Caffeine dosing strategies to optimize alertness during sleep loss.

PubMed

Vital-Lopez, Francisco G; Ramakrishnan, Sridhar; Doty, Tracy J; Balkin, Thomas J; Reifman, Jaques

2018-05-28

Sleep loss, which affects about one-third of the US population, can severely impair physical and neurobehavioural performance. Although caffeine, the most widely used stimulant in the world, can mitigate these effects, currently there are no tools to guide the timing and amount of caffeine consumption to optimize its benefits. In this work, we provide an optimization algorithm, suited for mobile computing platforms, to determine when and how much caffeine to consume, so as to safely maximize neurobehavioural performance at the desired time of the day, under any sleep-loss condition. The algorithm is based on our previously validated Unified Model of Performance, which predicts the effect of caffeine consumption on a psychomotor vigilance task. We assessed the algorithm by comparing the caffeine-dosing strategies (timing and amount) it identified with the dosing strategies used in four experimental studies, involving total and partial sleep loss. Through computer simulations, we showed that the algorithm yielded caffeine-dosing strategies that enhanced performance of the predicted psychomotor vigilance task by up to 64% while using the same total amount of caffeine as in the original studies. In addition, the algorithm identified strategies that resulted in equivalent performance to that in the experimental studies while reducing caffeine consumption by up to 65%. Our work provides the first quantitative caffeine optimization tool for designing effective strategies to maximize neurobehavioural performance and to avoid excessive caffeine consumption during any arbitrary sleep-loss condition. © 2018 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.

Cytogenetic, cytotoxic and GC-MS studies on concrete and absolute oils from Taif rose, Saudi Arabia.

PubMed

Hagag, Heba A; Bazaid, Salih A; Abdel-Hameed, El-Sayed S; Salman, Mahmood

2014-12-01

Taif rose (Rosa damascena trigintipetala Dieck) is a sort of damask rose, which is considered as one of the most important economic products of Taif. In this study, the authors investigated the possible cytotoxic, genotoxic, antimutagenic and anticancer effect of concrete and absolute rose oils. The results showed that both concrete and absolute rose oils were cytotoxically and genotoxically safe at a dose of 10 μg/ml when tested on cultures of normal human blood lymphocytes. Also, the results showed significant antimutagenic activity at p < 0.001 for absolute rose oil at the same dose level when tested on cultures of normal human blood lymphocytes supplemented with 300 ng/ml mitomycin C (MMC). On the other hand, concrete and absolute oils exerted a cytotoxic activity against two kinds of human cancer cell lines: HepG2 and MCF7. Concrete oil showed cytotoxic activity against HepG2 and MCF7 with a half maximal inhibitory concentration (IC50) of 16.28 and 18.09 μg/ml, respectively, whereas absolute rose oil showed its cytotoxic activity against HepG2 and MCF7 with an IC50 of 24.94 and 19.69, respectively. From this study, it is concluded that concrete and absolute rose oils are cytotoxically and genotoxically safe at a dose of 10 μg/ml when tested on cultures of normal human blood lymphocytes. In addition, absolute oil has an antimutagenic activity at the same dose. Further investigations are needed to study the activity of higher doses of both oils in vitro and in vivo in experimental animals in order to evaluate the capability of using these oils as therapeutic for treatment of some kinds of cancers.

Accuracy and Injection Force of the Gla-300 Injection Device Compared With Other Commercialized Disposable Insulin Pens.

PubMed

Klonoff, David; Nayberg, Irina; Thonius, Marissa; See, Florian; Abdel-Tawab, Mona; Erbstein, Frank; Haak, Thomas

2015-08-26

To deliver insulin glargine 300 U/mL (Gla-300), the widely used SoloSTAR(®) pen has been modified to allow for accurate and precise delivery of required insulin units in one-third of the volume compared with insulin glargine 100 U/mL, while improving usability. Here we compare the accuracy and injection force of 3 disposable insulin pens: Gla-300 SoloSTAR(®), FlexPen(®), and KwikPen™. For the accuracy assessment, 60 of each of the 3 tested devices were used for the delivery of 3 different doses (1 U, half-maximal dose, and maximal dose), which were measured gravimetrically. For the injection force assessment, 20 pens of each of the 3 types were tested twice at half-maximal and once at maximal dose, at an injection speed of 6 U/s. All tested pens met the International Organization for Standardization (ISO) requirements for dosing accuracy, with Gla-300 SoloSTAR showing the lowest between-dose variation (greatest reproducibility) at all dose levels. Mean injection force was significantly lower for Gla-300 SoloSTAR than for the other 2 pens at both half maximal and maximal doses (P < .0271). All tested pens were accurate according to ISO criteria, and the Gla-300 SoloSTAR pen displayed the greatest reproducibility and lowest injection force of any of the 3 tested devices. © 2015 Diabetes Technology Society.

Restricted Use of Erythropoiesis-Stimulating Agent is Safe and Associated with Deferred Dialysis Initiation in Stage 5 Chronic Kidney Disease

PubMed Central

Pan, Szu-Yu; Chiang, Wen-Chih; Chen, Ping-Min; Liu, Heng-Hsiu; Chou, Yu-Hsiang; Lai, Tai-Shuan; Lai, Chun-Fu; Chiu, Yen-Ling; Lin, Wan-Yu; Chen, Yung-Ming; Chu, Tzong-Shinn; Lin, Shuei-Liong

2017-01-01

The effect of erythropoiesis-stimulating agent (ESA) on dialysis initiation in advanced chronic kidney disease (CKD) patients is not clear. We retrospectively analyzed the outcome of dialysis initiation in a stage 5 CKD cohort with ESA reimbursement limited to the maximal standardized monthly ESA dose equivalent to epoetin beta 20,000 U by the National Health Insurance program. Totally 423 patients were followed up for a median of 1.37 year. A time-dependent Cox regression model, adjusted for monthly levels of estimated glomerular filtration rate (eGFR) and hemoglobin, was constructed to investigate the association between ESA and outcome. The standardized monthly ESA dose in ESA users was 16,000 ± 3,900 U of epoetin beta. Annual changes of hemoglobin were −0.29 ± 2.19 and −0.99 ± 2.46 g/dL in ESA users and ESA non-users, respectively (P = 0.038). However, annual eGFR decline rates were not different between ESA users and non-users. After adjustment, ESA use was associated with deferred dialysis initiation (hazard ratio 0.63, 95% confidence interval 0.42–0.93, P = 0.021). The protective effect remained when the monthly ESA doses were incorporated. Our data showed that restricted use of ESA was safe and associated with deferred dialysis initiation in stage 5 CKD patients. PMID:28272424

Characterizing Potentially Inappropriate Prescribing of Proton Pump Inhibitors in Older People in Primary Care in Ireland from 1997 to 2012.

PubMed

Moriarty, Frank; Bennett, Kathleen; Cahir, Caitriona; Fahey, Tom

2016-12-01

To characterize prescribing of proton pump inhibitors (PPIs) and medicines that increase gastrointestinal bleeding risk (ulcerogenic) in older people from 1997 to 2012 and assess factors associated with maximal-dose prescribing in long-term PPI users. Repeated cross-sectional study of pharmacy claims data. Eastern Health Board region of Ireland. Individuals aged 65 and older from a means-tested health plan in 1997, 2002, 2007, and 2012 (range 78,489-133,884 individuals). PPI prescribing prevalence was determined per study year, categorized according to duration (≤8 or >8 weeks), dosage (maximal or maintenance), and co-prescribed drugs. Logistic regression in long-term PPI users was used to determine whether age, sex, polypharmacy, and ulcerogenic medicine use were associated with being prescribed a maximal dose rather than a maintenance dose. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are presented. Half of this older population received a PPI in 2007 and 2012. Long-term use (>8 weeks) of maximal doses rose from 0.8% of individuals in 1997 to 23.6% in 2012. Although some ulcerogenic medicines and polypharmacy were significantly associated with maximal PPI doses, any nonsteroidal anti-inflammatory drug use was significantly associated with lower odds of maximal PPI dose (adjusted OR = 0.87, 95% CI = 0.85-0.89), as were aspirin use and older age. Adjusting for medication and demographic factors, odds of being prescribed a maximal PPI dose were significantly higher in 2012 than in 1997 (adjusted OR = 6.30, 95% CI = 5.76-6.88). Long-term maximal-dose PPI prescribing is highly prevalent in older adults and is not consistently associated with gastrointestinal bleeding risk factors. Interventions involving prescribers and patients may promote appropriate PPI use, reducing costs and adverse effects of PPI overprescribing. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Vitamin D compounds: clinical development as cancer therapy and prevention agents.

PubMed

Trump, Donald L; Muindi, Josephia; Fakih, Marwan; Yu, Wei-Dong; Johnson, Candace S

2006-01-01

While 1,25 dihydroxycholecalciferol (calcitriol) is best recognized for its effects on bone and mineral metabolism, epidemiological data indicate that low vitamin D levels may play a role in the genesis and progression of breast, lung, colorectal and prostate cancer, as well as malignant lymphoma and melanoma. Calcitriol has strong antiproliferative effects in prostate, breast, colorectal, head/neck and lung cancer, as well as lymphoma, leukemia and myeloma model systems. Antiproliferative effects are seen in vitro and in vivo. The mechanisms of these effects are associated with G0/G1 arrest, induction of apoptosis, differentiation and modulation of growth factor-mediated signaling in tumor cells. In addition to the direct effects on tumor cells, recent data strongly support the hypothesis that the stromal effects of vitamin D analogs (e.g., direct effects on tumor vasculature) are also important in the antiproliferative effects. Antitumor effects are seen in a wide variety of tumor types and there are few data to suggest that vitamin D-based approaches are more effective in any one tumor type. Glucocorticoids potentiate the antitumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. In addition, calcitriol potentiates the antitumor effects of many cytotoxic agents. Preclinical data indicate that maximal antitumor effects are seen with pharmacological doses of calcitriol and that such exposure can be safely achieved in animals using a high dose, intermittent schedule of administration. AUC and C(max) calcitriol concentrations of 32 ng.h/ml and 9.2 ng/ml are associated with striking antitumor effects in a murine squamous cell carcinoma model and there is increasing evidence from clinical trials that such exposures can be safely attained in patients. Another approach to maximizing intra-tumoral exposure to vitamin D analogs is to inhibit their catabolism. The data clearly indicate that agents which inhibit the major vitamin D catabolizing enzyme, CYP24 (24 hydroxylase), potentiate calcitriol killing of prostate tumor cells in vitro and in vivo. Phase I and II trials of calcitriol, either alone or in combination with carboplatin, taxanes or dexamethasone, as well as the non-specific CYP24 inhibitor, ketoconazole, have been initiated in patients with androgen-dependent and -independent prostate cancer and other advanced cancers. The data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered, but the optimal dose and schedule remain to be delineated. Clinical responses have been seen with the combination of high-dose calcitriol + dexamethasone in androgen-independent prostate cancer (AIPC) and, in a large randomized trial in men with AIPC, potentiation of the antitumor effects of docetaxel were seen.

Maximizing value in opioid utilization: Is oxycodone immediate release a good option for pain management?

PubMed

Pergolizzi, Joseph V; Köknel Talu, Gül; Zmponga, Gianpetrio; Erdine, Serdar; Taylor, Robert; Ayan, Burak; Raffa, Robert B

2015-01-01

The modern approach to the management of pain involves optimizing all aspects of the process. This includes utilization of pharmacologic and non-pharmacologic modalities, consideration of patient characteristics, proper matching of the physiology of the pain with the analgesic's mechanism of action (pharmacodynamics, PD), and the onset and duration of action (pharmacokinetics, PK). No single agent or formulation satisfies all of the requirements for all patients. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are effective options for inflammatory pain and, as is acetaminophen, for mild pain. Specialized agents are helpful for particular pains, such as for migraine headache. Opioids remain the standard option for severe pain. Although they are generally a safe and effective option, opioids can produce dose-limiting adverse effects and have abuse potential. The goal of pain therapy is thus to achieve the maximum pain relief with the least amount of opioid exposure. Against this background of measured approach to the use of analgesics, an immediate release (IR) oral formulation of the established opioid oxycodone has been developed to provide rapid onset of action and rate of titration, both of which could maximize temporal matching of dose with pain level and reduce total exposure to drug. This article considers the option of an immediate release (IR) oral formulation for the management of pain.

Estimated Maximal Safe Dosages of Tumescent Lidocaine.

PubMed

Klein, Jeffrey A; Jeske, Daniel R

2016-05-01

Tumescent lidocaine anesthesia consists of subcutaneous injection of relatively large volumes (up to 4 L or more) of dilute lidocaine (≤1 g/L) and epinephrine (≤1 mg/L). Although tumescent lidocaine anesthesia is used for an increasing variety of surgical procedures, the maximum safe dosage is unknown. Our primary aim in this study was to measure serum lidocaine concentrations after subcutaneous administration of tumescent lidocaine with and without liposuction. Our hypotheses were that even with large doses (i.e., >30 mg/kg), serum lidocaine concentrations would be below levels associated with mild toxicity and that the concentration-time profile would be lower after liposuction than without liposuction. Volunteers participated in 1 to 2 infiltration studies without liposuction and then one study with tumescent liposuction totally by local anesthesia. Serum lidocaine concentrations were measured at 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours after each tumescent lidocaine infiltration. Area under the curve (AUC∞) of the serum lidocaine concentration-time profiles and peak serum lidocaine concentrations (Cmax) were determined with and without liposuction. For any given milligram per kilogram dosage, the probability that Cmax >6 μg/mL, the threshold for mild lidocaine toxicity was estimated using tolerance interval analysis. In 41 tumescent infiltration procedures among 14 volunteer subjects, tumescent lidocaine dosages ranged from 19.2 to 52 mg/kg. Measured serum lidocaine concentrations were all <6 μg/mL over the 24-hour study period. AUC∞s with liposuction were significantly less than those without liposuction (P = 0.001). The estimated risk of lidocaine toxicity without liposuction at a dose of 28 mg/kg and with liposuction at a dose of 45 mg/kg was ≤1 per 2000. Preliminary estimates for maximum safe dosages of tumescent lidocaine are 28 mg/kg without liposuction and 45 mg/kg with liposuction. As a result of delayed systemic absorption, these dosages yield serum lidocaine concentrations below levels associated with mild toxicity and are a nonsignificant risk of harm to patients.

[Gradation in the level of vitamin consumption: possible risk of excessive consumption].

PubMed

Kodentsova, V M

2014-01-01

The ratio between the levels of consumption of certain vitamins and minerals [recommended daily allowance for labelling purposes < maximum supplement levels < tolerable upper intake level (UL) < safe level (limit) of consumption < or = therapeutic dose has been characterized. Vitamin A and beta-carotene maximum supplement levels coincides with UL, and recommended daily allowance for these micronutrients coincides with the maximal level of consumption through dietary supplements and/or multivitamins. Except for vitamin A and beta-carotene recommended daily allowance for other vitamins adopted in Russia are considerably lower than the upper safe level of consumption. For vitamin A and beta-carotene there is a potential risk for excess consumption. According to the literature data (meta-analysis) prolonged intake of high doses of antioxidant vitamins (above the RDA) both alone and in combination with two other vitamins or vitamin C [> 800 microg (R.E.) of vitamin A, > 9.6 mg of beta-carotene, > 15 mg (T.E.) of vitamin E] do not possess preventive effects and may be harmful with unwanted consequences to health, especially in well-nourished populations, persons having risk of lung cancer (smokers, workers exposed to asbestos), in certain conditions (in the atmosphere with high oxygen content, hyperoxia, oxygen therapy). Proposed mechanisms of such action may be due to the manifestation of prooxidant action when taken in high doses, shifting balance with other important natural antioxidants, their displacement (substitution), interference with the natural defense mechanisms. Athletes are the population group that requires attention as used antioxidant vitamins A, C, E, both individually and in combination in extremely high doses. In summary, it should be noted that intake of physiological doses which are equivalent to the needs of the human organism, as well as diet inclusion of fortified foods not only pose no threat to health, but will bring undoubted benefits, filling the existing lack of vitamins in the ration.

Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy.

PubMed

Singh, Anurag K; Lockett, Mary Ann; Bradley, Jeffrey D

2003-02-01

To evaluate the incidence and clinical/dosimetric predictors of acute and late Radiation Therapy Oncology Group Grade 3-5 esophageal toxicity in patients with non-small-cell lung cancer (NSCLC) treated with definitive three-dimensional conformal radiotherapy (3D-CRT). We retrospectively reviewed the charts of 207 consecutive patients with NSCLC who were treated with high-dose, definitive 3D-CRT between March 1991 and December 1998. This population consisted of 107 men and 100 women. The median age was 67 years (range 31-90). The following patient and treatment parameters were studied: age, gender, race, performance status, sequential chemotherapy, concurrent chemotherapy, presence of subcarinal nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy. All doses are reported without heterogeneity corrections. The median prescription dose to the isocenter in this population was 70 Gy (range 60-74) delivered in 2-Gy daily fractions. All patients were treated once daily. Acute and late esophageal toxicities were graded by Radiation Therapy Oncology Group criteria. Patient and clinical/dosimetric factors were coded and correlated with acute and late Grade 3-5 esophageal toxicity using univariate and multivariate regression analyses. Of 207 patients, 16 (8%) developed acute (10 patients) or late (13 patients) Grade 3-5 esophageal toxicity. Seven patients had both acute and late Grade 3-5 esophageal toxicity. One patient died (Grade 5 esophageal toxicity) of late esophageal perforation. Concurrent chemotherapy, maximal point dose to the esophagus >58 Gy, and a mean dose to the entire esophagus >34 Gy were significantly associated with a risk of Grade 3-5 esophageal toxicity on univariate analysis. Concurrent chemotherapy and maximal point dose to the esophagus >58 Gy retained significance on multivariate analysis. Of 207 patients, 53 (26%) received concurrent chemotherapy. Fourteen (88%) of the 16 patients who developed Grade 3-5 esophageal toxicity had received concurrent chemotherapy (p = 0.0001, Pearson's chi-square test). No case of Grade 3-5 esophageal toxicity occurred in patients who received a maximal point dose to the esophagus of <58 Gy (p = 0.0001, Fisher's exact test, two-tail). Only 2 patients developed Grade 3-5 esophageal toxicity in the absence of concurrent chemotherapy; both received a maximal esophageal point dose >69 Gy. All assessable patients who developed Grade 3-5 esophageal toxicity had a mean dose to the entire esophagus >34 Gy (p = 0.0351, Pearson's chi-square test). However, the mean dose was not predictive on multivariate analysis. Concurrent chemotherapy and the maximal esophageal point dose were significantly associated with a risk of Grade 3-5 esophageal toxicity in patients with NSCLC treated with high-dose 3D-CRT. In patients who received concurrent chemotherapy, the threshold maximal esophageal point dose for Grade 3-5 esophageal toxicity was 58 Gy. An insufficient number of patients developed Grade 3-5 esophageal toxicity in the absence of chemotherapy to allow a valid statistical analysis of the relationship between the maximal esophageal point dose and esophagitis.

The velocity of antihypertensive effect of losartan/hydrochlorothiazide and angiotensin II receptor blocker.

PubMed

Metoki, Hirohito; Ohkubo, Takayoshi; Kikuya, Masahiro; Asayama, Kei; Inoue, Ryusuke; Obara, Taku; Hirose, Takuo; Sato, Michihiro; Hashimoto, Takanao; Imai, Yutaka

2012-07-01

The hypotensive effect and the time to attain the maximum antihypertensive effect (stabilization time) of losartan/hydrochlorothiazide (HCTZ) combination therapy and therapy with a maximal dose of angiotensin II receptor blockers (ARBs) in patients who failed to achieve adequate blood pressure (BP) control on a medium-dose of ARBs were compared by analyzing exponential decay functions using daily serial morning home BP measurements. Essential hypertensive patients treated with a medium dose of ARB, in whom a target home SBP (135 mmHg) was not achieved, were randomized into two groups: a combination group (n = 110) and a maximal-dose ARB group (n = 111). The combination therapy provided additional reduction of 5.2 mmHg [95% confidence interval (CI) 1.8 to 8.5 mmHg, P = 0.003] in home SBP over the maximal-dose ARB therapy in 8 weeks after randomization. A greater reduction in the home SBP values was seen in the combination group than in the maximal-dose ARB group from the second day after randomization on the basis of a linear mixed model. The maximum antihypertensive effect and stabilization time for home SBP were 10.9 ± 5.0 mmHg and 7.3 ± 29.7 days, respectively, in the combination group, whereas the corresponding values in the maximal-dose ARB group were 7.9 ± 2.6  mmHg and 122.3 ± 42.7 days, respectively, on the basis of a nonlinear mixed model. Changing from a medium dose of ARB monotherapy to combination therapy was more effective in the reduction of home SBP and achieved goal BP more rapidly than increasing the ARB dose. Home BP measurement is a useful tool for characterizing the antihypertensive effects of drugs.

Immunotherapy safety: a prospective multi-centric monitoring study of biologically standardized therapeutic vaccines for allergic diseases.

PubMed

Moreno, C; Cuesta-Herranz, J; Fernández-Távora, L; Alvarez-Cuesta, E

2004-04-01

The fear of side-effects has led to strict regulations preventing a more widespread use of specific immunotherapy (SIT) in some countries, in spite of the low risk of systemic reactions (SRs) reported in well-controlled studies. The goal of the study was to carry out a prospective and multi-centric trial to evaluate the safety, risk factors and compliance degree of commercially available SIT. The study was carried out in 14 allergy departments from Spain. Four-hundred and eighty-eight patients with rhinitis and/or asthma were submitted to treatment with biologically standardized allergen extracts commercially available. They were administered following the European Academy of Allergy and Clinical Immunology guidelines. Four hundred and twenty-three patients (86.7%) completed the treatment and remained under control at the end of the trial. Out of 17,526 administered doses, 17,368 doses (99.1%) were not associated with a reaction. Eighteen patients (3.7%) experienced 53 (0.3% of the doses) SRs. All immediate SRs were mild or moderate and responded well to ordinary treatment measures. There were no fatal reactions, anaphylactic shock or life-threatening reactions. A higher ratio of SRs was found among asthmatic and dust mite allergic patients, although multi-variable logistic analysis did not demonstrate any risk factor associated with SRs. There was also a subgroup of patients at risk for recurrent reactions, and therefore 40% of SRs had been avoided if the maximal number of SRs had been previously limited to only three SRs. This multi-centric study showed that SIT was a safe treatment with a very good compliance. Future guidelines of SIT should limit the maximal number of SRs.

Compact D-D Neutron Source-Driven Subcritical Multiplier and Beam-Shaping Assembly for Boron Neutron Capture Therapy

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

Francesco Ganda; Jasmina Vujic; Ehud Greenspan

2010-12-01

This work assesses the feasibility of using a small, safe, and inexpensive keff 0.98 subcritical fission assembly [subcritical neutron multiplier (SCM)] to amplify the treatment neutron beam intensity attainable from a compact deuterium-deuterium (D-D) fusion neutron source delivering [approximately]1012 n/s. The objective is to reduce the treatment time for deep-seated brain tumors to [approximately]1 h. The paper describes the optimal SCM design and two optimal beam-shaping assemblies (BSAs) - one designed to maximize the dose rate and the other designed to maximize the total dose that can be delivered to a deep-seated tumor. The neutron beam intensity amplification achieved withmore » the optimized SCM and BSA results in an increase in the treatment dose rate by a factor of 18: from 0.56 Gy/h without the SCM to 10.1 Gy/h. The entire SCM is encased in an aluminum structure. The total amount of 20% enriched uranium required for the SCM is 8.5 kg, and the cost (not including fabrication) is estimated to be less than $60,000. The SCM power level is estimated at 400 W when driven by a 1012 n/s D-D neutron source. This translates into consumption of only [approximately]0.6% of the initially loaded 235U atoms during 50 years of continuous operation and implies that the SCM could operate continuously for the entire lifetime of the facility without refueling. Cooling the SCM does not pose a challenge; it may be accomplished by natural circulation as the maximum heat flux is only 0.034 W/cm2.« less

Population pharmacokinetics of conventional and intermittent dosing of liposomal amphotericin B in adults: a first critical step for rational design of innovative regimens.

PubMed

Hope, William W; Goodwin, Joanne; Felton, Timothy W; Ellis, Michael; Stevens, David A

2012-10-01

There is increased interest in intermittent regimen of liposomal amphotericin B, which may facilitate use in ambulatory settings. Little is known, however, about the most appropriate dosage and schedule of administration. Plasma pharmacokinetic data were acquired from 30 patients receiving liposomal amphotericin B for empirical treatment of suspected invasive fungal infection. Two cohorts were studied. The first cohort received 3 mg of liposomal amphotericin B/kg of body weight/day; the second cohort received 10 mg of liposomal amphotericin B/kg at time zero, followed by 5 mg/kg at 48 and 120 h. The levels of liposomal amphotericin B were measured by high-pressure liquid chromatography (HPLC). The pharmacokinetics were estimated by using a population methodology. Monte Carlo simulations were performed. D-optimal design was used to identify maximally informative sampling times for both conventional and intermittent regimens for future studies. A three-compartment pharmacokinetic model best described the data. The pharmacokinetics for both conventional and intermittent dosing were linear. The estimates for the mean (standard deviation) for clearance and the volume of the central compartment were 1.60 (0.85) liter/h and 20.61 (15.27) liters, respectively. Monte Carlo simulations demonstrated considerable variability in drug exposure. Bayesian estimates for clearance and volume increased in a linear manner with weight, but only the former was statistically significant (P = 0.039). D-optimal design provided maximally informative sampling times for future pharmacokinetic studies. The pharmacokinetics of a conventional and an intermittently administered high-dose regimen liposomal amphotericin B are linear. Further pharmacokinetic-pharmacodynamic preclinical and clinical studies are required to identify safe and effective intermittent regimens.

Population Pharmacokinetics of Conventional and Intermittent Dosing of Liposomal Amphotericin B in Adults: a First Critical Step for Rational Design of Innovative Regimens

PubMed Central

Goodwin, Joanne; Felton, Timothy W.; Ellis, Michael; Stevens, David A.

2012-01-01

There is increased interest in intermittent regimen of liposomal amphotericin B, which may facilitate use in ambulatory settings. Little is known, however, about the most appropriate dosage and schedule of administration. Plasma pharmacokinetic data were acquired from 30 patients receiving liposomal amphotericin B for empirical treatment of suspected invasive fungal infection. Two cohorts were studied. The first cohort received 3 mg of liposomal amphotericin B/kg of body weight/day; the second cohort received 10 mg of liposomal amphotericin B/kg at time zero, followed by 5 mg/kg at 48 and 120 h. The levels of liposomal amphotericin B were measured by high-pressure liquid chromatography (HPLC). The pharmacokinetics were estimated by using a population methodology. Monte Carlo simulations were performed. D-optimal design was used to identify maximally informative sampling times for both conventional and intermittent regimens for future studies. A three-compartment pharmacokinetic model best described the data. The pharmacokinetics for both conventional and intermittent dosing were linear. The estimates for the mean (standard deviation) for clearance and the volume of the central compartment were 1.60 (0.85) liter/h and 20.61 (15.27) liters, respectively. Monte Carlo simulations demonstrated considerable variability in drug exposure. Bayesian estimates for clearance and volume increased in a linear manner with weight, but only the former was statistically significant (P = 0.039). D-optimal design provided maximally informative sampling times for future pharmacokinetic studies. The pharmacokinetics of a conventional and an intermittently administered high-dose regimen liposomal amphotericin B are linear. Further pharmacokinetic-pharmacodynamic preclinical and clinical studies are required to identify safe and effective intermittent regimens. PMID:22869566

Application of a Pharmacokinetic Model of Metformin Clearance in a Population with Acute Myeloid Leukemia.

PubMed

Ceacareanu, Alice C; Brown, Geoffrey W; Moussa, Hoda A; Wintrob, Zachary A P

2018-01-01

We aimed to estimate the metformin-associated lactic acidosis (MALA) risk by assessing retrospectively the renal clearance variability and applying a pharmacokinetic (PK) model of metformin clearance in a population diagnosed with acute myeloid leukemia (AML) and diabetes mellitus (DM). All adults with preexisting DM and newly diagnosed AML at Roswell Park Cancer Institute were reviewed (January 2003-December 2010, n = 78). Creatinine clearance (CrCl) and total body weight distributions were used in a two-compartment PK model adapted for multiple dosing and modified to account for actual intra- and inter-individual variability. Based on this renal function variability evidence, 1000 PK profiles were simulated for multiple metformin regimens with the resultant PK profiles being assessed for safe CrCl thresholds. Metformin 500 mg up to three times daily was safe for all simulated profiles with CrCl ≥25 mL/min. Furthermore, the estimated overall MALA risk was below 10%, remaining under 5% for 500 mg given once daily. CrCl ≥65.25 mL/min was safe for administration in any of the tested regimens (500 mg or 850 mg up to three times daily or 1000 mg up to twice daily). PK simulation-guided prescribing can maximize metformin's beneficial effects on cancer outcomes while minimizing MALA risk.

Enhanced tolerance and antitumor efficacy by docetaxel-loaded albumin nanoparticles.

PubMed

Tang, Xiaolei; Wang, Guijun; Shi, Runjie; Jiang, Ke; Meng, Lingtong; Ren, Hao; Wu, Jinhui; Hu, Yiqiao

2016-10-01

Docetaxel is one of the most active chemotherapeutic agents for cancer treatment. The traditional docetaxel injection (TAXOTERE®) is currently formulated in the surfactant polysorbate 80, which has been associated with severe adverse reactions. To avoid the use of polysorbate 80 as well as to reduce the systemic toxicity of docetaxel, in this study, docetaxel-loaded albumin nanoparticles were fabricated by a novel simple self-assembly method. The resulting nanoparticles showed a mean diameter size of 150 nm. After being encapsulated into nanoparticles, docetaxel displayed similar cytotoxicity to traditional injection. Since polysorbate 80 was not involved in nanoparticles, the hemolysis was completely eliminated. The maximal tolerance dose of nanoparticles was also increased, which allowed a higher dose to be safely intravenously injected and produced ideal antitumor effects. The 150 nm diameter also allowed the nanoparticles to accumulate in tumor tissue via the enhanced permeability and retention effect. The passive targeting ability further caused the higher antitumor effects of nanoparticles than that of traditional injection at the same dose (7.5 mg/kg). Therefore, docetaxel-loaded albumin nanoparticles fabricated by our strategy showed higher promise in their safety and effectiveness than the traditional docetaxel injection.

Aggressive Treatment of Life-Threatening Hypophosphatemia During Recovery From Fulminant Hepatic Failure: A Case Report.

PubMed

Bissell, Brittany D; Davis, Jason E; Flannery, Alexander H; Adkins, David A; Thompson Bastin, Melissa L

2018-06-01

Acute liver failure secondary to acetaminophen overdose can be a life-threatening condition, characterized by severe electrolyte derangements. Hepatocyte regeneration is associated with phosphorous utilization and is a known complication of liver recovery following injury. We report the case of profound, life-threatening hypophosphatemia following recovery from acute fulminant liver failure. As the liver enzymes normalized, serum phosphorous levels plummeted. Our patient required an aggressive, individualized phosphorus replacement regimen, which resulted in a continuous infusion of intravenous (IV) sodium phosphate, titrated to a maximum rate of 30 mmol/h or 0.5 mmol/kg/h. The patient required over 400 mmol of total IV and oral phosphorous over the course of 48 hours. An aggressive approach to phosphorous replacement was done safely and effectively. Traditional replacement protocols are not adequate to sustain patients with this degree of hypophosphatemia. This is the first report to utilize a continuous infusion of phosphate with a maximum reported rate (0.5 mmol/kg/h). Our report summarizes a novel and safe approach for clinicians to maximally support these patients through high-dose, continuous infusion phosphorous administration.

Clinical Outcomes With Dose-Escalated Adaptive Radiation Therapy for Urinary Bladder Cancer: A Prospective Study

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

Murthy, Vedang, E-mail: vmurthy@actrec.gov.in; Masodkar, Renuka; Kalyani, Nikhil

Purpose: The purpose of this study was to assess feasibility, clinical outcomes, and toxicity in patients with bladder cancer treated with adaptive, image guided radiation therapy (IGRT) for bladder preservation as a part of trimodality treatment. The role of dose escalation was also studied. Methods and Materials: Forty-four patients with localized bladder cancer were enrolled in a prospective study. They underwent maximal safe resection of bladder tumor and concurrent platinum-based chemotherapy. Patients with large tumors were offered induction chemotherapy. Radiation therapy planning was done using either 3 (n=34) or 6 (n=10) concentrically grown planning target volumes (PTV). Patients received 64 Gymore » in 32 fractions to the whole bladder and 55 Gy to the pelvic nodes and, if appropriate, a simultaneous integrated boost to the tumor bed to 68 Gy (equivalent dose for 2-Gy fractions assuming α/β of 10 [EQD2]{sub 10} = 68.7 Gy). Daily megavoltage (MV) imaging helped to choose the most appropriate PTV encompassing bladder for the particular day (using plan-of-the-day approach). Results: Most patients (88%) had T2 disease. Sixteen patients (36%) received neoadjuvant chemotherapy. A majority of the patients (73%) received prophylactic nodal irradiation, whereas 55% of the patients received escalated dose to the tumor bed. With a median follow-up of 30 months, the 3-year locoregional control (LRC), disease-free survival, and overall survival (OS) were 78%, 66%, and 67%, respectively. The bladder preservation rate was 83%. LRC (87% vs 68%, respectively, P=.748) and OS (74% vs 60%, respectively, P=.36) rates were better in patients receiving dose escalation. Instances of acute and late Radiation Therapy Oncology Group (RTOG) grade 3 genitourinary toxicity was seen in 5 (11%) and 2 (4%) patients, respectively. There was no acute or late RTOG grade 3 or higher gastrointestinal toxicity. Conclusions: Adaptive IGRT using plan-of-the-day approach for bladder preservation is clinically feasible, with good oncological outcomes and low rates of acute and late toxicities. Dose escalation is safe and possibly improves outcomes in bladder preservation.« less

Perception of Radiation Risk by Japanese Radiation Specialists Evaluated as a Safe Dose Before the Fukushima Nuclear Accident.

PubMed

Miura, Miwa; Ono, Koji; Yamauchi, Motohiro; Matsuda, Naoki

2016-06-01

From October to December 2010, just before the radiological accident at the Fukushima Daiichi nuclear power plant, 71 radiation professionals from radiation facilities in Japan were asked what they considered as a "safe dose" of radiation for themselves, their partners, parents, children, siblings, and friends. Although the 'safe dose' they noted varied widely, from less than 1 mSv y to more than 100 mSv y, the average dose was 35.6 mSv y, which is around the middle point between the legal exposure dose limits for the annual average and for any single year. Similar results were obtained from other surveys of members of the Japan Radioisotope Association (36.9 mSv y) and of the Oita Prefectural Hospital (36.8 mSv y). Among family members and friends, the minimum average "safe" dose was 8.5 mSv y for children, for whom 50% of the responders claimed a "safe dose" of less than 1 mSv. Gender, age and specialty of the radiation professional also affected their notion of a "safe dose." These findings suggest that the perception of radiation risk varies widely even for radiation professionals and that the legal exposure dose limits derived from regulatory science may act as an anchor of safety. The different levels of risk perception for different target groups among radiation professionals appear similar to those in the general population. The gap between these characteristics of radiation professionals and the generally accepted picture of radiation professionals might have played a role in the state of confusion after the radiological accident.

Sublingual administration of detomidine in horses: sedative effect, analgesia and detection time.

PubMed

L'Ami, Jiske J; Vermunt, Lian E; van Loon, Johannes P A M; Sloet van Oldruitenborgh-Oosterbaan, Marianne M

2013-05-01

A single dose of 40 μg/kg bodyweight (BW) of oromucosal detomidine gel was administered sublingually to 10 healthy Dutch Warmblood mares aged 7 ± 4 years (mean ± SD) and BW 580 ± 69 kg. Blood and urine samples were collected before and for 8 days following administration and evaluated qualitatively in an FEI Reference Laboratory and quantitatively in a research laboratory. Clinical effects were evaluated at baseline and for 24 h after administration. Sedation was determined using head height and scores of reaction to auditory and mixed auditory/sensory stimuli. Mechanical nociceptive thresholds (MNTs) were assessed using pressure algometry to evaluate analgesia. Heart rate (HR) was measured and ataxia scored. All horses were considered negative for detomidine in blood samples by 48 h post-administration and in urine by 60 h. These results indicated that a safe withdrawal time for detomidine oromucosal gel may be 72 h following a single sublingual administration of 40 μg/kgBW. Decreases in HR and head height were maximal at 40 and 60 min post-administration, respectively. The maximal decrease in response to stimuli was observed at 100 min. Ataxia was maximal at 60 min. At 40 and 80 min MNTs were significantly increased compared to baseline. All parameters, except the MNTs of two locations, which were decreased, returned to baseline values within 24 h post-administration. Copyright © 2012 Elsevier Ltd. All rights reserved.

Volumetric tumor burden and its effect on brachial plexus dosimetry in head and neck intensity-modulated radiotherapy

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

Romesser, Paul B.; Qureshi, Muhammad M.; Kovalchuk, Nataliya

2014-07-01

To determine the effect of gross tumor volume of the primary (GTV-P) and nodal (GTV-N) disease on planned radiation dose to the brachial plexus (BP) in head and neck intensity-modulated radiotherapy (IMRT). Overall, 75 patients underwent definitive IMRT to a median total dose of 69.96 Gy in 33 fractions. The right BP and left BP were prospectively contoured as separate organs at risk. The GTV was related to BP dose using the unpaired t-test. Receiver operating characteristics curves were constructed to determine optimized volumetric thresholds of GTV-P and GTV-N corresponding to a maximum BP dose cutoff of > 66 Gy.more » Multivariate analyses were performed to account for factors associated with a higher maximal BP dose. A higher maximum BP dose (> 66 vs ≤ 66 Gy) correlated with a greater mean GTV-P (79.5 vs 30.8 cc; p = 0.001) and ipsilateral GTV-N (60.6 vs 19.8 cc; p = 0.014). When dichotomized by the optimized nodal volume, patients with an ipsilateral GTV-N ≥ 4.9 vs < 4.9 cc had a significant difference in maximum BP dose (64.2 vs 59.4 Gy; p = 0.001). Multivariate analysis confirmed that an ipsilateral GTV-N ≥ 4.9 cc was an independent predictor for the BP to receive a maximal dose of > 66 Gy when adjusted individually for BP volume, GTV-P, the use of a low anterior neck field technique, total planned radiation dose, and tumor category. Although both the primary and the nodal tumor volumes affected the BP maximal dose, the ipsilateral nodal tumor volume (GTV-N ≥ 4.9 cc) was an independent predictor for high maximal BP dose constraints in head and neck IMRT.« less

Prospective Clinical Trial of Bladder Filling and Three-Dimensional Dosimetry in High-Dose-Rate Vaginal Cuff Brachytherapy

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

Stewart, Alexandra J.; Cormack, Robert A.; Lee, Hang

2008-11-01

Purpose: To investigate the effect of bladder filling on dosimetry and to determine the best bladder dosimetric parameter for vaginal cuff brachytherapy. Methods and Materials: In this prospective clinical trial, a total of 20 women underwent vaginal cylinder high-dose-rate brachytherapy. The bladder was full for Fraction 2 and empty for Fraction 3. Dose-volume histogram and dose-surface histogram values were generated for the bladder, rectum, and urethra. The midline maximal bladder point (MBP) and the midline maximal rectal point were recorded. Paired t tests, Pearson correlations, and regression analyses were performed. Results: The volume and surface area of the irradiated bladdermore » were significantly smaller when the bladder was empty than when full. Of the several dose-volume histogram and dose-surface histogram parameters evaluated, the bladder maximal dose received by 2 cm{sup 3} of tissue, volume of bladder receiving {>=}50% of the dose, volume of bladder receiving {>=}70% of the dose, and surface area of bladder receiving {>=}50% of the dose significantly predicted for the difference between the empty vs. full filling state. The volume of bladder receiving {>=}70% of the dose and the maximal dose received by 2 cm{sup 3} of tissue correlated significantly with the MBP. Bladder filling did not alter the volume or surface area of the rectum irradiated. However, an empty bladder did result in the nearest point of bowel being significantly closer to the vaginal cylinder than when the bladder was full. Conclusions: Patients undergoing vaginal cuff brachytherapy treated with an empty bladder have a lower bladder dose than those treated with a full bladder. The MBP correlated well with the volumetric assessments of bladder dose and provided a noninvasive method for reporting the MBP dose using three-dimensional imaging. The MBP can therefore be used as a surrogate for complex dosimetry in the clinic.« less

Dexmedetomidine inhibits activation of the MAPK pathway and protects PC12 and NG108-15 cells from lidocaine-induced cytotoxicity at its maximum safe dose.

PubMed

Wang, Qiong; Tan, Yonghong; Zhang, Na; Xu, Yingyi; Wei, Wei; She, Yingjun; Bi, Xiaobao; Zhao, Baisong; Ruan, Xiangcai

2017-07-01

The developing brains of pediatric patients are highly vulnerable to anesthetic regimen (e.g., lidocaine), potentially causing neurological impairment. Recently, dexmedetomidine (DEX) has been used as an adjunct for sedation, and was shown to exert dose-dependent neuroprotective effects during brain injury. However, the maximum safe dose of DEX is unclear, and its protective effects against lidocaine-related neurotoxicity need to be confirmed. In this study, PC12 and NG108-15 cells were used to estimate safe, non-cytotoxic doses of DEX. We found that 100 and 60μM are the maximum safe dose of DEX for PC12 and NG108-15 cells, respectively, with no significant cytotoxicity. Lidocaine was found to remarkably inhibit cell vitality, but could be reversed by different doses of DEX, especially its maximum safe dose. Furthermore, the apoptosis induced by lidocaine was also assessed, and 100 and 60μM DEX showed optimal protective effects in PC12 and NG108-15 cells, respectively. Mechanistically, DEX activated the mitogen-activated protein kinase (MAPK) pathway, impaired caspase-3 expression, and enhanced anti-apoptotic factor Bcl-2 to resist lidocaine-induced apoptosis, indicating that the optimal dose of DEX alleviates lidocaine-induced cytotoxicity and should be considered in clinical application. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

First-in-human Phase I study of Pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors

PubMed Central

Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A.; Raynaud, Florence I.; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S.; Kaye, Stan B.; Derynck, Mika K.; Workman, Paul; de Bono, Johann S.

2014-01-01

Purpose This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal tolerated dose (MTD), dose limiting toxicities (DLTs), pharmacokinetics, pharmacodynamics and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent and selective inhibitor of the Class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450mg once-daily, initially on days 1-21 every 28 days and later, utilizing continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma and tumor tissue. Results Pictilisib was well-tolerated. The most common toxicities were grade 1-2 nausea, rash and fatigue while the DLT was grade 3 maculopapular rash (450mg, 2 of 3 patients; 330mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in platelet rich plasma at 3 hours post-dose at the MTD and in tumor at pictilisib doses associated with AUC >20uM.hr. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100mg and signs of antitumor activity. The recommended Phase II dose was continuous dosing at 330mg once-daily. PMID:25370471

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

PubMed

Sarker, Debashis; Ang, Joo Ern; Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A; Raynaud, Florence I; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S; Kaye, Stan B; Derynck, Mika K; Workman, Paul; de Bono, Johann S

2015-01-01

This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. ©2014 American Association for Cancer Research.

Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers

USDA-ARS?s Scientific Manuscript database

We measured plasma markers of cholesterol synthesis (lathosterol) and absorption (campesterol, sitosterol, and cholestanol) in order to compare the effects of maximal doses of rosuvastatin with atorvastatin and investigate the basis for the significant individual variation in lipid lowering response...

Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels

USDA-ARS?s Scientific Manuscript database

Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipo...

The H3 antagonist ABT-288 is tolerated at significantly higher exposures in subjects with schizophrenia than in healthy volunteers.

PubMed

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Gertsik, Lev; Dutta, Sandeep

2014-06-01

ABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia. This was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively. Of the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations. ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake. © 2013 The British Pharmacological Society.

Stereotactic Injection of DTI-015 into Recurrent Malignant Gliomas: Phase I/II Trial

PubMed Central

Hassenbusch, Samuel J; Nardone, Emilio M; Levin, Victor A; Leeds, Norman; Pietronigro, Dennis

2003-01-01

Abstract DTI-015 (BCNU in 100% ethanol) utilizes solvent facilitated perfusion for the intratumoral treatment of gliomas. The ethanol solvent vehicle facilitates a rapid and thorough saturation of the tumor with the dissolved anticancer agent BCNU. We conducted a phase I/II dose escalation study of DTI-015 in 40 heavily pretreated patients with inoperable recurrent malignant glioma. The study goals were to establish a maximally tolerated dose (MTD) for DTI-015 and assess its safety and activity. Patients received stereotactic intratumoral injection of DTI-015 under magnetic resonance imaging guidance. Dose escalation was performed in two phases. First, DTI-015 volume was escalated at a set BCNU concentration of 12.5 mg/ml; second, BCNU mg dose was escalated by increasing BCNU concentration to 30, 45, 60, and 75 mg/ml. A MTD of 5 ml and 240 mg was established. Twenty-five of 28 DTI-015 treatments (89%) using ≤MTD were administered safely without producing high-grade drug-related adverse events. Median survival for GBM patients administered DTI-015 at ≤MTD was 55 weeks. Magnetic resonance imaging demonstrated stable disease in 72% of evaluable patients with a median of 10.5 weeks. The results suggest that DTI-015 administered at ≤MTD is well tolerated and active in patients with inoperable recurrent GBM. PMID:12659665

Red cell aspartate aminotransferase saturation with oral pyridoxine intake.

PubMed

Oshiro, Marilena; Nonoyama, Kimiyo; Oliveira, Raimundo Antônio Gomes; Barretto, Orlando Cesar de Oliveira

2005-03-02

The coenzyme of aspartate aminotransferase is pyridoxal phosphate, generated from fresh vegetables containing pyridoxine. Vitamin B6-responsive sideroblastic anemia, myelofibrosis and Peyronies syndrome respond to high pyridoxine doses. The objective was to investigate the oral pyridoxine oral dose that would lead to maximized pyridoxal phosphate saturation of red cell aspartate aminotransferase. Controlled trial, in Hematology Division of Instituto Adolfo Lutz. Red cell aspartate aminotransferase activity was assayed (before and after) in normal volunteers who were given oral pyridoxine for 15-18 days (30 mg, 100 mg and 200 mg daily). In vitro study of blood from seven normal volunteers was also performed, with before and after assaying of aspartate aminotransferase activity. The in vivo study showed increasing aspartate aminotransferase saturation with increasing pyridoxine doses. 83% saturation was reached with 30 mg daily, 88% with 100 mg, and 93% with 200 mg after 20 days of oral supplementation. The in vitro study did not reach 100% saturation. Neither in vivo nor in vitro study demonstrated thorough aspartate aminotransferase saturation with its coenzyme pyridoxal phosphate in red cells, from increasing pyridoxine supplementation. However, the 200-mg dose could be employed safely in vitamin B6-responsive sideroblastic anemia, myelofibrosis and Peyronies syndrome treatment. Although maximum saturation in circulating red cells is not achieved, erythroblasts and other nucleated and cytoplasmic organelles containing cells certainly will reach thorough saturation, which possibly explains the results obtained in these diseases.

Estimated Maximal Safe Dosages of Tumescent Lidocaine

PubMed Central

Jeske, Daniel R.

2016-01-01

BACKGROUND: Tumescent lidocaine anesthesia consists of subcutaneous injection of relatively large volumes (up to 4 L or more) of dilute lidocaine (≤1 g/L) and epinephrine (≤1 mg/L). Although tumescent lidocaine anesthesia is used for an increasing variety of surgical procedures, the maximum safe dosage is unknown. Our primary aim in this study was to measure serum lidocaine concentrations after subcutaneous administration of tumescent lidocaine with and without liposuction. Our hypotheses were that even with large doses (i.e., >30 mg/kg), serum lidocaine concentrations would be below levels associated with mild toxicity and that the concentration-time profile would be lower after liposuction than without liposuction. METHODS: Volunteers participated in 1 to 2 infiltration studies without liposuction and then one study with tumescent liposuction totally by local anesthesia. Serum lidocaine concentrations were measured at 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours after each tumescent lidocaine infiltration. Area under the curve (AUC∞) of the serum lidocaine concentration-time profiles and peak serum lidocaine concentrations (Cmax) were determined with and without liposuction. For any given milligram per kilogram dosage, the probability that Cmax >6 μg/mL, the threshold for mild lidocaine toxicity was estimated using tolerance interval analysis. RESULTS: In 41 tumescent infiltration procedures among 14 volunteer subjects, tumescent lidocaine dosages ranged from 19.2 to 52 mg/kg. Measured serum lidocaine concentrations were all <6 μg/mL over the 24-hour study period. AUC∞s with liposuction were significantly less than those without liposuction (P = 0.001). The estimated risk of lidocaine toxicity without liposuction at a dose of 28 mg/kg and with liposuction at a dose of 45 mg/kg was ≤1 per 2000. CONCLUSIONS: Preliminary estimates for maximum safe dosages of tumescent lidocaine are 28 mg/kg without liposuction and 45 mg/kg with liposuction. As a result of delayed systemic absorption, these dosages yield serum lidocaine concentrations below levels associated with mild toxicity and are a nonsignificant risk of harm to patients. PMID:26895001

Evaluating the Safety and Tolerability of Sacubitril/Valsartan for HFrEF Managed Within a Pharmacist Clinic.

PubMed

Pogge, Elizabeth K; Davis, Lindsay E

2018-04-01

The objective of this research was to describe the use of pharmacist-managed sacubitril/valsartan therapy in a multi-center, outpatient cardiac group. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNi), is a novel agent for the treatment of heart failure. An ARNi is recommended by national guidelines to be used in place of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy for patients who remain symptomatic. A retrospective chart review was performed to identify patients initiated and fully titrated on sacubitril/valsartan therapy from July 7, 2015 to March 7, 2017. Fifty-two of the 72 symptomatic heart failure with reduced ejection fraction (HFrEF) patients prescribed sacubitril/valsartan during the 21-month period were included in this analysis. The average ejection fraction was 26%. The average age was 69 years. At baseline, 26.9% of patients were not on ACEi/ARB therapy and 13.5% were on target-dose therapy. After completing the uptitration process, the maximally tolerated dose of sacubitril/valsartan was 5.8% low-dose, 7.7% mid-dose, and 86.5% target-dose. Loop and thiazide diuretic use decreased significantly. There was a significant mean reduction in systolic blood pressure of 6 mmHg with no significant changes in serum creatinine, blood urea nitrogen, or potassium levels. With close monitoring and follow-up, ARNi therapy was a safe alternative to ACEi/ARB therapy for chronic symptomatic HFrEF when initiated within a pharmacist clinic.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy.

PubMed

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue; Wu, Yuan-Hung

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy

PubMed Central

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting. PMID:28662135

A phase I study of Foscan-mediated photodynamic therapy and surgery in patients with mesothelioma.

PubMed

Friedberg, Joseph S; Mick, Rosemarie; Stevenson, James; Metz, James; Zhu, Timothy; Buyske, Jo; Sterman, Daniel H; Pass, Harvey I; Glatstein, Eli; Hahn, Stephen M

2003-03-01

Photodynamic therapy (PDT) is a light-based cancer treatment that, in the correct setting, can be delivered intraoperatively as an adjuvant therapy. A phase I clinical trial combining surgical debulking with Foscan-mediated PDT was performed in patients with malignant pleural mesothelioma. The purpose of the study was to define the toxicities and to determine the maximally tolerated dose (MTD) of Foscan-mediated PDT. A total of 26 patients completed treatment. Tumor debulking was accomplished with either an extrapleural pneumonectomy (7 patients) or a lung-sparing pleurectomy-decortication (19 patients). Patients were injected with Foscan before surgery, and 652 nm light was delivered intraoperatively after completion of surgical debulking. Four light sensors were placed in the chest, allowing delivery of light to a uniform measured dose throughout the hemithorax. Four dose levels were explored. The MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J x cm(-2) 652 nm light. Dose limiting toxicity at the next higher dose was a systemic capillary leak syndrome leading to death in 2 of 3 patients treated at that dose. Other PDT-related toxicities included wound burns and skin photosensitivity. In all, 14 patients were treated at the MTD without significant complications. Foscan-mediated PDT can be safely combined with surgery at the established MTD. Unlike most other surgery-based multimodal treatments for mesothelioma, Foscan-mediated PDT affords the option, in selected patients, of accomplishing tumor debulking with a lung-sparing procedure rather than an extrapleural pneumonectomy. A phase II study is warranted.

Application of a Pharmacokinetic Model of Metformin Clearance in a Population with Acute Myeloid Leukemia

PubMed Central

Ceacareanu, Alice C.; Brown, Geoffrey W.; Moussa, Hoda A.; Wintrob, Zachary A. P.

2018-01-01

Objective: We aimed to estimate the metformin-associated lactic acidosis (MALA) risk by assessing retrospectively the renal clearance variability and applying a pharmacokinetic (PK) model of metformin clearance in a population diagnosed with acute myeloid leukemia (AML) and diabetes mellitus (DM). Methods: All adults with preexisting DM and newly diagnosed AML at Roswell Park Cancer Institute were reviewed (January 2003–December 2010, n = 78). Creatinine clearance (CrCl) and total body weight distributions were used in a two-compartment PK model adapted for multiple dosing and modified to account for actual intra- and inter-individual variability. Based on this renal function variability evidence, 1000 PK profiles were simulated for multiple metformin regimens with the resultant PK profiles being assessed for safe CrCl thresholds. Findings: Metformin 500 mg up to three times daily was safe for all simulated profiles with CrCl ≥25 mL/min. Furthermore, the estimated overall MALA risk was below 10%, remaining under 5% for 500 mg given once daily. CrCl ≥65.25 mL/min was safe for administration in any of the tested regimens (500 mg or 850 mg up to three times daily or 1000 mg up to twice daily). Conclusion: PK simulation-guided prescribing can maximize metformin's beneficial effects on cancer outcomes while minimizing MALA risk. PMID:29755998

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides

PubMed Central

Schuchardt, Christiane; Kulkarni, Harshad R.; Shahinfar, Mostafa; Singh, Aviral; Glatting, Gerhard; Baum, Richard P.; Beer, Ambros J.

2016-01-01

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25−29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1–3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably. PMID:27611841

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.

PubMed

Kletting, Peter; Schuchardt, Christiane; Kulkarni, Harshad R; Shahinfar, Mostafa; Singh, Aviral; Glatting, Gerhard; Baum, Richard P; Beer, Ambros J

2016-01-01

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25-29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1-3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably.

Exercise recommendations for childhood cancer survivors exposed to cardiotoxic therapies: an institutional clinical practice initiative.

PubMed

Okada, Maki; Meeske, Kathleen A; Menteer, Jondavid; Freyer, David R

2012-01-01

Childhood cancer survivors who have received treatment with anthracyclines are at risk for developing cardiomyopathy in dose-dependent fashion. Historically, restrictions on certain types of physical activity that were intended to preserve cardiac function have been recommended, based on a mixture of evidence-based and consensus-based recommendations. In the LIFE Cancer Survivorship & Transition Program at Children's Hospital Los Angeles, the authors reevaluated their recommendations for exercise in survivors who were exposed to anthracyclines, with or without irradiation in proximity to the myocardium. The primary goal was to develop consistent, specific, practical, safe, and (where possible) evidence-based recommendations for at-risk survivors in the program. To accomplish this, the authors referred to current exercise guidelines for childhood cancer survivors, consulted recent literature for relevant populations, and obtained input from the program's pediatric cardiology consultant. The resulting risk-based exercise recommendations are designed to complement current published guidelines, maximize safe exercise, and help childhood cancer survivors return to a normal life that emphasizes overall wellness and physical activity. This article describes a single institution's experience in modifying exercise recommendations for at-risk childhood survivors and includes the methods, findings, and current institutional practice recommendations along with sample education materials.

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

Pokhrel, D; Sood, S; Badkul, R

Purpose: To compare dose distributions calculated using PB-hete vs. XVMC algorithms for SRT treatments of cavernous sinus tumors. Methods: Using PB-hete SRT, five patients with cavernous sinus tumors received the prescription dose of 25 Gy in 5 fractions for planning target volume PTV(V100%)=95%. Gross tumor volume (GTV) and organs at risk (OARs) were delineated on T1/T2 MRI-CT-fused images. PTV (range 2.1–84.3cc, mean=21.7cc) was generated using a 5mm uniform-margin around GTV. PB-hete SRT plans included a combination of non-coplanar conformal arcs/static beams delivered by Novalis-TX consisting of HD-MLCs and a 6MV-SRS(1000 MU/min) beam. Plans were re-optimized using XVMC algorithm with identicalmore » beam geometry and MLC positions. Comparison of plan specific PTV(V99%), maximal, mean, isocenter doses, and total monitor units(MUs) were evaluated. Maximal dose to OARs such as brainstem, optic-pathway, spinal cord, and lenses as well as normal tissue volume receiving 12Gy(V12) were compared between two algorithms. All analysis was performed using two-tailed paired t-tests of an upper-bound p-value of <0.05. Results: Using either algorithm, no dosimetrically significant differences in PTV coverage (PTVV99%,maximal, mean, isocenter doses) and total number of MUs were observed (all p-values >0.05, mean ratios within 2%). However, maximal doses to optic-chiasm and nerves were significantly under-predicted using PB-hete (p=0.04). Maximal brainstem, spinal cord, lens dose and V12 were all comparable between two algorithms, with exception of one patient with the largest PTV who exhibited 11% higher V12 with XVMC. Conclusion: Unlike lung tumors, XVMC and PB-hete treatment plans provided similar PTV coverage for cavernous sinus tumors. Majority of OARs doses were comparable between two algorithms, except for small structures such as optic chiasm/nerves which could potentially receive higher doses when using XVMC algorithm. Special attention may need to be paid on a case-by-case basis when planning for sinus SRT based on tumor size and location to OARs particularly the optic apparatus.« less

EMP Attachment 3 DOE-SC PNNL Site Dose Assessment Guidance

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

Snyder, Sandra F.

2011-12-21

This Dose Assessment Guidance (DAG) describes methods to use to determine the Maximally-Exposed Individual (MEI) location and to estimate dose impact to that individual under the U.S. Department of Energy Office of Science (DOE-SC) Pacific Northwest National Laboratory (PNNL) Site Environmental Monitoring Plan (EMP). This guidance applies to public dose from radioactive material releases to the air from PNNL Site operations. This document is an attachment to the Pacific Northwest National Laboratory (PNNL) Environmental Monitoring Plan (EMP) and describes dose assessment guidance for radiological air emissions. The impact of radiological air emissions from the U.S. Department of Energy Office ofmore » Science (DOE-SC) PNNL Site is indicated by dose estimates to a maximally exposed member of the public, referred to as the maximally exposed individual (MEI). Reporting requirements associated with dose to members of the public from radiological air emissions are in 40 CFR Part 61.94, WAC 246-247-080, and DOE Order 458.1. The DOE Order and state standards for dose from radioactive air emissions are consistent with U.S. Environmental Protection Agency (EPA) dose standards in 40 CFR 61.92 (i.e., 10 mrem/yr to a MEI). Despite the fact that the current Contract Requirements Document (CRD) for the DOE-SC PNNL Site operations does not include the requirement to meet DOE CRD 458.1, paragraph 2.b, public dose limits, the DOE dose limits would be met when EPA limits are met.« less

Round table on RU486.

PubMed

Shallat, L

1993-01-01

As a non-invasive means of early abortion, RU-486 has the potential to increase women's reproductive options; at the same time, the "abortion pill" has stimulated debate about the ethics and safety of new medical technologies. When combined with a prostaglandin (PG), the success rate for RU-486 is 96% for pregnancies of up to 9 weeks' gestation. In France, over 120,000 women have used RU-486/PG to terminate pregnancy, and this regimen is now used in about 25% of abortions. Clinical trials of RU-486 are underway in Cuba, China, India, Singapore, and Zambia. The Program for Appropriate Technology has identified four considerations for introducing RU-486 to developing countries: whether abortion or menstrual regulation is legal; whether women find the method acceptable and can comply with the multiple visit treatment regimen; whether the health infrastructure can support safe method use, including prevention of misuse and provision of appropriate medical backup personnel and facilities; and whether the cost of the regimen is affordable to individuals and/or programs --conditions unlikely to be met in most such countries. Ideal would be development of a medical abortifacient that is single dose and the lowest possible dose of each drug, provokes miscarriage within a more predictable time frame with less acute and prolonged bleeding, is safe and effective beyond two months, has minimal side effects, and maximizes short-term safety and minimizes long-term effects. Technological advances are being undermined, however, by political and religious attacks on the method. Even some feminists have expressed concerns about potential long-term effects of RU-486 use.

Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice.

PubMed

Socała, Katarzyna; Nieoczym, Dorota; Kowalczuk-Vasilev, Edyta; Wyska, Elżbieta; Wlaź, Piotr

2017-07-01

Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. In addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD 50 value of sulforaphane in mice was estimated at 212.67mg/kg, while the TD 50 value - at 191.58mg/kg. In seizure tests, sulforaphane at the highest dose tested (200mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6Hz-induced psychomotor seizure. At doses of 10-200mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150-300mg/kg), hypothermia (at 150-300mg/kg), impairment of motor coordination (at 200-300mg/kg), decrease in skeletal muscle strength (at 250-300mg/kg), and deaths (at 200-300mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200mg/kg. In conclusion, since sulforaphane was proconvulsant at a toxic dose, the safety profile and the risk-to-benefit ratio of sulforaphane usage in epileptic patients should be further evaluated. Copyright © 2017 Elsevier Inc. All rights reserved.

Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects

PubMed Central

German, Polina; Kearney, Brian P.; Yang, Cheng Yong; Brainard, Diana; Link, John; McNally, John; Han, LingLing; Ling, John; Mathias, Anita

2017-01-01

ABSTRACT Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable in vitro and in vivo properties, including potent antiviral activity against hepatitis C virus genotype 1 to 6 replicons, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties, to warrant clinical evaluation. The phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple (n = 7) once-daily ascending doses and of VEL in the presence and absence of food. Following administration of single and multiple doses, VEL was safe and well tolerated when administered at up to 450 mg and when administered with food. The pharmacokinetic behavior of VEL observed in humans was generally in agreement with that seen during preclinical characterization. Following administration of multiple doses, VEL trough concentrations were significantly greater than the protein-adjusted half-maximal (50%) effective concentration of VEL against HCV genotype 1 to 6 replicons at all evaluated doses greater than 5 mg. The pharmacokinetics of VEL were not significantly affected by administration with food. Collectively, the results of this study support the further clinical investigation of VEL administered once daily as part of a regimen with other pangenotypic direct-acting antivirals for the treatment of HCV infection. PMID:28193657

Effect of Low-Dose Aspirin on Chronic Acid Reflux Esophagitis in Rats.

PubMed

Masuda, Takahiro; Yano, Fumiaki; Omura, Nobuo; Tsuboi, Kazuto; Hoshino, Masato; Yamamoto, Se Ryung; Akimoto, Shunsuke; Kashiwagi, Hideyuki; Yanaga, Katsuhiko

2018-01-01

Clinical role of low-dose aspirin (LDA) in pathogenesis of gastroesophageal reflux disease is by far controversial. This can be attributed to the paucity of basic research detailing the mechanism of LDA-induced esophageal mucosal injury (EI) on underlying chronic acid reflux esophagitis (RE). The aim of this study was to clarify the effect of LDA on chronic RE in rats. Esophagitis was induced in 8-week-old male Wistar rats by ligating the border between forestomach and glandular portion with a 2-0 silk tie and covering the duodenum with a small piece of 18-Fr Nélaton catheter. Seventy-eight chronic RE rat models were divided into five treatment groups, consisting of orally administered vehicle (controls), and aspirin doses of 2, 5, 50 or 100 mg/kg once daily for 28 days. EI was assessed by gross area of macroscopic mucosal injury, severity grade of esophagitis and microscopic depth of infiltration by inflammatory cells. Area of esophagitis in animals with aspirin dose of 100 mg/kg/day showed a 36.5% increase compared with controls, although it failed to achieve statistical significance (p = 0.812). Additionally, the rate of severe EI was increased in animals with aspirin dose of 100 mg/kg/day as compared with controls (p < 0.05). The grade of severity correlated with the depth of inflammation (r s  = 0.492, p < 0.001). Maximal dose aspirin (100 mg/kg/day) contributed in exacerbating preexisting EI. LDA (2 and 5 mg/kg/day), on the other hand, did not affect chronic RE in this model. LDA seems to be safe for use in patients with chronic RE.

Pre- and postnatal toxicity induced in guinea pigs by N-nitrosomethylurea.

PubMed

Hasumi, K; Wilber, J H; Berkowitz, J; Wilber, R G; Epstein, S S

1975-10-01

Oral administration of N-nitrosomethylurea at maximally tolerated doses to guinea pigs on alternate days from days 34-58 of pregnancy induced prenatal toxicity, as evidenced by a high frequency of stillbirths and intrauterine growth retardation, and postnatal toxicity, as evidenced by stunting and progressive mortality. Similar administration of N-nitrosomethylurethane at maximally tolerated doses did not induce such toxic effects.

A Phase I Study of Light Dose for Photodynamic Therapy (PDT) Using 2-[1-hexyloxyethyl]-2 devinyl Pyropheophorbide-a (HPPH) for Treatment of Non-small Cell Carcinoma in situ or Non-small Cell Microinvasive Bronchogenic Carcinoma. A Dose Ranging Study

PubMed Central

Dhillon, Samjot Singh; Demmy, Todd L.; Yendamuri, Sai; Loewen, Gregory; Nwogu, Chukwumere; Cooper, Michele; Henderson, Barbara W.

2015-01-01

Introduction We report a phase I trial of photodynamic therapy (PDT) of carcinoma-insitu (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH). HPPH has the advantage of minimal general phototoxicity over the commonly used PS porfimer sodium (Photofrin®). Methods The objectives of this study were 1) to determine the maximally tolerated light dose at a fixed PS dose and 2) to gain initial insight into the effectiveness of this treatment approach. Seventeen patients with 21 CIS/MIC lesions were treated with HPPH with light dose escalation starting from 75 J/cm2 to 85, 95,125, and 150 J/cm2 respectively. Follow-up bronchoscopy for response assessment was done at one and six months, respectively. Results The rate of pathological complete response (CR) was 82.4% (14/17 evaluable lesions; 14 patients) at one-month and 72.7% (8/11 lesions; 8 patients) at 6 months. Only 4 patients developed mild skin erythema. One of the three patients in 150 J/cm2 light dose group experienced a serious adverse event. This patient had respiratory distress due to mucus plugging, which precipitated cardiac ischemia. Two additional patients treated subsequently at this light dose had no adverse events. The third sixth patient in this dose group was not recruited and the study was terminated because of delays in HPPH supply. However, given the observed serious adverse event, it is recommended that the light dose not exceed 125J/cm2. Conclusions PDT with HPPH can be safely used for the treatment of CIS/MIC of the airways, with potential effectiveness comparable to that reported for porfimer sodium in earlier studies. PMID:26718878

The maximal cumulative solar UVB dose allowed to maintain healthy and young skin and prevent premature photoaging.

PubMed

Ichihashi, Masamitsu; Ando, Hideya

2014-10-01

The young facial skin of children with a smooth healthy appearance changes over time to photoaged skin having mottled pigmentation, solar lentigines, wrinkles, dry and rough skin, leathery texture, and benign and malignant tumors after exposure to chronic, repeated solar radiation. The first sign of photoaging in Japanese subjects is usually solar lentigines appearing around 20 years of age on the face. Fine wrinkles can then appear after 30 years of age, and benign skin tumors, seborrhoeic keratoses, can occur after 35 years of age in sun-exposed skin. We theoretically calculated the maximal daily exposure time to solar radiation, which could prevent the development of photoaged skin until 60 and 80 years of age, based on published data of personal solar UVB doses in sun-exposed skin. One MED (minimal erythema dose) was determined to be 20 mJ/cm(2) , and 200 MED was used as the average yearly dose of Japanese children. Further, we hypothesized that the annual dose of Japanese adults is the same as that of the children. The cumulative UVB dose at 20 years of age was thus calculated to be 4000 MED, and 22 MED was used as the maximal daily UVB dose based on data measured in Kobe, located in the central area of Japan. We used the solar UVB dose from 10:00 a.m. to 14:00 p.m. which occupies 60% of the total daily UV dose, to obtain the maximal UVB per hour in a day, and calculated the maximal daily UV exposure time that would delay the onset of solar lentigines until 60 or 80 years of age. The mean daily sun exposure time to maintain healthy skin until 80 years of age in the summer was calculated to be 2.54 min (0.14 MED) for unprotected skin and 127 min with the use of a sunscreen of SPF (sun protection factor) of 50. In this study, we did not evaluate the photoaging effect of UVA radiation, but findings of the adverse effects of UVA radiation on the skin have accumulated in the last decade. Therefore, it will be important to estimate the maximal dose of solar UV radiation to retard the onset of photoaging based on an evaluation of both solar UVB and UVA in the future. Finally, we expect that this study may contribute to keeping Japanese and other types of skin young and healthy by limiting the exposure of the skin to solar radiation outdoors during the day. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Safety and Efficacy of Docetaxel, Bevacizumab, and Everolimus for Castration-resistant Prostate Cancer (CRPC).

PubMed

Gross, Mitchell E; Dorff, Tanya B; Quinn, David I; Diaz, Patricia M; Castellanos, Olga O; Agus, David B

2017-07-14

Previous data suggests that co-targeting mammalian target of rapamycin and angiogenic pathways may potentiate effects of cytotoxic chemotherapy. We studied combining mammalian target of rapamycin and vascular endothelial growth factor inhibition with docetaxel in castrate-resistant prostate cancer (CRPC). Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Docetaxel and bevacizumab were given intravenously day 1 with everolimus orally daily on a 21-day cycle across 3 dose levels (75:15:2.5, 75:15:5, and 65:15:5; docetaxel mg/m 2 , mg/kg bevacizumab, and mg everolimus, respectively). Maintenance therapy with bevacizumab/everolimus without docetaxel was allowed after ≥ 6 cycles. Forty-three subjects were treated across all dose levels. Maximal tolerated doses for the combined therapies observed in the phase 1B portion of the trial were: docetaxel 75 mg/m 2 , bevacizumab 15 mg/kg, and everolimus 2.5 mg. Maximal prostate-specific antigen decline ≥ 30% and ≥ 50% was achieved in 33 (79%) and 31 (74%) of patients, respectively. Best response by modified Response Evaluation Criteria In Solid Tumors criteria in 25 subjects with measurable disease at baseline included complete or partial response in 20 (80%) patients. The median progression-free and overall survival were 8.9 months (95% confidence interval, 7.4-10.6 months) and 21.9 months (95% confidence interval, 18.4-30.3 months), respectively. Hematologic toxicities were the most common treatment-related grade ≥ 3 adverse events including: febrile neutropenia (12; 28%), lymphopenia (12; 28%), leukocytes (10; 23%), neutrophils (9; 21%), and hemoglobin (2; 5%). Nonhematologic grade ≥ 3 adverse events included: hypertension (8; 19%), fatigue (3; 7%), pneumonia (3; 7%), and mucositis (4; 5%). There was 1 treatment-related death owing to neutropenic fever and pneumonia in a patient treated at dose level 3 despite dose modifications and prophylactic growth factor support. Docetaxel, bevacizumab, and everolimus can be safely administered in CRPC and demonstrate a significant level of anticancer activity, meeting the predetermined response criteria. However, any potential benefit of combined therapy must be balanced against increased risk for toxicities. Our results do not support the hypothesis that this combination of agents improves upon the results obtained with docetaxel monotherapy in an unselected population of chemotherapy-naive patients with CRPC. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York Heart Association class-III heart failure.

PubMed

Tauchert, Michael

2002-05-01

The purpose of this study was to investigate whether long-term therapy with crataegus extract WS 1442 is efficacious as add-on therapy to preexisting diuretic treatment in patients with heart failure with a more advanced stage of the disease (New York Heart Association [NYHA] class III), whether effects are dose dependent, and whether the treatment is safe and well tolerated. Exercise capacity was assessed by use of seated bicycle ergometry with incremental workloads. Scores for subjective symptoms and complaints made by the patients were analyzed. Efficacy and tolerability of the treatments were judged by both the patients and investigators. Safety was assessed by the documentation of adverse events and the safety laboratory. A total of 209 patients were randomized to treatment with 1800 mg of WS 1442, 900 mg of WS 1442, or with placebo. After 16 weeks of therapy with 1800 mg of WS 1442 per day, maximal tolerated workload during bicycle exercise showed a statistically significant increase in comparison with both placebo and 900 mg of WS 1442. Typical heart failure symptoms as rated by the patients were reduced to a greater extent by WS 1442 than by placebo. This difference was significant for both doses of WS 1442. Both efficacy and tolerability were rated best for the 1800 mg of WS 1442 group by patients and investigators alike. The incidence of adverse events was lowest in the 1800 mg of WS 1442 group, particularly with respect to dizziness and vertigo. The data from this study confirm that there is a dose-dependent effect of WS 1442 on the exercise capacity of patients with heart failure and on typical heart failure-related clinical signs and symptoms. The drug was shown to be well tolerated and safe.

Citalopram in mentally retarded patients with depression: a long-term clinical investigation.

PubMed

Verhoeven, W M; Veendrik-Meekes, M J; Jacobs, G A; van den Berg, Y W; Tuinier, S

2001-03-01

The effect of citalopram was investigated in 20 mentally retarded patients suffering from a depressive disorder characterized by alterations in the domains of affectivity, motivation, motor activity and vital signs. The study followed a baseline-controlled open design. Citalopram was started in a daily dosage of 20 mg that was kept unchanged for 6 weeks. Thereafter dosage was adjusted to maximally 60 mg per day. Treatment effects were assessed according to the Clinical Global Improvement Scale (CGIS) after at least 6 months. In 12 of the 20 patients a moderate to marked improvement in all domains was observed upon treatment with 20-40 mg citalopram daily. Treatment for one year in the effective dose prevented recurrence of depressive symptomatology. Concomitant use of sedative anticonvulsants reduced responsiveness to treatment. No interactions were observed. It is concluded that citalopram is a well-tolerated, safe and effective antidepressant in mentally retarded subjects with depressive disorders.

Recurrent intracranial Rosai-Dorfman disease: Management of a challenging case.

PubMed

Das, Sudeep; Biswas, Ahitagni; Roy, Soumyajit; Sable, Mukund N; Singh, Daljit; Jana, Manisha; Sharma, Mehar Chand; Julka, Pramod Kumar

2017-01-01

Rosai-Dorfman disease (RDD) is a rare, idiopathic, benign histioproliferative disorder. Extranodal involvement is seen in around 25-40% of patients. Central nervous system manifestation of RDD is uncommon and suprasellar location of the lesion is a distinct rarity. Surgery is the cornerstone of management of intracranial RDD. However, tumor recurrence or regrowth is a potential problem. Hence, low dose conformal radiotherapy (RT) should be considered in patients undergoing sub-total resection or having unresectable recurrent disease. Though cranial RT usually leads to satisfactory improvement of symptoms and long-term disease stabilization or regression, in few patients there may be an eventual progression of disease for which systemic chemotherapy may be considered. We have highlighted the salient features of this enigmatic disease by citing a case of a 50-year-old male patient with suprasellar RDD treated by maximal safe surgery and deferred radiation therapy on progression.

Revisiting RAAS blockade in CKD with newer potassium-binding drugs.

PubMed

Georgianos, Panagiotis I; Agarwal, Rajiv

2018-02-01

Among patients with proteinuric chronic kidney disease (CKD), current guideline recommendations mandate the use of agents blocking the renin angiotensin aldosterone system (RAAS) as first-line antihypertensive therapy based on randomized trials demonstrating that RAAS inhibitors are superior to other antihypertensive drug classes in slowing nephropathy progression to end-stage renal disease. However, the opportunities for adequate RAAS blockade in CKD are often limited, and an important impediment is the risk of hyperkalemia, especially when RAAS inhibitors are used in maximal doses or are combined. Accordingly, a large proportion of patients with proteinuric CKD may not have the anticipated renoprotective benefits since RAAS blockers are often discontinued due to incident hyperkalemia or are administered at suboptimal doses for fear of the development of hyperkalemia. Two newer potassium binders, patiromer and sodium zirconium cyclosilicate (ZS-9), have been shown to effectively and safely reduce serum potassium levels and maintain long-term normokalemia in CKD patients receiving background therapy with RAAS inhibitors. Whether these novel potassium-lowering therapies can overcome the barrier of hyperkalemia and enhance the tolerability of RAAS inhibitor use in proteinuric CKD awaits randomized trials. Published by Elsevier Inc.

A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

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

Shaib, Walid L.; Hawk, Natalyn; Cassidy, Richard J.

Purpose: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV,more » and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.« less

Prenatal and postnatal toxicity induced in guinea-pigs by nitrosomethylurea.

PubMed

Epstein, S S; Hasumi, K; Iobal, Z M

1976-01-01

Oral administration of NMU at maximally tolerated doses of guinea-pigs from day 34 to 58 of pregnancy induced embryotoxic effects, as evidenced by a high incidence of stillbirths and reduction in birth weight, and postnatal toxic effects, as evidenced by stunting, progressive mortality and extensive fatty degeneration of the liver in F1 progeny. Similar administration of NMUT at maximally tolerated doses did not induce such toxic effects.

Subtle changes in brain functions produced by single doses of mevinphos (Phosdrin).

DOT National Transportation Integrated Search

1973-02-01

Mevinphos (Phosdrin) was found to inhibit the amplitude of hippocampal evoked potentials in unanesthetized squirrel monkeys with chronically indwelling electrodes. The threshold dose was 0.050 mg/kg and the maximal dose studied was 0.200 mg/kg. Doses...

Safely Intake Number of Macridiscus sp. (Kerang Ceplos) from Tambak Lorok Waters, Semarang, Central Java, Indonesia

NASA Astrophysics Data System (ADS)

Meirenno Tielman, Eduard; Suprijanto, Jusup; Widowati, Ita

2018-02-01

The dynamics pollution that supposed to be derived from industrial activities around Tambak Lorok waters will affect the quality of waters, and also biota such as Macridiscus sp. mussels (Kerang Ceplos) that live and accumulate pollutants such as heavy metals (Pb, Cu, Al, Mn and Fe). However, Macridiscus sp. mussels which have been contaminated by heavy metals is usually sold for consumption by the people and if they consume it in excess, it will be toxic in the people’s body. So that, this study was to analyze Safely Intake Number of Macridiscus sp. from Tambak Lorok waters. This study used AAS (Atomic Absorption Spectrophotometry) method to analyze the accumulation number of the pollutant (Pb, Cu, Al, Mn and Fe). Safely Intake Number calculation is used MWI (Maximal Weekly Intake) and MTI (Maximal Tolerable Intake) calculation method. The results of AAS showed that the highest numbers of pollutant was Al (reached 534,51 mg/kg in the body of Macridiscus sp. that taken in February, 2016) and has exceeded the safely intake number (MWI Al = 1 mg/kg, based on WHO/FAO) so that it’s MTI values was low (0,08 kg/week/person). It means that Macridiscus sp. was not safe to be consumed excessively at that time.

Extent of Resection in Glioma-A Review of the Cutting Edge.

PubMed

D'Amico, Randy S; Englander, Zachary K; Canoll, Peter; Bruce, Jeffrey N

2017-07-01

Modern glioma surgery has evolved from the principal belief that safe, maximal tumor resection improves symptom management, quality of life, progression-free survival, and overall survival in both low-grade and high-grade glioma. However, in the absence of level I data, the overwhelming support for this idea is derived largely from retrospective series. As a result, the influence of increasing extent of resection and reducing tumor burden on the efficacy of postoperative chemotherapy and radiotherapy, and survival, remains inadequately defined. This situation is particularly true because gliomas represent a widely heterogeneous group of tumors with varying behaviors and prognoses rooted in their complex molecular profile. The neurosurgical community has made a large effort to define the clinical benefits of maximizing tumor resection, with particular attention paid to the ever-evolving understanding of glioma molecular heterogeneity. Important new technologies have been developed concurrently to mitigate neurologic risks related to the pursuit of maximizing extent of resection. These advances reflect the modern goal of glioma surgery to find the optimal balance between tumor removal and neurologic compromise. We review the current literature supporting safe, maximal resection for gliomas. Copyright © 2017 Elsevier Inc. All rights reserved.

Can the risk of secondary cancer induction after breast conserving therapy be reduced using intraoperative radiotherapy (IORT) with low-energy x-rays?

PubMed

Aziz, Muhammad Hammad; Schneider, Frank; Clausen, Sven; Blank, Elena; Herskind, Carsten; Afzal, Muhammad; Wenz, Frederik

2011-12-16

Radiation induced secondary cancers are a rare but severe late effect after breast conserving therapy. Intraoperative radiotherapy (IORT) is increasingly used during breast conserving surgery. The purpose of this analysis was to estimate secondary cancer risks after IORT compared to other modalities of breast radiotherapy (APBI - accelerated partial breast irradiation, EBRT - external beam radiotherapy). Computer-tomography scans of an anthropomorphic phantom were acquired with an INTRABEAM IORT applicator (diameter 4 cm) in the outer quadrant of the breast and transferred via DICOM to the treatment planning system. Ipsilateral breast, contralateral breast, ipsilateral lung, contralateral lung, spine and heart were contoured. An INTRABEAM source (50 kV) was defined with the tip of the drift tube at the center of the spherical applicator. A dose of 20 Gy at 0 mm depth from the applicator surface was prescribed for IORT and 34 Gy (5 days × 2 × 3.4 Gy) at 10 mm depth for APBI. For EBRT a total dose of 50 Gy in 2 Gy fractions was planned using two tangential fields with wedges. The mean and maximal doses, DVHs and volumes receiving more than 0.1 Gy and 4 Gy of organs at risk (OAR) were calculated and compared. The life time risk for secondary cancers was estimated according to NCRP report 116. IORT delivered the lowest maximal doses to contralateral breast (< 0.3 Gy), ipsilateral (1.8 Gy) and contralateral lung (< 0.3 Gy), heart (1 Gy) and spine (< 0.3 Gy). In comparison, maximal doses for APBI were 2-5 times higher. EBRT delivered a maximal dose of 10.4 Gy to the contralateral breast and 53 Gy to the ipsilateral lung. OAR volumes receiving more than 4 Gy were 0% for IORT, < 2% for APBI and up to 10% for EBRT (ipsilateral lung). The estimated risk for secondary cancer in the respective OAR is considerably lower after IORT and/or APBI as compared to EBRT. The calculations for maximal doses and volumes of OAR suggest that the risk of secondary cancer induction after IORT is lower than compared to APBI and EBRT.

Vial usage, device dead space, vaccine wastage, and dose accuracy of intradermal delivery devices for inactivated poliovirus vaccine (IPV).

PubMed

Jarrahian, Courtney; Rein-Weston, Annie; Saxon, Gene; Creelman, Ben; Kachmarik, Greg; Anand, Abhijeet; Zehrung, Darin

2017-03-27

Intradermal delivery of a fractional dose of inactivated poliovirus vaccine (IPV) offers potential benefits compared to intramuscular (IM) delivery, including possible cost reductions and easing of IPV supply shortages. Objectives of this study were to assess intradermal delivery devices for dead space, wastage generated by the filling process, dose accuracy, and total number of doses that can be delivered per vial. Devices tested included syringes with staked (fixed) needles (autodisable syringes and syringes used with intradermal adapters), a luer-slip needle and syringe, a mini-needle syringe, a hollow microneedle device, and disposable-syringe jet injectors with their associated filling adapters. Each device was used to withdraw 0.1-mL fractional doses from single-dose IM glass vials which were then ejected into a beaker. Both vial and device were weighed before and after filling and again after expulsion of liquid to record change in volume at each stage of the process. Data were used to calculate the number of doses that could potentially be obtained from multidose vials. Results show wide variability in dead space, dose accuracy, overall wastage, and total number of doses that can be obtained per vial among intradermal delivery devices. Syringes with staked needles had relatively low dead space and low overall wastage, and could achieve a greater number of doses per vial compared to syringes with a detachable luer-slip needle. Of the disposable-syringe jet injectors tested, one was comparable to syringes with staked needles. If intradermal delivery of IPV is introduced, selection of an intradermal delivery device can have a substantial impact on vaccine wasted during administration, and thus on the required quantity of vaccine that needs to be purchased. An ideal intradermal delivery device should be not only safe, reliable, accurate, and acceptable to users and vaccine recipients, but should also have low dead space, high dose accuracy, and low overall wastage to maximize the potential number of doses that can be withdrawn and delivered. Copyright © 2017 PATH. Published by Elsevier Ltd.. All rights reserved.

Is There a Safe Level of Exposure to a Carcinogen?

ERIC Educational Resources Information Center

Hrudey, Steve E.; Krewski, Daniel

1995-01-01

Presents an approach to estimating the "safe" levels of low-dose exposure to carcinogens that involves working upward from the smallest conceivable chronic dose instead of extrapolating downward from high exposures. Discusses expert and public opinion and other issues related to quantitative cancer risk assessment. (LZ)

A safe and accurate method to perform esthetic mandibular contouring surgery for Far Eastern Asians.

PubMed

Hsieh, A M-C; Huon, L-K; Jiang, H-R; Liu, S Y-C

2017-05-01

A tapered mandibular contour is popular with Far Eastern Asians. This study describes a safe and accurate method of using preoperative virtual surgical planning (VSP) and an intraoperative ostectomy guide to maximize the esthetic outcomes of mandibular symmetry and tapering while mitigating injury to the inferior alveolar nerve (IAN). Twelve subjects with chief complaints of a wide and square lower face underwent this protocol from January to June 2015. VSP was used to confirm symmetry and preserve the IAN while maximizing the surgeon's ability to taper the lower face via mandibular inferior border ostectomy. The accuracy of this method was confirmed by superimposition of the perioperative computed tomography scans in all subjects. No subjects complained of prolonged paresthesia after 3 months. A safe and accurate protocol for achieving an esthetic lower face in indicated Far Eastern individuals is described. Copyright © 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

A comprehensive study on the relationship between the image quality and imaging dose in low-dose cone beam CT

NASA Astrophysics Data System (ADS)

Yan, Hao; Cervino, Laura; Jia, Xun; Jiang, Steve B.

2012-04-01

While compressed sensing (CS)-based algorithms have been developed for the low-dose cone beam CT (CBCT) reconstruction, a clear understanding of the relationship between the image quality and imaging dose at low-dose levels is needed. In this paper, we qualitatively investigate this subject in a comprehensive manner with extensive experimental and simulation studies. The basic idea is to plot both the image quality and imaging dose together as functions of the number of projections and mAs per projection over the whole clinically relevant range. On this basis, a clear understanding of the tradeoff between the image quality and imaging dose can be achieved and optimal low-dose CBCT scan protocols can be developed to maximize the dose reduction while minimizing the image quality loss for various imaging tasks in image-guided radiation therapy (IGRT). Main findings of this work include (1) under the CS-based reconstruction framework, image quality has little degradation over a large range of dose variation. Image quality degradation becomes evident when the imaging dose (approximated with the x-ray tube load) is decreased below 100 total mAs. An imaging dose lower than 40 total mAs leads to a dramatic image degradation, and thus should be used cautiously. Optimal low-dose CBCT scan protocols likely fall in the dose range of 40-100 total mAs, depending on the specific IGRT applications. (2) Among different scan protocols at a constant low-dose level, the super sparse-view reconstruction with the projection number less than 50 is the most challenging case, even with strong regularization. Better image quality can be acquired with low mAs protocols. (3) The optimal scan protocol is the combination of a medium number of projections and a medium level of mAs/view. This is more evident when the dose is around 72.8 total mAs or below and when the ROI is a low-contrast or high-resolution object. Based on our results, the optimal number of projections is around 90 to 120. (4) The clinically acceptable lowest imaging dose level is task dependent. In our study, 72.8 mAs is a safe dose level for visualizing low-contrast objects, while 12.2 total mAs is sufficient for detecting high-contrast objects of diameter greater than 3 mm.

A spatially encoded dose difference maximal intensity projection map for patient dose evaluation: A new first line patient quality assurance tool

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

Hu Weigang; Graff, Pierre; Boettger, Thomas

2011-04-15

Purpose: To develop a spatially encoded dose difference maximal intensity projection (DD-MIP) as an online patient dose evaluation tool for visualizing the dose differences between the planning dose and dose on the treatment day. Methods: Megavoltage cone-beam CT (MVCBCT) images acquired on the treatment day are used for generating the dose difference index. Each index is represented by different colors for underdose, acceptable, and overdose regions. A maximal intensity projection (MIP) algorithm is developed to compress all the information of an arbitrary 3D dose difference index into a 2D DD-MIP image. In such an algorithm, a distance transformation is generatedmore » based on the planning CT. Then, two new volumes representing the overdose and underdose regions of the dose difference index are encoded with the distance transformation map. The distance-encoded indices of each volume are normalized using the skin distance obtained on the planning CT. After that, two MIPs are generated based on the underdose and overdose volumes with green-to-blue and green-to-red lookup tables, respectively. Finally, the two MIPs are merged with an appropriate transparency level and rendered in planning CT images. Results: The spatially encoded DD-MIP was implemented in a dose-guided radiotherapy prototype and tested on 33 MVCBCT images from six patients. The user can easily establish the threshold for the overdose and underdose. A 3% difference between the treatment and planning dose was used as the threshold in the study; hence, the DD-MIP shows red or blue color for the dose difference >3% or {<=}3%, respectively. With such a method, the overdose and underdose regions can be visualized and distinguished without being overshadowed by superficial dose differences. Conclusions: A DD-MIP algorithm was developed that compresses information from 3D into a single or two orthogonal projections while hinting the user whether the dose difference is on the skin surface or deeper.« less

Adjunctive aripiprazole in the treatment of risperidone-induced hyperprolactinemia: A randomized, double-blind, placebo-controlled, dose-response study.

PubMed

Chen, Jing-Xu; Su, Yun-Ai; Bian, Qing-Tao; Wei, Li-He; Zhang, Rong-Zhen; Liu, Yan-Hong; Correll, Christoph; Soares, Jair C; Yang, Fu-De; Wang, Shao-Li; Zhang, Xiang-Yang

2015-08-01

Hyperprolactinemia is an unwanted adverse effect associated with several antipsychotics. The addition of partial dopamine receptor agonist aripiprazole may attenuate antipsychotic-induced hyperprolactinemia effectively. However, the ideal dosing regimen for this purpose is unknown. We aimed to evaluate the dose effects of adjunctive treatment with aripiprazole on prolactin levels and hyperprolactinemia in schizophrenia patients. Stable subjects 18-45 years old with schizophrenia and hyperprolactinemia (i.e., >24 ng/ml for females and >20 ng/ml for males) were randomly assigned to receive 8 weeks of placebo (n=30) or oral aripiprazole 5mg/day (n=30), 10mg/day (n=29), or 20mg/day (n=30) added on to fixed dose risperidone treatment. Serum prolactin levels were measured at baseline and after 2, 4 and 8 weeks; clinical symptoms and side effects were assessed at baseline and week 8 using the Positive and Negative Syndrome Scale, Clinical Global Impressions Severity scale, Barnes Akathisia Scale, Simpson-Angus Scale and UKU Side Effects Rating Scale. Of 119 randomized patients, 107 (89.9%) completed the 8-week study. At study end, all three aripiprazole doses resulted in significantly lower prolactin levels (beginning at week 2), higher response rates (≥30% prolactin reduction) and higher prolactin normalization rates than placebo. Effects were significantly greater in the 10 and 20mg/day groups than the 5mg/day group. No significant changes were observed in any treatment groups regarding psychopathology and adverse effect ratings. Adjunctive aripiprazole treatment was effective and safe for resolving risperidone-induced hyperprolactinemia, producing significant and almost maximal improvements by week 2 without significant effects on psychopathology and side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Using Opioids Safely After Surgery

MedlinePlus

... Adult , Geriatric Using Opioids Safely After Surgery Using Opioids Safely After Surgery Stick to the lowest dose ... need opioid pain medicine. If your doctor says opioids aren’t necessary. If your doctor thinks you ...

Comparative Benchmark Dose Modeling as a Tool to Make the First Estimate of Safe Human Exposure Levels to Lunar Dust

NASA Technical Reports Server (NTRS)

James, John T.; Lam, Chiu-wing; Scully, Robert R.

2013-01-01

Brief exposures of Apollo Astronauts to lunar dust occasionally elicited upper respiratory irritation; however, no limits were ever set for prolonged exposure ot lunar dust. Habitats for exploration, whether mobile of fixed must be designed to limit human exposure to lunar dust to safe levels. We have used a new technique we call Comparative Benchmark Dose Modeling to estimate safe exposure limits for lunar dust collected during the Apollo 14 mission.

Feasibility of TCP-based dose painting by numbers applied to a prostate case with (18)F-choline PET imaging.

PubMed

Dirscherl, Thomas; Rickhey, Mark; Bogner, Ludwig

2012-02-01

A biologically adaptive radiation treatment method to maximize the TCP is shown. Functional imaging is used to acquire a heterogeneous dose prescription in terms of Dose Painting by Numbers and to create a patient-specific IMRT plan. Adapted from a method for selective dose escalation under the guidance of spatial biology distribution, a model, which translates heterogeneously distributed radiobiological parameters into voxelwise dose prescriptions, was developed. At the example of a prostate case with (18)F-choline PET imaging, different sets of reported values for the parameters were examined concerning their resulting range of dose values. Furthermore, the influence of each parameter of the linear-quadratic model was investigated. A correlation between PET signal and proliferation as well as cell density was assumed. Using our in-house treatment planning software Direct Monte Carlo Optimization (DMCO), a treatment plan based on the obtained dose prescription was generated. Gafchromic EBT films were irradiated for evaluation. When a TCP of 95% was aimed at, the maximal dose in a voxel of the prescription exceeded 100Gy for most considered parameter sets. One of the parameter sets resulted in a dose range of 87.1Gy to 99.3Gy, yielding a TCP of 94.7%, and was investigated more closely. The TCP of the plan decreased to 73.5% after optimization based on that prescription. The dose difference histogram of optimized and prescribed dose revealed a mean of -1.64Gy and a standard deviation of 4.02Gy. Film verification showed a reasonable agreement of planned and delivered dose. If the distribution of radiobiological parameters within a tumor is known, this model can be used to create a dose-painting by numbers plan which maximizes the TCP. It could be shown, that such a heterogeneous dose distribution is technically feasible. Copyright © 2012. Published by Elsevier GmbH.

Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure.

PubMed

Simunkova, Katerina; Jovanovic, Nevena; Rostrup, Espen; Methlie, Paal; Øksnes, Marianne; Nilsen, Roy Miodini; Hennø, Hanne; Tilseth, Mira; Godang, Kristin; Kovac, Ana; Løvås, Kristian; Husebye, Eystein S

2016-01-01

Many patients with primary adrenal insufficiency (Addison's disease) take extra doses of glucocorticoids during stressful events, but a benefit has not been demonstrated in controlled trials. Here, we investigated the effects of a pre-exercise hydrocortisone dose on cardiorespiratory, hormonal and metabolic parameters in response to short-term strenuous physical activity. This was a randomized placebo-controlled, two-week cross-over clinical trial. Ten women with Addison's disease and 10 age-matched healthy females participated in the study. All women in the study underwent maximal incremental exercise testing. A stress dose of 10 mg hydrocortisone or placebo was given 1 h prior to exercise on two occasions. Blood samples were drawn before, and 0, 15 and 30 min post exercise. Oxygen uptake, maximal aerobic capacity, endocrine and metabolic responses to physical activity, as well as health status by questionnaires were evaluated. Maximal aerobic capacity and duration of exercise were significantly lower in patients than in healthy subjects and did not improve with the treatment. After an extra hydrocortisone dose serum cortisol was significantly higher than in the healthy subjects (P<0.001). Post-exercise glucose and adrenaline levels were significantly lower and free fatty acids insignificantly higher in patients irrespective of stress dose. Stress dosing did not alter other metabolic or hormonal parameters or quality of life after the exercise. The patients did not benefit from an extra dose of hydrocortisone in short strenuous exercise. Stress dosing may not be justified in this setting. Whether stress dosing is beneficial in other types of physical activity will have to be examined further. © 2016 European Society of Endocrinology.

Initial results utilizing combination therapy for patients with a suboptimal response to either alprostadil or sildenafil monotherapy.

PubMed

Mydlo, J H; Volpe, M A; Macchia, R J

2000-07-01

Intraurethral alprostadil and oral sildenafil are useful in selected patients. However, there continues to be a significant treatment failure rate. Since their mechanisms of action are different, we wanted to evaluate the effectiveness of combination therapy. Of 214 patients treated for erectile dysfunction (ED), 65 were not fully satisfied with the firmness of their erections via monotherapy. Responses were evaluated using the International Index for Erectile Function (IIEF) questionnaire before and after treatment. Group I consisted of 33 patients who tried maximal dose intraurethral alprostadil monotherapy initially, followed by the maximal dose of sildenafil monotherapy, and were still unsatisfied. Group II consisted of 32 patients who tried the maximal dose sildenafil monotherapy initially, followed by the maximal dose of alprostadil monotherapy, and were also unsatisfied. There 65 patients then underwent combination therapy. 60 out of the 65 patients stated they were satisfied with combination therapy. Questionnaire scores for erectile function were 23.1+/-2.0 (114%) for combination therapy vs. 19.2+/-1.8 (77%) and 15.2+/-1.6 (41%) for sildenafil and alprostadil monotherapies (p<0.05). There were no significant differences in responses between the two groups. The men also reported improvement in intercourse and overall satisfaction. Combination therapy may be an option for motivated patients who have a suboptimal response from monotherapy.

Oral Sulforaphane increases Phase II antioxidant enzymes in the human upper airway

PubMed Central

Riedl, Marc A.; Saxon, Andrew; Diaz-Sanchez, David

2009-01-01

Background Cellular oxidative stress is an important factor in asthma and is thought to be the principle mechanism by which oxidant pollutants such as ozone and particulates mediate their pro-inflammatory effects. Endogenous Phase II enzymes abrogate oxidative stress through the scavenging of reactive oxygen species and metabolism of reactive chemicals. Objective We conducted a placebo-controlled dose escalation trial to investigate the in vivo effects of sulforaphane, a naturally occurring potent inducer of Phase II enzymes, on the expression of glutathione-s-transferase M1 (GSTM1), glutathione-s-transferase P1 (GSTP1), NADPH quinone oxidoreductase (NQO1), and hemoxygenase-1 (HO-1) in the upper airway of human subjects. Methods Study subjects consumed oral sulforaphane doses contained in a standardized broccoli sprout homogenate (BSH). RNA expression for selected Phase II enzymes was measured in nasal lavage cells by RT-PCR before and after sulforaphane dosing. Results All subjects tolerated oral sulforaphane dosing without significant adverse events. Increased Phase II enzyme expression in nasal lavage cells occurred in a dose-dependent manner with maximal enzyme induction observed at the highest dose of 200 grams broccoli sprouts prepared as BSH. Significant increases were seen in all sentinel Phase II enzymes RNA expression compared to baseline. Phase II enzyme induction was not seen with ingestion of non-sulforaphane containing alfalfa sprouts. Conclusion Oral sulforaphane safely and effectively induces mucosal Phase II enzyme expression in the upper airway of human subjects. This study demonstrates the potential of antioxidant Phase II enzymes induction in the human airway as a strategy to reduce the inflammatory effects of oxidative stress. Clinical Implications This study demonstrates the potential of enhancement of Phase II enzyme expression as a novel therapeutic strategy for oxidant induced airway disease. Capsule Summary A placebo-controlled dose escalation trial demonstrated that naturally occurring sulforaphane from broccoli sprouts can induce a potent increase in antioxidant Phase II enzymes in airway cells. PMID:19028145

Opioid receptor mediated anticonvulsant effect of pentazocine.

PubMed

Khanna, N; Khosla, R; Kohli, J

1998-01-01

Intraperitoneal (i.p.) administration of (+/-) pentazocine (10, 30 & 50 mg/kg), a Sigma opioid agonist, resulted in a dose dependent anticonvulsant action against maximal electroshock seizures in mice. This anticonvulsant effect of pentazocine was not antagonized by both the doses of naloxone (1 and 10 mg/kg) suggesting thereby that its anticonvulsant action is probably mediated by Sigma opiate binding sites. Its anticonvulsant effect was potentiated by both the anticonvulsant drugs viz. diazepam and diphenylhydantoin. Morphine, mu opioid agonist, on the other hand, failed to protect the animals against maximal electroshock seizures when it was given in doses of 10-40 mg/kg body wt.

Impact of Dose to the Bladder Trigone on Long-Term Urinary Function After High-Dose Intensity Modulated Radiation Therapy for Localized Prostate Cancer

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

Ghadjar, Pirus; Zelefsky, Michael J.; Spratt, Daniel E.

2014-02-01

Purpose: To determine the potential association between genitourinary (GU) toxicity and planning dose–volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients. Methods and Materials: A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose–volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analysesmore » were done by the Kaplan-Meier method and Cox proportional hazard models, respectively. Results: Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19). Conclusions: The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the bladder trigone seems to be associated with a reduction in late GU toxicity.« less

Optimal and safe standard doses of midazolam and propofol to achieve patient and doctor satisfaction with dental treatment: A prospective cohort study

PubMed Central

Nonaka, Mutsumi; Nishimura, Akiko; Gotoh, Kinuko; Oka, Shuichirou; Iijima, Takehiko

2017-01-01

Background The incidences of morbidity and mortality caused by pharmacosedation for dental treatment have not yet reached zero. Adverse events are related to inappropriate respiratory management, mostly originating from an overdose of sedatives. Since sedation is utilized for the satisfaction of both the dentist and the patient, the optimal dose should be minimized to prevent adverse events. We attempted to define the optimal doses of midazolam and propofol required to achieve high levels of patient and dentist satisfaction. Methods One thousand dental patients, including those undergoing third molar extractions, were enrolled in this study. A dose of 1 mg of midazolam was administered at 1-minute intervals until adequate sedation was achieved. Propofol was then infused continuously to maintain the sedation level. Both the patients and the dentists were subsequently interviewed and asked to complete a questionnaire. A multivariate logistic regression analysis was used to examine the factors that contributed to patient and dentist satisfaction. Results The peak midazolam dose resulting in the highest percentage of patient satisfaction was 3 mg. Both a lower dose and a higher dose reduced patient satisfaction. Patient satisfaction increased with an increasing dosage of propofol up until 4 mg/kg/hr, reaching a peak of 78.6%. The peak midazolam dose resulting in the highest percentage of dentist satisfaction (78.8%) was 2 mg. Incremental propofol doses reduced dentist satisfaction, in contrast to their effect on patient satisfaction. The strongest independent predictors of patient satisfaction and dentist satisfaction were no intraoperative memory (OR, 5.073; 95% CI, 3.532–7.287; P<0.001) and unintentional movements by the patient (OR, 0.035; 95% CI, 0.012–0.104; P<0.001), respectively. No serious adverse events were reported. Conclusion We found that 3 mg of midazolam and 3 mg/kg/hr of propofol may be the optimal doses for maximizing both patient and dentist satisfaction. Although this level of sedation is relatively light, memory loss and an absence of unintentional patient movements can be expected without adverse events. PMID:28182732

Intensity-modulated radiotherapy for locally advanced non-small-cell lung cancer: a dose-escalation planning study.

PubMed

Lievens, Yolande; Nulens, An; Gaber, Mousa Amr; Defraene, Gilles; De Wever, Walter; Stroobants, Sigrid; Van den Heuvel, Frank

2011-05-01

To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT. Copyright © 2011 Elsevier Inc. All rights reserved.

Dopaminergic influence on rat tongue function and limb movement initiation.

PubMed

Ciucci, Michelle Renee; Connor, Nadine P

2009-04-01

Altering dopamine synaptic transmission can affect both cranial and limb sensorimotor function, but often to a different degree of severity. We hypothesized that haloperidol has dose-dependent but differential effects on lingual forces, lingual movement rates, and limb movement initiation. We measured average and maximal lingual force, tongue press rate and cataleptic descent time in nine Fischer 344/Brown Norway rats in varied doses of haloperidol. Decreases in lingual force and temporal parameters and increases in cataleptic descent time were related to haloperidol dose. However, they were related to a different degree as the relationships were strong between average force and tongue press rate, moderate between maximal force and tongue press rate, moderate between average force and cataleptic descent time, and weak between maximal force and cataleptic descent time. Elucidating the relationships between the cranial and limb sensorimotor systems in the context of altered dopamine synaptic transmission may assist in developing therapies for conditions such as Parkinson's disease.

SU-E-T-562: Motion Tracking Optimization for Conformal Arc Radiotherapy Plans: A QUASAR Phantom Based Study

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

Xu, Z; Wang, I; Yao, R

Purpose: This study is to use plan parameters optimization (Dose rate, collimator angle, couch angle, initial starting phase) to improve the performance of conformal arc radiotherapy plans with motion tracking by increasing the plan performance score (PPS). Methods: Two types of 3D conformal arc plans were created based on QUASAR respiratory motion phantom with spherical and cylindrical targets. Sinusoidal model was applied to the MLC leaves to generate motion tracking plans. A MATLAB program was developed to calculate PPS of each plan (ranges from 0–1) and optimize plan parameters. We first selected the dose rate for motion tracking plans andmore » then used simulated annealing algorithm to search for the combination of the other parameters that resulted in the plan of the maximal PPS. The optimized motion tracking plan was delivered by Varian Truebeam Linac. In-room cameras and stopwatch were used for starting phase selection and synchronization between phantom motion and plan delivery. Gaf-EBT2 dosimetry films were used to measure the dose delivered to the target in QUASAR phantom. Dose profiles and Truebeam trajectory log files were used for plan delivery performance evaluation. Results: For spherical target, the maximal PPS (PPSsph) of the optimized plan was 0.79: (Dose rate: 500MU/min, Collimator: 90°, Couch: +10°, starting phase: 0.83π). For cylindrical target, the maximal PPScyl was 0.75 (Dose rate: 300MU/min, Collimator: 87°, starting phase: 0.97π) with couch at 0°. Differences of dose profiles between motion tracking plans (with the maximal and the minimal PPS) and 3D conformal plans were as follows: PPSsph=0.79: %ΔFWHM: 8.9%, %Dmax: 3.1%; PPSsph=0.52: %ΔFWHM: 10.4%, %Dmax: 6.1%. PPScyl=0.75: %ΔFWHM: 4.7%, %Dmax: 3.6%; PPScyl=0.42: %ΔFWHM: 12.5%, %Dmax: 9.6%. Conclusion: By achieving high plan performance score through parameters optimization, we can improve target dose conformity of motion tracking plan by decreasing total MLC leaf travel distance and leaf speed.« less

Self-assembled amphiphilic zein-lactoferrin micelles for tumor targeted co-delivery of rapamycin and wogonin to breast cancer.

PubMed

Sabra, Sally A; Elzoghby, Ahmed O; Sheweita, Salah A; Haroun, Medhat; Helmy, Maged W; Eldemellawy, Maha A; Xia, Ying; Goodale, David; Allan, Alison L; Rohani, Sohrab

2018-07-01

Protein-based micelles have shown significant potential for tumor-targeted delivery of anti-cancer drugs. In this light, self-assembled nanocarriers based on GRAS (Generally recognized as safe) amphiphilic protein co-polymers were synthesized via carbodiimide coupling reaction. The new nano-platform is composed of the following key components: (i) hydrophobic zein core to encapsulate the hydrophobic drugs rapamycin (RAP) and wogonin (WOG) with high encapsulation efficiency, (ii) hydrophilic lactoferrin (Lf) corona to enhance the tumor targeting, and prolong systemic circulation of the nanocarriers, and (iii) glutaraldehyde (GLA)-crosslinking to reduce the particle size and improve micellar stability. Zein-Lf micelles showed relatively rapid release of WOG followed by slower diffusion of RAP from zein core. This sequential release may aid in efflux pump inhibition by WOG thus sensitizing tumor cells to RAP action. Interestingly, these micelles showed good hemocompatibility as well as enhanced serum stability owing to the brush-like architecture of Lf shell. Moreover, this combined nano-delivery system maximized synergistic cytotoxicity of RAP and WOG in terms of tumor inhibition in MCF-7 breast cancer cells and Ehrlich ascites tumor animal model as a result of enhanced active targeting. Collectively, GLA-crosslinked zein-Lf micelles hold great promise for combined RAP/WOG delivery to breast cancer with reduced drug dose, minimized side effects and maximized anti-tumor efficacy. Copyright © 2018. Published by Elsevier B.V.

Hydroxyethyl starch.

PubMed

Thompson, W L

1980-01-01

HES products should be designated by both their number average of molecular weight (that determines colloidal activity) and molar substitution ratios. In addition to the original HES-70/70 developed in 1960, a rapidly excreted HES-50/50 has been available since 1977. HES-70/70 and human albumin are equivalent in both healthy and hypoalbuminemia subjects in regard to maximal and total effects on plasma volume, intravascular colloidal activity and plasma concentration of ingested colloid. Albumin and HES-70/70 are extravasated at nearly equal rates. Albumin elimination is predominantly monoexponential. HES-70/70 however, is partly metabolized and partly excreted in urine at rates that decrease progressively as the amount remaining in the body decreases. HES-50/50 has maximal effects on plasma volume and colloidal activity similar to those of dextran-40, but it is eliminated twice as rapidly and unlike dextran-40, does not accumulate on repeated ingestion of large doses. HES ingestion increases apparent serum activity of alpha amylase by slowing enzyme elimination. Anaphylactoid reactions have been infrequent and mild, even on repetitive ingestion in recurrent "Phoresis" donors. The effect of HES on coagulation in urine but does not slow urine flow by hyperviscosity. Hydroxyethylation of waxy starches yields safe colloids with the advantage of permitting selective control of drug effects by altering independently molecular size and rate of enzymatic hydrolysis, tailoring drug kinetics to specific uses.

The influence of patient positioning uncertainties in proton radiotherapy on proton range and dose distributions

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

Liebl, Jakob, E-mail: jakob.liebl@medaustron.at; Francis H. Burr Proton Therapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Department of Therapeutic Radiology and Oncology, Medical University of Graz, 8036 Graz

2014-09-15

Purpose: Proton radiotherapy allows radiation treatment delivery with high dose gradients. The nature of such dose distributions increases the influence of patient positioning uncertainties on their fidelity when compared to photon radiotherapy. The present work quantitatively analyzes the influence of setup uncertainties on proton range and dose distributions. Methods: Thirty-eight clinical passive scattering treatment fields for small lesions in the head were studied. Dose distributions for shifted and rotated patient positions were Monte Carlo-simulated. Proton range uncertainties at the 50%- and 90%-dose falloff position were calculated considering 18 arbitrary combinations of maximal patient position shifts and rotations for two patientmore » positioning methods. Normal tissue complication probabilities (NTCPs), equivalent uniform doses (EUDs), and tumor control probabilities (TCPs) were studied for organs at risk (OARs) and target volumes of eight patients. Results: The authors identified a median 1σ proton range uncertainty at the 50%-dose falloff of 2.8 mm for anatomy-based patient positioning and 1.6 mm for fiducial-based patient positioning as well as 7.2 and 5.8 mm for the 90%-dose falloff position, respectively. These range uncertainties were correlated to heterogeneity indices (HIs) calculated for each treatment field (38% < R{sup 2} < 50%). A NTCP increase of more than 10% (absolute) was observed for less than 2.9% (anatomy-based positioning) and 1.2% (fiducial-based positioning) of the studied OARs and patient shifts. For target volumes TCP decreases by more than 10% (absolute) occurred in less than 2.2% of the considered treatment scenarios for anatomy-based patient positioning and were nonexistent for fiducial-based patient positioning. EUD changes for target volumes were up to 35% (anatomy-based positioning) and 16% (fiducial-based positioning). Conclusions: The influence of patient positioning uncertainties on proton range in therapy of small lesions in the human brain as well as target and OAR dosimetry were studied. Observed range uncertainties were correlated with HIs. The clinical practice of using multiple fields with smeared compensators while avoiding distal OAR sparing is considered to be safe.« less

A Phase I Study of Light Dose for Photodynamic Therapy Using 2-[1-Hexyloxyethyl]-2 Devinyl Pyropheophorbide-a for the Treatment of Non-Small Cell Carcinoma In Situ or Non-Small Cell Microinvasive Bronchogenic Carcinoma: A Dose Ranging Study.

PubMed

Dhillon, Samjot Singh; Demmy, Todd L; Yendamuri, Sai; Loewen, Gregory; Nwogu, Chukwumere; Cooper, Michele; Henderson, Barbara W

2016-02-01

We report a phase I trial of photodynamic therapy (PDT) of carcinoma in situ (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH). HPPH has the advantage of minimal general phototoxicity over the commonly used photosensitizer porfimer sodium (Photofrin; Pinnacle Biologics, Chicago, IL). The objectives of this study were (1) to determine the maximally tolerated light dose at a fixed photosensitizer dose and (2) to gain initial insight into the effectiveness of this treatment approach. Seventeen patients with 21 CIS/MIC lesions were treated with HPPH with light dose escalation starting from 75 J/cm2 and increasing to 85, 95,125, and 150 J/cm2 respectively. Follow-up bronchoscopy for response assessment was performed at 1 and 6 months, respectively. The rate of pathological complete response (CR) was 82.4% (14 of 17 evaluable lesions; 14 patients) at 1 month and 72.7% (8/11 evaluable lesions; 8 patients) at 6 months. Only four patients developed mild skin erythema. One of the three patients in the 150 J/cm2 light dose group experienced a serious adverse event. This patient had respiratory distress caused by mucus plugging, which precipitated cardiac ischemia. Two additional patients treated subsequently at this light dose had no adverse events. The sixth patient in this dose group was not recruited and the study was terminated because of delays in HPPH supply. However, given the observed serious adverse event, it is recommended that the light dose does not exceed 125 J/cm2. PDT with HPPH can be safely used for the treatment of CIS/MIC of the airways, with potential effectiveness comparable to that reported for porfimer sodium in earlier studies. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

The influence of patient positioning uncertainties in proton radiotherapy on proton range and dose distributions

PubMed Central

Liebl, Jakob; Paganetti, Harald; Zhu, Mingyao; Winey, Brian A.

2014-01-01

Purpose: Proton radiotherapy allows radiation treatment delivery with high dose gradients. The nature of such dose distributions increases the influence of patient positioning uncertainties on their fidelity when compared to photon radiotherapy. The present work quantitatively analyzes the influence of setup uncertainties on proton range and dose distributions. Methods: Thirty-eight clinical passive scattering treatment fields for small lesions in the head were studied. Dose distributions for shifted and rotated patient positions were Monte Carlo-simulated. Proton range uncertainties at the 50%- and 90%-dose falloff position were calculated considering 18 arbitrary combinations of maximal patient position shifts and rotations for two patient positioning methods. Normal tissue complication probabilities (NTCPs), equivalent uniform doses (EUDs), and tumor control probabilities (TCPs) were studied for organs at risk (OARs) and target volumes of eight patients. Results: The authors identified a median 1σ proton range uncertainty at the 50%-dose falloff of 2.8 mm for anatomy-based patient positioning and 1.6 mm for fiducial-based patient positioning as well as 7.2 and 5.8 mm for the 90%-dose falloff position, respectively. These range uncertainties were correlated to heterogeneity indices (HIs) calculated for each treatment field (38% < R2 < 50%). A NTCP increase of more than 10% (absolute) was observed for less than 2.9% (anatomy-based positioning) and 1.2% (fiducial-based positioning) of the studied OARs and patient shifts. For target volumes TCP decreases by more than 10% (absolute) occurred in less than 2.2% of the considered treatment scenarios for anatomy-based patient positioning and were nonexistent for fiducial-based patient positioning. EUD changes for target volumes were up to 35% (anatomy-based positioning) and 16% (fiducial-based positioning). Conclusions: The influence of patient positioning uncertainties on proton range in therapy of small lesions in the human brain as well as target and OAR dosimetry were studied. Observed range uncertainties were correlated with HIs. The clinical practice of using multiple fields with smeared compensators while avoiding distal OAR sparing is considered to be safe. PMID:25186386

Thermal Imaging Is a Noninvasive Alternative to PET/CT for Measurement of Brown Adipose Tissue Activity in Humans

PubMed Central

Law, James; Morris, David E.; Izzi-Engbeaya, Chioma; Salem, Victoria; Coello, Christopher; Robinson, Lindsay; Jayasinghe, Maduka; Scott, Rebecca; Gunn, Roger; Rabiner, Eugenii; Tan, Tricia; Dhillo, Waljit S.; Bloom, Stephen; Budge, Helen

2018-01-01

Obesity and its metabolic consequences are a major cause of morbidity and mortality. Brown adipose tissue (BAT) utilizes glucose and free fatty acids to produce heat, thereby increasing energy expenditure. Effective evaluation of human BAT stimulators is constrained by the current standard method of assessing BAT—PET/CT—as it requires exposure to high doses of ionizing radiation. Infrared thermography (IRT) is a potential noninvasive, safe alternative, although direct corroboration with PET/CT has not been established. Methods: IRT and 18F-FDG PET/CT data from 8 healthy men subjected to water-jacket cooling were directly compared. Thermal images were geometrically transformed to overlay PET/CT-derived maximum intensity projection (MIP) images from each subject, and the areas with the most intense temperature and glucose uptake within the supraclavicular regions were compared. Relationships between supraclavicular temperatures (TSCR) from IRT and the metabolic rate of glucose uptake (MR(gluc)) from PET/CT were determined. Results: Glucose uptake on MR(gluc)MIP was found to correlate positively with a change in TSCR relative to a reference region (r2 = 0.721; P = 0.008). Spatial overlap between areas of maximal MR(gluc)MIP and maximal TSCR was 29.5% ± 5.1%. Prolonged cooling, for 60 min, was associated with a further TSCR rise, compared with cooling for 10 min. Conclusion: The supraclavicular hotspot identified on IRT closely corresponded to the area of maximal uptake on PET/CT-derived MR(gluc)MIP images. Greater increases in relative TSCR were associated with raised glucose uptake. IRT should now be considered a suitable method for measuring BAT activation, especially in populations for whom PET/CT is not feasible, practical, or repeatable. PMID:28912148

Gene therapy delivery systems for enhancing viral and nonviral vectors for cardiac diseases: current concepts and future applications.

PubMed

Katz, Michael G; Fargnoli, Anthony S; Williams, Richard D; Bridges, Charles R

2013-11-01

Gene therapy is one of the most promising fields for developing new treatments for the advanced stages of ischemic and monogenetic, particularly autosomal or X-linked recessive, cardiomyopathies. The remarkable ongoing efforts in advancing various targets have largely been inspired by the results that have been achieved in several notable gene therapy trials, such as the hemophilia B and Leber's congenital amaurosis. Rate-limiting problems preventing successful clinical application in the cardiac disease area, however, are primarily attributable to inefficient gene transfer, host responses, and the lack of sustainable therapeutic transgene expression. It is arguable that these problems are directly correlated with the choice of vector, dose level, and associated cardiac delivery approach as a whole treatment system. Essentially, a delicate balance exists in maximizing gene transfer required for efficacy while remaining within safety limits. Therefore, the development of safe, effective, and clinically applicable gene delivery techniques for selected nonviral and viral vectors will certainly be invaluable in obtaining future regulatory approvals. The choice of gene transfer vector, dose level, and the delivery system are likely to be critical determinants of therapeutic efficacy. It is here that the interactions between vector uptake and trafficking, delivery route means, and the host's physical limits must be considered synergistically for a successful treatment course.

Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar.

PubMed

Kreisl, William C; Bhatia, Ritwik; Morse, Cheryl L; Woock, Alicia E; Zoghbi, Sami S; Shetty, H Umesha; Pike, Victor W; Innis, Robert B

2015-01-01

The permeability-glycoprotein (P-gp) efflux transporter is densely expressed at the blood-brain barrier, and its resultant spare capacity requires substantial blockade to increase the uptake of avid substrates, blunting the ability of investigators to measure clinically meaningful alterations in P-gp function. This study, conducted in humans, examined 2 P-gp inhibitors (tariquidar, a known inhibitor, and disulfiram, a putative inhibitor) and 2 routes of administration (intravenous and oral) to maximally increase brain uptake of the avid and selective P-gp substrate (11)C-N-desmethyl-loperamide (dLop) while avoiding side effects associated with high doses of tariquidar. Forty-two (11)C-dLop PET scans were obtained from 37 healthy volunteers. PET was performed with (11)C-dLop under the following 5 conditions: injected under baseline conditions without P-gp inhibition, injected 1 h after intravenous tariquidar infusion, injected during intravenous tariquidar infusion, injected after oral tariquidar, and injected after disulfiram. (11)C-dLop uptake was quantified with kinetic modeling using metabolite-corrected arterial input function or by measuring the area under the time-activity curve in the brain from 10 to 30 min. Neither oral tariquidar nor oral disulfiram increased brain uptake of (11)C-dLop. Injecting (11)C-dLop during tariquidar infusion, when plasma tariquidar concentrations reach their peak, resulted in a brain uptake of the radioligand approximately 5-fold greater than baseline. Brain uptake was similar with 2 and 4 mg of intravenous tariquidar per kilogram; however, the lower dose was better tolerated. Injecting (11)C-dLop after tariquidar infusion also increased brain uptake, though higher doses (up to 6 mg/kg) were required. Brain uptake of (11)C-dLop increased fairly linearly with increasing plasma tariquidar concentrations, but we are uncertain whether maximal uptake was achieved. We sought to increase the dynamic range of P-gp function measured after blockade. Performing (11)C-dLop PET during peak plasma concentrations of tariquidar, achieved with concurrent administration of intravenous tariquidar, resulted in greater P-gp inhibition at the human blood-brain barrier than delayed administration and allowed the use of a lower, more tolerable dose of tariquidar. On the basis of prior monkey studies, we suspect that plasma concentrations of tariquidar did not fully block P-gp; however, higher doses of tariquidar would likely be associated with unacceptable side effects. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice

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

Socała, Katarzyna, E-mail: ksocala@op.pl

Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. Inmore » addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD{sub 50} value of sulforaphane in mice was estimated at 212.67 mg/kg, while the TD{sub 50} value – at 191.58 mg/kg. In seizure tests, sulforaphane at the highest dose tested (200 mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6 Hz-induced psychomotor seizure. At doses of 10–200 mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100 mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150–300 mg/kg), hypothermia (at 150–300 mg/kg), impairment of motor coordination (at 200–300 mg/kg), decrease in skeletal muscle strength (at 250–300 mg/kg), and deaths (at 200–300 mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200 mg/kg. In conclusion, since sulforaphane was proconvulsant at a toxic dose, the safety profile and the risk-to-benefit ratio of sulforaphane usage in epileptic patients should be further evaluated. - Highlights: • Sulforaphane, an Nrf2 activator, is proconvulsant at toxic doses in mice. • Sulforaphane at 100 mg/kg produces a pharmacokinetic interaction with carbamazepine. • Sulforaphane has an LD{sub 50} of 212.67 mg/kg in mice (after ip administration). • The risk-to-benefit ratio of sulforaphane needs further evaluation.« less

Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review.

