved.

Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults

PubMed Central

Toms, Laurence; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

2014-01-01

Background This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additional adverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine using current data, and compare findings with other analgesics evaluated similarly. Objectives Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component, and associated adverse events. Search methods We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update. Selection criteria Randomised, double-blind, placebo-controlled trials of paracetamol plus codeine, compared with placebo or the same dose of paracetamol alone, for relief of acute postoperative pain in adults. Data collection and analysis Two authors assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four-to-six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). Proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain relief over four-to-six hours, with NNTs of 2.2 (95% CI 1.8 to 2.9) for 800 to 1000 mg paracetamol plus 60 mg codeine, 3.9 (2.9 to 4.5) for 600 to 650 mg paracetamol plus 60 mg codeine, and 6.9 (4.8 to 12) for 300 mg paracetamol plus 30 mg codeine. Time to use of rescue medication was over four hours with paracetamol plus codeine and two hours with placebo. The NNT to prevent remedication was 5.6 (4.0 to 9.0) for 600 mg paracetamol plus 60 mg codeine over four to six hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo. Fourteen studies, with 926 participants, were included in the comparison of paracetamol plus codeine with the same dose of paracetamol alone. Addition of codeine increased proportion of participants achieving at least 50% pain relief over four-to-six hours by 10 to 15%, increased time to use of rescue medication by about one hour, and reduced proportion of participants needing rescue medication by about 15% (NNT to prevent remedication 6.9 (4.2 to 19). Adverse events were mainly mild to moderate in severity and incidence did not differ between groups. Authors’ conclusions This update confirms previous findings that combining paracetamol with codeine provided clinically useful levels of pain relief in about 50% of patients with moderate to severe postoperative pain, compared with under 20% with placebo. New information for remedication shows that the combination extended the duration of analgesia by about one hour compared to treatment with the same dose of paracetamol alone. At higher doses, more participants experienced adequate pain relief, but the amount of information available for the 1000 mg paracetamol plus 60 mg codeine dose was small, and based on limited information. PMID:19160199

Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain.

PubMed

Derry, Christopher J; Derry, Sheena; Moore, R Andrew

2013-06-24

Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. Some combinations of ibuprofen and paracetamol are available for use without prescription in some acute pain situations. To assess the efficacy and adverse effects of single dose oral ibuprofen plus paracetamol for acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 4 of 12, 2013), MEDLINE (1950 to May 21st 2013), EMBASE (1974 to May 21st 2013), the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles. Randomised, double-blind clinical trials of single dose, oral ibuprofen plus paracetamol compared with placebo or the same dose of ibuprofen alone for acute postoperative pain in adults. Two review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used validated equations to calculate the area under the pain relief versus time curve and derive the proportion of participants with at least 50% of maximum pain relief over six hours. We calculated relative risk (RR) and number needed to treat to benefit (NNT) for ibuprofen plus paracetamol, ibuprofen alone, or placebo. We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse events. Searches identified three studies involving 1647 participants. Each of them examined several dose combinations. Included studies provided data from 508 participants for the comparison of ibuprofen 200 mg + paracetamol 500 mg with placebo, 543 participants for the comparison of ibuprofen 400 mg + paracetamol 1000 mg with placebo, and 359 participants for the comparison of ibuprofen 400 mg + paracetamol 1000 mg with ibuprofen 400 mg alone.The proportion of participants achieving at least 50% maximum pain relief over 6 hours was 69% with ibuprofen 200 mg + paracetamol 500 mg, 73% with ibuprofen 400 mg + paracetamol 1000 mg, and 7% with placebo, giving NNTs of 1.6 (1.5 to 1.8) and 1.5 (1.4 to 1.7) for the lower and higher doses respectively compared with placebo. For ibuprofen 400 mg alone the proportion was 52%, giving an NNT for ibuprofen 400 mg + paracetamol 1000 mg compared with ibuprofen alone of 5.4 (3.5 to 12).Ibuprofen + paracetamol at the 200/500 mg and 400/1000 mg doses resulted in longer times to remedication than placebo. The median time to use of rescue medication was 7.6 hours for ibuprofen 200 mg + paracetamol 500 mg, 8.3 hours with ibuprofen 400 mg + paracetamol 1000 mg, and 1.7 hours with placebo. Fewer participants needed rescue medication with ibuprofen + paracetamol combination than with placebo or ibuprofen alone. The proportion was 34% with ibuprofen 200 mg + paracetamol 500 mg, 25% with ibuprofen 400 mg + paracetamol 1000 mg, and 79% with placebo, giving NNTs to prevent use of rescue medication of 2.2 (1.8 to 2.9) and 1.8 (1.6 to 2.2) respectively compared with placebo. The proportion of participants using rescue medication with ibuprofen 400 mg was 48%, giving an NNT to prevent use for ibuprofen 400 mg + paracetamol 1000 mg compared with ibuprofen alone of 4.3 (3.0 to 7.7).The proportion of participants experiencing one or more adverse events was 30% with ibuprofen 200 mg + paracetamol 500 mg, 29% with ibuprofen 400 mg + paracetamol 1000 mg, and 48% with placebo, giving NNT values in favour of the combination treatment of 5.4 (3.6 to 10.5) and 5.1 (3.5 to 9.5) for the lower and higher doses respectively. No serious adverse events were reported in any of the included studies. Withdrawals for reasons other than lack of efficacy were fewer than 5% and balanced across treatment arms. Ibuprofen plus paracetamol combinations provided better analgesia than either drug alone (at the same dose), with a smaller chance of needing additional analgesia over about eight hours, and with a smaller chance of experiencing an adverse event.

Phase I trial of RV3-BB rotavirus vaccine: a human neonatal rotavirus vaccine.

PubMed

Danchin, M; Kirkwood, C D; Lee, K J; Bishop, R F; Watts, E; Justice, F A; Clifford, V; Cowley, D; Buttery, J P; Bines, J E

2013-05-28

RV3 is a human neonatal rotavirus strain (G3P[6]) that has been associated with asymptomatic neonatal infection and replicates well in the infant gut. RV3-BB rotavirus vaccine has been developed as a rotavirus vaccine candidate for administration at birth. A single-centre, double-blind, randomised placebo-controlled Phase I study evaluated the safety and tolerability of a single oral dose of the second generation RV3-BB rotavirus vaccine (8.3×10(6)FFU/mL) in 20 adults, 20 children and 20 infants (10 vaccine and 10 placebo per age cohort). Vaccine take was defined as seroconversion (a 3-fold increase in serum anti-rotavirus IgA or serum neutralising antibody (SNA) from baseline at day 28 post-dose) or evidence of RV3-BB viral replication in the faeces by RT-PCR analysis 3-6 days post-vaccination. RV3-BB presence was confirmed by sequence analysis. The RV3-BB vaccine was well tolerated in all participants, with no pattern of adverse events shown to be associated with the study vaccine. In the infant cohort, vaccine take was demonstrated in 8/9 infants following a single dose of vaccine compared with 2/7 placebo recipients. In the infant vaccine group, 5/9 infants exhibited either IgA or SNA seroconversion and 7/9 infants had evidence of RV3-BB replication on days 3-6, compared with 2/7 infants who seroconverted and 0/10 infants with evidence of replication in the placebo group. Two infants in the placebo group had serological evidence of a rotavirus infection within the 28-day study period: one demonstrated an IgA and the other an SNA response, with wild-type virus replication detected in another infant. A single dose of RV3-BB rotavirus vaccine was well tolerated in adults, children and infants. Most infants (8/9) who received RV3-BB demonstrated vaccine take following a single dose. These data support progression of RV3-BB to Phase II immunogenicity and efficacy trials. Copyright © 2013 Elsevier Ltd. All rights reserved.

Fast method for in-flight estimation of total dose from protons and electrons using RADE Minstrument on JUICE

NASA Astrophysics Data System (ADS)

Hajdas, Wojtek; Mrigakshi, Alankrita; Xiao, Hualin

2017-04-01

The primary concern of the ESA JUICE mission to Jupiter is the harsh particle radiation environment. Ionizing particles introduce radiation damage by total dose effects, displacement damages or single events effects. Therefore, both the total ionizing dose and the displacement damage equivalent fluence must be assessed to alert spacecraft and its payload as well as to quantify radiation levels for the entire mission lifetime. We present a concept and implementations steps for simplified method used to compute in flight a dose rate and total dose caused by protons. We also provide refinement of the method previously developed for electrons. The dose rates values are given for predefined active volumes located behind layers of materials with known thickness. Both methods are based on the electron and proton flux measurements provided by the Electron and Proton Detectors inside the Radiation Hard Electron Monitor (RADEM) located on-board of JUICE. The trade-off between method accuracy and programming limitations for in-flight computations are discussed. More comprehensive and precise dose rate computations based on detailed analysis of all stack detectors will be made during off-line data processing. It will utilize full spectral unfolding from all RADEM detector subsystems.

Multicentre dose audit for clinical trials of radiation therapy in Asia

PubMed Central

Fukuda, Shigekazu; Fukumura, Akifumi; Nakamura, Yuzuru-Kutsutani; Jianping, Cao; Cho, Chul-Koo; Supriana, Nana; Dung, To Anh; Calaguas, Miriam Joy; Devi, C.R. Beena; Chansilpa, Yaowalak; Banu, Parvin Akhter; Riaz, Masooma; Esentayeva, Surya; Kato, Shingo; Karasawa, Kumiko; Tsujii, Hirohiko

2017-01-01

Abstract A dose audit of 16 facilities in 11 countries has been performed within the framework of the Forum for Nuclear Cooperation in Asia (FNCA) quality assurance program. The quality of radiation dosimetry varies because of the large variation in radiation therapy among the participating countries. One of the most important aspects of international multicentre clinical trials is uniformity of absolute dose between centres. The National Institute of Radiological Sciences (NIRS) in Japan has conducted a dose audit of participating countries since 2006 by using radiophotoluminescent glass dosimeters (RGDs). RGDs have been successfully applied to a domestic postal dose audit in Japan. The authors used the same audit system to perform a dose audit of the FNCA countries. The average and standard deviation of the relative deviation between the measured and intended dose among 46 beams was 0.4% and 1.5% (k = 1), respectively. This is an excellent level of uniformity for the multicountry data. However, of the 46 beams measured, a single beam exceeded the permitted tolerance level of ±5%. We investigated the cause for this and solved the problem. This event highlights the importance of external audits in radiation therapy. PMID:27864507

Pharmacokinetics and Tolerability of Single-Ascending Doses of Desvenlafaxine Administered to Children and Adolescents with Major Depressive Disorder.

PubMed

Findling, Robert L; Groark, James; Tourian, Karen A; Ramaker, Sara A; Chiles, Deborah; Yang, Lingfeng; Nichols, Alice I

2016-12-01

To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the effect of desvenlafaxine on depression symptoms was exploratory. The 8-week, open-label study included an initial 3.5-day inpatient period followed by a 7.5-week outpatient period. Children (7-11 years) received a single desvenlafaxine dose of 10, 25, 50, or 100 mg on day 1; adolescents (12-17 years) received desvenlafaxine 25, 50, 100, or 200 mg/day. Plasma and urine samples were collected over the initial 72-hour inpatient period. Evaluations included treatment-emergent adverse events (TEAEs), physical examinations (including Tanner Staging), vital signs, laboratory assessments, 12-lead electrocardiogram, Columbia-Suicide Severity Rating Scale, and the Children's Depression Rating Scale-Revised (CDRS-R). In all, 29 children and 30 adolescents took at least one dose of desvenlafaxine and were included in the safety population (children: 10 mg, n = 6; 25 mg, n = 7; 50 mg, n = 9; 100 mg, n = 7; adolescents: 25 mg, n = 7; 50 mg, n = 7; 100 mg, n = 8; 200 mg, n = 8). Total area under the drug concentration-time curve from 0 to infinity (AUC) appeared to increase linearly with increasing dose. Mean (standard deviation [SD]) AUC ranged from 628 (346) ng/mL (desvenlafaxine 10 mg) to 6732 (3031) ng/mL (100 mg) in children and from 1123 (361) ng/mL (25 mg) to 11,730 (3113) ng/mL (200 mg) in adolescents. During the combined inpatient and outpatient period, 16/29 (55%) children and 21/30 (70%) adolescents reported at least one TEAE. One serious adverse event (suicidal behavior) was reported. Mean (SD) change from baseline in CDRS-R total scores at week 8 was -19.00 (9.87) for children and -21.57 (11.50) for adolescents. Desvenlafaxine AUC values increased linearly with dose; body weight alone provided an adequate prediction for dose-normalized AUC. Desvenlafaxine was generally safe and well tolerated in children and adolescents for treatment up to 8 weeks.

Pre-procedural antibiotics for endoscopic urological procedures: Initial experience in individuals with spinal cord injury and asymptomatic bacteriuria.

PubMed

Chong, Julio T; Klausner, Adam P; Petrossian, Albert; Byrne, Michael D; Moore, Jewel R; Goetz, Lance L; Gater, David R; Grob, B Mayer

2015-03-01

The objective of this study was to compare the safety, efficacy, quality-of-life impact, and costs of a single dose or a longer course of pre-procedural antibiotics prior to elective endoscopic urological procedures in individuals with spinal cord injury and disorders (SCI/D) and asymptomatic bacteriuria. A prospective observational study. Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA. Sixty persons with SCI/D and asymptomatic bacteriuria scheduled to undergo elective endoscopic urological procedures. A single pre-procedural dose of antibiotics vs. a 3-5-day course of pre-procedural antibiotics. Objective and subjective measures of health, costs, and quality of life. There were no significant differences in vital signs, leukocytosis, adverse events, and overall satisfaction in individuals who received short-course vs. long-course antibiotics. There was a significant decrease in antibiotic cost (33.1 ± 47.6 vs. 3.6 ± 6.1 US$, P = 0.01) for individuals in the short-course group. In addition, there was greater pre-procedural anxiety (18 vs. 0%, P < 0.05) for individuals who received long-course antibiotics. SCI/D individuals with asymptomatic bacteriuria may be able to safely undergo most endoscopic urological procedures with a single dose of pre-procedural antibiotics. However, further research is required and even appropriate pre-procedural antibiotics may not prevent severe infections.

Pharmacokinetics and bioequivalence of two strontium ranelate formulations after single oral administration in healthy Chinese subjects.

PubMed

Zhang, Dan; Du, Aihua; Wang, Xiaolin; Zhang, Lina; Yang, Man; Ma, Jingyi; Deng, Ming; Liu, Huichen

2018-05-08

Pharmacokinetics of exogenous strontium (Sr) and bioequivalence of a new oral formulation of strontium ranelate compared with the brand-name drug in healthy Chinese subjects was evaluated. A balanced, randomized, single-dose, two-treatment parallel study was conducted in 36 healthy Chinese subjects. Subjects were randomly allocated into two groups of 18 to receive a single oral dose of test formulation and reference formulation under a fasting state, respectively. Blood samples were collected at 19 designated time points up to 240-h post-dose. Serum concentrations of Sr were quantified by ICP-MS. A total of 36 subjects were enrolled and completed the study. Nine mild adverse events in 6 subjects were reported. The C max , AUC 0-72 h , AUC 0- t , and AUC 0-∞ of test and reference formulations shown as mean ± SD were 6.97 ± 1.78 and 6.78 ± 1.80 µg/mL, 199 ± 51 and 187 ± 38 µg·h/mL, 303 ± 89 and 278 ± 54 µg·h/mL, and 337 ± 109 and 305 ± 60 µg·h/mL, respectively. Two formulations were bioequivalent, and both were generally well tolerated.

Antibody response to vaccines for rhinotracheitis, caliciviral disease, panleukopenia, feline leukemia, and rabies in tigers (Panthera tigris) and lions (Panthera leo).

PubMed

Risi, Emmanuel; Agoulon, Albert; Allaire, Franck; Le Dréan-Quénec'hdu, Sophie; Martin, Virginie; Mahl, Philippe

2012-06-01

This article presents the results of a study of captive tigers (Panthera tigris) and lions (Panthera leo) vaccinated with a recombinant vaccine against feline leukemia virus; an inactivated adjuvanted vaccine against rabies virus; and a multivalent modified live vaccine against feline herpesvirus, calicivirus, and panleukopenia virus. The aim of the study was to assess the immune response and safety of the vaccines and to compare the effects of the administration of single (1 ml) and double (2 ml) doses. The animals were separated into two groups and received either single or double doses of vaccines, followed by blood collection for serologic response for 400 days. No serious adverse event was observed, with the exception of abortion in one lioness, potentially caused by the incorrect use of the feline panleukopenia virus modified live vaccine. There was no significant difference between single and double doses for all vaccines. The recombinant vaccine against feline leukemia virus did not induce any serologic response. The vaccines against rabies and feline herpesvirus induced a significant immune response in the tigers and lions. The vaccine against calicivirus did not induce a significant increase in antibody titers in either tigers or lions. The vaccine against feline panleukopenia virus induced a significant immune response in tigers but not in lions. This report demonstrates the value of antibody titer determination after vaccination of nondomestic felids.

The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel, comparative clinical trial.

PubMed

Yu, Zhaocai; Liu, Wenchao; Wang, Ling; Liang, Houjie; Huang, Ying; Si, Xiaoming; Zhang, Helong; Liu, Duhu; Zhang, Hongmei

2009-01-01

This clinical trial was conducted to evaluate the efficacy and safety of Palonosetron in preventing chemotherapy-induced vomiting (CIV) among the Chinese cancer patients. Two hundred and forty patients were scheduled to be enrolled and randomized to receive a single intravenous dose of palonosetron 0.25 mg, or granisetron 3 mg, 30 min before receiving highly emetogenic chemotherapy. The primary efficacy endpoint was the complete response (CR) rate for acute CIV (during the 0-24-h interval after chemotherapy). Secondary endpoints included the CR rates for delayed CIV (more than 24 h after chemotherapy). Two hundred and eight patients were accrued and received study medication. CR rates for acute CIV were 82.69% for palonosetron and 72.12% for granisetron, which demonstrated that palonosetron was not inferior to granisetron in preventing acute CIV. Comparisons of CR rates for delayed CIV yielded no statistical difference between palonosetron and granisetron groups and did not reveal non-inferiority of palonosetron to granisetron. Adverse events were mostly mild to moderate, with quite low rates among the two groups. A single dose (0.25 mg) of palonosetron is not inferior to a single dose (3 mg) of granisetron in preventing CIV and possesses an acceptable safety profile in the Chinese population.

Tafenoquine is not neurotoxic following supertherapeutic dosing in rats.

PubMed

Dow, Geoffrey S; Brown, Tracey; Reid, Mark; Smith, Bryan; Toovey, Stephen

Tafenoquine is a new drug for malaria prevention. The goal of the present work was to conduct a specific neurobehavioral study in rats with histopathological assessment of the brain. The clinical, hematological, behavioral, motor activity, and neurohistopathologic changes induced by different dose levels of tafenoquine were evaluated following single super-therapeutic dose administration. Toxicokinetic data were generated to allow extrapolation to clinical exposures. At the highest dose (500 mg/kg), two animals (of 12) died. Surviving animals showed clinical signs of toxicity and had reduced body weight 7-8 days after dosing. Decreases in motor activity were observed on more than one occasion at doses > 9-fold higher than the clinical exposure. No statistically significant changes were observed for other behavioral endpoints. No neurohistopathological changes were noted. Changes in hematological and clinical pathology endpoints were observed at the lowest dose level (125 mg/kg). For context, the human dosing regimen is a 10 mg/kg load followed by 3.3 mg/kg weekly (in a 60 kg person). As in humans, adverse events other than neurotoxicity were dose-limiting for tafenoquine in rats. This raises the prospect that a new weekly prophylactic, without neurologic liability, may become available in the near future. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

The effect of single low-dose dexamethasone on vomiting during awake craniotomy.

PubMed

Kamata, Kotoe; Morioka, Nobutada; Maruyama, Takashi; Komayama, Noriaki; Nitta, Masayuki; Muragaki, Yoshihiro; Kawamata, Takakazu; Ozaki, Makoto

2016-12-01

Intraoperative vomiting leads to serious respiratory complications that could influence the surgical decision-making process for awake craniotomy. However, the use of antiemetics is still limited in Japan. The aim of this study was to investigate the effect of prophylactically administered single low-dose dexamethasone on the incidence of vomiting during awake craniotomy. The frequency of hyperglycemia was also examined. We conducted a retrospective case review of awake craniotomy for glioma resection between 2012 and 2015. Of the 124 patients, 91 were included in the analysis. Dexamethasone was not used in 43 patients and the 48 remaining patients received an intravenous bolus of 4.95 mg dexamethasone at anesthetic induction. Because of stable operating conditions, no one required conscious sedation throughout functional mapping and tumor resection. Although dexamethasone pretreatment reduced the incidence of intraoperative vomiting (P = 0.027), the number of patients who complained of nausea was comparable (P = 0.969). No adverse events related to vomiting occurred intraoperatively. Baseline blood glucose concentration did not differ between each group (P = 0.143), but the samples withdrawn before emergence (P = 0.018), during the awake period (P < 0.0001) and at the end of surgery (P < 0.0001) showed significantly higher glucose levels in the dexamethasone group. Impaired wound healing was not observed in either group. A single low-dose of dexamethasone prevents intraoperative vomiting for awake craniotomy cases. However, as even a small dose of dexamethasone increases the risk for hyperglycemia, antiemetic prophylaxis with dexamethasone should be administered after careful consideration. Monitoring of perioperative blood glucose concentration is also necessary.

Bioavailability of Lumefantrine Is Significantly Enhanced with a Novel Formulation Approach, an Outcome from a Randomized, Open-Label Pharmacokinetic Study in Healthy Volunteers.

PubMed

Jain, Jay Prakash; Leong, F Joel; Chen, Lan; Kalluri, Sampath; Koradia, Vishal; Stein, Daniel S; Wolf, Marie-Christine; Sunkara, Gangadhar; Kota, Jagannath

2017-09-01

The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ∼48-fold and ∼24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2. Copyright © 2017 Jain et al.

Stochastic Modeling of Radioactive Material Releases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andrus, Jason; Pope, Chad

2015-09-01

Nonreactor nuclear facilities operated under the approval authority of the U.S. Department of Energy use unmitigated hazard evaluations to determine if potential radiological doses associated with design basis events challenge or exceed dose evaluation guidelines. Unmitigated design basis events that sufficiently challenge dose evaluation guidelines or exceed the guidelines for members of the public or workers, merit selection of safety structures, systems, or components or other controls to prevent or mitigate the hazard. Idaho State University, in collaboration with Idaho National Laboratory, has developed a portable and simple to use software application called SODA (Stochastic Objective Decision-Aide) that stochastically calculatesmore » the radiation dose associated with hypothetical radiological material release scenarios. Rather than producing a point estimate of the dose, SODA produces a dose distribution result to allow a deeper understanding of the dose potential. SODA allows users to select the distribution type and parameter values for all of the input variables used to perform the dose calculation. SODA then randomly samples each distribution input variable and calculates the overall resulting dose distribution. In cases where an input variable distribution is unknown, a traditional single point value can be used. SODA was developed using the MATLAB coding framework. The software application has a graphical user input. SODA can be installed on both Windows and Mac computers and does not require MATLAB to function. SODA provides improved risk understanding leading to better informed decision making associated with establishing nuclear facility material-at-risk limits and safety structure, system, or component selection. It is important to note that SODA does not replace or compete with codes such as MACCS or RSAC, rather it is viewed as an easy to use supplemental tool to help improve risk understanding and support better informed decisions. The work was funded through a grant from the DOE Nuclear Safety Research and Development Program.« less

Myeloablative therapy against high risk Ewing's sarcoma: A single institution experience and literature review

PubMed Central

Lopez, Jose Luis; Pérez, Concepcion; Marquez, Catalina; Cabrera, Patricia; Perez, Jose Maria; Ramirez, Gema Lucia; Ordoñez, Rafael; Praena-Fernandez, Juan Manuel; Ortiz, Maria Jose

2011-01-01

Background Attempts to improve survival outcomes of patients with high risk Ewing's sarcoma (ES) have focused on chemotherapy dose intensification strategies. Aim The objective of this study is to retrospectively evaluate clinical characteristics and outcome of pediatric patients with high risk ES treated at a single institution. Materials and methods From 1995 to 2008, seventeen patients (male:female, 14:3) were treated with dose-intensive therapy in our institution. Median age at diagnosis was 10 years (range: 2–15). Seven patients had metastases at diagnosis (lung in 6 cases and bone in one case). Eleven patients presented with unresectable disease. Fifteen (88.2%) received the Spanish Society of Pediatric Oncology protocol which includes six cycles of vincristine, doxorubicin, ifosfamide and etoposide. Two out of the six cases that were resectable received postoperative radiation. In addition, eleven patients received definitive radiation therapy. Finally, twelve (70.5%) out of 17 patients received myeloablative therapy with melphalan/etoposide. The rest of patients (N = 5) received busulfan/melphalan. Results Median follow-up was 78 months (range: 15–155 months). Initial responses were complete in all patients, but 9 of them developed progression disease. Seven patients became long-term event-free survivors. No patient died of toxicity after transplantation. The 2- and 5-year overall survival rates for all patients were 93% and 73%, respectively. Event-free survival rates were 74% and 54% at 2 and 5 years, respectively. Conclusion This single-institution experience suggests that myeloablative therapy against high risk ES is effective and safe. PMID:24376974

Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moussazadeh, Nelson; Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York; Lis, Eric

Purpose: To characterize local tumor control and toxicity risk in very long-term survivors (>5 years) after high-dose spinal image guided, intensity modulated radiation therapy delivered as single-dose stereotactic radiosurgery (SRS). Previously published spinal SRS outcome analyses have included a heterogeneous population of cancer patients, mostly with short survival. This is the first study reporting the long-term tumor control and toxicity profiles after high-dose single-fraction spinal SRS. Methods and Materials: The study population included all patients treated from June 2004 to July 2009 with single-fraction spinal SRS (dose 24 Gy) who had survived at least 5 years after treatment. The endpoints examined included diseasemore » progression, surgical or radiation retreatment, in-field fracture development, and radiation-associated toxicity, scored using the Radiation Therapy Oncology Group radiation morbidity scoring criteria and the Common Terminology Criteria for Adverse Events, version 4.0. Local control and fracture development were assessed using Kaplan-Meier analysis. Results: Of 278 patients, 31 (11.1%), with 36 segments treated for spinal tumors, survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 6.1 years (maximum 102 months). The histopathologic findings for the 5-year survivors included radiation-resistant metastases in 58%, radiation-sensitive metastases in 22%, and primary bone tumors in 19%. In this selected cohort, 3 treatment failures occurred at a median of 48.6 months, including 2 recurrences in the radiation field and 1 patient with demonstrated progression at the treatment margins. Ten lesions (27.8%) were associated with acute grade 1 cutaneous or gastrointestinal toxicity. Delayed toxicity ≥3 months after treatment included 8 cases (22.2%) of mild neuropathy, 2 (5.6%) of gastrointestinal discomfort, 8 (22.2%) of dermatitides, and 3 (8.3%) of myalgias/myositis. Thirteen treated levels (36.1%) in 12 patients demonstrated progressive vertebral body collapse or endplate fractures at a median of 25.7 months (range 11.6-76.0), of which 5 (14%) became symptomatic and subsequently required percutaneous cement augmentation or surgery. Conclusions: In the longest-term series to date, high-dose single-fraction spinal SRS retained an excellent safety profile among long-term survivors (>5 years)« less

Biology Based Lung Cancer Model for Chronic Low Radon Exposures

NASA Astrophysics Data System (ADS)

TruÅ£ǎ-Popa, Lucia-Adina; Hofmann, Werner; Fakir, Hatim; Cosma, Constantin

2008-08-01

Low dose effects of alpha particles at the tissue level are characterized by the interaction of single alpha particles, affecting only a small fraction of the cells within that tissue. Alpha particle intersections of bronchial target cells during a given exposure period were simulated by an initiation-promotion model, formulated in terms of cellular hits within the cycle time of the cell (dose-rate) and then integrated over the whole exposure period (dose). For a given average number of cellular hits during the lifetime of bronchial cells, the actual number of single and multiple hits was selected from a Poisson distribution. While oncogenic transformation is interpreted as the primary initiation step, stimulated mitosis by killing adjacent cells is assumed to be the primary radiological promotion event. Analytical initiation and promotion functions were derived from experimental in vitro data on oncogenic transformation and cellular survival. To investigate the shape of the lung cancer risk function at chronic, low level exposures in more detail, additional biological factors describing the tissue response and operating specifically at low doses were incorporated into the initiation-promotion model. These mechanisms modifying the initial response at the cellular level were: adaptive response, genomic instability, induction of apoptosis by surrounding cells, and detrimental as well as protective bystander mechanisms. To quantify the effects of these mechanisms as functions of dose, analytical functions were derived from the experimental evidence presently available. Predictions of lung cancer risk, including these mechanisms, exhibit a distinct sublinear dose-response relationship at low exposures, particularly for very low exposure rates.

Methylphenidate, cognition, and epilepsy

PubMed Central

Alipio-Jocson, Valerie; Inoyama, Katherine; Bartlett, Victoria; Sandhu, Saira; Oso, Jemima; Barry, John J.; Loring, David W.; Meador, Kimford

2017-01-01

Objective: To evaluate the potential efficacy of immediate-release methylphenidate (MPH) for treating cognitive deficits in epilepsy. Methods: This was a double-blind, randomized, single-dose, 3-period crossover study in patients with epilepsy and chronic cognitive complaints comparing the effects of placebo and MPH 10 and 20 mg given 1 week apart. Cognitive outcome was evaluated on the basis of an omnibus z score calculated from performance on the Conners Continuous Performance Test 3 (ability to discriminate between target and nontarget stimuli [d'] and hit reaction time standard deviation), Symbol-Digit Modalities Test, and Medical College of Georgia Paragraph Memory Test. Adverse events and seizure frequency were monitored. An open-label follow-up is reported elsewhere. Results: Thirty-five adult patients with epilepsy participated, of whom 31 finished. Demographics included the following: mean age = 35.3 years (range 20–62 years), 13 men and 18 women, and baseline seizure frequency of 2.8 per month. Epilepsy types were focal (n = 24), generalized (n = 6), or unclassified (n = 1). Mean epilepsy duration was 12.5 years. A statistically significant performance benefit was present at both 10-mg (p = 0.030) and 20-mg (p = 0.034) MPH doses. No seizures were associated with either MPH dose. Adverse effects leading to withdrawal included cognitive “fogginess” (n = 1 on 20 mg), anxiety/agitation (n = 1 on 10 mg), and tachycardia (n = 1). One participant was lost to follow-up after one 20-mg dose without side effect. Conclusions: This single-dose study suggests that MPH may be effective in ameliorating some cognitive deficits in patients with epilepsy. Additional studies are required. ClinicalTrials.gov identifier: NCT02178995. Classification of evidence: This study provides Class II evidence that single doses of MPH improve cognitive performance on some measures of attention and processing speed in patients with epilepsy and cognitive complaints. PMID:28031390

Efficacy and safety of a single 2 mg dose or 4 mg double dose of alteplase for 50 occluded chest ports using a unique instillation technique.