PubMed

Soleimani, Vahid; Sahebkar, Amirhossein; Hosseinzadeh, Hossein

2018-06-01

Curcumin is the major constituent of turmeric (Curcuma longa). Turmeric has been widely used as a spice in foods and for therapeutic applications such as anti-inflammatory, antihyperlipidemic, and antimicrobial activities. Turmeric and curcumin are nonmutagenic and nongenotoxic. Oral use of turmeric and curcumin did not have reproductive toxicity in animals at certain doses. Studies on human did not show toxic effects, and curcumin was safe at the dose of 6 g/day orally for 4-7 weeks. However, some adverse effects such as gastrointestinal upsets may occur. Moreover, oral bioavailable formulations of curcumin were safe for human at the dose of 500 mg two times in a day for 30 days, but there are still few trials and more studies are needed specially on nanoformulations and it should be discussed in a separate article. In addition, curcumin is known as a generally recognized as safe substance. This review discusses the safety and toxicity of turmeric and curcumin in medicine. Turmeric and curcumin are nontoxic for human especially in oral administration. Turmeric and curcumin are also safe in animals. They are nonmutagenic and are safe in pregnancy in animals but more studies in human are needed. Copyright © 2018 John Wiley & Sons, Ltd.

Use of the hyperinsulinemic euglycemic clamp to assess insulin sensitivity in guinea pigs: dose response, partitioned glucose metabolism, and species comparisons.

PubMed

Horton, Dane M; Saint, David A; Owens, Julie A; Gatford, Kathryn L; Kind, Karen L

2017-07-01

The guinea pig is an alternate small animal model for the study of metabolism, including insulin sensitivity. However, only one study to date has reported the use of the hyperinsulinemic euglycemic clamp in anesthetized animals in this species, and the dose response has not been reported. We therefore characterized the dose-response curve for whole body glucose uptake using recombinant human insulin in the adult guinea pig. Interspecies comparisons with published data showed species differences in maximal whole body responses (guinea pig ≈ human < rat < mouse) and the insulin concentrations at which half-maximal insulin responses occurred (guinea pig > human ≈ rat > mouse). In subsequent studies, we used concomitant d-[3- 3 H]glucose infusion to characterize insulin sensitivities of whole body glucose uptake, utilization, production, storage, and glycolysis in young adult guinea pigs at human insulin doses that produced approximately half-maximal (7.5 mU·min -1 ·kg -1 ) and near-maximal whole body responses (30 mU·min -1 ·kg -1 ). Although human insulin infusion increased rates of glucose utilization (up to 68%) and storage and, at high concentrations, increased rates of glycolysis in females, glucose production was only partially suppressed (~23%), even at high insulin doses. Fasting glucose, metabolic clearance of insulin, and rates of glucose utilization, storage, and production during insulin stimulation were higher in female than in male guinea pigs ( P < 0.05), but insulin sensitivity of these and whole body glucose uptake did not differ between sexes. This study establishes a method for measuring partitioned glucose metabolism in chronically catheterized conscious guinea pigs, allowing studies of regulation of insulin sensitivity in this species. Copyright © 2017 the American Physiological Society.

Clinical and dosimetric factors of radiation-induced esophageal injury: radiation-induced esophageal toxicity.

PubMed

Qiao, Wen-Bo; Zhao, Yan-Hui; Zhao, Yan-Bin; Wang, Rui-Zhi

2005-05-07

To analyze the clinical and dosimetric predictive factors for radiation-induced esophageal injury in patients with non-small-cell lung cancer (NSCLC) during three-dimensional conformal radiotherapy (3D-CRT). We retrospectively analyzed 208 consecutive patients (146 men and 62 women) with NSCLC treated with 3D-CRT. The median age of the patients was 64 years (range 35-87 years). The clinical and treatment parameters including gender, age, performance status, sequential chemotherapy, concurrent chemotherapy, presence of carinal or subcarinal lymph nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy were studied. Clinical and dosimetric factors for radiation-induced acute and late grade 3-5 esophageal injury were analyzed according to Radiation Therapy Oncology Group (RTOG) criteria. Twenty-five (12%) of the two hundred and eight patients developed acute or late grade 3-5 esophageal injury. Among them, nine patients had both acute and late grade 3-5 esophageal injury, two died of late esophageal perforation. Concurrent chemotherapy and maximal point dose to the esophagus > or =60 Gy were significantly associated with the risk of grade 3-5 esophageal injury. Fifty-four (26%) of the two hundred and eight patients received concurrent chemotherapy. Among them, 25 (46%) developed grade 3-5 esophageal injury (P = 0.0001<0.01). However, no grade 3-5 esophageal injury occurred in patients who received a maximal point dose to the esophagus <60 Gy (P = 0.0001<0.01). Concurrent chemotherapy and the maximal esophageal point dose > or =60 Gy are significantly associated with the risk of grade 3-5 esophageal injury in patients with NSCLC treated with 3D-CRT.

Using lean to improve medication administration safety: in search of the "perfect dose".

PubMed

Ching, Joan M; Long, Christina; Williams, Barbara L; Blackmore, C Craig

2013-05-01

At Virginia Mason Medical Center (Seattle), the Collaborative Alliance for Nursing Outcomes (CALNOC) Medication Administration Accuracy Quality Study was used in combination with Lean quality improvement efforts to address medication administration safety. Lean interventions were targeted at improving the medication room layout, applying visual controls, and implementing nursing standard work. The interventions were designed to prevent medication administration errors through improving six safe practices: (1) comparing medication with medication administration record, (2) labeling medication, (3) checking two forms of patient identification, (4) explaining medication to patient, (5) charting medication immediately, and (6) protecting the process from distractions/interruptions. Trained nurse auditors observed 9,244 doses for 2,139 patients. Following the intervention, the number of safe-practice violations decreased from 83 violations/100 doses at baseline (January 2010-March 2010) to 42 violations/100 doses at final follow-up (July 2011-September 2011), resulting in an absolute risk reduction of 42 violations/100 doses (95% confidence interval [CI]: 35-48), p < .001). The number of medication administration errors decreased from 10.3 errors/100 doses at baseline to 2.8 errors/100 doses at final follow-up (absolute risk reduction: 7 violations/100 doses [95% CI: 5-10, p < .001]). The "perfect dose" score, reflecting compliance with all six safe practices and absence of any of the eight medication administration errors, improved from 37 in compliance/100 doses at baseline to 68 in compliance/100 doses at the final follow-up. Lean process improvements coupled with direct observation can contribute to substantial decreases in errors in nursing medication administration.

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

Bai, Xian-Xu, E-mail: bai@hfut.edu.cn; Wereley, Norman M.

Magnetorheological (MR) energy absorbers (EAs) are an effective adaptive EA technology with which to maximize shock and vibration isolation. However, to realize maximum performance of the semi-active control system, the off-state (i.e., field off) stroking load of the MREA must be minimized at all speeds, and the dynamic range of the MREA must be maximized at high speed. This study presents a fail-safe MREA (MREA-FS) concept that, can produce a greater dynamic range at all piston speeds. A bias damping force is generated in the MREA-FS using permanent magnetic fields, which enables fail-safe behavior in the case of power failure.more » To investigate the feasibility and capability of the MREA-FS in the context of the semi-active control systems, a single-degree-of-freedom base excited rigid payload is mathematically constructed and simulated with skyhook control.« less

Statin Intolerance: A Literature Review and Management Strategies.

PubMed

Saxon, David R; Eckel, Robert H

Statin intolerance is a commonly encountered clinical problem for which useful management strategies exist. Although many patients report statin-related muscle symptoms, studies indicate that the majority of these patients can tolerate a statin upon re-challenge. Alternative statin dosing strategies are an effective way to modify and reintroduce statin therapy for patients reporting adverse symptoms. Correction of vitamin D deficiency and hypothyroidism may improve statin tolerability in some patients. CoQ10 supplementation has been found to be of no benefit for statin-related muscle symptoms in most recent clinical trials. PCSK9 inhibitors are a new therapeutic option that if confirmed as safe and effective by outcomes trials may be of substantial benefit to select patients at high ASCVD risk who are unable to achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on maximally tolerated statin therapy. Other available medications to lower LDL-C in statin intolerant patients include ezetimibe, bile acid sequestrants, niacin, and fibrates. Published by Elsevier Inc.

Development of a biologically based dose response (BBDR) model for arsenic induced cancer

EPA Science Inventory

We are developing a biologically based dose response (BBDR) model for arsenic carcinogenicity in order to reduce uncertainty in estimates of low dose risk by maximizing the use of relevant data on the mode of action. Expert consultation and literature review are being conducted t...

A Phase I Trial of a Human Papillomavirus (HPV) DNA Vaccine for HPV16+ Cervical Intraepithelial Neoplasia 2/3

PubMed Central

Trimble, Cornelia L.; Peng, Shiwen; Kos, Ferdynand; Gravitt, Patti; Viscidi, Raphael; Sugar, Elizabeth; Pardoll, Drew; Wu, TC

2010-01-01

Purpose: To evaluate the safety and immunogenicity of a therapeutic HPV16 DNA vaccine administered to women with HPV16+CIN2/3. Experimental Design: This phase I trial incorporated the standard ‘3+3” dose escalation design with an additional 6 patients allocated to the maximally tolerated dose (MTD). Healthy adult women with colposcopically-directed biopsy-proven HPV16+ CIN2/3 received three intramuscular (IM) vaccinations (0.5 mg, 1 mg, or 3mg) of a plasmid expressing a Sig-E7(detox)-HSP70 fusion protein on days 0, 28 and 56, and underwent standard therapeutic resection of the cervical squamocolumnar junction at day 105 (week 15). Safety and immunogenicity of the vaccine and histologic outcome based on resection at week 15 were assessed. Results: Fifteen patients were evaluable (3 each at 0.5 mg and 1mg, 9 at 3mg). The vaccine was well tolerated: most adverse events were mild transient injection-site discomfort; no dose-limiting toxicities were observed. Although HPVE7-specific T-cell responses to E7 detected by enzyme-linked immunospot assays (IFNγ) were of low frequency and magnitude, detectable increases in response subsequent to vaccination were identified in subjects in the second and third cohorts. Complete histologic regression occurred in 3/9 (33%, CI: 7%-70%)) individuals in the highest dose cohort, Although the difference is not significant, it is slightly higher than would be expected in an unvaccinated cohort (25%). Conclusions: This HPV16 DNA vaccine was safe and well tolerated. While it appears possible to elicit HPV-specific T cell responses in patients with established dysplastic lesions, other factors are likely to play a role in lesion regression. PMID:19118066

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

PubMed Central

Youn, Gilmer; Jones, Brenda; Jelliffe, Roger W.; Drusano, George L.; Rodvold, Keith A.; Lodise, Thomas P.

2014-01-01

The current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P = 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%; P = 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter. PMID:24165176

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.

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

Pokhrel, D; Badkul, R; Jiang, H

Purpose: To compare dose distributions calculated using the iPlan XVMC algorithm and heterogeneities corrected/uncorrected Pencil Beam (PB-hete/PB-homo) algorithms for SBRT treatments of lung tumors. Methods: Ten patients with centrally located solitary lung tumors were treated using MC-based SBRT to 60Gy in 5 fractions for PTVV100%=95%. ITV was delineated on MIP-images based on 4D-CT scans. PTVs(ITV+5mm margins) ranged from 10.1–106.5cc(mean=48.6cc). MC-SBRT plans were generated with a combination of non-coplanar conformal arcs/beams using iPlan-XVMC-algorithm (BrainLABiPlan ver.4.1.2) for Novalis-TX consisting of HD-MLCs and 6MV-SRS(1000MU/min) mode, following RTOG 0813 dosimetric criteria. For comparison, PB-hete/PB-homo algorithms were used to re-calculate dose distributions using same beammore » configurations, MLCs/monitor units. Plans were evaluated with isocenter/maximal/mean doses to PTV. Normal lung doses were evaluated with V5/V10/V20 and mean-lung-dose(MLD), excluding PTV. Other OAR doses such as maximal spinal cord/2cc-esophagus/max bronchial tree (BT/maximal heart doses were tabulated. Results: Maximal/mean/isocenter doses to PTV calculated by PB-hete were uniformly larger than MC plans by a factors of 1.09/1.13/1.07, on average, whereas they were consistently lower by PB-homo by a factors of 0.9/0.84/0.9, respectively. The volume covered by 5Gy/10Gy/20Gy isodose-lines of the lung were comparable (average within±3%) when calculated by PB-hete compared to XVMC, but, consistently lower by PB-homo by a factors of 0.90/0.88/0.85, respectively. MLD was higher with PB-hete by 1.05, but, lower by PB-homo by 0.9, on average, compared to XVMC. XVMC max-cord/max-BT/max-heart and 2cc of esophagus doses were comparable to PB-hete; however, PB-homo underestimates by a factors of 0.82/0.89/0.88/0.86, on average, respectively. Conclusion: PB-hete significantly overestimates dose to PTV relative to XVMC -hence underdosing the target. MC is more complex and accurate with tissue-heterogeneities.The magnitude of variation significantly varies with ‘small-island-tumor’ surrounded by low-density lung tissues -PB algorithms lacks later electron scattering. Dose calculation with XVMC for lung SBRT is routinely performed in our clinic, its performance for head'neck/sinus cases will also be investigated.« less

Quantitative comparison of the results obtained by the multiple-dose guinea pig maximization test and the non-radioactive murine local lymph-node assay for various biocides.

PubMed

Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu

2005-07-01

We compared the results of the multiple-dose guinea pig maximization test (GPMT) and the non-radioactive murine local lymph-node assay (LLNA) for various biocides. Thirteen out of 17 positive biocides in the GPMT gave positive results in the LLNA. In the GPMT, the minimum first induction doses ranged over four orders (0.00005-0.5%), while elicitation-threshold doses, which were evaluated using an optimally sensitized group of animals in the multiple-dose studies, ranged over five orders (0.00006-2.8%). In the LLNA, minimum induction doses ranged over more than three orders (0.01-30%). With respect to 13 biocides that were positive in both the GPMT and the LLNA, results were quantitatively compared. When compared after conversion to corresponding area doses (microg/cm), the minimum doses required to elicit skin reaction in guinea pigs were always lower than that for induction in mice with all biocides. Correlation between minimum induction doses from the GPMT and the LLNA seemed poor (r=0.57), while that between minimum induction doses in the LLNA and elicitation-threshold doses in the GPMT was relatively good (r=0.73). The results suggest the possibility to estimate human elicitation-threshold doses, which are definitely lacking in the process of risk assessment for skin-sensitizers, from the data of the LLNA.

Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study.

PubMed

Schulz, Craig A; Mehta, Minesh P; Badie, Benham; McGinn, Cornelius J; Robins, H Ian; Hayes, Lori; Chappell, Rick; Volkman, Jen; Binger, Kim; Arzoomanian, Rhoda; Simon, Kris; Alberti, Dona; Feierabend, Christine; Tutsch, Kendra D; Kunugi, Keith A; Wilding, George; Kinsella, Timothy J

2004-07-15

To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma. Patients were required to have biopsy-proven malignant glioma. Patients received 100 (n = 4), 200 (n = 3), 300 (n = 3), 400 (n = 6), 500 (n = 4), 625 (n = 5), or 781 (n = 6) mg/m(2)/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost [2.0 Gy for 5 Saturdays]). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used. Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (n = 3), thrombocytopenia (n = 3), and elevated liver function studies (n = 3). The maximal tolerated dose was 625 mg/m(2)/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 microM). In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m(2)/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.

Distribution of sulfamonomethoxine and trimethoprim in egg yolk and white.

PubMed

Bilandžić, Nina; Božić, Đurđica; Kolanović, Božica Solomun; Varenina, Ivana; Cvetnić, Luka; Cvetnić, Željko

2015-07-01

The distribution of sulfamonomethoxine (SMM) and trimethoprim (TMP) in egg yolk and white was measured during and after administration of a SMM/TMP combination in laying hens in doses of 8 g l(-)(1) and 12 g l(-)(1) in drinking water for 7 days. The SMM concentration reached maximal levels on day 2 of the post-treatment period for both doses (μg kg(-)(1)): 5920 and 9453 in yolk; 4831 and 6050 in white, in doses 1 and 2, respectively. Significant differences in the SMM and TMP concentrations between yolk and white in post treatment period were found. SMM dropped below the LOD (1.9 μg kg(-1)) in yolk after day 16 and 19 for doses 1 and 2. TMP reached maximal levels on day 3 after drug administration for doses 1 and 2 (μg kg(-)(1)): 6521 and 7329 in yolk, 1370 and 1539 in white. TMP residues were measured above LOD (0.3 μg kg(-)(1)) in yolk for both doses on day 37 post-treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.

PubMed

Maráz, Anikó; Cserháti, Adrienn; Uhercsák, Gabriella; Szilágyi, Éva; Varga, Zoltán; Révész, János; Kószó, Renáta; Varga, Linda; Kahán, Zsuzsanna

2018-03-15

In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.

Doing the math: A simple approach to topical timolol dosing for infantile hemangiomas.

PubMed

Dalla Costa, Renata; Prindaville, Brea; Wiss, Karen

2018-03-01

Topical timolol maleate has recently gained popularity as a treatment for superficial infantile hemangiomas, but calculating a safe dose of timolol can be time consuming, which may limit the medication's use in fast-paced clinical environments. This report offers a simplified calculation of the maximum daily safe dosage as 1 drop of medication per kilogram of body weight. © 2018 Wiley Periodicals, Inc.

Successful use of full-dose dexamethasone, high-dose cytarabine, and cisplatin as part of initial therapy in non-hodgkin and hodgkin lymphoma with severe hepatic dysfunction.

PubMed

McCarthy, Jeanne; Gopal, Ajay K

2009-04-01

Anthracycline-based chemotherapy is the cornerstone of modern curative regimens for aggressive lymphomas; however, these drugs cannot be safely administered in the setting of severe hepatic dysfunction. Alternative regimens for this setting are required. We describe 2 patients with newly diagnosed advanced aggressive lymphoma (diffuse large B-cell lymphoma [DLBCL] and classic Hodgkin lymphoma [HL]) presenting with severe hepatic dysfunction with hyperbilirubinemia (4.3-13.2 mg/dL). Because of the inability to safely administer unattenuated doses of anthracycline-based regimens, dexamethasone, high-dose cytarabine, and cisplatin (DHAP) was used at full doses (along with rituximab for the DLBCL patient) until hepatic function normalized (1-5 cycles). The treatment was then converted to R-CHOP (rituximab/cyclophosphamide/ doxorubicin/vincristine/prednisone) and ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) for the DLBCL and HL patient, respectively, to complete therapy. The patients had a partial remission and complete remission, respectively. These data suggest that DHAP is a safe and effective regimen that can be used without dose modification as part of initial therapy in the setting of aggressive lymphoma and hepatic failure. The literature on the use of treatment regimens for aggressive lymphoma in the setting of hepatic dysfunction is reviewed.

[Prophylaxis of alcoholic disease of the liver].

PubMed

Beliakin, S A

2009-08-01

Military doctors should have a uniform position to the use of alcohol. Now alcohol is the basic pathogenic factor in development of a lethal cirrhosis of a liver. The most known sayings justifying the use of alcohol, are insolvent. Useful doses of alcohol does not exist. The quantity of used alcohol has the great value. Only at achievement of age 21 year it is possible to use safe doses of alcohol. A safe dose of pure alcohol (ethanol) less than 30,0 in day. In a basis of prophylaxis of a cirrhosis of a liver there is a medical educational activity.

Can active proton interrogation find shielded nuclear threats at human-safe radiation levels?

NASA Astrophysics Data System (ADS)

Liew, Seth Van

2017-05-01

A new method of low-dose proton radiography is presented. The system is composed of an 800 MeV proton source, bending magnets, and compact detectors, and is designed for drive-through cargo scanning. The system has been simulated using GEANT4. Material identification algorithms and pixel sorting methods are presented that allow the system to perform imaging at doses low enough to scan passenger vehicles and people. Results are presented on imaging efficacy of various materials and cluttered cargoes. The identification of shielded nuclear materials at human-safe doses has been demonstrated.

Individualized Radical Radiotherapy of Non-Small-Cell Lung Cancer Based on Normal Tissue Dose Constraints: A Feasibility Study

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

Baardwijk, Angela van; Bosmans, Geert; Boersma, Liesbeth

2008-08-01

Purpose: Local recurrence is a major problem after (chemo-)radiation for non-small-cell lung cancer. We hypothesized that for each individual patient, the highest therapeutic ratio could be achieved by increasing total tumor dose (TTD) to the limits of normal tissues, delivered within 5 weeks. We report first results of a prospective feasibility trial. Methods and Materials: Twenty-eight patients with medically inoperable or locally advanced non-small-cell lung cancer, World Health Organization performance score of 0-1, and reasonable lung function (forced expiratory volume in 1 second > 50%) were analyzed. All patients underwent irradiation using an individualized prescribed TTD based on normal tissuemore » dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8-Gy fractions twice daily. No concurrent chemoradiation was administered. Toxicity was scored using the Common Terminology Criteria for Adverse Events criteria. An {sup 18}F-fluoro-2-deoxy-glucose-positron emission tomography-computed tomography scan was performed to evaluate (metabolic) response 3 months after treatment. Results: Mean delivered dose was 63.0 {+-} 9.8 Gy. The TTD was most often limited by the mean lung dose (32.1%) or spinal cord (28.6%). Acute toxicity generally was mild; only 1 patient experienced Grade 3 cough and 1 patient experienced Grade 3 dysphagia. One patient (3.6%) died of pneumonitis. For late toxicity, 2 patients (7.7%) had Grade 3 cough or dyspnea; none had severe dysphagia. Complete metabolic response was obtained in 44% (11 of 26 patients). With a median follow-up of 13 months, median overall survival was 19.6 months, with a 1-year survival rate of 57.1%. Conclusions: Individualized maximal tolerable dose irradiation based on normal tissue dose constraints is feasible, and initial results are promising.« less

MO-DE-BRA-04: Hands-On Fluoroscopy Safety Training with Real-Time Patient and Staff Dosimetry

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

Vanderhoek, M; Bevins, N

Purpose: Fluoroscopically guided interventions (FGI) are routinely performed across many different hospital departments. However, many involved staff members have minimal training regarding safe and optimal use of fluoroscopy systems. We developed and taught a hands-on fluoroscopy safety class incorporating real-time patient and staff dosimetry in order to promote safer and more optimal use of fluoroscopy during FGI. Methods: The hands-on fluoroscopy safety class is taught in an FGI suite, unique to each department. A patient equivalent phantom is set on the patient table with an ion chamber positioned at the x-ray beam entrance to the phantom. This provides a surrogatemore » measure of patient entrance dose. Multiple solid state dosimeters (RaySafe i2 dosimetry systemTM) are deployed at different distances from the phantom (0.1, 1, 3 meters), which provide surrogate measures of staff dose. Instructors direct participating clinical staff to operate the fluoroscopy system as they view live fluoroscopic images, patient entrance dose, and staff doses in real-time. During class, instructors work with clinical staff to investigate how patient entrance dose, staff doses, and image quality are affected by different parameters, including pulse rate, magnification, collimation, beam angulation, imaging mode, system geometry, distance, and shielding. Results: Real-time dose visualization enables clinical staff to directly see and learn how to optimize their use of their own fluoroscopy system to minimize patient and staff dose, yet maintain sufficient image quality for FGI. As a direct result of the class, multiple hospital departments have implemented changes to their imaging protocols, including reduction of the default fluoroscopy pulse rate and increased use of collimation and lower dose fluoroscopy modes. Conclusion: Hands-on fluoroscopy safety training substantially benefits from real-time patient and staff dosimetry incorporated into the class. Real-time dose display helps clinical staff visualize, internalize, and ultimately utilize the safety techniques learned during the training. RaySafe/Unfors/Fluke lent us a portable version of their RaySafe i2 Dosimetry System for 6 months.« less

ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design.

PubMed

Manini, Todd M; Anton, Stephen D; Beavers, Daniel P; Cauley, Jane A; Espeland, Mark A; Fielding, Roger A; Kritchevsky, Stephen B; Leeuwenburgh, Christiaan; Lewis, Kristina H; Liu, Christine; McDermott, Mary M; Miller, Michael E; Tracy, Russell P; Walston, Jeremy D; Radziszewska, Barbara; Lu, Jane; Stowe, Cindy; Wu, Samuel; Newman, Anne B; Ambrosius, Walter T; Pahor, Marco

2017-09-01

To test two interventions to reduce interleukin (IL)-6 levels, an indicator of low-grade chronic inflammation and an independent risk factor for impaired mobility and slow walking speed in older adults. The ENabling Reduction of low-Grade Inflammation in SEniors (ENRGISE) Pilot Study was a multicenter, double-blind, placebo-controlled randomized pilot trial of two interventions to reduce IL-6 levels. Five university-based research centers. Target enrollment was 300 men and women aged 70 and older with an average plasma IL-6 level between 2.5 and 30 pg/mL measured twice at least 1 week apart. Participants had low to moderate physical function, defined as self-reported difficulty walking one-quarter of a mile or climbing a flight of stairs and usual walk speed of less than 1 m/s on a 4-m usual-pace walk. Participants were randomized to losartan, omega-3 fish oil (ω-3), combined losartan and ω-3, or placebo. Randomization was stratified depending on eligibility for each group. A titration schedule was implemented to reach a dose that was safe and effective for IL-6 reduction. Maximal doses were 100 mg/d for losartan and 2.8 g/d for ω-3. IL-6, walking speed over 400 m, physical function (Short Physical Performance Battery), other inflammatory markers, safety, tolerability, frailty domains, and maximal leg strength were measured. Results from the ENRGISE Pilot Study will provide recruitment yields, feasibility, medication tolerance and adherence, and preliminary data to help justify a sample size for a more definitive randomized trial. The ENRGISE Pilot Study will inform a larger subsequent trial that is expected to have important clinical and public health implications for the growing population of older adults with low-grade chronic inflammation and mobility limitations. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Upper Face: Clinical Anatomy and Regional Approaches with Injectable Fillers.

PubMed

Sykes, Jonathan M; Cotofana, Sebastian; Trevidic, Patrick; Solish, Nowell; Carruthers, Jean; Carruthers, Alastair; Moradi, Amir; Swift, Arthur; Massry, Guy G; Lambros, Val; Remington, B Kent

2015-11-01

The use of facial fillers has been rapidly increased as the range of injectable products and indications continues to expand. Complications may arise from improper placement or technique. This article highlights the importance of anatomic knowledge when using injectable fillers in the face. A detailed review of the clinical anatomy of the upper face is performed. Regional approaches are described using the applied anatomy to efficiently and safely augment the different subunits of the upper face. Key aspects of safe and successful injection of fillers in the upper face include a thorough knowledge of the location of fat compartments and neurovascular structures. Awareness of these structures enables the practitioner to maximize injections, while avoiding damage to important nerves and vessels. A detailed knowledge of the anatomy and properties of the product is paramount to maximize the efficacy while minimizing the risk of complications.

The effect of lifelong exercise dose on cardiovascular function during exercise

PubMed Central

Carrick-Ranson, Graeme; Hastings, Jeffrey L.; Bhella, Paul S.; Fujimoto, Naoki; Shibata, Shigeki; Palmer, M. Dean; Boyd, Kara; Livingston, Sheryl; Dijk, Erika

2014-01-01

An increased “dose” of endurance exercise training is associated with a greater maximal oxygen uptake (V̇o2max), a larger left ventricular (LV) mass, and improved heart rate and blood pressure control. However, the effect of lifelong exercise dose on metabolic and hemodynamic response during exercise has not been previously examined. We performed a cross-sectional study on 101 (69 men) seniors (60 yr and older) focusing on lifelong exercise frequency as an index of exercise dose. These included 27 who had performed ≤2 exercise sessions/wk (sedentary), 25 who performed 2–3 sessions/wk (casual), 24 who performed 4–5 sessions/wk (committed) and 25 who performed ≥6 sessions/wk plus regular competitions (Masters athletes) over at least the last 25 yr. Oxygen uptake and hemodynamics [cardiac output, stroke volume (SV)] were collected at rest, two levels of steady-state submaximal exercise, and maximal exercise. Doppler ultrasound measures of LV diastolic filling were assessed at rest and during LV loading (saline infusion) to simulate increased LV filling. Body composition, total blood volume, and heart rate recovery after maximal exercise were also examined. V̇o2max increased in a dose-dependent manner (P < 0.05). At maximal exercise, cardiac output and SV were largest in committed exercisers and Masters athletes (P < 0.05), while arteriovenous oxygen difference was greater in all trained groups (P < 0.05). At maximal exercise, effective arterial elastance, an index of ventricular-arterial coupling, was lower in committed exercisers and Masters athletes (P < 0.05). Doppler measures of LV filling were not enhanced at any condition, irrespective of lifelong exercise frequency. These data suggest that performing four or more weekly endurance exercise sessions over a lifetime results in significant gains in V̇o2max, SV, and heart rate regulation during exercise; however, improved SV regulation during exercise is not coupled with favorable effects on LV filling, even when the heart is fully loaded. PMID:24458750

Sizes of particles formed during municipal wastewater treatment.

PubMed

Lech, Smoczynski; Marta, Kosobucka; Michal, Smoczynski; Harsha, Ratnaweera; Krystyna, Pieczulis-Smoczynska

2017-02-01

Volumetric diameters Dv and specific surface area SpS of sludge particles formed during chemical coagulation and electrocoagulation of sewage were determined. The obtained aggregate-flocs differed substantially in both Dv and SpS values. The differences in Dv and SpS values of the analyzed particles were interpreted based on theoretical models for expanding aggregates. The most uniform particles were formed under exposure to: (a) optimal and maximal doses of PIX, (b) optimal doses of PAX, (c) maximal doses of the Al electro-coagulant. The lowest PIX dose produced the least uniform particles. Sludge aggregates-particles produced under exposure to minimal doses of PIX and the Al electro-coagulant were characterized by the lowest SpS values. Sludge particles coagulated by PAX and the particles formed at higher doses of PIX and the Al electro-coagulant had higher SpS values. The particles formed at all doses of the applied coagulants and electro-coagulants were generally classified into two size ranges: the main range and the secondary range. Most particles belonged to the main size range. An increase in the percentage of colloidal hydroxide particles in sewage sludge increased SpS.

Benchmarking B-Cell Epitope Prediction with Quantitative Dose-Response Data on Antipeptide Antibodies: Towards Novel Pharmaceutical Product Development

PubMed Central

Caoili, Salvador Eugenio C.

2014-01-01

B-cell epitope prediction can enable novel pharmaceutical product development. However, a mechanistically framed consensus has yet to emerge on benchmarking such prediction, thus presenting an opportunity to establish standards of practice that circumvent epistemic inconsistencies of casting the epitope prediction task as a binary-classification problem. As an alternative to conventional dichotomous qualitative benchmark data, quantitative dose-response data on antibody-mediated biological effects are more meaningful from an information-theoretic perspective in the sense that such effects may be expressed as probabilities (e.g., of functional inhibition by antibody) for which the Shannon information entropy (SIE) can be evaluated as a measure of informativeness. Accordingly, half-maximal biological effects (e.g., at median inhibitory concentrations of antibody) correspond to maximally informative data while undetectable and maximal biological effects correspond to minimally informative data. This applies to benchmarking B-cell epitope prediction for the design of peptide-based immunogens that elicit antipeptide antibodies with functionally relevant cross-reactivity. Presently, the Immune Epitope Database (IEDB) contains relatively few quantitative dose-response data on such cross-reactivity. Only a small fraction of these IEDB data is maximally informative, and many more of them are minimally informative (i.e., with zero SIE). Nevertheless, the numerous qualitative data in IEDB suggest how to overcome the paucity of informative benchmark data. PMID:24949474

Influence of the Sampling Rate and Noise Characteristics on Prediction of the Maximal Safe Laser Exposure in Human Skin Using Pulsed Photothermal Radiometry

NASA Astrophysics Data System (ADS)

Vidovič, L.; Milanič, M.; Majaron, B.

2013-09-01

Pulsed photothermal radiometry (PPTR) allows for noninvasive determination of the laser-induced temperature depth profile in strongly scattering samples, including human skin. In a recent experimental study, we have demonstrated that such information can be used to derive rather accurate predictions of the maximal safe radiant exposure on an individual patient basis. This has important implications for efficacy and safety of several laser applications in dermatology and aesthetic surgery, which are often compromised by risk of adverse side effects (e.g., scarring, and dyspigmentation) resulting from nonselective absorption of strong laser light in epidermal melanin. In this study, the differences between the individual maximal safe radiant exposure values as predicted from PPTR temperature depth profiling performed using a commercial mid-IR thermal camera (as used to acquire the original patient data) and our customized PPTR setup are analyzed. To this end, the latter has been used to acquire 17 PPTR records from three healthy volunteers, using 1 ms laser irradiation at 532 nm and a signal sampling rate of 20 000 . The laser-induced temperature profiles are reconstructed first from the intact PPTR signals, and then by binning the data to imitate the lower sampling rate of the IR camera (1000 fps). Using either the initial temperature profile in a dedicated numerical model of heat transfer or protein denaturation dynamics, the predicted levels of epidermal thermal damage and the corresponding are compared. A similar analysis is performed also with regard to the differences between noise characteristics of the two PPTR setups.

Caffeine for apnea of prematurity: Effects on the developing brain.

PubMed

Atik, Anzari; Harding, Richard; De Matteo, Robert; Kondos-Devcic, Delphi; Cheong, Jeanie; Doyle, Lex W; Tolcos, Mary

2017-01-01

Caffeine is a methylxanthine that is widely used to treat apnea of prematurity (AOP). In preterm infants, caffeine reduces the duration of respiratory support, improves survival rates and lowers the incidence of cerebral palsy and cognitive delay. There is, however, little evidence relating to the immediate and long-term effects of caffeine on brain development, especially at the cellular and molecular levels. Experimental data are conflicting, with studies showing that caffeine can have either adverse or benefical effects in the developing brain. The aim of this article is to review current understanding of how caffeine ameliorates AOP, the cellular and molecular mechanisms by which caffeine exerts its effects and the effects of caffeine on brain development. A better knowledge of the effects of caffeine on the developing brain at the cellular and/or molecular level is essential in order to understand the basis for the impact of caffeine on postnatal outcome. The studies reviewed here suggest that while caffeine has respiratory benefits for preterm infants, it may have adverse molecular and cellular effects on the developing brain; indeed a majority of experimental studies suggest that regardless of dose or duration of administration, caffeine leads to detrimental changes within the developing brain. Thus there is an urgent need to assess the impact of caffeine, at a range of doses, on the structure and function of the developing brain in preclinical studies, particularly using clinically relevant animal models. Future studies should focus on determining the maximal dose of caffeine that is safe for the preterm brain. Copyright © 2017 Elsevier B.V. All rights reserved.

Acute and Late Toxicity After Dose Escalation to 82 GyE Using Conformal Proton Radiation for Localized Prostate Cancer: Initial Report of American College of Radiology Phase II Study 03-12

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

Coen, John J., E-mail: jcoen@partners.org; Bae, Kyounghwa; Zietman, Anthony L.

Purpose: Several randomized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer. Single-institution data suggest a benefit with even higher doses. American College of Radiology 03-12 is a Phase II trial testing the safety and efficacy of 82 GyE (Gray equivalent) delivered with conformal proton radiation. Methods and Materials: From 2003-2006, 85 men with localized prostate cancer were accrued to American College of Radiology 03-12. Eighty-four were eligible for analysis. They were treated with conformal proton radiation alone to a total dose of 82 GyE. Themore » study was designed to test whether the rate of 18-month Grade 3+ late toxicity was greater than 10%. Results: The median follow-up was 31.6 months. Regarding treatment-related acute toxicity, there were 39 Grade 1 cases (46%), 19 Grade 2 cases (23%) and 2 Grade 3 cases (2%). Regarding genitourinary/gastrointestinal toxicity, there were 42 Grade 1 cases (50%), 12 Grade 2 cases (14%) and 1 Grade 3 case (1%). Regarding late toxicity, there were 28 Grade 1 cases (33%), 22 Grade 2 cases (26%), 6 Grade 3 cases (7%), and 1 Grade 4 case (1%). The late genitourinary/gastrointestinal rates were the same. The estimated rate of Grade 3+ late toxicity at 18 months was 6.08%. Conclusions: Although not free of late toxicity, 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial. There was sufficient morbidity, however, that this may be the maximal dose that can be delivered safely with this technique and fractionation.« less

EPA's Safe and Sustainable Water Resources Research Program: Water Systems Research

EPA Science Inventory

Water systems challenged by limited resources, aging infrastructure, shifting demographics, climate change, and extreme weather events need transformative approaches to meet public health and environmental goals, while optimizing water treatment and maximizing resource recovery a...

The Role of Autocrine-Paracrine Cascades in Breast Tumor Metastasis

DTIC Science & Technology

1999-08-01

tested a large series of anti-oxidants at non- toxic doses. The only compounds that worked in this series were resveratrol and curcumin . The...resveratrol gave a 20-35% maximal inhibition while the curcumin gave a maximal response between 40 and 60% maximal inhibition. While the resveratrol inhibited...IL-8 expression in both -7- THIS REPORT CONTAINS PROPRIETARY AND/OR UNPUBLISHED DATA the MD-231 and MD-435s cells, the inhibitory effects of curcumin

Real-life indications to ivabradine treatment for heart rate optimization in patients with chronic systolic heart failure.

PubMed

Tondi, Lara; Fragasso, Gabriele; Spoladore, Roberto; Pinto, Giuseppe; Gemma, Marco; Slavich, Massimo; Godino, Cosmo; Salerno, Anna; Montanaro, Claudia; Margonato, Alberto

2018-05-11

: Ivabradine is a selective and specific inhibitor of If current. With its pure negative chronotropic action, it is recommended by European Society of Cardiology and American College of Cardiology/American Heart Association guidelines in symptomatic heart failure patients (NYHA ≥ 2) with ejection fraction 35% or less, sinus rhythm and heart rate (HR) at least 70 bpm, despite maximally titrated β-blocker therapy. Data supporting this indication mainly derive from the SHIFT study, in which ivabradine reduced the combined endpoint of mortality and hospitalization, despite the fact that only 26% of patients enrolled were on optimal β-blocker doses. The aim of the present analysis is to establish the real-life eligibility for ivabradine in a population of patients with systolic heart failure, regularly attending a single heart failure clinic and treated according to guideline-directed medical therapy (GDMT). The clinical cards of 308 patients with heart failure with reduced ejection fraction (HFrEF) through a 68-month period of observation were retrospectively analyzed. GDMT, including β-blocker up-titration to maximal tolerated dose, was implemented during consecutive visits at variable intervals. Demographic, clinical and echocardiographic data were collected at each visit, together with 12-leads ECG and N-terminal pro-B-type natriuretic peptide levels. Out of 308 analyzed HFrEF patients, 220 (71%) were on effective β-blocker therapy, up-titrated to effective/maximal tolerated dose (55 ± 28% of maximal dose) (HR 67 ± 10 bpm). Among the remaining 88 patients, 10 (3.2%) were on maximally tolerated β blocker and ivabradine; 21 patients (6.8%), despite being on maximal tolerated β-blocker dose, had still HR ≥70 bpm, ejection fraction 35% or less and were symptomatic NYHA ≥2, being therefore eligible for ivabradine treatment. The remaining 57 (18%) patients were not on β blocker due to either intolerance or major contraindications. Among them, 13 (4%) were taking ivabradine alone. Of the final 44 (14%) patients, 27 (9%) showed an inadequate HR control (74 ± 6 bpm). Of these, only eight (3%) patients resulted to be eligible for ivabradine introduction according to HR and ejection fraction parameters. Overall ivabradine was indicated in 52 patients (16.8%) out of 308 enrolled.In conclusion, in a carefully managed population of patients with moderate and stable HFrEF, in which optimal GDMT is properly attained, indication to ivabradine treatment is around 17%.

A novel and effective acupuncture modality as a complementary therapy to acute pain relief in inpatients with rib fractures.

PubMed

Ho, Hsin-Yi; Chen, Chao-Wei; Li, Ming-Chieh; Hsu, Yu-Pao; Kang, Shih-Ching; Liu, Erh-Hao; Lee, Ko-Hung

2014-01-01

Pain control has been emphasized as a priority for both practitioners and inpatients with rib fractures, since analgesia could only offer limited relief from severe pain. A prospective and randomized controlled trial was conducted to analyze the efficacy and efficiency of acupuncture in acute pain relief for inpatients with rib fractures. A total of 58 inpatients were recruited and allocated to two groups, receiving identical doses of conventional oral analgesics as well as filiform needles as treatment and thumbtack intradermal (TI) needles placed upon the skin surface as a control, respectively, via novel acupuncture modality once daily for three consecutive days. The effect of pain relief was evaluated during activities that induce pain, and sustained maximal inspiration (SMI) lung volumes and sleep quality were assessed. The patients treated with filiform needles had more effective pain relief than those in the TI needle group during deep breathing, coughing, and turning over the body (p < 0.05), and the effect persisted for at least 6 h in most patients. Sustained maximal inspiration lung volumes and sleep quality did not show improvement through every acupuncture intervention, and they could not respond accurately to pain relief via acupuncture. The active evaluation could provide a more adaptive model for assessing pain intensity due to rib fractures. This novel acupuncture modality in which the needle insertion sites are corresponding to the pain spots can be a safe and viable therapy for relieving pain in inpatients with rib fractures.

Phase I Study of Oxaliplatin in Combination With Capecitabine and Radiotherapy as Postoperative Treatment for Stage II and III Rectal Cancer

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

Jin Jing; Li Yexiong; Wang Jinwan

Purpose: A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicity (DLT) of oxaliplatin (OXA) combined with capecitabine and radiotherapy as adjuvant treatment in patients with operable rectal cancer. Patients and Methods: A total of 21 patients with Stage II or III rectal adenocarcinoma after curative surgery were treated with radiotherapy to a total dose of 50 Gy in 5 weeks. OXA was administered at a dosage of 40 (n = 6), 50 (n = 3),60 (n = 3), 70 (n = 3), or 80 mg/m{sup 2} (n = 6) once a week formore » 2 weeks (first cycle) followed by a second cycle after a 7-day break. Capecitabine at a fixed dose of 1,300 mg/m{sup 2}/d was administered orally at the same schedule as for OXA. DLT was defined as Grade 3 or 4 hematologic and nonhematologic toxicity. Results: Grade 1-3 leukopenia, diarrhea, and nausea/vomiting were the most common toxic side effects, and most were Grade 1-2. A DLT was first observed in 1 of 3 patients at 40 mg/m{sup 2} (Grade 3 diarrhea) but was not observed in the next 3 patients at the same level or in patients who received a dose level of 50-70 mg/m{sup 2}. At 80 mg/m{sup 2}, DLT occurred in 3 of 6 patients (1 Grade 4 leukopenia and 2 Grade 3 diarrhea). Conclusions: OXA combined with a fixed dose of capecitabine at 625 mg/m{sup 2} twice daily by mouth plus radiotherapy in the adjuvant setting was tolerable and clinically feasible. The maximal tolerated dose of OXA in this setting was 80 mg/m{sup 2}, comparable to the maximal tolerated dose of OXA in the neoadjuvant setting.« less

Quantification of the spatial distribution of rectally applied surrogates for microbicide and semen in colon with SPECT and magnetic resonance imaging

PubMed Central

Cao, Ying J; Caffo, Brian S; Fuchs, Edward J; Lee, Linda A; Du, Yong; Li, Liye; Bakshi, Rahul P; Macura, Katarzyna; Khan, Wasif A; Wahl, Richard L; Grohskopf, Lisa A; Hendrix, Craig W

2012-01-01

AIMS We sought to describe quantitatively the distribution of rectally administered gels and seminal fluid surrogates using novel concentration–distance parameters that could be repeated over time. These methods are needed to develop rationally rectal microbicides to target and prevent HIV infection. METHODS Eight subjects were dosed rectally with radiolabelled and gadolinium-labelled gels to simulate microbicide gel and seminal fluid. Rectal doses were given with and without simulated receptive anal intercourse. Twenty-four hour distribution was assessed with indirect single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI), and direct assessment via sigmoidoscopic brushes. Concentration–distance curves were generated using an algorithm for fitting SPECT data in three dimensions. Three novel concentration–distance parameters were defined to describe quantitatively the distribution of radiolabels: maximal distance (Dmax), distance at maximal concentration (DCmax) and mean residence distance (Dave). RESULTS The SPECT/CT distribution of microbicide and semen surrogates was similar. Between 1 h and 24 h post dose, the surrogates migrated retrograde in all three parameters (relative to coccygeal level; geometric mean [95% confidence interval]): maximal distance (Dmax), 10 cm (8.6–12) to 18 cm (13–26), distance at maximal concentration (DCmax), 3.8 cm (2.7–5.3) to 4.2 cm (2.8–6.3) and mean residence distance (Dave), 4.3 cm (3.5–5.1) to 7.6 cm (5.3–11). Sigmoidoscopy and MRI correlated only roughly with SPECT/CT. CONCLUSIONS Rectal microbicide surrogates migrated retrograde during the 24 h following dosing. Spatial kinetic parameters estimated using three dimensional curve fitting of distribution data should prove useful for evaluating rectal formulations of drugs for HIV prevention and other indications. PMID:22404308

Pharmacokinetics of detomidine administered to horses at rest and after maximal exercise.

PubMed

Hubbell, J A E; Sams, R A; Schmall, L M; Robertson, J T; Hinchcliff, K W; Muir, W W

2009-05-01

Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses. To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest. Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatography-mass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis. Median back-extrapolated time zero plasma concentration was significantly lower and median plasma half-life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations. Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect.

Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension.

PubMed

Iglarz, Marc; Bossu, Alexandre; Wanner, Daniel; Bortolamiol, Céline; Rey, Markus; Hess, Patrick; Clozel, Martine

2014-11-24

The endothelin (ET) system is a tissular system, as the production of ET isoforms is mostly autocrine or paracrine. Macitentan is a novel dual ETA/ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade. To determine if these features translate into improved efficacy in vivo, a study was designed in which rats with either systemic or pulmonary hypertension and equipped with telemetry were given macitentan on top of maximally effective doses of another dual ETA/ETB receptor antagonist, bosentan, which does not display sustained receptor occupancy and shows less tissue distribution. After establishing dose-response curves of both compounds in conscious, hypertensive Dahl salt-sensitive and pulmonary hypertensive bleomycin-treated rats, macitentan was administered on top of the maximal effective dose of bosentan. In hypertensive rats, macitentan 30 mg/kg further decreased mean arterial blood pressure (MAP) by 19 mm Hg when given on top of bosentan 100 mg/kg (n=9, p<0.01 vs. vehicle). Conversely, bosentan given on top of macitentan failed to induce an additional MAP decrease. In pulmonary hypertensive rats, macitentan 30 mg/kg further decreased mean pulmonary artery pressure (MPAP) by 4 mm Hg on top of bosentan (n=8, p<0.01 vs. vehicle), whereas a maximal effective dose of bosentan given on top of macitentan did not cause any additional MPAP decrease. The add-on effect of macitentan on top of bosentan in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy. Copyright © 2014. Published by Elsevier Inc.

A Single 30-s Stretch Is Sufficient to Inhibit Maximal Voluntary Strength

ERIC Educational Resources Information Center

Winchester, Jason B.; Nelson, Arnold G.; Kokkonen, Joke

2009-01-01

While it has been well established that an acute stretching program can inhibit maximal muscle performance, the amount of stretching needed to produce the deleterious response is unknown. Therefore this study examined the dose-response relationship between acute stretching and strength inhibition. Eighteen college students performed a one…

A rule-based, dose-finding design for use in stroke rehabilitation research: methodological development.

PubMed

Colucci, E; Clark, A; Lang, C E; Pomeroy, V M

2017-12-01

Dose-optimisation studies as precursors to clinical trials are rare in stroke rehabilitation. To develop a rule-based, dose-finding design for stroke rehabilitation research. 3+3 rule-based, dose-finding study. Dose escalation/de-escalation was undertaken according to preset rules and a mathematical sequence (modified Fibonacci sequence). The target starting daily dose was 50 repetitions for the first cohort. Adherence was recorded by an electronic counter. At the end of the 2-week training period, the adherence record indicated dose tolerability (adherence to target dose) and the outcome measure indicated dose benefit (10% increase in motor function). The preset increment/decrease and checking rules were then applied to set the dose for the subsequent cohort. The process was repeated until preset stopping rules were met. Participants had a mean age of 68 (range 48 to 81) years, and were a mean of 70 (range 9 to 289) months post stroke with moderate upper limb paresis. A custom-built model of exercise-based training to enhance ability to open the paretic hand. Repetitions per minute of extension/flexion of paretic digits against resistance. Usability of the preset rules and whether the maximally tolerated dose was identifiable. Five cohorts of three participants were involved. Discernibly different doses were set for each subsequent cohort (i.e. 50, 100, 167, 251 and 209 repetitions/day). The maximally tolerated dose for the model training task was 209 repetitions/day. This dose-finding design is a feasible method for use in stroke rehabilitation research. Copyright © 2017 Chartered Society of Physiotherapy. All rights reserved.

Gene Therapy Delivery Systems for Enhancing Viral and Nonviral Vectors for Cardiac Diseases: Current Concepts and Future Applications

PubMed Central

Katz, Michael G.; Fargnoli, Anthony S.; Williams, Richard D.

2013-01-01

Abstract Gene therapy is one of the most promising fields for developing new treatments for the advanced stages of ischemic and monogenetic, particularly autosomal or X-linked recessive, cardiomyopathies. The remarkable ongoing efforts in advancing various targets have largely been inspired by the results that have been achieved in several notable gene therapy trials, such as the hemophilia B and Leber's congenital amaurosis. Rate-limiting problems preventing successful clinical application in the cardiac disease area, however, are primarily attributable to inefficient gene transfer, host responses, and the lack of sustainable therapeutic transgene expression. It is arguable that these problems are directly correlated with the choice of vector, dose level, and associated cardiac delivery approach as a whole treatment system. Essentially, a delicate balance exists in maximizing gene transfer required for efficacy while remaining within safety limits. Therefore, the development of safe, effective, and clinically applicable gene delivery techniques for selected nonviral and viral vectors will certainly be invaluable in obtaining future regulatory approvals. The choice of gene transfer vector, dose level, and the delivery system are likely to be critical determinants of therapeutic efficacy. It is here that the interactions between vector uptake and trafficking, delivery route means, and the host's physical limits must be considered synergistically for a successful treatment course. PMID:24164239

Endothelial responses of magnesium and other alloying elements in magnesium-based stent materials

PubMed Central

Zhao, Nan; Zhu, Donghui

2016-01-01

Biodegradable tailored magnesium (Mg) alloys are some of the most promising scaffolds for cardiovascular stents. During the course of degradation after implantation, all the alloying elements in the scaffold will be released to the surrounding vascular tissues. However, fundamental questions regarding the toxicity of alloying elements towards vascular cells, the maximum amount of each element that could be used in alloy design, or how each of the alloying elements affects vascular cellular activity and gene expression, are still not fully answered. This work systematically addressed these questions by revealing how application of different alloying elements commonly used in Mg stent materials influences several indices of human endothelial cell health, i.e., viability, proliferations, cytoskeletal reorganizations, migration, and the gene expression profile. The overall cell viability and proliferation showed a decreasing trend with increasing concentrations of the ions, and the half maximal effective concentrations (EC50) for each element were determined. When applied at a low concentration of around 10 mM, Mg had no adverse effects but improved cell proliferation and migration instead. Mg ions also altered endothelial gene expression significantly in a dose dependent manner. Most of the changed genes are related to angiogenesis and the cell adhesion signaling pathways. Findings from this work provide useful information on maximum safe doses of these ions for endothelial cells, endothelial responses towards these metal ions, and some guidance for future Mg stent design. PMID:25363018

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation

PubMed Central

Grover, Anita; Benet, Leslie Z.

2013-01-01

Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives. PMID:21499748

Global Precipitation Measurement (GPM) and International Space Station (ISS) Coordination for Cubesat Deployments

NASA Technical Reports Server (NTRS)

Pawloski, James H.; Aviles, Jorge; Myers, Ralph; Parris, Joshua; Corley, Bryan; Hehn, Garrett; Pascucci, Joseph

2016-01-01

This paper describes the specific problem of collision threat to GPM and risk to ISS CubeSat deployment and the process that was implemented to keep both missions safe from collision and maximize their project goals.

LAND AND WATER USE CHARACTERISTICS AND HUMAN HEALTH INPUT PARAMETERS FOR USE IN ENVIRONMENTAL DOSIMETRY AND RISK ASSESSMENTS AT THE SAVANNAH RIVER SITE

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

Jannik, T.; Karapatakis, D.; Lee, P.

2010-08-06

Operations at the Savannah River Site (SRS) result in releases of small amounts of radioactive materials to the atmosphere and to the Savannah River. For regulatory compliance purposes, potential offsite radiological doses are estimated annually using computer models that follow U.S. Nuclear Regulatory Commission (NRC) Regulatory Guides. Within the regulatory guides, default values are provided for many of the dose model parameters but the use of site-specific values by the applicant is encouraged. A detailed survey of land and water use parameters was conducted in 1991 and is being updated here. These parameters include local characteristics of meat, milk andmore » vegetable production; river recreational activities; and meat, milk and vegetable consumption rates as well as other human usage parameters required in the SRS dosimetry models. In addition, the preferred elemental bioaccumulation factors and transfer factors to be used in human health exposure calculations at SRS are documented. Based on comparisons to the 2009 SRS environmental compliance doses, the following effects are expected in future SRS compliance dose calculations: (1) Aquatic all-pathway maximally exposed individual doses may go up about 10 percent due to changes in the aquatic bioaccumulation factors; (2) Aquatic all-pathway collective doses may go up about 5 percent due to changes in the aquatic bioaccumulation factors that offset the reduction in average individual water consumption rates; (3) Irrigation pathway doses to the maximally exposed individual may go up about 40 percent due to increases in the element-specific transfer factors; (4) Irrigation pathway collective doses may go down about 50 percent due to changes in food productivity and production within the 50-mile radius of SRS; (5) Air pathway doses to the maximally exposed individual may go down about 10 percent due to the changes in food productivity in the SRS area and to the changes in element-specific transfer factors; and (6) Air pathway collective doses may go down about 30 percent mainly due to the decrease in the inhalation rate assumed for the average individual.« less

Escalation to High Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease

PubMed Central

Triplett, Brandon M.; Kuttab, Hani I.; Kang, Guolian; Leung, Wing

2015-01-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those utilized in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial, 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. There was no observed increase in toxicity until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10–100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, while those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (p=0.008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose escalation strategy remains unclear, as outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. PMID:26278046

The protective effect of superoxide dismutase on isolated human mammary arteries preincubated with triglyceride-rich remnant lipoproteins.

PubMed

Savoiu, Germaine; Drăgan, Simona; Cristescu, Carmen; Serban, Corină; Noveanu, Lavinia; Ionescu, Daniela; Nicola, T; Duicu, Oana; Răducan, Andreea; Voicu, Mirela

2009-01-01

The main changes of the plasma lipid profile in patients with endothelial dysfunction are the increased triglyceride content of the lipoprotein remnant particles, the presence of the small and dense LDL particles and the decreasing of the HDL-cholesterol level. Considering these observations, we performed "in vitro" experiments using human mammary artery rings, in order to examine the effect of the lipoprotein "remnants" on endothelium-dependent vasodilatation induced by cumulative doses (10(-9) M - 10(-4) M) of adenosine (ADP) and to study the effect on endothelial--independent vasodilatation induced by cumulative doses (10(-9) M-10(-4) M) of sodium-nitropruside (NSP), respectively. Our results showed that 1 hour pre-incubation with triglyceride--rich lipoprotein remnants diminished the endothelial-dependent vasodilator response to ADP, but it has not modified the endothelial-independent vasodilator response to NSP. Vascular response was expressed as maximal vasodilatation from the 10(-4)M phenilephrine (PE) induced pre-contraction, considered as reference. In the case of ADP, the maximal vasodilatation was ranged in 36.50% +/- 10.81% interval, comparing with the control group that presented a maximal vasodilatation of 66.15% +/- 19.41% (p < 0.005). In the case of NSP the maximal vasodilatation was ranged in 99.78% +/- 10.53% interval, comparing with the control that presented a maximal vasodilatation of 98.99% +/- 12.45% (p = 0.44). One hour co-incubation of the rings with a solution containing lipoprotein remnants (1% oxidized IDL (ox-IDL) and antioxidant factor (150 U/mL 10(-4) M Superoxid dismutase (SOD) significantly reduced the impairment of the vasodilatation response to ADP. Maximal vasodilatation of ox-IDL and SOD coincubated human mammary artery rings was 58.50% +/- 10.63% compared to the control, were the maximal vasodilatation was 66.15% +/- 19.41% (p < 0.01), but has not modified the vasodilatation response to NSP (99% +/- 0.53% vs control 98.99% +/- 12.45%, p = 0.56). The endothelial dysfunction induced by the triglyceride-rich lipoprotein "remnants", could contribute to the pathogenesis of atherosclerosis and the treatment with high doses of antioxidants could "protect" the endothelium against the pro-atherogenic action of the lipoprotein "remnants".

State of the Science: Biologically Based Modeling in Risk Assessment [Editorial

EPA Science Inventory

The health risk assessment from exposure to a particular agent is preferred when the assessment is based on a relevant measure of internal dose (e.g., maximal concentration of an active metabolite in target tissue) rather than simply the administered dose or exposure concentratio...

GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers.

PubMed

McLeod, J F; Leempoels, J M; Peng, S X; Dax, S L; Myers, L J; Golder, F J

2014-11-01

Potassium-channels in the carotid body and the brainstem are important regulators of ventilation. The BKCa-channel contains response elements for CO, O2, and CO2. Its block increases carotid body signalling, phrenic nerve activity, and respiratory drive. GAL-021, a new BKCa-channel blocker, increases minute ventilation in rats and non-human primates. This study assessed the single-dose safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GAL-021 in healthy volunteers. Thirty subjects participated in a nine-period, randomized, double-blinded, placebo-controlled, crossover, ascending dose, first-in-human study with i.v. infusions of 0.1-0.96 mg kg(-1) h(-1) for 1 h and intermediate doses up to 4 h. Adverse event rates were generally similar among dose levels and between placebo- and GAL-021-treated subjects. At higher GAL-021 doses, a mild/moderate burning sensation at the infusion site occurred during the infusion. No clinically significant changes in vital signs or clinical chemistries were noted. Minute ventilation increased (AUE0-1 h ≈ 16%, P<0.05) and end-tidal carbon dioxide ([Formula: see text]) decreased (AUE0-1 h ≈ 6%, P<0.05) during the first hour at 0.96 mg kg(-1) h(-1) with 1/2-maximal [Formula: see text] and [Formula: see text]-change occurring by 7.5 min. Drug concentration rose rapidly during the infusion and decreased rapidly initially (distribution t1/2 of 30 min) and then more slowly (terminal t1/2 of 5.6 h). GAL-021 was safe and generally well tolerated with adverse events comparable with placebo except for an infusion site burning sensation. GAL-021 stimulated ventilation at the highest doses suggesting that greater infusion rates may be required for maximum PD effects. GAL-021 had PK characteristics consistent with an acute care medication. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

WASTE-TO-RESOURCE: NOVEL MEMBRANE SYSTEMS FOR SAFE AND SUSTAINABLE BRINE MANAGEMENT

EPA Science Inventory

Decentralized waste-to-reuse systems will be optimized to maximize resource and energy recovery and minimize chemicals and energy use. This research will enhance fundamental knowledge on simultaneous heat and mass transport through membranes, lower process costs, and furthe...

Escalation to High-Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease.

PubMed

Triplett, Brandon M; Kuttab, Hani I; Kang, Guolian; Leung, Wing

2015-12-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Somatotype, the risk of hydroxychloroquine retinopathy, and safe daily dosing guidelines.

PubMed

Browning, David J; Lee, Chong

2018-01-01

The aim of this study was to determine whether somatotype influences the risk of hydroxychloroquine (HC) retinopathy (HCR) and whether dosing by real body weight (RBW), ideal body weight (IBW), or the lesser of these better predicts the risk of HCR. A total of 565 patients taking HC for whom height and weight were recorded and a sensitive ancillary testing modality was used including 10-2 visual fields, spectral domain optical coherence tomography, fundus autofluorescence imaging, and multifocal electroretinography were enrolled. Body mass index (BMI) was compared for patients without and with HCR. Logistic regression models of age, cumulative dose, and daily dosing based on RBW, IBW, or lesser of these were compared. Area under the curve (AUC) of receiver operating characteristic plots was used to assess the diagnostic accuracy of RBW, IBW, and lesser of these guidelines for safe dosing. Probability plots for the risk of retinopathy versus BMI were compared for the different recommended guidelines on safe dosing. A total of 41 patients had HCR. The median BMI was 27.6 (interquartile range [IQR] 24.3, 32.6) and 24.0 (IQR 21.0, 31.6) for patients without and with HCR ( P =0.0102), respectively. AUC for univariate receiver operating characteristic plots of retinopathy versus dosing by RBW, IBW, and lesser of these was 0.71, 0.72, and 0.76, respectively. AUC for multivariate receiver operating characteristic plots of retinopathy versus models incorporating gender, age, cumulative dose, and BMI and differing by including dosing by RBW, IBW, and lesser of these was 0.82, 0.82, and 0.83, respectively. For all of the multivariate logistic models, the risk of retinopathy was higher for lower BMIs. Short, asthenic women are at higher risk for HCR. The 2011 American Academy of Ophthalmology (AAO) guidelines are safer for short, obese women. The 2016 AAO guidelines are safer for short, asthenic patients. Choosing daily dosing based on the lesser of the RBW and IBW guidelines is safer for all patients.