PubMed

Sharma, Rajinder P; Ree, Chung Ja; Ree, Alexander

2008-01-01

To evaluate the effectiveness and safety of a single 2 mg dose or a 4 mg double dose of alteplase for restoring function in occluded chest ports. A prospective, open-label, nonblinded study was performed on 40 enrolled patients with a total of 50 chest ports at the Henry Ford Hospital Interventional Radiology Department (Detroid, Michigan, USA). Alteplase (Cathflo Activase; Genentech, USA), a recombinant tissue plasminogen activator produced by recombinant DNA technology, was used to restore the function of 50 occluded chest ports. Occlusion was defined as the inability to withdraw blood freely from the port, or the inability to flush the port easily. A 2 mg (2 mL) dose of alteplase was injected into the port through a Huber needle, using a gentle push and pull technique, and was left to dwell for 30 min. If the port remained occluded after the initial 2 mg alteplase treatment, an additional 2 mg alteplase treatment was administered with the same dwell time of 30 min. If a port had remained occluded despite the above regimen, this outcome would have been considered a failure and the chest port would have required surgical intervention. However, all ports were successfully treated, and no surgical intervention was required. The safety end points included minor or major hemorrhages, such as intracranial hemorrhages, or sepsis. Safety end points were determined by a 24 h follow-up telephone call. Of the 50 chest ports (30 single ports and 10 double ports) treated with alteplase, 36 required 2 mg (72%) and 14 required 4 mg (28%). The efficacy end point was 100% for all chest ports treated, without any adverse events. High efficacy and safety rates of restoring function in occluded chest ports were obtained with 2 mg or 4 mg doses of alteplase. Part of this high efficacy rate may be due to the gentle push and pull technique used in the present study.

Orodispersible sublingual piribedil to abort OFF episodes: a single dose placebo-controlled, randomized, double-blind, cross-over study.

PubMed

Rascol, Olivier; Azulay, Jean-Philippe; Blin, Olivier; Bonnet, Anne-Marie; Brefel-Courbon, Christine; Césaro, Pierre; Damier, Philippe; Debilly, Bérengère; Durif, Frank; Galitzky, Monique; Grouin, Jean-Marie; Pennaforte, Sylvie; Villafane, Gabriel; Yaici, Sadek; Agid, Yves

2010-02-15

S90049, a novel sublingual formulation of the non-ergoline D(2)-D(3) agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single-dose double-blind double-placebo 3 x 3 cross-over study. Optimal tested doses were determined during a previous open-label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (Delta UPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 +/- 8 years, PD duration: 12 +/- 6 years, UPDRS III OFF: 37 +/- 15) participated. S90049 was superior to placebo on Delta UPDRS III (-13 +/- 12 versus -7 +/- 9 respectively; estimated difference -5.2, 95% Confidence Interval (CI)[-10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, Delta UPDRS III was similar on S90049 (-21.2 +/- 10.1) and apomorphine (-23.6 +/- 14.1) (estimated difference: 4.0 95% CI [-2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate. (c) 2009 Movement Disorder Society.

Tumor Control Outcomes After Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases From Renal Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zelefsky, Michael J., E-mail: zelefskm@mskcc.org; Greco, Carlo; Motzer, Robert

2012-04-01

Purpose: To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Patients and Methods: Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18-24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20-30 Gy. The median follow-up was 12 months (range, 1-48). Results: The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a highmore » single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). Conclusion: High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking.« less

Genetic variation in aryl N-acetyltransferase results in significant differences in the pharmacokinetic and safety profiles of amifampridine (3,4-diaminopyridine) phosphate.

PubMed

Haroldsen, Peter E; Garovoy, Marvin R; Musson, Donald G; Zhou, Huiyu; Tsuruda, Laurie; Hanson, Boyd; O'Neill, Charles A

2015-02-01

The clinical use of amifampridine phosphate for neuromuscular junction disorders is increasing. The metabolism of amifampridine occurs via polymorphic aryl N-acetyltransferase (NAT), yet its pharmacokinetic (PK) and safety profiles, as influenced by this enzyme system, have not been investigated. The objective of this study was to assess the effect of NAT phenotype and genotype on the PK and safety profiles of amifampridine in healthy volunteers (N = 26). A caffeine challenge test and NAT2 genotyping were used to delineate subjects into slow and fast acetylators for PK and tolerability assessment of single, escalating doses of amifampridine (up to 30 mg) and in multiple daily doses (20 mg QID) of amifampridine. The results showed that fast acetylator phenotypes displayed significantly lower C max, AUC, and shorter t 1/2 for amifampridine than slow acetylators. Plasma concentrations of the N-acetyl metabolite were approximately twofold higher in fast acetylators. Gender differences were not observed. Single doses of amifampridine demonstrated dose linear PKs. Amifampridine achieved steady state plasma levels within 1 day of dosing four times daily. No accumulation or time-dependent changes in amifampridine PK parameters occurred. Overall, slow acetylators reported 73 drug-related treatment-emergent adverse events versus 6 in fast acetylators. Variations in polymorphic NAT corresponding with fast and slow acetylator phenotypes significantly affects the PK and safety profiles of amifampridine.

Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.

PubMed

Kothare, Prajakti A; Linnebjerg, Helle; Isaka, Yoshitaka; Uenaka, Kazunori; Yamamura, Ayuko; Yeo, Kwee Poo; de la Peña, Amparo; Teng, Choo Hua; Mace, Kenneth; Fineman, Mark; Shigeta, Hirofumi; Sakata, Yukikuni; Irie, Shin

2008-12-01

In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN-D0501 in healthy subjects

PubMed Central

Round, Patrick; Priestley, Anthony; Robinson, Jan

2011-01-01

AIMS XEN-D0501, a novel TRPV1 antagonist, is being developed to treat overactive bladder. This study investigated the safety and pharmacokinetics of repeat-dose XEN-D0501 in healthy subjects. METHODS The study was conducted in two parts. Part 1 was a double-blind, randomized, placebo-controlled, two-way crossover study in three cohorts of 12 young male subjects. Each subject received XEN-D0501 and placebo (in random order) twice daily for 13 days, with a final single dose on day 14. Doses of 1, 2.5 and 5 mg XEN-D0501 were investigated. Part 2 was an open-label, randomized, two-way crossover study in male and female subjects (45 to 65 years). Subjects received single doses of 5 mg XEN-D0501 under fasted and fed conditions in random order. Blood sampling and safety assessments were conducted throughout the study. RESULTS XEN-D0501 was rapidly absorbed (tmax generally 0.5–4 h post dose). XEN-D0501 exposure increased less than proportionally to dose over the range studied and exhibited minimal accumulation with twice daily dosing. Food had no clinically relevant effects on the pharmacokinetics of XEN-D0501. There were no severe or serious adverse events and all doses were well tolerated. A dose-related increase in body temperature was seen with XEN-D0501 which attenuated over time. Differences from placebo in mean maximum core body temperatures were 0.22°C, 0.5°C and 0.74°C following 1 mg, 2.5 mg and 5 mg twice daily XEN-D0501. The observed increase in body temperature was not considered to be of clinical concern. CONCLUSIONS XEN-D0501 appeared safe and well tolerated at doses up to 5 mg twice daily for 14 days in healthy subjects. PMID:21676011

The relative bioavailability and fasting pharmacokinetics of three formulations of olmesartan medoxomil 20-mg capsules and tablets in healthy Chinese male volunteers: An open-label, randomized-sequence, single-dose, three-way crossover study.

PubMed

Li, Kun-Yan; Liang, Jian-Ping; Hu, Bing-Qiang; Qiu, Yu; Luo, Chen-Hui; Jiang, Yun; Lin, Xiao-Ping; Yang, Nong

2010-08-01

Olmesartan medoxomil is an angiotensin II-receptor antagonist used in the treatment of hypertension. It is a prodrug and is converted to the pharmacologically active compound on de-esterification by arylesterase in the gastrointestinal tract. This study investigated the relative bioavailability and fasting pharmacokinetic properties of olmesartan after single doses of a 20-mg test tablet, a 20-mg test capsule, and a commercially available 20-mg reference tablet in healthy Chinese male volunteers. The study was conducted to satisfy Chinese State Food and Drug Administration regulatory requirements for approval of a generic formulation of olmesartan medoxomil. This study had an open-label, randomized-sequence, single-dose, 3-treatment, 3-period crossover design. Healthy volunteers were randomly assigned in a 1:1:1 ratio to receive a single 20-mg dose of the test tablet, test capsule, or reference tablet, each administered after a 12-hour overnight fast, followed by a 1-week washout period and administration of the alternate formulation. Blood samples were obtained at baseline and at 0.5, 1, 1.5,2,2.5,3,4,6,8,12,24,36, and 48 hours after dosing. Tolerability was assessed based on vital signs and laboratory values obtained before and after administration of study drug. The formulations were assumed to be bioequivalent if the 90% CIs for the log-transformed ratios of C(max), AUC(0-t), and AUC(0-∞) were within the predetermined equivalence range (70%-143% for C(max); 80%-125% for AUC(0-t) and AUC(0-∞)), as established by the Chinese State Food and Drug Administration. Twenty-one healthy male subjects (mean age, 21 years [range, 18-25 years]; weight, 62.1 kg [range, 54.0-80.0 kg]) were enrolled in and completed the study. No period or sequence effect was observed. The mean AUC(0-∞) values for the test tablet, test capsule, and reference tablet were 3993 (1070), 3567 (850), and 3849 (872) ng/mL/h, respectively. The 90% CIs for the log-transformed ratios of test tablet to reference tablet for C(max), AUC(0-48), and AUC(0-∞) were 103.9 to 124.9, 94.0 to 111.5, and 94.4 to 111.7, respectively (all, P = NS). The corresponding 90% CIs for the log-transformed ratios of test capsule to reference tablet were 90.8 to 109.2, 84.9 to 107.9, and 85.1 to 100.7 (all, P = NS). Ten adverse events were reported during the study; 7 subjects complained of pain during blood sampling, and 3 had a blocked venous catheter. No treatment-related adverse events were reported or observed. In this single-dose crossover study in healthy Chinese male volunteers, the test and reference formulations of olmesartan medoxomil 20-mg capsules and tablets met the regulatory criteria for assuming bioequivalence. The 3 formulations were well tolerated. Copyright © 2010 Excerpta Medica Inc. All rights reserved.

Biodistribution and tolerance of intravenous iodine-131-labelled hypericin in healthy dogs.

PubMed

Abma, E; Peremans, K; De Vos, F; Bosmans, T; Kitshoff, A M; Daminet, S; Ni, Y; Dockx, R; de Rooster, H

2018-01-04

Hypericin (Hyp) is a necrosis-avid compound that can be efficiently labelled with radioiodine for both diagnostic and therapeutic purposes. Before 131 I-Hyp can be considered as a clinically useful drug in a combination therapy for canine cancer patients, evaluation of its toxicity is necessary. The aim of this study was to investigate the biodistribution and tolerance of a single dose administration of 131 I-Hyp. Three healthy dogs were included. 131 I-Hyp at a dose of 0.2 mg/kg and an activity of 185 MBq was intravenously injected. The effects on physical, haematological and biochemical parameters were characterized and the biodistribution and elimination pattern, the effective half-life and dose rate were assessed. Drug-related adverse events were limited to mild gastrointestinal signs, resolving within 48 hours. No significant differences were found in blood haematology and serum biochemistry before and after treatment. Following administration, highest percentage of injected dose (%ID ± SD) was found in the liver (5.5 ± 0.33), the lungs (4.17 ± 0.14) and the heart (3.11 ± 0.78). After 24 hours, highest %ID was found in colon (4.25 ± 1.45) and liver (3.45 ± 0.60). Clearance from all organs was effective within 7 days. Effective half-life was established at 80 hours, and the dose rate fell below <20 μSv/h at 1 m within 1 day. The current study reveals that single dose treatment with 131 I-Hyp at the described dose is well tolerated by healthy dogs and supports the use of radioiodinated hypericin in a combination therapy for canine cancer patients. © 2018 John Wiley & Sons Ltd.

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study.

PubMed

Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Schachtel, Emily

2014-07-03

The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Adults (n=198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n=101) or matching placebo lozenges (n=97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P<0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P<0.01). There were no serious adverse events. Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010.

Single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews.

PubMed

Moore, R Andrew; Derry, Sheena; Aldington, Dominic; Wiffen, Philip J

2015-09-28

This is an updated version of the original Cochrane overview published in Issue 9, 2011. That overview considered both efficacy and adverse events, but adverse events are now dealt with in a separate overview.Thirty-nine Cochrane reviews of randomised trials have examined the analgesic efficacy of individual drug interventions in acute postoperative pain. This overview brings together the results of those individual reviews and assesses the reliability of available data. To summarise the efficacy of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery who have been given a single dose of oral analgesic. We identified systematic reviews in the Cochrane Database of Systematic Reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group, had a standard title, and had as their primary outcome the number of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews, we extracted the number needed to treat for an additional beneficial outcome (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, and the percentage of participants remedicating by six, eight, 12, or 24 hours. Where there was adequate information for pairs of drug and dose (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. The overview included 39 separate Cochrane Reviews with 41 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 50,000 participants in approximately 460 individual studies. The individual reviews included only high-quality trials of standardised design, methods, and efficacy outcome reporting. No statistical comparison was undertaken.Reliable results (high quality information) were obtained for 53 pairs of drug and dose in painful postsurgical conditions; these included various fixed dose combinations, and fast acting formulations of some analgesics. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours. Good (low) NNTs were obtained with ibuprofen 200 mg plus paracetamol (acetaminophen) 500 mg (NNT compared with placebo 1.6; 95% confidence interval 1.5 to 1.8), ibuprofen fast acting 200 mg (2.1; 1.9 to 2.3); ibuprofen 200 mg plus caffeine 100 mg (2.1; 1.9 to 3.1), diclofenac potassium 50 mg (2.1; 1.9 to 2.5), and etoricoxib 120 mg (1.8; 1.7 to 2.0). For comparison, ibuprofen acid 400 mg had an NNT of 2.5 (2.4 to 2.6). Not all participants had good pain relief and, for many pairs of drug and dose, 50% or more did not achieve at least 50% maximum pain relief over four to six hours.Long duration of action (eight hours or greater) was found for etoricoxib 120 mg, diflunisal 500 mg, paracetamol 650 mg plus oxycodone 10 mg, naproxen 500/550 mg, celecoxib 400 mg, and ibuprofen 400 mg plus paracetamol 1000 mg.There was no evidence of analgesic effect for aceclofenac 150 mg, aspirin 500 mg, and oxycodone 5 mg (low quality evidence). No trial data were available in reviews of acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for nine drugs and doses, and data potentially susceptible to publication bias for 13 drugs and doses (very low quality evidence). There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. Fast acting formulations and fixed dose combinations of analgesics can produce good and often long-lasting analgesia at relatively low doses. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers.

Heart dosimetric analysis of three types of cardiac toxicity in patients treated on dose-escalation trials for Stage III non-small-cell lung cancer.

PubMed

Wang, Kyle; Pearlstein, Kevin A; Patchett, Nicholas D; Deal, Allison M; Mavroidis, Panayiotis; Jensen, Brian C; Lipner, Matthew B; Zagar, Timothy M; Wang, Yue; Lee, Carrie B; Eblan, Michael J; Rosenman, Julian G; Socinski, Mark A; Stinchcombe, Thomas E; Marks, Lawrence B

2017-11-01

To assess associations between radiation dose/volume parameters for cardiac subvolumes and different types of cardiac events in patients treated on radiation dose-escalation trials. Patients with Stage III non-small-cell lung cancer received dose-escalated radiation (median 74 Gy) using 3D-conformal radiotherapy on six prospective trials from 1996 to 2009. Volumes analyzed included whole heart, left ventricle (LV), right atrium (RA), and left atrium (LA). Cardiac events were divided into three categories: pericardial (symptomatic effusion and pericarditis), ischemia (myocardial infarction and unstable angina), and arrhythmia. Univariable competing risks analysis was used. 112 patients were analyzed, with median follow-up 8.8 years for surviving patients. Nine patients had pericardial, seven patients had ischemic, and 12 patients had arrhythmic events. Pericardial events were correlated with whole heart, RA, and LA dose (eg, heart-V30 [p=0.024], RA-V30 [p=0.013], and LA-V30 [p=0.001]), but not LV dose. Ischemic events were correlated with LV and whole heart dose (eg, LV-V30 [p=0.012], heart-V30 [p=0.048]). Arrhythmic events showed borderline significant associations with RA, LA, and whole heart dose (eg, RA-V30 [p=0.082], LA-V30 [p=0.076], heart-V30 [p=0.051]). Cardiac events were associated with decreased survival on univariable analysis (p=0.008, HR 2.09), but only disease progression predicted for decreased survival on multivariable analysis. Cardiac events were heterogeneous and associated with distinct heart subvolume doses. These data support the hypothesis of distinct etiologies for different types of radiation-associated cardiotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Long-term safety and effectiveness of once-daily, single-entity, extended-release hydrocodone over 76 weeks of an open-label study in patients with chronic noncancer and nonneuropathic pain.

PubMed

Taber, Louise; Lynch, Shau Yu; He, Ellie; Ripa, Steven R

2016-01-01

To evaluate long-term use of Hysingla(®) ER (HYD), a single-entity, extended-release, once-daily hydrocodone bitartrate tablet with abuse-deterrent properties in patients with moderate-to-severe chronic noncancer and nonneuropathic pain. This open-label study consisted of a dose-titration period (up to 45 days), a 52-week maintenance period and a 24-week extension period. Opioid-naïve or opioid-experienced patients with controlled or uncontrolled chronic pain conditions were treated with HYD 20-120 mg daily. Supplemental nonopioid and short-acting opioid analgesics were permitted. This paper presents the results of 106 patients who continued HYD treatment for up to 76 weeks. Primary safety measures included the incidence of adverse events, as well as audiologic, clinical laboratory and electrocardiogram measurements. Effectiveness was measured by the change between baseline and the overall 76-week treatment period in "average pain over the last 24 h" (0 = no pain, 10 = pain as bad as you can imagine), Brief Pain Inventory-Short Form survey, Medical Outcomes Study 36-Item Short Form Health Survey, Medical Outcomes Study Sleep Scale-Revised and concomitant nonstudy opioid analgesic use. Among 410 patients who completed the maintenance period, 106 continued into the extension. Of these, 83 (78%) completed the entire 76-week treatment period. Treatment-emergent adverse events were typical of those observed with μ-opioid agonists. No study drug abuse or diversion was reported. Clinically important analgesia and functional improvement were achieved during the dose-titration period and were maintained in most patients throughout 76 weeks without the need for continued HYD dose increases or changes in concomitant nonstudy opioid analgesics. The mean pain score was 6.1 at baseline, 3.8 at the end of the dose titration period and 3.8 through 76 weeks. HYD was generally well tolerated. No unexpected safety concerns emerged. Pain control was sustained throughout 76 weeks of treatment.

Flow cytometry, morphometry and histopathology as biomarkers of benzo[a]pyrene exposure in brown bullheads (ameiurus nebulosus)

USGS Publications Warehouse

Grady, Andrew W.; McLaughlin, Ronald M.; Caldwell, Charles W.; Schmitt, Christopher J.; Stalling, David L.

1992-01-01

Brown bullheads were given a single intraperitoneal dose of 0, 5, 25 or 125 mg kg−1 benzo[a]pyrene (BaP), a carcinogenic polycyclic aromatic hydrocarbon, and evaluated over 18 months. Flow cytometric analyses of hepatocyte DNA content indicated an increase in DNA synthesis in BaP-exposed fish prior to day 14 post-exposure. Thereafter, all flow cytometric variables returned to initial levels. Histopathological evaluation of livers from fish sampled at 18 months revealed significant differences among treatments in the amount of hepatic macrophage ceroid pigmentation and basophilic staining intensity. No neoplasms or changes in blood cell DNA content were detected. Significant morphometric variations existed among fish, but differences between sexes overshadowed differences attributable to dose. Flow cytometry yielded no evidence of long-term DNA alterations from a single exposure to BaP; however, the differences detected by DNA analysis shortly after the toxic event suggest that flow cytometric cell cycle analysis may be useful for documenting continuing exposures.

Perioperative single high dose ATG-Fresenius S administration as induction immunosuppressive therapy in cadaveric renal transplantation--preliminary results.

PubMed

Samsel, R; Chmura, A; Włodarczyk, Z; Wyzgał, J; Cieciura, T; Lagiewska, B; Pliszczyński, J; Korczak, G; Lazowski, T; Paczek, L; Wałaszewski, J; Lao, M; Rowiński, W

1999-01-01

Monoclonal and polyclonal antilymphocyte antibodies have been used successfully in organ transplantation as induction therapy and in the treatment of acute graft rejection. Used for induction the medication is generally given for the first 7-10 days. The aim of this study was to assess the safety and efficacy of single high dose (9 mg/kg) ATG Fresenius S given perioperatively, before revascularization, to kidney allograft recipients. During last twelve months seventy six, first cadaveric kidney adult recipients were included into the study in two centers (center A-64, center B-12). All patients received triple drug immunosuppression (Neoral, steroids and Cellcept which was replaced by azathioprine after 4 months), and were randomized to receive ATG or not. The follow-up period ranged from 1 month up to 1 year. The preliminary results are very promising, the rejection rate in bolus group was significantly lower than in control. No significant side effects or serious adverse events in both groups were observed.

Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy.

PubMed

Vaduganathan, Muthiah; Bhatt, Deepak L; Cryer, Byron L; Liu, Yuyin; Hsieh, Wen-Hua; Doros, Gheorghe; Cohen, Marc; Lanas, Angel; Schnitzer, Thomas J; Shook, Thomas L; Lapuerta, Pablo; Goldsmith, Mark A; Laine, Loren; Cannon, Christopher P

2016-04-12

The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin. The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets. Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into "low-dose" (≤ 100 mg) and "high-dose" (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists. Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group. Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial [COGENT]; NCT00557921). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Evaluation of Salmonella enterica serovar Typhi (Ty2 aroC-ssaV-) M01ZH09, with a defined mutation in the Salmonella pathogenicity island 2, as a live, oral typhoid vaccine in human volunteers.

PubMed

Kirkpatrick, B D; McKenzie, Robin; O'Neill, J Patrick; Larsson, Catherine J; Bourgeois, A Louis; Shimko, Janet; Bentley, Matthew; Makin, Jill; Chatfield, Steve; Hindle, Zoë; Fidler, Christine; Robinson, Brad E; Ventrone, Cassandra H; Bansal, Nivedita; Carpenter, Colleen M; Kutzko, Deborah; Hamlet, Sandra; LaPointe, Casey; Taylor, David N

2006-01-12

Salmonella enterica serovar Typhi strains with mutations in the Salmonella pathogenicity island-2 (SPI-2) may represent an effective strategy for human vaccine development, and a vectoring system for heterologous antigens. S. Typhi (Ty2 aroC-ssaV-) M01ZH09 is an attenuated, live, oral typhoid vaccine harboring defined deletion mutations in ssaV, which encodes an integral component in the SPI-2 type III secretion system (TTSS), as well as a mutation in an aromatic biosynthetic pathway needed for bacterial growth in vivo (aroC). SPI-2 mutant vaccines have yet to be evaluated in a large, randomized human trial. A simplified or single-oral dose oral typhoid vaccine using the SPI-2 strategy would offer significant advantages over the currently licensed typhoid vaccines. We performed a double-blinded, placebo-controlled, dose-escalating clinical trial in 60 healthy adult volunteers to determine the tolerability and immunogenicity of a single dose of M01ZH09. Three groups of 20 healthy adult volunteers were enrolled; 16 in each group received a single oral dose of the freeze-dried vaccine at 5 x 10(7), 5 x 10(8) or 5 x 10(9)CFU in a bicarbonate buffer. Four volunteers in each cohort received placebo in the same buffer. Adverse events were infrequent and not statistically different between vaccine and placebo recipients, although two subjects in the mid-range dose and three subjects in the highest dose had temperature measurements >37.5 degrees C. No blood or urine cultures were positive for M01ZH09, and fecal shedding was brief. The immune response was dose-related; the highest vaccine dose (5 x 10(9)CFU) was the most immunogenic. All tested subjects receiving the highest dose had a significant ASC response (mean 118 spots/10(6) cells). A >or=4-fold increase in antibody titer for S. Typhi LPS or flagellin was detected in 75% of volunteers in the highest-dose cohort by day 28. The SPI-2 mutant vaccine, M01ZH09, is a promising typhoid vaccine candidate and deserves further study as a vectoring system for heterologous vaccine antigens.

Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy

DTIC Science & Technology

2012-09-01

diarrhea and interstitial lung disease/pneumonitis. From largest to smallest, our multiple dose (1,250 mg q24 h) model-predicted ratios of lapatinib...1977) A model for the kinetics of distribution of actinomycin-D in the beagle dog . J Pharmacol Exp Ther 200(3):469–478 31. Collins JM, Dedrick RL, King...a single agent for various tumor types (n = 2045), nausea (39%), diarrhea (39%) and vomiting (22%) were observed; other gastrointestinal events

Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy

DTIC Science & Technology

2013-03-01

diarrhea and interstitial lung disease/pneumonitis. From largest to smallest, our multiple dose (1,250 mg q24 h) model-predicted ratios of lapatinib...1977) A model for the kinetics of distribution of actinomycin-D in the beagle dog . J Pharmacol Exp Ther 200(3):469–478 31. Collins JM, Dedrick RL, King...as a single agent for various tumor types (n = 2045), nausea (39%), diarrhea (39%) and vomiting (22%) were observed; other gastrointestinal events

Role for a Steroid Sulfontransferase (SULT2B) in the Intratumoral Androgen Metabolism and in Prostate Cancer

DTIC Science & Technology

2015-10-01

failure and other adverse events. AUC for atorvastatin was elevated more than 600% in healthy volunteers when a single dose of rifampin was co...administered with the statin. Rifampin-induced inhibition of OATP for atorvastatin caused elevated AUC (Lau et al, 2007). Long-term rifampin treatment...however, reduced atorvastatin bioavailability due to induced expression of CYP3A4 and efflux transporters by rifampin-activated PXR. Various

Investigation of the impact of sarizotan on the pharmacokinetics of levodopa.

PubMed

Krösser, Sonja; Neugebauer, Roland; Chassard, Didier; Kovar, Andreas

2007-10-01

To investigate the effect of sarizotan on the pharmacokinetics of levodopa in fixed combination with carbidopa or benserazide. In this open-label, randomized, crossover study, healthy male subjects (n=16) received levodopa 100 mg t.i.d. over two 5-day periods, alone or in combination with sarizotan 5 mg b.i.d. Levodopa was administered with a dopa-decarboxylase inhibitor (carbidopa 25 mg, n=8 or benserazide 25 mg, n=8). Pharmacokinetic parameters of levodopa were obtained on days 1 and 5. ANOVA showed the C(max) values for levodopa were not significantly different with or without sarizotan after single doses (1001 vs 1082 ng/ml; point estimate [PE] 1.10, 90% confidence intervals [CI] 0.83-1.45) or at steady-state (1549 vs 1663 ng/ml; PE 1.06, 90% CI 0.89-1.27); nor were AUC values for single doses (1661 vs 1665 ng h/ml; PE 1.01, 90% CI 0.91-1.11) or at steady-state (2462 vs 2482 ng h/ml; PE 1.01, 90% CI 0.97-1.05). Seven subjects reported adverse events of mild-to-moderate intensity; the most frequent were headaches and dizziness. Coadministration of sarizotan with levodopa, in combination with a dopa-decarboxylase inhibitor had no effect on the pharmacokinetics or adverse event profile of levodopa. (c) 2007 John Wiley & Sons, Ltd.

Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment

PubMed Central

Cohen, Stanley; Zwillich, Samuel H; Chow, Vincent; LaBadie, Robert R; Wilkinson, Bethanie

2010-01-01

AIMS To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX. METHODS This was a fixed-dose drug–drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15–25 mg per week). RESULTS All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC12 ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC12 ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments. CONCLUSIONS Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX. PMID:20233177

Safety and immunogenicity of a booster dose of meningococcal (groups A, C, W, and Y) polysaccharide diphtheria toxoid conjugate vaccine.

PubMed

Robertson, Corwin A; Greenberg, David P; Hedrick, James; Pichichero, Michael; Decker, Michael D; Saunders, Martha

2016-10-17

Quadrivalent meningococcal conjugate vaccines (MenACWY) were developed to offer long-term protection against invasive disease caused by serogroups A, C, W, and Y. Reduced MenACWY effectiveness within 5 years after primary vaccination (likely due to declining bactericidal antibody titers) has been described, particularly with respect to C and Y disease in the United States. We evaluated the safety and immunogenicity of a single booster dose of quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D) in adolescents and adults who received a previous dose 4-6 years earlier. This phase 2, open-label, multicenter study of 834 persons was conducted in the United States. Participants received a single 0.5-mL booster dose of MenACWY-D. Serogroup-specific bactericidal antibody geometric mean titers (GMTs) were measured with a serum bactericidal antibody assay using human complement (hSBA). Proportions of participants achieving antibody titers of ⩾1:8 for each vaccine serogroup on Days 6 and 28 were determined. Rates of adverse events (AEs), including serious adverse events (SAEs), were also assessed. Before booster vaccination, 38.7-68.5% of participants had an hSBA titer ⩾1:8, depending on vaccine serogroup. By Day 6 post-vaccination, 98.2-99.1% of participants had hSBA titers ⩾1:8. By Day 28, >99% of participants achieved this threshold and the primary hypothesis (lower limit of the one-sided 95% confidence limit ⩾85% for each serogroup) was met. The GMT ratios (post-vaccination divided by pre-vaccination) at Day 28 ranged from 47.2 (serogroup A) to 209.1 (serogroup Y). Rates of AEs, including SAEs, were similar to those observed among adolescents and adults who received a primary dose of MenACWY-D in previous studies. There were no study discontinuations due to an AE and no deaths. Booster vaccination with MenACWY-D was safe and induced robust bactericidal antibody responses, consistent with immune memory, among adolescents and adults 4-6 years after primary vaccination. ClinicalTrials.gov registration: NCT01442675. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Octanoic acid in alcohol-responsive essential tremor

PubMed Central

McCrossin, Gayle; Lungu, Codrin; Considine, Elaine; Toro, Camilo; Nahab, Fatta B.; Auh, Sungyoung; Buchwald, Peter; Grimes, George J.; Starling, Judith; Potti, Gopal; Scheider, Linda; Kalowitz, Daniel; Bowen, Daniel; Carnie, Andrea; Hallett, Mark

2013-01-01

Objective: To assess safety and efficacy of an oral, single, low dose of octanoic acid (OA) in subjects with alcohol-responsive essential tremor (ET). Methods: We conducted a double-blind, placebo-controlled, crossover, phase I/II clinical trial evaluating the effect of 4 mg/kg OA in 19 subjects with ET. The primary outcome was accelerometric postural tremor power of the dominant hand 80 minutes after administration. Secondary outcomes included digital spiral analysis, pharmacokinetic sampling, as well as safety measures. Results: OA was safe and well tolerated. Nonserious adverse events were mild (Common Terminology Criteria for Adverse Events grade 1) and equally present after OA and placebo. At the primary outcome, OA effects were not different from placebo. Secondary outcome analyses of digital spiral analysis, comparison across the entire time course in weighted and nonweighted accelerometry, as well as nondominant hand tremor power did not show a benefit of OA over placebo. The analysis of individual time points showed that OA improved tremor at 300 minutes (dominant hand, F1,16 = 5.49, p = 0.032 vs placebo), with a maximum benefit at 180 minutes after OA (both hands, F1,16 = 6.1, p = 0.025). Conclusions: Although the effects of OA and placebo at the primary outcome were not different, secondary outcome measures suggest superiority of OA in reducing tremor at later time points, warranting further trials at higher dose levels. Classification of evidence: This study provides Class I evidence that a single 4-mg/kg dose of OA is not effective in reducing postural tremor in patients with ET at a primary outcome of 80 minutes, but is effective for a secondary outcome after 180 minutes. PMID:23408867

The impact of diet liberalization on bowel preparation for colonoscopy.