Improved delivery of fenoterol plus ipratropium bromide using Respimat compared with a conventional metered dose inhaler.

PubMed

Goldberg, J; Freund, E; Beckers, B; Hinzmann, R

2001-02-01

Asthma can be effectively treated by the use of bronchodilator therapies administered by inhalation. The objective of this study was to describe the dose-response relationship of combined doses of fenoterol hydrobromide (F) and ipratropium bromide (I) (F/I) delivered via Respimat, a soft mist inhaler, and to establish the Respimat dose which is as efficacious and as safe as the standard marketed dose of F/I (100/40 microg) which is delivered via a conventional metered dose inhaler (MDI). In a double-blind (within device) cross-over study with a balanced incomplete block design, 62 patients with stable bronchial asthma (mean forced expiratory volume in one second (FEV1) 63% predicted) were randomized at five study centres to receive five out of eight possible treatments: placebo, F/I 12.5/5, 25/10, 50/20, 100/40 or 200/80 microg delivered via Respimat; F/I 50/20 or 100/40 microg delivered via MDI. Pulmonary function results were based on the per-protocol dataset, comprising 47 patients. All F/I doses produced greater increases in FEV1 than placebo. A log-linear dose-response was obtained for the average increase in FEV1 up to 6 h (AUC0-6 h) and peak FEV1 across the dose range administered by Respimat. Statistically, therapeutic equivalence was not demonstrated between any F/I dose administered by Respimat compared with the MDI. However 12.5/5 and 25/10 microg F/I administered via Respimat were closest (slightly superior) to the F/I dose of 100/40 microg delivered via MDI. Pharmacokinetic data from 34 patients indicated a two-fold greater systemic availability of both drugs following inhalation by Respimat compared to MDI. In general, the active treatments were well tolerated and safe with regard to vital signs, electrocardiography, laboratory parameters and adverse events. In conclusion, combined administration of fenoterol hydrobromide and ipratropium bromide via Respimat, is as effective and as safe as higher doses given via a metered dose inhaler.

Efficacy and Safety of Adjuvant Proton Therapy Combined With Surgery for Chondrosarcoma of the Skull Base: A Retrospective, Population-Based Study.

PubMed

Feuvret, Loïc; Bracci, Stefano; Calugaru, Valentin; Bolle, Stéphanie; Mammar, Hamid; De Marzi, Ludovic; Bresson, Damien; Habrand, Jean-Louis; Mazeron, Jean-Jacques; Dendale, Rémi; Noël, Georges

2016-05-01

Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS). From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE]; range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively. With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age <40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS. Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended. Copyright © 2016 Elsevier Inc. All rights reserved.

Responses of Szarvasi-1 energy grass to sewage sludge treatments in hydroponics.

PubMed

Rév, Ambrus; Tóth, Brigitta; Solti, Ádám; Sipos, Gyula; Fodor, Ferenc

2017-09-01

Sewage sludge (SS) originating from communal wastewater is a hazardous material but have a potentially great nutritive value. Its disposal after treatment in agricultural lands can be a very economical and safe way of utilization once fast growing, high biomass, perennial plants of renewable energy production are cultivated. Szarvasi-1 energy grass (Elymus elongatus subsp. ponticus cv. Szarvasi-1), a good candidate for this application, was grown in hydroponics in order to assess its metal accumulation and tolerance under increasing SS amendments. The applied SS had a composition characteristic to SS from communal wastes and did not contain any toxic heavy metal contamination from industrial sludge in high concentration. Toxic effects was assessed in quarter strength Hoagland nutrient solution and only the two highest doses (12.5-18.75 g dm -3 ) caused decreases in root growth, shoot water content and length and stomatal conductance whereas shoot growth, root water content, chlorophyll concentration and the maximal quantum efficiency of photosystem II was unaffected. Shoot K, Ca, Mg, Mn, Zn and Cu content decreased but Na and Ni increased in the shoot compared to the unamended control. The nutritive effect was tested in 1/40 strength Hoagland solution and only the highest dose (12.5 g dm -3 ) decreased root growth and stomatal conductance significantly while lower doses (1.25-6.25 g dm -3 ) had a stimulative effect. Shoot K, Na, Fe and Ni increased and Ca, Mg, Mn, Zn and Cu decreased in this treatment. It was concluded that SS with low heavy metal content can be a potentially good fertilizer for high biomass non-food crops such as Szarvasi-1 energy grass. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Efficacy and Safety of Adjuvant Proton Therapy Combined With Surgery for Chondrosarcoma of the Skull Base: A Retrospective, Population-Based Study

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

Feuvret, Loïc, E-mail: loic.feuvret@psl.aphp.fr; Department of Radiation Oncology, Institut Curie–Centre de protonthérapie d'Orsay; Bracci, Stefano

Purpose: Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS). Methods and Materials: From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE];more » range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively. Results: With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age <40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS. Conclusions: Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended.« less

Safety and efficacy of high-dose chemotherapy with autologous stem cell transplantation for patients with malignant astrocytomas.

PubMed

Chen, Benjamin; Ahmed, Tauseef; Mannancheril, Anney; Gruber, Michael; Benzil, Deborah L

2004-05-15

Malignant astrocytomas are among the most resistant tumors to curative treatments. Mean survival without treatment is measured in weeks, and even with maximal surgery and radiation, the mean reported survival is < 1 year. The advent of supportive treatments and newer agents has resulted in benefits for many patients with cancer. The authors investigated the safety and effect on survival of a high-dose thiotepa and carboplatin regimen with autologous stem cell transplantation (ASCT) in patients with malignant astrocytomas who were enrolled in a prospective trial approved by an institutional review board (IRB). Twenty-one patients were enrolled in an IRB-approved, prospective trial. After baseline testing was completed, patients underwent peripheral stem cell mobilization with cyclophosphamide (4 g/m2) and etoposide (450 mg/m2) followed by granulocyte-colony-stimulating factor (10 microg/kg). Peripheral stem cells were harvested when leukocyte counts recovered. Patients received 2 cycles of thiotepa (750 mg/m2) and carboplatin (1600 mg/m2) followed by infusion of the preserved stem cells. The cycles were administered 6-10 weeks apart. Primary outcome measures were patient survival (Kaplan-Meier analysis) and treatment toxicity (using National Cancer Institute common toxicity criteria). Autologous stem cells were harvested effectively and transfused in all patients. Kaplan-Meier survival analysis demonstrated a survival time of 34.3 +/- 5.5 months (range, 9-94 months). Despite significant myelosuppression, only three patients experienced Grade 4 complications and eight experienced Grade 3 complications. High-dose chemotherapy with thiotepa and carboplatin with concomitant ASCT was used safely to treat patients with malignant astrocytomas and may provide a survival advantage. Copyright 2004 American Cancer Society.

Hydrocortisone at stress-associated concentrations helps maintain human heart rate variability during subsequent endotoxin challenge.

PubMed

Rassias, Athos J; Guyre, Paul M; Yeager, Mark P

2011-12-01

We evaluated the differential impact of stress-associated vs high pharmacologic concentrations of hydrocortisone pretreatment on heart rate variability (HRV) during a subsequent systemic inflammatory stimulus. Healthy volunteers were randomized to receive placebo (Control) and hydrocortisone at 1.5 μg/kg per minute (STRESS) or at 3.0 μg/kg per minute (PHARM) as a 6-hour infusion. The STRESS dose was chosen to replicate the condition of physiologic adrenal cortical output during acute systemic stress. The PHARM dose was chosen to induce a supraphysiologic concentration of cortisol. The next day, all subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide). Heart rate variability was analyzed with the statistic approximate entropy (ApEn). A lower ApEn correlates with decreased HRV. At the 3-hour nadir, the decrease in ApEn in the STRESS group was significantly less compared to placebo (P < .03), whereas ApEn in the PHARM group was not statistically different. We also found that the maximal decrease in ApEn preceded maximal increase in heart rate in all groups. The decrease in R-R interval was maximal at 4 hours, whereas the ApEn nadir was 1 hour earlier at 3 hours. Pretreatment with a stress dose of hydrocortisone but not a higher pharmacologic dose maintained a significantly higher ApEn after endotoxin exposure when compared to a placebo. In addition, decreases in ApEn preceded increases in heart rate. Copyright © 2011 Elsevier Inc. All rights reserved.

Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women.

PubMed

Ng, Juki; Chwalisz, Kristof; Carter, David C; Klein, Cheri E

2017-05-01

Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women. We evaluated the pharmacokinetics and pharmacodynamics of elagolix. This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days. Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events. Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women. Copyright © 2017 Endocrine Society

The clinical pharmacology of alkylating agents in high-dose chemotherapy.

PubMed

Huitema, A D; Smits, K D; Mathôt, R A; Schellens, J H; Rodenhuis, S; Beijnen, J H

2000-08-01

Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is to summarize the clinical pharmacology of the alkylating agents (including the platinum compounds) in high-dose chemotherapy. Differences between conventional and high doses will be discussed.

Quantitative Prediction of the Effect of CYP3A Inhibitors and Inducers on Venetoclax Pharmacokinetics Using a Physiologically Based Pharmacokinetic Model.

PubMed

Freise, Kevin J; Shebley, Mohamad; Salem, Ahmed Hamed

2017-06-01

The objectives of the analysis were to develop and verify a venetoclax physiologically based pharmacokinetic (PBPK) model to predict the effects of cytochrome P450 3A (CYP3A) inhibitors and inducers on the PK of venetoclax and inform dosing recommendations. A minimal PBPK model was developed based on prior in vitro and in vivo clinical data using a "middle-out" approach. The PBPK model was independently verified against clinical studies of the strong CYP3A inhibitor ketoconazole, the strong CYP3A inducer, multiple-dose rifampin, and the steady-state venetoclax PK in chronic lymphocytic leukemia (CLL) subjects by comparing predicted to observed ratios of the venetoclax maximum concentration (C max R) and area under the curve from time 0 to infinity (AUC ∞ R) from these studies. The verified PBPK model was then used to simulate the effects of different CYP3A inhibitors and inducers on the venetoclax PK. Comparison of the PBPK model predicted to the observed PK parameters indicated good agreement. Verification of the PBPK model demonstrated that the ratios of the predicted:observed C max R and AUC ∞ R of venetoclax were within 0.8- to 1.25-fold range for strong CYP3A inhibitors and inducers. Model simulations indicated no effect of weak CYP3A inhibitors or inducers on C max or AUC ∞ , while both moderate and strong CYP3A inducers were estimated to decrease venetoclax exposure. Moderate and strong CYP3A inhibitors were estimated to increase venetoclax AUC ∞ , by 100% to 390% and 480% to 680%, respectively. The recommended venetoclax dose reductions of at least 50% and 75% when coadministered with moderate and strong CYP3A inhibitors, respectively, maintain venetoclax exposures between therapeutic and maximally administered safe doses. © 2017, The American College of Clinical Pharmacology.

Principles for designing future regimens for multidrug-resistant tuberculosis.

PubMed

Brigden, Grania; Nyang'wa, Bern-Thomas; du Cros, Philipp; Varaine, Francis; Hughes, Jennifer; Rich, Michael; Horsburgh, C Robert; Mitnick, Carole D; Nuermberger, Eric; McIlleron, Helen; Phillips, Patrick P J; Balasegaram, Manica

2014-01-01

Fewer than 20% of patients with multidrug-resistant (MDR) tuberculosis are receiving treatment and there is an urgent need to scale up treatment programmes. One of the biggest barriers to scale-up is the treatment regimen, which is lengthy, complex, ineffective, poorly tolerated and expensive. For the first time in over 50 years, new drugs have been developed specifically to treat tuberculosis, with bedaquiline and potentially delamanid expected to be available soon for treatment of MDR cases. However, if the new drugs are merely added to the current treatment regimen, the new regimen will be at least as lengthy, cumbersome and toxic as the existing one. There is an urgent need for strategy and evidence on how to maximize the potential of the new drugs to improve outcomes and shorten treatment. We devised eight key principles for designing future treatment regimens to ensure that, once they are proven safe in clinical trials, they will be clinically effective and programmatically practicable. Regimens should contain at least one new class of drug; be broadly applicable for use against MDR and extensively drug-resistant Mycobacterium tuberculosis complex strains; contain three to five effective drugs, each from a different drug class; be delivered orally; have a simple dosing schedule; have a good side-effect profile that allows limited monitoring; last a maximum of 6 months; and have minimal interaction with antiretrovirals. Following these principles will maximize the potential of new compounds and help to overcome the clinical and programmatic disadvantages and scale-up constraints that plague the current regimen.

A new dose of maximal-intensity interval training in hypoxia to improve body composition and hemoglobin and hematocrit levels: a pilot study.

PubMed

Camacho-Cardenosa, Marta; Camacho-Cardenosa, Alba; Martínez Guardado, Ismael; Marcos-Serrano, Marta; Timon, Rafael; Olcina, Guillermo

2017-01-01

This pilot study had the aim to determine the effects of a new dose of maximal-intensity interval training in hypoxia in active adults. Twenty-four university student volunteers were randomly assigned to three groups: hypoxia group, normoxia group or control group. The eight training sessions consisted of 2 sets of 5 repeated sprints of 10 seconds with a recovery of 20 seconds between sprints and a recovery period of 10 minutes between sets. Body composition was measured following standard procedures. A blood sample was taken for an immediate hematocrit (HCT) and hemoglobin (Hb) concentration assessment. An all-out 3-ute test was performed to evaluate ventilation parameters and power. HCT and Hb were significantly higher for the hypoxia group in Post- and Det- (P=0.01; P=0.03). Fat mass percentage was significantly lower for the hypoxia group in both assessments (P=0.05; P=0.05). The hypoxia group underwent a significant increase in mean power after the recovery period. A new dose of 8 sessions of maximal-intensity interval training in hypoxia is enough to decrease the percentage of fat mass and to improve HCT and Hb parameters and mean muscle power in healthy and active adults.

Dose-finding study of carbamylated monomeric allergoid tablets in grass-allergic rhinoconjunctivitis patients.

PubMed

Mösges, Ralph; Rohdenburg, Christina; Eichel, Andrea; Zadoyan, Gregor; Kasche, Elena-Manja; Shah-Hosseini, Kija; Lehmacher, Walter; Schmalz, Petra; Compalati, Enrico

2017-11-01

To determine the optimal effective and safe dose of sublingual immunotherapy tablets containing carbamylated monomeric allergoids in patients with grass pollen-induced allergic rhinoconjunctivitis. In this prospective, randomized, double-blind, active-controlled, multicenter, Phase II study, four different daily doses were applied preseasonally for 12 weeks. Of 158 randomized adults, 155 subjects (safety population) received 300 units of allergy (UA)/day (n = 36), 600 UA/day (n = 43), 1000 UA/day (n = 39), or 2000 UA/day (n = 37). After treatment, 54.3, 47.6, 59.0 and 51.4% of patients, respectively, ceased to react to the highest allergen concentration in a conjunctival provocation test. Furthermore, the response threshold improved in 70.4, 62.9, 76.7 and 66.7% of patients, respectively. No serious adverse events occurred. This study found 1000 UA/day to be the optimal effective and safe dose.

Effective and Safe Use of Glucocorticosteroids for Rescue of Late ARDS

PubMed Central

Diana, Paolo; Money, Dustin T.; Gelvin, Michael G.

2017-01-01

We describe a case of severe refractory hypoxemia requiring prolonged extra corporeal membrane oxygenation (ECMO) support in a case of postpartum acute respiratory distress syndrome (ARDS). The clinical course was marked by persistently poor lung compliance and several complications of ECMO, that is, significant hemolysis, hemothorax, and intracranial bleeding. We report marked improvement of lung mechanics and respiratory function, leading to accelerated separation from ECMO, following rescue administration of low dose methylprednisolone 24 days after the onset of ARDS. Corticosteroid treatment was safe and well tolerated. In contrast with the conclusions of the 2006 ARDS Network trial, our report establishes a case in support of the use of low dose methylprednisolone as a safe and effective rescue treatment option in selected subsets of patients with nonresolving ARDS. PMID:28337348

Equivalence of Gyn GEC-ESTRO guidelines for image guided cervical brachytherapy with EUD-based dose prescription

PubMed Central

2013-01-01

Background To establish a generalized equivalent uniform dose (gEUD) -based prescription method for Image Guided Brachytherapy (IGBT) that reproduces the Gyn GEC-ESTRO WG (GGE) prescription for cervix carcinoma patients on CT images with limited soft tissue resolution. Methods The equivalence of two IGBT planning approaches was investigated in 20 patients who received external beam radiotherapy (EBT) and 5 concomitant high dose rate IGBT treatments. The GGE planning strategy based on dose to the most exposed 2 cm3 (D2cc) was used to derive criteria for the gEUD-based planning of the bladder and rectum. The safety of gEUD constraints in terms of GGE criteria was tested by maximizing dose to the gEUD constraints for individual fractions. Results The gEUD constraints of 3.55 Gy for the rectum and 5.19 Gy for the bladder were derived. Rectum and bladder gEUD-maximized plans resulted in D2cc averages very similar to the initial GGE criteria. Average D2ccs and EUDs from the full treatment course were comparable for the two techniques within both sets of normal tissue constraints. The same was found for the tumor doses. Conclusions The derived gEUD criteria for normal organs result in GGE-equivalent IGBT treatment plans. The gEUD-based planning considers the entire dose distribution of organs in contrast to a single dose-volume-histogram point. PMID:24225184

Differences in Clinical Results After LINAC-Based Single-Dose Radiosurgery Versus Fractionated Stereotactic Radiotherapy for Patients With Vestibular Schwannomas

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

Combs, Stephanie E., E-mail: Stephanie.Combs@med.uni-heidelberg.d; Welzel, Thomas; Schulz-Ertner, Daniela

2010-01-15

Purpose: To evaluate the outcomes of patients with vestibular schwannoma (VS) treated with fractionated stereotactic radiotherapy (FSRT) vs. those treated with stereotactic radiosurgery (SRS). Methods and Materials: This study is based on an analysis of 200 patients with 202 VSs treated with FSRT (n = 172) or SRS (n = 30). Patients with tumor progression and/or progression of clinical symptoms were selected for treatment. In 165 out of 202 VSs (82%), RT was performed as the primary treatment for VS, and for 37 VSs (18%), RT was conducted for tumor progression after neurosurgical intervention. For patients receiving FSRT, a medianmore » total dose of 57.6 Gy was prescribed, with a median fractionation of 5 x 1.8 Gy per week. For patients who underwent SRS, a median single dose of 13 Gy was prescribed to the 80% isodose. Results: FSRT and SRS were well tolerated. Median follow-up time was 75 months. Local control was not statistically different for both groups. The probability of maintaining the pretreatment hearing level after SRS with doses of <=13 Gy was comparable to that of FSRT. The radiation dose for the SRS group (<=13 Gy vs. >13 Gy) significantly influenced hearing preservation rates (p = 0.03). In the group of patients treated with SRS doses of <=13 Gy, cranial nerve toxicity was comparable to that of the FSRT group. Conclusions: FSRT and SRS are both safe and effective alternatives for the treatment of VS. Local control rates are comparable in both groups. SRS with doses of <=13 Gy is a safe alternative to FSRT. While FSRT can be applied safely for the treatment of VSs of all sizes, SRS should be reserved for smaller lesions.« less

Using Microsoft Excel to compute the 5% overall site X/Q value and the 95th percentile of the distribution of doses to the nearest maximally exposed offsite individual (MEOI).

PubMed

Vickers, Linda D

2010-05-01

This paper describes the method using Microsoft Excel (Microsoft Corporation One Microsoft Way Redmond, WA 98052-6399) to compute the 5% overall site X/Q value and the 95th percentile of the distribution of doses to the nearest maximally exposed offsite individual (MEOI) in accordance with guidance from DOE-STD-3009-1994 and U.S. NRC Regulatory Guide 1.145-1982. The accurate determination of the 5% overall site X/Q value is the most important factor in the computation of the 95th percentile of the distribution of doses to the nearest MEOI. This method should be used to validate software codes that compute the X/Q. The 95th percentile of the distribution of doses to the nearest MEOI must be compared to the U.S. DOE Evaluation Guide of 25 rem to determine the relative severity of hazard to the public from a postulated, unmitigated design basis accident that involves an offsite release of radioactive material.

Quantification of the spatial distribution of rectally applied surrogates for microbicide and semen in colon with SPECT and magnetic resonance imaging.

PubMed

Cao, Ying J; Caffo, Brian S; Fuchs, Edward J; Lee, Linda A; Du, Yong; Li, Liye; Bakshi, Rahul P; Macura, Katarzyna; Khan, Wasif A; Wahl, Richard L; Grohskopf, Lisa A; Hendrix, Craig W

2012-12-01

We sought to describe quantitatively the distribution of rectally administered gels and seminal fluid surrogates using novel concentration-distance parameters that could be repeated over time. These methods are needed to develop rationally rectal microbicides to target and prevent HIV infection. Eight subjects were dosed rectally with radiolabelled and gadolinium-labelled gels to simulate microbicide gel and seminal fluid. Rectal doses were given with and without simulated receptive anal intercourse. Twenty-four hour distribution was assessed with indirect single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI), and direct assessment via sigmoidoscopic brushes. Concentration-distance curves were generated using an algorithm for fitting SPECT data in three dimensions. Three novel concentration-distance parameters were defined to describe quantitatively the distribution of radiolabels: maximal distance (D(max) ), distance at maximal concentration (D(Cmax) ) and mean residence distance (D(ave) ). The SPECT/CT distribution of microbicide and semen surrogates was similar. Between 1 h and 24 h post dose, the surrogates migrated retrograde in all three parameters (relative to coccygeal level; geometric mean [95% confidence interval]): maximal distance (D(max) ), 10 cm (8.6-12) to 18 cm (13-26), distance at maximal concentration (D(Cmax) ), 3.8 cm (2.7-5.3) to 4.2 cm (2.8-6.3) and mean residence distance (D(ave) ), 4.3 cm (3.5-5.1) to 7.6 cm (5.3-11). Sigmoidoscopy and MRI correlated only roughly with SPECT/CT. Rectal microbicide surrogates migrated retrograde during the 24 h following dosing. Spatial kinetic parameters estimated using three dimensional curve fitting of distribution data should prove useful for evaluating rectal formulations of drugs for HIV prevention and other indications. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema.

PubMed

Farrell, Colm; Hayes, Siobhan; Relan, Anurag; van Amersfoort, Edwin S; Pijpstra, Rienk; Hack, C Erik

2013-12-01

To characterize the pharmacokinetics (PK) of recombinant human C1 inhibitor (rhC1INH) in healthy volunteers and hereditary angioedema (HAE) patients. Plasma levels of C1INH following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme. A one-compartment model with Michaelis-Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 [95% confidence interval (CI): 0.839-0.968] and 0.176 U ml(-1) (95% CI: 0.154-0.200) in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 l (95% CI: 2.68-3.03). The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 U ml(-1) h(-1) (95% CI: 1.41-1.88) and 1.60 U ml(-1) (95% CI: 1.14-2.24), respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Bodyweight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U ml(-1)) for at least 94% of all patients. The population PK model for C1INH supports a dosing scheme on a 50 U kg(-1) basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration. © 2013 The British Pharmacological Society.

Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema

PubMed Central

Farrell, Colm; Hayes, Siobhan; Relan, Anurag; van Amersfoort, Edwin S; Pijpstra, Rienk; Hack, C Erik

2013-01-01

Aims To characterize the pharmacokinetics (PK) of recombinant human C1 inhibitor (rhC1INH) in healthy volunteers and hereditary angioedema (HAE) patients. Methods Plasma levels of C1INH following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme. Results A one-compartment model with Michaelis–Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 [95% confidence interval (CI): 0.839–0.968] and 0.176 U ml−1 (95% CI: 0.154–0.200) in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 l (95% CI: 2.68–3.03). The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 U ml−1 h−1 (95% CI: 1.41–1.88) and 1.60 U ml−1 (95% CI: 1.14–2.24), respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Bodyweight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U ml−1) for at least 94% of all patients. Conclusions The population PK model for C1INH supports a dosing scheme on a 50 U kg−1 basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration. PMID:23594263

Using nonfaculty registered nurses to facilitate high-fidelity human patient simulation activities.

PubMed

Foster, Janet G; Sheriff, Susan; Cheney, Susan

2008-01-01

Maximizing faculty resources using nonfaculty registered nurses to supervise high-fidelity human-patient simulation is an innovative strategy for addressing the nursing faculty shortage and preparing graduates to practice safely in hospitals. The authors describe their use of nonfaculty registered nurses and its outcomes.

Projectile Motion without Calculus

ERIC Educational Resources Information Center

Rizcallah, Joseph A.

2018-01-01

Projectile motion is a constant theme in introductory-physics courses. It is often used to illustrate the application of differential and integral calculus. While most of the problems used for this purpose, such as maximizing the range, are kept at a fairly elementary level, some, such as determining the safe domain, involve not so elementary…

Plenary lecture: innovative modeling approaches applicable to risk assessments

USDA-ARS?s Scientific Manuscript database

Proper identification of safe and unsafe food at the processing plant is important for maximizing the public health benefit of food by ensuring both its consumption and safety. Risk assessment is a holistic approach to food safety that consists of four steps: 1) hazard identification; 2) exposure a...

LanDPro: Landscape Dynamics Program

DTIC Science & Technology

2012-09-18

of Major Accomplishments............................................................... 7 1. Landscape history and response to land use change and...site potential using geologic, geomorphic, and geophysical techniques, U.S. Marine Corps Base Camp Pendleton, CA...safe, realistic military training environments while maximizing use for active training, DoD spends upwards of $100 million annually on land management

Charter School Discipline: Examples of Policies and School Climate Efforts from the Field

ERIC Educational Resources Information Center

Kern, Nora; Kim, Suzie

2016-01-01

Students need a safe and supportive school environment to maximize their academic and social-emotional learning potential. A school's discipline policies and practices directly impact school climate and student achievement. Together, discipline policies and positive school climate efforts can reinforce behavioral expectations and ensure student…

Estimated ultraviolet radiation doses in wetlands in six national parks

USGS Publications Warehouse

Diamond, S.A.; Trenham, P.C.; Adams, Michael J.; Hossack, B.R.; Knapp, R.A.; Stark, L.; Bradford, D.; Corn, P.S.; Czarnowski, K.; Brooks, P.D.; Fagre, D.B.; Breen, B.; Dentenbeck, N.E.; Tonnessen, K.

2005-01-01

Ultraviolet-B radiation (UV-B, 280–320-nm wavelengths) doses were estimated for 1024 wetlands in six national parks: Acadia (Acadia), Glacier (Glacier), Great Smoky Mountains (Smoky), Olympic (Olympic), Rocky Mountain (Rocky), and Sequoia/Kings Canyon (Sequoia). Estimates were made using ground-based UV-B data (Brewer spectrophotometers), solar radiation models, GIS tools, field characterization of vegetative features, and quantification of DOC concentration and spectral absorbance. UV-B dose estimates were made for the summer solstice, at a depth of 1 cm in each wetland. The mean dose across all wetlands and parks was 19.3 W-h m−2 (range of 3.4–32.1 W-h m−2). The mean dose was lowest in Acadia (13.7 W-h m−2) and highest in Rocky (24.4 W-h m−2). Doses were significantly different among all parks. These wetland doses correspond to UV-B flux of 125.0 μW cm−2 (range 21.4–194.7 μW cm−2) based on a day length, averaged among all parks, of 15.5 h. Dissolved organic carbon (DOC), a key determinant of water-column UV-B flux, ranged from 0.6 (analytical detection limit) to 36.7 mg C L−1 over all wetlands and parks, and reduced potential maximal UV-B doses at 1-cm depth by 1%–87 %. DOC concentration, as well as its effect on dose, was lowest in Sequoia and highest in Acadia (DOC was equivalent in Acadia, Glacier, and Rocky). Landscape reduction of potential maximal UV-B doses ranged from zero to 77% and was lowest in Sequoia. These regional differences in UV-B wetland dose illustrate the importance of considering all aspects of exposure in evaluating the potential impact of UV-B on aquatic organisms.

Ivabradine, a novel heart rate slower: is it a sword of double blades in patients with idiopathic dilated cardiomyopathy?

PubMed

Rayan, Mona; Tawfik, Mazen; Alabd, Ali; Gamal, Amr

2011-08-01

To prospectively assess the safety and efficacy of ivabradine in patients with idiopathic dilated cardiomyopathy. We included 35 patients with idiopathic dilated cardiomyopathy with an ejection fraction (EF) <40% and heart rate >70 beats/min despite optimal medical therapy, according to the international guidelines in this prospective, non-randomized, single-arm, open-label safety study. Ivabradine was used as an add-on therapy to the maximally tolerated b-blocker in an increasing titrated dose till a target dose of 15 mg/day or resting heart rate of 60 beats/min for 3 months. During follow-up period the safety, patient tolerance and efficacy of this drug were assessed. All patients underwent 12-lead resting electrocardiography and Holter monitoring at inclusion and after 3 months. Statistical analysis was accomplished using paired t-test and Pearson correlation analysis. We found a significant reduction in the resting heart rate by a mean of 25.9 ± 9.4%, without a significant change of blood pressure. There was no prolongation of PR, QTc or QRS durations. Ventricular ectopic activity showed significant reduction (p<0.001). There was a significant correlation between the resting heart rate, NYHA and left ventricular ejection fraction (p<0.001 for both). One patient developed photopsia and decompensation was observed in another patient. Ivabradine is a safe and effective drug in reducing resting heart rate, improving NYHA functional class without undesirable effects on conduction parameters or ectopic activity.

Multiple effects of sibutramine on ejaculation and on vas deferens and seminal vesicle contractility.

PubMed

Nojimoto, Fernanda D; Piffer, Renata C; Kiguti, Luiz Ricardo de A; Lameu, Claudiana; de Camargo, Antônio C M; Pereira, Oduvaldo C M; Pupo, André S

2009-09-15

Sibutramine is an inhibitor of norepinephrine and 5-HT reuptake largely used in the management of obesity. Although a fairly safe drug, postmarketing adverse effects of sibutramine were reported including abnormal ejaculation in men. This study investigates the effects of sibutramine on ejaculation and vas deferens and seminal vesicle contractility. Adult male rats received sibutramine (5; 20; or 50 mg kg(-1), ip) and after 60 min were exposed to receptive females for determination of ejaculation parameters. The vasa deferentia and seminal vesicles of untreated rats were mounted in isolated organ baths for recording of isometric contractions and HEK293 cells loaded with fluorescent calcium indicator were used to measure intracellular Ca(2+) transients. Sibutramine 5 and 20 mg kg(-1) reduced ejaculation latency whereas 50 mg kg(-1) increased ejaculation latency. Sibutramine 3 to 30 microM greatly increased the sensitivity of the seminal vesicle and vas deferens to norepinephrine, but at concentrations higher than 10 microM there were striking depressions of maximal contractions induced by norepinephrine, carbachol and CaCl(2). In HEK293 cells, sibutramine 10 to 100 microM inhibited intracellular Ca(2+) transients induced by carbachol. Depending on the doses, sibutramine either facilitates or inhibits ejaculation. Apart from its actions in the central nervous system, facilitation of ejaculation may result from augmented sensitivity of smooth muscles to norepinephrine while reductions of intracellular Ca(2+) may be involved in the delayed ejaculation observed with high doses of sibutramine.

Effectiveness of a management program for outpatient clinic or remote titration of beta-blockers in CRT patients: The RESTORE study.

PubMed

D'Onofrio, Antonio; Palmisano, Pietro; Rapacciuolo, Antonio; Ammendola, Ernesto; Calò, Leonardo; Ruocco, Antonio; Bianchi, Valter; Maresca, Fabio; Del Giorno, Giuseppe; Martino, Annamaria; Mauro, Ciro; Campari, Monica; Valsecchi, Sergio; Accogli, Michele

2017-06-01

Many patients fail to receive β-blockers before cardiac resynchronization therapy defibrillator (CRT-D) implantation, or receive them at a suboptimal dose, and require optimization after implantation. We assessed the effectiveness of a structured program for β-blocker titration in CRT-D patients followed up by means of conventional in-clinic visits or remote monitoring. 130 patients undergoing CRT implantation and treated according to the standard practice of the centers were included as a control group. A second group of 124 CRT-D candidates (Study Group) underwent up-titration visits every 2weeks after implantation (target dose: 10mg/day of bisoprolol or 50mg/day of carvedilol). In the Study Group, remote monitoring was undertaken in 66 patients, who received additional equipment for daily transmission of weight and blood pressure data, and scheduled titration telephone calls. In the Control Group, the maximal dose of β-blockers was being administered to 12 (9%) patients on implantation and 21 (16%) on 6-month follow-up examination (p>0.05). In the Study Group, 25 (20%) patients were receiving the maximal dose of β-blockers on implantation and 72 (58%) on follow-up examination (p<0.001). The 66 Study Group patients on remote monitoring underwent fewer in-clinic visits (p=0.034). Of these, 50 (76%) were on the maximal dose after remote up-titration (versus 38% of patients followed up conventionally, p<0.001). The decrease in left ventricular end-systolic volume was larger in the Study Group (p=0.040). The program for β-blocker up-titration increased the number of patients reaching the target dose and improved the response to the therapy. The use of remote monitoring and daily transfer of weight and blood pressure data facilitated β-blocker titration. URL: http://clinicaltrials.gov/ Identifier: NCT02173028. Copyright © 2017. Published by Elsevier B.V.

Pharmacokinetic Comparison of Once-Daily Topical Minocycline Foam 4% vs Oral Minocycline for Moderate-to-Severe Acne.

PubMed

Jones, Terry M; Ellman, Herman; deVries, Tina

2017-10-01

To characterize minocycline pharmacokinetics and relative bioavailability following multiple-dose topical administration of minocycline hydrochloride (HCl) foam 4% (FMX101 4%) as compared with single-dose oral administration of minocycline HCl extended-release tablets (Solodyn®) in subjects with moderate-to-severe acne. A Phase 1, single-center, nonrandomized, open-label, active-controlled, 2-period, 2-treatment crossover clinical study. The study included 30 healthy adults (mean age, 22.6 years; 90% white, and 60% females) who had moderate-to-severe acne. Subjects were assigned to first receive a single oral dose of a minocycline HCl extended-release tablet (approximately 1 mg/kg). At 10 days after the oral minocycline dose, topical minocycline foam 4% was applied, once daily for 21 days. Serial blood samples were obtained before and after administration of oral minocycline and each topical application of minocycline foam 4% on days 1, 12, and 21. Following oral administration of minocycline (approximately 1 mg/kg), plasma minocycline concentration increased until 3 hours, followed by a log-linear decrease over the remainder of the 96-hour sampling period. Following topical application of a 4-g maximal-use dose of minocycline foam 4% for 21 days, plasma minocycline concentration was very low, with geometric mean Cmax values ranging from 1.1 ng/mL to 1.5 ng/mL. Steady state was achieved by day 6. Overall, minocycline exposure with topical minocycline foam 4% was 730 to 765 times lower than that with oral minocycline. There was no evidence of minocycline accumulation over the 21 days of topical application of minocycline foam 4%. Topical minocycline foam 4% appeared to be safe and well tolerated, with no serious treatment-emergent adverse events (TEAEs), treatment-related TEAEs, or TEAEs that led to treatment discontinuation. Once-daily topical application of minocycline foam 4% did not lead to significant systemic exposure to minocycline. It appears to be a well-tolerated treatment option for individuals with moderate-to-severe acne.

J Drugs Dermatol. 2017;16(10):1022-1028.

Influence of Residual Tumor Volume and Radiation Dose Coverage in Outcomes for Clival Chordoma

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

McDonald, Mark W., E-mail: markmcdonaldmd@gmail.com; Indiana University Health Proton Therapy Center, Bloomington, Indiana; Linton, Okechukwu R.

2016-05-01

Purpose: The purpose of this study was to evaluate factors associated with tumor control in clival chordomas. Methods and Materials: A retrospective review of 39 patients treated with surgery and proton therapy for clival chordomas between 2004 and 2014 was performed. The median prescribed dose was 77.4 Gy (relative biological effectiveness [RBE]); range was 70.2-79.2 Gy (RBE). Minimum and median doses to gross tumor volume (GTV), radiation dose received by 1 cm{sup 3} of GTV (D1cm{sup 3}), and the equivalent uniform dose were calculated. Receiver operating characteristics curves evaluated the predictive sensitivity and specificity for local failure of potential cutpoint values for GTVmore » and D1cm{sup 3}. Results: After a median follow-up of 51 months, the 5-year estimate of local control (LC) was 69.6% (95% confidence interval [CI] 50.0%-89.2%), and overall survival (OS) was 81.4% (95% CI: 65.3%-97.5%). Tumor histology, GTV at the time of radiation, and prescribed radiation dose were significantly associated with local control on multivariate analysis, whereas D1cm{sup 3} was associated with overall survival. Compared to those patients whose conditions remained controlled, patients experiencing tumor failure had statistically significant larger GTVs and lower D1cm{sup 3}, and prescribed and median doses to GTV. A subset of 21 patients with GTV of ≤20 cm{sup 3} and D1cm{sup 3} of >67 Gy (RBE) had a median follow-up of 47 months. The 5-year estimate of local control in this subset was 81.1% (95% CI: 61.7%-100%; P=.004, overall comparison by GTV ≤20 cm{sup 3} stratified by D1cm{sup 3}). A D1cm{sup 3} of 74.5 Gy (RBE) had 80% sensitivity for local control and 60% specificity, whereas a GTV of 9.3 cm{sup 3} had 80% sensitivity for local control and 66.7% specificity. Conclusions: Local control of clival chordomas was associated with both smaller size of residual tumor and more complete high-dose coverage of residual tumor. Multidisciplinary care should seek maximal safe surgical resection, particularly to facilitate delivery of high-dose radiation therapy in proximity to critical structures. A D1cm{sup 3} ≥74.5 Gy (RBE) represents a proposed treatment planning objective.« less

Captopril in hypertension after renal transplantation.

PubMed Central

Chan, M. K.; Sweny, P.; El Nahas, A. M.; Farrington, K.; Fernando, O. N.; Moorhead, J. F.

1984-01-01

Eight hypertensive renal allograft recipients who had received captopril are presented. Captopril in a maximal daily dose of 250 mg enabled the withdrawal of large doses of beta-blocking agents and vasodilators. Blood pressure was satisfactorily controlled in all except one. No adverse side effects were observed other than the 'first dose' effect which resulted in transient anuria in one patient. Captopril appears to be a useful agent in the management of severe hypertension after renal transplantation. PMID:6369287

SU-E-T-619: Planning 131I Thyroid Treatments for Patients Requiring Hemodialysis

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

Stroud, D

Purpose: Treatment of 131I thyroid cancer patients who also require regular hemodialysis (HD) treatments requires consideration of the administered activity and the HD schedule. In this work the red bone marrow is considered the dose limiting organ and the treatment plan optimized the HD schedule with the amount of radioactivity administered. Methods: The ‘Safe’ dose was considered to be 2 Gy (200 rad) to the red bone marrow.1 131Iodine doses of 50 mCi to 100 mCi were modeled and found to require a range of HD schedules. In order to achieve the safe dose to the red marrow, more aggressivemore » HD schedules are required. 100 mCi required an aggressive HD treatment of every 24 hours for at least one week to achieve the ‘safe’ dose and an exposure appropriate for release from the hospital. A more normal schedule of HD beginning at 18 hours then every 48 hours allowed for up to 60 mCi administered dose allowed for a safe dose and expected release after less than one week.2In addition room was equipped with video cameras cameras for monitoring the patient and their vital signs from an adjacent room during HD. In this way the dialysis nurses were able to monitor the patient closely from an adjoining room. Results: Two HD patients were administered adjusted doses of about 50 mCi. The medical and nursing staff were exposed to no more than 4 mR for the entire treatment. The residual Iodine in the patient appeared to be normal after 4 to 6 days when the patient was released. Conclusion: With careful treatment planning 131Iodine treatments can be performed safely for patients needing HD and treatments appear to be as effective as those for patients with normal renal function.« less

Continuous Exposure to Low-Dose-Rate Gamma Irradiation Reduces Airway Inflammation in Ovalbumin-Induced Asthma.

PubMed

Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Seung Sook; Park, Sun Hoo; Lee, Hae June; Lee, Soong In; Lee, Chang Geun; Kim, Sung Dae; Jo, Wol Soon; Kim, Sung Ho; Shin, In Sik

2015-01-01

Although safe doses of radiation have been determined, concerns about the harmful effects of low-dose radiation persist. In particular, to date, few studies have investigated the correlation between low-dose radiation and disease development. Asthma is a common chronic inflammatory airway disease that is recognized as a major public health problem. In this study, we evaluated the effects of low-dose-rate chronic irradiation on allergic asthma in a murine model. Mice were sensitized and airway-challenged with ovalbumin (OVA) and were exposed to continuous low-dose-rate irradiation (0.554 or 1.818 mGy/h) for 24 days after initial sensitization. The effects of chronic radiation on proinflammatory cytokines and the activity of matrix metalloproteinase-9 (MMP-9) were investigated. Exposure to low-dose-rate chronic irradiation significantly decreased the number of inflammatory cells, methylcholine responsiveness (PenH value), and the levels of OVA-specific immunoglobulin E, interleukin (IL)-4, and IL-5. Furthermore, airway inflammation and the mucus production in lung tissue were attenuated and elevated MMP-9 expression and activity induced by OVA challenge were significantly suppressed. These results indicate that low-dose-rate chronic irradiation suppresses allergic asthma induced by OVA challenge and does not exert any adverse effects on asthma development. Our findings can potentially provide toxicological guidance for the safe use of radiation and relieve the general anxiety about exposure to low-dose radiation.

NESHAP Dose-Release Factor Isopleths for Five Source-to-Receptor Distances from the Center of Site and H-Area for all Compass Sectors at SRS using CAP88-PC Version 4.0

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

Trimor, P.

The Environmental Protection Agency (EPA) requires the use of the computer model CAP88-PC to estimate the total effective doses (TED) for demonstrating compliance with 40 CFR 61, Subpart H (EPA 2006), the National Emission Standards for Hazardous Air Pollutants (NESHAP) regulations. As such, CAP88 Version 4.0 was used to calculate the receptor dose due to routine atmospheric releases at the Savannah River Site (SRS). For estimation, NESHAP dose-release factors (DRFs) have been supplied to Environmental Compliance and Area Closure Projects (EC&ACP) for many years. DRFs represent the dose to a maximum receptor exposed to 1 Ci of a specified radionuclidemore » being released into the atmosphere. They are periodically updated to include changes in the CAP88 version, input parameter values, site meteorology, and location of the maximally exposed individual (MEI). This report presents the DRFs of tritium oxide released at two onsite locations, center-of-site (COS) and H-Area, at 0 ft. elevation to maximally exposed individuals (MEIs) located 1000, 3000, 6000, 9000, and 12000 meters from the release areas for 16 compass sectors. The analysis makes use of area-specific meteorological data (Viner 2014).« less

Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial.

PubMed

Takahashi, Fumihiro; Morita, Satoshi

2018-02-08

Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.

Beyond the Yellow Bus: Promising Practices for Maximizing Access to Opportunity through Innovations in Student Transportation

ERIC Educational Resources Information Center

Vincent, Jeffrey M.; Makarewicz, Carrie; Miller, Ruth; Ehrman, Julia; McKoy, Deborah L.

2014-01-01

Access to safe, affordable, and convenient transportation shapes the 'geography of opportunity' for many children and youth. This study looks at how ?localities acrossthe country are implementing new and innovative alternative approaches to student transportation that expand regionaltransportation access for K-12 students, improve…

Keys to Success: School Facilities Primer, Questions & Answers 101.

ERIC Educational Resources Information Center

Brady, Jim

This publication provides answers to basic questions to help school board members more fully address the complexities of the planning, design, and construction process in order to maximize the goal of student success. The 101 questions and answers are in the areas of: facility planning; learning environment; information technology; safe schools;…

Designing High Fidelity Simulation to Maximize Student Registered Nursing Decision-Making Ability

ERIC Educational Resources Information Center

Deckers, Cathleen

2011-01-01

The current healthcare environment is a complex system of patients, procedures, and equipment that strives to deliver safe and effective medical care. High fidelity simulation provides healthcare educators with a tool to create safety conscious practitioners utilizing an environment that replicates practice without risk to patients. Using HFS…

Aligning Comprehensive School Counseling Programs and Positive Behavioral Interventions and Supports to Maximize School Counselors' Efforts

ERIC Educational Resources Information Center

Goodman-Scott, Emily; Betters-Bubon, Jennifer; Donohue, Peg

2015-01-01

School counselors are tasked with contributing to a safe and preventative school climate serving students' academic, career, and social/emotional needs through comprehensive school counseling program implementation. Positive Behavioral Interventions and Supports (PBIS) prioritizes a positive school climate, is widely implemented in the United…

Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure–response relations from two phase II clinical trials

PubMed Central

Savic, RM; MacKenzie, WR; Engle, M; Whitworth, WC; Johnson, JL; Nsubuga, P; Nahid, P; Nguyen, NV; Peloquin, CA; Dooley, KE; Dorman, SE

2017-01-01

Rifapentine is a highly active antituberculosis antibiotic with treatment‐shortening potential; however, exposure–response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive‐phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed‐effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses. PMID:28124478

Predictive parameters for selection of electronic tissue compensation radiotherapy in early-stage breast cancer patients after breast-conserving surgery.

PubMed

Song, Yanbo; Zhang, Miao; Gan, Lu; Chen, Xiaopin; Zhang, Tao; Yue, Ning J; Goyal, Sharad; Haffty, Bruce; Ren, Guosheng

2016-05-31

Electronic tissue compensation (eComp) is an external beam planning technique allowing user to manually generate dynamic beam fluence to produce more uniform or modulated dose distribution. In this study, we compared the effectiveness between conventional three-dimensional conformal radiotherapy (3DCRT) and eComp for whole breast irradiation. 3DCRT and eComp planning techniques were used to generate treatment plans for 60 whole breast patients, respectively. The planning goal was to cover 95% of the planning target volume (PTV) with 95% of the prescription dose while minimizing doses to lung, heart, and skin. Comparing to 3DCRT plans, on the average, eComp treatment planning process was about 7 minutes longer, but resulted in lower lung V20Gy, lower mean skin dose, with similar heart dose. The benefits were more pronounced for larger breast patients. Statistical analyses were performed between critical organ doses and patient anatomic features, i.e., central lung distance (CLD), maximal heart distance (MHD), maximal heart length (MHL) and breast separation (BS) to explore any correlations and planning method selection. It was found that to keep the lung V20Gy lower than 20% and mean skin dose lower than 85% of the prescription dose, eComp was the preferred method for patients with more than 2.3 cm CLD or larger than 22.5 cm BS. The study results may be useful in providing a handy criterion in clinical practice allowing us to easily choose between different planning techniques to satisfy the planning goal with minimal increase in complexity and cost.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy.

PubMed

Landen, Jaren W; Cohen, Sharon; Billing, Clare B; Cronenberger, Carol; Styren, Scot; Burstein, Aaron H; Sattler, Catherine; Lee, Jae-Hong; Jack, Clifford R; Kantarci, Kejal; Schwartz, Pamela F; Duggan, William T; Zhao, Qinying; Sprenger, Ken; Bednar, Martin M; Binneman, Brendon

2017-09-01

Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ 1-x and Aβ 1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Exclusion Area Radiation Release during the MIT Reactor Design Basis Accident.

DTIC Science & Technology

1983-05-06

Concrete Wall 116 6.2 Concrete Albedo Dose 121 6.3 Steel Door Scattering Dose 124 7.1 Total Dose Results 133 A.1 Values of N /NO for Neutron -Capture...plate fuel elements arranged in x a compact hexagonal core. This core design maximizes the neutron flux in the DO2 reflector region where numerous...sec) V = Volume of the fuel (cm 3 f Ef = Macroscopic fission cross section (cm ) = Thermal neutron flux ( neutrons /cm2 - sec) = Core-averaged value Yi

SPIRIT: A seamless phase I/II randomized design for immunotherapy trials.

PubMed

Guo, Beibei; Li, Daniel; Yuan, Ying

2018-06-07

Immunotherapy-treatments that enlist the immune system to battle tumors-has received widespread attention in cancer research. Due to its unique features and mechanisms for treating cancer, immunotherapy requires novel clinical trial designs. We propose a Bayesian seamless phase I/II randomized design for immunotherapy trials (SPIRIT) to find the optimal biological dose (OBD) defined in terms of the restricted mean survival time. We jointly model progression-free survival and the immune response. Progression-free survival is used as the primary endpoint to determine the OBD, and the immune response is used as an ancillary endpoint to quickly screen out futile doses. Toxicity is monitored throughout the trial. The design consists of two seamlessly connected stages. The first stage identifies a set of safe doses. The second stage adaptively randomizes patients to the safe doses identified and uses their progression-free survival and immune response to find the OBD. The simulation study shows that the SPIRIT has desirable operating characteristics and outperforms the conventional design. Copyright © 2018 John Wiley & Sons, Ltd.

Genetic engineering of cell lines using lentiviral vectors to achieve antibody secretion following encapsulated implantation.

PubMed

Lathuilière, Aurélien; Bohrmann, Bernd; Kopetzki, Erhard; Schweitzer, Christoph; Jacobsen, Helmut; Moniatte, Marc; Aebischer, Patrick; Schneider, Bernard L

2014-01-01

The controlled delivery of antibodies by immunoisolated bioimplants containing genetically engineered cells is an attractive and safe approach for chronic treatments. To reach therapeutic antibody levels there is a need to generate renewable cell lines, which can long-term survive in macroencapsulation devices while maintaining high antibody specific productivity. Here we have developed a dual lentiviral vector strategy for the genetic engineering of cell lines compatible with macroencapsulation, using separate vectors encoding IgG light and heavy chains. We show that IgG expression level can be maximized as a function of vector dose and transgene ratio. This approach allows for the generation of stable populations of IgG-expressing C2C12 mouse myoblasts, and for the subsequent isolation of clones stably secreting high IgG levels. Moreover, we demonstrate that cell transduction using this lentiviral system leads to the production of a functional glycosylated antibody by myogenic cells. Subsequent implantation of antibody-secreting cells in a high-capacity macroencapsulation device enables continuous delivery of recombinant antibodies in the mouse subcutaneous tissue, leading to substantial levels of therapeutic IgG detectable in the plasma.

Dietary 2-oxoglutarate prevents bone loss caused by neonatal treatment with maximal dexamethasone dose

PubMed Central

Tomaszewska, Ewa; Muszyński, Siemowit; Blicharski, Tomasz; Pierzynowski, Stefan G

2017-01-01

Synthetic glucocorticoids (GCs) are widely used in the variety of dosages for treatment of premature infants with chronic lung disease, respiratory distress syndrome, allergies, asthma, and other inflammatory and autoimmune conditions. Yet, adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Conversely, 2-oxoglutarate (2-Ox), a precursor of glutamine, glutamate, and collagen amino acids, exerts protective effects on bone development. Our aim was to elucidate the effect of dietary administered 2-Ox on bone loss caused by neonatal treatment with clinically relevant maximal therapeutic dexamethasone (Dex) dose. Long bones of neonatal female piglets receiving Dex, Dex+2-Ox, or untreated were examined through measurements of mechanical properties, density, mineralization, geometry, histomorphometry, and histology. Selected hormones, bone turnover, and growth markers were also analyzed. Neonatal administration of clinically relevant maximal dose of Dex alone led to over 30% decrease in bone mass and the ultimate strength (P < 0.001 for all). The length (13 and 7% for femur and humerus, respectively) and other geometrical parameters (13–45%) decreased compared to the control (P < 0.001 for all). Dex impaired bone growth and caused hormonal imbalance. Dietary 2-Ox prevented Dex influence and vast majority of assessed bone parameters were restored almost to the control level. Piglets receiving 2-Ox had heavier, denser, and stronger bones; higher levels of growth hormone and osteocalcin concentration; and preserved microarchitecture of trabecular bone compared to the Dex group. 2-Ox administered postnatally had a potential to maintain bone structure of animals simultaneously treated with maximal therapeutic doses of Dex, which, in our opinion, may open up a new opportunity in developing combined treatment for children treated with GCs. Impact statement The present study has showed, for the first time, that dietary 2-oxoglutarate (2-Ox) administered postnatally has a potential to improve/maintain bone structure of animals simultaneously treated with maximal therapeutic doses of dexamethasone (Dex). It may open the new direction in searching and developing combined treatment for children treated with glucocorticoids (GCs) since growing group of children is exposed to synthetic GCs and adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Currently proposed combined therapies have numerous side effects. Thus, this study proposed a new direction in combined therapies utilizing dietary supplementation with glutamine derivative. Impairment caused by Dex in presented long bones animal model was prevented by dietary supplementation with 2-Ox and vast majority of assessed bone parameters were restored almost to the control level. These results support previous thesis on the regulatory mechanism of nutrient utilization regulated by glutamine derivatives and enrich the nutritional science. PMID:28178857

Vocal Dose Measures: Quantifying Accumulated Vibration Exposure in Vocal Fold Tissues

PubMed Central

Titze, Ingo R.; Švec, Jan G.; Popolo, Peter S.

2011-01-01

To measure the exposure to self-induced tissue vibration in speech, three vocal doses were defined and described: distance dose, which accumulates the distance that tissue particles of the vocal folds travel in an oscillatory trajectory; energy dissipation dose, which accumulates the total amount of heat dissipated over a unit volume of vocal fold tissues; and time dose, which accumulates the total phonation time. These doses were compared to a previously used vocal dose measure, the vocal loading index, which accumulates the number of vibration cycles of the vocal folds. Empirical rules for viscosity and vocal fold deformation were used to calculate all the doses from the fundamental frequency (F0) and sound pressure level (SPL) values of speech. Six participants were asked to read in normal, monotone, and exaggerated speech and the doses associated with these vocalizations were calculated. The results showed that large F0 and SPL variations in speech affected the dose measures, suggesting that accumulation of phonation time alone is insufficient. The vibration exposure of the vocal folds in normal speech was related to the industrial limits for hand-transmitted vibration, in which the safe distance dose was derived to be about 500 m. This limit was found rather low for vocalization; it was related to a comparable time dose of about 17 min of continuous vocalization, or about 35 min of continuous reading with normal breathing and unvoiced segments. The voicing pauses in normal speech and dialogue effectively prolong the safe time dose. The derived safety limits for vocalization will likely require refinement based on a more detailed knowledge of the differences in hand and vocal fold tissue morphology and their response to vibrational stress, and on the effect of recovery of the vocal fold tissue during voicing pauses. PMID:12959470

Vocal dose measures: quantifying accumulated vibration exposure in vocal fold tissues.

PubMed

Titze, Ingo R; Svec, Jan G; Popolo, Peter S

2003-08-01

To measure the exposure to self-induced tissue vibration in speech, three vocal doses were defined and described: distance dose, which accumulates the distance that tissue particles of the vocal folds travel in an oscillatory trajectory; energy dissipation dose, which accumulates the total amount of heat dissipated over a unit volume of vocal fold tissues; and time dose, which accumulates the total phonation time. These doses were compared to a previously used vocal dose measure, the vocal loading index, which accumulates the number of vibration cycles of the vocal folds. Empirical rules for viscosity and vocal fold deformation were used to calculate all the doses from the fundamental frequency (F0) and sound pressure level (SPL) values of speech. Six participants were asked to read in normal, monotone, and exaggerated speech and the doses associated with these vocalizations were calculated. The results showed that large F0 and SPL variations in speech affected the dose measures, suggesting that accumulation of phonation time alone is insufficient. The vibration exposure of the vocal folds in normal speech was related to the industrial limits for hand-transmitted vibration, in which the safe distance dose was derived to be about 500 m. This limit was found rather low for vocalization; it was related to a comparable time dose of about 17 min of continuous vocalization, or about 35 min of continuous reading with normal breathing and unvoiced segments. The voicing pauses in normal speech and dialogue effectively prolong the safe time dose. The derived safety limits for vocalization will likely require refinement based on a more detailed knowledge of the differences in hand and vocal fold tissue morphology and their response to vibrational stress, and on the effect of recovery of the vocal fold tissue during voicing pauses.

Optimizing fluorescently tethered Hsp90 inhibitor dose for maximal specific uptake by breast tumors

NASA Astrophysics Data System (ADS)

Crouch, Brian T.; Duer, Joy; Wang, Roujia; Gallagher, Jennifer; Hall, Allison; Soo, Mary Scott; Hughes, Philip; Haystead, Timothy A. J.; Ramanujam, Nirmala

2018-03-01

Despite improvements in surgical resection, 20-40% of patients undergoing breast conserving surgery require at least one additional re-excision. Leveraging the unique surface expression of heat shock protein 90 (Hsp90), a chaperone protein involved in several key hallmarks of cancer, in breast cancer provides an exciting opportunity to identify residual disease during surgery. We developed a completely non-destructive strategy using HS-27, a fluorescently-tethered Hsp90 inhibitor, to assay surface Hsp90 expression on intact tissue specimens using a fluorescence microendoscope with a field of view of 750 μm and subcellular resolution of 4 μm. HS-27 consists of an FDA approved Hsp90 inhibitor tethered to fluorescein isothiocyanate (EX 488nm, EM 525nm). Here, we optimized ex vivo HS-27 administration in pre-clinical breast cancer models and validated our approach on 21 patients undergoing standard of care ultrasound guided core needle biopsy. HS-27 administration time was fixed at 1- minute to minimize imaging impact on clinical workflow. HS-27 and HS-217 (non-specific control) doses were modulated from 1 μM up to 100 μM to identify the dose maximizing the ratio of specific uptake (HS-27 fluorescence) to non-specific uptake (HS-217 fluorescence). The specificity ratio was maximized at 100 μM and was significantly greater than all other doses (p<0.05). We applied our optimized imaging protocol to clinical samples and demonstrated significantly greater uptake of HS-27 by tumor than non-tumor tissue (p<0.05). The ubiquitous nature of HS-27 binding to all subtypes of breast cancer makes this technology attractive for assessing tumor margins, as one agent can be used for all subtypes.

The effects of low and moderate doses of caffeine supplementation on upper and lower body maximal voluntary concentric and eccentric muscle force.

PubMed

Tallis, Jason; Yavuz, Harley C M

2018-03-01

Despite the growing quantity of literature exploring the effect of caffeine on muscular strength, there is a dearth of data that directly explores differences in erogenicity between upper and lower body musculature and the dose-response effect. The present study sought to investigate the effects of low and moderate doses of caffeine on the maximal voluntary strength of the elbow flexors and knee extensors. Ten nonspecifically strength-trained, recreationally active participants (aged 21 ± 0.3 years) completed the study. Using a randomised, counterbalanced, and double-blind approach, isokinetic concentric and eccentric strength was measured at 60 and 180°/s following administration of a placebo, 3 mg·kg -1 body mass caffeine, and 6 mg·kg -1 body mass caffeine. There was no effect of caffeine on the maximal voluntary concentric and eccentric strength of the elbow flexors, or the eccentric strength of the knee extensors. Both 3 and 6 mg·kg -1 body mass caffeine caused a significant increase in peak concentric force of the knee extensors at 180°/s. No difference was apparent between the 2 concentrations. Only 6 mg·kg -1 body mass caused an increase in peak concentric force during repeated contractions. The results infer that the effective caffeine concentration to evoke improved muscle performance may be related to muscle mass and contraction type. The present work indicates that a relatively low dose of caffeine treatment may be effective for improving lower body muscular strength, but may have little benefit for the strength of major muscular groups of the upper body.

Dosimetric effects of endorectal balloons on intensity-modulated radiation therapy plans for prostate cancer

NASA Astrophysics Data System (ADS)

Kim, Jae-Sung; Chung, Jin-Beom; Kim, In-Ah; Eom, Keun-Yong

2013-10-01

We used an endorectal balloon (ERB) for prostate immobilization during intensity-modulated radiotherapy (IMRT) for prostate cancer treatment. To investigate the dosimetric effects of ERB-filling materials, we changed the ERB Hounsfield unit (HU) from 0 to 1000 HU in 200-HU intervals to simulate the various ERB fillings; 0 HU simulated a water-filled ERB, and 1000 HU simulated the densest material-filled ERB. Dosimetric data (coverage, homogeneity, conformity, maximal dose, and typical volume dose) for the tumor and the organs at risk (OARs) were evaluated in prostate IMRT treatment plans with 6-MV and 15-MV beams. The tumor coverage appeared to differ by approximately 1%, except for the clinical target volume (CTV) V100% and the planning target volume (PTV) V100%. The largest difference for the various ERB fillings was observed in the PTV V100%. In spite of increasing HU, the prostate IMRT plans at both energies had relatively low dosimetric effects on the PTV and the CTV. However, the maximal and the typical volume doses (D25%, D30%, and D50%) to the rectal wall and the bladder increased with increasing HU. For an air-filled ERB, the maximal doses to the rectal wall and the monitor units were lower than the corresponding values for the water-filled and the densest material-filled ERBs. An air-filled ERB spared the rectal wall because of its dosimetric effect. Thus, we conclude that the use of an air-filled ERB provides a dosimetric benefit to the rectal wall without a loss of target coverage and is an effective option for prostate IMRT treatment.

Beyond the Yellow Bus: Promising Practices for Maximizing Access to Opportunity through Innovations in Student Transportation. Policy Brief 2014

ERIC Educational Resources Information Center

Center for Cities & Schools, 2014

2014-01-01

Access to safe, affordable, and convenient transportation shapes the "geography of opportunity" for many children and youth. This study looks at how ?localities across the country are implementing new and innovative alternative approaches to student transportation that expand regional transportation access for K-12 students, improve…

Minimizing Harm and Maximizing Pleasure: Considering the Harm Reduction Paradigm for Sexuality Education

ERIC Educational Resources Information Center

Naisteter, Michal A.; Sitron, Justin A.

2010-01-01

This article explores the potential for introducing harm reduction into sexuality education. When the goal of sexuality education is on prevention and focuses on risk and public health concerns, a discussion of pleasure is rendered problematic, as many pleasurable behaviors are inherently "unsafe" or "risky" when considered using a safe-sex lens.…

Balancing Student Rights and the Need for Safe Schools

ERIC Educational Resources Information Center

Hachiya, Robert Francis

2010-01-01

The purpose of this study was to examine if school safety and security can be maximized without reducing student rights and freedoms. A review of school violence literature supports the early research on how schools should respond to school violence. An analysis of court cases that have arisen from legislative and school responses to school…

Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers.

PubMed

Gobburu, J V; Agersø, H; Jusko, W J; Ynddal, L

1999-09-01

To examine the pharmacokinetics (PK) and pharmacodynamics (PD) of ipamorelin, a growth hormone (GH) releasing peptide, in healthy volunteers. A trial was conducted with a dose escalation design comprising 5 different infusion rates (4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg over 15 minutes) with eight healthy male subjects at each dose level. Concentrations of ipamorelin and growth hormone were measured. The PK parameters showed dose-proportionality, with a short terminal half-life of 2 hours, a clearance of 0.078 L/h/kg and a volume of distribution at steady-state of 0.22 L/kg. The time course of GH stimulation by ipamorelin showed a single episode of GH release with a peak at 0.67 hours and an exponential decline to negligible GH concentration at all doses. The ipamorelin-GH concentration relationship was characterized using an indirect response model and population fitting. The model employed a zero-order GH release rate over a finite duration of time to describe the episodic release of GH. Ipamorelin induces the release of GH at all dose levels with the concentration (SC50) required for half-maximal GH stimulation of 214 nmol/L and a maximal GH production rate of 694 mIU/L/h. The inter-individual variability of the PD parameters was larger than that of the PK parameters. The proposed PK/PD model provides a useful characterization of ipamorelin disposition and GH responses across a range of doses.

Renal Insufficiency in Concert with Renin-angiotensin-aldosterone Inhibition Is a Major Risk Factor for Hyperkalemia Associated with Low-dose Trimethoprim-sulfamethoxazole in Adults.

PubMed

Higashioka, Kazuhiko; Niiro, Hiroaki; Yoshida, Kenji; Oryoji, Kensuke; Kamada, Kazuo; Mizuki, Shinichi; Yokota, Eisuke

2016-01-01

Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used to prevent pneumocystis pneumonia in daily practice. Previous reports have shown a relationship between high- or standard-dose of TMP-SMX and hyperkalemia, however it remains unclear whether this is true for low-dose TMP-SMX. In this study we sought to determine the risk factors for hyperkalemia associated with low-dose TMP-SMX. In this retrospective cohort study, 186 consecutive adult patients who received TMP-SMX as prophylaxis for pneumocystis pneumonia from January 2014 to January 2015 were evaluated. Data on the patients' age, gender, baseline estimated glomerular filtration rate (eGFR), baseline serum potassium, maximum serum potassium, duration reaching the maximal serum potassium level, dosage, and concomitant use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), β-blockers, non-steroidal anti-inflammatory drugs and potassium-sparing diuretics were retrospectively collected. Hyperkalemia was defined as a serum potassium level ≥5 mEq/L. Univariate and multivariate analyses were performed. The median age of the patients was 66 years and 51.1% were men. Hyperkalemia associated with low-dose TMP-SMX was observed in 32 patients (17.2%). The median duration to reach the maximal serum potassium level was 12 days. The multivariate logistic regression analysis identified renal insufficiency to be a major risk factor for hyperkalemia associated with low-dose TMP-SMX (eGFR <60 mL/min/1.73 m(2), adjusted OR 4.62). Moreover, in the subpopulation of patients with renal insufficiency, ACEi/ARB use was considered to be a major risk factor for hyperkalemia (adjusted OR 3.96). Renal insufficiency in concert with ACEi/ARB use is a major risk factor for hyperkalemia induced by low-dose TMP-SMX.

SU-F-T-499: Anatomic Features for Selection of Electronic Tissue Compensation Radiotherapy in Early-Stage Breast Cancer Patients After Breast-Conserving Surgery

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

Song, Y; Gan, L; Chen, X

Purpose: To explore the correlations between anatomic features and dose-volumetric parameters in 3DCRT and eComp whole breast irradiation and identify the feasibility of anatomic parameters to predict the planning method selection. Methods: We compared the effectiveness between conventional three-dimensional conformal radiotherapy (3DCRT) and electronic tissue compensation (eComp) for whole breast irradiation. 3DCRT and eComp planning techniques were used to generate treatment plans for 60 whole breast patients, respectively. The planning goal was to cover 95% of the planning target volume (PTV) with 95% of the prescription dose while minimizing dose to lung, heart, and skin. Statistical analyses were performed betweenmore » critical organ doses and patient anatomic features, i.e., central lung distance (CLD), maximal heart distance (MHD), maximal heart length (MHL) and breast separation (BS). Results: Comparing to 3DCRT plans, on the average, eComp treatment planning process was about 7 minutes longer, but resulted in lower lung V20Gy, lower mean skin dose, with similar heart dose. The benefits were more pronounced for larger breast patients. To keep the lung V20Gy lower than 20% and mean skin dose lower than 85% of the prescription dose, eComp was the preferred method for patients with more than 2.3 cm CLD or larger than 22.5 cm BS. Conclusion: The study results may be useful in providing a handy criterion in clinical practice allowing us to easily choose between different planning techniques to satisfy the planning goal with minimal increase in complexity and cost. This study was supported by National Natural Science Foundation of China (NO. 31420103915) and Chongqing Health and Family Planning Commission Project (2015MSXM012).« less

The Key Events Dose-Response Framework: A cross-Disciplinary Mode-of-Action Based Approach to Examining Does-Response and Thresholds

EPA Science Inventory

the ILSI Research Foundation conveded a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categoreis of bioactive agents: food allergens, nutrients, pathogenic microorganisms, and ...

High-Dose Intravenous Ribavirin Therapy for Subacute Sclerosing Panencephalitis

PubMed Central

Hosoya, Mitsuaki; Shigeta, Shiro; Mori, Shuichi; Tomoda, Akemi; Shiraishi, Seiji; Miike, Teruhisa; Suzuki, Hitoshi

2001-01-01

Two patients with subacute sclerosing panencephalitis (SSPE) were treated safely and effectively with high doses of intravenous ribavirin combined with intraventricular alpha interferon. The ribavirin concentrations maintained in the serum and cerebrospinal fluid were higher than those which inhibit SSPE virus replication in vitro and in vivo. PMID:11181386

A new biostimulation approach based on the concept of remaining P for soil bioremediation.

PubMed

Júlio, Aline Daniela Lopes; Fernandes, Rita de Cássia Rocha; Costa, Maurício Dutra; Neves, Júlio César Lima; Rodrigues, Edmo Montes; Tótola, Marcos Rogério

2018-02-01

C:N:P ratio is generally adopted to estimate the amount of nitrogen and phosphorus to be added to soils to accelerate biodegradation of organic contaminants. However, differences in P fixation among soils lead to varying amounts of available P when a specific dose of the element is applied to different soils. Thus, the application of fertilizers to achieve a previously established C:P ratio leads to biodegradation rates that can be lower than the theoretical maximum. In this study, we developed an equation to estimate the dose of P required to maximize organic contaminant biodegradation in soils as a function of remaining P (P-rem), using diesel as a model contaminant. The soils were contaminated with diesel and received six doses of P. CO 2 emission was used to estimate biodegradation of hydrocarbons. Biodegradation increased with P doses. The P level that provided the highest hydrocarbon biodegradation rate showed linear and negative correlation with P-rem. The result shows that the requirement for P decreases as the P-rem of the soil increases (or the P-fixing capacity decreases). The dose of P recommended to maximize hydrocarbon biodegradation rate in soil can be estimated by the formula P (mg/dm 3 ) = 436.5-5.39 × P-rem (mg/L). Copyright © 2017 Elsevier Ltd. All rights reserved.

Solution formulation development of a VEGF inhibitor for intravitreal injection.

PubMed

Marra, Michelle T; Khamphavong, Penney; Wisniecki, Peter; Gukasyan, Hovhannes J; Sueda, Katsuhiko

2011-03-01

PF-00337210 is a potent, selective small molecule inhibitor of VEGFRs and has been under consideration for the treatment of age-related macular degeneration. An ophthalmic solution formulation intended for intravitreal injection was developed. This formulation was designed to maximize drug properties such that the formulation would precipitate upon injection into the vitreous for sustained delivery. As a parenteral formulation with additional constraints dictated by this specialized delivery route, multiple features were balanced in order to develop a successful formulation. Some of these considerations included low dosing volumes (≤0.1 mL), a limited repertoire of safe excipients for intravitreal injection, and the unique physical chemical properties of the drug. The aqueous solubility as a function of pH was characterized, buffer stressing studies to select the minimal amount of buffer were conducted, and both chemical and physical stability studies were executed. The selected formulation consisted of an isotonic solution comprised of PF-00337210 free base in a citrate-buffered vehicle containing NaCl for tonicity. The highest strength for regulatory toxicology studies was 60 mg/mL. The selected formulation exhibited sufficient chemical stability upon storage with no precipitation, and acceptable potency and recovery through an intravitreal dosing syringe. Formulation performance was simulated by precipitation experiments using extracted vitreous humor. In simulated injection experiments, PF-00337210 solutions reproducibly precipitated upon introduction to the vitreous so that a depot was formed. To our knowledge, this is the first time that a nonpolymeric in situ-forming depot formulation has been developed for intravitreal delivery, with the active ingredient as the precipitating agent. © 2011 American Association of Pharmaceutical Scientists

Role of beta-alanine supplementation on muscle carnosine and exercise performance.

PubMed

Artioli, Guilherme Giannini; Gualano, Bruno; Smith, Abbie; Stout, Jeffrey; Lancha, Antonio Herbert

2010-06-01

In this narrative review, we present and discuss the current knowledge available on carnosine and beta-alanine metabolism as well as the effects of beta-alanine supplementation on exercise performance. Intramuscular acidosis has been attributed to be one of the main causes of fatigue during intense exercise. Carnosine has been shown to play a significant role in muscle pH regulation. Carnosine is synthesized in skeletal muscle from the amino acids l-histidine and beta-alanine. The rate-limiting factor of carnosine synthesis is beta-alanine availability. Supplementation with beta-alanine has been shown to increase muscle carnosine content and therefore total muscle buffer capacity, with the potential to elicit improvements in physical performance during high-intensity exercise. Studies on beta-alanine supplementation and exercise performance have demonstrated improvements in performance during multiple bouts of high-intensity exercise and in single bouts of exercise lasting more than 60 s. Similarly, beta-alanine supplementation has been shown to delay the onset of neuromuscular fatigue. Although beta-alanine does not improve maximal strength or VO2max, some aspects of endurance performance, such as anaerobic threshold and time to exhaustion, can be enhanced. Symptoms of paresthesia may be observed if a single dose higher than 800 mg is ingested. The symptoms, however, are transient and related to the increase in plasma concentration. They can be prevented by using controlled release capsules and smaller dosing strategies. No important side effect was related to the use of this amino acid so far. In conclusion, beta-alanine supplementation seems to be a safe nutritional strategy capable of improving high-intensity anaerobic performance.

Multiple effects of sibutramine on ejaculation and on vas deferens and seminal vesicle contractility

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

Nojimoto, Fernanda D.; Piffer, Renata C.; Kiguti, Luiz Ricardo de A.

Sibutramine is an inhibitor of norepinephrine and 5-HT reuptake largely used in the management of obesity. Although a fairly safe drug, postmarketing adverse effects of sibutramine were reported including abnormal ejaculation in men. This study investigates the effects of sibutramine on ejaculation and vas deferens and seminal vesicle contractility. Adult male rats received sibutramine (5; 20; or 50 mg kg{sup -1}, ip) and after 60 min were exposed to receptive females for determination of ejaculation parameters. The vasa deferentia and seminal vesicles of untreated rats were mounted in isolated organ baths for recording of isometric contractions and HEK293 cells loadedmore » with fluorescent calcium indicator were used to measure intracellular Ca{sup 2+} transients. Sibutramine 5 and 20 mg kg{sup -1} reduced ejaculation latency whereas 50 mg kg{sup -1} increased ejaculation latency. Sibutramine 3 to 30 {mu}M greatly increased the sensitivity of the seminal vesicle and vas deferens to norepinephrine, but at concentrations higher than 10 {mu}M there were striking depressions of maximal contractions induced by norepinephrine, carbachol and CaCl{sub 2}. In HEK293 cells, sibutramine 10 to 100 {mu}M inhibited intracellular Ca{sup 2+} transients induced by carbachol. Depending on the doses, sibutramine either facilitates or inhibits ejaculation. Apart from its actions in the central nervous system, facilitation of ejaculation may result from augmented sensitivity of smooth muscles to norepinephrine while reductions of intracellular Ca{sup 2+} may be involved in the delayed ejaculation observed with high doses of sibutramine.« less

Suppression of follicular rupture with meloxicam, a cyclooxygenase-2 inhibitor: potential for emergency contraception.

PubMed

Jesam, Cristián; Salvatierra, Ana María; Schwartz, Jill L; Croxatto, Horacio B

2010-02-01

There is evidence that cyclooxygenase-2 (COX-2) inhibitors can prevent or delay follicular rupture. COX-2 inhibitors, such as meloxicam, may offer advantages over emergency contraception with levonorgestrel, such as extending the therapeutic window for up to 24 h. We assessed the effect of meloxicam administered in the late follicular phase upon ovulation in women. This was a single center, double blind, crossover study designed to assess the effects in 27 eligible women (18-40 years old, surgically sterilized with regular menstrual cycles) of meloxicam, 15 or 30 mg/day, administered orally for five consecutive days during the late follicular phase, starting when the leading follicle reached 18 mm diameter. Volunteers underwent two treatment cycles separated by one resting cycle, with randomization to dose sequence. Main outcomes were follicular rupture; serum LH, progesterone and estradiol (E2) levels; and incidence of adverse events. Twenty-two volunteers completed the study. There were no differences between meloxicam doses in menstrual cycle length. Dysfunctional ovulation was observed in 11/22 (50%) cycles treated with 15 mg/day and 20/22 (90.9%) cycles with 30 mg/day (P = 0.0068). All women had normal luteal phase progesterone levels; mean maximal values +/- SEM were 42 +/- 4.1 and 46.8 +/- 2.6 nmol/l for 15 and 30 mg/day groups, respectively. There were no serious adverse events, and no changes in LH and E2 levels or in cycle length. Meloxicam 30 mg given for five consecutive days in the late follicular phase is safe, effective and may be an alternative form of emergency contraception.

ESTIMATION OF EXPOSURE DOSES FOR THE SAFE MANAGEMENT OF NORM WASTE DISPOSAL.

PubMed

Jeong, Jongtae; Ko, Nak Yul; Cho, Dong-Keun; Baik, Min Hoon; Yoon, Ki-Hoon

2018-03-16

Naturally occurring radioactive materials (NORM) wastes with different radiological characteristics are generated in several industries. The appropriate options for NORM waste management including disposal options should be discussed and established based on the act and regulation guidelines. Several studies calculated the exposure dose and mass of NORM waste to be disposed in landfill site by considering the activity concentration level and exposure dose. In 2012, the Korean government promulgated an act on the safety control of NORM around living environments to protect human health and the environment. For the successful implementation of this act, we suggest a reference design for a landfill for the disposal of NORM waste. Based on this reference landfill, we estimate the maximum exposure doses and the relative impact of each pathway to exposure dose for three scenarios: a reference scenario, an ingestion pathway exclusion scenario, and a low leach rate scenario. Also, we estimate the possible quantity of NORM waste disposal into a landfill as a function of the activity concentration level of U series, Th series and 40K and two kinds of exposure dose levels, 1 and 0.3 mSv/y. The results of this study can be used to support the establishment of technical bases of the management strategy for the safe disposal of NORM waste.

Oral ketamine for children with chronic pain: a pilot phase 1 study

PubMed Central

Bredlau, Amy-Lee; McDermott, Michael P.; Adams, Heather; Dworkin, Robert H; Venuto, Charles; Fisher, Susan; Dolan, James G; Korones, David N

2013-01-01

Objective To assess whether oral ketamine aids is is safe at higher dosages for sedating children and whether it may be an option for control of chronic pain in children. Study design A prospective study was performed on 12 children with chronic pain to identify the maximum tolerated dosage of oral ketamine. Participants were given 14 days of oral ketamine, three times daily, at dosages ranging from 0.25–1.5 mg/kg/dose. Participants were assessed for toxicity and for pain severity at baseline and on day 14 of treatment. Results Two participants, both treated at 1.5 mg/kg/dose, experienced dose-limiting toxicities (sedation and anorexia). One participant, treated at 1 mg/kg/dose, opted to stop ketamine treatment due to new pain on treatment. Nine participants completed their course of ketamine treatment. Of these 12 children, 5 experienced improvement in their pain scores, two with complete resolution of pain, lasting for more than 4 weeks off ketamine treatment. Conclusion Oral ketamine at dosages of 0.25–1 mg/kg/dose appears to be safe when given for 14 days to children with chronic pain. PMID:23403253

Analgesic and anti-inflammatory effects of Mangifera indica L. extract (Vimang).

PubMed

Garrido, G; González, D; Delporte, C; Backhouse, N; Quintero, G; Núñez-Sellés, A J; Morales, M A

2001-02-01

Vimang is an aqueous extract of Mangifera indica used in Cuba to improve the quality of life in patients suffering from elevated stress. To assess its possible analgesic and antiinflammatory effects, the results of a standard extract evaluation are presented. Analgesia was determined using acetic acid-induced abdominal constriction and formalin-induced licking. Antiinflammatory effects were evaluated using carrageenan- and formalin-induced oedema. Vimang (50-1000 mg/kg, p.o.) exhibited a potent and dose-dependent antinociceptive effect against acetic acid test in mice. The mean potency (DE(50)) was 54.5 mg/kg and the maximal inhibition attained was 94.4%. Vimang (20-1000 mg/kg, p.o.) dose-dependently inhibited the second phase of formalin-induced pain but not the first phase. The DE(50) of the second phase was 8.4 mg/kg and the maximal inhibition was 99.5%, being more potent than indomethacin at doses of 20 mg/kg. Vimang (20-1000 mg/kg, p.o.) significantly inhibited oedema formation (p < 0.01 or p < 0.05) of both carrageenan- and formalin-induced oedema in rat, guinea-pigs and mice (maximal inhibitions: 39.5, 45.0 and 48.6, respectively). The inhibitions were similar to those produced by indomethacin and sodium naproxen, p.o. The different polyphenols found in Vimang could account for the antinociceptive and antiinflammatory actions reported here for the first time for M. indica bark aqueous extract. Copyright 2001 John Wiley & Sons, Ltd.

Determinants of cell-to-cell variability in protein kinase signaling.

PubMed

Jeschke, Matthias; Baumgärtner, Stephan; Legewie, Stefan

2013-01-01

Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds ('pathway sensitivity') and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s) or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability.

Effect of insulin-like factors on glucose transport activity in unweighted rat skeletal muscle

NASA Technical Reports Server (NTRS)

Henriksen, Erik J.; Ritter, Leslie S.

1993-01-01

The effect of 3 or 6 days of unweighting on glucose transport activity, as assessed by 2-deoxyglucose uptake, in soleus strips stimulated by maximally effective concentrations of insulin, IGF-I, vanadate, or phospholipase C (PLC) is examined. Progressively increased responses to maximally effective doses of insulin or insulin-like growth factor were observed after 3 and 6 days of unweighting compared with weight matched control strips. Enhanced maximal responses to vanadate (6 days only) and PLC (3 and 6 days) were also observed. The data provide support for the existance of postreceptor binding mechanisms for the increased action of insulin on the glucose transport system in unweighted rat skeletal muscle.

Screening of the anticonvulsant activity of some plants from Fabaceae family in experimental seizure models in mice

PubMed Central

Sayyah, M.; Khodaparast, A.; Yazdi, A.; Sardari, S.

2011-01-01

Background and purpose of the study Fabaceae is the third largest family of flowering plants. Lack of essential oils in the plants of this family can be an advantage in search for safe and effective medicines. In this study the anticonvulsant effect of the leaves of Albizzia julibrissin, Acacia juliflora, Acacia nubica and aerial parts of Astragalus obtusifolius was evaluated in pentylenetetrazole (PTZ) and maximal electroshock (MES) seizure tests. Methods The hydroalcoholic extracts of the plants were obtained by percolation. Different doses of the extracts were injected to the mice intraperitoneally (i.p.) and occurrence of clonic seizures induced by PTZ (60 mg/kg, i.p.) or tonic seizures induced by MES (50 mA, 50Hz, 1sec) were monitored up to 30 min after administration. Acute toxicity of the extracts was also assessed. The safe and effective extract was then fractionated by dichloromethane and anticonvulsant activity of the fractions was determined. Finally, the constituents of the extract and the fractions were screened by thin layer chromatography. Results Among the extracts, only A. obtusifolius extract showed low toxicity and protective effect against clonic seizures with ED50 value of 3.97 g/kg. Fractionation of the extract led to increase in anticonvulsant activity and ED50 value of 2.86 g/kg was obtained for the aqueous fraction. Phytochemical screening revealed the presence of alkaloids, flavonoids, anthrones and saponins in the aqueous fraction. Major conclusion The presence of anticonvulsant compounds in A. obtusifolius suggests further activity-guided fractionation and analytical studies to find out the potential of this plant as a source of anticonvulsant agent. PMID:22615673

Injectable contraception. New and existing options.

PubMed

Kaunitz, A M

2000-12-01

DMPA and MPA/E2C contraception offer women safe, effective, convenient, and reversible birth control choices. The use of DMPA, a 3-month injectable, is characteristically associated with amenorrhea. Lactating women and women in whom contraceptive doses of estrogen are contraindicated can use this progestin-only birth control method. Return of fertility can be delayed in women discontinuing DMPA to become pregnant. In some cases, the use of DMPA also confers important noncontraceptive and therapeutic benefits. A monthly estrogen/progestin injectable contraceptive, MPA/E2C should appeal to women who are concerned about daily pill taking, who prefer regular cycles to amenorrhea, and who find monthly injections acceptable and accessible. As is true for oral contraceptives, MPA/E2C represents an appropriate choice for women who prefer a rapidly reversible contraceptive. Currently, the proposed contraindications for MPA/E2C parallel those for combined oral contraceptives. As MPA/E2C contraception becomes available for American women, clinicians will learn how to best include this new method among the array of contraceptive choices. By individualizing contraceptive selection, counseling, and management approaches based on the relevant behavioral and medical considerations reviewed herein, clinicians can maximize their patients' success with injectable contraceptives. The more innovative that clinicians, family planning agencies, and insurers are in facilitating access to care (including reinjections), the more women will be able to avail themselves of safe, effective, and reversible methods of contraception. In addition to the physician's office or health clinic, other sites at which women might receive contraceptive injections include employee health clinics, college health clinics, or perhaps the pharmacy where the prescription is filled. Self-administration may become an appropriate option for some users of injectable contraception.

Hepatic veno-occlusive disease during chemotherapy for nephroblastoma: successful and safe treatment with defibrotide. Report of a clinical case.

PubMed

Cecinati, Valerio; Giordano, Paola; De Leonardis, Francesco; Grassi, Massimo; Arcamone, Giampaolo; De Mattia, Domenico; Santoro, Nicola

2009-01-01

Here we report a case of administration of defibrotide in an 11 months old infant with hepatic veno-occlusive disease during chemotherapy for nephroblastoma. He presented with abdominal distension, a weight gain of 15%, ascites, hepatomegaly with right upper quadrant pain, thrombocytopenia and hypertransaminasemia. Despite therapy, his clinical conditions aggravated, and, therefore intravenous administration of defibrotide on a compassionate-use basis was started. The dosage was 15 mg/kg/day in 4 divided doses, which was increased gradually (in 3 days) to 40 mg/kg/day in 4 divided doses. Defibrotide proved safe and effective in resolving clinical symptoms and normalizing serological findings in the syndrome.

Nonclinical Safety Assessment of SYN-004: An Oral β-lactamase for the Protection of the Gut Microbiome From Disruption by Biliary-Excreted, Intravenously Administered Antibiotics.

PubMed

Kokai-Kun, John F; Bristol, J Andrew; Setser, John; Schlosser, Michael

2016-05-01

SYN-004 is a first in class, recombinant β-lactamase that degrades β-lactam antibiotics and has been formulated to be administered orally to patients receiving intravenous β-lactam antibiotics including cephalosporins. SYN-004 is intended to degrade unmetabolized antibiotics excreted into the intestines and thus has the potential to protect the gut microbiome from disruption by these antibiotics. Protection of the gut microbiome is expected to protect against opportunistic enteric infections such as Clostridium difficile infection as well as antibiotic-associated diarrhea. In order to demonstrate that oral SYN-004 is safe for human clinical trials, 2 Good Laboratory Practice-compliant toxicity studies were conducted in Beagle dogs. In both studies, SYN-004 was administered orally 3 times per day up to the maximum tolerated dose of the formulation. In the first study, doses of SYN-004 administered over 28 days were safe and well tolerated in dogs with the no-observed-adverse-effect level at the high dose of 57 mg/kg/day. Systemic absorption of SYN-004 was minimal and sporadic and showed no accumulation during the study. In the second study, doses up to 57 mg/kg/day were administered to dogs in combination with an intravenous dose of ceftriaxone (300 mg/kg) given once per day for 14 days. Coadministration of oral SYN-004 with intravenous ceftriaxone was safe and well tolerated, with SYN-004 having no noticeable effect on the plasma pharmacokinetics of ceftriaxone. These preclinical studies demonstrate that SYN-004 is well tolerated and, when coadministered with ceftriaxone, does not interfere with its systemic pharmacokinetics. These data supported advancing SYN-004 into human clinical trials. © The Author(s) 2015.

Maximizing School Counselors' Efforts by Implementing School-Wide Positive Behavioral Interventions and Supports: A Case Study from the Field

ERIC Educational Resources Information Center

Goodman-Scott, Emily

2014-01-01

School-Wide Positive Behavioral Interventions and Supports (PBIS) are school-wide, data-driven frameworks for promoting safe schools and student learning. This article explains PBIS and provides practical examples of PBIS implementation by describing a school counselor-run PBIS framework in one elementary school, as part of a larger, district-wide…

Prevention of Human Mammary Carcinogenesis

DTIC Science & Technology

1995-06-30

selected naturally-occurring agents (-)- epigallocatechin gallate ( EGCG ), indole-3-carbinol (13C) and genistein (GEN) for growth inhibition of 184-B5...mechanisms of BP-induced and GEN-induced alterations in cell cycle are being investigated in the ongoing studies. In addition, effects of 13C and EGCG are...rodent mammary tumorigenesis. The maximally nontoxic doses of EGCG , 13C and GEN identified by initial dose-response experiments, were used. The data

A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment.

PubMed

Morimoto, Bruce H; Schmechel, Don; Hirman, Joe; Blackwell, Andrew; Keith, Julian; Gold, Michael

2013-01-01

AL-108-211 was a placebo-controlled, ascending-dose study that explored the safety, tolerability and efficacy of 12 weeks of treatment with AL-108 in subjects with amnestic mild cognitive impairment. A total of 144 subjects were randomized in a 2:1 drug:placebo ratio. Subjects were enrolled into the low-dose group or placebo and then to the high-dose group or placebo. Pooling of the placebo groups yielded 3 groups (approx. 48/group) whose baseline demographics and disease characteristics were well matched. AL-108 was generally safe and well tolerated. Analyses of efficacy data failed to detect a statistically significant difference between the treatment groups on the composite cognitive memory score. Analyses of the individual cognitive tasks identified signals of potential efficacy in 2 tests of memory and attention. These data suggest that AL-108 was generally safe, well tolerated and merits additional investigation as a treatment for Alzheimer's disease. Copyright © 2013 S. Karger AG, Basel.

Analysis of radiation environmental safety for China's Spallation Neutron Source (CSNS)

NASA Astrophysics Data System (ADS)

Wang, Qing-Bin; Wu, Qing-Biao; Ma, Zhong-Jian; Zhang, Qing-Jiang; Li, Nan; Wu, Jing-Min; Liu, Jian; Zhang, Gang

2010-07-01

The China Spallation Neutron Source (CSNS) is going to be located in Dalang Town, Dongguan City in the Guangdong Province. In this paper we report the results of the parameters related with environment safety based on experiential calculations and Monte Carlo simulations. The main project of the accelerator is an under ground construction. On top there is a 0.5 m concrete and 5.0 m soil covering for shielding, which can reduce the dose out of the tunnel's top down to 0.2 μSv/h. For the residents on the boundary of the CSNS, the dose produced by skyshine, which is caused by the penetrated radiation leaking from the top of the accelerator, is no more than 0.68 μSv/a. When CSNS is operating normally, the maximal annual effective dose due to the emission of gas from the tunnel is 2.40×10-3 mSv/a to the public adult, and 2.29×10-3 mSv/a to a child, both values are two orders of magnitude less than the limiting value for control and management. CSNS may give rise to an activation of the soil and groundwater in the nearest tunnels, where the main productions are 3H, 7Be, 22Na, 54Mn, etc. But the specific activity is less than the exempt specific activity in the national standard GB13376-92. So it is safe to say that the environmental impact caused by the activation of soil and groundwater is insignificant. To sum up, for CSNS, as a powerful neutron source device, driven by a high-energy high-current proton accelerator, a lot of potential factors affecting the environment exist. However, as long as effective shieldings for protection are adopted and strict rules are drafted, the environmental impact can be kept under control within the limits of the national standard.

Liraglutide and obesity in elderly: efficacy in fat loss and safety in order to prevent sarcopenia. A perspective case series study.

PubMed

Perna, Simone; Guido, Davide; Bologna, Chiara; Solerte, Sebastiano Bruno; Guerriero, Fabio; Isu, Antonio; Rondanelli, Mariangela

2016-12-01

For the growing numbers of obese elderly with diabetes, the glucagon-like peptide-1 (GLP-1) receptor analogue (liraglutide) appears a safe way to promote and maintain substantial weight loss. Given this background, the aim of this study was to assess the effect of the liraglutide treatment, at doses up to 3.0 mg per day, on the body composition, focusing on sarcopenia, in overweight and obese elderly with type 2 diabetes mellitus (T2DM). A perspective study was carried out in overweight and obese T2DM patients with HbA1c equal to 7.0 % (53 mmol/mol) ~10.0 % (86), under 3-month treatment (at least) of maximal dose of metformin at stable regime, and additional liraglutide at doses up to 3.0 mg per day. Body composition markers such as skeletal muscle index (SMI), android and gynoid fat mass, and arms and legs fat free mass, was measured by dual-energy X-ray densitometry (DXA) at baseline and after 24 weeks of liraglutide treatment. Glucose control was also carried out by glucose and HbA1c. Nine subjects (male/female 6/3, mean age 68.22 ± 3.86 years, BMI 32.34 ± 4.89 kg/m 2 ) were evaluated. We noted a median decrease in BMI (-0.78 kg/m 2 ), weight (-2000 g), fat mass (-1498 g) and android fat (-0.9 %), and a increase in SMI (+0.03 kg/m 2 ) from baseline. Glycemic control also improved, with a median change HbA1c of -0.80 %. Twenty-four weeks of liraglutide treatment was associated with reductions in fat mass and android fat. In addition, in order to prevent sarcopenia, it preserved the muscular tropism.

Getting to goal in newly diagnosed type 2 diabetes using combination drug "subtraction therapy".

PubMed

Jennings, Anthony S; Lovett, Alexandra J; George, Tina M; Jennings, Jonathan S

2015-09-01

The treatment of newly diagnosed type 2 diabetes mellitus is diverse, with no clear consensus regarding the initial drug regimen or dosing to achieve optimal glycemic control. We treated 44 consecutive patients with newly diagnosed type 2 diabetes with maximally tolerated doses of pioglitazone 45 mg/day, metformin 1000-2000 mg/day, and repaglinide 1-4 mg before meals. The doses and drugs were subsequently decreased ("subtraction therapy") to achieve optimal glycemic control and minimize side effects. Three primary outcomes were measured: the short term HbA1c response, the long term HbA1c response, and the incidence of hypoglycemia. All 44 patients responded with a rapid, progressive decline in their HbA1c levels from 11.43±2.3% to 6.17±0.72% (101±25.1 mmol/mol to 44±7.9 mmol/mol) by three months, and remained stable thereafter. An HbA1c ≤7.0% (≤53 mmol/mol) was reached within 1-4 months in 42 of 44 patients, and in every patient by 12 months. Each patient's lowest HbA1c level, 5.65±0.6% (38±6.6 mmol/mol), was reached over 6.3±2.9 months. Patients with initial HbA1c levels >10% (>86 mmol/mol) (n=33) responded similarly as those with HbA1c levels <10% (<86 mmol/mol) (n=11). Combination drug therapy maintained HbA1c levels between 5.0 and 7.0% (31 and 53 mmol/mol) for up to 14.83 years. Only one clinically significant hypoglycemic event occurred during 261.08 person-years of follow-up. In our experience, combination drug "subtraction therapy" was safe and effective for treating all newly diagnosed type 2 diabetic patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical impact of (99m)Tc-MAA SPECT/CT-based dosimetry in the radioembolization of liver malignancies with (90)Y-loaded microspheres.

PubMed

Garin, Etienne; Rolland, Yan; Laffont, Sophie; Edeline, Julien

2016-03-01

Radioembolization with (90)Y-loaded microspheres is increasingly used in the treatment of primary and secondary liver cancer. Technetium-99 m macroaggregated albumin (MAA) scintigraphy is used as a surrogate of microsphere distribution to assess lung or digestive shunting prior to therapy, based on tumoral targeting and dosimetry. To date, this has been the sole pre-therapeutic tool available for such evaluation. Several dosimetric approaches have been described using both glass and resin microspheres in hepatocellular carcinoma (HCC) and liver metastasis. Given that each product offers different specific activities and numbers of spheres injected, their radiobiological properties are believed to lightly differ. This paper summarizes and discusses the available studies focused on MAA-based dosimetry, particularly concentrating on potential confounding factors like clinical context, tumor size, cirrhosis, previous or concomitant therapy, and product used. In terms of the impact of tumoral dose in HCC, the results were concordant and a response relationship and tumoral threshold dose was clearly identified, especially in studies using glass microspheres. Tumoral dose has also been found to influence survival. The concept of treatment intensification has recently been introduced, yet despite several studies publishing interesting findings on the tumor dose-metastasis relationship, no consensus has been reached, and further clarification is thus required. Nor has the maximal tolerated dose to the liver been well documented, requiring more accurate evaluation. Lung dose was well described, despite recently identified factors influencing its evaluation, requiring further assessment. Conclusion: MAA SPECT/CT dosimetry is accurate in HCC and can now be used in order to achieve a fully customized approach, including treatment intensification. Yet further studies are warranted for the metastasis setting and evaluating the maximal tolerated liver dose.

Determination of the efficiency of commercially available dose calibrators for beta-emitters.

PubMed

Valley, Jean-François; Bulling, Shelley; Leresche, Michel; Wastiel, Claude

2003-03-01

The goals of this investigation are to determine whether commercially available dose calibrators can be used to measure the activity of beta-emitting radionuclides used in pain palliation and to establish whether manufacturer-supplied calibration factors are appropriate for this purpose. Six types of commercially available dose calibrators were studied. Dose calibrator response was controlled for 5 gamma-emitters used for calibration or typically encountered in routine use. For the 4 most commonly used beta-emitters ((32)P, (90)Sr, (90)Y, and (169)Er) dose calibrator efficiency was determined in the syringe geometry used for clinical applications. Efficiency of the calibrators was also measured for (153)Sm and (186)Re, 2 beta-emitters with significant gamma-contributions. Source activities were traceable to national standards. All calibrators measured gamma-emitters with a precision of +/-10%, in compliance with Swiss regulatory requirements. For beta-emitters, dose calibrator intrinsic efficiency depends strongly on the maximal energy of the beta-spectrum and is notably low for (169)Er. Manufacturer-supplied calibration factors give accurate results for beta-emitters with maximal beta-energy in the middle-energy range (1 MeV) but are not appropriate for use with low-energy ((169)Er) or high-energy ((90)Y) beta-emitters. beta-emitters with significant gamma-contributions behave like gamma-emitters. Commercially available dose calibrators have an intrinsic efficiency that is sufficient for the measurement of beta-emitters, including beta-emitters with a low maximum beta-energy. Manufacturer-supplied calibration factors are reliable for gamma-emitters and beta-emitters in the middle-energy range. For low- and high-energy beta-emitters, the use of manufacturer-supplied calibration factors introduces significant measurement inaccuracy.

Rapid detection and destruction of squamous cell carcinoma of the head and neck by nano-quadrapeutics.

PubMed

Lukianova-Hleb, Ekaterina Y; Lapotko, Dmitri O

2015-10-01

Survival and quality of life remain poor for patients with head and neck squamous cell carcinoma (HNSCC) that cannot be fully resected safely, and form therapy-resistant residual and recurrent tumors. We report novel cell-level technology, quadrapeutics. Quadrapeutics converts surgery, drug, and radiation therapies into on-demand microtreatment that unites the diagnosis and treatment in 1 rapid procedure by using 4 standard components: (1) targeted gold colloids; (2) liposomal drugs; (3) a laser pulse; and (4) radiation, all at safe doses. The therapeutic strength of quadrapeutics increases with cancer aggressiveness. In animal models of a primary and microscopic residual HNSCC, quadrapeutics increased the efficacy of standard chemoradiation therapy by more than 17-fold by using only 3% to 6% of clinical doses of drug and radiation, did not cause side effects, and detected residual microtumors in vivo intraoperatively. Quadrapeutics can be applied to detect and eradicate HNSCC and similar microtumors in a safe and rapid theranostic procedure. © 2015 Wiley Periodicals, Inc.

Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer.

PubMed

Bruera, Gemma; Massacese, Silvia; Galvano, Antonio; Mas, Antonella Dal; Guadagni, Stefano; Calvisi, Giuseppe; Ciacco, Eugenio; Russo, Antonio; Ricevuto, Enrico

2018-04-17

Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m 2 /d 1-2, 8-9, 15-16, 22-23, with 100 mg/m 2 /d increase for dose level; DTX 50 mg/m 2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m 2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m 2 /d and 80 mg/m 2 , respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy.

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

WE-AB-209-07: Explicit and Convex Optimization of Plan Quality Metrics in Intensity-Modulated Radiation Therapy Treatment Planning

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

Engberg, L; KTH Royal Institute of Technology, Stockholm; Eriksson, K

Purpose: To formulate objective functions of a multicriteria fluence map optimization model that correlate well with plan quality metrics, and to solve this multicriteria model by convex approximation. Methods: In this study, objectives of a multicriteria model are formulated to explicitly either minimize or maximize a dose-at-volume measure. Given the widespread agreement that dose-at-volume levels play important roles in plan quality assessment, these objectives correlate well with plan quality metrics. This is in contrast to the conventional objectives, which are to maximize clinical goal achievement by relating to deviations from given dose-at-volume thresholds: while balancing the new objectives means explicitlymore » balancing dose-at-volume levels, balancing the conventional objectives effectively means balancing deviations. Constituted by the inherently non-convex dose-at-volume measure, the new objectives are approximated by the convex mean-tail-dose measure (CVaR measure), yielding a convex approximation of the multicriteria model. Results: Advantages of using the convex approximation are investigated through juxtaposition with the conventional objectives in a computational study of two patient cases. Clinical goals of each case respectively point out three ROI dose-at-volume measures to be considered for plan quality assessment. This is translated in the convex approximation into minimizing three mean-tail-dose measures. Evaluations of the three ROI dose-at-volume measures on Pareto optimal plans are used to represent plan quality of the Pareto sets. Besides providing increased accuracy in terms of feasibility of solutions, the convex approximation generates Pareto sets with overall improved plan quality. In one case, the Pareto set generated by the convex approximation entirely dominates that generated with the conventional objectives. Conclusion: The initial computational study indicates that the convex approximation outperforms the conventional objectives in aspects of accuracy and plan quality.« less

Optimization of the temporal pattern of radiation: An IMRT based study

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

Altman, Michael B.; Chmura, Steven J.; Deasy, Joseph O.

Purpose: To investigate how the temporal pattern of dose applied during a single-intensity modulated radiation therapy (IMRT) fraction can be arranged to maximize or minimize cell kill. Methods and Materials: Using the linear-quadratic repair-time model and a simplified IMRT delivery pattern model, the surviving fraction of cells for a single fraction was calculated for all permutations of the dose delivery pattern for an array of clinically based IMRT cases. Maximization of cell kill was achieved by concentrating the highest doses in the middle of a fraction, while minimization was achieved by spreading the highest doses between the beginning and end.more » The percent difference between maximum and minimum cell kill (%Diff{sub min/max}) and the difference between maximum and minimum total doses normalized to 2 Gy/fx ({delta}NTD{sub 2Gy}) was calculated for varying fraction durations (T), {alpha}/{beta} ratios, and doses/fx. Results: %Diff{sub min/max} and {delta}NTD{sub 2Gy} both increased with increasing T and with decreasing {alpha}/{beta}. The largest increases occurred with dose/fx. With {alpha}/{beta} = 3 Gy and 30 min/fx, %Diff{sub min/max} ranged from 2.7-5.3% for 2 Gy/fx to 48.6-74.1% for 10 Gy/fx, whereas {delta}NTD{sub 2Gy} ranged from 1.2 Gy-2.4 Gy for 30 fractions of 2 Gy/fx to 2.3-4.8 Gy for 2 fractions of 10.84 Gy/fx. Using {alpha}/{beta} = 1.5 Gy, an analysis of prostate hypofractionation schemes yielded differences in clinical outcome based on the pattern of applied dose ranging from 3.2%-6.1% of the treated population. Conclusions: Rearrangement of the temporal pattern of dose for a single IMRT fraction could be used to optimize cell kill and to directly, though modestly, affect treatment outcome.« less

Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn.

PubMed

Yang, Danlin; Giragossian, Craig; Castellano, Steven; Lasaro, Marcio; Xiao, Haiguang; Saraf, Himanshu; Hess Kenny, Cynthia; Rybina, Irina; Huang, Zhong-Fu; Ahlberg, Jennifer; Bigwarfe, Tammy; Myzithras, Maria; Waltz, Erica; Roberts, Simon; Kroe-Barrett, Rachel; Singh, Sanjaya

2017-10-01

Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool to conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due to high target burden. However, the requirements for optimal binding kinetic framework and extent of pH dependence for these antibodies to maximize target clearance from circulation are not well understood. We have identified a series of naturally-occurring high affinity antibodies with pH-dependent target binding properties. By in vivo studies in cynomolgus monkeys, we show that pH-dependent binding to the target alone is not sufficient for effective target removal from circulation, but requires Fc mutations that increase antibody binding to FcRn. Affinity-enhanced pH-dependent FcRn binding that is double-digit nM at pH 7.4 and single-digit nM at pH 6 achieved maximal target reduction when combined with similar target binding affinities in reverse pH directions. Sustained target clearance below the baseline level was achieved 3 weeks after single-dose administration at 1.5 mg/kg. Using the experimentally derived mechanistic model, we demonstrate the essential kinetic interplay between target turnover and antibody pH-dependent binding during the FcRn recycling, and identify the key components for achieving maximal target clearance. These results bridge the demand for improved patient dosing convenience with the "know-how" of therapeutic modality by design.

Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease

PubMed Central

Pan, Lin; Schaefer, Caralee; Nicholas, John; Lim, Sharlene; Misialek, Shawn; Stevens, Sarah; Hooi, Lisa; Aleskovski, Natalia; Ruhrmund, Donald; Kossen, Karl; Huang, Lea; Yap, Sophia; Beigelman, Leonid; Serebryany, Vladimir; Liu, Jyanwei; Sastry, Srikonda; Seiwert, Scott; Buckman, Brad

2016-01-01

Abstract The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other directly acting antiviral agents in vitro displayed additive antiviral efficacy. A 30-mg/kg of body weight dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through day 5 in a chimeric mouse model of HCV. A 3-mg/kg oral dose administered to rats, dogs, or monkeys yielded concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection. PMID:27795376

The safety of green tea and green tea extract consumption in adults - Results of a systematic review.

PubMed

Hu, Jiang; Webster, Donna; Cao, Joyce; Shao, Andrew

2018-06-01

A systematic review of published toxicology and human intervention studies was performed to characterize potential hazards associated with consumption of green tea and its preparations. A review of toxicological evidence from laboratory studies revealed the liver as the target organ and hepatotoxicity as the critical effect, which was strongly associated with certain dosing conditions (e.g. bolus dose via gavage, fasting), and positively correlated with total catechin and epigallocatechingallate (EGCG) content. A review of adverse event (AE) data from 159 human intervention studies yielded findings consistent with toxicological evidence in that a limited range of concentrated, catechin-rich green tea preparations resulted in hepatic AEs in a dose-dependent manner when ingested in large bolus doses, but not when consumed as brewed tea or extracts in beverages or as part of food. Toxico- and pharmacokinetic evidence further suggests internal dose of catechins is a key determinant in the occurrence and severity of hepatotoxicity. A safe intake level of 338 mg EGCG/day for adults was derived from toxicological and human safety data for tea preparations ingested as a solid bolus dose. An Observed Safe Level (OSL) of 704 mg EGCG/day might be considered for tea preparations in beverage form based on human AE data. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study.

PubMed

Dellinger, Ryan W; Santos, Santiago Roel; Morris, Mark; Evans, Mal; Alminana, Dan; Guarente, Leonard; Marcotulli, Eric

2017-01-01

NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD +) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD + in whole blood demonstrated that NRPT significantly increases the concentration of NAD + in a dose-dependent manner. NAD + levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD + levels was sustained throughout the entire 8-week trial. NAD + levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD + levels sustainably.

Can we safely administer the recommended dose of phenobarbital in very low birth weight infants?

PubMed

Oztekin, Osman; Kalay, Salih; Tezel, Gonul; Akcakus, Mustafa; Oygur, Nihal

2013-08-01

We investigated whether the recommended phenobarbital loading dose of 15-20 mg/kg with maintenance of 3-4 mg/kg/day can safely be administered to very low birth weight preterm newborns with seizures. Twenty-four convulsive preterms of <1,500 g were enrolled in the study. Phenobarbital was administered intravenously with a loading dose of 15 mg/kg in approximately 10-15 min. After 24 h, the maintenance dose of 3 mg/kg/day was administered as a single injection. Blood samples were obtained 2, 24, 48, 72, and 96 h after the phenobarbital loading dose was administered, immediately before the next phenobarbital dose was injected. None of the cases had plasma phenobarbital concentrations above the therapeutic upper limit of 40 μg/mL on the 2nd hour; one case (4.7%), on the 24th; 11 cases (45.8%), on the 48th; 15 cases (62.5%), on the 72nd; and 17 cases (70.8%), on the 96th hour. A negative correlation was detected between the serum concentrations of phenobarbital and gestational age on the 72th (p, 0.036; r, -0.608) and 96th hour (p, 0.043; r, -0.769). We suggest that particular attention should be done while administering phenobarbital in preterms, as blood levels of phenobarbital are higher than the reference ranges that those are often reached with the recommended doses in these groups of babies.

Ibogaine for treating drug dependence. What is a safe dose?

PubMed

Schep, L J; Slaughter, R J; Galea, S; Newcombe, D

2016-09-01

The indole alkaloid ibogaine, present in the root bark of the West African rain forest shrub Tabernanthe iboga, has been adopted in the West as a treatment for drug dependence. Treatment of patients requires large doses of the alkaloid to cause hallucinations, an alleged integral part of the patient's treatment regime. However, case reports and case series continue to describe evidences of ataxia, gastrointestinal distress, ventricular arrhythmias and sudden and unexplained deaths of patients undergoing treatment for drug dependence. High doses of ibogaine act on several classes of neurological receptors and transporters to achieve pharmacological responses associated with drug aversion; limited toxicology research suggests that intraperitoneal doses used to successfully treat rodents, for example, have also been shown to cause neuronal injury (purkinje cells) in the rat cerebellum. Limited research suggests lethality in rodents by the oral route can be achieved at approximately 263mg/kg body weight. To consider an appropriate and safe initial dose for humans, necessary safety factors need to be applied to the animal data; these would include factors such as intra- and inter-species variability and for susceptible people in a population (such as drug users). A calculated initial dose to treat patients could be approximated at 0.87mg/kg body weight, substantially lower than those presently being administered to treat drug users. Morbidities and mortalities will continue to occur unless practitioners reconsider doses being administered to their susceptible patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

CERTAIN PHYSICO-CHEMICAL AND CHEMICAL INDICES OF THE BLOOD IN CHRONIC ACTION OF LOW DOSES OF IONIZING RADIATION (in Russian)

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

Gorn, L.E.

1960-06-01

Results are reported from a study on 45 persons subjected during work to the protracted action of rontgen and gamma rays in doses exceeding the maximal permissible ones. It was found that the creatine, aromatic amino acids, and non- hemoglobin iron, as well as the redox potential of the serum, do not differ from the respective values in healthy subjects. (auth)

Pharmacokinetic properties and tolerability of single-dose terbutaline in patients with severe asthma treated in the pediatric intensive care unit

PubMed Central

Lebovitz, Daniel J; Smith, Paul G; O'Riordan, MaryAnn; Reed, Michael D

2004-01-01

Background: Asthmatic children requiring treatment in the pediatric intensive care unit (PICU) receive aggressive drug therapy that may include IV administration of β2-receptor agonists to prevent progression to life-threatening respiratory failure. The only pharmacologic agent in this class currently available for parenteral use in the United States is terbutaline. Study of IV dosing of terbutaline in the pediatric population has been limited. Objective: The aim of this study was to determine the pharmacokinetic (PK) properties and tolerability of single-dose terbutaline in pediatric patients across a broad age range who were admitted to the PICU and were receiving maximal conventional asthma drug therapy. Methods: This study was conducted at the PICU at Rainbow Babies and Children's Hospital (Cleveland, Ohio). Patients aged 6 months to 16 years with severe exacerbation of reactive airways disease and who were undergoing maximal conventional therapy and had an arterial catheter were enrolled. Patients were arbitrarily assigned to receive a single IV infusion of 1 of 3 doses of terbutaline (10, 20, or 30 μg/kg), infused over 5 minutes. Blood samples were obtained for the determination of plasma terbutaline concentrations just before terbutaline was administered (baseline), immediately on completion of the IV infusion, and at 10, 20, and 40 minutes and 1, 2, 4, 8, 16, 32, 48, and 72 hours after the 5-minute infusion. PK properties (elimination half-life [tl2], mean residence time [MRT], apparent steady-state volume of distribution [Vdss], and total body clearance [CI]) were determined and adverse effects were recorded. Results: The determination of terbutaline PK properties was possible in 50 of 56 enrolled patients (31 boys, 19 girls; mean [SD] age, 6.5 [4.5] years). The PK properties of terbutaline were linear over the dose range studied and, with the exception of the expected dose-dependent increases in peak terbutaline plasma concentration and area under the terbutaline plasma concentration-time curve, no statistically significant differences were observed in PK relative to dose. Therefore, we pooled the data for all subsequent analyses. Statistically significant correlations with patient age were observed with tl2 (r = 0.4, P < 0.006), MRT (r = 0.4, P < 0.002), and Vdss (r = 0.33, P < 0.02), but not C1 (r = −0.03, P = NS). Single-dose terbutaline administration was generally well tolerated. Conclusions: Single-dose IV terbutaline was well tolerated in this study. In maximally treated asthmatic patients in the PICU, terbutaline elimination may be more rapid than in nonacutely ill children. These PK data suggest that if the drug is to be administered intravenously, the continuous IV infusion method, including loading doses for any subsequent dose escalations, may be the most appropriate. The influence of age and safety of long-term, continuous terbutaline IV infusion requires further study. PMID:24936108

NASA Headquarters/Kennedy Space Center: Organization and Small Spacecraft Launch Services

NASA Technical Reports Server (NTRS)

Sierra, Albert; Beddel, Darren

1999-01-01

The objectives of the Kennedy Space Center's (KSC) Expendable Launch Vehicles (ELV) Program are to provide safe, reliable, cost effective ELV launches, maximize customer satisfaction, and perform advanced payload processing capability development. Details are given on the ELV program organization, products and services, foreign launch vehicle policy, how to get a NASA launch service, and some of the recent NASA payloads.

Minor oral surgery without stopping daily low-dose aspirin therapy: a study of 51 patients.

PubMed

Madan, Gautam A; Madan, Sonal G; Madan, Gauri; Madan, A D

2005-09-01

The risk of excessive bleeding prompts physicians to stop low-dose long-term aspirin regimens before surgery, which puts the patient at risk from adverse thrombotic events. We hypothesize that most minor oral surgical procedures can be carried out safely without stopping low-dose aspirin. All minor oral surgery patients at our hospital (Madan Dental Hospital, Ahmedabad, India) from May 2002 to May 2003, who were also on long-term low-dose aspirin therapy regimens (acetylsalicylic acid 75 mg to 100 mg/day), were included. Investigation of bleeding time and platelet count was performed. If within normal limits, aspirin was not stopped before surgery. Patients were operated under local anesthesia on an outpatient basis. All wounds were sutured and followed up at 24, 48, and 72 hours, 1 week, and 2 weeks after the procedure. The study included 51 patients (32 males, 19 females), ranging in age from 45 to 70 years. Preoperative values were within normal limits for all patients. Aspirin was not stopped for a single patient. There was no excessive intraoperative bleeding in all cases except 1; there was no postoperative bleeding in all cases. We conclude that most minor oral surgery procedures can be carried out safely without stopping long-term low-dose aspirin regimen.

Heart Rate Variability (HRV) modifications in adult hemiplegic patients after botulinum toxin type A (nt-201) injection.

PubMed

Invernizzi, M; Carda, S; Molinari, C; Stagno, D; Cisari, C; Baricich, A

2015-08-01

The most important adverse effect of BoNT-A is the systemic diffusion of the toxin. There is some evidence that the administration of high doses can increase the risk of systemic diffusion and the development of clinically evident adverse effects, however an international consensus does not exist about its maximum dose. The aim of this study was to evaluate changes in autonomic heart drive induced by high doses (higher than 600 units) of incobotulinumtoxinA injection in spastic stroke patients. Moreover, the treatment safety by monitoring adverse events occurrence was assessed. Case control study. Eleven stroke survivors with spastic hemiplegia. Patients were treated with intramuscular focal injections of IncobotulinumtoxinA (NT 201; Xeomin®, Merz Pharmaceuticals GmbH, Frankfurt, Germany). Doses were below 12 units/Kg. Each patient underwent an ECG recording before injection and 10 days after treatment. Linear and non-linear Heart Rate variability (HRV) measures were derived from ECGs with a dedicated software. None of the variable considered showed statistically significant changes after BoNT-A injection. The use of incobotulinumtoxinA in adult patients at doses up to 12 units/kg seems to be safe regarding autonomic heart drive. The use of IncobotulinumtoxinA up to 600 units could be a safe therapeutic option in spastic hemiplegic stroke survivors.

Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS

PubMed Central

Madigan, Nicolas N.; Morris, Jonathan; Jentoft, Mark; Sorenson, Eric J.; Butler, Greg; Gastineau, Dennis; Dietz, Allan; Windebank, Anthony J.

2016-01-01

Objective: To determine the safety of intrathecal autologous adipose-derived mesenchymal stromal cell treatment for amyotrophic lateral sclerosis (ALS). Methods: Participants with ALS were enrolled and treated in this phase I dose-escalation safety trial, ranging from 1 × 107 (single dose) to 1 × 108 cells (2 monthly doses). After intrathecal treatments, participants underwent standardized follow-up, which included clinical examinations, revised ALS Functional Rating Scale (ALSFRS-R) questionnaire, blood and CSF sampling, and MRI of the neuroaxis. Results: Twenty-seven patients with ALS were enrolled and treated in this study. The safety profile was positive, with the most common side effects reported being temporary low back and radicular leg pain at the highest dose level. These clinical findings were associated with elevated CSF protein and nucleated cells with MRI of thickened lumbosacral nerve roots. Autopsies from 4 treated patients did not show evidence of tumor formation. Longitudinal ALSFRS-R questionnaires confirmed continued progression of disease in all treated patients. Conclusions: Intrathecal treatment of autologous adipose-derived mesenchymal stromal cells appears safe at the tested doses in ALS. These results warrant further exploration of efficacy in phase II trials. Classification of evidence: This phase I study provides Class IV evidence that in patient with ALS, intrathecal autologous adipose-derived mesenchymal stromal cell therapy is safe. PMID:27784774

Risk Factors for Symptomatic Avascular Necrosis in Childhood-onset Systemic Lupus Erythematosus.

PubMed

Yang, Yelin; Kumar, Sathish; Lim, Lily Siok Hoon; Silverman, Earl D; Levy, Deborah M

2015-12-01

To examine the frequency and risk factors for symptomatic avascular necrosis (AVN) in childhood-onset systemic lupus erythematosus (cSLE). A single-center, nested, matched, case-control design was used. There were 617 patients with cSLE followed at the Hospital for Sick Children (SickKids) Lupus Clinic between July 1982 and June 2013 included in the study. The AVN cohort consisted of 37 patients identified with clinical findings of symptomatic AVN and diagnosis was confirmed by 1 or more imaging modalities. Three controls were matched to each patient with AVN by date and age at diagnosis. Baseline clinical, laboratory, and treatment characteristics were compared between patients with AVN and controls by univariable analyses and if statistically significant, were included in a multivariable logistic regression model. A total of 37/617 patients (6%) developed symptomatic AVN in 91 joints during followup at SickKids. The mean duration to disease was 2.3 years. The hip was the most commonly involved joint (26/37, 70%). Compared with the matched non-AVN cohort, patients with AVN had a higher incidence of central nervous system (CNS) involvement and nephritis, required greater cumulative prednisone (PRED) from cSLE diagnosis to AVN, received a greater maximal daily PRED dose, and had more frequent use of pulse methylprednisolone therapy. Multivariable regression analysis confirmed major organ involvement (CNS disease and/or nephritis) and maximal daily PRED dose as significant predictors of symptomatic AVN development. Patients with cSLE with severe organ involvement including nephritis and CNS disease and higher maximal daily dose of PRED are more likely to develop symptomatic AVN.

Plasma concentration of ketorolac after local infiltration analgesia in hip arthroplasty.

PubMed

Affas, F; Eksborg, S; Wretenberg, P; Olofsson, C; Stephanson, N; Stiller, C-O

2014-10-01

Local infiltration analgesia (LIA) with local anaesthetic (ropivacaine), a nonsteroidal anti-inflammatory drug (ketorolac) and epinephrine after lower extremity arthroplasty has gained increasing popularity during the last decade. This method has certain advantages, which include minimal systemic side effects, faster post-operative mobilization, earlier post-operative discharge from hospital and less opioid consumption. However, information regarding plasma concentrations of ketorolac after LIA mixture is insufficient to predict the risk of renal impairment in patients subjected to arthroplasty. To determine the maximal plasma concentration and the exposure of ketorolac during the first 30 h following LIA in hip arthroplasty. Thirteen patients scheduled for primary total hip arthroplasty with LIA (ropivacaine 200 mg, ketorolac 30 mg and epinephrine 0.5 mg in a volume of 106 ml) were included. Plasma concentration of ketorolac was quantified by liquid chromatography-mass spectrometry. In addition, we assessed the effect of increasing age and decreasing glomerular filtration rate on the maximal plasma concentration and the total exposure to ketorolac during 30 h. The range of the maximal plasma concentration, 0.3-2.2 mg/l, was detected 30 min-4 h after completing the infiltration. Similar plasma levels have been reported after intramuscular injection of the same dose of ketorolac to healthy elderly volunteers. Exposure to ketorolac after LIA may be comparable to an intramuscular injection of the same dose. Decision of dose reduction should be based on clinical assessment of risk factors. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Effect of Varient Dosages of Amphetamine Upon Endurance

ERIC Educational Resources Information Center

Williams, Melvin H.; Thompson, John

1973-01-01

This study sought to provide basic information concerning the acute effects of a small, moderate, and large dose of d-amphetamine sulfate upon muscular endurance; a secondary purpose involved the effect upon submaximal and maximal heart rate. (Author/JA)

Estimation of safe exposure time from an ophthalmic operating microscope with regard to ultraviolet radiation and blue-light hazards to the eye

NASA Astrophysics Data System (ADS)

Michael, Ralph; Wegener, Alfred

2004-08-01

Hazards from the optical radiation of an operating microscope that cause damage at the corneal, lenticular, and retinal levels were investigated; we considered, in particular, ultraviolet radiation (UVR) and blue light. The spectral irradiance from a Zeiss operation microscope OPMI VISU 200 was measured in the corneal plane between 300 and 1100 nm. Effective irradiance and radiance were calculated with relative spectral effectiveness data from the American Conference for Governmental and Industrial Hygienists. Safe exposure time to avoid UVR injury to the lens and cornea was found to be 2 h without a filter, 4 h with a UVR filter, 200 h with a yellow filter, and 400 h with a filter combination. Safe exposure time to avoid retinal photochemical injury was found to be 3 min without a filter and with a UVR filter, 10 min with a yellow filter, and 49 min with a filter combination. The effective radiance limit for retinal thermal injury was not exceeded. The hazard due to the UVR component from the operating microscope is not critical, and operation time can be safely prolonged with the use of appropriate filters. The retinal photochemical hazard appears critical without appropriate filters, permitting only some minutes of safe exposure time. The calculated safe exposure times are for worst-case conditions and maximal light output and include a safety factor.