PubMed

Walter, James; Francis, Gloria; Matro, Rebecca; Kedika, Ramalinga; Grosso, Rachael; Keith, Scott W; Kastenberg, David

2017-04-01

Background and study aims  Dietary restrictions are integral to colonoscopy preparation and impact patient satisfaction. Utilizing split-dose, lower-volume polyethylene glycol 3350-electrolyte solution (PEG-ELS), this study compared colon preparation adequacy of a low-residue diet to clear liquids using a validated grading scale. Patients and methods  This was a prospective, randomized, single-blinded, single-center non-inferiority study evaluating diet the day prior to outpatient colonoscopy. Subjects were randomized to a Low-Residue diet for breakfast and lunch, or Clears only. All subjects received split dose PEG-ELS. The primary endpoint was preparation adequacy using the Boston Bowel Preparation Scale (BBPS), with adequate defined as a score > 5. Secondary endpoints included mean BBPS scores for the entire colon and individual segments, satisfaction, adverse events, polyp and adenoma detection rates, and impact on sleep and daily activities. Results  Final analysis included 140 subjects, 72 assigned to Clears and 68 to Low-Residue. The Low-Residue diet was non-inferior to Clears (risk difference = - 5.08 %, P  = 0.04) after adjusting for age. Mean colon cleansing scores were not significantly different overall and for individual colonic segments. Satisfaction with the Low-Residue diet was significantly greater ( P  = 0.01). The adenoma detection rate was not statistically significantly different between study groups, but the number of adenomas detected was significantly greater with Clears ( P  = 0.01). Adverse events and impact on sleep and activities did not differ significantly between diet arms. Conclusions  A low-residue diet for breakfast and lunch the day prior to colonoscopy was non-inferior to clear liquids alone for achieving adequate colon cleansing when using split dose PEG-ELS.

Letrozole combined with low dose highly purified HMG for ovulation induction in clomiphene citrate-resistant infertile Chinese women with polycystic ovary syndrome: a prospective study.

PubMed

Zhao, Yue; Ruan, Xiangyan; Mueck, Alfred O

2017-06-01

There are still open questions about ovulation induction in clomiphene citrate-(CC)-resistant infertile women. Especially little is known about efficacy and safety of letrozole (LTZ) combined with low-dose highly purified human menopausal gonadotropin (Hp-HMG) in women with polycystic ovary syndrome (PCOS). Prospective, single-arm single-center trial in 200 infertile PCOS patients refractory for at least three CC-treatment cycles. Women with hyperandrogenism took Diane-35 for at least 3 months. All patients got LTZ on day 3 for 5 d in combination with Hp-HMG, starting with 75 IU from cycle day 7 and maintained for up to 3 d. The maximum dose was 150 IU. Primary end-points were ongoing and clinical pregnancy rate, secondary end-points mono-follicular development, ovulation rate, OHSS, multiple pregnancy and early pregnancy loss. Major safety end-point was the incidence of adverse events. Within 395 cycles the ongoing pregnancy rate was 28.24%, for cycles 35.23%, for patients 68%. The rate of ovulation per cycle was 97.7%, percentage of mono-follicular development 70.9%. No severe OHSS, multiple pregnancy, local or systemic side effects were seen. LTZ combined with low-dose Hp-HMG is an effective and safe choice for reducing hyperstimulation and increasing pregnancy rate in CC-resistant women with PCOS.

Platelet Aggregation Inhibitory Effects and Pharmacokinetics of Prasugrel Used in Combination With Aspirin in Healthy Japanese Subjects.

PubMed

Umemura, Kazuo; Ikeda, Yasuhiko; Matsushima, Nobuko; Kondo, Kazunao

2017-07-01

We evaluated the pharmacokinetics and pharmacodynamics of prasugrel used in combination with aspirin in healthy Japanese subjects. All subjects received aspirin 100 mg/day. Subsequently, in the single-administration study, 23 subjects also received prasugrel 20 or 30 mg, and in the multiple-administration study, 20 subjects received a loading dose of prasugrel 20 or 30 mg on day 1, followed by a maintenance dose of prasugrel 5 or 7.5 mg/day, respectively, on days 2-5. In both studies, the plasma concentration of the active metabolite of prasugrel, R-138727, reached a maximum 0.5 hours after administration and rapidly decreased within 4 hours. In the single-administration study, the inhibitory effect on adenosine diphosphate-induced platelet aggregation was significantly higher in the prasugrel 20- and 30-mg groups than in the placebo group at all times (1-144 hours) after administration. In the multiple-administration study, a similar antiplatelet effect was found after both the loading dose and the maintenance dose and was maintained for 3-6 days after the last administration. There were study drug-related adverse events; however, all were mild, and none was clinically significant. © 2016 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Single dose oral naproxen and naproxen sodium for acute postoperative pain (Review)

PubMed Central

Mason, L; Edwards, JE; Moore, RA; McQuay, HJ

2014-01-01

Background Postoperative pain is often poorly managed. Treatment options include a range of drug therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) of which naproxen is one. Naproxen is used to treat a variety of painful conditions including acute postoperative pain, and is often combined with sodium to improve its solubility for oral administration. Naproxen sodium 550 mg (equivalent to 500 mg of naproxen) is considered to be an effective dose for treating postoperative pain but to date no systematic review of the effectiveness of naproxen/naproxen sodium at different doses has been published. Objectives To assess the efficacy, safety and duration of action of a single oral dose of naproxen or naproxen sodium for acute postoperative pain in adults. Search strategy We searched The Cochrane Library, MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies. Additional studies were identified from the reference list of retrieved reports. The most recent search was undertaken in July 2004. Selection criteria Included studies were randomised, double blind, placebo-controlled trials of a single dose of orally administered naproxen or naproxen sodium in adults with moderate to severe acute postoperative pain. Data collection and analysis Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of patients with at least 50% pain relief over four to six hours. Relative risk estimates (RR) and the number-needed-to-treat (NNT) for at least 50% pain relief were then calculated. Information was sought on the percentage of patients experiencing any adverse event, and the number-needed-to-harm was derived. Time to remedication was also estimated. Main results Ten trials (996 patients) met the inclusion criteria: nine assessed naproxen sodium; one combined the results from two small trials of naproxen alone. Included studies scored well for methodological quality. Meta-analysis of six trials (500 patients) that compared naproxen sodium 550 mg with placebo gave a RR for at least 50% pain relief over 4 to 6 hours of 4.2 (95% confidence interval (CI) 2.9 to 6.0) and an NNT of 2.6 (95% CI 2.2 to 3.2). Three trials (334 patients) assessed naproxen 400 mg and naproxen sodium 440 mg, giving a RR of 4.8 (95% CI 2.75 to 8.38). Two small studies indicated that naproxen 200 mg and naproxen sodium 220 mg may provide effective postoperative pain relief. There was no significant difference between the number of patients experiencing any adverse event on treatment compared with placebo. Weighted mean time to remedication for naproxen sodium 550 mg was 7.6 hours compared with 2.6 hours for placebo. Authors’ conclusions Naproxen sodium 550 mg, naproxen 400 mg and naproxen sodium 440 mg administered orally are effective analgesics for the treatment of acute postoperative pain in adults. A low incidence of adverse events was found but reporting was not consistent. PMID:15495091

Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia.

PubMed

Mahlangu, J N; Coetzee, M J; Laffan, M; Windyga, J; Yee, T T; Schroeder, J; Haaning, J; Siegel, J E; Lemm, G

2012-05-01

BAY 86-6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86-6150 in non-bleeding hemophilia subjects. The study included non-bleeding men (18-65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or 90 μg kg(-1) [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data-monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. At the tested doses, BAY 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 5-7 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26-237 nm thrombin from 6.5 to 90 μg kg(-1)). Peak thrombin levels over time paralleled BAY 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti-BAY 86-6150 neutralizing antibodies during the 50-day follow-up. In this first-in-human, multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study, BAY 86-6150 was tolerated at the highest dose (90 μg kg(-1)), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies. © 2012 International Society on Thrombosis and Haemostasis.

A Single Zidovudine (AZT) Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver.

PubMed

Butanda-Ochoa, Armando; Hernández-Espinosa, Diego Rolando; Olguín-Martínez, Marisela; Sánchez-Sevilla, Lourdes; Rodríguez, Mario R; Chávez-Rentería, Benito; Aranda-Fraustro, Alberto; Hernández-Muñoz, Rolando

2017-01-01

The 3'-azido-3'-deoxythymidine or Zidovudine (AZT) was the first antiretroviral drug used in the treatment of HIV patients, which has good effectiveness but also hepatotoxic side effects that include cell cycle arrest and oxidative/nitrative mitochondrial damage. Whether such an oxidative damage may affect the proliferative-regenerative capacity of liver remains to be clearly specified at doses commonly used in the clinical practice. In this study, we described the oxidative-proliferative effect of AZT administered at a common clinical dose in rat liver submitted to 70% partial hepatectomy (PH). The results indicate that AZT significantly decreased DNA synthesis and the number of mitosis in liver subjected to PH in a synchronized way with the promotion of organelle-selective lipid peroxidation events (especially those observed in plasma membrane and cytosolic fractions) and with liver enzyme release to the bloodstream. Then at the dose used in clinical practice AZT decreased liver regeneration but stimulates oxidative events involved during the proliferation process in a way that each membrane system inside the cell preserves its integrity in order to maintain the cell proliferative process. Here, the induction of large amounts of free ammonia in the systemic circulation could become a factor capable of mediating the deleterious effects of AZT on PH-induced rat liver regeneration.

Operation of commercial R3000 processors in the low earth orbit (LEO) space environment

NASA Astrophysics Data System (ADS)

Kaschmitter, J. L.; Shaeffer, D. L.; Colella, N. J.; McKnett, C. L.; Coakley, P. G.

1991-12-01

Spacecraft processors must operate with minimal degradation of performance in the LEO radiation environment, which includes the effects of total accumulated ionizing dose and single event phenomena (SEP) caused by protons and cosmic rays. Commercially available microprocessors can offer a number of advantages relative to radiation-hardened devices but are not normally designed to tolerate effects induced by the LEO environment. Extensive testing of the MIPS R3000 Reduced Instruction Set Computer (RISC) microprocessor family for operation in LEO environments is reported. The authors have characterized total dose and SEP effects for altitudes and inclinations of interest to systems operating in LEO, and they postulate techniques for detection and alleviation of SEP effects based on experimental results.

Tumor Control Outcomes Following Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases from Renal Cell Carcinoma

PubMed Central

Zelefsky, Michael J; Greco, Carlo; Motzer, Robert; Magsanoc, Juan Martin; Pei, Xin; Lovelock, Michael; Mechalakos, Jim; Zatcky, Joan; Fuks, Zvi; Yamada, Yoshiya

2014-01-01

Purpose To report tumor local progression-free outcomes following treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Methods and Materials Between 2004 and 2010, a total of 105 lesions from renal cell carcinomas were treated with either SD-IGRT to prescription doses of 18–24 Gy (median, 24 Gy) or hypofractionation (3 or 5 fractions) with prescription doses ranging between 20 and 30 Gy. The median follow-up was 12 months (range, 1–48 months). Results The overall 3-year actuarial local progression-free survival (LPFS) for all lesions was 44%. The 3-year LPFS for those who received high single-dose (24 Gy; n = 45), low single-dose (< 24 Gy; n = 14), and hypofractionation regimens (n = 46) were 88%, 21%, and 17%, respectively (high single dose versus low single dose, p = 0.001; high single dose versus hypofractionation, p < 0.001). Multivariate analysis revealed the following variables as significant predictors of improved LPFS: dose of 24 Gy compared with lower dose (p = 0.009), and single dose versus hypofractionation (p = 0.008). Conclusion High-dose SD-IGRT is a non-invasive procedure resulting in high probability of local tumor control for metastatic renal cell cancers, generally considered radioresistant according to classical radiobiological ranking. PMID:21596489

Safety, reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults: a phase I/II randomized clinical study.

PubMed

Leroux-Roels, Geert; Maes, Cathy; De Boever, Fien; Traskine, Magali; Rüggeberg, Jens U; Borys, Dorota

2014-11-28

New vaccines containing highly conserved Streptococcus pneumoniae proteins such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) are being developed to provide broader protection against pneumococcal disease. This study evaluated the safety, reactogenicity and immunogenicity of different pneumococcal protein-containing formulations in adults. In a phase I double-blind study (www.clinicaltrials.gov: NCT00707798), healthy adults (18-40 years) were randomized (1:2:2:2:2:2:2) to receive two doses of one of six investigational vaccine formulations 2 months apart, or a single dose of the control 23-valent pneumococcal polysaccharide vaccine (23PPV; Pneumovax23™, Sanofi Pasteur MSD) followed by placebo. The investigational formulations contained dPly alone (10 or 30 μg), or both dPly and PhtD (10 or 30 μg each) alone or combined with the polysaccharide conjugates of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix™, GlaxoSmithKline Vaccines). Two groups primed with a formulation containing dPly and PhtD (10 or 30 μg each) continued to the follow-up phase II study (NCT00896064), in which they received a booster dose at 5-9 months after primary vaccination. Of 156 enrolled and vaccinated adults, 146 completed the primary immunization and 43 adults received a booster dose. During primary and booster vaccination, for any formulation, ≤ 8.9% of doses were followed by grade 3 solicited local or general adverse events. No fever >39.5°C (oral temperature) was reported. Unsolicited adverse events considered causally related to vaccination were reported following ≤ 33.3% of investigational vaccine doses. No serious adverse events were reported for adults receiving investigational vaccine formulations. Formulations containing dPly with or without PhtD were immunogenic for these antigens; polysaccharide conjugate-containing formulations were also immunogenic for those 10 polysaccharides. Investigational vaccine formulations containing dPly and PhtD were well tolerated and immunogenic when administered to healthy adults as standalone protein vaccine or combined with PHiD-CV conjugates. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Relative bioavailability of tizanidine hydrochloride capsule formulation compared with capsule contents administered in applesauce: a single-dose, open-label, randomized, two-way, crossover study in fasted healthy adult subjects.

PubMed

Henney, Herbert R; Fitzpatrick, Anthony; Stewart, Johnston; Runyan, Jacob D

2008-12-01

The alpha2-adrenergic agonist tizanidine has been reported to have a narrow therapeutic index. A multiparticulate capsule formulation of tizanidine has been developed in an attempt to improve patient tolerability. This study assessed bioequivalence between a single, intact, 6-mg capsule of tizanidine and the capsule contents sprinkled in applesauce in fasted healthy subjects. Healthy male and female subjects aged 18 to 45 years completed 2 treatment periods: one with a tizanidine 6-mg capsule administered intact and the other with capsule contents sprinkled in applesauce. The 2 treatment periods had a 6-day washout period between administrations. Plasma tizanidine concentrations were determined for blood samples collected over 24 hours after administration. All treatment-emergent adverse events were recorded and graded by intensity and relationship to the study drug (not, improbable, possible, probable, definite) by the attending physician based on his or her clinical impression. A total of 19 men and 9 women (mean age, 26 years) completed the trial. Geometric mean natural logarithm-transformed AUC values (AUC(0-infinity) [AUC to infinity] and AUC(0-t) [AUC to the last measurable time point]) and C(max) ratios were significantly (P

Overnight switching from oxcarbazepine to eslicarbazepine acetate: an observational study.

PubMed

Schmid, E; Kuchukhidze, G; Kirschner, M; Leitinger, M; Höfler, J; Rohracher, A; Kalss, G; Wendling, A-S; Steinhoff, B J; Trinka, E

2017-04-01

There are clinical situations where it might be appropriate to switch patients from immediate-release oxcarbazepine (OXC) to eslicarbazepine acetate (ESL). We investigated the effects of transitioning patients overnight from OXC to ESL. A retrospective, single-center study was conducted in which patients with drug-resistant focal epilepsy on a stable dose of immediate-release OXC for at least 4 weeks were switched overnight to ESL. Patients were switched because they experienced persistent seizures with OXC but were unable to tolerate increased OXC dosing due to adverse events. Tolerability was assessed using the Adverse Events Profile (AEP), quality of life was assessed using the Quality of Life in Epilepsy Inventory 10 (QOLIE-10), and alertness was assessed as reaction time using a subtest of the Test Battery for Attention Performance version 2.3. Assessments were performed immediately prior to and 5 days after switching from OXC to ESL (days 0 and 5, respectively). The analysis included 21 patients (12 women, 9 men; mean age 36 years). After switching from OXC to ESL, there were significant improvements in mean scores for AEP (P<.001), QOLIE-10 (P=.001), and alertness (P<.05). Adverse Events Profile total scores improved for 21/21 (100.0%) patients, QOLIE-10 total scores improved for 17/21 (81.0%) patients, and alertness scores improved for 16/21 (76.2%) patients. In this short-term, single-center study, an overnight switch from twice-daily OXC to once-daily ESL in patients with drug-resistant focal epilepsies resulted in improvements in side effects, quality of life, and alertness. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.

PubMed

Ray, Kausik K; Landmesser, Ulf; Leiter, Lawrence A; Kallend, David; Dufour, Robert; Karakas, Mahir; Hall, Tim; Troquay, Roland P T; Turner, Traci; Visseren, Frank L J; Wijngaard, Peter; Wright, R Scott; Kastelein, John J P

2017-04-13

In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).

Shortcomings in ground testing, environment simulations, and performance predictions for space applications

NASA Technical Reports Server (NTRS)

Stassinopoulos, E. G.; Brucker, G. J.

1992-01-01

This paper addresses the issues involved in radiation testing of devices and subsystems to obtain the data that are required to predict the performance and survivability of satellite systems for extended missions in space. The problems associated with space environmental simulations, or the lack thereof, in experiments intended to produce information to describe the degradation and behavior of parts and systems are discussed. Several types of radiation effects in semiconductor components are presented, as for example: ionization dose effects, heavy ion and proton induced Single Event Upsets (SEUs), and Single Event Transient Upsets (SETUs). Examples and illustrations of data relating to these ground testing issues are provided. The primary objective of this presentation is to alert the reader to the shortcomings, pitfalls, variabilities, and uncertainties in acquiring information to logically design electronic subsystems for use in satellites or space stations with long mission lifetimes, and to point out the weaknesses and deficiencies in the methods and procedures by which that information is obtained.

South Atlantic anomaly and CubeSat design considerations

NASA Astrophysics Data System (ADS)

Fennelly, Judy A.; Johnston, William R.; Ober, Daniel M.; Wilson, Gordon R.; O'Brien, T. Paul; Huston, Stuart L.

2015-09-01

Effects of the South Atlantic Anomaly (SAA) on spacecraft in low Earth orbit (LEO) are well known and documented. The SAA exposes spacecraft in LEO to high dose of ionizing radiation as well as higher than normal rates of Single Event Upsets (SEU) and Single Event Latch-ups (SEL). CubeSats, spacecraft built around 10 x 10 x 10 cm cubes, are even more susceptible to SEUs and SELs due to the use of commercial off-the-shelf components for electronics and payload instrumentation. Examination of the SAA using both data from the Defense Meteorological Satellite Program (DMSP) and a new set of models for the flux of particles is presented. The models, AE9, AP9, and SPM for energetic electrons, energetic protons and space plasma, were developed for use in space system design. These models introduce databased statistical constraints on the uncertainties from measurements and climatological variability. Discussion of the models' capabilities and limitations with regard to LEO CubeSat design is presented.

Low dose evaluation of the antiandrogen flutamide following a Mode of Action approach.

PubMed

Sarrabay, A; Hilmi, C; Tinwell, H; Schorsch, F; Pallardy, M; Bars, R; Rouquié, D

2015-12-15

The dose-response characterization of endocrine mediated toxicity is an on-going debate which is controversial when exploring the nature of the dose-response curve and the effect at the low-end of the curve. To contribute to this debate we have assessed the effects of a wide range of dose levels of the antiandrogen flutamide (FLU) on 7-week male Wistar rats. FLU was administered by oral gavage at doses of 0, 0.001, 0.01, 0.1, 1 and 10mg/kg/day for 28 days. To evaluate the reproducibility, the study was performed 3 times. The molecular initiating event (MIE; AR antagonism), the key events (LH increase, Leydig cell proliferation and hyperplasia increases) and associated events involved in the mode of action (MOA) of FLU induced testicular toxicity were characterized to address the dose response concordance. Results showed no effects at low doses (<0.1mg/kg/day) for the different key events studied. The histopathological changes (Leydig cell hyperplasia) observed at 1 and 10mg/kg/day were associated with an increase in steroidogenesis gene expression in the testis from 1mg/kg/day, as well as an increase in testosterone blood level at 10mg/kg/day. Each key event dose-response was in good concordance with the MOA of FLU on the testis. From the available results, only monotonic dose-response curves were observed for the MIE, the key events, associated events and in effects observed in other sex related tissues. All the results, so far, show that the reference endocrine disruptor FLU induces threshold effects in a standard 28-day toxicity study on adult male rats. Copyright © 2015 Elsevier Inc. All rights reserved.

A multicentre randomized controlled trial of the efficacy and safety of single-dose praziquantel at 40 mg/kg vs. 60 mg/kg for treating intestinal schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil.

PubMed

Olliaro, Piero L; Vaillant, Michel T; Belizario, Vincente J; Lwambo, Nicholas J S; Ouldabdallahi, Mohamed; Pieri, Otavio S; Amarillo, Maria L; Kaatano, Godfrey M; Diaw, Mamadou; Domingues, Analucia C; Favre, Tereza C; Lapujade, Olivier; Alves, Fabiana; Chitsulo, Lester

2011-06-01

Praziquantel at 40 mg/kg in a single dose is the WHO recommended treatment for all forms of schistosomiasis, but 60 mg/kg is also deployed nationally. Four trial sites in the Philippines, Mauritania, Tanzania and Brazil enrolled 856 patients using a common protocol, who were randomised to receive praziquantel 40 mg/kg (n  =  428) or 60 mg/kg (n  =  428). While the sites differed for transmission and infection intensities (highest in Tanzania and lowest in Mauritania), no bias or heterogeneity across sites was detected for the main efficacy outcomes. The primary efficacy analysis was the comparison of cure rates on Day 21 in the intent-to-treat population for the pooled data using a logistic model to calculate Odd Ratios allowing for baseline characteristics and study site. Both doses were highly effective: the Day 21 cure rates were 91.7% (86.6%-98% at individual sites) with 40 mg/kg and 92.8% (88%-97%) with 60 mg/kg. Secondary parameters were eggs reduction rates (ERR), change in intensity of infection and reinfection rates at 6 and 12 months. On Day 21 the pooled estimate of the ERR was 91% in both arms. The Hazard Ratio for reinfections was only significant in Brazil, and in favour of 60 mg/kg on the pooled estimate (40 mg/kg: 34.3%, 60 mg/kg: 23.9%, HR  =  0.78, 95% CI  = [0.63;0.96]). Analysis of safety could not distinguish between disease- and drug-related events. 666 patients (78%) reported 1327 adverse events (AE) 4 h post-dosing. The risk of having at least one AE was higher in the 60 than in the 40 mg/kg group (83% vs. 73%, p<0.001). At 24 h post-dosing, 456 patients (54%) had 918 AEs with no difference between arms. The most frequent AE was abdominal pain at both 4 h and 24 h (40% and 24%). A higher dose of 60 mg/kg of praziquantel offers no significant efficacy advantage over standard 40 mg/kg for treating intestinal schistosomiasis caused by either S. mansoni or S. japonicum. The results of this study support WHO recommendation and should be used to inform policy decisions in the countries.

Effects of D-004, a lipid extract of the fruit of the Cuban royal palm (Roystonea regia) or the lipidosterolic extract of saw palmetto (Serenoa repens) on the sexual activity in male rats: A controlled, experimental study.

PubMed

Fernández, Lilia C; Mas, Rosa; Fernández, Julio; Mendoza, Sarahí; Gámez, Rafael; Pardo, Balia

2008-02-01

The etiology of benign prostatic hyperplasia (BPH) is not completely understood, but hormonal changes in aging men seem to be pivotal. Dihydrotestosterone, a potent, active metabolite of testosterone, is formed by the enzymatic action of prostate 5α-reductase and causes cell growth and hyperplasia. Consistent with this action, male sexual dysfunction has been clinically documented to be among the drug-related adverse events associated with 5α-reductase inhibitors. The lipidosterolic extract of saw palmetto (LESP) fruit (Serenoa repens) has been used to treat BPH. D-004, a lipid extract of Roystonea regia Royal palm fruit, has been found to prevent prostatic hyperplasia induced by testoste-rone in rodents and to competitively inhibit prostate 5α-reductase activity in vitro. The purpose of this study was to assess the effects of D-004 and LESP, administered as single or repeated doses, on the sexual activity in male rats. This controlled, experimental study was conducted at the Pharmacology Department, Centre of Natural Products, National Centre for Scientific Research, Havana City, Cuba. Adult male Wistar rats weighing 250 to 300 g were randomized into 5 groups: 2 groups treated orally with D-004 (400 and 800 mg/kg); 2 groups treated orally with LESP (400 and 800 mg/kg); and 1 control group orally administered a water vehicle. Sexual activity behavior (the number of mounts and intromissions, mount latency, and intromission latency) was assessed during 2 observation periods: 90 minutes after the initial dose and at the end of the 30-day treatment. Latency was defined as time elapsed between the first mount and intromission. A total of 50 rats (mean [SD] age, 10 [3] weeks; mean [SD] weight, 295 [10] g) were included in the experiment. There were no significant difterences in the mean number of mounts, intromissions, mount latency, or intromission latency in the groups treated with single or repeated doses of D-004 or LESP (400 and 800 mg/kg) compared with the controls. There was also no between-group difterence in mating behavior among the active treatment groups. All rats survived up to study completion, with normal behavior (weight gain, food intake, daily observations, without any sign of toxicity). There were no observable adverse events during the study. D-004 and LESP administered as a single dose or repeated doses for 30 days did not significantly affect male rat sexual activity behavior compared with a vehicle control group.

Predicting astronaut radiation doses from major solar particle events using artificial intelligence

NASA Astrophysics Data System (ADS)

Tehrani, Nazila H.

1998-06-01

Space radiation is an important issue for manned space flight. For long missions outside of the Earth's magnetosphere, there are two major sources of exposure. Large Solar Particle Events (SPEs) consisting of numerous energetic protons and other heavy ions emitted by the Sun, and the Galactic Cosmic Rays (GCRs) that constitute an isotropic radiation field of low flux and high energy. In deep-space missions both SPEs and GCRs can be hazardous to the space crew. SPEs can provide an acute dose, which is a large dose over a short period of time. The acute doses from a large SPE that could be received by an astronaut with shielding as thick as a spacesuit maybe as large as 500 cGy. GCRs will not provide acute doses, but may increase the lifetime risk of cancer from prolonged exposures in a range of 40-50 cSv/yr. In this research, we are using artificial intelligence to model the dose-time profiles during a major solar particle event. Artificial neural networks are reliable approximators for nonlinear functions. In this study we design a dynamic network. This network has the ability to update its dose predictions as new input dose data is received while the event is occurring. To accomplish this temporal behavior of the system we use an innovative Sliding Time-Delay Neural Network (STDNN). By using a STDNN one can predict doses received from large SPEs while the event is happening. The parametric fits and actual calculated doses for the skin, eye and bone marrow are used. The parametric data set obtained by fitting the Weibull functional forms to the calculated dose points has been divided into two subsets. The STDNN has been trained using some of these parametric events. The other subset of parametric data and the actual doses are used for testing with the resulting weights and biases of the first set. This is done to show that the network can generalize. Results of this testing indicate that the STDNN is capable of predicting doses from events that it has not seen before.

Single preoperative dose of prophylactic amoxicillin versus a 2-day postoperative course in dental implant surgery: A two-centre randomised controlled trial.

PubMed

Arduino, Paolo G; Tirone, Federico; Schiorlin, Emanuele; Esposito, Marco

2015-01-01

To evaluate the difference between a single preoperative dose versus an additional two-day postoperative course of oral amoxicillin in patients undergoing conventional dental implant placement. Two dentists in two different private practices conducted this study. One hour prior to surgery, patients had to take a single prophylactic antibiotic dose, consisting of 2 g of amoxicillin orally; after implant placement, patients were randomly allocated to two different groups: protocol A (no other antibiotic administration) and protocol B, (1 g of amoxicillin in the evening of the day of surgery and 1 g twice a day for the 2 days after). Outcome measures were prosthetic and implant failures, adverse events and early postoperative complications. Patients were followed up to 6 months after functional loading. Three hundred and sixty patients were randomised and treated (192 patients in one centre and 168 in the other). Five hundred and sixty-seven implants were placed. Protocol A was applied to 180 patients (278 implants) and protocol B also to 180 patients (289 implants). Data for 17 patients, 14 from protocol A and three from protocol B, were not available. No statistically significant differences were found for the reported outcomes. Two patients of protocol B experienced a prosthetic failure, losing four implants, while no prosthetic failures were reported for protocol A (P=0.4836; difference in proportions=-0.0110; 95% CI: -0.0412 to 0.0119). Five patients (3.0%) of protocol A lost five implants versus 5 patients (2.8%) who lost eight implants in protocol B (P=1.0000; difference in proportions=0.0020; 95% CI: -0.0384 to 0.0438). Three adverse events were observed in the total population, all occurring in protocol B (1.69%), with no statistically significant differences between the two groups (P=0.1199; difference in proportions=-0.0170; 95% CI: -0.0487 to 0.0059). However, one patient experienced a severe allergic reaction requiring therapy discontinuation and hospital admission. Early postoperative complications occurred in six patients of protocol A and in four patients of protocol B, with no statistically significant differences (P=0.5170; difference in proportions=0.0130; 95% CI: -0.0254 to 0.0568). No statistically significant differences were observed between 2 g of preoperative amoxicillin and an additional 2-day postoperative course, although adverse events were reported only in the additional 2-day postoperative group. Based on these findings, it might be sufficient to routinely administer preoperatively 2 g of amoxicillin to patients undergoing routine dental implant placement procedures rather than administering additional postoperative doses.

Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial.

PubMed

Dodick, David W; Silberstein, Stephen D; Bigal, Marcelo E; Yeung, Paul P; Goadsby, Peter J; Blankenbiller, Tricia; Grozinski-Wolff, Melissa; Yang, Ronghua; Ma, Yuju; Aycardi, Ernesto

2018-05-15

Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose. Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95% CI, -2.01 to -0.93 days; P < .001) and with single higher dosing vs placebo of -1.3 days (95% CI, -1.79 to -0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy. clinicaltrials.gov Identifier: NCT02629861.

Efficacy of Single-Dose and Triple-Dose Albendazole and Mebendazole against Soil-Transmitted Helminths and Taenia spp.: A Randomized Controlled Trial

PubMed Central

Steinmann, Peter; Utzinger, Jürg; Du, Zun-Wei; Jiang, Jin-Yong; Chen, Jia-Xu; Hattendorf, Jan; Zhou, Hui; Zhou, Xiao-Nong

2011-01-01

Background The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China. Methodology/Principal findings The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3–4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed. Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55–81%) and 29% (95% CI: 20–45%); triple dose: respective CRs 92% (95% CI: 81–98%) and 54% (95% CI: 46–71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole – the most efficacious treatment tested – cured 71% (95% CI: 57–82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93–97%; ERR: all >99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them. Conclusions/Significance Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are warranted. Trial Registration www.controlled-trials.com ISRCTN47375023 PMID:21980373

Safety and pharmacokinetics of the oral iron chelator SP-420 in β-thalassemia.

PubMed

Taher, Ali T; Saliba, Antoine N; Kuo, Kevin H; Giardina, Patricia J; Cohen, Alan R; Neufeld, Ellis J; Aydinok, Yesim; Kwiatkowski, Janet L; Jeglinski, Brenda I; Pietropaolo, Keith; Berk, Gregory; Viprakasit, Vip

2017-12-01

Our phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent β-thalassemia. SP-420 was administered as a single dose of 1.5 (n = 3), 3 (n = 3), 6 (n = 3), 12 (n = 3), and 24 (n = 6) mg/kg or as a twice-daily dose of 9 mg/kg (n = 6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for C max and AUC 0-τ over the dose range evaluated. The median t max ranged from 0.5 to 2.25 h and was not dose dependent. The study was prematurely terminated by the sponsor due to renal adverse events (AE) including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal AE observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug. © 2017 Wiley Periodicals, Inc.

Quantification of the memory imprint effect for a charged particle environment

NASA Technical Reports Server (NTRS)

Bhuva, B. L.; Johnson, R. L., Jr.; Gyurcsik, R. S.; Kerns, S. E.; Fernald, K. W.

1987-01-01

The effects of total accumulated dose on the single-event vulnerability of NMOS resistive-load SRAMs are investigated. The bias-dependent shifts in device parameters can imprint the memory state present during exposure or erase the imprinted state. Analysis of these effects is presented along with an analytic model developed for the quantification of these effects. The results indicate that the imprint effect is dominated by the difference in the threshold voltage of the n-channel devices.

Overview of the AFRL’s Demonstration and Science Experiments (DSX) Program

DTIC Science & Technology

2006-09-01

most of the space weather data to-date has been accumulated in the LEO and GEO regimes, as illustrated in Figure 11 with data from dosimeters aboard...Composed of two dosimeters , two particle telescopes and a Single Event Effect detector, CEASE has the capability to monitor a broad range of space...panel of the payload module. One change for DSX is that CEASE will capture and downlink the full dose spectra from each dosimeter , whereas prior

Microcircuit radiation effects databank

NASA Technical Reports Server (NTRS)

1983-01-01

This databank is the collation of radiation test data submitted by many testers and serves as a reference for engineers who are concerned with and have some knowledge of the effects of the natural radiation environment on microcircuits. It contains radiation sensitivity results from ground tests and is divided into two sections. Section A lists total dose damage information, and section B lists single event upset cross sections, I.E., the probability of a soft error (bit flip) or of a hard error (latchup).

Exploration Technology Developments Program's Radiation Hardened Electronics for Space Environments (RHESE) Project Overview

NASA Technical Reports Server (NTRS)

Keys, Andrew S.; Adams, James H.; Darty, Ronald C.; Patrick, Marshall C.; Johnson, Michael A.; Cressler, John D.

2008-01-01

Primary Objective: 1) A computational tool to accurately predict electronics performance in the presence of space radiation in support of spacecraft design: a) Total dose; b) Single Event Effects; and c) Mean Time Between Failure. (Developed as successor to CR ME96.) Secondary Objectives: 2) To provide a detailed description of the natural radiation environment in support of radiation health and instrument design: a) In deep space; b) Inside the magnetosphere; and c) Behind shielding.

Proton irradiation and endometriosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wood, D.H.; Yochmowitz, M.G.; Salmon, Y.L.

1983-08-01

Female rhesus monkeys given single total-body exposures of protons of varying energies developed endometriosis at a frequency significantly higher than that of nonirradiated animals of the same age. The minimum latency period was 7 years after exposure. The doses and energies of the radiation received were within the range that could be received by an aircrew member in near-earth orbit during a random solar flare event, leading to the conclusion that endometriosis should be a consideration in assessing the risk of delayed radiation effects in female crewmembers.

Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study.

PubMed

Fernández, Oscar; Izquierdo, Guillermo; Fernández, Victoria; Leyva, Laura; Reyes, Virginia; Guerrero, Miguel; León, Antonio; Arnaiz, Carlos; Navarro, Guillermo; Páramo, Maria Dolores; Cuesta, Antonio De la; Soria, Bernat; Hmadcha, Abdelkrim; Pozo, David; Fernandez-Montesinos, Rafael; Leal, Maria; Ochotorena, Itziar; Gálvez, Patricia; Geniz, Maria Angeles; Barón, Francisco Javier; Mata, Rosario; Medina, Cristina; Caparrós-Escudero, Carlos; Cardesa, Ana; Cuende, Natividad

2018-01-01

Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures. In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded. Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy. Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.

The efficacy and safety of a low-dose, 91-day, extended-regimen oral contraceptive with continuous ethinyl estradiol.

PubMed

Kroll, Robin; Reape, Kathleen Z; Margolis, Marya

2010-01-01

This clinical trial was conducted to demonstrate the efficacy and safety of a 91-day extended-regimen, low-dose combination oral contraceptive (OC) consisting of 84 days of ethinyl estradiol (EE) 20 mcg/levonorgestrel (LNG) 100 mcg, followed by 7 days of 10 mcg EE in place of placebo. A multicenter open-label, single-treatment, Phase 3 study evaluated women aged 18 through 40 years over a treatment period of up to 1 year (four 91-day extended cycles). All subjects completed daily paper diaries to monitor compliance, bleeding and additional forms of contraception used during the course of the study. A total of 1249 subjects completed the study. The Pearl Index was 2.74 (95% confidence interval, 1.92-3.78), based on 36 pregnancies that occurred after the onset of treatment and within 14 days after the last combination tablet in women aged 18-35 years. Among compliant-use subjects 18-35 years old, the Pearl Index was 1.73 based on 22 on-treatment pregnancies. The life table pregnancy rate for subjects 18-35 years of age was 2.39%. Cycle control and adverse events reported with this regimen were similar to those reported with other low-dose OCs. This study demonstrated effective prevention of pregnancy with a 20-mcg EE, 91-day extended-regimen OC. In addition, the regimen was well tolerated and incidence of adverse events were consistent with what has been reported with other low-dose OCs.

Optically stimulated luminescence dating of Holocene alluvial fans, East Anatolian Fault System, Turkey

NASA Astrophysics Data System (ADS)

Dogan, Tamer; Cetin, Hasan; Yegingil, Zehra; Topaksu, Mustafa; Yüksel, Mehmet; Duygun, Fırat; Nur, Necmettin; Yegingil, İlhami

2015-07-01

In this study, the optically stimulated luminescence dating technique was used to determine the time of deposition of alluvial sediment samples from the Türkoğlu-Antakya segment of the East Anatolian Fault System (EAFS) in Turkey. The double-single aliquot regenerative dose protocol on fine grain samples was used to estimate equivalent doses (De). Annual dose rate was computed using elemental concentration of uranium (U) and thorium (Th) determined by using thick-source alpha counting and potassium (K) concentrations using X-ray fluorescence and/or atomic absorption spectroscopy. The environmental dose was measured in situ using α-Al2O3:C chips inside plastic tubes for a year. The two different bulk sediment samples collected from the Islahiye trench yielded ages of 4.54 ± 0.28 and 2.91 ± 0.23 ka. We also obtained a 2.60 ± 0.18 ka age for the alluvial deposit in the Kıranyurdu trench and 2.31 ± 0.14 ka age for an excavation area called Malzeme Ocağı. These ages were consistent with the corresponding calibrated Carbon-14 (14C) ages of the region. The differences between the determined ages were insufficient to clearly distinguish the disturbance event from the effects of bioturbation, biological mixing, or other sources of De variation in the region. They provide a record of alluvial aggradation in the region and may determine undocumented historical earthquake events.

Multicentre dose audit for clinical trials of radiation therapy in Asia.

PubMed

Mizuno, Hideyuki; Fukuda, Shigekazu; Fukumura, Akifumi; Nakamura, Yuzuru-Kutsutani; Jianping, Cao; Cho, Chul-Koo; Supriana, Nana; Dung, To Anh; Calaguas, Miriam Joy; Devi, C R Beena; Chansilpa, Yaowalak; Banu, Parvin Akhter; Riaz, Masooma; Esentayeva, Surya; Kato, Shingo; Karasawa, Kumiko; Tsujii, Hirohiko

2017-05-01

A dose audit of 16 facilities in 11 countries has been performed within the framework of the Forum for Nuclear Cooperation in Asia (FNCA) quality assurance program. The quality of radiation dosimetry varies because of the large variation in radiation therapy among the participating countries. One of the most important aspects of international multicentre clinical trials is uniformity of absolute dose between centres. The National Institute of Radiological Sciences (NIRS) in Japan has conducted a dose audit of participating countries since 2006 by using radiophotoluminescent glass dosimeters (RGDs). RGDs have been successfully applied to a domestic postal dose audit in Japan. The authors used the same audit system to perform a dose audit of the FNCA countries. The average and standard deviation of the relative deviation between the measured and intended dose among 46 beams was 0.4% and 1.5% (k = 1), respectively. This is an excellent level of uniformity for the multicountry data. However, of the 46 beams measured, a single beam exceeded the permitted tolerance level of ±5%. We investigated the cause for this and solved the problem. This event highlights the importance of external audits in radiation therapy. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Technological advances in hybrid imaging and impact on dose.

PubMed

Mattsson, Sören; Andersson, Martin; Söderberg, Marcus

2015-07-01

New imaging technologies utilising X-rays and radiopharmaceuticals have developed rapidly. Clinical application of computed tomography (CT) has revolutionised medical imaging and plays an enormous role in medical care. Due to technical improvements, spatial, contrast and temporal resolutions have continuously improved. In spite of significant reduction of CT doses during recent years, CT is still a dominating source of radiation exposure to the population. Combinations with single photon emission computed tomography (SPECT) and positron emission tomography (PET) and especially the use of SPECT/CT and PET/CT, provide important additional information about physiology as well as cellular and molecular events. However, significant dose contributions from SPECT and PET occur, making PET/CT and SPECT/CT truly high dose procedures. More research should be done to find optimal activities of radiopharmaceuticals for various patient groups and investigations. The implementation of simple protocol adjustments, including individually based administration, encouraged hydration, forced diuresis and use of optimised voiding intervals, laxatives, etc., can reduce the radiation exposure to the patients. New data about staff doses to fingers, hands and eye lenses indicate that finger doses could be a problem, but not doses to the eye lenses and to the whole body. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Results From the First‐in‐Human Study With Ozanimod, a Novel, Selective Sphingosine‐1‐Phosphate Receptor Modulator

PubMed Central

Hartung, Jeffrey P.; Peach, Robert J.; Boehm, Marcus F.; Rosen, Hugh; Smith, Heather; Brooks, Jennifer L.; Timony, Gregg A.; Olson, Allan D.; Gujrathi, Sheila; Frohna, Paul A.

2017-01-01

Abstract The sphingosine‐1‐phosphate 1 receptor (S1P1R) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune‐mediated, inflammatory diseases. This first‐in‐human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose‐escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose‐limiting toxicities. The most common ozanimod‐related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady‐state volume of distribution (73–101 L/kg), moderate oral clearance (204–227 L/h), and an elimination half‐life of approximately 17 to 21 hours. Ozanimod produced a robust dose‐dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose‐dependent negative chronotropic effect was observed following the first dose, with the dose‐escalation regimen attenuating the first‐dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once‐daily regimens under clinical investigation. PMID:28398597

Design and statistical considerations for studies evaluating the efficacy of a single dose of the human papillomavirus (HPV) vaccine.

PubMed

Sampson, Joshua N; Hildesheim, Allan; Herrero, Rolando; Gonzalez, Paula; Kreimer, Aimee R; Gail, Mitchell H

2018-05-01

Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix ® or Gardasil ®, prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomédicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution. Copyright © 2018. Published by Elsevier Inc.

Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects.

PubMed

Edwards, Jeffrey E; Eliot, Lise; Parkinson, Andrew; Karan, Sharon; MacConell, Leigh

2017-09-01

Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin). OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max ) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs. In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin). Intercept Pharmaceuticals, Inc.

High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies.

PubMed

Zohar, Joseph; Yahalom, Hila; Kozlovsky, Nitsan; Cwikel-Hamzany, Shlomit; Matar, Michael A; Kaplan, Zeev; Yehuda, Rachel; Cohen, Hagit

2011-11-01

High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100-140 mg) or placebo within 6 h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. In parallel, a comparative study of morphological arborization in dentate gyrus and its modulating molecules was performed in stress-exposed animals treated with high-dose hydrocortisone. Steroid-treated stressed animals displayed significantly increased dendritic growth and spine density, with increased levels of brain-derived neurotrophic factor (BDNF) and obtunded postsynaptic density-95 (PSD-95) levels. The animal study provided insights into the potential mechanism of this intervention, as it identified relevant morphological and biochemical associations to the clinical observations. Thus, evidence from clinical and animal studies suggests that there is a "window of opportunity" in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD. Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.

Bioequivalence between two serum-free recombinant factor VIII preparations (N8 and ADVATE®)--an open-label, sequential dosing pharmacokinetic study in patients with severe haemophilia A.

PubMed

Martinowitz, U; Bjerre, J; Brand, B; Klamroth, R; Misgav, M; Morfini, M; Santagostino, E; Tiede, A; Viuff, D

2011-11-01

Recombinant coagulation factor VIII (rFVIII) concentrates provide a safe and efficacious replacement therapy for treatment and prevention of bleeding in patients with severe haemophilia A. The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of two serum-free rFVIII products: N8, a new rFVIII manufactured by Novo Nordisk and Advate(®), a marketed product. Patients with severe haemophilia A with >150 exposure days to FVIII, without current or past inhibitors, were enrolled in an open-label, first human dose (FHD), multicentre trial. Twenty-three patients first received a single dose of 50 IU kg(-1) body weight Advate(®) followed by 50 IU kg(-1) body weight N8 at the next visit. A 4-day washout period was required prior to each dosing. Blood samples for PK and safety analyses were drawn prior to dosing and at intervals up until 48 h postdosing. The PK parameters were based on FVIII clotting activity (FVIII:C) measurements. Occurrence of adverse events was closely monitored. The mean profiles of FVIII:C and all primary and secondary parameters for Advate(®) and N8 were comparable. The 90% CI for the treatment ratio (Advate(®)/N8) for all primary endpoints (incremental recovery, t(1/2), AUC and Cl), and the secondary endpoints (AUC(last) and C(max)) were within the bioequivalence interval of 0.8-1.25. There were no safety concerns in the study and no reports of inhibitor formation in the 72-h period following exposure to a single N8 dose. In conclusion, N8 is bioequivalent to Advate(®). Furthermore, N8 is well tolerated in the FHD trial. © 2011 Blackwell Publishing Ltd.

Mucuna pruriens in Parkinson disease

PubMed Central

Laguna, Janeth; Cassani, Erica; Cereda, Emanuele; Pozzi, Nicolò G.; Isaias, Ioannis U.; Contin, Manuela; Barichella, Michela; Pezzoli, Gianni

2017-01-01

Objective: To investigate whether Mucuna pruriens (MP), a levodopa-containing leguminous plant growing in all tropical areas worldwide, may be used as alternative source of levodopa for indigent individuals with Parkinson disease (PD) who cannot afford long-term therapy with marketed levodopa preparations. Methods: We investigated efficacy and safety of single-dose intake of MP powder from roasted seeds obtained without any pharmacologic processing. Eighteen patients with advanced PD received the following treatments, whose sequence was randomized: (1) dispersible levodopa at 3.5 mg/kg combined with the dopa-decarboxylase inhibitor benserazide (LD+DDCI; the reference treatment); (2) high-dose MP (MP-Hd; 17.5 mg/kg); (3) low-dose MP (MP-Ld; 12.5 mg/kg); (4) pharmaceutical preparation of LD without DDCI (LD−DDCI; 17.5 mg/kg); (5) MP plus benserazide (MP+DDCI; 3.5 mg/kg); (6) placebo. Efficacy outcomes were the change in motor response at 90 and 180 minutes and the duration of on state. Safety measures included any adverse event (AE), changes in blood pressure and heart rate, and the severity of dyskinesias. Results: When compared to LD+DDCI, MP-Ld showed similar motor response with fewer dyskinesias and AEs, while MP-Hd induced greater motor improvement at 90 and 180 minutes, longer ON duration, and fewer dyskinesias. MP-Hd induced less AEs than LD+DDCI and LD−DDCI. No differences in cardiovascular response were recorded. Conclusion: Single-dose MP intake met all noninferiority efficacy and safety outcome measures in comparison to dispersible levodopa/benserazide. Clinical effects of high-dose MP were similar to levodopa alone at the same dose, with a more favorable tolerability profile. ClinicalTrials.gov identifier: NCT02680977. PMID:28679598

Mucuna pruriens in Parkinson disease: A double-blind, randomized, controlled, crossover study.

PubMed

Cilia, Roberto; Laguna, Janeth; Cassani, Erica; Cereda, Emanuele; Pozzi, Nicolò G; Isaias, Ioannis U; Contin, Manuela; Barichella, Michela; Pezzoli, Gianni

2017-08-01

To investigate whether Mucuna pruriens (MP), a levodopa-containing leguminous plant growing in all tropical areas worldwide, may be used as alternative source of levodopa for indigent individuals with Parkinson disease (PD) who cannot afford long-term therapy with marketed levodopa preparations. We investigated efficacy and safety of single-dose intake of MP powder from roasted seeds obtained without any pharmacologic processing. Eighteen patients with advanced PD received the following treatments, whose sequence was randomized: (1) dispersible levodopa at 3.5 mg/kg combined with the dopa-decarboxylase inhibitor benserazide (LD+DDCI; the reference treatment); (2) high-dose MP (MP-Hd; 17.5 mg/kg); (3) low-dose MP (MP-Ld; 12.5 mg/kg); (4) pharmaceutical preparation of LD without DDCI (LD-DDCI; 17.5 mg/kg); (5) MP plus benserazide (MP+DDCI; 3.5 mg/kg); (6) placebo. Efficacy outcomes were the change in motor response at 90 and 180 minutes and the duration of on state. Safety measures included any adverse event (AE), changes in blood pressure and heart rate, and the severity of dyskinesias. When compared to LD+DDCI, MP-Ld showed similar motor response with fewer dyskinesias and AEs, while MP-Hd induced greater motor improvement at 90 and 180 minutes, longer ON duration, and fewer dyskinesias. MP-Hd induced less AEs than LD+DDCI and LD-DDCI. No differences in cardiovascular response were recorded. Single-dose MP intake met all noninferiority efficacy and safety outcome measures in comparison to dispersible levodopa/benserazide. Clinical effects of high-dose MP were similar to levodopa alone at the same dose, with a more favorable tolerability profile. NCT02680977. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

PubMed Central

2012-01-01

Introduction Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Methods In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. Results Seventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. Conclusions The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies. PMID:22340283

Low Efficacy of Single-Dose Albendazole and Mebendazole against Hookworm and Effect on Concomitant Helminth Infection in Lao PDR

PubMed Central

Soukhathammavong, Phonepasong Ayé; Sayasone, Somphou; Phongluxa, Khampheng; Xayaseng, Vilavanh; Utzinger, Jürg; Vounatsou, Penelope; Hatz, Christoph; Akkhavong, Kongsap; Keiser, Jennifer; Odermatt, Peter

2012-01-01

Background Albendazole and mebendazole are increasingly deployed for preventive chemotherapy targeting soil-transmitted helminth (STH) infections. We assessed the efficacy of single oral doses of albendazole (400 mg) and mebendazole (500 mg) for the treatment of hookworm infection in school-aged children in Lao PDR. Since Opisthorchis viverrini is co-endemic in our study setting, the effect of the two drugs could also be determined against this liver fluke. Methodology We conducted a randomized, open-label, two-arm trial. In total, 200 children infected with hookworm (determined by quadruplicate Kato-Katz thick smears derived from two stool samples) were randomly assigned to albendazole (n = 100) and mebendazole (n = 100). Cure rate (CR; percentage of children who became egg-negative after treatment), and egg reduction rate (ERR; reduction in the geometric mean fecal egg count at treatment follow-up compared to baseline) at 21–23 days posttreatment were used as primary outcome measures. Adverse events were monitored 3 hours post treatment. Principal Findings Single-dose albendazole and mebendazole resulted in CRs of 36.0% and 17.6% (odds ratio: 0.4; 95% confidence interval: 0.2–0.8; P = 0.01), and ERRs of 86.7% and 76.3%, respectively. In children co-infected with O. viverrini, albendazole and mebendazole showed low CRs (33.3% and 24.2%, respectively) and moderate ERRs (82.1% and 78.2%, respectively). Conclusions/Significance Both albendazole and mebendazole showed disappointing CRs against hookworm, but albendazole cured infection and reduced intensity of infection with a higher efficacy than mebendazole. Single-dose administrations showed an effect against O. viverrini, and hence it will be interesting to monitor potential ancillary benefits of a preventive chemotherapy strategy that targets STHs in areas where opisthorchiasis is co-endemic. Clinical Trial Registration Current Controlled Trials ISRCTN29126001 PMID:22235353

Orally Formulated Artemisinin in Healthy Fasting Vietnamese Male Subjects: A Randomized, Four-Sequence, Open-Label, Pharmacokinetic Crossover Study

PubMed Central

Hien, Tran Tinh; Hanpithakpong, Warunee; Truong, Nguyen Thanh; Dung, Nguyen Thi; Toi, Pham Van; Farrar, Jeremy; Lindegardh, Niklas; Tarning, Joel; Ashton, Michael

2011-01-01

Background Artemisinin derivatives are used in antimalarial drug combination therapy. Artemisinin and piperaquine have recently been proven to be prospective candidates for combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria. Objective The goal of this study was to evaluate the relative bioavailability and to characterize the pharmacokinetic properties of a new micronized powder formulation of artemisinin against the previous standard Vietnamese formulation when administered as a single oral dose or in combination with piperaquine. Methods This was a single-center, randomized, 4-sequence, open-label, crossover study conducted in 15 healthy male Vietnamese volunteers under fasting conditions with a washout period of 3 weeks between study visits. A single oral dose of 160 or 500 mg of artemisinin was administered alone or in combination with piperaquine. Potential adverse events were monitored daily by the clinician and by using laboratory test results. Frequent blood samples were drawn for 12 hours after dose. Artemisinin was quantified in plasma using LC-MS/MS. Pharmacokinetic parameters were computed from the plasma concentration–time profiles using a noncompartmental analysis method. Results Pharmacokinetic parameters Tmax, Cmax, AUC0-∞, Vd/F, CL/F, and t1/2 (mean [SD]) for the new formulation of artemisinin were 1.83 (0.88) hours, 178 (97) ng/mL, 504 (210) h × ng/mL, 1270 (780) L, 401 (260) L/h, and 2.21 (0.29) hours, respectively. The mean percentage of the test/reference formulation ratio for the logarithmically transformed values of Cmax, AUC0–last, and AUC0–∞ were 121% (90% CI, 92.5–158), 122% (90% CI, 101–148), and 120% (90% CI, 98.0–146), respectively. Conclusions This single-dose study found that the dose-normalized Cmax, AUC0–last, and AUC0–∞ mean geometric differences between the test and reference formulations were relatively small (<40%) and will probably not have a clinical impact in the treatment of malaria infections. PMID:21665048

Evaluation of a new continuous mononuclear cell collection procedure in a single transplant center cohort enriched for AL amyloidosis patients.

PubMed

Pudusseri, Anita; Smith, India; Sarnacki, Diane; Brauneis, Dina; Shelton, Anthony; Sanchorawala, Vaishali; Sloan, J Mark; Sarosiek, Shayna; Quillen, Karen

2018-04-26

The Spectra Optia continuous mononuclear cell (CMNC) program is newly available, and herein validated in a single-center cohort enriched with AL amyloidosis patients to collect a target CD34+ yield of 2.5 × 10 6 cells/kg within 2 days. Consecutive autologous transplant patients in 2016 are included. Patients undergo leukapheresis with Optia CMNC and Spectra v4.7 over a 2-day cycle. Data collection includes collection efficiency, adverse events and engraftment kinetics. 36 leukapheresis procedures on 18 patients are included. The diagnoses are AL amyloidosis (9), myeloma (7), lymphoma (2), and scleroderma (1). Median age is 60; 12 are men. Plerixafor was employed pre-emptively in 6 cycles. Median blood CD34+ on Day 1 of leukapheresis was 46 cells/uL. Median number of blood volumes processed on Day 1 was 3.1. All collection cycles were completed within 2 days; only one in a heavily pretreated lymphoma patient did not reach the target requiring a second mobilization attempt. Mean collection efficiencies were comparable between the two devices. There were 2 adverse events: tubing rupture on the Optia; and one case of hypotension. All 18 patients underwent high-dose chemotherapy: median cell dose infused was 7.7 × 10 6 CD34+ cells/kg. Median days to neutrophil and platelet engraftment were 10 and 13 respectively. The Optia CMNC collection protocol is safe and effective in a small single-center autologous stem cell transplant cohort enriched for high-risk patients with AL amyloidosis and cardiac involvement. Caution is needed for tubing setup because there is less cumulative experience with Optia. Copyright © 2018 Elsevier Ltd. All rights reserved.

Systematic literature review comparing rapid 3-dose administration of the GSK tick-borne encephalitis vaccine with other primary immunization schedules.

PubMed

Galgani, Ilaria; Bunge, Eveline M; Hendriks, Lisa; Schludermann, Christopher; Marano, Cinzia; De Moerlooze, Laurence

2017-09-01

Tick-borne encephalitis (TBE), which is endemic across large regions of Europe and Asia, is most effectively prevented through vaccination. Three-dose primary TBE vaccination schedules are either rapid (0,7,21-days) or conventional (0,28-84-days, 9-12-months). The second dose can also be administered at 14 days for faster priming and sero-protection). Areas covered: We used a three-step selection process to identify 21 publications comparing the immunogenicity and/or safety of different schedules. Expert commentary: Priming with two or three TBE vaccine doses was highly immunogenic. After conventional priming (0-28 days), 95% adults and ≥95% children had neutralization test (NT) titers ≥10 at 14 days post-dose-2 compared with 92% adults and 99% children at 21 days post-dose-3 (rapid schedule). Most subjects retained NT titers ≥10 at day 300. A single booster dose induced a strong immune response in all subjects irrespective of primary vaccination schedule or elapsed time since priming. GMT peaked at 42 days post-dose-1 (i.e., 21 days post-dose 3 [rapid-schedule], or 14-28 days post-dose-2 [conventional-schedule]), and declined thereafter. Adverse events were generally rare and declined with increasing doses. In the absence of data to recommend one particular schedule, the regimen choice will remain at the physician's discretion, based on patient constraints and availability.

Is there any connection between a second pneumonia shot and hospitalization among Medicare beneficiaries?

PubMed

Snow, R; Babish, J D; McBean, A M

1995-01-01

To learn whether the risk of revaccination in adults should limit its use, the authors investigated whether adverse events requiring hospitalization occurred in a group of Medicare enrollees revaccinated with pneumococcal polysaccharide vaccine. A prospective cohort analysis and case study of revaccinated people involved five percent of all elderly Medicare enrollees from 1985 through 1988, consisting of 66,256 people receiving one dose of vaccine and 1,099 receiving two doses. Comparison was made of the hospitalization rate within 30 days after revaccination and rates of singly vaccinated persons using discharge diagnosis for all those hospitalized during the 30 days after revaccination. No significant difference was found between the hospitalization rate of the revaccinated cohort and comparison group. No adverse reactions attributable to pneumococcal polysaccharide vaccine causing hospitalization were identified among 39 revaccinated persons who were hospitalized within 30 days of revaccination. Revaccination of elderly Medicare beneficiaries does not cause events serious enough to require hospitalization. Vaccination of persons according to the Public Health Service Immunization Practice Advisory Committee guidelines is recommended when the prior immunization status is unknown.

Microbeam studies of the sensitivity of structures within living cells

NASA Technical Reports Server (NTRS)

Braby, L. A.

1992-01-01

Determining the biological effects of low doses of radiation with high linear energy transfer (LET) is complicated by the stochastic nature of charged-particle interactions. Populations of cells exposed to very low radiation doses contain a few cells which have been hit by a charged particle, while the majority of the cells receive no radiation damage. At somewhat higher doses, a few cells receive two or more events. Because the effects of damage produced by separate events can interact in the cell, we have had to make assumptions about the nature of these interactions in order to interpret the results of the experiments. Many of those assumptions can be tested if we can be sure of the number of charged-particle events which occur in individual cells, and correlate this number with the biological effect. We have developed a special irradiation facility at Pacific Northwest Laboratory (PNL) to control the actual number of charged particle tracks that pass through cell nuclei. The beam from a 2 MeV tandem accelerator is collimated to approximately 5 microns. Cells, grown in special dishes with 1.5 microns thick plastic bottoms, are positioned so that the desired portion of the cell aligns with the collimator. A shutter in the beam line is opened and closed after the desired number of particle tracks has been counted. This approach can be used to investigate the effects of the interaction between irradiated and unirradiated cells in an organized system, as well as to study the effects of spatial and temporal distribution of radiation damage within single cells.(ABSTRACT TRUNCATED AT 250 WORDS).

Pharmacokinetics of Dalfampridine Extended Release 7.5-mg Tablets in Healthy Subjects and Individuals With Mild and Moderate Renal Impairment: An Open-Label Study

PubMed Central

Samara, Emil; Winkle, Peter; Pardo, Patricia; Henney, Herbert R; Way, Susan L; Brown, Eppie; Lee, Angela; Blight, Andrew R

2014-01-01

Dalfampridine extended release tablets (D-ER; prolonged-release fampridine in Europe) are available to improve walking in patients with multiple sclerosis (MS). D-ER is mainly renally eliminated; the approved 10-mg twice daily dose is contraindicated in the United States in patients with moderate or severe renal impairment. This study evaluated single-dose and steady-state pharmacokinetics of a 7.5-mg dose of D-ER in healthy subjects (n = 13) and subjects with mild (n = 17) and moderate (n = 12) renal impairment. D-ER plasma concentrations were consistently higher in subjects with renal impairment relative to healthy individuals with a significant (P < .0001) inverse linear relationship between creatinine clearance and drug exposure. Steady-state AUC0–12 among healthy subjects, 167.0 ± 55.3 ng h/mL, increased 74% and 151% with mild and moderate renal impairment, respectively. The overall incidence of adverse events was 61.5%, 47.1%, and 33.3% in healthy subjects, and subjects with mild and moderate renal impairment, respectively, and for treatment-related adverse events the rates were 0%, 17.6%, and 8.3%, respectively. The most common adverse events were headache, dizziness, and arthralgia. The pharmacokinetics of D-ER 7.5-mg twice daily in subjects with mild renal impairment was comparable to 10-mg twice daily in patients with MS who had normal renal function. Exposure was significantly higher in moderate renal impairment. PMID:24150835

Flight attendant radiation dose from solar particle events.