Estimation of safe exposure time from an ophthalmic operating microscope with regard to ultraviolet radiation and blue-light hazards to the eye.

PubMed

Michael, Ralph; Wegener, Alfred

2004-08-01

Hazards from the optical radiation of an operating microscope that cause damage at the corneal, lenticular, and retinal levels were investigated; we considered, in particular, ultraviolet radiation (UVR) and blue light. The spectral irradiance from a Zeiss operation microscope OPMI VISU 200 was measured in the corneal plane between 300 and 1100 nm. Effective irradiance and radiance were calculated with relative spectral effectiveness data from the American Conference for Governmental and Industrial Hygienists. Safe exposure time to avoid UVR injury to the lens and cornea was found to be 2 h without a filter, 4 h with a UVR filter, 200 a yellow filter, and 400 h with a filter combination. Safe exposure time to avoid retinal photochemical injury was found to be 3 min without a filter and with a UVR filter, 10 min with a yellow filter, and 49 min with a filter combination. The effective radiance limit for retinal thermal injury was not exceeded. The hazard due to the UVR component from the operating microscope is not critical, and operation time can be safely prolonged with the use of appropriate filters. The retinal photochemical hazard appears critical without appropriate filters, permitting only some minutes of safe exposure time. The calculated safe exposure times are for worst-case conditions and maximal light output and include a safety factor.

Cross-contamination of foods and implications for food allergic patients.

PubMed

Taylor, Steve L; Baumert, Joseph L

2010-07-01

Cross-contamination presents a risk of unknown magnitude for food allergic consumers. Published cases likely represent the tip of a rather large iceberg. Cross-contamination can occur in homes, restaurants, food manufacturing plants, and on farms. The frequency of cross-contamination as the cause of accidental exposures to allergenic foods is unknown. Food allergic individuals can react to ingestion of trace levels of the offending food, although a highly variable range of threshold doses exist among populations of food allergic individuals. The magnitude of the risk posed to food allergic consumers by cross-contamination is characterized by the frequency of exposure to cross-contaminated foods, the dose of exposure, and the individual's threshold dose. The food and food service industry (and food preparers in homes as well) have the responsibility to provide and prepare foods that are safe for food allergic consumers, but quality of life may be improved with the recognition that safe (though very low) thresholds do exist.

Consumption of açai (Euterpe oleracea Mart.) functional beverage reduces muscle stress and improves effort tolerance in elite athletes: a randomized controlled intervention study.

PubMed

Carvalho-Peixoto, Jacqueline; Moura, Mirian Ribeiro Leite; Cunha, Felipe Amorim; Lollo, Pablo Christiano B; Monteiro, Walace David; Carvalho, Lucia Maria Jaeger de; Farinatti, Paulo de Tarso Veras

2015-07-01

The study analyzed the effect of an açai (Euterpe oleracea Mart.) functional beverage (AB) on muscle and oxidative stress markers, cardiorespiratory responses, perceived exertion, and time-to-exhaustion during maximal treadmill running. The beverage was developed as an ergogenic aid for athletes and contained 27.6 mg of anthocyanins per dose. Fourteen athletes performed 3 exercise tests: a ramp-incremental maximal exercise test and 2 maximal exercise bouts performed in 2 conditions (AB and without AB (control)) at 90% maximal oxygen uptake. Blood was collected at baseline and after maximal exercise in both conditions to determine biomarkers. AB increased time to exhaustion during short-term high-intensity exercise (mean difference: 69 s, 95% confidence interval = -296 s to 159 s, t = 2.2, p = 0.045), attenuating the metabolic stress induced by exercise (p < 0.05). AB also reduced perceived exertion and enhanced cardiorespiratory responses (p < 0.05). The AB may be a useful and practical ergogenic aid to enhance performance during high-intensity training.

Physics considerations in MV-CBCT multi-layer imager design.

PubMed

Hu, Yue-Houng; Fueglistaller, Rony; Myronakis, Marios E; Rottmann, Joerg; Wang, Adam; Shedlock, Daniel; Morf, Daniel; Baturin, Paul; Huber, Pascal; Star-Lack, Josh M; Berbeco, Ross I

2018-05-30

Megavoltage (MV) cone-beam computed tomography (CBCT) using an electronic portal imaging (EPID) offers advantageous features, including 3D mapping, treatment beam registration, high-z artifact suppression, and direct radiation dose calculation. Adoption has been slowed by image quality limitations and concerns about imaging dose. Developments in imager design, including pixelated scintillators, structured phosphors, inexpensive scintillation materials, and multi-layer imager (MLI) architecture have been explored to improve EPID image quality and reduce imaging dose. The present study employs a hybrid Monte Carlo and linear systems model to determine the effect of detector design elements, such as multi-layer architecture and scintillation materials. We follow metrics of image quality including modulation transfer function (MTF) and noise power spectrum (NPS) from projection images to 3D reconstructions to in-plane slices and apply a task based figure-of-merit, the ideal observer signal-to-noise ratio (d') to determine the effect of detector design on object detectability. Generally, detectability was limited by detector noise performance. Deploying an MLI imager with a single scintillation material for all layers yields improvement in noise performance and d' linear with the number of layers. In general, improving x-ray absorption using thicker scintillators results in improved DQE(0). However, if light yield is low, performance will be affected by electronic noise at relatively high doses, resulting in rapid image quality degradation. Maximizing image quality in a heterogenous MLI detector (i.e. multiple different scintillation materials) is most affected by limiting imager noise. However, while a second-order effect, maximizing total spatial resolution of the MLI detector is a balance between the intensity contribution of each layer against its individual MTF. So, while a thinner scintillator may yield a maximal individual-layer MTF, its quantum efficiency will be relatively low in comparison to a thicker scintillator and thus, intensity contribution may be insufficient to noticeably improve the total detector MTF. © 2018 Institute of Physics and Engineering in Medicine.

High doses of anti-inflammatory drugs compromise muscle strength and hypertrophic adaptations to resistance training in young adults.

PubMed

Lilja, M; Mandić, M; Apró, W; Melin, M; Olsson, K; Rosenborg, S; Gustafsson, T; Lundberg, T R

2018-02-01

This study tested the hypothesis that high doses of anti-inflammatory drugs would attenuate the adaptive response to resistance training compared with low doses. Healthy men and women (aged 18-35 years) were randomly assigned to daily consumption of ibuprofen (IBU; 1200 mg; n = 15) or acetylsalicylic acid (ASA; 75 mg; n = 16) for 8 weeks. During this period, subjects completed supervised knee-extensor resistance training where one leg was subjected to training with maximal volitional effort in each repetition using a flywheel ergometer (FW), while the other leg performed conventional (work-matched across groups) weight-stack training (WS). Before and after training, muscle volume (MRI) and strength were assessed, and muscle biopsies were analysed for gene and protein expression of muscle growth regulators. The increase in m. quadriceps volume was similar between FW and WS, yet was (averaged across legs) greater in ASA (7.5%) compared with IBU (3.7%, group difference 34 cm 3 ; P = 0.029). In the WS leg, muscle strength improved similarly (11-20%) across groups. In the FW leg, increases (10-23%) in muscle strength were evident in both groups yet they were generally greater (interaction effects P < 0.05) for ASA compared with IBU. While our molecular analysis revealed several training effects, the only group interaction (P < 0.0001) arose from a downregulated mRNA expression of IL-6 in IBU. Maximal over-the-counter doses of ibuprofen attenuate strength and muscle hypertrophic adaptations to 8 weeks of resistance training in young adults. Thus, young individuals using resistance training to maximize muscle growth or strength should avoid excessive intake of anti-inflammatory drugs. © 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin and cyclophosphamide as adjuvant chemotherapy for early breast cancer.

PubMed

Abe, Hajime; Mori, Tsuyoshi; Kawai, Yuki; Cho, Hirotomi; Kubota, Yoshihiro; Umeda, Tomoko; Kurumi, Yoshimasa; Tani, Tohru

2013-06-01

The tolerance and safety associated with the administration order of the anthracycline and taxane drugs have not been evaluated. Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The feasibility and toxicity were evaluated in the following regimens--arm A, 3 courses of fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2) and cyclophosphamide 500 mg/m(2) (FEC) followed by 3 courses of docetaxel 100 mg/m(2) (DOC); arm B, 3 courses of DOC followed by 3 courses of FEC. Forty-two patients were registered. The relative dose intensity was 94.2 % for FEC and 97.8 % for DOC in arm A, and 98.9 % for DOC and 95.2 % for FEC in arm B. In arm A, grade 3 or higher hematological toxicity was observed in nine patients, and febrile neutropenia developed in three patients with FEC. In arm B, grade 3 or higher hematological toxicity was observed in seven patients, but febrile neutropenia was not noted in any patient. The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early breast cancer. However, DOC followed by FEC might be more tolerable. Further studies will maximize the results obtained with DOC followed by FEC.

Ion-Responsive Drug Delivery Systems.

PubMed

Yoshida, Takayuki; Shakushiro, Kohsuke; Sako, Kazuhiro

2018-02-08

Some kinds of cations and anions are contained in body fluids such as blood, interstitial fluid, gastrointestinal juice, and tears at relatively high concentration. Ionresponsive drug delivery is available to design the unique dosage formulations which provide optimized drug therapy with effective, safe and convenient dosing of drugs. The objective of the present review was to collect, summarize, and categorize recent research findings on ion-responsive drug delivery systems. Ions in body fluid/formulations caused structural changes of polymers/molecules contained in the formulations, allow formulations exhibit functions. The polymers/molecules responding to ions were ion-exchange resins/fibers, anionic or cationic polymers, polymers exhibiting transition at lower critical solution temperature, self-assemble supramolecular systems, peptides, and metalorganic frameworks. The functions of ion-responsive drug delivery systems were categorized to controlled drug release, site-specific drug release, in situ gelation, prolonged retention at the target sites, and enhancement of drug permeation. Administration of the formulations via oral, ophthalmic, transdermal, and nasal routes has showed significant advantages in the recent literatures. Many kinds of drug delivery systems responding to ions have been reported recently for several administration routes. Improvement and advancement of these systems can maximize drugs potential and contribute to patients in the world. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design of spray dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose.

PubMed

Ung, Keith T; Rao, Nagaraja; Weers, Jeffry G; Huang, Daniel; Chan, Hak-Kim

2016-09-25

Inhaled drugs all too often deliver only a fraction of the emitted dose to the target lung site due to deposition in the extrathoracic region (i.e., mouth and throat), which can lead to increased variation in lung exposure, and in some instances increases in local and systemic side effects. For aerosol medications, improved targeting to the lungs may be achieved by tailoring the micromeritic properties of the particles (e.g., size, density, rugosity) to minimize deposition in the mouth-throat and maximize the total lung dose. This study evaluated a co-solvent spray drying approach to modulate particle morphology and dose delivery characteristics of engineered powder formulations of insulin microparticles. The binary co-solvent system studied included water as the primary solvent mixed with an organic co-solvent, e.g., ethanol. Factors such as the relative rate of evaporation of each component of a binary co-solvent mixture, and insulin solubility in each component were considered in selecting feedstock compositions. A water-ethanol co-solvent mixture with a composition range considered suitable for modulating particle shell formation during drying was selected for experimental investigation. An Alberta Idealized Throat model was used to evaluate the in vitro total lung dose of a series of spray dried insulin formulations engineered with different bulk powder properties and delivered with two prototype inhalers that fluidize and disperse powder using different principles. The in vitro total lung dose of insulin microparticles was improved and favored for powders with low bulk density and small primary particle size, with reduction of deposition in the extrathoracic region. The results demonstrated that a total lung dose >95% of the delivered dose can be achieved with engineered particles, indicating a high degree of lung targeting, almost completely bypassing deposition in the mouth-throat. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

Pressurised metered dose inhaler-spacer technique in young children improves with video instruction.

PubMed

Shaw, Nicole; Le Souëf, Peter; Turkovic, Lidija; McCahon, Lucy; Kicic, Anthony; Sly, Peter D; Devadason, Sunalene; Schultz, André

2016-07-01

The importance of good device technique to maximise delivery of aerosolised medications is widely recognised. Pressurised metered dose inhaler (pMDI)-spacer technique was investigated in 122 children, aged 2-7 years, with asthma. Eight individual steps of device technique were evaluated before and after viewing an instructional video for correct device technique. Video measurements were repeated every three months for nine months. Device technique improved directly after video instruction at the baseline study visit (p < 0.001) but had no immediate effect at subsequent visits. Additionally, pMDI-spacer technique improved with successive visits over one year for the group overall as evidenced by increases in the proportion of children scoring maximal (p = 0.02) and near-maximal (p = 0.04) scores. Repeated video instruction over time improves inhaler technique in young children. • Correct device technique is considered essential for sufficient delivery of inhaled medication. • Poor inhaler use is common in young asthmatic children using pressurised metered dose inhalers and spacers. What is New: • Video instruction could be used as a strategy to improve device technique in young children.

Estimating Likelihood of Fetal In Vivo Interactions Using In ...

EPA Pesticide Factsheets

Tox21/ToxCast efforts provide in vitro concentration-response data for thousands of compounds. Predicting whether chemical-biological interactions observed in vitro will occur in vivo is challenging. We hypothesize that using a modified model from the FDA guidance for drug interaction studies, Cmax/AC50 (i.e., maximal in vivo blood concentration over the half-maximal in in vitro activity concentration), will give a useful approximation for concentrations where in vivo interactions are likely. Further, for doses where maternal blood concentrations are likely to elicit an interaction (Cmax/AC50>0.1), where do the compounds accumulate in fetal tissues? In order to estimate these doses based on Tox21 data, in silico parameters of chemical fraction unbound in plasma and intrinsic hepatic clearance were estimated from ADMET predictor (Simulations-Plus Inc.) and used in the HTTK R-package to obtain Cmax values from a physiologically-based toxicokinetics model. In silico estimated Cmax values predicted in vivo human Cmax with median absolute error of 0.81 for 93 chemicals, giving confidence in the R-package and in silico estimates. A case example evaluating Cmax/AC50 values for peroxisome proliferator-activated receptor gamma (PPARγ) and glucocorticoid receptor revealed known compounds (glitazones and corticosteroids, respectively) highest on the list at pharmacological doses. Doses required to elicit likely interactions across all Tox21/ToxCast assays were compared to

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy.

PubMed

Estepp, Jeremie H; Smeltzer, Matthew P; Kang, Guolian; Li, Chen; Wang, Winfred C; Abrams, Christina; Aygun, Banu; Ware, Russell E; Nottage, Kerri; Hankins, Jane S

2017-12-01

Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P < .0001), including vaso-occlusive pain (P < .01) and acute chest syndrome (ACS) (P < .01), and more than four times the odds of admission for fever (P < .001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1000 × 10 6 /L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%. © 2017 Wiley Periodicals, Inc.

Maximizing dermal targeting and minimizing transdermal penetration by magnolol/honokiol methoxylation.

PubMed

Lin, Chwan-Fwu; Hwang, Tsong-Long; Al-Suwayeh, Saleh A; Huang, Yu-Ling; Hung, Yi-Yun; Fang, Jia-You

2013-03-10

Magnolol and honokiol, predominant active compounds in the family Magnoliaceae, are known to exhibit strong anti-inflammatory activities against dermal disorders. We attempted to modify the structures of magnolol and honokiol by methoxylation to optimize the skin delivery ability. Absorption of these permeants into and through the skin was performed at both an infinite dose and saturated solubility. Superoxide anion and elastase released from human neutrophils were the biomarkers used to examine anti-inflammatory potencies of these permeants. The safety of the permeants was evaluated by keratinocyte viability and in vivo bioengineering techniques. Topical magnolol and honokiol at an infinite dose (7.5 mM) showed skin accumulations of 0.22 and 0.16 nmol/mg, respectively. Methoxylation significantly enhanced their skin absorption. Deposition amounts of dimethylmagnolol and dimethylhonokiol were respectively 15- and 7-fold greater than those of magnolol and honokiol. Contrary to the skin accumulation results, the transdermal penetration across skin decreased following methoxylation. No transdermal delivery occurred for dimethylhonokiol. Skin uptake of 4'-O-methylhonokiol was 2-fold higher than that of 2-O-methylhonokiol, although they are isomers. Methoxylated permeants demonstrated selective absorption into follicles, which showed 3-5-fold higher follicular amounts compared to magnolol and honokiol. The relative order of anti-inflammatory activities was honokiol>2-O-methylmagnolol>dimethylhonokiol>magnolol. The other compounds exhibited negligible or negative responses in activated neutrophils. Magnolol and honokiol induced slight but significant keratinocyte cytotoxicity and stratum corneum disruption. Daily administration of methoxylated permeants, especially dimethylhonokiol, produced no skin irritation for up to 7 days. Methoxylated magnolol and honokiol can be efficient and safe candidates for treating inflammatory skin disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users

PubMed Central

Marks, Katherine R.; Lile, Joshua A.; Stoops, William W.

2014-01-01

Rationale Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. Objectives The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone. Methods Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Results Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. Conclusions The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration. PMID:24464531

Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users.

PubMed

Marks, Katherine R; Lile, Joshua A; Stoops, William W; Rush, Craig R

2014-07-01

Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone. Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration.

Long-Term Outcomes of Stereotactic Radiosurgery for Treatment of Cavernous Sinus Meningiomas

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

Santos, Marcos Antonio dos, E-mail: marcosrxt@gmail.com; Bustos Perez de Salcedo, Jose; Gutierrez Diaz, Jose Angel

2011-12-01

Purpose: Patients with cavernous sinus meningiomas (CSM) have an elevated risk of surgical morbidity and mortality. Recurrence is often observed after partial resection. Stereotactic radiosurgery (SRS), either alone or combined with surgery, represents an important advance in CSM management, but long-term results are lacking. Methods and Materials: A total of 88 CSM patients, treated from January 1991 to December 2005, were retrospectively reviewed. The mean follow-up was 86.8 months (range, 17.1-179.4 months). Among the patients, 22 were followed for more than 10 years. There was a female predominance (84.1%). The age varied from 16 to 90 years (mean, 51.6). Inmore » all, 47 patients (53.4%) received SRS alone, and 41 patients (46.6%) had undergone surgery before SRS. A dose of 14 Gy was prescribed to isodose curves from 50% to 90%. In 25 patients (28.4%), as a result of the proximity to organs at risk, the prescribed dose did not completely cover the target. Results: After SRS, 65 (73.8%) patients presented with tumor volume reduction; 14 (15.9%) remained stable, and 9 (10.2%) had tumor progression. The progression-free survival was 92.5% at 5 years, and 82.5% at 10 years. Age, sex, maximal diameter of the treated tumor, previous surgery, and complete target coverage did not show significant associations with prognosis. Among the 88 treated patients, 17 experienced morbidity that was related to SRS, and 6 of these patients spontaneously recovered. Conclusions: SRS is an effective and safe treatment for CSM, feasible either in the primary or the postsurgical setting. Incomplete coverage of the target did not worsen outcomes. More than 80% of the patients remained free of disease progression during long-term follow-up.« less

Exploring Boron Neutron Capture Therapy for non-small cell lung cancer.

PubMed

Farías, Rubén O; Bortolussi, Silva; Menéndez, Pablo R; González, Sara J

2014-12-01

Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with (10)B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells. The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced. Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments. The optimal neutron energy is within [500 eV-3 keV], lower than the 10 keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases. Conclusions drawn from [Suzuki et al., Int Canc Conf J 1 (4) (2012) 235-238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options. Copyright © 2014 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Is Tamsulosin 0.2 mg Effective and Safe as a First-Line Treatment Compared with Other Alpha Blockers?: A Meta-Analysis and a Moderator Focused Study

PubMed Central

Shim, Sung Ryul; Chang, In Ho; Shin, In Soo; Hwang, Sung Dong; Kim, Khae Hwan; Yoon, Sang Jin; Song, Yun Seob

2016-01-01

Purpose Tamsulosin 0.2 mg is used widely in Asian people, but the low dose has been studied less than tamsulosin 0.4 mg or other alpha blockers of standard dose. This study investigated the efficacy and safety of tamsulosin 0.2 mg by a meta-analysis and meta-regression. Materials and Methods We conducted a meta-analysis of efficacy of tamsulosin 0.2 mg using International Prostate Symptom Score (IPSS), maximal urinary flow rate (Qmax), post-voided residual volume (PVR), and quality of life (QoL). Safety was analyzed using adverse events. Relevant studies were searched using MEDLINE, EMBASE, and Cochrane library from January 1980 to June 2013. Results Ten studies were included with a total sample size of 1418 subjects [722 tamsulosin 0.2 mg group and 696 other alpha-blockers (terazosin, doxazosin, naftopidil, silodosin) group]. Study duration ranged from 4 to 24 weeks. The pooled overall standardized mean differences (SMD) in the mean change of IPSS from baseline for the tamsulosin group versus the control group was 0.02 [95% confidence interval (CI); -0.20, 0.25]. The pooled overall SMD in the mean change of QoL from baseline for the tamsulosin group versus the control group was 0.16 (95% CI; -0.16, 0.48). The regression analysis with the continuous variables (number of patients, study duration) revealed no significance in all outcomes as IPSS, QoL, and Qmax. Conclusion This study clarifies that tamsulosin 0.2 mg has similar efficacy and fewer adverse events compared with other alpha-blockers as an initial treatment strategy for men with lower urinary tract symptoms. PMID:26847294

Respiratory muscle impairment in dialysis patients: can minimal dose of exercise limit the damage? A Preliminary study in a sample of patients enrolled in the EXCITE trial.

PubMed

Pomidori, Luca; Lamberti, Nicola; Malagoni, Anna Maria; Manfredini, Fabio; Pozzato, Enrico; Felisatti, Michele; Catizone, Luigi; Barillà, Antonio; Zuccalà, Alessandro; Tripepi, Giovanni; Mallamaci, Francesca; Zoccali, Carmine; Cogo, Annalisa

2016-12-01

Skeletal muscle atrophy and dysfunction with associated weakness may involve the respiratory muscles of dialysis patients. We evaluated the effect of moderate-intensity exercise on lung function and respiratory muscle strength. Fifty-nine patients (25 F, aged 65 ± 13 years) from two centers participating in the multicenter randomized clinical trial EXerCise Introduction To Enhance Performance in Dialysis (EXCITE) were studied. Subjects were randomized into a prescribed exercise group (E), wherein subjects performed two 10-min walking sessions every second day at an intensity below the self-selected speed, or a control group (C) with usual care. Physical performance was assessed by the 6-min walk test (6MWT). Patient lung function and respiratory muscle strength were evaluated by spirometry and maximal inspiratory pressure (MIP), respectively. Forty-two patients (14 F) completed the study. At baseline, the groups did not differ in any parameters. In total, 7 patients (4 in E; 3 in C) showed an obstructive pattern. The pulmonary function parameters were significantly correlated with 6MWT but not with any biochemical measurements. Group E safely performed the exercise program. At follow-up, the spirometry parameters did not change in either group. A deterioration of MIP (-7 %; p = 0.008) was observed in group C, but not in group E (+3.3 %, p = ns). In E, an increase of 6MWT was also found (+12 vs. 0 % in C; p = 0.038). In dialysis patients, a minimal dose of structured exercise improved physical capacity and maintained a stable respiratory muscle function, in contrast to the control group where it worsened.

INITIAL SYMPTOMATIC PITUITARY METASTASIS IN A PATIENT WITH PROSTATE FOAMY GLAND CARCINOMA: TAILORING SAFE AND EFFECTIVE THERAPY.

PubMed

Prpić, Marin; Fröbe, Ana; Zadravec, Dijana; Pažanin, Leo; Jakšić, Blanka; Bolanča, Ante; Kusić, Zvonko

2015-06-01

Metastases to pituitary gland are unusual and mostly asymptomatic, presenting with local symptoms in one of ten patients, and only 3%-5% of them are of prostate origin. Here we report and evaluate the effectiveness and safety of multimodal treatment in a patient with pituitary metastasis of a prostate foamy gland carcinoma. A 78-year-old male patient presented with blurred vision and headache without a previous history of malignancy. Magnetic resonance imaging scans revealed a large sellar mass, with infiltration of the surrounding structures. Maximal transsphenoidal reduction of pituitary metastasis was performed, with a histologic finding of metastatic prostate foamy gland adenocarcinoma. Evaluation of the prostate specific antigen revealed a very high level (1461 ng/mL) and foamy gland carcinoma was found on prostate needle biopsy. The patient received 3D conformal external beam radiotherapy with 6 MV photons to the sellar and parasellar region with a tumor dose of 44 Gy, followed by androgen deprivation therapy. Follow up magnetic resonance imaging done after radiotherapy showed shrinkage of the tumor process, with rapid prostate specific antigen decline to 0.3 ng/mL. The visual function was fully established and headache resolved. On the last follow up 14 months after the diagnosis, the patient was alive and free from clinical signs of disease. Tailored treatment, including limited radiotherapy in a higher palliative dose, in a patient with foamy gland symptomatic pituitary metastatic disease resulted in good local and systemic control of the disease. In older male patients with clinical and/or radiologic characteristics suggestive of metastatic pituitary disease, the prostate specific antigen test should be included as part of the work-up.

Preclinical profiling of the immunogenicity of a two-component subunit malaria vaccine candidate based on virosome technology.

PubMed

Okitsu, Shinji L; Mueller, Markus S; Amacker, Mario; Vogel, Denise; Westerfeld, Nicole; Robinson, John A; Zurbriggen, Rinaldo; Pluschke, Gerd

2008-01-01

Presentation of synthetic peptides on immunopotentiating reconstituted influenza virosomes is a promising technology for subunit vaccine development. An optimized virosomally delivered peptide representing 5 NPNA repeats of P. falciparum circumsporozoite protein is highly immunogenic in mice. Antibodies against this peptide (UK-39) inhibit sporozoite invasion of human hepatocytes. A second peptide (AMA49-C1) based on domain III of apical membrane antigen 1, induces antibodies that inhibit blood-stage parasite growth in vitro. Here we show a detailed pre-clinical profiling of these virosomally formulated peptides alone and in combination in mice and rabbits. Two immunizations with virosomally formulated UK-39 or AMA49-C1 were enough to elicit high titers of parasite cross-reactive antibodies in both species. A low dose of 10 microg UK-39 was enough to induce maximal titers in rabbits. Higher doses of peptide did not increase antibody titers. In contrast, AMA49-C1 induced higher antibody titers with 25 and 50 microg peptide. Combination of UK-39 and AMA49- C1 on separate virosomes did not have any negative effect on anti-peptide antibody titers in mice or rabbits. No MHC restriction was observed in the development of humoral responses in outbred rabbits with different immunogenetic backgrounds. All vaccine formulations were safe in toxicity studies in rabbits and rats. Taken together, low amounts of synthetic peptides delivered on virosomes induced high antibody titers in mice and rabbits. Moreover, different peptides could be combined without interfering with individual anti-peptide responses, augmenting the value of this system for the development of a multivalent malaria vaccine.

Introduction: the goals of antimicrobial therapy.

PubMed

Song, Jae-Hoon

2003-03-01

Antimicrobial agents are generally evaluated in preclinical studies assessing in vitro activity, animal models demonstrating in vivo bacteriologic efficacy, and clinical trials primarily investigating safety and clinical efficacy. However, large sample sizes are required to detect any differences in outcomes between antimicrobials in clinical trials, and, generally, studies are powered to show only clinical equivalence. In addition, diagnosis is often based on clinical symptoms, rather than microbiological evidence of bacterial infection, and the patients most likely to have resistant pathogens are often excluded. Clinical efficacy can be achieved in some bacterial infections in which antimicrobials are suboptimal or even not prescribed. However, bacterial eradication maximizes clinical efficacy and may also reduce the development and spread of resistant organisms. The goal of antimicrobial therapy is, therefore, to eradicate bacteria at the site of infection. Bacterial eradication is not usually assessed as a primary endpoint within the limits of currently recommended clinical trial design. However, pharmacokinetic (PK) (serum concentration profiles, penetration to site of infection) and pharmacodynamic (PD) (susceptibility, concentration- versus time-dependent killing, post-antimicrobial effects) criteria can be used to predict bacteriologic efficacy. PK/PD predictions should be confirmed during all phases of antimicrobial development and throughout clinical use in response to changing patterns of resistance. A clear rationale for dose recommendations can be determined preclinically based on PK/PD parameters, and correlated with efficacy, safety and resistance endpoints in clinical trials. The duration of treatment and dose should be the shortest that will reliably eradicate the pathogen(s), and that is safe and well tolerated. Currently available agents vary significantly in their ability to achieve PK/PD parameters necessary for bacteriologic eradication. Recommendations for appropriate antimicrobial therapy should be based on PK/PD parameters, with the aim of achieving the maximum potential for eradication of both existing and emerging resistant pathogens.

Continuous, low-dose oral exposure to sodium chlorate reduces fecal Enterobacteriaceae coliforms in sheep feces without inducing subclinical chlorate toxicosis

USDA-ARS?s Scientific Manuscript database

Our objectives were to determine a minimal daily dose of sodium chlorate, to be included in the drinking water for 5 days, that is safe yet maintains efficacy in reducing fecal shedding of Escherichia coli in mature ewes. In a complete randomized experimental design, 25 Targhee ewes (age = 18- to 20...

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents.

PubMed

Albuquerque, Edson X; Pereira, Edna F R; Aracava, Yasco; Fawcett, William P; Oliveira, Maristela; Randall, William R; Hamilton, Tracey A; Kan, Robert K; Romano, James A; Adler, Michael

2006-08-29

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

PubMed Central

Albuquerque, Edson X.; Pereira, Edna F. R.; Aracava, Yasco; Fawcett, William P.; Oliveira, Maristela; Randall, William R.; Hamilton, Tracey A.; Kan, Robert K.; Romano, James A.; Adler, Michael

2006-01-01

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer’s disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning. PMID:16914529

Assessment of Safety Margin of an Antipsychotic Drug Haloperidol for Torsade de Pointes Using the Chronic Atrioventricular Block Dogs.

PubMed

Izumi-Nakaseko, Hiroko; Nakamura, Yuji; Cao, Xin; Wada, Takeshi; Ando, Kentaro; Sugiyama, Atsushi

2017-07-01

Since an antipsychotic drug haloperidol has been clinically reported to induce QT interval prolongation and torsade de pointes, in this study its risk stratification for the onset of torsade de pointes was performed by using the chronic atrioventricular block canine model with a Holter electrocardiogram. Haloperidol in a dose of 3 mg kg -1 p.o. prolonged the QT interval, but it did not induce torsade de pointes during the observation period of 21 h (n = 4), indicating that the dose would be safe. Meanwhile, haloperidol in a dose of 30 mg kg -1 p.o. significantly increased the short-term variability in beat-to-beat analysis of QT interval (n = 4), and it induced torsade de pointes in 4 animals out of 4, showing that the dose could be torsadogenic. Since 3 mg kg -1 p.o. of haloperidol in this study can be estimated to provide about 8 times higher plasma concentrations than its therapeutic level, haloperidol may be used safely for most of the patients, as long as its plasma drug concentration is kept within the therapeutic range.

Angiotensin converting enzyme inhibitors potentiate the bronchoconstriction induced by substance P in the guinea-pig.

PubMed Central

Subissi, A.; Guelfi, M.; Criscuoli, M.

1990-01-01

1. The effects of intravenous captopril and enalaprilic acid on the increase in pulmonary inflation pressure induced by different bronchoconstrictor agents were evaluated in the anaesthetized guinea-pig. 2. Captopril and enalaprilic acid (1.6-200 micrograms kg-1) enhanced dose-dependently the bronchoconstriction (BC) induced by substance P. The threshold effective dose was 1.6 micrograms kg-1 and maximal potentiation over the control response was more than 400% for both agents. Enalaprilic acid was also assayed for serum and lung angiotensin converting enzyme (ACE) inhibition in anaesthetized guinea-pigs. This drug produced a dose-dependent inhibition of ACE in both tissues, with ED50 s of 7.6 and 9.4 micrograms kg-1, respectively: this inhibitory activity was positively correlated to substance P potentiation. 3. Captopril (8-1000 micrograms kg-1) enhanced dose-dependently the BC induced by capsaicin. The threshold effective dose was 40 micrograms kg-1 and maximal potentiation about 90%. 4. Captopril (200-1000 micrograms kg-1) did not affect BC induced by bradykinin. However, this response was markedly enhanced (about 200%) by captopril 200 micrograms kg-1 in propranolol-pretreated animals. 5. Captopril and enalaprilic acid (200-1000 micrograms kg-1) slightly (20-40%) but significantly enhanced the BC induced by 5-hydroxytryptamine. However, this response was potentiated to the same extent by a dose of prazosin, which produced a degree of hypotension similar to that observed after administration of the ACE inhibitors. 6. In conclusion, ACE inhibitors potentiate the BC induced by substance P and, to a minor extent, that induced by capsaicin in the anaesthetized guinea-pig.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1697196

Radiosurgery for Para-IAC Meningiomas: The Effect of Radiation Dose to the Cochlea on Hearing Outcome

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

Kim, Young-Hoon; Department of Neurosurgery, Seoul National University College of Medicine, Seoul; Kim, Dong Gyu, E-mail: gknife@plaza.snu.ac.kr

2012-11-01

Purpose: This study was performed to assess the radiosurgical results of meningiomas extending into the internal acoustic canal (para-IAC meningiomas), with a particular focus on the effect of radiation dose to the cochlea on hearing outcome. Methods and Materials: A total of 50 patients who underwent radiosurgery for para-IAC meningiomas between 1998 and 2009, which were followed for 2 years, were enrolled. The mean age was 55.8 years (range, 15-75). The mean tumor volume was 6.1 cm{sup 3} (range, 1.0-19.0), the mean tumor length in the IAC was 6.9 mm (range, 1.3-13.3), and the mean prescribed marginal dose was 13.1more » Gy (range, 10-15) at an isodose line of 50%. The mean follow-up duration was 46 months (range, 24-122). Results: Eight (16.0%) patients had nonserviceable hearing at the time of surgery. At the last follow-up, the tumor control rate was 94%; unchanged in 17 patients, decreased in 30 patients, and increased in 3 patients. Among 42 patients with serviceable hearing at the time of radiosurgery, it was preserved in 41 (97.6%) patients at the last follow-up. The maximal and mean radiation doses to the cochleae of these 41 patients were 5.8 Gy {+-} 0.3 (range, 3.1-11.5) and 4.3 Gy {+-} 0.2 (range, 2.2-7.5), respectively. The maximal dose to the cochlea of the patient who lost hearing after radiosurgery was 4.7 Gy. Conclusions: The radiation dose to the cochlea may have the minimal toxic effect on the hearing outcome in patients who undergo radiosurgery for para-IAC meningiomas.« less

Silicon Schottky Diode Safe Operating Area

NASA Technical Reports Server (NTRS)

Casey, Megan C.; Campola, Michael J.; Lauenstein, Jean-Marie; Wilcox, Edward P.; Phan, Anthony M.; LaBel, Kenneth A.

2016-01-01

Vulnerability of a variety of candidate spacecraft electronics to total ionizing dose and displacement damage is studied. Devices tested include optoelectronics, digital, analog, linear bipolar devices, and hybrid devices.

Papaya

MedlinePlus

... has been fermented can lower blood sugar. In theory, this form of papaya might affect blood sugary ... appropriate range of doses for papaya. Keep in mind that natural products are not always necessarily safe ...

Sodium phenylbutyrate in Huntington's disease: a dose-finding study.

PubMed

Hogarth, Penelope; Lovrecic, Luca; Krainc, Dimitri

2007-10-15

Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de-escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose-response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well-tolerated in human HD. 2007 Movement Disorder Society

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

Lee, E; Yuan, F; Templeton, A

Purpose: The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor-control-probability(TCP) with an acceptable normal-tissue-complication probability(NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. We design treatment plans that optimize TCP directly and contrast them with the clinical dose-based plans. PET image is incorporated to evaluate gain in TCP for dose escalation. Methods: We build a nonlinear mixed integer programming optimization model that maximizes TCP directly while satisfying the dose requirements on themore » targeted organ and healthy tissues. The solution strategy first fits the TCP function with a piecewise-linear approximation, then solves the problem that maximizes the piecewise linear approximation of TCP, and finally performs a local neighborhood search to improve the TCP value. To gauge the feasibility, characteristics, and potential benefit of PET-image guided dose escalation, initial validation consists of fifteen cervical cancer HDR patient cases. These patients have all received prior 45Gy of external radiation dose. For both escalated strategies, we consider 35Gy PTV-dose, and two variations (37Gy-boost to BTV vs 40Gy-boost) to PET-image-pockets. Results: TCP for standard clinical plans range from 59.4% - 63.6%. TCP for dose-based PET-guided escalated-dose-plan ranges from 63.8%–98.6% for all patients; whereas TCP-optimized plans achieves over 91% for all patients. There is marginal difference in TCP among those with 37Gy-boosted vs 40Gy-boosted. There is no increase in rectum and bladder dose among all plans. Conclusion: Optimizing TCP directly results in highly conformed treatment plans. The TCP-optimized plan is individualized based on the biological PET-image of the patients. The TCP-optimization framework is generalizable and has been applied successfully to other external-beam delivery modalities. A clinical trial is on-going to gauge the clinical significance. Partially supported by the National Science Foundation.« less

Geosciences help to protect human health: estimation of the adsorbed radiation doses while flight journeys, as important step to radiation risk assessment

NASA Astrophysics Data System (ADS)

Chernov, Anatolii; Shabatura, Olexandr

2016-04-01

Estimation of the adsorbed radiation dose while flight journeys is a complex problem, which should be solved to get correct evaluation of equivalent effective doses and radiation risk assessment. Direct measurements of the adsorbed dose in the aircrafts during regional flights (3-10 hours) has shown that the radiation in the plane may increase 10-15 times (to 2-4 mSv/h) compared to the values on the surface of the Earth (0.2-0.5 mSv/h). Results of instrumental research confirmed by the other investigations. It is a fact that adsorbed doses per year while flight journeys are less than doses from medical tests. However, while flight journeys passengers get the same doses as nuclear power plant staff, people in zones of natural radiation anomalies and so should be evaluated. According to the authors' research, flight journeys are safe enough, when solar activity is normal and if we fly under altitude of 18 km (as usual, while intercontinental flights). Most of people travel by plane not so often, but if flight is lasting in dangerous periods of solar activity (powerful solar winds and magnetic field storms), passengers and flight crew can adsorb great amount of radiation doses. People, who spend more than 500 hours in flight journeys (pilots, business oriented persons', government representatives, etc.) get amount of radiation, which can negatively influence on health and provoke diseases, such as cancer. Authors consider that problem actual and researches are still going on. It is revealed, that radiation can be calculated, using special equations. Great part of radiation depends on very variable outer-space component and less variable solar. Accurate calculations of doses will be possible, when we will take into account all features of radiation distribution (time, season of year and exact time of the day, duration of flight), technical features of aircraft and logistics of flight (altitude, latitude). Results of first attempts of radiation doses modelling confirmed instrumental evaluation of doses, which passengers get while flight journeys. Further researches of radiation doses while flight journeys are going on. That example of researches shows that geoscience and social interests and problems are closely connected. Human society could not develop properly and safely without cooperation with geological science. As we see, geophysical methods can be used to count variations of natural radiation in spatial and time dimensions, which influence on level of radiation in aircrafts. As a result of such researches important conclusions to reduce radiation risks and collective doses of adsorbed radiation can be done. Geophysicists work hard on solving different problems of monitoring and analysis of natural surroundings to protect humanity and create safe, well-organized living surroundings. Key words: Solar radiation, flight journeys, dose of adsorbed radiation.

Dose Effect of Rhenium (I)-diselenoether as Anticancer Drug in Resistant Breast Tumor-bearing Mice After Repeated Administrations.

PubMed

Collery, Philippe; Santoni, François; Ciccolini, Joseph; Tran, Thi Ngoc Nga; Mohsen, Ahmed; Desmaele, Didier

2016-11-01

Rhenium (I)-diselenoether has shown promising antiproliferative efficacy in both in vitro and in vivo models. However, the maximal tolerated dose and dose-effect relationships have not been fully addressed for this compound. Here, we evaluated the tolerance and efficacy of three dose-levels (namely 10, 40 and 100 mg/kg) intraperitoneally administered daily over 28 days in mice bearing the resistant MDA-MB231 breast cancer cell line. The upper dose was found to be toxic and was reduced to 60 mg/kg. The 10 mg/kg dose well tolerated, whereas 40 mg/kg was associated with 10% mortality (LD 10 ). Both 10 and 40 mg/kg dosing achieved a significantly similar regression of tumor growth compared with untreated animals. This study suggests that 10 mg/kg daily is the recommended dose for rhenium (I) diselenoether. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Clinical application of a nomogram based on age, serum FSH and AMH to select the FSH starting dose in IVF/ICSI cycles: a retrospective two-centres study.

PubMed

Papaleo, Enrico; Zaffagnini, Stefano; Munaretto, Maria; Vanni, Valeria Stella; Rebonato, Giorgia; Grisendi, Valentina; Di Paola, Rossana; La Marca, Antonio

2016-12-01

To externally validate a nomogram based on ovarian reserve markers as a tool to optimize the FSH starting dose in IVF/ICSI cycles. A two-centres retrospective study including 398 infertile women undergoing their first IVF/ICSI cycle (June 2013-June 2014). IVF data were retrieved from two independent IVF centres in Italy (San Raffaele Hospital, Centre 1; Verona Hospital, Centre 2). A central lab for the routine measurement of AMH and FSH was used for both centres. All women were treated based on physical and hormonal characteristics according to locally adopted protocols. The nomogram was then retrospectively applied to the patients comparing the calculated starting dose to the one actually given. In Centre 1, 64/131 women (48.8%) had an ovarian response below the target. While 45 of these patients were treated with a maximal FSH starting dose (≥225 IU), n=19/131 (14.5%) were treated with a submaximal dose. The vast majority of them (n=17/19) would have received a higher FSH starting dose by using the nomogram. Seventeen patients (n=17/131) had hyper response and about half of them would have been treated with a reduced FSH starting dose according to the nomogram. In Centre 2, 142/267 patients (53.2%) had an ovarian response below the target. While 136 of these were treated with a maximal FSH starting dose (≥225 IU), n=6/267 were treated with a submaximal dose. The majority of them (n=5/6) would have received a higher FSH starting dose. Thirty-two (n=32/267) patients had hyper response and more than half of them would have been treated with a reduced FSH dose. In both Centres, applying the nomogram would have resulted in more appropriate FSH starting doses compared to the the ones actually given based on clinicians choices. The use of an objective algorithm based on patient's age, serum FSH and AMH levels may thus be an effective advice on the selection of the tailored FSH starting dose. Hence, the use of this easily available nomogram could increase the proportion of patients achieving the optimal ovarian response. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ultraviolet Light Emitting Diode Optical Power Characterization

DTIC Science & Technology

2014-03-01

radicals and use the radicals to break down hazardous chemicals. The second project that will be referenced is the drinking water disinfection ...measurements to understand the voltage needed to maximize the UV LEDs performance for the disinfection of drinking water and the production of...way to produce safe drinking water is not only a priority of almost every residential community in the United States, but the Department of Defense

Whole-body strength training with Huber Motion Lab and traditional strength training in cardiac rehabilitation: A randomized controlled study.

PubMed

Guiraud, Thibaut; Labrunée, Marc; Besnier, Florent; Sénard, Jean-Michel; Pillard, Fabien; Rivière, Daniel; Richard, Lisa; Laroche, Davy; Sanguignol, Frédéric; Pathak, Atul; Gayda, Mathieu; Gremeaux, Vincent

2017-01-01

Isometric strengthening has been rarely studied in patients with coronary heart disease (CHD), mainly because of possible potential side effects and lack of appropriate and reliable devices. We aimed to compare 2 different modes of resistance training, an isometric mode with the Huber Motion Lab (HML) and traditional strength training (TST), in CHD patients undergoing a cardiac rehabilitation program. We randomly assigned 50 patients to HML or TST. Patients underwent complete blinded evaluation before and after the rehabilitation program, including testing for cardiopulmonary exercise, maximal isometric voluntary contraction, endothelial function and body composition. After 4 weeks of training (16 sessions), the groups did not differ in body composition, anthropometric characteristics, or endothelial function. With HML, peak power output (P=0.035), maximal heart rate (P<0.01) and gain of force measured in the chest press position (P<0.02) were greater after versus before training. Both protocols appeared to be well tolerated, safe and feasible for these CHD patients. A training protocol involving 6s phases of isometric contractions with 10s of passive recovery on an HML device could be safely implemented in rehabilitation programs for patients with CHD and improve functional outcomes. Copyright © 2016. Published by Elsevier Masson SAS.

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.

Influence of arachidonyl-2'-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the anticonvulsant and acute side-effect potentials of clobazam, lacosamide, and pregabalin in the maximal electroshock-induced seizure model and chimney test in mice.

PubMed

Florek-Luszczki, Magdalena; Zagaja, Miroslaw; Luszczki, Jarogniew J

2015-08-01

The influence of arachidonyl-2'-chloroethylamide (ACEA - a selective cannabinoid CB1 receptor agonist) on the anticonvulsant potency and acute adverse-effect potentials of clobazam, lacosamide, and pregabalin was determined in the maximal electroshock-induced seizure model and chimney test in mice. ACEA (2.5 mg/kg, i.p.) significantly enhanced the anticonvulsant potency of pregabalin in the mouse maximal electroshock-induced seizure model by decreasing the median effective dose (ED50 ) of pregabalin from 125.39 to 78.06 mg/kg (P < 0.05). In contrast, ACEA (2.5 mg/kg) had no significant impact on the anticonvulsant potency of clobazam and lacosamide in the mouse maximal electroshock-induced seizure model. On the other hand, ACEA (2.5 mg/kg) did not affect acute adverse effects of clobazam, lacosamide or pregabalin, and the median toxic doses (TD50 ) for the studied anti-epileptic drugs in combination with ACEA did not differ from the TD50 values as determined for the drugs administered alone in the chimney test. In conclusion, ACEA ameliorates the pharmacological profile of pregabalin, when considering both the anticonvulsant and the acute adverse effects of the drug in preclinical study on animals. The combination of pregabalin with ACEA can be of pivotal importance for patients with epilepsy as a potentially advantageous combination if the results from this study translate into clinical settings. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Enhancement of High-Intensity Actions and Physical Performance During a Simulated Brazilian Jiu-Jitsu Competition With a Moderate Dose of Caffeine.

PubMed

Diaz-Lara, Francisco Javier; Del Coso, Juan; Portillo, Javier; Areces, Francisco; García, Jose Manuel; Abián-Vicén, Javier

2016-10-01

Although caffeine is one of the most commonly used substances in combat sports, information about its ergogenic effects on these disciplines is very limited. To determine the effectiveness of ingesting a moderate dose of caffeine to enhance overall performance during a simulated Brazilian jiu-jitsu (BJJ) competition. Fourteen elite BJJ athletes participated in a double-blind, placebo-controlled experimental design. In a random order, the athletes ingested either 3 mg/kg body mass of caffeine or a placebo (cellulose, 0 mg/kg) and performed 2 simulated BJJ combats (with 20 min rest between them), following official BJJ rules. Specific physical tests such as maximal handgrip dynamometry, maximal height during a countermovement jump, permanence during a maximal static-lift test, peak power in a bench-press exercise, and blood lactate concentration were measured at 3 specific times: before the first combat and immediately after the first and second combats. The combats were video-recorded to analyze fight actions. After the caffeine ingestion, participants spent more time in offensive actions in both combats and revealed higher blood lactate values (P < .05). Performance in all physical tests carried out before the first combat was enhanced with caffeine (P < .05), and some improvements remained after the first combat (eg, maximal static-lift test and bench-press exercise; P < .05). After the second combat, the values in all physical tests were similar between caffeine and placebo. Caffeine might be an effective ergogenic aid for improving intensity and physical performance during successive elite BJJ combats.

Comparison of the anticonvulsant potency of various diuretic drugs in the maximal electroshock-induced seizure threshold test in mice.

PubMed

Załuska, Katarzyna; Kondrat-Wróbel, Maria W; Łuszczki, Jarogniew J

2018-05-01

The coexistence of seizures and arterial hypertension requires an adequate and efficacious treatment involving both protection from seizures and reduction of high arterial blood pressure. Accumulating evidence indicates that some diuretic drugs (with a well-established position in the treatment of arterial hypertension) also possess anticonvulsant properties in various experimental models of epilepsy. The aim of this study was to assess the anticonvulsant potency of 6 commonly used diuretic drugs (i.e., amiloride, ethacrynic acid, furosemide, hydrochlorothiazide, indapamide, and spironolactone) in the maximal electroshock-induced seizure threshold (MEST) test in mice. Doses of the studied diuretics and their corresponding threshold increases were linearly related, allowing for the determination of doses which increase the threshold for electroconvulsions in drug-treated animals by 20% (TID20 values) over the threshold in control animals. Amiloride, hydrochlorothiazide and indapamide administered systemically (intraperitoneally - i.p.) increased the threshold for maximal electroconvulsions in mice, and the experimentally-derived TID20 values in the maximal electroshock seizure threshold test were 30.2 mg/kg for amiloride, 68.2 mg/kg for hydrochlorothiazide and 3.9 mg/kg for indapamide. In contrast, ethacrynic acid (up to 100 mg/kg), furosemide (up to 100 mg/kg) and spironolactone (up to 50 mg/kg) administered i.p. had no significant impact on the threshold for electroconvulsions in mice. The studied diuretics can be arranged with respect to their anticonvulsant potency in the MEST test as follows: indapamide > amiloride > hydrochlorothiazide. No anticonvulsant effects were observed for ethacrynic acid, furosemide or spironolactone in the MEST test in mice.

An inactivated, adjuvanted whole virion clade 2.2 H5N1 (A/Chicken/Astana/6/05) influenza vaccine is safe and immunogenic in a single dose in humans.

PubMed

Sansyzbay, Abylay R; Erofeeva, Marianna K; Khairullin, Berik M; Sandybayev, Nurlan T; Kydyrbayev, Zhailaubay K; Mamadaliyev, Seidigapbar M; Kassenov, Markhabat M; Sergeeva, Maria V; Romanova, Julia R; Krivitskaya, Vera Z; Kiselev, Oleg I; Stukova, Marina A

2013-08-01

In this study, we assessed in humans the immunogenicity and safety of one dose (7.5 or 15 μg of hemagglutinin [HA]) of a whole-virion inactivated prepandemic influenza vaccine adjuvanted with aluminum hydroxide. The vaccine strain was made by reverse genetics from the highly pathogenic avian A/Chicken/Astana/6/05 (H5N1) clade 2.2 strain isolated from a dead bird in Kazakhstan. The humoral immune response was evaluated after a single vaccination by hemagglutination inhibition (HI) and microneutralization (MN) assays. The vaccine was safe and immunogenic, inducing seroconversion in 55% of the evaluated patients, with a geometric mean titer (GMT) of 17.1 and a geometric mean increase (GMI) of 3.42 after a dose of 7.5 μg in the HI test against the vaccine strain. The rate of seroconversion increased up to 70% when the dose of 15 μg was used. The percentages of individuals achieving anti-HA titers of ≥1:40 were 52.5% and 57.5% for the 7.5- and 15-μg dose groups, respectively. Similar results were obtained when antibodies were analyzed in an MN test. Substantial cross-neutralization titers (seroconversion in 35% and 52.5% of subjects in the two dose groups, respectively) were detected against heterologous clade 1 strain NIBRG14 (H5N1). Thus, one dose of this whole-virion prepandemic vaccine adjuvanted with aluminum has the potential to be effective against H5N1 viruses of different clades.

High-dose-rate prostate brachytherapy inverse planning on dose-volume criteria by simulated annealing.

PubMed

Deist, T M; Gorissen, B L

2016-02-07

High-dose-rate brachytherapy is a tumor treatment method where a highly radioactive source is brought in close proximity to the tumor. In this paper we develop a simulated annealing algorithm to optimize the dwell times at preselected dwell positions to maximize tumor coverage under dose-volume constraints on the organs at risk. Compared to existing algorithms, our algorithm has advantages in terms of speed and objective value and does not require an expensive general purpose solver. Its success mainly depends on exploiting the efficiency of matrix multiplication and a careful selection of the neighboring states. In this paper we outline its details and make an in-depth comparison with existing methods using real patient data.

Estimate of safe human exposure levels for lunar dust based on comparative benchmark dose modeling.

PubMed

James, John T; Lam, Chiu-Wing; Santana, Patricia A; Scully, Robert R

2013-04-01

Brief exposures of Apollo astronauts to lunar dust occasionally elicited upper respiratory irritation; however, no limits were ever set for prolonged exposure to lunar dust. The United States and other space faring nations intend to return to the moon for extensive exploration within a few decades. In the meantime, habitats for that exploration, whether mobile or fixed, must be designed to limit human exposure to lunar dust to safe levels. Herein we estimate safe exposure limits for lunar dust collected during the Apollo 14 mission. We instilled three respirable-sized (∼2 μ mass median diameter) lunar dusts (two ground and one unground) and two standard dusts of widely different toxicities (quartz and TiO₂) into the respiratory system of rats. Rats in groups of six were given 0, 1, 2.5 or 7.5 mg of the test dust in a saline-Survanta® vehicle, and biochemical and cellular biomarkers of toxicity in lung lavage fluid were assayed 1 week and one month after instillation. By comparing the dose--response curves of sensitive biomarkers, we estimated safe exposure levels for astronauts and concluded that unground lunar dust and dust ground by two different methods were not toxicologically distinguishable. The safe exposure estimates were 1.3 ± 0.4 mg/m³ (jet-milled dust), 1.0 ± 0.5 mg/m³ (ball-milled dust) and 0.9 ± 0.3 mg/m³ (unground, natural dust). We estimate that 0.5-1 mg/m³ of lunar dust is safe for periodic human exposures during long stays in habitats on the lunar surface.

Obstetric therapeutics-how pharmacogenetics may inform drug therapy for pregnant women in the future.

PubMed

Haas, David M

2013-09-01

Most pregnant women take prescription medications. There are many factors related to pregnancy that make finding the most effective and safe dose of a therapeutic drug difficult for providers. Genetic differences in drug-metabolizing enzymes, transporters, and receptors may also account for some of the differences in drug response. Single-nucleotide polymorphisms in drug-metabolizing enzymes, such as the cytochrome P450 families, have been studied in relation to drugs used in pregnancy. Combining clinical characteristics, physiologic parameters in pregnancy, and possibly pharmacogenetic models may allow for providers to individualize pharmacotherapy in pregnancy and get to the most effective and safe dose of medication more quickly than in the current practice model. This article discusses these issues along with helpful Web sites and references for providers.

Using lean "automation with a human touch" to improve medication safety: a step closer to the "perfect dose".

PubMed

Ching, Joan M; Williams, Barbara L; Idemoto, Lori M; Blackmore, C Craig

2014-08-01

Virginia Mason Medical Center (Seattle) employed the Lean concept of Jidoka (automation with a human touch) to plan for and deploy bar code medication administration (BCMA) to hospitalized patients. Integrating BCMA technology into the nursing work flow with minimal disruption was accomplished using three steps ofJidoka: (1) assigning work to humans and machines on the basis of their differing abilities, (2) adapting machines to the human work flow, and (3) monitoring the human-machine interaction. Effectiveness of BCMA to both reinforce safe administration practices and reduce medication errors was measured using the Collaborative Alliance for Nursing Outcomes (CALNOC) Medication Administration Accuracy Quality Study methodology. Trained nurses observed a total of 16,149 medication doses for 3,617 patients in a three-year period. Following BCMA implementation, the number of safe practice violations decreased from 54.8 violations/100 doses (January 2010-September 2011) to 29.0 violations/100 doses (October 2011-December 2012), resulting in an absolute risk reduction of 25.8 violations/100 doses (95% confidence interval [CI]: 23.7, 27.9, p < .001). The number of medication errors decreased from 5.9 errors/100 doses at baseline to 3.0 errors/100 doses after BCMA implementation (absolute risk reduction: 2.9 errors/100 doses [95% CI: 2.2, 3.6,p < .001]). The number of unsafe administration practices (estimate, -5.481; standard error 1.133; p < .001; 95% CI: -7.702, -3.260) also decreased. As more hospitals respond to health information technology meaningful use incentives, thoughtful, methodical, and well-managed approaches to technology deployment are crucial. This work illustrates how Jidoka offers opportunities for a smooth transition to new technology.

Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease.

PubMed

Rajagopalan, Ravi; Pan, Lin; Schaefer, Caralee; Nicholas, John; Lim, Sharlene; Misialek, Shawn; Stevens, Sarah; Hooi, Lisa; Aleskovski, Natalia; Ruhrmund, Donald; Kossen, Karl; Huang, Lea; Yap, Sophia; Beigelman, Leonid; Serebryany, Vladimir; Liu, Jyanwei; Sastry, Srikonda; Seiwert, Scott; Buckman, Brad

2017-01-01

The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other directly acting antiviral agents in vitro displayed additive antiviral efficacy. A 30-mg/kg of body weight dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through day 5 in a chimeric mouse model of HCV. A 3-mg/kg oral dose administered to rats, dogs, or monkeys yielded concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection. Copyright © 2016 American Society for Microbiology.

Parent Preferences and Perceptions of Milliliters and Teaspoons: Role of Health Literacy and Experience.

PubMed

Torres, Alejandro; Parker, Ruth M; Sanders, Lee M; Wolf, Michael S; Bailey, Stacy Cooper; Patel, Deesha A; Jimenez, Jessica J; Kim, Kwang-Youn A; Dreyer, Benard P; Mendelsohn, Alan L; Yin, H Shonna

A recent American Academy of Pediatrics policy statement recommends milliliter-exclusive dosing for pediatric liquid medications. Little is known about parent preferences regarding units, perceptions about moving to milliliters only, and the role of health literacy and prior milliliter-dosing experience. Cross-sectional analysis of data collected as part of a randomized controlled study in 3 urban pediatric clinics (SAFE Rx for Kids study). English- and Spanish-speaking parents (n = 493) of children aged ≤8 years were randomized to 1 of 4 study arms and given labels and dosing tools which varied in label instruction format (text plus pictogram, text only) and units (milliliter only ["mL"], milliliter/teaspoon ["mL"/"tsp"]). Outcomes included teaspoon preference in dosing instructions and perceived difficulty with milliliter-only dosing. The predictor variable was health literacy (Newest Vital Sign; low [0-1], marginal [2-3], adequate [4-6]). The mediating variable was prior milliliter-dosing experience. Over two-thirds of parents had low or marginal health literacy. The majority (>70%) preferred to use milliliters, perceived milliliter-only dosing to be easy, and had prior milliliter-dosing experience; 11.5% had a teaspoon preference, 18.1% perceived milliliter-only dosing will be difficult, and 17.7% had no prior milliliter-dosing experience. Parents with lower health literacy had a higher odds of having a teaspoon preference (low vs adequate: adjusted odds ratio [AOR] = 2.9 [95% confidence interval [CI] 1.3-6.2]), and greater odds of perceiving difficulty with milliliter-only dosing (low vs adequate: AOR = 13.9 [95% CI 4.8-40.6], marginal vs adequate: AOR = 7.1 [95% CI 2.5-20.4]). Lack of experience with milliliter dosing partially mediated the impact of health literacy. Most parents were comfortable with milliliter-only dosing. Parents with low health literacy were more likely to perceive milliliter-only dosing to be difficult; educational efforts will need to target this group to ensure safe medication use. Copyright © 2017 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

AXAOTHER XL -- A spreadsheet for determining doses for incidents caused by tornadoes or high-velocity straight winds

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

Simpkins, A.A.

1996-09-01

AXAOTHER XL is an Excel Spreadsheet used to determine dose to the maximally exposed offsite individual during high-velocity straight winds or tornado conditions. Both individual and population doses may be considered. Potential exposure pathways are inhalation and plume shine. For high-velocity straight winds the spreadsheet has the capability to determine the downwind relative air concentration, however for the tornado conditions, the user must enter the relative air concentration. Theoretical models are discussed and hand calculations are performed to ensure proper application of methodologies. A section has also been included that contains user instructions for the spreadsheet.

Radiation Therapy for Locally Advanced Esophageal Cancer.

PubMed

Chun, Stephen G; Skinner, Heath D; Minsky, Bruce D

2017-04-01

The treatment of locally advanced esophageal cancer is controversial. For patients who are candidates for surgical resection, multiple prospective clinical trials have demonstrated the advantages of neoadjuvant chemoradiation. For patients who are medically inoperable, definitive chemoradiation is an alternative approach with survival rates comparable to trimodality therapy. Although trials of dose escalation are ongoing, the standard radiation dose remains 50.4 Gy. Modern radiotherapy techniques such as image-guided radiation therapy with motion management and intensity-modulated radiation therapy are strongly encouraged with a planning objective to maximize conformity to the intended target volume while reducing dose delivered to uninvolved normal tissues. Copyright © 2016 Elsevier Inc. All rights reserved.