PubMed

Anderson, Jeri L; Mertens, Christopher J; Grajewski, Barbara; Luo, Lian; Tseng, Chih-Yu; Cassinelli, Rick T

2014-08-01

Research has suggested that work as a flight attendant may be related to increased risk for reproductive health effects. Air cabin exposures that may influence reproductive health include radiation dose from galactic cosmic radiation and solar particle events. This paper describes the assessment of radiation dose accrued during solar particle events as part of a reproductive health study of flight attendants. Solar storm data were obtained from the National Oceanic and Atmospheric Administration Space Weather Prediction Center list of solar proton events affecting the Earth environment to ascertain storms relevant to the two study periods (1992-1996 and 1999-2001). Radiation dose from exposure to solar energetic particles was estimated using the NAIRAS model in conjunction with galactic cosmic radiation dose calculated using the CARI-6P computer program. Seven solar particle events were determined to have potential for significant radiation exposure, two in the first study period and five in the second study period, and over-lapped with 24,807 flight segments. Absorbed (and effective) flight segment doses averaged 6.5 μGy (18 μSv) and 3.1 μGy (8.3 μSv) for the first and second study periods, respectively. Maximum doses were as high as 440 μGy (1.2 mSv) and 20 flight segments had doses greater than 190 μGy (0.5 mSv). During solar particle events, a pregnant flight attendant could potentially exceed the equivalent dose limit to the conceptus of 0.5 mSv in a month recommended by the National Council on Radiation Protection and Measurements.

Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study.

PubMed

Sparks, Jeffrey A; Barbhaiya, Medha; Karlson, Elizabeth W; Ritter, Susan Y; Raychaudhuri, Soumya; Corrigan, Cassandra C; Lu, Fengxin; Selhub, Jacob; Chasman, Daniel I; Paynter, Nina P; Ridker, Paul M; Solomon, Daniel H

2017-08-01

The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15-20mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.

Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation.

PubMed

Ottoboni, Tom; Keller, Mary Rose; Cravets, Matt; Clendeninn, Neil; Quart, Barry

2018-01-01

Fosaprepitant, an intravenous (IV) aprepitant prodrug for chemotherapy-induced nausea and vomiting prophylaxis, is associated with systemic and infusion-site reactions attributed in part to its surfactant, polysorbate 80. HTX-019 is an IV aprepitant formulation free of polysorbate 80 and other synthetic surfactants. This open-label, single-dose, randomized, two-way crossover bioequivalence study compared pharmacokinetics and safety of HTX-019 and fosaprepitant. Healthy subjects received single-dose HTX-019 (130 mg) or fosaprepitant (150 mg) IV over 30 min, with ≥7-day washout between doses. Blood samples were evaluated for pharmacokinetics and bioequivalence; safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Ninety-seven of one hundred enrolled subjects completed the study. Baseline characteristics were comparable between treatment sequences. For HTX-019, mean (percent coefficient of variation) area under the curve (AUC) from time 0 to time of last measurable plasma concentration (AUC 0-t ), AUC from time 0 to infinity (AUC 0-inf ), and plasma concentration at 12 h (C 12 h ) for HTX-019 were 43,729 h*ng/mL (32.7), 45,460 h*ng/mL (36.8), and 988.4 ng/mL (27.5), respectively; corresponding fosaprepitant values were 44,130 h*ng/mL (32.0), 46,163 h*ng/mL (36.6), and 1,022 ng/mL (28.5). Also, 90% CIs (94.186-101.354) were within bioequivalence bounds (80%-125%). Within 1 h following infusion start, one (1%) HTX-019 recipient reported one TEAE, while 20 (20%) fosaprepitant recipients reported 32 TEAEs. Dyspnea occurred in three fosaprepitant recipients (at <1 min in two subjects and at 18 min in one subject, considered study drug related) and one HTX-019 recipient (at 120 h, associated with a respiratory tract infection and considered not related to the study drug). No severe TEAEs, serious adverse events, or deaths occurred; all TEAEs resolved. HTX-019 was bioequivalent to fosaprepitant and may provide a safer alternative to fosaprepitant for chemotherapy-induced nausea and vomiting prophylaxis.

Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation

PubMed Central

Ottoboni, Tom; Keller, Mary Rose; Cravets, Matt; Clendeninn, Neil; Quart, Barry

2018-01-01

Introduction Fosaprepitant, an intravenous (IV) aprepitant prodrug for chemotherapy-induced nausea and vomiting prophylaxis, is associated with systemic and infusion-site reactions attributed in part to its surfactant, polysorbate 80. HTX-019 is an IV aprepitant formulation free of polysorbate 80 and other synthetic surfactants. Materials and methods This open-label, single-dose, randomized, two-way crossover bioequivalence study compared pharmacokinetics and safety of HTX-019 and fosaprepitant. Healthy subjects received single-dose HTX-019 (130 mg) or fosaprepitant (150 mg) IV over 30 min, with ≥7-day washout between doses. Blood samples were evaluated for pharmacokinetics and bioequivalence; safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Ninety-seven of one hundred enrolled subjects completed the study. Results Baseline characteristics were comparable between treatment sequences. For HTX-019, mean (percent coefficient of variation) area under the curve (AUC) from time 0 to time of last measurable plasma concentration (AUC0−t), AUC from time 0 to infinity (AUC0−inf), and plasma concentration at 12 h (C12 h) for HTX-019 were 43,729 h*ng/mL (32.7), 45,460 h*ng/mL (36.8), and 988.4 ng/mL (27.5), respectively; corresponding fosaprepitant values were 44,130 h*ng/mL (32.0), 46,163 h*ng/mL (36.6), and 1,022 ng/mL (28.5). Also, 90% CIs (94.186–101.354) were within bioequivalence bounds (80%–125%). Within 1 h following infusion start, one (1%) HTX-019 recipient reported one TEAE, while 20 (20%) fosaprepitant recipients reported 32 TEAEs. Dyspnea occurred in three fosaprepitant recipients (at <1 min in two subjects and at 18 min in one subject, considered study drug related) and one HTX-019 recipient (at 120 h, associated with a respiratory tract infection and considered not related to the study drug). No severe TEAEs, serious adverse events, or deaths occurred; all TEAEs resolved. Conclusion HTX-019 was bioequivalent to fosaprepitant and may provide a safer alternative to fosaprepitant for chemotherapy-induced nausea and vomiting prophylaxis. PMID:29535504

Absolute bioavailability and safety of a novel rivastigmine nasal spray in healthy elderly individuals

PubMed Central

Soh, Bob

2016-01-01

Aims To test the feasibility of a novel rivastigmine nasal spray as prospective treatment for dementia. Methods A single dose, crossover absolute bioavailability and safety study was conducted with rivastigmine intravenous solution (1 mg) and nasal spray (3.126 mg) in eight healthy elderly individuals, aged 58–75 years. Results Absolute bioavailability (F) of the nasal spray was significant at 0.62 (0.15) for F > 0 (P < 0.001, n = 8). The systemic dose absorbed was 2.0 (0.6) mg, time to maximum plasma concentration was 1.1 (0.5) h and maximum plasma concentration was 6.9 (2.0) ng ml−1. The NAP226–90 to rivastigmine AUC0–∞ ratio was 0.78 (0.19). The single dose safety was good with two of five mild adverse events related to the nasal spray. Nasal and throat irritation were perceived as mild and transient, and both had resolved at 20 min post‐nasal dose. An estimated dose of two or three sprays twice‐daily with nasal spray would deliver comparable rivastigmine exposure and efficacy as a 6–9.7 mg day–1 oral dose and a 10 cm2 transdermal patch, respectively. Conclusions The rivastigmine nasal spray had superior absolute bioavailability compared to historical values for oral capsule and transdermal patch determined by other researchers. It had rapid onset of action, low NAP226–90 to rivastigmine exposure ratio and a favourable safety and tolerability profile. The ability to achieve adjustable, individual, twice‐daily dosing during waking hours has good potential to minimise undesirable cholinergic burden and sleep disturbances whilst delivering an effective dose for the treatment of dementia associated with Alzheimer's and Parkinson's disease. PMID:27639640

A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

PubMed

Sayed, Sehrish; Van Dam, Nicholas T; Horn, Sarah R; Kautz, Marin M; Parides, Michael; Costi, Sara; Collins, Katherine A; Iacoviello, Brian; Iosifescu, Dan V; Mathé, Aleksander A; Southwick, Steven M; Feder, Adriana; Charney, Dennis S; Murrough, James W

2018-01-01

Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519). © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

Immunogenicity and safety of a combined DTaP-IPV vaccine compared with separate DTaP and IPV vaccines when administered as pre-school booster doses with a second dose of MMR vaccine to healthy children aged 4-6 years.

PubMed

Black, Steven; Friedland, Leonard R; Schuind, Anne; Howe, Barbara

2006-08-28

Combination vaccines represent one solution to the problem of increased numbers of injections during single clinic visits. A combined DTaP-IPV (Infanrix-IPV) vaccine has been developed for use as a pre-school booster. Four hundred healthy children aged 4-6 years previously primed with 4 doses of DTaP vaccine (Infanrix), 3 doses of poliovirus vaccine and 1 dose of MMR vaccine were randomized to receive single doses of either the combined DTaP-IPV vaccine or separate DTaP and IPV vaccines in a Phase II trial (DTaP-IPV-047). All children also received a second dose of MMR vaccine. Immunogenicity was assessed in serum samples taken before and 1 month after booster administration. Safety was actively assessed for 42 days post-vaccination. Non-inferiority of the DTaP-IPV vaccine to separate DTaP and IPV vaccines was demonstrated for all DTaP antigen booster response rates and poliovirus geometric mean titers of antibody ratios. Post-vaccination, > or =99.4% of children in both groups had seroprotective levels of anti-diphtheria and anti-tetanus antibodies (> or =0.1IU/mL) and seroprotective anti-poliovirus antibody titers (> or =1:8). All children in both groups were seropositive for measles, mumps and rubella antibodies, with similar post-vaccination geometric mean concentrations/titers. No significant differences were observed in the incidence of solicited local or general symptoms, unsolicited symptoms and serious adverse events between the two groups. This combined DTaP-IPV appeared safe and immunogenic when given as a booster dose at 4-6 years of age. The DTaP-IPV vaccine had no negative effect on the response to co-administered MMR vaccine, making it well-suited for use as a pre-school booster.

Exposure-response evaluations of venetoclax efficacy and safety in patients with non-Hodgkin lymphoma.

PubMed

Parikh, Apurvasena; Gopalakrishnan, Sathej; Freise, Kevin J; Verdugo, Maria E; Menon, Rajeev M; Mensing, Sven; Salem, Ahmed Hamed

2018-04-01

Exposure-response analyses were performed for a venetoclax monotherapy study in 106 patients with varying subtypes of non-Hodgkin lymphoma (NHL) (NCT01328626). Logistic regression, time-to-event, and progression-free survival (PFS) analyses were used to evaluate the relationship between venetoclax exposure, NHL subtype and response, PFS, or occurrence of serious adverse events. Trends for small increases in the probability of response with increasing venetoclax exposures were identified, and became more evident when assessed by NHL subtype. Trends in exposure-PFS were shown for the mantle cell lymphoma (MCL) subtype, but not other subtypes. There was no increase in the probability of experiencing a serious adverse event with increasing exposure. Overall, the results indicate that venetoclax doses of 800-1200 mg as a single agent may be appropriate to maximize efficacy in MCL, follicular lymphoma, and diffuse large B-cell lymphoma subtypes with no expected negative impact on safety.

DNA variants in DHFR gene and response to treatment in children with childhood B ALL: revisited in AIEOP-BFM protocol.

PubMed

Ceppi, Francesco; Gagné, Vincent; Douyon, Laurance; Quintin, Camille J; Colombini, Antonella; Parasole, Rosanna; Buldini, Barbara; Basso, Giuseppe; Conter, Valentino; Cazzaniga, Giovanni; Krajinovic, Maja

2018-01-01

We have previously reported an association of dihydrofolate reductase promoter polymorphisms with reduced event-free survival in childhood acute lymphoblastic leukemia (ALL) patients treated with Dana Farber Cancer Institute protocol. Here, we assessed whether these associations are applicable to other protocol, based on different methotrexate doses. Genotypes for six tag polymorphisms and resulting haplotypes were analyzed for an association with ALL outcome. The association was found with the polymorphisms A-680C, A-317G and C-35T in high-risk group patients. Carriers of haplotype *1 had a remarkably higher risk of events compared with noncarriers and a lower probability of event-free survival (21.4 vs 81.3%). The role of DHFR variants in predicting the outcome of childhood ALL extends beyond single-treatment protocol and can be useful biomarker in personalizing treatment.

Effects of food and grapefruit juice on single-dose pharmacokinetics of blonanserin in healthy Chinese subjects.

PubMed

Shang, De-Wei; Wang, Zhan-Zhang; Hu, Hai-Tang; Zhang, Yue-Feng; Ni, Xiao-Jia; Lu, Hao-Yang; Zhang, Ming; Hu, Jin-Qing; Qiu, Chang; Peng, Huan; Shen, Ling-Fang; Wen, Yu-Guan

2018-01-01

The purpose of this study was to investigate the potential effects of a meal and grapefruit juice on the pharmacokinetics of blonanserin and its metabolite N-desethyl blonanserin in healthy Chinese volunteers. This was a single-centre, open-label, fixed-sequence study, where 12 healthy Chinese volunteers received a single dose of 8 mg blonanserin after an overnight fast in period 1 (reference), a high-fat meal during period 2 and with co-administration of 250 mL of grapefruit juice in period 3. The washout period was 7 days. Series of plasma samples were collected after each dose to determine concentrations of blonanserin and its metabolite N-desethyl blonanserin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis and compared between periods by standard average bioequivalence ANOVA. Adverse events were monitored throughout the study. All subjects completed the study. High-fat meals significantly increased blonanserin exposure (AUC t ) 2.58-fold (90% CI 2.21, 3.02), relative to the reference period. Co-administration of blonanserin with grapefruit juice remarkably prolonged elimination half-life of blonanserin (from 9.7 to 21.4 h) and significantly increased exposures to blonanserin and N-desethyl blonanserin by 5.82-fold (90% CI 4.57, 7.42) and 1.81-fold (90% CI 1.65, 1.98), respectively. These results suggested that blonanserin was largely metabolised in the intestinal tract before becoming systemically available, and both food and grapefruit juice enhanced exposure to blonanserin and N-desethyl blonanserin. Grapefruit juice increased bioavailability and may have reduced systemic clearance of blonanserin. Further intestinal CYP3A4 and hepatic CYP3A4 might be postulated to explain the delayed elimination of blonanserin. Dose adjustment of blonanserin is needed on the basis of co-intake of known strong CYP3A4 inhibitor. Patients taking high-dose blonanserin also need to be cautious about the ingestion of grapefruit juice.

Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants.

PubMed

Karim, Aziz; Laurent, Aziz; Munsaka, Melvin; Wann, Elisabeth; Fleck, Penny; Mekki, Qais

2009-10-01

Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a > or =10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy.

Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study.

PubMed

Mohan, Vadrevu Krishna; Varanasi, Vineeth; Singh, Anit; Pasetti, Marcela F; Levine, Myron M; Venkatesan, Ramasamy; Ella, Krishna M

2015-08-01

Enteric fever caused by Salmonella Typhi remains a major public health problem in developing countries. Typbar-TCV is a single-dose typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine for persons ≥6 months of age. Six hundred fifty-four healthy subjects aged 2-45 years enrolled in a double-blind, randomized controlled trial (RCT) received a single dose of Typbar-TCV or comparator "Vi polysaccharide" (Typbar), and 327 healthy subjects aged 6-23 months received a single dose of Typbar-TCV in an open-label trial (OLT); both received single- or multidose presentations from different lots. After 2 years, subsets in each group received a booster dose. The primary objective included analysis of geometric mean titer (GMTs) and 4-fold rise of anti-Vi serum immunoglobulin G (IgG) enzyme-linked immunosorbent assay titers over baseline (seroconversion [SCN]) 42 days after immunization. Typbar-TCV recipients in the RCT attained higher anti-Vi IgG GMTs 42 days after immunization (SCN, 97%; GMT, 1293 [95% confidence interval {CI}, 1153-1449]) than recipients of Typbar (SCN, 93%; GMT, 411 [95% CI, 359-471]) (P < .001). Typbar-TCV was highly immunogenic in the OLT (SCN, 98%; GMT, 1937 [95% CI, 1785-2103]). Two years after vaccination, anti-Vi titers remained higher in Typbar-TCV subjects (GMT, 82 [95% CI, 73-92]); and exhibited higher avidity (geometric mean avidity index [GMAI], 60%) than in Typbar recipients (GMT, 46 [95% CI, 40-53]; GMAI 46%) in the RCT (P < .001). OLT Typbar-TCV recipients achieved GMT of 48 (95% CI, 42-55) and GMAI of 57%. Typbar-TCV induced multiple IgG subclasses and strong booster responses in all ages. No serious vaccine-attributable adverse events were observed. Single-dose Typbar-TCV is well tolerated and induces robust and long-lasting serum anti-Vi IgG across age groups. CTRI/2011/08/001957, CTRI/2014/01/004341. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours.

PubMed

Weihrauch, Martin R; Richly, Heike; von Bergwelt-Baildon, Michael S; Becker, Hans Jiro; Schmidt, Manuel; Hacker, Ulrich T; Shimabukuro-Vornhagen, Alexander; Holtick, Udo; Nokay, Bahar; Schroff, Matthias; Wittig, Burghardt; Scheulen, Max E

2015-01-01

This study was initiated to evaluate safety, toxicity, pharmacokinetics, and pharmacodynamics of treatment with MGN1703, a novel synthetic DNA-based toll-like receptor 9 (TLR9)-immunomodulator. The study consisted of an escalating single dose regimen followed by a multiple dose part. Dose levels of 0.25, 2, 10, 30, and 60 mg of MGN1703 were administered subcutaneously over 6 weeks twice weekly. Patients with at least stable disease (SD) could participate in the extension phase of the study for six further weeks. Effects on the immune status were monitored. 28 patients with metastatic solid tumours were included. Fatigue and activated partial thromboplastin time (aPTT) prolongation were the only two cases of drug-related grade 3 Common Terminology Criteria adverse events (CTCAE). The most frequently reported drug-related adverse events were of CTC Grade ⩽2. There was no relationship between toxicity and dose and no patient was withdrawn from the study due to drug-related AE. No drug-related serious AE (SAE) were reported. Six out of 24 patients had SD after 6 weeks of treatment and three of those remained in SD after a total of 12 weeks. Four patients were further treated in a compassionate use programme showing long-term disease stabilisation for up to 18 months. Immune assessment of cell compartments showed a non-significant increase of TLR9 expressing naïve B cells during therapy. Twice weekly subcutaneous applications of MGN1703 in a dose of up to 60 mg are safe and well tolerated without dose-limiting toxicities. MGN1703 shows immune activation and anti-tumour efficacy in heavily pretreated patients. The recommended dose of 60 mg twice weekly is currently used in a phase II trial in small cell lung cancer and a phase III trial in colorectal cancer patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma.

PubMed

Saeki, Issei; Yamamoto, Naoki; Yamasaki, Takahiro; Takami, Taro; Maeda, Masaki; Fujisawa, Koichi; Iwamoto, Takuya; Matsumoto, Toshihiko; Hidaka, Isao; Ishikawa, Tsuyoshi; Uchida, Koichi; Tani, Kenji; Sakaida, Isao

2016-10-28

To evaluate the inhibitory effects of deferasirox (DFX) against hepatocellular carcinoma (HCC) through basic and clinical studies. In the basic study, the effect of DFX was investigated in three hepatoma cell lines (HepG2, Hep3B, and Huh7), as well as in an N-nitrosodiethylamine-induced murine HCC model. In the clinical study, six advanced HCC patients refractory to chemotherapy were enrolled. The initial dose of DFX was 10 mg/kg per day and was increased by 10 mg/kg per day every week, until the maximum dose of 30 mg/kg per day. The duration of a single course of DFX therapy was 28 consecutive days. In the event of dose-limiting toxicity (according to the Common Terminology Criteria for Adverse Events v.4.0), DFX dose was reduced. Administration of DFX inhibited the proliferation of hepatoma cell lines and induced the activation of caspase-3 in a dose-dependent manner in vitro . In the murine model, DFX treatment significantly suppressed the development of liver tumors ( P < 0.01), and significantly upregulated the mRNA expression levels of hepcidin ( P < 0.05), transferrin receptor 1 ( P < 0.05), and hypoxia inducible factor-1α ( P < 0.05) in both tumor and non-tumor tissues, compared with control mice. In the clinical study, anorexia and elevated serum creatinine were observed in four and all six patients, respectively. However, reduction in DFX dose led to decrease in serum creatinine levels in all patients. After the first course of DFX, one patient discontinued the therapy. We assessed the tumor response in the remaining five patients; one patient exhibited stable disease, while four patients exhibited progressive disease. The one-year survival rate of the six patients was 17%. We demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.

Monitoring Haloperidol Plasma Concentration and Associated Adverse Events in Critically Ill Children With Delirium: First Results of a Clinical Protocol Aimed to Monitor Efficacy and Safety.

PubMed

Slooff, Valerie D; van den Dungen, Desley K; van Beusekom, Babette S; Jessurun, Naomi; Ista, Erwin; Tibboel, Dick; de Wildt, Saskia N

2018-02-01

As delirium in critically ill children is increasingly recognized, more children are treated with the antipsychotic drug haloperidol, while current dosing guidelines are lacking solid evidence and appear to be associated with a high risk of adverse events. We aim to report on the safety and efficacy of a recently implemented clinical dose-titration protocol with active monitoring of adverse events. From July 2014 until June 2015, when a potential delirium was identified by regular delirium scores and confirmed by a child psychiatrist, haloperidol was prescribed according to the Dutch Pediatric Formulary. Daily, adverse events were systematically assessed, haloperidol plasma concentrations were measured, and delirium symptoms followed. Dependent on the clinical response, plasma concentration, and adverse event, the dose was adjusted. A 28-bed tertiary PICU in the Netherlands. All patients admitted to the PICU diagnosed with delirium. Treatment with haloperidol according to a dose-titration protocol MEASUREMENTS AND MAIN RESULTS:: Thirteen children (median age [range] 8.3 yr [0.4-13.8 yr]) received haloperidol, predominantly IV (median dose [range] 0.027 mg/kg/d [0.005-0.085 mg/kg/d]). In all patients, pediatric delirium resolved, but five of 13 patients developed possible adverse event. These were reversed after biperiden (n = 2), discontinuing (n = 3), and/or lowering the dose (n = 3). Plasma concentrations were all below the presumed therapeutic threshold of 3-12 µg/L. Prospective systematic monitoring of adverse event in critically ill children receiving haloperidol revealed a significant proportion of possible adverse events. Adverse event developed despite low plasma concentrations and recommended dose administration in the majority of the patients. Our data suggest that haloperidol can potentially improve pediatric delirium, but it might also put patients at risk for developing adverse events.

Efficacy of single-dose, extended-release naproxen sodium 660 mg in postsurgical dental pain: two double-blind, randomized, placebo-controlled trials.

PubMed

Laurora, Irene; An, Robert

2016-01-01

To evaluate the efficacy of a novel formulation of extended-release/immediate-release (ER) naproxen sodium over 24 h in a dental pain model. Two randomized, double-blind, placebo-controlled trials in moderate to severe pain after extraction of one or two impacted third molars (at least one partial mandibular bony impaction). Treatment comprised oral ER naproxen sodium 660 mg (single dose), placebo (both studies) or immediate-release (IR) naproxen sodium 220 mg tid (study 2). Primary efficacy endpoint: 24-h summed pain intensity difference (SPID). Secondary variables included total pain relief (TOTPAR), use of rescue medication. All treatment-emergent adverse events were recorded. NCT00720057 (study 1), NCT01389284 (study 2). Primary efficacy analyses: pain intensity was significantly lower over 24 h with ER naproxen sodium vs. placebo (p < 0.001), with significant relief from 15 min (study 2). In study 2, ER naproxen sodium was non-inferior to IR naproxen sodium, reducing pain intensity to a comparable extent over 24 h. TOTPAR was significantly greater with ER and IR naproxen sodium vs. placebo at all time points, with generally comparable differences between active treatments. Significantly more placebo patients required rescue medication vs. ER and IR naproxen sodium from 2-24 h post-dose. Once daily ER naproxen sodium was generally safe and well tolerated, with a similar safety profile to IR naproxen sodium tid. The studies were single dose, with limited ability to assess efficacy or safety of multiple doses over time. As the imputed pain score meant that estimated treatment differences may have been biased in favor of ER naproxen sodium, a post hoc analysis evaluated the robustness of the results for pain relief. A single dose of ER naproxen sodium 660 mg significantly reduced moderate to severe dental pain vs. placebo and was comparable to IR naproxen sodium 220 mg tid. Significant pain relief was experienced from 15 min and sustained over 24 h, resulting in a reduced need for rescue medication. ER naproxen sodium 660 mg once daily is a convenient and effective therapy providing 24 h relief of pain.

Real-time Molecular Study of Bystander Effects of Low dose Low LET radiation Using Living Cell Imaging and Nanoparticale Optics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Natarajan, Mohan; Xu, Nancy R; Mohan, Sumathy

2013-06-03

In this study two novel approaches are proposed to investigate precisely the low dose low LET radiation damage and its effect on bystander cells in real time. First, a flow shear model system, which would provide us a near in vivo situation where endothelial cells in the presence of extra cellular matrix experiencing continuous flow shear stress, will be used. Endothelial cells on matri-gel (simulated extra cellular matrix) will be subjected to physiological flow shear (that occurs in normal blood vessels). Second, a unique tool (Single nano particle/single live cell/single molecule microscopy and spectroscopy; Figure A) will be used tomore » track the molecular trafficking by single live cell imaging. Single molecule chemical microscopy allows one to single out and study rare events that otherwise might be lost in assembled average measurement, and monitor many target single molecules simultaneously in real-time. Multi color single novel metal nanoparticle probes allow one to prepare multicolor probes (Figure B) to monitor many single components (events) simultaneously and perform multi-complex analysis in real-time. These nano-particles resist to photo bleaching and hence serve as probes for unlimited timeframe of analysis. Single live cell microscopy allows one to image many single cells simultaneously in real-time. With the combination of these unique tools, we will be able to study under near-physiological conditions the cellular and sub-cellular responses (even subtle changes at one molecule level) to low and very low doses of low LET radiation in real time (milli-second or nano-second) at sub-10 nanometer spatial resolution. This would allow us to precisely identify, at least in part, the molecular mediators that are responsible of radiation damage in the irradiated cells and the mediators that are responsible for initiating the signaling in the neighboring cells. Endothelial cells subjected to flow shear (2 dynes/cm2 or 16 dynes/cm2) and exposed to 0.1, 1 and 10 cGy on coverslips will be examined for (a) low LET radiation-induced alterations of cellular function and its physiological relevance in real time; and (b) radiation damage triggered bystander effect on the neighboring unirradiated cells. First, to determine the low LET radiation induced alteration of cellular function we will examine: (i) the real time transformation of single membrane transporters in single living cells; (ii) the pump efficiency of membrane efflux pump of live cells in real time at the molecular level; (iii) the kinetics of single-ligand receptor interaction on single live cell surface (Figure C); and (iv) alteration in chromosome replication in living cell. Second, to study the radiation triggered bystander responses, we will examine one of the key signaling pathway i.e. TNF- alpha/NF-kappa B mediated signaling. TNF-alpha specific nano particle sensors (green) will be developed to detect the releasing dynamics, transport mechanisms and ligand-receptor binding on live cell surface in real time. A second sensor (blue) will be developed to simultaneously monitor the track of NF-kB inside the cell. The proposed nano-particle optics approach would complement our DOE funded study on biochemical mechanisms of TNF-alpha- NF-kappa B-mediated bystander effect.« less

Acute and repeated dose (28 days) oral safety studies of an alkoxyglycerol extract from shark liver oil in rats.

PubMed

Anadón, Arturo; Martínez, Maria A; Ares, Irma; Ramos, Eva; Señoráns, Francisco J; Reglero, Guillermo; Torres, Carlos

2010-02-10

Shark liver oil has been used for over 50 years as both a therapeutic and preventive agent. The active ingredients in shark liver oil have been found to be a group of ether-linked glycerols known as alkoxyglycerols. Despite its popularity, there is little published toxicology data on alkoxyglycerols. The toxicity of a supercritical fluid extract of shark liver oil (AKG-1 extract) has been evaluated in acute and repeated dose (28 days) oral toxicity studies in rats at doses of 200 and 100 times the maximum recommended dose by supplement manufacturers in humans, respectively. The AKG-1 extract administered in a single oral gavage dose of 2000 mg kg(-1) of body weight resulted in no adverse events or mortality. The AKG-1 extract administered as a daily dose of 1000 mg kg(-1) of body weight for 28 days by gavage resulted in no adverse effects or mortality. For both studies, no abnormal clinical signs, behavioral changes, body weight changes, or change in food and water consumption occurred. There were no changes in hematological and serum chemistry values, organ weights, or gross or histological characteristics. It is concluded that the AKG-1 extract is well tolerated in rats at an acute dose of 2000 mg kg(-1) and at a subchronic (28 days) dose of 1000 mg kg(-1).

Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies.

PubMed

Tobinai, Kensei; Ogura, Michinori; Ishizawa, Kenichi; Suzuki, Tatsuya; Munakata, Wataru; Uchida, Toshiki; Aoki, Tomohiro; Morishita, Takanobu; Ushijima, Yoko; Takahara, Satoko

2016-01-01

In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. NCT01704963.

The efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis.

PubMed

Concoff, Andrew; Sancheti, Parag; Niazi, Faizan; Shaw, Peter; Rosen, Jeffrey

2017-12-21

Intra-articular hyaluronic acid (IA-HA) is a common therapy used to treat knee pain and suppress knee inflammation in knee osteoarthritis (OA), typically prescribed in regimens ranging from a single injection to 5 weekly injections given once weekly. We conducted a systematic review to determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens. We conducted a systematic search of the literature to identify studies evaluating IA-HA for the management of knee OA compared to IA-saline. Primary outcome measure was the mean knee pain score at 13 Weeks (3 months) or 26 weeks (6 months). Secondary outcome was the number of treatment-related AEs and treatment-related serious adverse events (SAEs). We evaluated differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline. Thirty articles were included. Overall, IA-HA injections were associated with less knee pain compared to IA-Saline injections for all dosing regimens. 2-4 injections of IA-HA vs. IA-Saline produced the largest effect size at both 3-months and 6-months (Standard mean difference [SMD] = -0.76; -0.98 to -0.53, 95% CI, P < 0.00001, and SMD = -0.36; -0.63 to -0.09 95% CI, P = 0.008, respectively). Additionally, single injection studies yielded a non-significant treatment effect at 3 and 6 months, while ≥5 5 injections demonstrated a significant improvement in pain only at 6 months. Five or more injections of IA-HA were associated with a higher risk of treatment-related AEs compared to IA-Saline (Risk ratio [RR] = 1.67; 1.09 to 2.56 95% CI, p = 0.02), which was a result not seen within the 1 and 2-4 injection subgroups. Overall, 2-4 and ≥5 injection regimens provided pain relief over IA-Saline, while single injection did not. Intra-articular injections of HA used in a 2-4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee OA, and was generally deemed safe with few to no treatment-related AEs reported across studies. Future research is needed to directly compare these treatment regimens.

Intermittency ratio: A metric reflecting short-term temporal variations of transportation noise exposure

PubMed Central

Wunderli, Jean Marc; Pieren, Reto; Habermacher, Manuel; Vienneau, Danielle; Cajochen, Christian; Probst-Hensch, Nicole; Röösli, Martin; Brink, Mark

2016-01-01

Most environmental epidemiology studies model health effects of noise by regressing on acoustic exposure metrics that are based on the concept of average energetic dose over longer time periods (i.e. the Leq and related measures). Regarding noise effects on health and wellbeing, average measures often cannot satisfactorily predict annoyance and somatic health effects of noise, particularly sleep disturbances. It has been hypothesized that effects of noise can be better explained when also considering the variation of the level over time and the frequency distribution of event-related acoustic measures, such as for example, the maximum sound pressure level. However, it is unclear how this is best parametrized in a metric that is not correlated with the Leq, but takes into account the frequency distribution of events and their emergence from background. In this paper, a calculation method is presented that produces a metric which reflects the intermittency of road, rail and aircraft noise exposure situations. The metric termed intermittency ratio (IR) expresses the proportion of the acoustical energy contribution in the total energetic dose that is created by individual noise events above a certain threshold. To calculate the metric, it is shown how to estimate the distribution of maximum pass-by levels from information on geometry (distance and angle), traffic flow (number and speed) and single-event pass-by levels per vehicle category. On the basis of noise maps that simultaneously visualize Leq, as well as IR, the differences of both metrics are discussed. PMID:26350982

Solar particle dose rate buildup and distribution in critical body organs

NASA Technical Reports Server (NTRS)

Atwell, William; Weyland, Mark D.; Simonsen, Lisa C.

1993-01-01

Human body organs have varying degrees of radiosensitivity as evidenced by radioepidemiologic tables. The major critical organs for both the male and female that have been identified include the lung, thyroid, stomach, and breast (female). Using computerized anatomical models of the 50th percentile United States Air Force male and female, we present the self-shielding effects of these various body organs and how the shielding effects change as the location (dose point) in the body varies. Several major solar proton events from previous solar cycles and several events from the current 22nd solar cycle have been analyzed. The solar particle event rise time, peak intensity, and decay time vary considerably from event to event. Absorbed dose and dose equivalent rate calculations and organ risk assessment data are presented for each critical body organ. These data are compared with the current NASA astronaut dose limits as recommended by the National Council on Radiation Protection and Measurements.

Abacavir/dolutegravir/lamivudine single-tablet regimen: a review of its use in HIV-1 infection.

PubMed

Greig, Sarah L; Deeks, Emma D

2015-04-01

A fixed-dose, single-tablet regimen comprising the integrase strand transfer inhibitor (INSTI) dolutegravir and the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq®) is now available for the treatment of HIV-1 infection. In a randomized, double-blind, phase III trial in antiretroviral therapy (ART)-naive adults (SINGLE), once-daily dolutegravir plus abacavir/lamivudine had noninferior efficacy to once-daily efavirenz/tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine with regard to establishing and sustaining virological suppression over 144 weeks, and subsequent superiority testing significantly favoured dolutegravir plus abacavir/lamivudine. This outcome was predominantly driven by more favourable rates of discontinuation due to adverse events versus the efavirenz/tenofovir DF/emtricitabine group. These data were generally supported by findings from other phase III trials in ART-naive adults receiving dolutegravir plus either abacavir/lamivudine or tenofovir DF/emtricitabine (SPRING-2 and FLAMINGO). Dolutegravir plus abacavir/lamivudine is generally well tolerated, with a tolerability profile that appears to be more favourable than efavirenz/tenofovir DF/emtricitabine. In the SINGLE trial, there were no major treatment-emergent INSTI or NRTI resistance-associated mutations in dolutegravir plus abacavir/lamivudine recipients with protocol-defined virological failure, indicating a high genetic barrier to resistance. Thus, triple combination therapy with abacavir, dolutegravir and lamivudine is an effective, generally well tolerated option for the management of HIV-1 infection, with the convenient once-daily fixed-dose tablet providing the first single-tablet regimen option without tenofovir DF.

Investigation of HZETRN 2010 as a Tool for Single Event Effect Qualification of Avionics Systems

NASA Technical Reports Server (NTRS)

Rojdev, Kristina; Atwell, William; Boeder, Paul; Koontz, Steve

2014-01-01

NASA's future missions are focused on deep space for human exploration that do not provide a simple emergency return to Earth. In addition, the deep space environment contains a constant background Galactic Cosmic Ray (GCR) radiation exposure, as well as periodic Solar Particle Events (SPEs) that can produce intense amounts of radiation in a short amount of time. Given these conditions, it is important that the avionics systems for deep space human missions are not susceptible to Single Event Effects (SEE) that can occur from radiation interactions with electronic components. The typical process to minimizing SEE effects is through using heritage hardware and extensive testing programs that are very costly. Previous work by Koontz, et al. [1] utilized an analysis-based method for investigating electronic component susceptibility. In their paper, FLUKA, a Monte Carlo transport code, was used to calculate SEE and single event upset (SEU) rates. This code was then validated against in-flight data. In addition, CREME-96, a deterministic code, was also compared with FLUKA and in-flight data. However, FLUKA has a long run-time (on the order of days), and CREME-96 has not been updated in several years. This paper will investigate the use of HZETRN 2010, a deterministic transport code developed at NASA Langley Research Center, as another tool that can be used to analyze SEE and SEU rates. The benefits to using HZETRN over FLUKA and CREME-96 are that it has a very fast run time (on the order of minutes) and has been shown to be of similar accuracy as other deterministic and Monte Carlo codes when considering dose [2, 3, 4]. The 2010 version of HZETRN has updated its treatment of secondary neutrons and thus has improved its accuracy over previous versions. In this paper, the Linear Energy Transfer (LET) spectra are of interest rather than the total ionizing dose. Therefore, the LET spectra output from HZETRN 2010 will be compared with the FLUKA and in-flight data to validate HZETRN 2010 as a computational tool for SEE qualification by analysis. Furthermore, extrapolation of these data to interplanetary environments at 1 AU will be investigated to determine whether HZETRN 2010 can be used successfully and confidently for deep space mission analyses.

A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine.

PubMed

Saper, Joel R; Mathew, Ninan T; Loder, Elizabeth W; DeGryse, Ronald; VanDenburgh, Amanda M

2007-09-01

Several randomized, controlled studies have reported benefits of botulinum toxin type A (BoNTA; Allergan Inc., Irvine, CA, USA) over placebo in the treatment of migraine. Some studies reported significant benefits at dosages as low as 16 U, while other studies reported safety, tolerability, and efficacy at dosages up to 260 U. However, the optimal treatment paradigm and patient population have yet to be defined. To compare different injection sites and doses of BoNTA in the prevention of episodic migraine. This was a randomized, double-blind, placebo-controlled study of 232 patients with a history of four to eight moderate to severe migraines per month, with or without aura. Patients were randomized to placebo or one of four BoNTA groups that received injections into different muscle regions: frontal (10 U), temporal (6 U), glabellar (9 U), or all three areas (total dose 25 U). For 3 months following a single treatment, patients recorded migraine-related variables in a daily diary. BoNTA and placebo produced comparable decreases from baseline in the frequency of migraines (P > or = 0.411). In general, no statistically significant differences were observed for any efficacy variable. The overall rates of adverse events (any type) or treatment-related adverse events were similar among the groups. In this exploratory study of episodic migraine patients, low-dose injections of BoNTA into the frontal, temporal, and/or glabellar muscle regions were not more effective than placebo. BoNTA was safe and well tolerated. Future studies may examine higher BoNTA doses, flexible injection sites, multiple treatments, and disallow concomitant prophylactic medications.

Pharmacokinetics of betamethasone after single-dose intramuscular administration of betamethasone phosphate and betamethasone acetate to healthy subjects.

PubMed

Salem, Isam I; Najib, Naji M

2012-01-01

Betamethasone is used for its antiinflammatory and immunosuppressive effects in disorders of many organ systems. However, the pharmacokinetic properties of betamethasone in plasma after intramuscular injection of betamethasone sodium phosphate and betamethasone acetate dual-acting suspension need further investigation. The main aim of this study was to determine the pharmacokinetic parameters of betamethasone, betamethasone acetate, and betamethasone phosphate after the administration of a single intramuscular dose of the dual-acting suspension to healthy human volunteers. Two different studies were conducted in healthy males. Volunteers were judged healthy based on their medical history, physical examination, and laboratory test results. Before confinement, all volunteers were tested for freedom from alcohol and drugs of abuse. Following a 10-hour overnight fasting, a single dose of 1 mL of the dual-acting suspension containing 3 mg of betamethasone phosphate and 3 mg of betamethasone acetate was administered by intramuscular injection. Blood sampling covered 48 hours. The plasma samples obtained in the second study were stabilized to enable pharmacokinetic profiling of betamethasone esters. Twenty-four healthy males with mean (SD) age of 27 (6.62) years participated in each study. No incidences of serious adverse events were recorded during the studies. Six mild adverse events were reported in 2 subjects in the second study. One subject suffered from pain at the injection site and insomnia, and another subject complained of heartburn and drowsiness. Betamethasone phosphate appeared to be readily absorbed with a mean AUC(0-t) of 96.01 ng/h/mL and an AUC(0-∞) of 97.96 (23.38) ng/h/mL. Betamethasone peak plasma concentration reached a mean t(½) of 12.92 hours. Betamethasone acetate was not detected in the volunteers' plasma in either study (total of 2208 plasma samples). The observed pharmacokinetic parameters suggested that the acetate ester, and not the phosphate ester, of betamethasone acts as a prodrug or reservoir for betamethasone, conferring on it sustained- and extended-release characteristics. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

NSR&D Program Fiscal Year 2015 Funded Research Stochastic Modeling of Radioactive Material Releases Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andrus, Jason P.; Pope, Chad; Toston, Mary

2016-12-01

Nonreactor nuclear facilities operating under the approval authority of the U.S. Department of Energy use unmitigated hazard evaluations to determine if potential radiological doses associated with design basis events challenge or exceed dose evaluation guidelines. Unmitigated design basis events that sufficiently challenge dose evaluation guidelines or exceed the guidelines for members of the public or workers, merit selection of safety structures, systems, or components or other controls to prevent or mitigate the hazard. Idaho State University, in collaboration with Idaho National Laboratory, has developed a portable and simple to use software application called SODA (Stochastic Objective Decision-Aide) that stochastically calculatesmore » the radiation dose distribution associated with hypothetical radiological material release scenarios. Rather than producing a point estimate of the dose, SODA produces a dose distribution result to allow a deeper understanding of the dose potential. SODA allows users to select the distribution type and parameter values for all of the input variables used to perform the dose calculation. Users can also specify custom distributions through a user defined distribution option. SODA then randomly samples each distribution input variable and calculates the overall resulting dose distribution. In cases where an input variable distribution is unknown, a traditional single point value can be used. SODA, developed using the MATLAB coding framework, has a graphical user interface and can be installed on both Windows and Mac computers. SODA is a standalone software application and does not require MATLAB to function. SODA provides improved risk understanding leading to better informed decision making associated with establishing nuclear facility material-at-risk limits and safety structure, system, or component selection. It is important to note that SODA does not replace or compete with codes such as MACCS or RSAC; rather it is viewed as an easy to use supplemental tool to help improve risk understanding and support better informed decisions. The SODA development project was funded through a grant from the DOE Nuclear Safety Research and Development Program.« less

Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.

PubMed

Bendell, Johanna C; Patel, Manish R; Infante, Jeffrey R; Kurkjian, Carla D; Jones, Suzanne F; Pant, Shubham; Burris, Howard A; Moreno, Ofir; Esquibel, Vanessa; Levin, Wendy; Moore, Kathleen N

2015-04-01

The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle. A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥ 52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥ 40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥ 31 weeks]). The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy. © 2014 American Cancer Society.

NSR&D Program Fiscal Year 2015 Funded Research Stochastic Modeling of Radioactive Material Releases Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andrus, Jason P.; Pope, Chad; Toston, Mary

Nonreactor nuclear facilities operating under the approval authority of the U.S. Department of Energy use unmitigated hazard evaluations to determine if potential radiological doses associated with design basis events challenge or exceed dose evaluation guidelines. Unmitigated design basis events that sufficiently challenge dose evaluation guidelines or exceed the guidelines for members of the public or workers, merit selection of safety structures, systems, or components or other controls to prevent or mitigate the hazard. Idaho State University, in collaboration with Idaho National Laboratory, has developed a portable and simple to use software application called SODA (Stochastic Objective Decision-Aide) that stochastically calculatesmore » the radiation dose distribution associated with hypothetical radiological material release scenarios. Rather than producing a point estimate of the dose, SODA produces a dose distribution result to allow a deeper understanding of the dose potential. SODA allows users to select the distribution type and parameter values for all of the input variables used to perform the dose calculation. Users can also specify custom distributions through a user defined distribution option. SODA then randomly samples each distribution input variable and calculates the overall resulting dose distribution. In cases where an input variable distribution is unknown, a traditional single point value can be used. SODA, developed using the MATLAB coding framework, has a graphical user interface and can be installed on both Windows and Mac computers. SODA is a standalone software application and does not require MATLAB to function. SODA provides improved risk understanding leading to better informed decision making associated with establishing nuclear facility material-at-risk limits and safety structure, system, or component selection. It is important to note that SODA does not replace or compete with codes such as MACCS or RSAC; rather it is viewed as an easy to use supplemental tool to help improve risk understanding and support better informed decisions. The SODA development project was funded through a grant from the DOE Nuclear Safety Research and Development Program.« less

A phase III, open-label, single-arm study of tenecteplase for restoration of function in dysfunctional central venous catheters.

PubMed

Tebbi, Cameron; Costanzi, John; Shulman, Robert; Dreisbach, Luke; Jacobs, Brian R; Blaney, Martha; Ashby, Mark; Gillespie, Barbara S; Begelman, Susan M

2011-08-01

To evaluate, in a phase III, single-arm study, the safety and efficacy of the thrombolytic agent tenecteplase in restoring function to dysfunctional central venous catheters (CVCs). Pediatric and adult patients with dysfunctional CVCs were eligible to receive as much as 2 mL (2 mg) of intraluminal tenecteplase, which was left to dwell in the CVC lumen for a maximum of 120 minutes. If CVC function was not restored at 120 minutes, a second dose was instilled for an additional 120 minutes. Tenecteplase was administered to 246 patients. Mean patient age was 44 years (range, 0-92 y); 72 patients (29%) were younger than 17 years of age. Chemotherapy was the most common reason for catheter insertion. Restoration of CVC function was achieved in 177 patients (72%) within 120 minutes after the first dose. After instillation of a maximum of two doses of tenecteplase, CVC function was restored in 200 patients (81%), with similar frequencies in pediatric (83%) and adult (80%) patients. Adverse events (AEs) were reported in 31 patients (13%); fever (2%), neutropenia (1%), and nausea (0.8%) were most common. One serious AE, an allergic hypersensitivity reaction, was judged to be related to tenecteplase and/or a chemotherapeutic agent that the patient was receiving concurrently. Consecutive administration of one or two doses of tenecteplase into CVCs showed efficacy in the restoration of catheter function in patients with dysfunctional CVCs. Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.

Effect of food on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended release formulation of oxycodone with sequestered naltrexone.

PubMed

Gandelman, Kuan; Lamson, Michael; Salageanu, Joanne; Bramson, Candace; Matschke, Kyle; Malhotra, Bimal

2015-09-01

ALO-02 is being developed as an abuse-deterrent formulation of extended-release oxycodone hydrochloride with naltrexone hydrochloride sequestered in the core of pellets contained in capsules. The primary objective of this study was to assess the effects of administration of ALO-02 capsule whole under fed conditions or sprinkling the pellets from ALO-02 capsule on applesauce under fasting conditions on the pharmacokinetics (PK) of oxycodone, naltrexone and 6-ß-naltrexol compared with ALO-02 capsule administered whole under fasting conditions. The plasma naltrexone and 6-ß-naltrexol concentrations were used to assess the sequestration of naltrexone in the ALO-02 formulation. The secondary objective was to evaluate the safety and tolerability of single 40 mg doses of ALO-02 in healthy volunteers. This was an IRB-approved, open-label, single-dose, randomized, 3-period crossover study in 24 healthy adult volunteers, aged 18-55 years. Each subject was assigned to receive single 40 mg doses of ALO-02 administered whole (intact capsule) under fasting conditions, administered whole under fed conditions (high-fat breakfast ∼ 950 calories), or sprinkling the contents of the ALO-02 capsule (pellets) over applesauce and swallowing the dose without chewing under fasting conditions. Each treatment was separated by a 7-day washout interval. Plasma samples were analyzed just before dosing through 48 hours postdose for oxycodone, and through 120 hours postdose for naltrexone and its major metabolite, 6-ß-naltrexol. Pharmacokinetic parameters included maximum plasma concentration [Cmax ], area under the plasma concentration-time profile from time 0 to infinity [AUCinf ] and to the last quantifiable concentration [AUClast ], time to Cmax [Tmax ], and terminal half life [t1/2 ]. Adverse events, vital signs, and laboratory parameters were monitored for safety assessment. The t1/2 and Tmax values for oxycodone were similar for all 3 treatments. There was a lack of effect of food (whole capsule, fed vs. fasted) or of sprinkling on applesauce (pellets vs. whole capsule, fasted) on oxycodone bioavailability. The Test/Reference ratios of adjusted geometric means for oxycodone AUCinf , AUClast , and Cmax were 99.2%, 100%, and 107%, respectively, for the effect of food; and 101%, 101%, and 97.5%, respectively, for the effect of sprinkling on applesauce. The 90% confidence intervals contained entirely within the bioequivalence limits of 80% to 125% for each comparison. Naltrexone remained sequestered during each treatment, based on the sporadic and low measurable plasma concentrations of naltrexone and 6-ß-naltrexol. Single doses of ALO-02 40 mg were well tolerated, and adverse events were mild, with no apparent difference in frequency for all 3 treatments. Results indicate that ALO-02 can be administered without regard to food. Also, the contents of ALO-02 can be sprinkled over applesauce and consumed without chewing as an alternative treatment option by subjects with difficulty swallowing. Naltrexone remained sequestered in the ALO-02 formulation under all 3 treatments. © 2015, The American College of Clinical Pharmacology.

An airport community noise-impact assessment model

NASA Technical Reports Server (NTRS)

Deloach, R.

1980-01-01

A computer model was developed to assess the noise impact of an airport on the community which it serves. Assessments are made using the Fractional Impact Method by which a single number describes the community aircraft noise environment in terms of exposed population and multiple event noise level. The model is comprised of three elements: a conventional noise footprint model, a site specific population distribution model, and a dose response transfer function. The footprint model provides the noise distribution for a given aircraft operating scenario. This is combined with the site specific population distribution obtained from a national census data base to yield the number of residents exposed to a given level of noise. The dose response relationship relates noise exposure levels to the percentage of individuals highly annoyed by those levels.

Honey for treatment of cough in children

PubMed Central

Goldman, Ran D.

2014-01-01

Abstract Question Cough is a very common presentation among sick children in my clinic. There is almost no day without a child being examined for upper respiratory tract infection and cough. While I understand that no medications are recommended for relief of cough—prescribed or over the counter—is it true that honey might help relieve cough symptoms in children? Answer Most prescribed and over-the-counter preparations for cough in children are not effective and might carry the risk of adverse events. A single dose of honey before bedtime was shown in recent studies to diminish cough and the discomfort experienced by children and their parents. Recent evidence also supports administering a few daily doses, but this practice will need further study to assess its effectiveness and safety. PMID:25642485

Delivery of fenoterol via Respimat, a novel 'soft mist' inhaler. a randomised, double-blind (within device), placebo-controlled, cross-over, dose-ranging study in asthmatic patients.

PubMed

van Noord, J A; Smeets, J J; Creemers, J P; Greefhorst, L P; Dewberry, H; Cornelissen, P J

2000-01-01

The phase-out of chlorofluorocarbons (CFCs) for metered dose inhalers (MDIs) has prompted the development of alternative propellants and the design of propellant-free devices for inhalation therapy. This study was carried out to determine the dose of fenoterol inhaled from Respimat (RMT), a new propellant-free soft mist inhaler, which is equivalent in terms of efficacy and safety to 1 puff of either 100 or 200 microg fenoterol inhaled from a conventional CFC-MDI (Berotec). Sixty-two asthmatic patients (35 male, 27 female) with a mean baseline FEV(1) of 1.7 liters, corresponding to 55% of the predicted normal value, were randomized at two study centers to 4 of a total of 8 possible treatments: placebo; 12.5, 25, 50, 100, or 200 microg fenoterol via RMT, and 100 or 200 microg fenoterol delivered via the MDI. Fifty-nine patients completed the study as planned. Results of the therapeutic equivalence test for the primary endpoint, average FEV(1) (AUC(0-6))/6 and for the secondary endpoint, peak FEV(1), showed that the 12.5- and 25-microg fenoterol doses administered via RMT were equivalent to the 100 microg fenoterol dose from the MDI. The 50-, 100- and 200-microg fenoterol doses delivered by RMT did not meet the criterion for therapeutic equivalence with the 100-microg dose from the MDI, and if tested for a difference would have been significantly different in favor of RMT. All 5 RMT fenoterol doses were therapeutically equivalent to the MDI 200-microg fenoterol dose. Headache, reported by 4 patients on test days and 2 patients between test days in those randomized to RMT, was the most common adverse event, but the active treatments were generally well tolerated with no dose-dependent increases in incidence or severity of adverse events observed. The results from the study suggest that safe and efficacious bronchodilation can be obtained from single-dose fenoterol administered via RMT. Use of lower absolute doses to obtain a clinically significant improvement in pulmonary function may be possible because of the increased lung deposition achievable with the novel soft mist inhaler. Copyright 2000 S. Karger AG, Basel

Defining unnecessary disinfection procedures for single-dose and multiple-dose vials.

PubMed

Buckley, T; Dudley, S M; Donowitz, L G

1994-11-01

Recommendations in the literature conflict on the necessity of disinfecting single-use vials prior to aspiration of fluid. Interventions to disinfect the stopper surface on multiple-dose vials vary considerably. To determine the necessity of alcohol disinfection of the stopper on single-dose vials and to compare povidone-iodine and alcohol versus alcohol-only disinfection of the stopper prior to each needle penetration on multiple-dose vials. The rubber stopper surfaces of 100 single-dose vials were cultured for the presence of bacteria. To determine the efficacy of two procedures for disinfection of multiple-dose vials, 87 stopper surfaces routinely disinfected with both povidone-iodine and alcohol were cultured for bacteria. After a change in practice, 100 multiple-dose vials routinely disinfected with alcohol only were cultured for the presence of bacteria. Of the cultures done on single-dose vial stoppers, 99% were sterile. A comparison of the two disinfection techniques for multiple-dose vials revealed that 83 (95%) of the 87 vials prepped with both povidone-iodine and alcohol were sterile, compared with all stoppers disinfected with alcohol only. This study shows the lack of necessity of any disinfection procedure on the rubber stopper of single-dose vials and the efficacy of alcohol only for disinfecting the stopper of multiple-dose vials.

Efficacy and safety of a single 2 mg dose or 4 mg double dose of alteplase for 50 occluded chest ports using a unique instillation technique

PubMed Central

Sharma, Rajinder P; Ree, Chung Ja; Ree, Alexander

2008-01-01

PURPOSE: To evaluate the effectiveness and safety of a single 2 mg dose or a 4 mg double dose of alteplase for restoring function in occluded chest ports. METHODS: A prospective, open-label, nonblinded study was performed on 40 enrolled patients with a total of 50 chest ports at the Henry Ford Hospital Interventional Radiology Department (Detroid, Michigan, USA). Alteplase (Cathflo Activase; Genentech, USA), a recombinant tissue plasminogen activator produced by recombinant DNA technology, was used to restore the function of 50 occluded chest ports. Occlusion was defined as the inability to withdraw blood freely from the port, or the inability to flush the port easily. A 2 mg (2 mL) dose of alteplase was injected into the port through a Huber needle, using a gentle push and pull technique, and was left to dwell for 30 min. If the port remained occluded after the initial 2 mg alteplase treatment, an additional 2 mg alteplase treatment was administered with the same dwell time of 30 min. If a port had remained occluded despite the above regimen, this outcome would have been considered a failure and the chest port would have required surgical intervention. However, all ports were successfully treated, and no surgical intervention was required. The safety end points included minor or major hemorrhages, such as intracranial hemorrhages, or sepsis. Safety end points were determined by a 24 h follow-up telephone call. RESULTS: Of the 50 chest ports (30 single ports and 10 double ports) treated with alteplase, 36 required 2 mg (72%) and 14 required 4 mg (28%). The efficacy end point was 100% for all chest ports treated, without any adverse events. CONCLUSION: High efficacy and safety rates of restoring function in occluded chest ports were obtained with 2 mg or 4 mg doses of alteplase. Part of this high efficacy rate may be due to the gentle push and pull technique used in the present study. PMID:22477414

Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease.

PubMed

Hatorp, V; Walther, K H; Christensen, M S; Haug-Pihale, G

2000-02-01

Repaglinide is a novel insulin secretagogue developed in response to the need for a fast-acting, oral prandial glucose regulator for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Repaglinide is metabolized mainly in the liver; its pharmacokinetics may therefore be altered by hepatic dysfunction. This open, parallel-group study compared the pharmacokinetics and tolerability of a single 4 mg dose of repaglinide in healthy subjects (n = 12) and patients with chronic liver disease (CLD) (n = 12). Values for AUC and Cmax were significantly higher in CLD patients compared with healthy subjects, and the MRT was prolonged in CLD patients. Values for tmax did not differ between the groups, but t1/2 was significantly prolonged in CLD patients compared with previously determined values in healthy subjects. AUC was inversely correlated with caffeine clearance in CLD patients but not in healthy subjects. Blood glucose profiles were similar in both groups. Adverse events (principally hypoglycemia) were similar in the two groups; none was serious. Repaglinide clearance is significantly reduced in patients with hepatic impairment; the agent should be used with caution in this group.

Randomised controlled field study to evaluate the efficacy and clinical safety of a single 8 mg/kg injectable dose of marbofloxacin compared with one or two doses of 7.5 mg/kg injectable enrofloxacin for the treatment of Actinobacillus pleuropneumoniae infections in growing-fattening pigs in Europe.

PubMed

Grandemange, Erik; Perrin, Pierre-Alexandre; Cvejic, Dejean; Haas, Miriam; Rowan, Tim; Hellmann, Klaus

2017-01-01

Acute outbreaks of Actinobacillus pleuropneumoniae (APP) require rapid, effective, parenteral antimicrobial treatment. The efficacy and safety of a single, short-acting, high dose of marbofloxacin (Forcyl® swine 160 mg/mL) compared with 1 or 2 doses of 7.5 mg/kg enrofloxacin in APP outbreaks in European farms was studied. A controlled, randomised block, blinded, multicentre, field study was conducted on four farms with acute respiratory disease associated with APP. Animals with clinical signs of respiratory disease were allocated similarly to intramuscular treatments of either a single dose 8 mg/kg marbofloxacin on day 0 or, 7.5 mg/kg enrofloxacin (Baytril 1nject®) on day 0 and again on day 2, if clinical signs had not improved. The results were similar for intention to treat (242 pigs) and per protocol populations (239 pigs). On day 0, all pigs had pyrexia (means, 40.6 °C), moderate to severe clinical signs (depression, cough, dyspnoea). Following treatment, animals improved rapidly and on day 7, clinical signs were absent or mild in all pigs and mean temperatures for each treatment were <39.5 °C ( P  > 0.05). The primary efficacy criterion, animals cured, for marbofloxacin and enrofloxacin was 81.8 and 81.4% on day 7, and 84.2 and 82.2% on day 21, respectively. Results for cure, respiratory disease removals and mortalities, and relapses were compared using confidence intervals and confirmed that marbofloxacin was non-inferior to enrofloxacin ( P  > 0.05). There were no significant treatment differences in live weight gains, adverse events and injection site reactions (<2.5% animals) ( P  > 0.05). Significantly more animals developed concurrent disorders in the enrofloxacin (7.5%) than marbofloxacin (0.0%) group ( P  < 0.01). On day 0, the MIC 90 values of APP for marbofloxacin and enrofloxacin were 0.06 μg/mL for APP, less than the clinical breakpoints. Marbofloxacin (single dose of 8 mg/kg) and enrofloxacin (1 or 2 doses of 7.5 mg/kg) were clinically safe and effective in the treatment of clinical respiratory disease associated predominantly with APP in four European commercial, fattening pig herds.

Pharmacokinetic comparison of sustained- and immediate-release oral formulations of cilostazol in healthy Korean subjects: a randomized, open-label, 3-part, sequential, 2-period, crossover, single-dose, food-effect, and multiple-dose study.