Cryoradiolytic reduction of heme proteins: Maximizing dose-dependent yield

NASA Astrophysics Data System (ADS)

Denisov, Ilia G.; Victoria, Doreen C.; Sligar, Stephen G.

2007-04-01

Radiolytic reduction in frozen solutions and crystals is a useful method for generation of trapped intermediates in protein-based radical reactions. In this communication we define the conditions which provide the maximum yield of one electron-reduced myoglobin at 77 K using 60Co γ-irradiation in aqueous glycerol glass. The yield reached 50% after 20 kGy, was almost complete at ˜160 kGy total dose, and does not depend on the protein concentration in the range 0.01-5 mM.

Annual Research Report on Projects of the Armed Forces Radiobiology Research Institute, 1 October 1979 - 30 September 1980.

DTIC Science & Technology

1980-09-30

by radio- immunoassay after doses of high-energy electrons (1). Both cGMP and cAMP were reduced maximally 10 minutes after exposure in the cerebellum...rays, high-energy electrons , or neutrons. Using the probes diphenylhexatriene and anilinonaphthalene sulfonate, fluorescence inten- sity was reduced to...energy electrons . Alterations in the EEG patterns were observed only at radiation doses of 10 krad. No effect was obtained at 5 krad. EEG amplitude and

Is There a Role for Intravenous Subdissociative-Dose Ketamine Administered as an Adjunct to Opioids or as a Single Agent for Acute Pain Management in the Emergency Department?

PubMed

Motov, Sergey; Rosenbaum, Steven; Vilke, Gary M; Nakajima, Yuko

2016-12-01

Whether acute or chronic, emergency physicians frequently encounter patients reporting pain. It is the responsibility of the emergency physician to assess and evaluate, and if appropriate, safely and effectively reduce pain. Recently, analgesics other than opioids are being considered in an effort to provide safe alternatives for pain management in the emergency department (ED). Opioids have significant adverse effects such as respiratory depression, hypotension, and sedation, to say nothing of their potential for abuse. Although ketamine has long been used in the ED for procedural sedation and rapid sequence intubation, it is used infrequently for analgesia. Recent evidence suggests that ketamine use in subdissociative doses proves to be effective for pain control and serves as a feasible alternative to traditional opioids. This paper evaluates ketamine's analgesic effectiveness and safety in the ED. This is a literature review of randomized controlled trials, systematic reviews, meta-analyses, and observational studies evaluating ketamine for pain control in the ED setting. Based on these search parameters, eight studies were included in the final analysis and graded based on the American Academy of Emergency Medicine Clinical Practice Committee manuscript review process. A total of eight papers were reviewed in detail and graded. Recommendations were given based upon this review process. Subdissociative-dose ketamine (low-dose ketamine) is effective and safe to use alone or in combination with opioid analgesics for the treatment of acute pain in the ED. Its use is associated with higher rates of minor, but well-tolerated adverse side effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Dose-dependent effect of fluoride on clinical and subclinical indices of fluorosis in school going children and its mitigation by supply of safe drinking water for 5 years: an Indian study.

PubMed

Khandare, Arjun L; Validandi, Vakdevi; Gourineni, Shankar Rao; Gopalan, Viswanathan; Nagalla, Balakrishna

2018-02-02

Fluorosis is a public health problem in India; to know its prevalence and severity along with its mitigation measures is very important. The present study has been undertaken with the aim to assess the F dose-dependent clinical and subclinical symptoms of fluorosis and reversal of the disease by providing safe drinking water. For this purpose, a cross-sectional study was undertaken in 1934 schoolgoing children, Nalgonda district. Study villages were categorized into control (category I, F = 0.87 mg/L), affected (category II, F = 2.53 mg/L, and category III, F = 3.77 mg/L), and intervention categories (category IV, F = < 1.0 mg/L). School children were enrolled for dental grading by modified Dean Index criteria. Anthropometric measurements (height and weight) were used to assess nutritional status of the children. The biochemical parameters like serum T3, T4, TSH, PTH, ALP, 25-OH vitamin D, and 1,25-(OH) 2 vitamin D were analyzed. The results showed a positive correlation between the drinking water and urinary fluoride (UF) in different categories. However, there was a significant decrease in the UF levels in the intervention category IV compared to affected group (category III). Fluoride altered the clinical (dental fluorosis and stunting) and subclinical indices (urine and blood) of fluorosis in a dose-dependent manner. In conclusion, the biochemical indices were altered in a dose-dependent manner and intervention with safe drinking water for 5 years in intervention group-mitigated clinical and subclinical symptoms of fluorosis.

Negative Impact of Total Body Irradiation on the Antitumor Activity of Rhenium-(I)-diselenoether.

PubMed

Collery, Philippe; Santoni, Francois; Mohsen, Ahmed; Mignard, Caroline; Desmaele, Didier

2016-11-01

It has been shown that a rhenium-(I)-diselenoether complex had significant antitumor activity in MDA-MB231 tumor-bearing mice after repeated oral or intraperitoneal administrations for 4 weeks at safe doses of 10 mg/kg/day. It has also been suggested that lower doses could be as effective as this dose. We, thus, tested two doses (5 and 10 mg/kg). The drug was orally administered daily by gavage for 4 weeks and for a further 2 weeks with or without 15 mg/kg paclitaxel treatment (intravenously, once a week). This experiment was performed in MDA-MB 231 tumor-bearing mice, as a model of resistant breast tumor. However, in contrast to previous studies, the mice were pretreated with total body irradiation to increase the tumor growth. These two doses were safe, even in combination with paclitaxel. The expected tumor regression was not observed with the rhenium-(I)-diselenoether complex, and there was even a significant increase of the tumor volume in mice treated with 10 mg/kg versus controls. No synergism was observed with paclitaxel. We comment on the possible negative impact of radiotherapy on the antitumor activity of the drug. Plasma and tumor rhenium and selenium concentrations are also reported. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

[Diuretic-based therapy].

PubMed

Presne, Claire; Monge, Matthieu; Mansour, Janette; Oprisiu, Roxana; Choukroun, Gabriel; Achard, Jean Michel; Fournier, Albert

2007-10-01

Diuretics are pharmacological agents that increase natriuresis through inhibition of tubular re-absorption of sodium. The mechanisms and site of this inhibition differ with each drug class, accounting for their additive effects on natriuresis increase and their hydroelectrolytic side effects. The response to a given diuretic dose depends on the diuretic concentration on the urine at its action site. This concentration may be decreased by pharmacokinetic factors such as encountered in renal insufficiency or in nephrotic syndrome. These resistance mechanisms of diuretics may be corrected by dose increase, previous diuretic fixation on albumin or warfarin administration. Once these mechanisms are opposed, the diuretic concentration for maximal efficacy is reached at is action site and the natriuresis obtained as the normal maximal plateau. This is not the case when an oedematous systemic disease with effective hypovolemia is present, like in heart failure or cirrhosis, or when chronic use of loop diuretics has induced a hypertrophy of the more distant part of the tubule. In theses cases, a pharmacodynamic resistance exists, resulting in a lower maximal natriuresis plateau in spite of adequate concentration of the diuretic at its action site, even in the absence of pharmacokinetic resistance factors. The main indications of diuretics are systemic oedematous disease and hypertension. In the oedematous diseases, diuretics indication is both straightforward and sufficient only if effective hypervolemia is present. The therapeutic approach is discussed according to the various clinical conditions and pathophysiological background. In uncomplicated hypertension, diuretics are the cornerstone of the therapy. The most suitable diuretic treatment for hypertension is an association of low doses thiazide (12.5-50 mg/day) with potassium sparing diuretics. Rare indications of diuretics are also reviewed.

Optimization of the temporal pattern of applied dose for a single fraction of radiation: Implications for radiation therapy

NASA Astrophysics Data System (ADS)

Altman, Michael B.

The increasing prevalence of intensity modulated radiation therapy (IMRT) as a treatment modality has led to a renewed interest in the potential for interaction between prolonged treatment time, as frequently associated with IMRT, and the underlying radiobiology of the irradiated tissue. A particularly relevant aspect of radiobiology is cell repair capacity, which influences cell survival, and thus directly relates to the ability to control tumors and spare normal tissues. For a single fraction of radiation, the linear quadratic (LQ) model is commonly used to relate the radiation dose to the fraction of cells surviving. The LQ model implies a dependence on two time-related factors which correlate to radiobiological effects: the duration of radiation application, and the functional form of how the dose is applied over that time (the "temporal pattern of applied dose"). Although the former has been well studied, the latter has not. Thus, the goal of this research is to investigate the impact of the temporal pattern of applied dose on the survival of human cells and to explore how the manipulation of this temporal dose pattern may be incorporated into an IMRT-based radiation therapy treatment planning scheme. The hypothesis is that the temporal pattern of applied dose in a single fraction of radiation can be optimized to maximize or minimize cell kill. Furthermore, techniques which utilize this effect could have clinical ramifications. In situations where increased cell kill is desirable, such as tumor control, or limiting the degree of cell kill is important, such as the sparing of normal tissue, temporal sequences of dose which maximize or minimize cell kill (temporally "optimized" sequences) may provide greater benefit than current clinically used radiation patterns. In the first part of this work, an LQ-based modeling analysis of effects of the temporal pattern of dose on cell kill is performed. Through this, patterns are identified for maximizing cell kill for a given radiation pattern by concentrating the highest doses in the middle of a fraction (a "Triangle" pattern), or minimizing cell kill by placing the highest doses near the beginning and end (a "V-shaped" pattern). The conditions under which temporal optimization effects are most acute are also identified: irradiation of low alpha/beta tissues, long fraction durations, and high doses/fx. An in vitro study is then performed which verifies that the temporal effects and trends predicted by the modeling study are clearly manifested in human cells. Following this a phantom which could allow similar in vitro radiobiological experiments in a 3-dimensional clinically-based environment is designed, created, and dosimetrically assessed using TLDs, film, and biological assay-based techniques. The phantom is found to be a useful and versatile tool for such experiments. A scheme for utilizing the phantom in a clinical treatment environment is then developed. This includes a demonstration of prototype methods for optimizing the temporal pattern of applied dose in clinical IMRT plans to manipulate tissue-dependent effects. Looking toward future experimental validation of such plans using the phantom, an analysis of the suitability of biological assays for use in phantom-based in vitro experiments is performed. Finally, a discussion is provided about the steps necessary to integrate temporal optimization into in vivo experiments and ultimately into a clinical radiation therapy environment. If temporal optimization is ultimately shown to have impact in vivo, the successful implementation of the methods developed in this study could enhance the efficacy and care of thousands of patients receiving radiotherapy.

Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs

PubMed Central

Wickham, Kristina S.; Baresel, Paul C.; Sousa, Jason; Vuong, Chau T.; Reichard, Gregory A.; Campo, Brice; Tekwani, Babu L.; Walker, Larry A.

2016-01-01

Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) are at risk for developing hemolytic anemia when given the antimalarial drug primaquine (PQ). The WHO Evidence Review Group released a report suggesting that mass administration of a single dose of PQ at 0.25 mg of base/kg of body weight (mpk) (mouse equivalent of 3.125 mpk) could potentially reduce malaria transmission based on its gametocytocidal activity and could be safely administered to G6PD-deficient individuals, but there are limited safety data available confirming the optimum single dose of PQ. A single-dose administration of PQ was therefore assessed in our huRBC-SCID mouse model used to predict hemolytic toxicity with respect to G6PD deficiency. In this model, nonobese diabetic (NOD)/SCID mice are engrafted with human red blood cells (huRBC) from donors with the African or Mediterranean variant of G6PDd (A-G6PDd or Med-G6PDd, respectively) and demonstrate dose-dependent sensitivity to PQ. In mice engrafted with A-G6PD-deficient huRBC, single-dose PQ at 3.125, 6.25, or 12.5 mpk had no significant loss of huRBC compared to the vehicle control group. In contrast, in mice engrafted with Med-G6PDd huRBC, a single dose of PQ at 3.125, 6.25, or 12.5 mpk resulted in a significant, dose-dependent loss of huRBC compared to the value for the vehicle control group. Our data suggest that administration of a single low dose of 0.25 mpk of PQ could induce hemolytic anemia in Med-G6PDd individuals but that use of single-dose PQ at 0.25 mpk as a gametocytocidal drug to block transmission would be safe in areas where A-G6PDd predominates. PMID:27458212

Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs.

PubMed

Wickham, Kristina S; Baresel, Paul C; Marcsisin, Sean R; Sousa, Jason; Vuong, Chau T; Reichard, Gregory A; Campo, Brice; Tekwani, Babu L; Walker, Larry A; Rochford, Rosemary

2016-10-01

Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) are at risk for developing hemolytic anemia when given the antimalarial drug primaquine (PQ). The WHO Evidence Review Group released a report suggesting that mass administration of a single dose of PQ at 0.25 mg of base/kg of body weight (mpk) (mouse equivalent of 3.125 mpk) could potentially reduce malaria transmission based on its gametocytocidal activity and could be safely administered to G6PD-deficient individuals, but there are limited safety data available confirming the optimum single dose of PQ. A single-dose administration of PQ was therefore assessed in our huRBC-SCID mouse model used to predict hemolytic toxicity with respect to G6PD deficiency. In this model, nonobese diabetic (NOD)/SCID mice are engrafted with human red blood cells (huRBC) from donors with the African or Mediterranean variant of G6PDd (A-G6PDd or Med-G6PDd, respectively) and demonstrate dose-dependent sensitivity to PQ. In mice engrafted with A-G6PD-deficient huRBC, single-dose PQ at 3.125, 6.25, or 12.5 mpk had no significant loss of huRBC compared to the vehicle control group. In contrast, in mice engrafted with Med-G6PDd huRBC, a single dose of PQ at 3.125, 6.25, or 12.5 mpk resulted in a significant, dose-dependent loss of huRBC compared to the value for the vehicle control group. Our data suggest that administration of a single low dose of 0.25 mpk of PQ could induce hemolytic anemia in Med-G6PDd individuals but that use of single-dose PQ at 0.25 mpk as a gametocytocidal drug to block transmission would be safe in areas where A-G6PDd predominates. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Tyre-road grip coefficient assessment - Part II: online estimation using instrumented vehicle, extended Kalman filter, and neural network

NASA Astrophysics Data System (ADS)

Luque, Pablo; Mántaras, Daniel A.; Fidalgo, Eloy; Álvarez, Javier; Riva, Paolo; Girón, Pablo; Compadre, Diego; Ferran, Jordi

2013-12-01

The main objective of this work is to determine the limit of safe driving conditions by identifying the maximal friction coefficient in a real vehicle. The study will focus on finding a method to determine this limit before reaching the skid, which is valuable information in the context of traffic safety. Since it is not possible to measure the friction coefficient directly, it will be estimated using the appropriate tools in order to get the most accurate information. A real vehicle is instrumented to collect information of general kinematics and steering tie-rod forces. A real-time algorithm is developed to estimate forces and aligning torque in the tyres using an extended Kalman filter and neural networks techniques. The methodology is based on determining the aligning torque; this variable allows evaluation of the behaviour of the tyre. It transmits interesting information from the tyre-road contact and can be used to predict the maximal tyre grip and safety margin. The maximal grip coefficient is estimated according to a knowledge base, extracted from computer simulation of a high detailed three-dimensional model, using Adams® software. The proposed methodology is validated and applied to real driving conditions, in which maximal grip and safety margin are properly estimated.

2010 Children's Health Protection Advisory Committee Meeting Agendas

EPA Pesticide Factsheets

Objectives for three meetings in 2010 include discussions on safe chemicals management, risk assessment, unified dose response, indoor environments, prenatal exposures, asthma disparities, rulemaking, and air toxics monitoring near schools.

Assessment of chest CT at CTDIvol less than 1 mGy with iterative reconstruction techniques.

PubMed

Padole, Atul; Digumarthy, Subba; Flores, Efren; Madan, Rachna; Mishra, Shelly; Sharma, Amita; Kalra, Mannudeep K

2017-03-01

To assess the image quality of chest CT reconstructed with image-based iterative reconstruction (SafeCT; MedicVision ® , Tirat Carmel, Israel), adaptive statistical iterative reconstruction (ASIR; GE Healthcare, Waukesha, WI) and model-based iterative reconstruction (MBIR; GE Healthcare, Waukesha, WI) techniques at CT dose index volume (CTDI vol ) <1 mGy. In an institutional review board-approved study, 25 patients gave written informed consent for acquisition of three reduced dose (0.25-, 0.4- and 0.8-mGy) chest CT after standard of care CT (8 mGy) on a 64-channel multidetector CT (MDCT) and reconstructed with SafeCT, ASIR and MBIR. Two board-certified thoracic radiologists evaluated images from the lowest to the highest dose of the reduced dose CT series and subsequently for standard of care CT. Out of the 182 detected lesions, the missed lesions were 35 at 0.25, 24 at 0.4 and 9 at 0.8 mGy with SafeCT, ASIR and MBIR, respectively. The most missed lesions were non-calcified lung nodules (NCLNs) 25/112 (<5 mm) at 0.25, 18/112 (<5 mm) at 0.4 and 3/112 (<4 mm) at 0.8 mGy. There were 78%, 84% and 97% lung nodules detected at 0.25, 0.4 and 0.8 mGy, respectively regardless of iterative reconstruction techniques (IRTs), Most mediastinum structures were not sufficiently seen at 0.25-0.8 mGy. NCLNs can be missed in chest CT at CTDI vol of <1 mGy (0.25, 0.4 and 0.8 mGy) regardless of IRTs. The most lung nodules (97%) were detected at CTDI vol of 0.8 mGy. The most mediastinum structures were not sufficiently seen at 0.25-0.8 mGy. Advances in knowledge: NCLNs can be missed regardless of IRTs in chest CT at CTDI vol of <1 mGy. The performance of ASIR, SafeCT and MBIR was similar for lung nodule detection at 0.25, 0.4 and 0.8 mGy.

Fixed-dose combination of sitagliptin and metformin for the treatment of type 2 diabetes

PubMed Central

Reynolds, Jonathan K

2009-01-01

JanumetTM, a fixed dose combination of sitagliptin/metformin HCL manufactured by Merck Pharmaceuticals, has received US Food and Drug Administration approval for treatment of patients with type 2 diabetes, that are inadequately controlled, either by sitagliptin or metformin alone or together in free-dose combination form. Sitagliptin, an inhibitor of the enzyme DDP-4, assists patients with type 2 diabetes mellitus to achieve glycemic control. It has been shown to be safe and effective at 100 mg daily doses. The effect of giving sitagliptin in combination with metformin is thought to have a complimentary and possibly additive effect on glycemic control. PMID:21437126

Lack of Osteoradionecrosis of the Mandible After Intensity-Modulated Radiotherapy for Head and Neck Cancer: Likely Contributions of Both Dental Care and Improved Dose Distributions

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

Ben-David, Merav A.; Diamante, Maximiliano; Radawski, Jeffrey D.

Purpose: To assess the prevalence and dosimetric and clinical predictors of mandibular osteoradionecrosis (ORN) in patients with head and neck cancer who underwent a pretherapy dental evaluation and prophylactic treatment according to a uniform policy and were treated with intensity-modulated radiotherapy (IMRT). Methods and Materials: Between 1996 and 2005, all patients with head-and-neck cancer treated with parotid gland-sparing IMRT in prospective studies underwent a dental examination and prophylactic treatment according to a uniform policy that included extractions of high-risk, periodontally involved, and nonrestorable teeth in parts of the mandible expected to receive high radiation doses, fluoride supplements, and the placementmore » of guards aiming to reduce electron backscatter off metal teeth restorations. The IMRT plans included dose constraints for the maximal mandibular doses and reduced mean parotid gland and noninvolved oral cavity doses. A retrospective analysis of Grade 2 or worse (clinical) ORN was performed. Results: A total of 176 patients had a minimal follow-up of 6 months. Of these, 31 (17%) had undergone teeth extractions before RT and 13 (7%) after RT. Of the 176 patients, 75% and 50% had received {>=}65 Gy and {>=}70 Gy to {>=}1% of the mandibular volume, respectively. Falloff across the mandible characterized the dose distributions: the average gradient (in the axial plane containing the maximal mandibular dose) was 11 Gy (range, 1-27 Gy; median, 8 Gy). At a median follow-up of 34 months, no cases of ORN had developed (95% confidence interval, 0-2%). Conclusion: The use of a strict prophylactic dental care policy and IMRT resulted in no case of clinical ORN. In addition to the dosimetric advantages offered by IMRT, meticulous dental prophylactic care is likely an essential factor in reducing ORN risk.« less

Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline.

PubMed

Arrossi, Silvina; Temin, Sarah; Garland, Suzanne; Eckert, Linda O'Neal; Bhatla, Neerja; Castellsagué, Xavier; Alkaff, Sharifa Ezat; Felder, Tamika; Hammouda, Doudja; Konno, Ryo; Lopes, Gilberto; Mugisha, Emmanuel; Murillo, Rául; Scarinci, Isabel C; Stanley, Margaret; Tsu, Vivien; Wheeler, Cosette M; Adewole, Isaac Folorunso; de Sanjosé, Silvia

2017-10-01

To provide resource-stratified (four tiers), evidence-based recommendations on the primary prevention of cervical cancer globally. The American Society of Clinical Oncology convened a multidisciplinary, multinational panel of oncology, obstetrics/gynecology, public health, cancer control, epidemiology/biostatistics, health economics, behavioral/implementation science, and patient advocacy experts. The Expert Panel reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus-based process with additional experts (consensus ratings group) for one round of formal ratings. Existing sets of guidelines from five guideline developers were identified and reviewed; adapted recommendations formed the evidence base. Five systematic reviews, along with cost-effectiveness analyses, provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75%. In all resource settings, two doses of human papillomavirus vaccine are recommended for girls age 9 to 14 years, with an interval of at least 6 months and possibly up to 12 to 15 months. Individuals with HIV positivity should receive three doses. Maximal and enhanced settings: if girls are age ≥ 15 years and received their first dose before age 15 years, they may complete the series; if no doses were received before age 15 years, three doses should be administered; in both scenarios, vaccination may be through age 26 years. Limited and basic settings: if sufficient resources remain after vaccinating girls age 9 to 14 years, girls who received one dose may receive additional doses between age 15 and 26 years. Maximal, enhanced, and limited settings: if ≥ 50% coverage in the priority female target population, sufficient resources, and cost effectiveness, boys may be vaccinated to prevent other noncervical human papillomavirus-related cancers and diseases. Basic settings: vaccinating boys is not recommended. It is the view of the American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Phase I Trial of Simultaneous In-Field Boost With Helical Tomotherapy for Patients With One to Three Brain Metastases

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

Rodrigues, George, E-mail: george.rodrigues@lhsc.on.ca; Yartsev, Slav; Yaremko, Brian

2011-07-15

Purpose: Stereotactic radiosurgery is an alternative to surgical resection for selected intracranial lesions. Integrated image-guided intensity-modulated-capable radiotherapy platforms such as helical tomotherapy (HT) could potentially replace traditional radiosurgery apparatus. The present study's objective was to determine the maximally tolerated dose of a simultaneous in-field boost integrated with whole brain radiotherapy for palliative treatment of patients with one to three brain metastases using HT. Methods and Materials: The inclusion/exclusion criteria and endpoints were consistent with the Radiation Therapy Oncology Group 9508 radiosurgery trial. The cohorts were constructed with a 3 + 3 design; however, additional patients were enrolled in the lowermore » dose tolerable cohorts during the toxicity assessment periods. Whole brain radiotherapy (30 Gy in 10 fractions) was delivered with a 5-30-Gy (total lesion dose of 35-60 Gy in 10 fractions) simultaneous in-field boost delivered to the brain metastases. The maximally tolerated dose was determined by the frequency of neurologic Grade 3-5 National Cancer Institute Common Toxicity Criteria, version 3.0, dose-limiting toxicity events within each Phase I cohort. Results: A total of 48 patients received treatment in the 35-Gy (n = 3), 40-Gy (n = 16), 50-Gy (n = 15), 55-Gy (n = 8), and 60-Gy (n = 6) cohorts. No patients experienced dose-limiting toxicity events in any of the trial cohorts. The 3-month RECIST assessments available for 32 of the 48 patients demonstrated a complete response in 2, a partial response in 16, stable disease in 6, and progressive disease in 8 patients. Conclusion: The delivery of 60 Gy in 10 fractions to one to three brain metastases synchronously with 30 Gy whole brain radiotherapy was achieved without dose-limiting central nervous system toxicity as assessed 3 months after treatment. This approach is being tested in a Phase II efficacy trial.« less

Pharmacological validation of individual animal locomotion, temperature and behavioural analysis in group-housed rats using a novel automated home cage analysis system: A comparison with the modified Irwin test.

PubMed

Tse, Karen; Sillito, Rowland; Keerie, Amy; Collier, Rachel; Grant, Claire; Karp, Natasha A; Vickers, Cathy; Chapman, Kathryn; Armstrong, J Douglas; Redfern, William S

2018-04-01

The ActualHCA™ system continuously monitors the activity, temperature and behavior of group-housed rats without invasive surgery. The system was validated to detect the contrasting effects of sedative and stimulant test agents (chlorpromazine, clonidine and amphetamine), and compared with the modified Irwin test (mIT) with rectal temperature measurements. Six male Han Wistar rats per group were used to assess each test agent and vehicle controls in separate ActualHCA™ recordings and mIT. The mIT was undertaken at 15, 30 mins, 1, 2, 4 and 24 h post-dose. ActualHCA™ recorded continuously for 24 h post-dose under 3 experimental conditions: dosed during light phase, dark phase, and light phase with a scheduled cage change at the time of peak effects determined by mIT. ActualHCA™ detected an increase stimulated activity from the cage change at 1-2 h post-dose which was obliterated by chlorpromazine and clonidine. Amphetamine increased activity up to 4 h post-dose in all conditions. Temperature from ActualHCA™ was affected by all test agents in all conditions. The mIT showed effects on all 3 test agents up to 4 h post-dose, with maximal effects at 1-2 h post-dose. The maximal effects on temperature from ActualHCA™ differed from mIT. Delayed effects on activity were detected by ActualHCA™, but not on mIT. Continuous monitoring has the advantage of capturing effects over time that may be missed with manual tests using pre-determined time points. This automated behavioural system does not replace the need for conventional methods but could be implemented simultaneously to improve our understanding of behavioural pharmacology. Copyright © 2018 Elsevier Inc. All rights reserved.

Prostanoid-induced expression of matrix metalloproteinase-1 messenger ribonucleic acid in rat osteosarcoma cells

NASA Technical Reports Server (NTRS)

Clohisy, J. C.; Connolly, T. J.; Bergman, K. D.; Quinn, C. O.; Partridge, N. C.

1994-01-01

Individual prostanoids have distinct potencies in activating intracellular signaling pathways and regulating gene expression in osteoblastic cells. The E-series prostaglandins (PGs) are known to stimulate matrix metalloproteinase-1 (MMP-1) synthesis and secretion in certain rodent and human osteoblastic cells, yet the intracellular events involved remain unclear. To further characterize this response and its signal transduction pathway(s), we examined prostanoid-induced expression of the MMP-1 gene in the rat osteoblastic osteosarcoma cell line UMR 106-01. Northern blot analysis demonstrated that prostaglandin E2 (PGE2) and PGE1 were very potent stimulators (40-fold) of MMP-1 transcript abundance, PGF2 alpha and prostacyclin were weak stimulators (4-fold), and thromboxane-B2 had no effect. The marked increase in MMP-1 transcript abundance after PGE2 treatment was first detected at 2 h, became maximal at 4 h, and persisted beyond 24 h. This response was dose dependent and elicited maximal and half-maximal effects with concentrations of 10(-6) and 0.6 x 10(-7) M, respectively. Cycloheximide, a protein synthesis inhibitor, completely blocked this effect of PGE2, suggesting that the expression of other genes is required. Nuclear run-on experiments demonstrated that PGE2 rapidly activates MMP-1 gene transcription, with a maximal increase at 2-4 h. The second messenger analog, 8-bromo-cAMP, mimicked the effects of PGE2 by stimulating a dose-dependent increase in MMP-1 messenger RNA (mRNA) levels, with a maximal effect quantitatively similar to that observed with PGE2. Thus, in UMR 106-01 cells, different prostanoids have distinct potencies in stimulating MMP-1 mRNA abundance. Our data suggest that PGE2 stimulation of MMP-1 synthesis is due to activation of MMP-1 gene transcription and a subsequent marked increase in MMP-1 mRNA abundance. This effect is dependent on de novo protein synthesis and is mimicked by protein kinase-A activation.

2,3-Diphosphoglycerate is a nonselective inhibitor of inositol 1,4,5-trisphosphate action and metabolism.

PubMed

Guillemette, G; Favreau, I; Lamontagne, S; Boulay, G

1990-04-25

Inositol 1,4,5-trisphosphate (InsP3) is an important second messenger generated from the hydrolysis of phosphatidylinositol 4,5-bisphosphate by phospholipase C in response to Ca2(+)-mobilizing stimuli. InsP3 interacts with specific intracellular receptors and triggers the release of sequestered Ca2+ from an intracellular store. We have looked at the influence of 2,3-diphosphoglycerate on the action and metabolism of InsP3 in the bovine adrenal cortex. 2,3-Diphosphoglycerate blocked InsP3 binding to adrenal cortex microsomes with a half-maximal efficiency of 0.5 mM. Scatchard analyses revealed that 2,3-diphosphoglycerate did not change the maximal capacity of the microsomes, but decreased their binding affinity for InsP3. The Ca2(+)-releasing activity of InsP3 on the same microsomal preparation was monitored with the fluorescent indicator, Fura-2. 2,3-Diphosphoglycerate blocked this activity with a half-maximal efficiency of 2 mM. The effect of 2,3-diphosphoglycerate could be overcome by supramaximal doses of InsP3, indicating a competitive inhibitory effect. The activity of InsP3 phosphatase from bovine adrenal cortex microsomes was also studied. 2,3-Diphosphoglycerate inhibited the activity of the phosphatase with a half-maximal efficiency of 0.3 mM. Lineweaver-Burke plots revealed that this effect was competitive. Finally, 2,3-diphosphoglycerate was also able to inhibit the activity of a partially purified preparation of InsP3 kinase from bovine adrenal cortex cytosol. The half-maximal dose was around 10 mM and the Lineweaver-Burke plot showed that the inhibition was competitive. These results show that 2,3-diphosphoglycerate can be considered as a structural analog of InsP3. Its inhibitory effects, however, are not selective enough to use it as an InsP3 protective agent in Ca2(+)-mobilization studies.

Effects of long term supplementation of anabolic androgen steroids on human skeletal muscle.

PubMed

Yu, Ji-Guo; Bonnerud, Patrik; Eriksson, Anders; Stål, Per S; Tegner, Yelverton; Malm, Christer

2014-01-01

The effects of long-term (over several years) anabolic androgen steroids (AAS) administration on human skeletal muscle are still unclear. In this study, seventeen strength training athletes were recruited and individually interviewed regarding self-administration of banned substances. Ten subjects admitted having taken AAS or AAS derivatives for the past 5 to 15 years (Doped) and the dosage and type of banned substances were recorded. The remaining seven subjects testified to having never used any banned substances (Clean). For all subjects, maximal muscle strength and body composition were tested, and biopsies from the vastus lateralis muscle were obtained. Using histochemistry and immunohistochemistry (IHC), muscle biopsies were evaluated for morphology including fiber type composition, fiber size, capillary variables and myonuclei. Compared with the Clean athletes, the Doped athletes had significantly higher lean leg mass, capillary per fibre and myonuclei per fiber. In contrast, the Doped athletes had significantly lower absolute value in maximal squat force and relative values in maximal squat force (relative to lean body mass, to lean leg mass and to muscle fiber area). Using multivariate statistics, an orthogonal projection of latent structure discriminant analysis (OPLS-DA) model was established, in which the maximal squat force relative to muscle mass and the maximal squat force relative to fiber area, together with capillary density and nuclei density were the most important variables for separating Doped from the Clean athletes (regression  =  0.93 and prediction  =  0.92, p<0.0001). In Doped athletes, AAS dose-dependent increases were observed in lean body mass, muscle fiber area, capillary density and myonuclei density. In conclusion, long term AAS supplementation led to increases in lean leg mass, muscle fiber size and a parallel improvement in muscle strength, and all were dose-dependent. Administration of AAS may induce sustained morphological changes in human skeletal muscle, leading to physical performance enhancement.

Effects of Long Term Supplementation of Anabolic Androgen Steroids on Human Skeletal Muscle

PubMed Central

Yu, Ji-Guo; Bonnerud, Patrik; Eriksson, Anders; Stål, Per S.; Tegner, Yelverton; Malm, Christer

2014-01-01

The effects of long-term (over several years) anabolic androgen steroids (AAS) administration on human skeletal muscle are still unclear. In this study, seventeen strength training athletes were recruited and individually interviewed regarding self-administration of banned substances. Ten subjects admitted having taken AAS or AAS derivatives for the past 5 to 15 years (Doped) and the dosage and type of banned substances were recorded. The remaining seven subjects testified to having never used any banned substances (Clean). For all subjects, maximal muscle strength and body composition were tested, and biopsies from the vastus lateralis muscle were obtained. Using histochemistry and immunohistochemistry (IHC), muscle biopsies were evaluated for morphology including fiber type composition, fiber size, capillary variables and myonuclei. Compared with the Clean athletes, the Doped athletes had significantly higher lean leg mass, capillary per fibre and myonuclei per fiber. In contrast, the Doped athletes had significantly lower absolute value in maximal squat force and relative values in maximal squat force (relative to lean body mass, to lean leg mass and to muscle fiber area). Using multivariate statistics, an orthogonal projection of latent structure discriminant analysis (OPLS-DA) model was established, in which the maximal squat force relative to muscle mass and the maximal squat force relative to fiber area, together with capillary density and nuclei density were the most important variables for separating Doped from the Clean athletes (regression  =  0.93 and prediction  =  0.92, p<0.0001). In Doped athletes, AAS dose-dependent increases were observed in lean body mass, muscle fiber area, capillary density and myonuclei density. In conclusion, long term AAS supplementation led to increases in lean leg mass, muscle fiber size and a parallel improvement in muscle strength, and all were dose-dependent. Administration of AAS may induce sustained morphological changes in human skeletal muscle, leading to physical performance enhancement. PMID:25207812

Reinforcing effects of sigma-receptor agonists in rats trained to self-administer cocaine.

PubMed

Hiranita, Takato; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

2010-02-01

sigma-Receptor (sigmaR) antagonists have been reported to block certain effects of psychostimulant drugs. The present study examined the effects of sigmaR ligands in rats trained to self-administer cocaine (0.032-1.0 mg/kg/inj i.v.) under fixed-ratio 5-response schedules of reinforcement. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine, or by the sigmaR agonists, 1,3-di-(2-tolyl)guanidine (DTG; 1.0 mg/kg/inj) or 2-(4-morpholinethyl) 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084; 0.32 mg/kg/inj), when substituted for cocaine. Lower response rates were maintained at higher and lower doses of the compounds. No dose of the sigmaR antagonists [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD 1047), N-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD 1063)] maintained responding appreciably above levels obtained when responding had no consequences. Presession treatment with sigmaR agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, (-)-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (WIN 35,428), dose-dependently shifted the DTG and PRE-084 self-administration dose-effect curves leftward. Treatment with the sigmaR antagonists dose-dependently decreased response rates maintained by DTG or PRE-084, but did not affect cocaine self-administration. Response rates maintained by maximally effective DTG or PRE-084 doses were decreased by sigmaR antagonists at lower doses than those that decreased response rates maintained by food reinforcement. Although sigmaR antagonists block some cocaine-induced effects, the lack of effect on cocaine self-administration suggests that the primary reinforcing effects of cocaine do not involve direct effects at sigmaRs. However, the self-administration of sigmaR agonists in cocaine-trained subjects, facilitation of cocaine self-administration by sigmaR-agonist pretreatment, and the facilitation of sigmaR-agonist self-administration by WIN 35,428, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically mediated actions and sigmaR-mediated actions of the drugs.

Reinforcing Effects of σ-Receptor Agonists in Rats Trained to Self-Administer Cocaine

PubMed Central

Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi

2010-01-01

σ-Receptor (σR) antagonists have been reported to block certain effects of psychostimulant drugs. The present study examined the effects of σR ligands in rats trained to self-administer cocaine (0.032–1.0 mg/kg/inj i.v.) under fixed-ratio 5-response schedules of reinforcement. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine, or by the σR agonists, 1,3-di-(2-tolyl)guanidine (DTG; 1.0 mg/kg/inj) or 2-(4-morpholinethyl) 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084; 0.32 mg/kg/inj), when substituted for cocaine. Lower response rates were maintained at higher and lower doses of the compounds. No dose of the σR antagonists [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD 1047), N-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD 1063)] maintained responding appreciably above levels obtained when responding had no consequences. Presession treatment with σR agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, (−)-2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), dose-dependently shifted the DTG and PRE-084 self-administration dose-effect curves leftward. Treatment with the σR antagonists dose-dependently decreased response rates maintained by DTG or PRE-084, but did not affect cocaine self-administration. Response rates maintained by maximally effective DTG or PRE-084 doses were decreased by σR antagonists at lower doses than those that decreased response rates maintained by food reinforcement. Although σR antagonists block some cocaine-induced effects, the lack of effect on cocaine self-administration suggests that the primary reinforcing effects of cocaine do not involve direct effects at σRs. However, the self-administration of σR agonists in cocaine-trained subjects, facilitation of cocaine self-administration by σR-agonist pretreatment, and the facilitation of σR-agonist self-administration by WIN 35,428, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically mediated actions and σR-mediated actions of the drugs. PMID:19892920

The effects of perphenazine on self-administration behavior.

PubMed

Johanson, C E; Kandel, D A; Bonese, K

1976-04-01

In Experiment 1.6 rhesus monkeys prepared with intravenous catheters responded on a fixed-ratio 10 schedule for either an injection of 0.2 mg/kg of cocaine or 0.5 mg/kg of pentobarbital during a daily 3 hr session. The substitution of saline or various doses of perphenazine resulted in very low rates of responding. These results indicate that perphenazine is not a positive reinforcer. Pretreating animals maintained on 0.1 mg/kg or 0.2 mg/kg of cocaine with perphenazine resulted in increases in rate of self-administration at some doses and a decrease in rate at higher doses. The dose of perphenazine which resulted in the maximal increase in cocaine self-administration was directly related to the dose of cocaine maintaining responding. Pretreating animals maintained on 0.5 mg/kg of pentobarbital with perphenazine had no effect at doses which increased cocaine self-administration but decreased rate of pentobarbital self-administration at higher doses. These results indicate that perphenazine is capable of antagonizing some of the effects of cocaine.

Quantities for assessing high photon doses to the body: a calculational approach.

PubMed

Eakins, Jonathan S; Ainsbury, Elizabeth A

2018-06-01

Tissue reactions are the most clinically significant consequences of high-dose exposures to ionising radiation. However, currently there is no universally recognized dose quantity that can be used to assess and report generalised risks to individuals following whole body exposures in the high-dose range. In this work, a number of potential dose quantities are presented and discussed, with mathematical modelling techniques employed to compare them and explore when their differences are most or least manifest. The results are interpreted to propose the average (D GRB ) of the absorbed doses to the stomach, small intestine, red bone marrow, and brain as the optimum quantity for informing assessments of risk. A second, maximally conservative dose quantity (D Max ) is also suggested, which places limits on any under-estimates resulting from the adoption of D GRB . The primary aim of this work is to spark debate, with further work required to refine the final choice of quantity or quantities most appropriate for the full range of different potential exposure scenarios.

Red marrow and blood dosimetry in 131I treatment of metastatic thyroid carcinoma: pre-treatment versus in-therapy results

NASA Astrophysics Data System (ADS)

Giostra, A.; Richetta, E.; Pasquino, M.; Miranti, A.; Cutaia, C.; Brusasco, G.; Pellerito, R. E.; Stasi, M.

2016-06-01

Treatment with radioiodine is a standard procedure for patients with well-differentiated thyroid cancer, but the main approach to the therapy is still empiric, consisting of the administration of fixed activities. A predictive individualized dosimetric study may represent an important tool for physicians to determine the best activity to prescribe. The aim of this work is to compare red marrow and blood absorbed dose values obtained in the pre-treatment (PT) dosimetry phase with those obtained in the in-treatment (IT) dosimetry phase in order to estimate the predictive power of PT trial doses and to determine if they can be used as a decision-making tool to safely administer higher 131I activity to potentially increase the efficacy of treatment. The PT and IT dosimetry for 50 patients has been evaluated using three different dosimetric approaches. In all three approaches blood and red marrow doses, are calculated as the sum of two components, the dose from 131I activity in the blood and the dose from 131I activity located in the remainder of the body (i.e. the blood and whole-body contributions to the total dose). PT and IT dose values to blood and red marrow appear to be well correlated irrespective of the dosimetric approach used. Linear regression analyses of PT and IT total doses, for blood and red marrow, and the whole-body contribution to these doses, showed consistent best fit slope and correlation coefficient values of approximately 0.9 and 0.6, respectively: analyses of the blood dose contribution to the total doses also yielded similar values for the best fit slope but with correlation coefficient values of approximately 0.4 reflecting the greater variance in these dose estimates. These findings suggest that pre-treatment red marrow dose assessments may represent an important tool to personalize metastatic thyroid cancer treatment, removing the constraints of a fixed activity approach and permitting potentially more effective higher 131I activities to be safely used in-treatment.

SU-E-J-228: MRI-Based Planning: Dosimetric Feasibility of Dose Painting for ADCDefined Intra-Prostatic Tumor

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

Chen, X; Dalah, E; Prior, P

Purpose: Apparent diffusion coefficient (ADC) map may help to delineate the gross tumor volume (GTV) in prostate gland. Dose painting with external beam radiotherapy for GTV might increase the local tumor control. The purpose of this study is to explore the maximum boosting dose on GTV using VMAT without sacrificing sparing of organs at risk (OARs) in MRI based planning. Methods: VMAT plans for 5 prostate patients were generated following the commonly used dose volume (DV) criteria based on structures contoured on T2 weighted MRI with bulk electron density assignment using electron densities derived from ICRU46. GTV for each patientmore » was manually delineated based on ADC maps and fused to T2-weighted image set for planning study. A research planning system with Monte Carlo dose engine (Monaco, Elekta) was used to generate the VMAT plans with boosting dose on GTV gradually increased from 85Gy to 100Gy. DV parameters, including V(boosting-dose) (volume covered by boosting dose) for GTV, V75.6Gy for PTV, V45Gy, V70Gy, V72Gy and D1cc (Maximum dose to 1cc volume) for rectum and bladder, were used to measure plan quality. Results: All cases achieve at least 99.0% coverage of V(boosting-dose) on GTV and 95% coverage of V75.6Gy to the PTV. All the DV criteria, V45Gy≤50% and V70Gy≤15% for bladder and rectum, D1cc ≤77Gy (Rectum) and ≤80Gy (Bladder), V72Gy≤5% (rectum and bladder) were maintained when boosting GTV to 95Gy for all cases studied. Except for two patients, all the criteria were also met when the boosting dose goes to 100Gy. Conclusion: It is dosimetrically feasible safe to boost the dose to at least 95Gy to ADC defined GTV in prostate cancer using MRI guided VMAT delivery. Conclusion: It is dosimetrically feasible safe to boost the dose to at least 95Gy to ADC defined GTV in prostate cancer using MRI guided VMAT delivery. This research is partially supported by Elekta Inc.« less

Transcriptional response of rat frontal cortex following acute In Vivo exposure to the pyrethroid insecticides permethrin and deltamethrin

PubMed Central

Harrill, Joshua A; Li, Zhen; Wright, Fred A; Radio, Nicholas M; Mundy, William R; Tornero-Velez, Rogelio; Crofton, Kevin M

2008-01-01

Background Pyrethroids are neurotoxic pesticides that interact with membrane bound ion channels in neurons and disrupt nerve function. The purpose of this study was to characterize and explore changes in gene expression that occur in the rat frontal cortex, an area of CNS affected by pyrethroids, following an acute low-dose exposure. Results Rats were acutely exposed to either deltamethrin (0.3 – 3 mg/kg) or permethrin (1 – 100 mg/kg) followed by collection of cortical tissue at 6 hours. The doses used range from those that cause minimal signs of intoxication at the behavioral level to doses well below apparent no effect levels in the whole animal. A statistical framework based on parallel linear (SAM) and isotonic regression (PIR) methods identified 95 and 53 probe sets as dose-responsive. The PIR analysis was most sensitive for detecting transcripts with changes in expression at the NOAEL dose. A sub-set of genes (Camk1g, Ddc, Gpd3, c-fos and Egr1) was then confirmed by qRT-PCR and examined in a time course study. Changes in mRNA levels were typically less than 3-fold in magnitude across all components of the study. The responses observed are consistent with pyrethroids producing increased neuronal excitation in the cortex following a low-dose in vivo exposure. In addition, Significance Analysis of Function and Expression (SAFE) identified significantly enriched gene categories common for both pyrethroids, including some relating to branching morphogenesis. Exposure of primary cortical cell cultures to both compounds resulted in an increase (~25%) in the number of neurite branch points, supporting the results of the SAFE analysis. Conclusion In the present study, pyrethroids induced changes in gene expression in the frontal cortex near the threshold for decreases in ambulatory motor activity in vivo. The penalized regression methods performed similarly in detecting dose-dependent changes in gene transcription. Finally, SAFE analysis of gene expression data identified branching morphogenesis as a biological process sensitive to pyrethroids and subsequent in vitro experiments confirmed this predicted effect. The novel findings regarding pyrethroid effects on branching morphogenesis indicate these compounds may act as developmental neurotoxicants that affect normal neuronal morphology. PMID:19017407

Optimizing Preseason Training Loads in Australian Football.

PubMed

Carey, David L; Crow, Justin; Ong, Kok-Leong; Blanch, Peter; Morris, Meg E; Dascombe, Ben J; Crossley, Kay M

2018-02-01

To investigate whether preseason training plans for Australian football can be computer generated using current training-load guidelines to optimize injury-risk reduction and performance improvement. A constrained optimization problem was defined for daily total and sprint distance, using the preseason schedule of an elite Australian football team as a template. Maximizing total training volume and maximizing Banister-model-projected performance were both considered optimization objectives. Cumulative workload and acute:chronic workload-ratio constraints were placed on training programs to reflect current guidelines on relative and absolute training loads for injury-risk reduction. Optimization software was then used to generate preseason training plans. The optimization framework was able to generate training plans that satisfied relative and absolute workload constraints. Increasing the off-season chronic training loads enabled the optimization algorithm to prescribe higher amounts of "safe" training and attain higher projected performance levels. Simulations showed that using a Banister-model objective led to plans that included a taper in training load prior to competition to minimize fatigue and maximize projected performance. In contrast, when the objective was to maximize total training volume, more frequent training was prescribed to accumulate as much load as possible. Feasible training plans that maximize projected performance and satisfy injury-risk constraints can be automatically generated by an optimization problem for Australian football. The optimization methods allow for individualized training-plan design and the ability to adapt to changing training objectives and different training-load metrics.

Aspirin during Pregnancy: Is It Safe?

MedlinePlus

... 2015. LeFevre ML, et al. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine. 2014;161: ...

The effects of febuxostat on the pharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate

PubMed Central

Naik, Himanshu; Wu, Jing-tao; Palmer, Robert; McLean, Lachy

2012-01-01

AIMS To determine the effect of febuxostat on cytochrome P450 2C8 (CYP2C8) activity using rosiglitazone as a CYP2C8 substrate. METHODS Healthy subjects received febuxostat 120 mg daily (regimen A) or matching placebo (regimen B) for 9 days along with a single oral dose of rosiglitazone 4 mg on day 5 in a double-blind, randomized, cross-over fashion (≥7 day washout between periods). Plasma samples for analysis of the impact of febuxostat on the pharmacokinetics (PK) of rosiglitazone and its metabolite, N-desmethylrosiglitazone, were collected for 120 h after co-administration. RESULTS Of the 39 subjects enrolled, 36 completed the study and were included in the PK analyses. Rosiglitazone PK parameters were comparable between regimens A and B. Median time to maximal plasma concentration, mean maximal plasma concentration (Cmax), area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC0–tlqc), AUC from time zero to infinity (AUC0–∞), and terminal elimination half-life for regimen A were 0.50 h, 308.6 ng ml−1, 1594.9 ng h ml−1, 1616.0 ng h ml−1 and 4.1 h, respectively, and for regimen B they were 0.50 h, 327.6 ng ml−1, 1564.5 ng h ml−1, 1584.2 ng h ml−1 and 4.0 h, respectively. Point estimates for the ratio of regimen A to regimen B (90% confidence intervals) for rosiglitazone Cmax, AUC0–tlqc and AUC0–∞ central values were 0.94 (0.89–1.00), 1.02 (1.00–1.04) and 1.02 (1.00–1.04), respectively. CONCLUSIONS Co-administration of febuxostat had no effect on rosiglitazone or N-desmethylrosiglitazone PK parameters, suggesting that febuxostat can be given safely with drugs metabolized through CYP2C8. PMID:22242967

Acute and sub-chronic oral toxicity studies of erythritol in Beagle dogs.

PubMed

Eapen, Alex K; de Cock, Peter; Crincoli, Christine M; Means, Charlotte; Wismer, Tina; Pappas, Christopher

2017-07-01

Polyols, also known as sugar alcohols, are widely used in the formulation of tooth-friendly and reduced-calorie foods. Considering the significant health benefits of polyols in products formulated for human use, there is increased interest in evaluating potential uses in companion animal applications. Erythritol and xylitol are two polyols which are currently widely used in products ranging from reduced-sugar foods to personal care and cosmetics. Published studies have shown that both of these compounds are well-tolerated in rodents. Their toxicity profiles differ when comparing canine safety data. Doses of xylitol as low as 0.15 g/kg-BW in dogs can result in life-threatening hypoglycemia and acute liver failure, whereas erythritol is well-tolerated in dogs with reported No Adverse Effect Levels upwards of 5 g/kg-BW/day in repeat-dose studies. While pivotal studies substantiating the safe use of erythritol in humans have been published, there are limited published studies to support the safe use of erythritol in dogs. Here we present the results of an acute oral and a sub-chronic oral toxicity study in Beagle dogs. Given the potential health benefits of oral products formulated with erythritol and the data presented herein substantiating the safe use in dogs, erythritol can be safely used in products for canines. Copyright © 2017 Elsevier Ltd. All rights reserved.

Low-dose mitomycin C, etoposide, and cisplatin for invasive vulvar Paget's disease.

PubMed

Watanabe, Yoh; Hoshiai, H; Ueda, H; Nakai, H; Obata, K; Noda, K

2002-01-01

We report the effect of low-dose mitomycin C, etoposide, and cisplatin (low-dose MEP) therapy for three patients with invasive vulvar Paget's disease (invasive VPD) who declined radical vulvectomy and skin grafting. One patient achieved a complete response, while the other two showed partial responses (PR) without grade 3 or 4 adverse effects. The two patients with PR were undergone partial vulvectomy and inguinal lymph node dissection. All patients have no sign of recurrence for 10 months after chemotherapy. Our present results suggest that low-dose MEP is an effective and safe chemotherapy for invasive VPD and low-dose MEP may significantly improve postoperative quality of life in patients with invasive VPD by avoiding extensive vulvar resection and skin grafting.

Paracetamol overdose.

PubMed

Skinner, Anita

2015-02-20

Paracetamol is safe and effective at the therapeutic dose. It is beneficial as an analgesic and is an effective antipyretic. Paracetamol is cheap and easy to buy over the counter, which makes it a common choice in intentional overdose.

Effect of harmane on the convulsive threshold in epilepsy models in mice.

PubMed

Aricioglu, Feyza; Yillar, Okan; Korcegez, Eylem; Berkman, Kemal

2003-12-01

The study investigated the activity of harmane on maximal electroshock seizures (MES) and seizures induced by pentilentetrazole (PTZ) in mice. Initial studies established convulsive current 50 (CC(50)) values or MES and effective dose 50 (ED(50)) for PTZ to produce seizures. Harmane (2.5, 5.0, or 10 mg/kg intraperitoneally) increased the threshold of seizures in MES dose-dependently. The convulsions produced by PTZ were decreased by the low dose of harmane (2.5 mg/kg), but the high dose of harmane (10 mg/kg) resulted in worse grade V convulsions followed by more lethality compared with PTZ alone. Therefore, harmane seems to be protective against grand mal seizures in the MES model but not against a petit mal seizure model (PTZ) in mice.

Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

PubMed

Pei, Zhonghua; Li, Xiaofeng; von Geldern, Thomas W; Madar, David J; Longenecker, Kenton; Yong, Hong; Lubben, Thomas H; Stewart, Kent D; Zinker, Bradley A; Backes, Bradley J; Judd, Andrew S; Mulhern, Mathew; Ballaron, Stephen J; Stashko, Michael A; Mika, Amanda K; Beno, David W A; Reinhart, Glenn A; Fryer, Ryan M; Preusser, Lee C; Kempf-Grote, Anita J; Sham, Hing L; Trevillyan, James M

2006-11-02

Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.

Technology, safety and costs of decommissioning reference independent spent fuel storage installations. [Contains glossary

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

Ludwick, J D; Moore, E B

1984-01-01

Safety and cost information is developed for the conceptual decommissioning of five different types of reference independent spent fuel storage installations (ISFSIs), each of which is being given consideration for interim storage of spent nuclear fuel in the United States. These include one water basin-type ISFSI (wet) and four dry ISFSIs (drywell, silo, vault, and cask). The reference ISFSIs include all component parts necessary for the receipt, handling and storage of spent fuel in a safe and efficient manner. Three decommissioning alternatives are studied to obtain comparisons between costs (in 1981 dollars), occupational radiation doses, and potential radiation doses tomore » the public. The alternatives considered are: DECON (immediate decontamination), SAFSTOR (safe storage followed by deferred decontamination), and ENTOMB (entombment followed by long-term surveillance).« less

Can triptans safely be used for airplane headache?

PubMed

Ipekdal, H Ilker; Karadaş, Ömer; Öz, Oğuzhan; Ulaş, Ümit H

2011-12-01

A few cases of airplane headache (AH) have been reported in the literature. Treatment strategies of AHs are also controversial. We followed-up five patients with AH. They were symptom-free during the daytime. Their physical, neurological, and ear-nose-throat examinations were all normal. Blood chemistries, cerebral magnetic resonance imaging, cerebral magnetic resonance imaging angiography, and paranasal sinus tomography studies of the patients were also normal. We preferred triptans because of the possible effect on the mechanism of AH. Patients were recommended to use single-dose of their drugs half an hour prior to flights. All of the patients had a good response to single dose triptan treatment and became headache-free during flights. This is the first study which puts forward the usefulness of the triptans as a safe treatment choice for airplane AH.

Progestins to control feline reproduction: Historical abuse of high doses and potentially safe use of low doses.

PubMed

Romagnoli, Stefano

2015-09-01

The high fertility rate of cats means that methods to control feline reproduction are a requirement for cat breeders and pet owners, as well as for those involved in the management of feral cat populations. Progestins continue to be used to prevent queens from cycling, and also as an adjunct or alternative to surgical sterilization within trap-neuter-return (TNR) programs. A considerable body of information exists on megestrol acetate (MA) and medroxyprogesterone acetate (MPA), thanks to the many studies and case reports published in the scientific literature over the past 50 years documenting their clinical use in cats. Comparatively less is known about the use in cats of more recent progestins such as levonorgestrel, proligestone, delmadinone, chlormadinone and altrenogest. Based on a combination of dose, frequency and duration of treatment, MA can be categorized into low (0.625 mg/kg/week for up to 30 weeks), medium (0.625 mg/kg q24h for 1 week or q48h for up to 2 weeks) and high (0.625 mg/kg q24h or q48h for several weeks, or weekly for months or years) dosages. Studies suggest that low dosages can be used relatively safely in cats, while higher dosages increase the risk and severity of adverse reactions. Early work showing that an oral MPA dosage of 0.01 mg/kg administered q24h for 12 months suppresses oestrus in queens effectively and safely has not been considered, and much higher MPA dosages (>6.25 mg/kg q24h) have been used in cats over the past 40 years. Progestins should always be used with caution. Using the lowest possible dosages, MA and MPA may, however, continue to be used safely in pet queens as well as (in conjunction with TNR programs) for the control of feral cat colonies. More recent progestins appear to be effective and safe, albeit their efficacy and safety need to be further investigated. © The Author(s) 2015.

Pharmacological profile of the aerial parts of Rubus ulmifolius Schott.

PubMed

Ali, Niaz; Shaoib, Mohammad; Shah, Syed Wadood Ali; Shah, Ismail; Shuaib, Muhammad

2017-01-19

As aerial parts of Rubus ulmifolius contains phytochemicals like flavonoids and tannins. And whereas flavonoids and tannins have antioxidant and antipyretic activity, hence, current work is carried out to screen crude methanolic extract of aerial parts of Rubus ulmifolius (Ru.Cr) and crude flavonoids rich extract of Rubus ulmifolius (Ru.F) for possible antioxidant and antipyretic activity. Ru.Cr and Ru.F are also tested for brine shrimps lethality bioassay. Ru.F is tested for the first time for possible antioxidant and antipyretic activity. Preliminary phytochemical screening of Ru.Cr and Ru.F was performed as it provides rapid finger printing for targeting a pharmacological activity. Acute toxicity and Brine shrimps' cytotoxicity studies of Ru.Cr and Ru.F were performed to determine its safe dose range. Antioxidant and antipyretic studies were also performed as per reported procedures. Ru.Cr tested positive for presence of tannins, alkaloids, flavonoids and steroids. Ru.Cr is safe up to 6 g/kg following oral doses for acute toxicity study. Ru.Cr is safe up to 75 μg/kg (p.o), LC 50 for Ru.Cr and Ru.F are 16.7 ± 1.4 μg/ml 10.6 ± 1.8 μg/ml, respectively (n = 3). Both Ru.Cr and Ru.F demonstrated comparable antioxidant activity using vitamin C as standard (p ≤ 0.05). In test dose of 300 mg of Ru.Cr, rectal temperature was reduced by 74% (p ≤ 0.05) on 4 th hour of the administration. More, Ru.F produced 72% reduction in pyrexia (p ≤ 0.05) on 4 th hour of administration of paracetamol in Westar rats. The current work confirms that aerial parts of Rubus ulmifolius contain flavonoids that are safe up to 6 g/kg (p.o). Crude methanolic extract and flavonoids rich fraction of Rubus ulmifolius have significant antioxidant and antipyretic activity. Further work is required to isolate the pharmacologically active substances for relatively safe and effective antipyretics and antioxidants.

Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension: Safe and Tolerable.

PubMed

El-Kersh, Karim; Ruf, Kathryn M; Smith, J Shaun

There is no standard protocol for intravenous treprostinil dose escalation. In most cases, slow up-titration is performed in the outpatient setting. However, rapid up-titration in an inpatient setting is an alternative that provides opportunity for aggressive treatment of common side effects experienced during dose escalation. In this study, we describe our experience with inpatient rapid up-titration of intravenous treprostinil. This was a single-center, retrospective study in which we reviewed the data of subjects with pulmonary arterial hypertension treated at our center who underwent inpatient rapid up-titration of intravenous treprostinil. Our treprostinil dose escalation protocol included initiation at 2 ng·kg·min with subsequent up-titration by 1 ng·kg·min every 6 to 8 hours as tolerated by side effects. A total of 16 subjects were identified. Thirteen subjects were treprostinil naive (naive group), and 3 subjects were receiving subcutaneous treprostinil but were hospitalized for further intravenous up-titration of treprostinil dose (nonnaive group). In the naive group, the median maximum dose achieved was 20 ng·kg·min with an interquartile range (IQR) of 20-23 ng·kg·min. The median up-titration interval was 6 days (IQR: 4-9). In the nonnaive group, the median maximum dose achieved was 20 ng·kg·min (range: 17-30). The median up-titration interval was 8.5 days (range: 1.5-11). Overall, the median maximum dose achieved was 20 ng·kg·min (IQR: 20-23.5), and the median up-titration interval was 6 days (IQR: 4.6-9.25), with no reported significant adverse hemodynamic events. In patients with pulmonary arterial hypertension, rapid inpatient titration of intravenous treprostinil is safe and tolerable.

Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy

PubMed Central

Tseliou, Eleni; Cheng, Ke; Luthringer, Daniel J.; Ho, Chak-Sum; Takayama, Kentaro; Minamino, Naoto; Dawkins, James F.; Chowdhury, Supurna; Duong, Doan Trang; Seinfeld, Jeffrey; Middleton, Ryan C.; Dharmakumar, Rohan; Li, Debiao; Marbán, Linda; Makkar, Raj R.; Marbán, Eduardo

2014-01-01

Background Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy. Methods and Results We studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22) post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled (“dose optimization”) study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16). Finally, the superior product and dose (150 million cardiospheres) were tested in a blinded, randomized, placebo-controlled (“pivotal”) study (n = 22). Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells) was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo. Conclusions Dose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration. PMID:25460005

Overnight efficacy of polyethylene glycol laxative.