PubMed

Lee, Donghwan; Lim, Lay Ahyoung; Jang, Seong Bok; Lee, Yoon Jung; Chung, Jae Yong; Choi, Jong Rak; Kim, Kiyoon; Park, Jin Woo; Yoon, Hosang; Lee, Jaeyong; Park, Min Soo; Park, Kyungsoo

2011-12-01

A sustained-release (SR) formulation of cilostazol was recently developed in Korea and was expected to yield a lower C(max) and a similar AUC to the immediate-release (IR) formulation. The goal of the present study was to compare the pharmacokinetic profiles of a newly developed SR formulation and an IR formulation of cilostazol after single- and multiple-dose administration and to evaluate the influence of food in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. This was a randomized, 3-part, sequential, open-label, 2-period crossover study. Each part consisted of different subjects between the ages of 19 and 55 years. In part 1, each subject received a single dose of SR (200 mg × 1 tablet, once daily) and IR (100 mg × 2 tablets, BID) formulations of cilostazol orally 7 days apart in a fasted state. In part 2, each subject received a single dose of the SR (200 mg × 1 tablet, once daily) formulation of cilostazol 7 days apart in a fasted and a fed state. In part 3, each subject received multiple doses of the 2 formulations for 8 consecutive days 21 days apart. Blood samples were taken for 72 hours after the dose. Cilostazol pharmacokinetics were determined for both the parent drug and its metabolites (OPC-13015 and OPC-13213). Adverse events were evaluated through interviews and physical examinations. Among the 92 enrolled subjects (66 men, 26 women; part 1, n = 26; part 2, n = 26; part 3, n = 40), 87 completed the study. In part 1, all the primary pharmacokinetic parameters satisfied the criterion for assumed bioequivalence both in cilostazol and its metabolites, yielding 90% CI ratios of 0.9624 to 1.2323, 0.8873 to 1.1208, and 0.8919 to 1.1283 for C(max) and 0.8370 to 1.0134, 0.8204 to 0.9807, and 0.8134 to 0.9699 for AUC(0-last) of cilostazol, OPC-13015, and OPC-13213, respectively. In part 2, food intake increased C(max) and AUC significantly (P < 0.0001), yielding geometric mean ratios of 3.2879, 2.9894, and 3.0592 for C(max) and 1.7001, 1.7689, and 1.6976 for AUC(0-last) of cilostazol, OPC-13015, and OPC-13213. In part 3, only the C(ssmax) of clilostazol in the reference formulation did not satisfy the criterion for assumed bioequivalence, yielding 90% CI ratios of 1.2693 to 1.4238 and 1.2038 to 1.3441, respectively. When each dose was normalized, the C(max) for the SR formulation was significantly lower (P < 0.005 for cilostazol). Headache was the most frequently noted adverse effect (part 1, a total of 14 subjects with the IR formulation and 14 with the SR formulation; part 2, a total of 10 without food and 23 with a high-fat meal; part 3, a total of 10 with the IR formulation and 24 with the SR formulation), followed by nausea (part 1, none; part 2, only 1 without food and 3 with a high-fat meal; part 3, a total of 3 with the IR formulation and 3 with the SR formulation), and then dizziness (parts 1 and 2, none; part 3, a total of 4 with the IR formulation and 5 with the SR formulation). All other AEs, including fever, cough, vomiting, palpitation, diarrhea, and epigastric pain, occurred in <3 subjects. These findings suggest that in this select group of healthy Korean volunteers, the SR formulation of cilostazol was not significantly different in AUC compared with that of the IR formulation, although it did display a significantly lower C(max) per dose in both the single- and multiple-dose groups. Food significantly increased the bioavailability of the SR formulation. The cilostazol SR and IR formulations were well tolerated in all parts of the study, with no serious adverse events reported. ClinicalTrials.gov identifier: NCT01455558. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

Bioavailability, safety, and pharmacodynamics of delayed-release dexlansoprazole administered as two 30 mg orally disintegrating tablets or one 60 mg capsule.

PubMed

Kukulka, Michael; Nudurupati, Sai; Perez, Maria Claudia

2016-11-01

Dual delayed-release dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics, pharmacodynamics, and safety profile of two dexlansoprazole 30 mg ODTs were compared with one dexlansoprazole 60 mg capsule in this randomized, phase I, open-label, single-center, multiple-dose, two-period crossover study. Participants were randomized in one of two treatment sequences, each comprised two 5-day treatment periods during which two dexlansoprazole 30 mg ODTs or one 60 mg capsule was administered once daily. Pharmacokinetic parameters and the mean intragastric pH profile for the 24-hour period after dosing on days 1 and 5 were described. Adverse events were monitored during study duration and followed up with a phone call 5-10 days after the last dose of study drug. On day 1, peak observed plasma concentration ( C max ) values were similar between two 30 mg ODTs (1047 ng/ml) and one 60 mg capsule (1164 ng/ml). Systemic exposure, measured by the area under the plasma concentration-time curve (AUC), was approximately 25% lower after ODT administration. On day 5, mean pH after daily doses of two 30 mg ODT or one 60 mg capsule was 4.33 and 4.36, respectively; both regimens maintained intragastric pH above 4.0 for 60% of the 24-hour period. Headache was the most commonly reported adverse event (observed in 19.2% of participants); no adverse events leading to study withdrawal occurred. While systemic exposure (AUC) was 25% lower with ODT, peak concentrations ( C max ) after administration of two dexlansoprazole 30 mg ODTs and one 60 mg capsule were similar. The 24-hour intragastric pH control after administration of two dexlansoprazole 30 mg ODTs was equivalent to one dexlansoprazole 60 mg capsule. Both ODT and capsule were well tolerated.

A Single Zidovudine (AZT) Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver

PubMed Central

Butanda-Ochoa, Armando; Hernández-Espinosa, Diego Rolando; Olguín-Martínez, Marisela; Sánchez-Sevilla, Lourdes; Rodríguez, Mario R.; Chávez-Rentería, Benito; Aranda-Fraustro, Alberto

2017-01-01

The 3′-azido-3′-deoxythymidine or Zidovudine (AZT) was the first antiretroviral drug used in the treatment of HIV patients, which has good effectiveness but also hepatotoxic side effects that include cell cycle arrest and oxidative/nitrative mitochondrial damage. Whether such an oxidative damage may affect the proliferative-regenerative capacity of liver remains to be clearly specified at doses commonly used in the clinical practice. In this study, we described the oxidative-proliferative effect of AZT administered at a common clinical dose in rat liver submitted to 70% partial hepatectomy (PH). The results indicate that AZT significantly decreased DNA synthesis and the number of mitosis in liver subjected to PH in a synchronized way with the promotion of organelle-selective lipid peroxidation events (especially those observed in plasma membrane and cytosolic fractions) and with liver enzyme release to the bloodstream. Then at the dose used in clinical practice AZT decreased liver regeneration but stimulates oxidative events involved during the proliferation process in a way that each membrane system inside the cell preserves its integrity in order to maintain the cell proliferative process. Here, the induction of large amounts of free ammonia in the systemic circulation could become a factor capable of mediating the deleterious effects of AZT on PH-induced rat liver regeneration. PMID:28479956

A single-blind study of the efficacy and safety of intravenous granisetron compared with alizapride plus dexamethasone in the prophylaxis and control of emesis in patients receiving 5-day cytostatic therapy. The Granisetron Study Group.

PubMed

Bremer, K

1992-01-01

200 cancer patients who were due to receive fractionated chemotherapy (cisplatin greater than or equal to 15, ifosfamide greater than or equal to 1.2 or etoposide greater than or equal to 120, all mg/m2 per day) for 5 days, entered a multicentre study. Patients were randomised single-blind to receive either prophylactic intravenous granisetron (40 micrograms/kg) or alizapride (4 mg/kg followed by 4 mg/kg at 4 and 8 h post-treatment) plus dexamethasone 8 mg. Granistron was superior to the combination in preventing nausea and vomiting (54% vs. 43% complete responders). The differences were in the cisplatin-treated group. The time to first episode of moderate to severe nausea was significantly longer in the granisetron group (P = 0.03). Dosing with granisetron was more simple, with over 85% of patients requiring only a single prophylactic dose. Fewer patients receiving granisetron experienced adverse events (48% vs. 62%, P = 0.047). The frequency of constipation was, as expected, significantly higher in the granisetron group. Extrapyramidal effects, which were not noted by any granisetron patient, occurred in 5.3% of comparator patients.

Safety and Immunogenicity of Cell Culture-Derived A/H3N2 Variant Influenza Vaccines: A Phase I Randomized, Observer-Blind, Dose-Ranging Study.

PubMed

Johnson, Casey; Hohenboken, Matthew; Poling, Terry; Jaehnig, Peter; Kanesa-Thasan, Niranjan

2015-07-01

A/H3N2 variant (H3N2v) influenza may sustain human-to-human transmission, and an available candidate vaccine would be important. In this phase I, randomized, observer-blind, dose-ranging study, 627 healthy subjects ≥ 3 years of age were randomized to receive 2 vaccinations with H3N2c cell-culture-derived vaccine doses containing 3.75 µg, 7.5 µg, or 15 µg hemagglutinin antigen of H3N2v with or without MF59 (registered trademark of Novartis AG) adjuvant (an oil-in-water emulsion). This paper reports Day 43 planned interim data. Single MF59-adjuvanted H3N2c doses elicited immune responses in almost all subjects regardless of antigen and adjuvant dose; the Center for Biologics Evaluation Research and Review (CBER) licensure criteria were met for all groups. Subjects with prevaccination hemagglutination inhibition titers <10 and children 3-<9 years achieve CBER criteria only after receiving 2 doses of nonadjuvanted H3N2c vaccine. Highest antibody titers were observed in the 7.5 µg + 0.25 mL MF59 groups in all age cohorts. MF59-adjuvanted H3N2c vaccines showed the highest rates of solicited local and systemic events, predominately mild or moderate. A single dose of H3N2c vaccine may be immunogenic and supports further development of MF59-adjuvanted H3N2c vaccines, especially for pediatric populations. ClinicalTrials.gov identifier NCT01855945 (http://clinicaltrials.gov/ct2/show/NCT01855945). © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study

PubMed Central

2014-01-01

Background The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Methods Adults (n = 198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n = 101) or matching placebo lozenges (n = 97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Results Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P <0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P <0.01). There were no serious adverse events. Conclusions Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. Trial registration This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010. PMID:24988909

Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study

PubMed Central

2014-01-01

Introduction Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc. Methods Subjects (≥18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes. Results Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days. Conclusion The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546. Trial Registration ClinicalTrials.gov NCT00930683 PMID:24559157

Dose Reconstruction of Di(2-ethylhexyl) Phthalate Using a Simple Pharmacokinetic Model

PubMed Central

Calafat, Antonia M.

2012-01-01

Background: Di(2-ethylhexyl) phthalate (DEHP), used primarily as a plasticizer for polyvinyl chloride, is found in a variety of products. Previous studies have quantified human exposure by back calculating intakes based on DEHP metabolite concentrations in urine and by determining concentrations of DEHP in exposure media (e.g., air, food, dust). Objectives: To better understand the timing and extent of DEHP exposure, we used a simple pharmacokinetic model to “reconstruct” the DEHP dose responsible for the presence of DEHP metabolites in urine. Methods: We analyzed urine samples from eight adults for four DEHP metabolites [mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(2-ethyl-5-carboxypentyl) phthalate]. Participants provided full volumes of all voids over 1 week and recorded the time of each void and information on diet, driving, and outdoor activities. Using a model previously calibrated on a single person self-dosed with DEHP in conjunction with the eight participants’ data, we used a simple trial-and-error method to determine times and doses of DEHP that resulted in a best fit of predicted and observed urinary concentrations of the metabolites. Results: The average daily mean and median reconstructed DEHP doses were 10.9 and 5.0 µg/kg-day, respectively. The highest single modeled dose of 60 µg/kg occurred when one study participant reported consuming coffee and a bagel with egg and sausage that was purchased at a gas station. About two-thirds of all modeled intake events occurred near the time of reported food or beverage consumption. Twenty percent of the modeled DEHP exposure occurred between 2200 hours and 0500 hours. Conclusions: Dose reconstruction using pharmacokinetic models—in conjunction with biomonitoring data, diary information, and other related data—can provide a powerful means to define timing, magnitude, and possible sources of exposure to a given contaminant. PMID:23010619

A phase III, randomized, open-label study to assess the tolerability and immunogenicity of an H5N1 influenza vaccine administered to healthy adults with a 1-, 2-, 3-, or 6-week interval between first and second doses.

PubMed

Beran, Jiri; Abdel-Messih, Ibrahim A; Raupachova, Jolana; Hobzova, Lenka; Fragapane, Elena

2010-12-01

Preparedness for an H5N1 influenza pre-pandemic requires effective and well-tolerated emergency vaccination strategies that provide both pandemic strain-specific and heterologous protection. This was a pivotal study for the regulatory approval process for a candidate MF59-adjuvanted H5N1 vaccine. Its goals were to identify the preferred primary 2-dose vaccination schedule in adults and to assess whether the vaccine met European Committee for Medicinal Products for Human Use (CHMP) licensure criteria. Healthy volunteers aged 18 to 60 years received 1 of 4 randomized schedules in which the 2 doses of vaccine were separated by a 1-, 2-, 3-, or 6-week interval. Three blood samples (~20 mL(-1)) were obtained from each subject: the first sample, immediately before administration of the first dose of vaccine; the second, immediately before administration of the second dose; and the third, 21 days after administration of the second dose. Hemagglutination inhibition (HI), microneutralization (MN), and single radial hemolysis (SRH) were assayed after each dose. Immunogenicity was assessed based on the CHMP licensure criteria for annual influenza vaccines (number of seroconversions or significant increase in HI titer >40%; mean geometric increase >2.5; and proportion of subjects achieving an HI titer ≥40 or SRH titer >25 mm(2) should be >70% [seroprotection]). Subjects recorded all adverse events occurring within 7 days of vaccine administration; information on any serious adverse events was collected throughout the study (duration, 202 days). All study participants (N = 240) were white, with a mean age of 33 years and a mean body mass index of 24.6 kg/m(2). Equal numbers of men and women were assigned to each vaccination schedule. The CHMP criterion for seroprotection was achieved when the 2 doses of vaccine were separated by 2 (76%), 3 (72%), and 6 (79%) weeks; similar results were obtained on MN and SRH analysis. On the SRH analysis, the candidate vaccine showed a heterologous immune response to the H5N1/turkey/Turkey/1/05 (NIBRG-23; clade 2) influenza antigen. The vaccine met 2 of the 3 European licensure criteria, with seroconversion rates of 69% and 65% in the groups assigned to a 2- and 3-week interval between doses, respectively, and geometric mean ratios of 4.3 and 4.5. There were no serious adverse events related to vaccination. The most common adverse events reported within 7 days of the first and second doses of vaccine were mild to moderate injection-site pain (63%-73% and 34%-48%, respectively) and fatigue (25%-30% and 13%-24%). Two 7.5-μg doses of MF59-adjuvanted H5N1 influenza vaccine given 2, 3, or 6 weeks apart afforded H5N1-specific immunity and met the CHMP licensure criterion for seroprotection in these healthy volunteers. Clinically relevant levels of heterologous immunity were observed when the 2 doses of vaccine were administered either 2 or 3 weeks apart; however, the licensure criterion for seroprotection was not met in this case. Copyright © 2010 Elsevier HS Journals, Inc. Published by EM Inc USA.. All rights reserved.

Tumor Induction in Mice After Localized Single- or Fractionated-Dose Irradiation: Differences in Tumor Histotype and Genetic Susceptibility Based on Dose Scheduling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Edmondson, Elijah F., E-mail: elijah.edmondson@colostate.edu; Hunter, Nancy R.; Weil, Michael M.

2015-07-15

Purpose: To investigate differences in tumor histotype, incidence, latency, and strain susceptibility in mice exposed to single-dose or clinically relevant, fractioned-dose γ-ray radiation. Methods and Materials: C3Hf/Kam and C57BL/6J mice were locally irradiated to the right hindlimb with either single large doses between 10 and 70 Gy or fractionated doses totaling 40 to 80 Gy delivered at 2-Gy/d fractions, 5 d/wk, for 4 to 8 weeks. The mice were closely evaluated for tumor development in the irradiated field for 800 days after irradiation, and all tumors were characterized histologically. Results: A total of 210 tumors were induced within the radiation field in 788 mice. Anmore » overall decrease in tumor incidence was observed after fractionated irradiation (16.4%) in comparison with single-dose irradiation (36.1%). Sarcomas were the predominant postirradiation tumor observed (n=201), with carcinomas occurring less frequently (n=9). The proportion of mice developing tumors increased significantly with total dose for both single-dose and fractionated schedules, and latencies were significantly decreased in mice exposed to larger total doses. C3Hf/Kam mice were more susceptible to tumor induction than C57BL/6J mice after single-dose irradiation; however, significant differences in tumor susceptibilities after fractionated radiation were not observed. For both strains of mice, osteosarcomas and hemangiosarcomas were significantly more common after fractionated irradiation, whereas fibrosarcomas and malignant fibrous histiocytomas were significantly more common after single-dose irradiation. Conclusions: This study investigated the tumorigenic effect of acute large doses in comparison with fractionated radiation in which both the dose and delivery schedule were similar to those used in clinical radiation therapy. Differences in tumor histotype after single-dose or fractionated radiation exposures provide novel in vivo evidence for differences in tumor susceptibility among stromal cell populations.« less

Subcutaneous Implants of a Cholesterol-Triglyceride-Buprenorphine Suspension in Rats.

PubMed

Guarnieri, M; Brayton, C; Sarabia-Estrada, R; Tyler, B; McKnight, P; DeTolla, L

2017-01-01

A Target Animal Safety protocol was used to examine adverse events in male and female Fischer F344/NTac rats treated with increasing doses of a subcutaneous implant of a lipid suspension of buprenorphine. A single injection of 0.65 mg/kg afforded clinically significant blood levels of drug for 3 days. Chemistry, hematology, coagulation, and urinalysis values with 2- to 10-fold excess doses of the drug-lipid suspension were within normal limits. Histopathology findings were unremarkable. The skin and underlying tissue surrounding the drug injection were unremarkable. Approximately 25% of a cohort of rats given the excess doses of 1.3, 3.9, and 6.5 mg/kg displayed nausea-related behavior consisting of intermittent and limited excess grooming and self-gnawing. These results confirm the safety of cholesterol-triglyceride carrier systems for subcutaneous drug delivery of buprenorphine in laboratory animals and further demonstrate the utility of lipid-based carriers as scaffolds for subcutaneous, long-acting drug therapy.

Subcutaneous Implants of a Cholesterol-Triglyceride-Buprenorphine Suspension in Rats

PubMed Central

Brayton, C.; Sarabia-Estrada, R.; McKnight, P.; DeTolla, L.

2017-01-01

A Target Animal Safety protocol was used to examine adverse events in male and female Fischer F344/NTac rats treated with increasing doses of a subcutaneous implant of a lipid suspension of buprenorphine. A single injection of 0.65 mg/kg afforded clinically significant blood levels of drug for 3 days. Chemistry, hematology, coagulation, and urinalysis values with 2- to 10-fold excess doses of the drug-lipid suspension were within normal limits. Histopathology findings were unremarkable. The skin and underlying tissue surrounding the drug injection were unremarkable. Approximately 25% of a cohort of rats given the excess doses of 1.3, 3.9, and 6.5 mg/kg displayed nausea-related behavior consisting of intermittent and limited excess grooming and self-gnawing. These results confirm the safety of cholesterol-triglyceride carrier systems for subcutaneous drug delivery of buprenorphine in laboratory animals and further demonstrate the utility of lipid-based carriers as scaffolds for subcutaneous, long-acting drug therapy. PMID:28492060

A comparative study of calcium absorption following a single serving administration of calcium carbonate powder versus calcium citrate tablets in healthy premenopausal women

PubMed Central

Wang, Haiyuan; Bua, Peter; Capodice, Jillian

2014-01-01

Background Calcium is an essential mineral often taken as a daily, long-term nutritional supplement. Data suggests that once-daily dosing is important with regard to long-term compliance of both drugs and nutritional supplements. Objective This study was undertaken to compare the bioavailability of a single serving of two calcium supplements in healthy, premenopausal women. Design A two-period, crossover bioavailability study of a single serving of calcium citrate tablets (two tablets=500 mg calcium) versus a single serving of calcium carbonate powder (one packet of powder=1,000 mg calcium) was performed in healthy women aged between 25 and 45. All subjects were on a calcium-restricted diet 7 days prior to testing and fasted for 12 h before being evaluated at 0, 1, 2, and 4 h after oral administration of the test agents. Blood measurements for total and ionized calcium and parathyroid hormone were performed and adverse events were monitored. Results Twenty-three women were evaluable with a mean age of 33.2±8.71. Results showed that administration of a single serving of a calcium carbonate powder resulted in greater absorption in total and ionized calcium versus a single serving of calcium citrate tablets at 4 h (4.25±0.21 vs. 4.16±0.16, p=0.001). There were minimal side effects and no reported serious adverse events. Conclusions This study shows that a single serving of a calcium carbonate powder is more bioavailable than a single serving of calcium citrate tablets. This may be beneficial for long-term compliance. PMID:24772062

Cumulative exposure to traumatic events in older adults.

PubMed

Ogle, Christin M; Rubin, David C; Siegler, Ilene C

2014-01-01

The present study examined the impact of cumulative trauma exposure on current posttraumatic stress disorder (PTSD) symptom severity in a nonclinical sample of adults in their 60s. The predictive utility of cumulative trauma exposure was compared to other known predictors of PTSD, including trauma severity, personality traits, social support, and event centrality. Community-dwelling adults (n = 2515) from the crest of the Baby Boom generation completed the Traumatic Life Events Questionnaire, the PTSD Checklist, the NEO Personality Inventory, the Centrality of Event Scale, and rated their current social support. Cumulative trauma exposure predicted greater PTSD symptom severity in hierarchical regression analyses consistent with a dose-response model. Neuroticism and event centrality also emerged as robust predictors of PTSD symptom severity. In contrast, the severity of individuals' single most distressing life event, as measured by self-report ratings of the A1 PTSD diagnostic criterion, did not add explanatory variance to the model. Analyses concerning event categories revealed that cumulative exposure to childhood violence and adulthood physical assaults were most strongly associated with PTSD symptom severity in older adulthood. Moreover, cumulative self-oriented events accounted for a larger percentage of variance in symptom severity compared to events directed at others. Our findings suggest that the cumulative impact of exposure to traumatic events throughout the life course contributes significantly to posttraumatic stress in older adulthood above and beyond other known predictors of PTSD.

Less than 3 doses of the HPV vaccine – Review of efficacy against virological and disease end points

PubMed Central

Basu, Partha; Bhatla, Neerja; Ngoma, Twalib; Sankaranarayanan, Rengaswamy

2016-01-01

ABSTRACT World Health Organization (WHO) recommended 2 doses of the Human Papillomavirus (HPV) vaccine for girls below 15 y on the basis of the immune-bridging studies demonstrating non-inferior immune response of 2 doses in the adolescent girls compared to 3 doses in the young adult women in whom the efficacy against disease is established. The biological nature of the antigens (virus-like particles) constituting the HPV vaccine is responsible for the vigorous antibody response that may make the third dose redundant. The protection offered by 2 doses has been demonstrated in non-randomized clinical trials to be comparable to that offered by 3 doses against incident and persistent infections of vaccine targeted HPV types. However, results emerging from the ecological and nested case-control studies embedded in the population based screening programs of different countries indicate reduced efficacy of 2 doses against virological and disease end points. Some recent studies observed the protective effect of single dose of the vaccine against incident and persistent infections of the vaccine targeted HPV types to be similar to 3 doses in spite of immunological inferiority. The sample size, duration of follow-ups and number of events were limited in these studies. Longer follow ups of the less than 3 doses cohorts in the ongoing studies as well as appropriately designed and ethically justifiable randomized studies are needed to establish the protection offered by the alternative schedules at least beyond 10 y of vaccination. PMID:26933961

Heterogeneous distribution of exocytotic microdomains in adrenal chromaffin cells resolved by high-density diamond ultra-microelectrode arrays.

PubMed

Gosso, Sara; Turturici, Marco; Franchino, Claudio; Colombo, Elisabetta; Pasquarelli, Alberto; Carbone, Emilio; Carabelli, Valentina

2014-08-01

Here we describe the ability of a high-density diamond microelectrode array targeted to resolve multi-site detection of fast exocytotic events from single cells. The array consists of nine boron-doped nanocrystalline diamond ultra-microelectrodes (9-Ch NCD-UMEA) radially distributed within a circular area of the dimensions of a single cell. The device can be operated in voltammetric or chronoamperometric configuration. Sensitivity to catecholamines, tested by dose-response calibrations, set the lowest detectable concentration of adrenaline to ∼5 μm. Catecholamine release from bovine or mouse chromaffin cells could be triggered by electrical stimulation or external KCl-enriched solutions. Spikes detected from the cell apex using carbon fibre microelectrodes showed an excellent correspondence with events measured at the bottom of the cell by the 9-Ch NCD-UMEA, confirming the ability of the array to resolve single quantal secretory events. Subcellular localization of exocytosis was provided by assigning each quantal event to one of the nine channels based on its location. The resulting mapping highlights the heterogeneous distribution of secretory activity in cell microdomains of 12-27 μm2. In bovine chromaffin cells, secretion was highly heterogeneous with zones of high and medium activity in 54% of the cell surface and zones of low or no activity in the remainder. The 'non-active' ('silent') zones covered 24% of the total and persisted for 6-8 min, indicating stable location. The 9-Ch NCD-UMEA therefore appears suitable for investigating the microdomain organization of neurosecretion with high spatial resolution. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Randomized, open-label, single-dose, crossover, relative bioavailability study in healthy adults, comparing the pharmacokinetics of rabeprazole granules administered using soft food or infant formula as dosing vehicle versus suspension.

PubMed

Thyssen, An; Solanki, Bhavna; Treem, William

2012-07-01

A sprinkle capsule formulation containing enteric-coated, delayed-release rabeprazole granules is being developed for the treatment of children with gastrointestinal reflux disease. The granules are designed to be mixed with vehicles that facilitate delivery to children, who may be unable to swallow solid formulations. The primary objective of this study-conducted on the sponsor's initiative-was to compare the bioavailability of rabeprazole granules when mixed with various dosing vehicles (small amount of soft food or infant formula) with that of a rabeprazole suspension with inactive vehicle granules (reference), to determine which dosing vehicle can be used to deliver rabeprazole in children. Tolerability was also assessed. This single-center, single-dose, randomized, open-label, 5-period crossover study was conducted in 35 healthy adult subjects. In a randomized sequence, fasting subjects received a single dose of 10-mg rabeprazole granules per treatment period, mixed with small amounts of 1 of 5 dosing vehicles (a strawberry-flavored suspension of rabeprazole granules with inactive vehicle granules reconstituted with water, yogurt [1 tablespoon], applesauce [1 tablespoon], or infant formula [5 mL], or a suspension of rabeprazole granules with inactive vehicle tablet reconstituted with water). Full plasma pharmacokinetic (PK) profiles of rabeprazole and its thioether metabolite were collected; concentrations were estimated via LC-MS/MS. PK properties were estimated using noncompartmental methods; 90% CIs around least squares mean test-to-reference ratios were calculated for C(max) and AUC values. All treatment-emergent adverse events (TEAEs) were recorded and assessed for severity (mild, moderate, or severe) and relationship to study drug. A total of 35 subjects were enrolled (mean age, 38 years; 54.3% female; 100% white; mean weight, 71.4 kg). Thirty-four subjects completed the study. Rabeprazole and rabeprazole thioether plasma PK properties were comparable between all of the dosing vehicles tested. Median T(max) was 2.5 to 3.0 hours, and mean elimination half-life was 1.27 to 1.43 hours. The 90%CIs for the least squares mean ratios for rabeprazole and rabeprazole thioether exposure were within the 80% to 125% bioequivalence limits for all relevant comparisons. All TEAEs were of mild or moderate intensity, with headache being the most commonly reported; 21 subjects (60%) experienced TEAEs during the study. No deaths or serious AEs were reported during the study; 1 subject experienced a TEAE (urinary tract infection) that led to the discontinuation of treatment. In these healthy adult subjects, the bioavailability of rabeprazole granules was comparable between all of the dosing vehicles tested, and rabeprazole was well tolerated. Soft food suitable for young children or infant formula may be appropriate for use as dosing vehicles for rabeprazole granules. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Efficacy of oral palonosetron compared to intravenous palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: a phase 3 trial.

PubMed

Boccia, Ralph; Grunberg, Steven; Franco-Gonzales, Edwin; Rubenstein, Edward; Voisin, Daniel

2013-05-01

Palonosetron (Aloxi(®), Onicit(®)) is a pharmacologically unique 5-HT3 receptor antagonist (RA) approved as a single IV injection for the prevention of nausea and vomiting induced by chemotherapy (CINV) of either moderate or highly emetogenic potential (MEC and HEC, respectively). An oral palonosetron formulation has been developed and compared to the IV formulation. In this multinational, multicenter, double-blind, double-dummy, dose-ranging trial, 651 patients were randomly assigned to receive one of the following as a single dose prior to moderately emetogenic chemotherapy: oral palonosetron 0.25, 0.50, and 0.75 mg or IV palonosetron 0.25 mg. Patients were also randomized (1:1) to receive dexamethasone 8 mg IV or matched placebo on day 1. The primary endpoint was complete response (CR; no emesis, no rescue therapy) during the acute phase (0-24 h). Acute CR rates were 73.5, 76.3, 74.1, and 70.4 % for all patients receiving the palonosetron 0.25, 0.50, and 0.75 mg oral doses, and for IV palonosetron 0.25 mg, respectively; delayed CR (24-120 h) rates were 59.4, 62.5, 60.1, and 65.4 %, and overall CR (0-120 h) rates were 53.5, 58.8, 53.2, and 59.3 %, respectively. The addition of dexamethasone improved emetic control (acute CR rate) by at least 15 % for all groups except oral palonosetron 0.25 mg, where the acute CR improvement was approximately 7 %. Adverse events were similar in nature, incidence, and intensity for all oral and IV palonosetron groups, and were the expected adverse events for 5-HT3 RAs (primarily headache and constipation). Oral palonosetron has a similar efficacy and safety profile as IV palonosetron 0.25 mg and may be the preferred formulation in certain clinical situations. Among the tested oral treatments, a palonosetron 0.50-mg oral dose has been favored for the prevention of CINV in patients receiving moderately emetogenic chemotherapy due to a numerical gain in efficacy without a side effect disadvantage.

Multiple-dose pharmacokinetics and safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers.

PubMed

Martin, David E; Blum, Robert; Doto, Judy; Galbraith, Hal; Ballow, Charles

2007-01-01

Bevirimat [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] is a novel inhibitor of HIV-1 maturation. This study was performed to investigate the pharmacokinetics and safety of bevirimat during repeated dosing in healthy volunteers. The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 bevirimat, 2 placebo). The doses of bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Plasma bevirimat levels were measured from blood samples collected pre-dose on days 1-10 and then at approximately 48-hour intervals until 21 days after dosing started. On days 1 and 10, further blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours after dosing. Urine samples were collected in the morning on days 1, 5 and 11 and at the end of the study for the measurement of cortisol and 6beta-hydroxycortisol. The pharmacokinetic parameters of bevirimat were estimated using non-compartmental methods. Dose proportionality of exposure to bevirimat, assessed by the maximum plasma concentration and the area under the plasma concentration-time curve. The mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour. Bevirimat showed approximately 4-fold greater accumulation on day 10 compared with day 1, and the degree of accumulation was similar with all doses. Maximum plasma concentrations ranged from 8 to 58 microg/mL at day 10. Testing for dose-proportionality showed that exposure to bevirimat was proportional to the dose, both after a single dose and after repeat dosing for 10 days. Measurement of the urinary 6beta-hydroxycortisol/cortisol ratio indicated that bevirimat did not affect cytochrome P450 3A activity. Repeated dosing with bevirimat for 10 days was well tolerated. There was no increase in adverse events observed for bevirimat compared with placebo, and no serious adverse events occurred. No clinically relevant changes in vital signs, physical examination or clinical laboratory evaluations were observed. Bevirimat shows dose-proportional pharmacokinetics during repeated dosing for 10 days. Its accumulation is approximately 4-fold greater on day 10 compared with day 1. Repeated dosing with bevirimat is well tolerated. These properties make bevirimat potentially suitable for inclusion in highly active antiretroviral therapy regimens.

Single-dose extended-release azithromycin versus a 10-day regimen of amoxicillin/clavulanate for the treatment of children with acute otitis media.

PubMed

Arguedas, Adriano; Soley, Carolina; Kamicker, Barbara J; Jorgensen, Daniel M

2011-04-01

A randomized, double-blind, double-dummy, multicenter international study was conducted to assess the clinical and bacteriologic response, safety, and compliance of a single 60-mg/kg dose of azithromycin extended-release (ER) versus a 10-day regimen of amoxicillin/clavulanate 90/6.4 mg/kg per day in children with acute otitis media at high risk of persistent or recurrent middle ear infection. Children aged 3 to 48 months were enrolled and stratified into two age groups (≤ 24 months and >24 months). Pretreatment tympanocentesis was performed at all sites and was repeated during treatment at selected sites. The primary endpoint, clinical response at the test-of-cure visit in the bacteriologic eligible population, was achieved in 80.5% of children in the azithromycin ER group and 84.5% of children in the amoxicillin/clavulanate group (difference-3.9%; 95% confidence interval-10.4, 2.6). Bacteriologic eradication was 82.6% in the azithromycin ER group and 92% in the amoxicillin/clavulanate group (p=0.050). Children who received amoxicillin/clavulanate had significantly higher rates of dermatitis and diarrhea, a greater burden of adverse events, and a lower rate of compliance to study drug compared to those who received azithromycin ER. A single 60-mg/kg dose of azithromycin ER provides near equivalent effectiveness to a 10-day regimen of amoxicillin/clavulanate 90/6.4 mg/kg per day in the treatment of children with acute otitis media. Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Nonvolatile Memory Technology for Space Applications

NASA Technical Reports Server (NTRS)

Oldham, Timothy R.; Irom, Farokh; Friendlich, Mark; Nguyen, Duc; Kim, Hak; Berg, Melanie; LaBel, Kenneth A.

2010-01-01

This slide presentation reviews several forms of nonvolatile memory for use in space applications. The intent is to: (1) Determine inherent radiation tolerance and sensitivities, (2) Identify challenges for future radiation hardening efforts, (3) Investigate new failure modes and effects, and technology modeling programs. Testing includes total dose, single event (proton, laser, heavy ion), and proton damage (where appropriate). Test vehicles are expected to be a variety of non-volatile memory devices as available including Flash (NAND and NOR), Charge Trap, Nanocrystal Flash, Magnetic Memory (MRAM), Phase Change--Chalcogenide, (CRAM), Ferroelectric (FRAM), CNT, and Resistive RAM.

Statistical Modeling for Radiation Hardness Assurance

NASA Technical Reports Server (NTRS)

Ladbury, Raymond L.

2014-01-01

We cover the models and statistics associated with single event effects (and total ionizing dose), why we need them, and how to use them: What models are used, what errors exist in real test data, and what the model allows us to say about the DUT will be discussed. In addition, how to use other sources of data such as historical, heritage, and similar part and how to apply experience, physics, and expert opinion to the analysis will be covered. Also included will be concepts of Bayesian statistics, data fitting, and bounding rates.

Total Ionizing Dose Influence on the Single Event Effect Sensitivity in Samsung 8Gb NAND Flash Memories

NASA Astrophysics Data System (ADS)

Edmonds, Larry D.; Irom, Farokh; Allen, Gregory R.

2017-08-01

A recent model provides risk estimates for the deprogramming of initially programmed floating gates via prompt charge loss produced by an ionizing radiation environment. The environment can be a mixture of electrons, protons, and heavy ions. The model requires several input parameters. This paper extends the model to include TID effects in the control circuitry by including one additional parameter. Parameters intended to produce conservative risk estimates for the Samsung 8 Gb SLC NAND flash memory are given, subject to some qualifications.

Radiation dose to critical body organs for October 1989 proton event

NASA Technical Reports Server (NTRS)

Simonsen, Lisa C.; Atwell, William; Nealy, John E.; Cucinotta, Francis A.

1992-01-01

The Geostationary Operational Environmental Satellite (GOES-7) provides high-quality environmental data about the temporal development and energy characteristics of the protons emitted during a solar particle event. The GOES-7 time history of the hourly averaged integral proton flux for various particle kinetic energies are analyzed for the solar proton event occurring October 19-29, 1989. This event is similar to the August 1972 event that has been widely studied to estimate free-space and planetary radiation-protection requirements. By analyzing the time-history data, the dose rates, which can vary over many orders of magnitude in the early phases of the flare, can be estimated as well as the cumulative dose as a function of time. When basic transport results are coupled with detailed body organ thickness distributions calculated with the Computerized Anatomical Man and Computerized Anatomical Female models, the dose rates and cumulative doses to specific organs can be predicted. With these results, the risks of cancer incidence and mortality are estimated for astronauts in free space protected by various water shield thicknesses.

Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects

PubMed Central

Abbas, Richat; Hug, Bruce A; Leister, Cathie; Burns, Jaime; Sonnichsen, Daryl

2011-01-01

AIM The primary objective was to evaluate the pharmacokinetics of a single dose of neratinib, a potent, low-molecular-weight, orally administered, irreversible pan-ErbB (ErbB-1, -2, -4) receptor tyrosine kinase inhibitor, during co-administration with ketoconazole, a potent CYP3A4 inhibitor. METHODS This was an open-label, randomized, two-period, crossover study. Fasting healthy adults received a single oral dose of neratinib 240 mg alone and with multiple oral doses of ketoconazole 400 mg. Blood samples were collected up to 72 h after each neratinib dose. Plasma concentration data were analyzed using a noncompartmental method. The least square geometric mean ratios [90% confidence interval (CI)] of Cmax(neratinib+ketoconazole) : Cmax(neratinib alone), and AUC(neratinib+ketoconazole) : AUC(neratinib alone) were assessed. RESULTS Twenty-four subjects were enrolled. Compared with neratinib administered alone, co-administration of ketoconazole increased neratinib Cmax by 3.2-fold (90% CI: 2.4, 4.3) and AUC by 4.8-fold (3.6, 6.5). Median tmax was 6.0 h with both regimens. Ketoconazole decreased mean apparent oral clearance of neratinib from 346 l h−1 to 87.1 l h−1 and increased mean elimination half-life from 11.7 h to 18.0 h. The incidence of adverse events was comparable between the two regimens (50% neratinib alone, 65% co-administration with ketoconazole). CONCLUSION Co-administration of neratinib with ketoconazole, a potent CYP3A inhibitor, increased neratinib Cmax by 3.2-fold and AUC by 4.8-fold compared with administration of neratinib alone. These results indicate that neratinib is a substrate of CYP3A and is susceptible to interaction with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds. PMID:21395644

Pharmacokinetic equivalence of a levothyroxine sodium soft capsule manufactured using the new food and drug administration potency guidelines in healthy volunteers under fasting conditions.

PubMed

Colucci, Philippe; D'Angelo, Pina; Mautone, Giuseppe; Scarsi, Claudia; Ducharme, Murray P

2011-06-01

To assess the pharmacokinetic equivalence of a new soft capsule formulation of levothyroxine versus a marketed reference product and to assess the soft capsule formulated with stricter potency guidelines versus the capsule before the implementation of the new potency rule. Two single-dose randomized two-way crossover pharmacokinetic equivalence studies and one dosage form proportionality single-dose study comparing low, medium, and high strengths of the new formulation. All three studies were performed in a clinical setting. Participants were healthy male and female adult subjects with normal levothyroxine levels. A total of 90 subjects participated in the three studies. Pharmacokinetic parameters were calculated on baseline- adjusted concentrations. The first pharmacokinetic equivalence study compared the levothyroxine sodium soft capsule formulation (Tirosint) with the reference Synthroid tablets and the two products were considered bioequivalent. The dosage form proportionality study compared the 50-, 100-, and 150-μg test capsules strengths dosed at the same level (600 μg) and all three strengths were considered equivalent when given at the same dosage. The last study compared the test capsule used in the first two studies with a new capsule formulation following the new potency guideline (±5%) set forward by the Food and Drug Administration and the two capsules were considered bioequivalent. Doses were well tolerated by subjects in all three studies with no serious adverse events reported. The levothyroxine soft capsule formulated with the stricter new potency guideline set forward by the Food and Drug Administration met equivalence criteria in terms of rate and extent of exposure under fasting conditions to the reference tablet formulation. Clinical doses of the capsule formulation can be given using any combination of the commercialized strengths.

An in-beam PET system for monitoring ion-beam therapy: test on phantoms using clinical 62 MeV protons

NASA Astrophysics Data System (ADS)

Camarlinghi, N.; Sportelli, G.; Battistoni, G.; Belcari, N.; Cecchetti, M.; Cirrone, G. A. P.; Cuttone, G.; Ferretti, S.; Kraan, A.; Retico, A.; Romano, F.; Sala, P.; Straub, K.; Tramontana, A.; Del Guerra, A.; Rosso, V.

2014-04-01

Ion therapy allows the delivery of highly conformal dose taking advantage of the sharp depth-dose distribution at the Bragg-peak. However, patient positioning errors and anatomical uncertainties can cause dose distortions. To exploit the full potential of ion therapy, an accurate monitoring system of the ion range is needed. Among the proposed methods to monitor the ion range, Positron Emission Tomography (PET) has proven to be the most mature technique, allowing to reconstruct the β+ activity generated in the patient by the nuclear interaction of the ions, that can be acquired during or after the treatment. Taking advantages of the spatial correlation between positron emitters created along the ions path and the dose distribution, it is possible to reconstruct the ion range. Due to the high single rates generated during the beam extraction, the acquisition of the β+ activity is typically performed after the irradiation (cyclotron) or in between the synchrotron spills. Indeed the single photon rate can be one or more orders of magnitude higher than normal for cyclotron. Therefore, acquiring the activity during the beam irradiation requires a detector with a very short dead time. In this work, the DoPET detector, capable of sustaining the high event rate generated during the cyclotron irradiation, is presented. The capability of the system to acquire data during and after the irradiation will be demonstrated by showing the reconstructed activity for different PMMA irradiations performed using clinical dose rates and the 62 MeV proton beam at the CATANA-LNS-INFN. The reconstructed activity widths will be compared with the results obtained by simulating the proton beam interaction with the FLUKA Monte Carlo. The presented data are in good agreement with the FLUKA Monte Carlo.

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial

PubMed Central

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-01-01

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD. PMID:27552585

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial.

PubMed

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-08-23

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

Bioequivalence of budesonide plus formoterol (BF) Spiromax® and BF Turbohaler® (with and without charcoal block) in healthy volunteers.

PubMed

Weisfeld, Lori; Shu, Youyi; Shah, Tushar P

2015-07-01

Budesonide formoterol (BF) Spiromax® is a breath-actuated dry-powder inhaler designed to deliver similar combinations of budesonide and formoterol as Symbicort® Turbohaler®. We performed two studies to demonstrate pharmacokinetic (PK) equivalence of BF Spiromax with BF Turbohaler. Two single-center, open-label, randomized, 5-period crossover studies were performed. The first study compared BF Spiromax 160/4.5 μg with BF Turbohaler 200/6 μg, while the second study compared BF Spiromax 320/9 μg with BF Turbohaler 400/12 μg. All treatments were administered with and without charcoal. PK parameters were calculated by measuring plasma drug concentrations from blood samples taken pre-dose and up to 24 hours post-dose. In each study, 90 healthy volunteers were randomized. Bioequivalence of BF Spiromax with BF Turbohaler was demonstrated for budesonide and formoterol (AUC0-t and Cmax (90% confidence intervals of the geometric mean between-device ratios for both parameters were within the predefined range of 0.80-1.25 in both studies)). Equivalence was observed without use of charcoal (overall absorption post-inhalation) and with charcoal (pulmonary absorption). There were no major differences between treatments in tmax for either budesonide or formoterol. All study treatments were well tolerated (one treatment-emergent adverse event (TEAE) in the medium-dose study and four TEAEs in the high-dose study). These studies indicate that BF Spiromax (±charcoal block) is bioequivalent to BF Turbohaler with respect to the PK parameters assessed. Single doses of BF Spiromax were well tolerated; the overall safety profile of BF Spiromax and BF Turbohaler was similar.

Immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine in infants: a comparative, observer-blind, randomised, controlled trial.

PubMed

Sáez-Llorens, Xavier; Clemens, Ralf; Leroux-Roels, Geert; Jimeno, José; Clemens, Sue Ann Costa; Weldon, William C; Oberste, M Steven; Molina, Natanael; Bandyopadhyay, Ananda S

2016-03-01

Following the proposed worldwide switch from trivalent oral poliovirus vaccine (tOPV) to bivalent types 1 and 3 OPV (bOPV) in 2016, inactivated poliovirus vaccine (IPV) will be the only source of protection against poliovirus type 2. With most countries opting for one dose of IPV in routine immunisation schedules during this transition because of cost and manufacturing constraints, optimisation of protection against all poliovirus types will be a priority of the global eradication programme. We assessed the immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine (mIPV2HD) in infants. This observer-blind, comparative, randomised controlled trial was done in a single centre in Panama. We enrolled healthy infants who had not received any previous vaccination against poliovirus. Infants were randomly assigned (1:1) by computer-generated randomisation sequence to receive a single dose of either mIPV2HD or standard trivalent IPV given concurrently with a third dose of bOPV at 14 weeks of age. At 18 weeks, all infants were challenged with one dose of monovalent type 2 OPV (mOPV2). Primary endpoints were seroconversion and median antibody titres to type 2 poliovirus 4 weeks after vaccination with mIPV2HD or IPV; and safety (as determined by the proportion and nature of serious adverse events and important medical events for 8 weeks after vaccination). The primary immunogenicity analyses included all participants for whom a post-vaccination blood sample was available. All randomised participants were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02111135. Between April 14 and May 9, 2014, 233 children were enrolled and randomly assigned to receive mIPV2HD (117 infants) or IPV (116 infants). 4 weeks after vaccination with mIPV2HD or IPV, seroconversion to poliovirus type 2 was recorded in 107 (93·0%, 95% CI 86·8-96·9) of 115 infants in the mIPV2HD group compared with 86 (74·8%, 65·8-82·4) of 115 infants in the IPV group (difference between groups 18·3%, 95% CI 5·0-31·1; p<0·0001), and median antibody titres against poliovirus type 2 were 181 (95% CI 72·0-362·0) in the mIPV2HD group and 36 (18·0-113·8) in the IPV group (difference between groups 98·8, 95% CI 60·7-136·9; p<0·0001). Serious adverse events were reported for six (5%) of 117 infants in the mIPV2HD group and seven (6%) of 116 infants in the IPV group during the 8-week period after vaccination; none were related to vaccination. No important medical events were reported. Our findings lend support to the use of mIPV2HD as an option for stockpiling for outbreak response or primary protection in selected areas at risk for emergence of poliovirus type 2 during the next phase of the polio eradication plan. Bill & Melinda Gates Foundation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery.

PubMed

Fujita, Ai; Ishibe, Natsuki; Yoshihara, Tatsuya; Ohashi, Jun; Makino, Hideichi; Ikeda, Mizuko; Setoguchi, Hidekazu

2014-06-01

Sugammadex rapidly reverses neuromuscular blockade (NMB) induced by rocuronium. NMB induced by rocuronium is prolonged in patients with liver dysfunction, because the drug is mainly excreted into the bile. However, the efficacy and safety of sugammadex in terms of reversing rocuronium-induced NMB in patients with liver dysfunction undergoing hepatic surgery have not been evaluated. This observational study investigated the efficacy and safety of sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Remifentanil/propofol anesthesia was administered to 31 patients: 15 patients in the control group, and 16 patients from a group with liver dysfunction. Rocuronium (0.6 mg/kg) was administered, followed by continuous infusion. The enrolled patients were then subdivided into two groups according to the dose of sugammadex. In the first group a single dose of sugammadex (2.0 mg/kg) was given at the reappearance of the second twitch (T2). In the second group a single dose of sugammadex (4.0 mg/kg) was given at the first twitch response if T2 did not reappear in 15 minutes after stopping rocuronium. The primary outcome was time from administration of sugammadex to recovery of a train-of-four ratio to 0.9. The dose of rocuronium required in the liver dysfunction group was lower than that in the control group (6.2 vs. 8.2 μg/kg/min, p = 0.002). The mean time from the administration of sugammadex to recovery of the train-of-four ratio to 0.9 was not significantly different between the liver dysfunction group and the control group (2.2 minutes vs. 2.0 minutes in the 2 mg/kg administration group, p = 0.44 and 1.9 minutes vs. 1.7 minutes in the 4 mg/kg administration group, p = 0.70, respectively). No evidence of recurarization was observed in any of the patients. Most of the adverse events were found to be mild and such events were not related to the use of sugammadex. None of the patients was eliminated from the study because of an adverse event. One patient died due to cholestatic liver cirrhosis because of repeated hepatic surgery. Sugammadex can rapidly reverse NMB after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Sugammadex was found to be safe and well tolerated. However, further studies of sugammadex under similar conditions should be conducted involving a large number of patients with liver dysfunction undergoing hepatic surgery. Copyright © 2014. Published by Elsevier B.V.

Pathogenic Events in a Nonhuman Primate Model of Oral Poliovirus Infection Leading to Paralytic Poliomyelitis

PubMed Central

Chen, Crystal Y.; Huang, Dan; Wang, Richard; Zhang, Meihong; Qian, Lixia; Zhu, Yanfen; Zhang, Alvin Zhuoran; Yang, Enzhuo; Qaqish, Arwa; Kouiavskaia, Diana; Nathanson, Neal; Macadam, Andrew J.; Andino, Raul; Kew, Olen; Xu, Junfa

2017-01-01

ABSTRACT Despite a great deal of prior research, the early pathogenic events in natural oral poliovirus infection remain poorly defined. To establish a model for study, we infected 39 macaques by feeding them single high doses of the virulent Mahoney strain of wild type 1 poliovirus. Doses ranging from 107 to 109 50% tissue culture infective doses (TCID50) consistently infected all the animals, and many monkeys receiving 108 or 109 TCID50 developed paralysis. There was no apparent difference in the susceptibilities of the three macaque species (rhesus, cynomolgus, and bonnet) used. Virus excretion in stool and nasopharynges was consistently observed, with occasional viremia, and virus was isolated from tonsils, gut mucosa, and draining lymph nodes. Viral replication proteins were detected in both epithelial and lymphoid cell populations expressing CD155 in the tonsil and intestine, as well as in spinal cord neurons. Necrosis was observed in these three cell types, and viral replication in the tonsil/gut was associated with histopathologic destruction and inflammation. The sustained response of neutralizing antibody correlated temporally with resolution of viremia and termination of virus shedding in oropharynges and feces. For the first time, this model demonstrates that early in the infectious process, poliovirus replication occurs in both epithelial cells (explaining virus shedding in the gastrointestinal tract) and lymphoid/monocytic cells in tonsils and Peyer's patches (explaining viremia), extending previous studies of poliovirus pathogenesis in humans. Because the model recapitulates human poliovirus infection and poliomyelitis, it can be used to study polio pathogenesis and to assess the efficacy of candidate antiviral drugs and new vaccines. IMPORTANCE Early pathogenic events of poliovirus infection remain largely undefined, and there is a lack of animal models mimicking natural oral human infection leading to paralytic poliomyelitis. All 39 macaques fed with single high doses ranging from 107 to 109 TCID50 Mahoney type 1 virus were infected, and many of the monkeys developed paralysis. Virus excretion in stool and nasopharynges was consistently observed, with occasional viremia; tonsil, mesentery lymph nodes, and intestinal mucosa served as major target sites of viral replication. For the first time, this model demonstrates that early in the infectious process, poliovirus replication occurs in both epithelial cells (explaining virus shedding in the gastrointestinal tract) and lymphoid/monocytic cells in tonsils and Peyer's patches (explaining viremia), thereby supplementing historical reconstructions of poliovirus pathogenesis. Because the model recapitulates human poliovirus infection and poliomyelitis, it can be used to study polio pathogenesis, candidate antiviral drugs, and the efficacy of new vaccines. PMID:28356537

Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial

PubMed Central

Meininger, Vincent; Pradat, Pierre-François; Corse, Andrea; Al-Sarraj, Safa; Rix Brooks, Benjamin; Caress, James B.; Cudkowicz, Merit; Kolb, Stephen J.; Lange, Dale; Leigh, P. Nigel; Meyer, Thomas; Milleri, Stefano; Morrison, Karen E.; Orrell, Richard W.; Peters, Gary; Rothstein, Jeffrey D.; Shefner, Jeremy; Lavrov, Arseniy; Williams, Nicola; Overend, Phil; Price, Jeffrey; Bates, Stewart; Bullman, Jonathan; Krull, David; Berges, Alienor; Abila, Bams; Meno-Tetang, Guy; Wurthner, Jens

2014-01-01

The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS. Trial Registration ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330 PMID:24841795

A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells

PubMed Central

Rosenthal, Mark; McArthur, Grant A.; Pattison, Scott T.; Pattison, Stacey L.; MacDiarmid, Jennifer; Brahmbhatt, Himanshu; Scott, Andrew M.

2015-01-01

Background We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors. Methodology Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity. Principal Findings Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response. Conclusions/Significance This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients with advanced solid tumors with modest clinical efficacy observed. Further study in Phase II trials is planned. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000672257 PMID:26659127

First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours.

PubMed

Rodon, Jordi; Postel-Vinay, Sophie; Hollebecque, Antoine; Nuciforo, Paolo; Azaro, Analia; Cattan, Valérie; Marfai, Lucie; Sudey, Isabelle; Brendel, Karl; Delmas, Audrey; Malasse, Stéphanie; Soria, Jean-Charles

2017-08-01

S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD. Pharmacokinetic (PK) parameters were assessed and pharmacodynamic end-points were evaluated in pre- and post-treatment tumour biopsies. Preliminary anti-tumour activity was evaluated as per the Response Evaluation Criteria In Solid Tumours 1.1 criteria. A total of 103 patients were treated: 79 in the dose-escalation and 24 in the expansion. Doses from 15 to 900 mg were evaluated. Dose-limiting toxicities were reported in 9 patients and occurred at 30, 760 and 900 mg in the qd arm and at 180, 225 and 285 mg in the bid arm. The RD was defined at 600 mg qd. Adverse events (AEs) occurred with similar frequency in both regimens at an equivalent total daily dose. Overall, 83 patients (81.4%) had drug-related AEs, the majority (93%) of which were grade I-II (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and only 3% led to drug discontinuation. Intratumoural PK analysis at the RD suggested hitting of MET, AXL and FGFR. S49076 demonstrated a tolerable safety profile with limited single-agent activity. PK/pharmacodynamic readouts of S49076 are encouraging for further investigation of S49076 in combination therapies. ISRCTN00759419. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunogenicity is not improved by increased antigen dose or booster dosing of seasonal influenza vaccine in a randomized trial of HIV infected adults.

PubMed

Cooper, Curtis; Thorne, Anona; Klein, Marina; Conway, Brian; Boivin, Guy; Haase, David; Shafran, Stephen; Zubyk, Wendy; Singer, Joel; Halperin, Scott; Walmsley, Sharon

2011-03-25

The risk of poor vaccine immunogenicity and more severe influenza disease in HIV necessitate strategies to improve vaccine efficacy. A randomized, multi-centered, controlled, vaccine trial with three parallel groups was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies were used in HIV infected adults (18 to 60 years): two standard doses over 28 days, two double doses over 28 days and a single standard dose of influenza vaccine, administered prior to the 2008 influenza season. A trivalent killed split non-adjuvanted influenza vaccine (Fluviral™) was used. Serum hemagglutinin inhibition (HAI) activity for the three influenza strains in the vaccine was measured to assess immunogenicity. 297 of 298 participants received at least one injection. Baseline CD4 (median 470 cells/µL) and HIV RNA (76% of patients with viral load <50 copies/mL) were similar between groups. 89% were on HAART. The overall immunogenicity of influenza vaccine across time points and the three influenza strains assessed was poor (Range HAI ≥ 40 =  31-58%). Double dose plus double dose booster slightly increased the proportion achieving HAI titre doubling from baseline for A/Brisbane and B/Florida at weeks 4, 8 and 20 compared to standard vaccine dose. Increased immunogenicity with increased antigen dose and booster dosing was most apparent in participants with unsuppressed HIV RNA at baseline. None of 8 serious adverse events were thought to be immunization-related. Even with increased antigen dose and booster dosing, non-adjuvanted influenza vaccine immunogenicity is poor in HIV infected individuals. Alternative influenza vaccines are required in this hyporesponsive population. ClinicalTrials.gov NCT00764998.

Efficacy and Safety of Nitazoxanide, Albendazole, and Nitazoxanide-Albendazole against Trichuris trichiura Infection: A Randomized Controlled Trial

PubMed Central

Speich, Benjamin; Ame, Shaali M.; Ali, Said M.; Alles, Rainer; Hattendorf, Jan; Utzinger, Jürg; Albonico, Marco; Keiser, Jennifer

2012-01-01

Background The currently used anthelmintic drugs, in single oral application, have low efficacy against Trichuris trichiura infection, and hence novel anthelmintic drugs are needed. Nitazoxanide has been suggested as potential drug candidate. Methodology The efficacy and safety of a single oral dose of nitazoxanide (1,000 mg), or albendazole (400 mg), and a nitazoxanide-albendazole combination (1,000 mg–400 mg), with each drug administered separately on two consecutive days, were assessed in a double-blind, randomized, placebo-controlled trial in two schools on Pemba, Tanzania. Cure and egg reduction rates were calculated by per-protocol analysis and by available case analysis. Adverse events were assessed and graded before treatment and four times after treatment. Principal Findings Complete data for the per-protocol analysis were available from 533 T. trichiura-positive children. Cure rates against T. trichiura were low regardless of the treatment (nitazoxanide-albendazole, 16.0%; albendazole, 14.5%; and nitazoxanide, 6.6%). Egg reduction rates were 54.9% for the nitazoxanide-albendazole combination, 45.6% for single albendazole, and 13.4% for single nitazoxanide. Similar cure and egg reduction rates were calculated using the available case analysis. Children receiving nitazoxanide had significantly more adverse events compared to placebo recipients. Most of the adverse events were mild and had resolved within 24 hours posttreatment. Conclusions/Significance Nitazoxanide shows no effect on T. trichiura infection. The low efficacy of albendazole against T. trichiura in the current setting characterized by high anthelmintic drug pressure is confirmed. There is a pressing need to develop new anthelmintics against trichuriasis. Trial Registration Controlled-Trials.com ISRCTN08336605 PMID:22679525

Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide

PubMed Central

Abel, Samantha; Nichols, Donald J; Brearley, Christopher J; Eve, Malcolm D

2000-01-01

Aims The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide. Methods Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 μg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1–2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms. Results Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml−1 increase in plasma dofetilide concentration produced a 17–19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities. Conclusions These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H2-receptor antagonist class effect but is specific to cimetidine. If therapy with an H2-receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative. PMID:10606839

The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation

PubMed Central

Brooks, Antone L.; Hoel, David G.; Preston, R. Julian

2016-01-01

Abstract Purpose: This review evaluates the role of dose rate on cell and molecular responses. It focuses on the influence of dose rate on key events in critical pathways in the development of cancer. This approach is similar to that used by the U.S. EPA and others to evaluate risk from chemicals. It provides a mechanistic method to account for the influence of the dose rate from low-LET radiation, especially in the low-dose region on cancer risk assessment. Molecular, cellular, and tissues changes are observed in many key events and change as a function of dose rate. The magnitude and direction of change can be used to help establish an appropriate dose rate effectiveness factor (DREF). Conclusions: Extensive data on key events suggest that exposure to low dose-rates are less effective in producing changes than high dose rates. Most of these data at the molecular and cellular level support a large (2–30) DREF. In addition, some evidence suggests that doses delivered at a low dose rate decrease damage to levels below that observed in the controls. However, there are some data human and mechanistic data that support a dose-rate effectiveness factor of 1. In summary, a review of the available molecular, cellular and tissue data indicates that not only is dose rate an important variable in understanding radiation risk but it also supports the selection of a DREF greater than one as currently recommended by ICRP (2007) and BEIR VII (NRC/NAS 2006). PMID:27266588

Effects of D-004, a lipid extract of the fruit of the Cuban royal palm (Roystonea regia) or the lipidosterolic extract of saw palmetto (Serenoa repens) on the sexual activity in male rats: A controlled, experimental study

PubMed Central

Fernández, Lilia C.; Mas, Rosa; Fernández, Julio; Mendoza, Sarahí; Gámez, Rafael; Pardo, Balia

2008-01-01

Background: The etiology of benign prostatic hyperplasia (BPH) is not completely understood, but hormonal changes in aging men seem to be pivotal. Dihydrotestosterone, a potent, active metabolite of testosterone, is formed by the enzymatic action of prostate 5α-reductase and causes cell growth and hyperplasia. Consistent with this action, male sexual dysfunction has been clinically documented to be among the drug-related adverse events associated with 5α-reductase inhibitors. The lipidosterolic extract of saw palmetto (LESP) fruit (Serenoa repens) has been used to treat BPH. D-004, a lipid extract of Roystonea regia Royal palm fruit, has been found to prevent prostatic hyperplasia induced by testoste-rone in rodents and to competitively inhibit prostate 5α-reductase activity in vitro. Objective: The purpose of this study was to assess the effects of D-004 and LESP, administered as single or repeated doses, on the sexual activity in male rats. Methods: This controlled, experimental study was conducted at the Pharmacology Department, Centre of Natural Products, National Centre for Scientific Research, Havana City, Cuba. Adult male Wistar rats weighing 250 to 300 g were randomized into 5 groups: 2 groups treated orally with D-004 (400 and 800 mg/kg); 2 groups treated orally with LESP (400 and 800 mg/kg); and 1 control group orally administered a water vehicle. Sexual activity behavior (the number of mounts and intromissions, mount latency, and intromission latency) was assessed during 2 observation periods: 90 minutes after the initial dose and at the end of the 30-day treatment. Latency was defined as time elapsed between the first mount and intromission. Results: A total of 50 rats (mean [SD] age, 10 [3] weeks; mean [SD] weight, 295 [10] g) were included in the experiment. There were no significant difterences in the mean number of mounts, intromissions, mount latency, or intromission latency in the groups treated with single or repeated doses of D-004 or LESP (400 and 800 mg/kg) compared with the controls. There was also no between-group difterence in mating behavior among the active treatment groups. All rats survived up to study completion, with normal behavior (weight gain, food intake, daily observations, without any sign of toxicity). There were no observable adverse events during the study. Conclusions: D-004 and LESP administered as a single dose or repeated doses for 30 days did not significantly affect male rat sexual activity behavior compared with a vehicle control group. PMID:24692784

A two-phase Poisson process model and its application to analysis of cancer mortality among A-bomb survivors.

PubMed

Ohtaki, Megu; Tonda, Tetsuji; Aihara, Kazuyuki

2015-10-01

We consider a two-phase Poisson process model where only early successive transitions are assumed to be sensitive to exposure. In the case where intensity transitions are low, we derive analytically an approximate formula for the distribution of time to event for the excess hazard ratio (EHR) due to a single point exposure. The formula for EHR is a polynomial in exposure dose. Since the formula for EHR contains no unknown parameters except for the number of total stages, number of exposure-sensitive stages, and a coefficient of exposure effect, it is applicable easily under a variety of situations where there exists a possible latency time from a single point exposure to occurrence of event. Based on the multistage hypothesis of cancer, we formulate a radiation carcinogenesis model in which only some early consecutive stages of the process are sensitive to exposure, whereas later stages are not affected. An illustrative analysis using the proposed model is given for cancer mortality among A-bomb survivors. Copyright © 2015 Elsevier Inc. All rights reserved.