PubMed

Di Palma, Jack A; Smith, Julie R; Cleveland, Mark vB

2002-07-01

Clinical studies in constipated adult patients have shown that a 17- or 34-g daily dose of polyethylene glycol (PEG) 3350 (MiraLax) is safe and effective for the treatment of constipation, with the best efficacy seen in wk 2 of treatment. The purpose of this study was to determine an optimal dose of PEG to provide satisfactory relief of constipation within 24 h. A total of 24 adult study subjects who met Rome II criteria for constipation were randomized in a double-blind, parallel pilot study to receive a single dose of placebo or PEG laxative at doses of 51, 68, or 85 g in 500 ml of flavored water. Over a 72-h period, subjects rated bowel movements (BM), completeness of evacuation, and satisfaction. The 68-g dose seemed to be most satisfactory. Five of six subjects had a BM within 24 h. The time to first BM was 14.8 h for 68 g versus 27.3 h for placebo (p = NS). The time to second BM was 19.2 h versus 47.2 h for 68 g and placebo, respectively (p = 0.003). Of the subjects receiving 68 g of PEG, 50% and 100% reported complete evacuation for the first and second BM, respectively. The average number of BMs in 24 h for placebo, 51 g, 68 g, and 84 g were 0.5, 2.2, 2.2, and 4.2, respectively (p = 0.004). There were no adverse reactions, and no patient reported incontinence or complained of cramps or diarrhea at any dose. There were no changes in measured electrolytes, calcium, glucose, BUN, creatinine, or serum osmolality. A 68-g dose of PEG laxative seems to provide safe and effective relief in constipated adults within a 24-h period.

Effect of electron beam irradiation on bacterial and Ascaris ova loads and volatile organic compounds in municipal sewage sludge

NASA Astrophysics Data System (ADS)

Engohang-Ndong, Jean; Uribe, R. M.; Gregory, Roger; Gangoda, Mahinda; Nickelsen, Mike G.; Loar, Philip

2015-07-01

Wastewater treatment plants produce large amounts of biosolids that can be utilized for land applications. However, prior to their use, these biosolids must be treated to eliminate risks of infections and to reduce upsetting odors. In this study, microbiological and chemical analyzes were performed before and after treatment of sewage sludge with 3 MeV of an electron beam accelerator in a pilot processing plant. Thus, we determined that dose 4.5 kGy was required to reduce fecal coliform counts to safe levels for land applications of sludge while, 14.5 kGy was necessary to decrease Ascaris ova counts to safe levels. Furthermore, at low doses, electron beam irradiation showed little effect on the concentrations of volatile organic compounds, while some increase were recorded at high doses. The concentration of dimethyl sulfide was reduced by 50-70% at irradiation doses of 25.7 kGy and 30.7 kGy respectively. By contrast, electron beam irradiation increased dimethyl disulfide concentrations. We also showed that electron beam treatment was less energy-consuming with shorter processing times than conventional techniques used to decontaminate sludge. Hence opening new avenues for large urban agglomerations to save money and time when treating biosolids for land application.

Hypertension study in anaesthetized rabbits: protocol proposal for AT1 antagonists screening.

PubMed

Politi, Aggeliki P; Zervou, Maria V; Triantafyllidi, Helen; Zoumpoulakis, Panagiotis G; Mavromoustakos, Thomas M; Zoga, Anastasia A; Moutevelis-Minakakis, Panagiota; Kokotos, George; Iliodromitis, Efstathios K; Kremastinos, Dimitris Th

2010-06-01

The aim of this study was to establish an optimized fast and safe protocol for the pharmacological screening of AT(1) antagonists. The pharmaceutical prototype AT(1) antagonist losartan, its active metabolite EXP3174 and the synthetic compound MMK1 were analysed in order to validate the protocol. Ang II was continuously infused while the animals received the drugs in two procedures. In the post-treatment procedure drugs were administered either in a single bolus dose or in a sequential manner. When losartan was administered in a single bolus dose, efficacy was evident until the 7th min (p=0.012) whilst EXP3174 infusion extended the efficiency up to the end of the study (p=0.006). In addition, the sequential injections of losartan prolonged the inhibitory time interval until the end of the study (p=0.045). In the pre-treatment procedure, results suggested a dose-dependent inhibitory effect for both antagonists. The pressor response to Ang II was unchanged after MMK1 administration either in the post- or in the pre-treatment mode. The proposed protocol appears to be safe, simple and fast for the pharmacological screening of AT(1) antagonists and enables the evaluation of new antagonists using lower doses than any other reported in the literature.

Effects of atorvastatin on human c reactive protein metabolism

USDA-ARS?s Scientific Manuscript database

Statins are known to reduce plasma C-reactive protein (CRP) concentrations. Our goals were to define the mechanisms by which CRP was reduced by maximal dose atorvastatin. Eight subjects with combined hyperlipidemia (5 men and 3 postmenopausal women) were enrolled in a randomized, placebo-controlled...

High dose Intravenous Anti-D Immune Globulin is More Effective and Safe in Indian Paediatric Patients of Immune Thrombocytopenic Purpura

PubMed Central

Jena, Rabindra Kumar; Swain, Kali Prasanna

2016-01-01

Introduction Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. Aim To compare the safety and efficacy of higher dose (75μg/kg) intravenous Anti-D immune globulin against the standard dose of 50μg/kg for the management of ITP in Indian patients. Materials and Methods One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50μg/kg (standard dose) or 75μg /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. Results Seventy one out of 84 patients treated with Anti-D at 75μg/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50μg/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. Conclusion A 75μg/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50μg dose for treatment of newly diagnosed Indian patients of ITP. PMID:28208873

Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women.

PubMed

McKeand, William

2017-09-01

Bazedoxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism while having neutral or estrogen antagonist effects on the breast and endometrium. The present report describes findings from 3 Phase I clinical studies that evaluated the single-dose pharmacokinetics (study 1; n = 84), multiple-dose pharmacokinetics (study 2; n = 23), and absolute bioavailability (study 3; n = 18) of bazedoxifene. All 3 studies enrolled healthy postmenopausal women who were either naturally postmenopausal or had undergone bilateral oophorectomy at least 6 months before the start of the study. Study 1 showed that unconjugated and total (unconjugated and conjugated) bazedoxifene levels increased proportionally with ascending oral doses of bazedoxifene (through the dose range of 5-120 mg). Evaluation with or without food intake was conducted at the 10-mg dose, with no clinically relevant effect on pharmacokinetic parameters. Study 2 showed that bazedoxifene achieved steady state in 1 week and exhibited linear pharmacokinetics in doses of 5 to 40 mg with no unexpected accumulation over the dose range. In accordance with a linear pharmacokinetic profile, mean maximum plasma concentration values increased with increasing dose, with values of 1.6, 6.2, and 12.5 ng/mL for the 5-, 20-, and 40-mg doses, respectively. In study 3, tablet and capsule formulations of bazedoxifene formulations had an estimated oral bioavailability of ~6%. The clearance of bazedoxifene was 0.4 (0.1) L/h/kg based on intravenous administration. The oral formulations had comparable exposure profiles with respect to AUC and AUC0-t, and the 90% CIs for these values were within the bioequivalence limits of 80% to 125%. Bazedoxifene was safe and well tolerated in all 3 studies. These pharmacokinetic evaluations in healthy postmenopausal women found that bazedoxifene displayed linear pharmacokinetics with doses ranging from 5 to 40 mg, with no unexpected accumulation. Food did not seem to have any clinically relevant impact on pharmacokinetic parameters. Bazedoxifene had an estimated oral bioavailability of ~6% and was safe and well tolerated in the range of doses evaluated. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Sensitization by SR-2508 plus Ro 03-8799

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

Stone, H.B.; Luu, Y.H.; Lam, K.N.

1986-07-01

The primary toxicity of Ro 03-8799 is a central nervous system toxicity, whereas that of SR-2508 is a peripheral neuropathy. The feasibility of reducing overall toxicity while maintaining maximal radiosensitization by using the two sensitizers together was tested. The LD50/2 of Ro 03-8799 was 0.68 mg/g body wt (mg/gbw) after intravenous (i.v.) administration, and that of SR-2508 was 4.4 mg/gbw after i.v. administration. When both drugs were given together in equitoxic proportions, the LD50/2 was 0.45 mg of Ro 03-8799 plus 2.9 mg of SR-2508/gbw. These doses are 66% of the respective LD50/2 values of the drugs when given separately.more » Radiosensitization was evaluated using in vivo-in vitro assays with EMT6/SF tumors in BALB/c mice. At drug doses between 10 and 60% of the LD50/2, sensitization was generally maximal and similar to that from misonidazole, but there was less sensitization below this dose, both with the drugs given separately and together. If chronic toxicities of these drugs overlap as do the acute toxicities there will be little or no additional benefit from using these drugs in combination, compared to using them separately.« less

Activities of Various 4-Aminoquinolines Against Infections with Chloroquine-Resistant Strains of Plasmodium falciparum1

PubMed Central

Schmidt, L. H.; Vaughan, Dennis; Mueller, Donna; Crosby, Ruth; Hamilton, Rebecca

1977-01-01

The studies reported here stemmed from a personal report by Geiman on the capacity of the 4-aminoquinoline amodiaquin to inhibit in vitro maturation of ring stages of the chloroquine-resistant Monterey strain of Plasmodium falciparum. This observation, confirmed in owl monkeys infected with this strain, led to a comparison of the activities of chloroquine, amodiaquin, amopyroquin, and dichlorquinazine (12,278 RP) against infections with various chloroquine-susceptible and chloroquine-resistant strains. The results showed that: (i) these 4-aminoquinolines were essentially equally active against infections with chloroquine-susceptible strains and (ii) the activities of amodiaquin, amopyroquin, and dichlorquinazine were reduced significantly in the face of chloroquine resistance, but (iii) well-tolerated doses of these compounds would cure infections with strains that fully resisted treatment with maximally tolerated doses of chloroquine. Two other 4-aminoquinolines, SN-8137 and SN-9584, which also exhibited activity against chloroquine-resistant parasites in vitro, displayed curative activity in monkeys infected with a chloroquine-resistant strain. These observations show that there is cross-resistance among the 4-aminoquinolines, confirming earlier findings, but indicate that the dimensions of this phenomenon are sufficiently limited so that some derivatives are therapeutically effective against infections refractory to maximally tolerated doses of chloroquine. PMID:406829

Biological optimization of simultaneous boost on intra-prostatic lesions (DILs): sensitivity to TCP parameters.

PubMed

Azzeroni, R; Maggio, A; Fiorino, C; Mangili, P; Cozzarini, C; De Cobelli, F; Di Muzio, N G; Calandrino, R

2013-11-01

The aim of this investigation was to explore the potential of biological optimization in the case of simultaneous integrated boost on intra-prostatic dominant lesions (DIL) and evaluating the impact of TCP parameters uncertainty. Different combination of TCP parameters (TD50 and γ50 in the Poisson-like model), were considered for DILs and the prostate outside DILs (CTV) for 7 intermediate/high-risk prostate patients. The aim was to maximize TCP while constraining NTCPs below 5% for all organs at risk. TCP values were highly depending on the parameters used and ranged between 38.4% and 99.9%; the optimized median physical doses were in the range 94-116 Gy and 69-77 Gy for DIL and CTV respectively. TCP values were correlated with the overlap PTV-rectum and the minimum distance between rectum and DIL. In conclusion, biological optimization for selective dose escalation is feasible and suggests prescribed dose around 90-120 Gy to the DILs. The obtained result is critically depending on the assumptions concerning the higher radioresistence in the DILs. In case of very resistant clonogens into the DIL, it may be difficult to maximize TCP to acceptable levels without violating NTCP constraints. Copyright © 2012 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Modeling the effect of boost timing in murine irradiated sporozoite prime-boost vaccines

PubMed Central

Zhang, Min; Herrero, Miguel A.; Acosta, Francisco J.; Tsuji, Moriya

2018-01-01

Vaccination with radiation-attenuated sporozoites has been shown to induce CD8+ T cell-mediated protection against pre-erythrocytic stages of malaria. Empirical evidence suggests that successive inoculations often improve the efficacy of this type of vaccines. An initial dose (prime) triggers a specific cellular response, and subsequent inoculations (boost) amplify this response to create a robust CD8+ T cell memory. In this work we propose a model to analyze the effect of T cell dynamics on the performance of prime-boost vaccines. This model suggests that boost doses and timings should be selected according to the T cell response elicited by priming. Specifically, boosting during late stages of clonal contraction would maximize T cell memory production for vaccines using lower doses of irradiated sporozoites. In contrast, single-dose inoculations would be indicated for higher vaccine doses. Experimental data have been obtained that support theoretical predictions of the model. PMID:29329308

Foods for a Mission to Mars: Investigations of Low-Dose Gamma Radiation Effects

NASA Technical Reports Server (NTRS)

Gandolph, J.; Shand, A.; Stoklosa, A.; Ma, A.; Weiss, I.; Alexander, D.; Perchonok, M.; Mauer, L. J.

2007-01-01

Food must be safe, nutritious, and acceptable throughout a long duration mission to maintain the health, well-being, and productivity of the astronauts. In addition to a developing a stable pre-packaged food supply, research is required to better understand the ability to convert edible biomass into safe, nutritious, and acceptable food products in a closed system with many restrictions (mass, volume, power, crew time, etc.). An understanding of how storage conditions encountered in a long-term space mission, such as elevated radiation, will impact food quality is also needed. The focus of this project was to contribute to the development of the highest quality food system possible for the duration of a mission, considering shelf-stable extended shelf-life foods, bulk ingredients, and crops to be grown in space. The impacts of space-relevant radiation doses on food, bulk ingredient, and select candidate crop quality and antioxidant capacity were determined. Interestingly, increasing gamma-radiation doses (0 to 1000 Gy) did not always increase dose-related effects in foods. Intermediate radiation doses (10 to 800Gy) often had significantly larger impact on the stability of bulk ingredient oils than higher (1000Gy) radiation doses. Overall, most food, ingredient, and crop systems investigated showed no significant differences between control samples and those treated with 3 Gy of gamma radiation (the upper limit estimated for a mission to Mars). However, this does not mean that all foods will be stable for 3-5 years, nor does it mean that foods are stable to space radiation comprising more than gamma rays.

A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors.

PubMed

Lin, Jianqing; Gilbert, Jill; Rudek, Michelle A; Zwiebel, James A; Gore, Steve; Jiemjit, Anchalee; Zhao, Ming; Baker, Sharyn D; Ambinder, Richard F; Herman, James G; Donehower, Ross C; Carducci, Michael A

2009-10-01

This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. EBV titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC. The three dose regimens of 5-AC and phenylbutyrate were generally well tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression-related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response. The administration of phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies. The combination of 5-AC and phenylbutyrate across three dose schedules was generally well tolerated and safe, yet lacked any real evidence for clinical benefit.

The Affinity of D2-Like Dopamine Receptor Antagonists Determines the Time to Maximal Effect on Cocaine Self-Administration

PubMed Central

Tabet, Michael R.; Norman, Mantana K.; Fey, Brittney K.; Tsibulsky, Vladimir L.; Millard, Ronald W.

2011-01-01

Differences in the time to maximal effect (Tmax) of a series of dopamine receptor antagonists on the self-administration of cocaine are not consistent with their lipophilicity (octanol-water partition coefficients at pH 7.4) and expected rapid entry into the brain after intravenous injection. It was hypothesized that the Tmax reflects the time required for maximal occupancy of receptors, which would occur as equilibrium was approached. If so, the Tmax should be related to the affinity for the relevant receptor population. This hypothesis was tested using a series of nine antagonists having a 2500-fold range of Ki or Kd values for D2-like dopamine receptors. Rats self-administered cocaine at regular intervals and then were injected intravenously with a dose of antagonist, and the self-administration of cocaine was continued for 6 to 10 h. The level of cocaine at the time of every self-administration (satiety threshold) was calculated throughout the session. The satiety threshold was stable before the injection of antagonist and then increased approximately 3-fold over the baseline value at doses of antagonists selected to produce this approximately equivalent maximal magnitude of effect (maximum increase in the equiactive cocaine concentration, satiety threshold; Cmax). Despite the similar Cmax, the mean Tmax varied between 5 and 157 min across this series of antagonists. Furthermore, there was a strong and significant correlation between the in vivo Tmax values for each antagonist and the affinity for D2-like dopamine receptors measured in vitro. It is concluded that the cocaine self-administration paradigm offers a reliable and predictive bioassay for measuring the affinity of a competitive antagonist for D2-like dopamine receptors. PMID:21606176

Short-term safety and efficacy of left atrial appendage closure with the WATCHMAN device in patients with small left atrial appendage ostia.

PubMed

Venkataraman, Ganesh; Strickberger, S Adam; Doshi, Shephal; Ellis, Christopher R; Lakkireddy, Dhanunjaya; Whalen, S Patrick; Cuoco, Frank

2018-01-01

Left atrial appendage (LAA) closure with the WATCHMAN device, according to FDA labelling, is recommended in patients with a maximal LAA ostial width between 17 and 31 mm. The safety and efficacy of LAA closure in patients with a maximal LAA ostial width < 17 mm has not been evaluated. The goal of this study was to determine the acute and short-term safety and efficacy of LAA closure with the WATCHMAN device in patients with a maximal LAA ostial width < 17 mm. Thirty-two consecutive patients with a maximal LAA ostial width < 17 mm as determined by a screening transesophageal echocardiogram (TEE) underwent LAA closure with the WATCHMAN device between March 2015 and November 2016 at five medical centers, and were included in this study. Mean age, body mass index (BMI), and CHA 2 DS 2 -VASC score were 70.8 ± 8.6 years, 29.3 ± 6.5 kg/m 2 , and 3.9 ±1.2, respectively. At the screening TEE, mean maximal LAA ostial width and depth were 15.6 ± 0.6 mm (range 14-16) and 23.2 ± 4.5 mm (range 13-31), respectively. Successful LAA closure with the WATCHMAN device was achieved in 31 of 32 patients (97%), with no major complications. TEE performed 45 days after LAA closure demonstrated no peridevice leak > 5 mm and no device related thrombi. Warfarin was discontinued in all 31 patients 45 days after LAA closure. LAA closure with the WATCHMAN device can be successfully and safely achieved in patients with a maximal LAA ostial width < 17 mm. © 2017 Wiley Periodicals, Inc.

Non-nutritive sweeteners are not super-normal stimuli

PubMed Central

Antenucci, Rachel G.; Hayes, John E.

2014-01-01

Background It is often claimed that non-nutritive sweeteners (NNS) are ‘sweeter than sugar’, with the implicit implication high potency sweeteners are super-normal stimuli that encourage exaggerated responses. This study aimed to investigate the perceived sweetness intensity of a variety of nutritive (Sucrose, Maple Syrup, and Agave Nectar) and NNS (Acesulfame-K (AceK), Rebaudioside A (RebA), Aspartame, and Sucralose) in a large cohort of untrained participants using contemporary psychophysical methods. Methods Participants (n=401 total) rated the intensity of sweet, bitter, and metallic sensations for nutritive and NNS in water using the general labeled magnitude scale (gLMS). Results Sigmoidal Dose-Response functions were observed for all stimuli except AceK. That is, sucrose follows a sigmoidal function if the data are not artifactually linearized via prior training. More critically, there is no evidence that NNS have a maximal sweetness (intensity) greater than sucrose; indeed, the maximal sweetness for AceK, RebA and Sucralose were significantly lower than for concentrated sucrose. For these sweeteners, mixture suppression due to endogenous dose-dependent bitter or metallic sensations appears to limit maximal perceived sweetness. Conclusions In terms of perceived sweetness, non-nutritive sweeteners cannot be considered super-normal stimuli. These data do not support the view that non-nutritive sweeteners hijack or over-stimulate sweet receptors to product elevated sweet sensations. PMID:24942868

Assessment of the Combined Treatment with Umbelliferone and Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice.

PubMed

Zagaja, Mirosław; Andres-Mach, Marta; Skalicka-Woźniak, Krystyna; Rękas, Anna R; Kondrat-Wróbel, Maria W; Gleńsk, Michał; Łuszczki, Jarogniew J

2015-01-01

The aim of this study was to determine the effects of umbelliferone (7-hydroxycoumarin; UMB) on the anticonvulsant potency of four classical antiepileptic drugs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) and valproate (VPA)) in the mouse maximal electroshock-induced seizure (MES) model. UMB administered systemically intraperitoneally (ip) in a dose of 150 mg/kg significantly elevated the threshold for maximal electroconvulsions (p < 0.05) in mice. Moreover, UMB (150 mg/kg) co-administered with PB and VPA significantly enhanced the anticonvulsant potency of these drugs by reducing their median effective doses (ED50 values) from 35.39 to 21.78 mg/kg (p < 0.01) for PB, and from 281.4 to 215.5 mg/kg (p < 0.01) for VPA. In contrast, UMB (150 mg/kg, ip) had no significant effect on the antiseizure activity of CBZ and PHT in the mouse MES model. Neither total brain PB, nor total brain VPA concentrations were altered after ip administration of UMB, indicating a pharmacodynamic nature of interactions between the tested drugs. The selective potentiation of the anticonvulsant potency of PB and VPA by UMB, and lack of any pharmacokinetic interactions between drugs, make the combinations of UMB with PB or VPA worthy of consideration for epileptic patients who are refractory to standard antiepileptic treatment. © 2015 S. Karger AG, Basel.

Reduced Sodium Transport With Nasal Administration of the Prostasin Inhibitor Camostat in Subjects With Cystic Fibrosis

PubMed Central

Reeves, Ginger; Hathorne, Heather; Solomon, G. Martin; Abbi, Smita; Renard, Didier; Lock, Ruth; Zhou, Ping; Danahay, Henry; Clancy, John P.; Waltz, David A.

2013-01-01

Background: Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF). Methods: To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing Na+ transport in the CF airway, we conducted a two-part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered through a nasal spray pump in subjects with CF. Nasal potential difference (PD) was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach. Results: In part 1, nine subjects were enrolled, and six completed crossover dosing at the maximally tolerated dose. The change in maximal (most polarizing) basal PD 2 h following administration of camostat was +13.1 mV (1.6-mg dose group) compared with −8.6 mV following placebo (P < .005). Intrasubject change in Ringer and amiloride-sensitive PDs exhibited similar and consistent responses. Bayesian analysis in an additional six subjects in part 2 estimated a dose of 18 μg/mL to provide 50% of the maximum effect. There was no significant change in chloride transport or total nasal symptom score, nasal examination rating, and laboratory parameters. Conclusions: This study establishes the proof of concept that a reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease. Trial registration: ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov PMID:23412700

The guinea-pig skin sensitization test revisited: an evaluation formula to predict possible sensitization levels for eight chemicals used in household products.

PubMed

Momma, J; Kitajima, S; Inoue, T

1998-02-20

In predicting human skin sensitization due to possible risky chemicals, it is not sufficient to evaluate solely the minimum induction dose (MID) or the standard challenge dose (SCD) in the Guinea Pig Maximization Test (GPMT). Nakamura et al. (1994) (Nakamura, A., Momma, J., Sekiguchi, H., Noda, T., Yamano, T., Kaniwa, M., Kojima, S., Tsuda, M., Kurokawa, Y., 1994. A new protocol and criteria for quantitative determination of sensitization potencies of chemicals by guinea pig maximization test. Contact Dermatitis 31, 72-85) previously measured the residual dose of chemicals in the products implicated in human allergic accidents, and stated that '... the level of chemical in the products (direct exposure-dose = DED) was similar to or higher than value of sensitization potency.' However, several of the chemicals listed in their article, show an even lower value of sensitization potency than the DED, although a potential correlation between results of the GPMT and the DED was seemed to be evident; a key question about the essential rule of those parameters therefore remains open. Using the data of Nakamura et al. (1994), we analyzed the functional rules of the three independent parameters, the MID, the SCD, and the DED on which the GPMT is based. Calculations of the degree of allergic reactions elicited in humans provided a range of discrimination constants (D) using the formula; D = DED/(MID*SCD). Possible human allergic accidents may be predicted when the dose of a candidate chemical in a chemical product (equal to DED) exceeds the value; D*(MID*SCD), following the correct evaluation of the MID as well as the SCD.

Accelerated Partial Breast Irradiation: What is Dosimetric Effect of Advanced Technology Approaches?

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

Moran, Jean M.; Ben-David, Merav A.; Marsh, Robin B.

2009-09-01

Purpose: The present treatment planning study compared whole breast radiotherapy (WBRT) to accelerated partial breast irradiation (APBI) for different external beam techniques and geometries (e.g., free breathing [FB] and deep inspiration breath hold [DIBH]). Methods and Materials: After approval by our institutional review board, a treatment planning study was performed of 10 patients with left-sided Stage 0-I breast cancer enrolled in a Phase I-II study of APBI using intensity-modulated radiotherapy (IMRT). After lumpectomy, patients underwent planning computed tomography scans during FB and using an active breathing control device at DIBH. For the FB geometry, standard WBRT and three-dimensional conformal radiotherapymore » (3D-CRT) APBI plans were created. For the DIBH geometry with active breathing control, WBRT, 3D-CRT, and IMRT APBI plans were created. Results: All APBI techniques had excellent planning target volume coverage. The maximal planning target volume dose was reduced from 116% of the prescription dose to 108% with the IMRT(DIBH) APBI plan. The maximal heart dose was >30 Gy for the WBRT techniques, 8.2 Gy for 3D-CRT(FB), and <5.0 Gy for 3D-CRT(DIBH) and IMRT(DIBH) techniques. The mean left anterior descending artery dose was significantly reduced from 11.4 Gy with WBRT(FB) to 4.2 with WBRT(DIBH) and <2.0 Gy with all APBI techniques. Conclusion: Although planning target volume coverage was acceptable with all techniques, the plans using the DIBH geometry resulted in a marked reduction in the normal tissue dose compared with WBRT planned in the absence of cardiac blocking. Additional study is needed to determine whether these techniques result in clinical benefits.« less

Effects of caffeine on fractional flow reserve values measured using intravenous adenosine triphosphate.

PubMed

Nakayama, Masafumi; Chikamori, Taishiro; Uchiyama, Takashi; Kimura, Yo; Hijikata, Nobuhiro; Ito, Ryosuke; Yuhara, Mikio; Sato, Hideaki; Kobori, Yuichi; Yamashina, Akira

2018-04-01

We investigated the effects of caffeine intake on fractional flow reserve (FFR) values measured using intravenous adenosine triphosphate (ATP) before cardiac catheterization. Caffeine is a competitive antagonist for adenosine receptors; however, it is unclear whether this antagonism affects FFR values. Patients were evenly randomized into 2 groups preceding the FFR study. In the caffeine group (n = 15), participants were given coffee containing 222 mg of caffeine 2 h before the catheterization. In the non-caffeine group (n = 15), participants were instructed not to take any caffeine-containing drinks or foods for at least 12 h before the catheterization. FFR was performed in patients with more than intermediate coronary stenosis using the intravenous infusion of ATP at 140 μg/kg/min (normal dose) and 170 μg/kg/min (high dose), and the intracoronary infusion of papaverine. FFR was followed for 30 s after maximal hyperemia. In the non-caffeine group, the FFR values measured with ATP infusion were not significantly different from those measured with papaverine infusion. However, in the caffeine group, the FFR values were significantly higher after ATP infusion than after papaverine infusion (P = 0.002 and P = 0.007, at normal and high dose ATP vs. papaverine, respectively). FFR values with ATP infusion were significantly increased 30 s after maximal hyperemia (P = 0.001 and P < 0.001 for normal and high dose ATP, respectively). The stability of the FFR values using papaverine showed no significant difference between the 2 groups. Caffeine intake before the FFR study affected FFR values and their stability. These effects could not be reversed by an increased ATP dose.

Comparison of capnovolumetry-derived dead space parameters with pulmonary function test in normal adults using histamine provocation.

PubMed

Sun, Xiaoli; Zhang, Yan; Yang, Wenlan; Liu, Jinming

2015-04-01

This study in healthy adults was conducted to explore the clinical application of capnovolumetric indices as compared to lung function parameters using histamine provocation. Forty healthy subjects received aerosol histamine or salbutamol in an automatic stimulation system with escalating doses of histamine. Dead space volumes of capnovolumetry and lung function parameters were examined with increased concentrations of histamine at a fixed time interval. The doses of histamine were selected from 0.0562 mg-2.2 mg and 0.1 mg salbutamol was inhaled when a maximal dose of histamine was reached. Baseline values in each group were calculated prior to histamine inhalation. Fowler dead space (VDF), Wolff dead space (VDW), threshold dead space (VDT), Bohr dead space (VDB), forced expiratory volume in 1 s (FEV1 ) and peak expiratory flow (PEF) showed a dose-dependent reduction following histamine provocation, but there were no statistical differences in the measurements at baseline and post S6 provocation. The value of dC3/DV at the maximal dose was significantly increased over its baseline value (P < 0.05). VDF, VDT and VDW were significantly increased after bronchodilator use (P < 0.05 or <0.01). The changes in capnovolumetry did not correspond with the results of lung function test. The dC3/DV and airway dead spaces of capnovolumetry in healthy adults are significantly increased compared to lung function parameters before or after bronchodilator use, suggesting that capnovolumetry is feasible in diagnostic evaluation of airway reactivity, especially for persons who are unable to undertake lung function test. © 2014 John Wiley & Sons Ltd.

Site-Specific Reference Person Parameters and Derived Concentration Standards for the Savannah River Site

DOE PAGES

Stone, Daniel K.; Higley, Kathryn A.; Jannik, G. Timothy

2014-05-01

The U.S. Department of Energy Order 458.1 states that the compliance with the 1 mSv annual dose constraint to a member of the public may be demonstrated by calculating dose to the maximally exposed individual (MEI) or to a representative person. Historically, the MEI concept was used for dose compliance at the Savannah River Site (SRS) using adult dose coefficients and adult male usage parameters. For future compliance, SRS plans to use the representative person concept for dose estimates to members of the public. The representative person dose will be based on the reference person dose coefficients from the U.S.more » DOE Derived Concentration Technical Standard and on usage parameters specific to SRS for the reference and typical person. Usage parameters and dose coefficients were determined for inhalation, ingestion and external exposure pathways. The parameters for the representative person were used to calculate and tabulate SRS-specific derived concentration standards (DCSs) for the pathways not included in DOE-STD-1196-2011.« less

Dissolving the engineering moral dilemmas within the Islamic ethico-legal praxes.

PubMed

Solihu, Abdul Kabir Hussain; Ambali, Abdul Rauf

2011-03-01

The goal of responsible engineers is the creation of useful and safe technological products and commitment to public health, while respecting the autonomy of the clients and the public. Because engineers often face moral dilemma to resolve such issues, different engineers have chosen different course of actions depending on their respective moral value orientations. Islam provides a value-based mechanism rooted in the Maqasid al-Shari'ah (the objectives of Islamic law). This mechanism prioritizes some values over others and could help resolve the moral dilemmas faced in engineering. This paper introduces the Islamic interpretive-evaluative maxims to two core issues in engineering ethics: genetically modified foods and whistleblowing. The study aims primarily to provide problem-solving maxims within the Maqasid al-Shari'ah matrix through which such moral dilemmas in science and engineering could be studied and resolved.

SU-F-BRB-12: A Novel Haar Wavelet Based Approach to Deliver Non-Coplanar Intensity Modulated Radiotherapy Using Sparse Orthogonal Collimators

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

Nguyen, D; Ruan, D; Low, D

2015-06-15

Purpose: Existing efforts to replace complex multileaf collimator (MLC) by simple jaws for intensity modulated radiation therapy (IMRT) resulted in unacceptable compromise in plan quality and delivery efficiency. We introduce a novel fluence map segmentation method based on compressed sensing for plan delivery using a simplified sparse orthogonal collimator (SOC) on the 4π non-coplanar radiotherapy platform. Methods: 4π plans with varying prescription doses were first created by automatically selecting and optimizing 20 non-coplanar beams for 2 GBM, 2 head & neck, and 2 lung patients. To create deliverable 4π plans using SOC, which are two pairs of orthogonal collimators withmore » 1 to 4 leaves in each collimator bank, a Haar Fluence Optimization (HFO) method was used to regulate the number of Haar wavelet coefficients while maximizing the dose fidelity to the ideal prescription. The plans were directly stratified utilizing the optimized Haar wavelet rectangular basis. A matching number of deliverable segments were stratified for the MLC-based plans. Results: Compared to the MLC-based 4π plans, the SOC-based 4π plans increased the average PTV dose homogeneity from 0.811 to 0.913. PTV D98 and D99 were improved by 3.53% and 5.60% of the corresponding prescription doses. The average mean and maximal OAR doses slightly increased by 0.57% and 2.57% of the prescription doses. The average number of segments ranged between 5 and 30 per beam. The collimator travel time to create the segments decreased with increasing leaf numbers in the SOC. The two and four leaf designs were 1.71 and 1.93 times more efficient, on average, than the single leaf design. Conclusion: The innovative dose domain optimization based on compressed sensing enables uncompromised 4π non-coplanar IMRT dose delivery using simple rectangular segments that are deliverable using a sparse orthogonal collimator, which only requires 8 to 16 leaves yet is unlimited in modulation resolution. This work is supported in part by Varian Medical Systems, Inc. and NIH R43 CA18339.« less

[Intravenous clomipramine for depressive disorders].

PubMed

Landowski, Jerzy; Lamparska, Ewa; Wichowicz, Hubert; Gizińska, Dorota; Godlewska, Beata; Wiglusz, Mariusz

2002-01-01

51 patients with depressive episode (40--recurrent depressive disorder, 11--bipolar affective disorder) were treated by the clomipramine intravenous infusions. The number of infusions varied from 5 to 21 (mostly 10-16). The median of maximal dose was 150 mg. There were significant clinical improvement measured by CGI. The therapy was well tolerated.

Chemotherapy dosing in achondroplastic dwarfism: a case report and review of literature.

PubMed

Elsoueidi, R; Gresham, C; Michael, L; Chaney, D; Mourad, H

2016-12-01

CASE DESCRIPTION: A 74-year-old female with achondroplastic dwarfism was diagnosed with ER-, BR- and HER2- breast cancer. No guideline currently exists to direct chemotherapy dosing in this population. She received neoadjuvant chemotherapy based on body surface area utilizing actual height and weight with dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with the use of granulocyte colony-stimulating factor. Satisfactory clinical response and remission were achieved, and treatment proceeded without any significant toxicity or delays. In the absence of guideline recommendations, dosing chemotherapy based on actual height and weight in patients with achondroplastic dwarfism may be safe and appropriate. © 2016 John Wiley & Sons Ltd.

Evaluation of a 15-week CHOP protocol for the treatment of canine multicentric lymphoma.

PubMed

Burton, J H; Garrett-Mayer, E; Thamm, D H

2013-12-01

Dose intense CHOP protocols have been shown to improve outcome for people with non-Hodgkin's lymphoma, but evaluation of dose intense CHOP protocols for canine lymphoma is currently limited. The hypothesis of this retrospective study was that a 15-week dose intense CHOP protocol would have shorter treatment duration with similar efficacy to other doxorubicin-based multidrug protocols. Thirty-one client owned dogs with multicentric lymphoma were treated with a 15-week CHOP chemotherapy protocol with an overall response rate of 100% and a median progression-free interval (PFI) of 140 days [95% confidence interval (CI) 91-335 days]. Dogs that had two or more treatment delays had significantly prolonged PFI and overall survival in multivariate analysis. Dose intensity did not correlate with patient outcome. Dogs experiencing multiple treatment delays secondary to adverse events may receive their individual maximally tolerated dose while dogs with no adverse events may be underdosed. Future studies should focus on individual patient dose optimization. © 2012 Blackwell Publishing Ltd.

The study of mechanical behavior on the interface between calcar-defect femur and restorations by means of finite element analysis

NASA Astrophysics Data System (ADS)

Shi, X. H.; Jiang, W.; Chen, H. Z.; Zou, W.; Wang, W. D.; Guo, Z.; Luo, J. M.; Gu, Z. W.; Zhang, X. D.

2008-11-01

The mechanical behaviors of calcar-defected femur and restorations under physiological load are the key factors that will greatly influence the success of femur calcar defect repairing, especially the stress distribution on the bone-restoration interface. 3D finite elements analysis (FEA) was used to analyze the mechanical characters on the interfaces between femoral calcar defects and bone cement or HA restorations. Under the load of two times of a human weight (1436.03 N) and with the increase of the defect dimension from 6 mm to 12 mm, the maximal stresses on the surface of restorations are from 7.06 MPa to 11.89 MPa for bone cement and 2.97-9 MPa for HA separately. In this condition, HA restoration will probably be broken on the bone-restoration interface when the defect diameter is beyond 8 mm. Furthermore, under the load of 1.5 times of a human weight, HA restoration would not be safe unless the defect dimension is smaller than 10 mm, because the maximal stress (4.62 MPa) on the restoration is only a little lower than compressive strength of HA, otherwise the bone fixation device should be applied to ensure the safety. It is relatively safe for all restorations under all the tested defect sizes when the load is just the weight of a human body.

SU-F-T-134: Can We Use the Same Dose Constrains Learnt From Photon World to Plan Proton for Lung Cancer?

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

Xiao, Z; Zou, J; Yue, N

Purpose: To evaluate if the same DVH constrains used in photon plans can be safely used to plan proton therapy for lung cancer. Since protons and photons have different dose deposition patterns, the hypothesis is following DVH constrains derived from photon world is not safe for proton. Methods: We retrospectively evaluated plans for 11 lung cancer patients. Each patient was planned with photon and proton following the same dose constrains. Dose statistics on PTV, normal lung, heart and esophagus were extracted for comparison. gEUD for normal lung was calculated and compared between proton and photon plans. We calculated series ofmore » gEUDs for each plan by varying the parameter “a” in gEUD formula from 0.1 to 3, covering the whole confidence interval. Results: For all patients, proton plans yield similar PTV coverage and lower dose to heart and esophagus than photon plans. Normal lung V5 was 32.3 % on average in proton plans than 55.4 % in photon. Normal lung gEUD monotonically increased with increasing “a” for all proton and photon plans. For a given patient, the gEUD-proton(a) had a steeper slope than gEUD-photon(a). The two curves crossed for 8 out of 11 patients when “a” = [0.1, 3]. a-crossing ranged from 0.8 to 2.44 with an average of 1.15. For a« less

An Hourly Dose-Escalation Desensitization Protocol for Aspirin-Exacerbated Respiratory Disease.

PubMed

Chen, Justin R; Buchmiller, Brett L; Khan, David A

2015-01-01

Aspirin desensitization followed by maintenance therapy effectively improves symptom control in patients with aspirin exacerbated respiratory disease (AERD). The majority of current desensitization protocols use 3-hour dosing intervals and often require 2 to 3 days to complete. We evaluated hourly dose escalations in a subset of patients with chronic rhinosinusitis, nasal polyps, and asthma who historically reacted to aspirin within 1 hour or were avoiding aspirin with the goal of developing a safe and efficient desensitization protocol. Fifty-seven aspirin desensitizations were performed under the hourly protocol. All patients had refractory nasal polyposis as an indication for aspirin desensitization. The clinical characteristics of each subject were analyzed in relation to aspects of his or her reactions during the procedure. Ninety-eight percent of study patients were successfully treated under the hourly protocol, including those with a history of severe reactions and intubation. None required further medication than is available in an outpatient allergy clinic. A total of 96% of reactors recorded a bronchial or naso-ocular reaction within 1 hour of the preceding dose. Of the total patients on this protocol, 40% were able to complete the procedure in a single day, and 60% within 2 days. Patients with AERD who have a history of symptoms less than 1 hour after aspirin exposure can be safely desensitized with a 1-hour dose-escalation protocol that can often be completed in a single day. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

A practical method of I-131 thyroid cancer therapy dose optimization using estimated effective renal clearance.

PubMed

Howard, Brandon A; James, Olga G; Perkins, Jennifer M; Pagnanelli, Robert A; Borges-Neto, Salvador; Reiman, Robert E

2017-01-01

In thyroid cancer patients with renal impairment or other complicating factors, it is important to maximize I-131 therapy efficacy while minimizing bone marrow and lung damage. We developed a web-based calculator based on a modified Benua and Leeper method to calculate the maximum I-131 dose to reduce the risk of these toxicities, based on the effective renal clearance of I-123 as measured from two whole-body I-123 scans, performed at 0 and 24 h post-administration.

Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia.

PubMed

Vahdat, L; Wong, E T; Wile, M J; Rosenblum, M; Foley, K M; Warrell, R P

1994-11-15

Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove active primarily in lymphoproliferative diseases, early reports suggested unexpected high activity of this drug in heavily pretreated children with acute myeloblastic leukemia (AML) at a maximally tolerated dose of 8.9 mg/m2/day for 5 days. In view of these findings, we conducted an escalating dose trial of 2-CdA in adult patients with relapsed or resistant AML. Thirty-six patients who had received extensive prior therapy were treated at 9 dose levels of 2-CdA at daily doses ranging from 5 to 21 mg/m2 for 5 days. 2-CdA eliminated leukemic blasts from the peripheral blood in 32 of 36 cases; however, bone marrow hypoplasia was seen only at daily dose levels > or = 15 mg/m2. We observed a total of 3 complete remissions: 1 at the 15 mg/m2/d dose level and 2 at the 21 mg/m2/d dose level; these responses persisted for 3, 2, and 3 months, respectively. Although prolonged myelosuppression would have been dose-limiting at 21 mg/m2/d for 5 days, the most important adverse effect was the development of a sensorimotor peripheral neuropathy. This reaction, whose onset was substantially delayed after completion of drug treatment, was observed in 2 of 5 patients at the 19 mg/m2/d level and in 4 of 4 evaluable patients at the 21 mg/m2/d level. Pathologically, this process was characterized by axonal degeneration and secondary demyelination. Other side effects included reactivation of a posttransplant Epstein-Barr virus-related lymphoma in 1 patient and tumor lysis syndrome. We conclude that the maximally tolerable dose of 2-CdA in adult patients (17 mg/m2/d for 5 days) in approximately twofold in excess of that previously reported in children and that the limiting toxic effect is a degenerative neuropathic disorder. We confirm that this drug has definite activity in AML, but the magnitude of this effect needs to be determined in larger numbers of patients who have received less extensive therapy. This agent deserves further evaluation in patients with both AML and acute lymphoblastic leukemia at these higher doses and perhaps as part of a preparative regimen for patients undergoing bone marrow transplantation.

The impact of different dose response parameters on biologically optimized IMRT in breast cancer

NASA Astrophysics Data System (ADS)

Costa Ferreira, Brigida; Mavroidis, Panayiotis; Adamus-Górka, Magdalena; Svensson, Roger; Lind, Bengt K.

2008-05-01

The full potential of biologically optimized radiation therapy can only be maximized with the prediction of individual patient radiosensitivity prior to treatment. Unfortunately, the available biological parameters, derived from clinical trials, reflect an average radiosensitivity of the examined populations. In the present study, a breast cancer patient of stage I II with positive lymph nodes was chosen in order to analyse the effect of the variation of individual radiosensitivity on the optimal dose distribution. Thus, deviations from the average biological parameters, describing tumour, heart and lung response, were introduced covering the range of patient radiosensitivity reported in the literature. Two treatment configurations of three and seven biologically optimized intensity-modulated beams were employed. The different dose distributions were analysed using biological and physical parameters such as the complication-free tumour control probability (P+), the biologically effective uniform dose (\\bar{\\bar{D}} ), dose volume histograms, mean doses, standard deviations, maximum and minimum doses. In the three-beam plan, the difference in P+ between the optimal dose distribution (when the individual patient radiosensitivity is known) and the reference dose distribution, which is optimal for the average patient biology, ranges up to 13.9% when varying the radiosensitivity of the target volume, up to 0.9% when varying the radiosensitivity of the heart and up to 1.3% when varying the radiosensitivity of the lung. Similarly, in the seven-beam plan, the differences in P+ are up to 13.1% for the target, up to 1.6% for the heart and up to 0.9% for the left lung. When the radiosensitivity of the most important tissues in breast cancer radiation therapy was simultaneously changed, the maximum gain in outcome was as high as 7.7%. The impact of the dose response uncertainties on the treatment outcome was clinically insignificant for the majority of the simulated patients. However, the jump from generalized to individualized radiation therapy may significantly increase the therapeutic window for patients with extreme radio sensitivity or radioresistance, provided that these are identified. Even for radiosensitive patients a simple treatment technique is sufficient to maximize the outcome, since no significant benefits were obtained with a more complex technique using seven intensity-modulated beams portals.

Protective effects of long-term administration of Ziziphus jujuba fruit extract on cardiovascular responses in L-NAME hypertensive rats.

PubMed

Mohebbati, Reza; Bavarsad, Kosar; Rahimi, Maryam; Rakhshandeh, Hasan; Khajavi Rad, Abolfazl; Shafei, Mohammad Naser

2018-01-01

Ziziphus jujuba stimulates the release of nitric oxide (NO). Because NO is involved in cardiovascular regulations, in this study the effects of hydroalcoholic extract of Z. jujuba on cardiovascular responses in acute NG-nitro-L-arginine methyl ester (L-NAME) hypertensive rats were evaluated. Rats were divided into 6 group (n=6): 1) saline, 2) L-NAME received (10mg/kg) intravenously, 3) sodium nitroprusside (SNP) (50µg/kg)+L-NAME group received SNP before L-NAME and 4-6) three groups of Z. jujuba (100, 200 and 400mg/kg) that treated for four weeks and on the 28 th day, L-NAME was injected. Femoral artery and vein were cannulated for recording cardiovascular responses and drug injection, respectively. Systolic blood pressure (SBP), Mean arterial pressure (MAP) and heart rate (HR) were recorded continuously. Maximal changes (∆) of SBP, MAP and HR were calculated and compared to control and L-NAME groups. In L-NAME group, maximal ΔSBP (L-NAME: 44.15±4.0 mmHg vs control: 0.71±2.1 mmHg) and ΔMAP (L-NAME: 40.8±4.0 mmHg vs control: 0.57±1.6 mmHg) significantly increased (p<0.001 in both) but ∆HR was not significant as compared to control (p>0.05). All doses of Z. jujuba attenuated maximal ∆SBP and ∆MAP induced by L-NAME but only the lowest dose (100 mg/kg) had significant effects (ΔSBP: 20.36±5.6 mmHg vs L-NAME: 44.1±4.0 mmHg and ΔMAP: 20.8±4.5 mmHg vs L-NAME: 40.8±3.8 mmHg (p<0.05 to p<0.01)). The ∆HR at three doses was not significantly different from that of L-NAME group (p>0.05). Because long-term consumption of Z. jujuba extract, especially its lowest dose, attenuated cardiovascular responses induced by L-NAME, we suggest that Z. jujuba has potential beneficial effects in prevention of hypertension induced by NO deficiency.

Sensitive Targeted Quantification of ERK Phosphorylation Dynamics and Stoichiometry in Human Cells without Affinity Enrichment

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

Shi, Tujin; Gao, Yuqian; Gaffrey, Matthew J.

2014-12-17

Mass spectrometry-based targeted quantification is a promising technology for site-specific quantification of posttranslational modifications (PTMs). However, a major constraint of most targeted MS approaches is the limited sensitivity for quantifying low-abundance PTMs, requiring the use of affinity reagents to enrich specific PTMs. Herein, we demonstrate the direct site-specific quantification of ERK phosphorylation isoforms (pT, pY, pTpY) and their relative stoichiometries using a highly sensitive targeted MS approach termed high-pressure, high-resolution separations with intelligent selection and multiplexing (PRISM). PRISM provides effective enrichment of target peptides within a given fraction from complex biological matrix with minimal sample losses, followed by selected reactionmore » monitoring (SRM) quantification. The PRISM-SRM approach enabled direct quantification of ERK phosphorylation in human mammary epithelial cells (HMEC) from as little as 25 µg tryptic peptides from whole cell lysates. Compared to immobilized metal-ion affinity chromatography, PRISM provided >10-fold improvement in signal intensities, presumably due to the better peptide recovery of PRISM for handling small size samples. This approach was applied to quantify ERK phosphorylation dynamics in HMEC treated by different doses of EGF at both the peak activation (10 min) and steady state (2 h). At 10 min, the maximal ERK activation was observed with 0.3 ng/mL dose, whereas the maximal steady state level of ERK activation at 2 h was at 3 ng/ml dose, corresponding to 1200 and 9000 occupied receptors, respectively. At 10 min, the maximally activated pTpY isoform represented ~40% of total ERK, falling to less than 10% at 2 h. The time course and dose-response profiles of individual phosphorylated ERK isoforms indicated that singly phosphorylated pT-ERK never increases significantly, while the increase of pY-ERK paralleled that of pTpY-ERK. This data supports for a processive, rather than distributed, model of ERK phosphorylation. The PRISM-SRM quantification of protein phosphorylation illustrates the potential for simultaneous quantification of multiple PTMs.« less

Dose response effects of a caffeine-containing energy drink on muscle performance: a repeated measures design

PubMed Central

2012-01-01

Background Energy drinks have become the most used caffeine-containing beverages in the sport setting. The aim of this study was to determine the effects of two doses of a caffeine-containing energy drink on muscle performance during upper- and lower-body power-load tests. Methods In a randomized order, twelve active participants ingested 1 and 3 mg of caffeine per kg of body weight using a commercially available energy drink (Fure®, ProEnergetics) or the same drink without caffeine (placebo; 0 mg/kg). After sixty minutes, resting metabolic rate, heart rate and blood pressure were determined. Then, half-squat and bench-press power production with loads from 10 to 100% of 1 repetition maximum was determined using a rotator encoder. Results In comparison to the placebo, the ingestion of the caffeinated drink increased mean arterial pressure (82 ± 7 < 88 ± 8 ≈ 90 ± 6 mmHg for 0 mg/kg, 1 mg/kg, 3 mg/kg of caffeine, respectively; P < 0.05) and heart rate (57 ± 7 < 59 ± 8 < 62 ± 8 beats/min, respectively; P < 0.05) at rest in a dose response manner, though it did not affect resting metabolic rate. While the ingestion of 1 mg/kg of caffeine did not affect maximal power during the power-load tests with respect to the placebo, 3 mg/kg increased maximal power in the half-squat (2554 ± 167 ≈ 2549 ± 161 < 2726 ± 167 W, respectively; P < 0.05) and bench-press actions (349 ± 34 ≈ 358 ± 35 < 375 ± 33 W, respectively; P < 0.05). Conclusions A caffeine dose of at least 3 mg/kg in the form of an energy drink is necessary to significantly improve half-squat and bench-press maximal muscle power. PMID:22569090

The effects of JWB1-84-1 on memory-related task performance by amyloid Abeta transgenic mice and by young and aged monkeys.

PubMed

Sood, Ajay; Warren Beach, J; Webster, Scott J; Terry, Alvin V; Buccafusco, Jerry J

2007-10-01

JWB1-84-1 is one of 50 tertiary amine analogs of choline synthesized with expectation that they would be high potency compounds for cytoprotection. As one of the more potent analogs in this regard, JWB1-84-1, a piperazine derivative, was selected for testing as a cognition-enhancing agent. The compound was evaluated for efficacy in Alzheimer's disease transgenic mice (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J). A separate cohort of mice (AD Tg) were first subjected to a behavioral test battery in which the transgenic strain was compared with the wild-type strain. AD Tg mice were shown to exhibit specific deficits in the acquisition of a working memory (5-trial/session radial arm water maze, RAWM) task at a time when the animals exhibited maximal cerebral amyloid burden. JWB1-84-1 produced a dose-dependent decrease in the number of errors made by well trained AD-Tg mice the RAWM task that was maximal after the 20 microg/kg dose. Aged macaques (20-32 y) were trained to proficiency in their performance of a computer-assisted delayed matching-to-sample task. Vehicle (normal saline) or JWB1-84-1 (5-150 microg/kg, i.m.) was administered 10 min before the initiating of testing. On average, JWB1-84-1 treatment significantly improved task accuracy after all but the lowest dose. The maximal degree of improvement was attained after animals received the 100 microg/kg dose. The drug's effects were restricted primarily to Medium and Long delay trials - the most difficult portions of the task, which were improved by up to 18% above control. In young macaques JWB1-84-1 treatment also significantly reversed the decrements in task accuracy associated with the random presentation of a task distractor. Thus JWB1-84-1exhibits the potential for treating the cognitive symptoms associated with neurodegenerative diseases and attention deficit disorders. Its cytoprotective action might also work to slow the progression of Alzheimer's disease.

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation

PubMed Central

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F.; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

Objective CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). Methods and Results CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. Conclusions These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression. PMID:26335690

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

PubMed

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.

Evaluation of safety of lipomer doxycycline hydrochloride (lipomer DH).

PubMed

Dhumal, Rohit; Soni, Mahesh; Devarajan, Padma; Samad, Abdul; Gaikwad, Rajiv; Vanage, Geeta

2011-02-01

The nanoparticulate formulation of lipomer doxycycline hydrochloride (lipomer DH) has been synthesized for the treatment of Brucellosis to increase efficacy of the drug. The present study was undertaken to determine the intravenous safety of blank lipomer and Lipomer DH in terms of maximum tolerated dose in rats. It was observed that blank lipomer and lipomer DH were safe when administered intravenously at doses 2000 mg/kg Bw and 18 mg/kg bw respectively.

Dosing antiretroviral medication when crossing time zones: a review

PubMed Central

Lewis, Joseph M.; Volny-Anne, Alain; Waitt, Catriona; Boffito, Marta; Khoo, Saye

2016-01-01

International tourism continues to increase worldwide, and people living with HIV and their clinicians are increasingly confronted with the problem of how to dose antiretroviral therapy during transmeridian air travel across time zones. No guidance on this topic currently exists. This review is a response to requests from patient groups for clear, practical and evidence-based guidance for travelling on antiretroviral therapy; we present currently available data on the pharmacokinetic forgiveness and toxicity of various antiretroviral regimens, and synthesize this data to provide guidelines on how to safely dose antiretrovirals when travelling across time zones. PMID:26684823

A study of the 200-metre fast walk test as a possible new assessment tool to predict maximal heart rate and define target heart rate for exercise training of coronary heart disease patients.

PubMed

Casillas, Jean-Marie; Joussain, Charles; Gremeaux, Vincent; Hannequin, Armelle; Rapin, Amandine; Laurent, Yves; Benaïm, Charles

2015-02-01

To develop a new predictive model of maximal heart rate based on two walking tests at different speeds (comfortable and brisk walking) as an alternative to a cardiopulmonary exercise test during cardiac rehabilitation. Evaluation of a clinical assessment tool. A Cardiac Rehabilitation Department in France. A total of 148 patients (133 men), mean age of 59 ±9 years, at the end of an outpatient cardiac rehabilitation programme. Patients successively performed a 6-minute walk test, a 200 m fast-walk test (200mFWT), and a cardiopulmonary exercise test, with measure of heart rate at the end of each test. An all-possible regression procedure was used to determine the best predictive regression models of maximal heart rate. The best model was compared with the Fox equation in term of predictive error of maximal heart rate using the paired t-test. Results of the two walking tests correlated significantly with maximal heart rate determined during the cardiopulmonary exercise test, whereas anthropometric parameters and resting heart rate did not. The simplified predictive model with the most acceptable mean error was: maximal heart rate = 130 - 0.6 × age + 0.3 × HR200mFWT (R(2) = 0.24). This model was superior to the Fox formula (R(2) = 0.138). The relationship between training target heart rate calculated from measured reserve heart rate and that established using this predictive model was statistically significant (r = 0.528, p < 10(-6)). A formula combining heart rate measured during a safe simple fast walk test and age is more efficient than an equation only including age to predict maximal heart rate and training target heart rate. © The Author(s) 2014.

What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery?

PubMed

Hodgson, Sam; Larvin, Joseph T; Dearman, Charles

2015-09-01

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: what dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Altogether 586 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Current evidence shows clinical benefit of using high-dose tranexamic acid (>80 mg/kg total dose) as opposed to low-dose tranexamic acid (<50 mg/kg total dose) in cardiac surgery with cardiopulmonary bypass. Evidence from a large randomized controlled trial shows that patients receiving high-dose tranexamic acid lose less blood postoperatively than patients receiving low-dose tranexamic acid (590 vs 820 ml, P = 0.01). Patients receiving high-dose tranexamic acid also require fewer units of blood product transfusion (2.5 units vs 4.1 units; P = 0.02) and are less likely to undergo repeat surgery to achieve haemostasis. This effect is larger in those who are at high risk of bleeding. Several prospective studies comparing doses found no difference in clinical outcomes between high- and low-dose regimens, but excluded patients at high risk of bleeding. However, data from numerous observational studies demonstrate that tranexamic acid use is associated with an increased risk of postoperative seizure; one analysis showed tranexamic acid use to be a very strong independent predictor (odds ratio = 14.3, P < 0.001). There is also evidence that this risk of seizure is dose-dependent, with the greatest risk at higher doses of tranexamic acid. We conclude that, in general, patients with a high risk of bleeding should receive high-dose tranexamic acid, while those at low risk of bleeding should receive low-dose tranexamic acid with consideration given to potential dose-related seizure risk. We recommend the regimens of high-dose (30 mg kg(-1) bolus + 16 mg kg(-1) h(-1) + 2 mg kg(-1) priming) and low-dose (10 mg kg(-1) bolus + 1 mg kg(-1) h(-1) + 1 mg kg(-1) priming) tranexamic acid, as these are well established in terms of safety profile and have the strongest evidence for efficacy. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Non-myeloablative allogeneic stem cell transplantation focusing on immunotherapy of life-threatening malignant and non-malignant diseases.

PubMed

Slavin, S; Nagler, A; Shapira, M; Panigrahi, S; Samuel, S; Or, A

2001-01-01

Allogeneic bone marrow transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and non-malignant diseases. Until recently, myeloablative regimens were considered mandatory for eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion (DLI) following BMT. Thus, eradication of blood cancer cells, especially in patients with CML can be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft versus leukemia (GVL) effects might be a useful tool for eradication of otherwise resistant tumor cells of host origin. The latter working hypothesis suggested that effective BMT procedures may be accomplished without lethal conditioning of the host, using new well tolerated non-myeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical data that will be presented suggests that safe non-myeloablative stem cell transplantation (NST), with no major toxicity can replace the conventional BMT. Thus, NST may provide an option for cure for a large spectrum of clinical indications in children and elderly individuals without lower or upper age limit, while minimizing procedure-related toxicity and mortality.

[Seven Cases of Surgery for Breast Cancer under Tumescent Local Anesthesia].

PubMed

Hosoya, Tokuko; Nakagawa, Tsuyoshi; Oda, Goshi; Uetake, Hiroyuki

2015-11-01

Surgical procedures for breast cancer are usually performed under general anesthesia. However, general anesthesia needs to be avoided in some cases due to patient-related factors such as the presence of comorbid diseases. In these cases, we perform surgery under tumescent local anesthesia(TLA)in our department. Seven patients who were diagnosed with breast cancer underwent surgery under TLA instead of general anesthesia due to their comorbidities. The planned surgical procedures were successfully completed under TLA. A shift to general anesthesia could be avoided in all cases. The operative procedures for the breasts included modified radical mastectomy (Bt) in 3 cases and wide excision (Bp) in 4 cases. In addition, axillary lymph node dissection was performed in 2 cases; sampling, in 1 case; sentinel lymph node biopsy, in 2 cases; and no procedure for the axilla, in 2 cases. In terms of anesthesia, 2 cases were managed under TLA alone and 5 cases were managed under TLA combined with epidural anesthesia. Lidocaine was used for local anesthesia and did not reach the maximal permissive dose in all cases. No postoperative complication was observed. No local recurrence or new metastasis was observed during the observation period, which ranged from 1 to 67 months after the surgery. These findings demonstrate that surgery for breast cancer under TLA is safe and offers high curability for patients at high risk for complications of general anesthesia.

The in vitro sub-cellular localization and in vivo efficacy of novel chitosan/GMO nanostructures containing paclitaxel.

PubMed

Trickler, W J; Nagvekar, A A; Dash, A K

2009-08-01

To determine the in vitro sub-cellular localization and in vivo efficacy of chitosan/GMO nanostructures containing paclitaxel (PTX) compared to a conventional PTX treatment (Taxol). The sub-cellular localization of coumarin-6 labeled chitosan/GMO nanostructures was determined by confocal microscopy in MDA-MB-231 cells. The antitumor efficacy was evaluated in two separate studies using FOX-Chase (CB17) SCID Female-Mice MDA-MB-231 xenograph model. Treatments consisted of intravenous Taxol or chitosan/GMO nanostructures with or without PTX, local intra-tumor bolus of Taxol or chitosan/GMO nanostructures with or without PTX. The tumor diameter and animal weight was monitored at various intervals. Histopathological changes were evaluated in end-point tumors. The tumor diameter increased at a constant rate for all the groups between days 7-14. After a single intratumoral bolus dose of chitosan/GMO containing PTX showed significant reduction in tumor diameter on day 15 when compared to control, placebo and intravenous PTX administration. The tumor diameter reached a maximal decrease (4-fold) by day 18, and the difference was reduced to approximately 2-fold by day 21. Qualitatively similar results were observed in a separate study containing PTX when administered intravenously. Chitosan/GMO nanostructures containing PTX are safe and effective administered locally or intravenously. Partially supported by DOD Award BC045664.

Myrrh (Commiphora molmol) in treatment of human and sheep dicrocoeliasis dendriticum in Saudi Arabia.

PubMed

Al-Mathal, Ebtesam M; Fouad, Mahmoud A H

2004-08-01

Dicrocoeliasis dendriticum is now imposing itself as an animal and zoonotic helminthic disease in many Arabian countries. Myrrh extract of Commiphora molmol (Mirazid) successfully and safely treated clinically and parasitologically proven 18 human dicrocoeliasis dendriticum patients. The dose was 2 capsules (300 mg each) given on an empty stomach an hour before the breakfast for six successive days. Cure (100%) was achieved clinically and by stool analysis for two months follow up. Besides, fifteen sheep naturally infected with Dicrocoelium dendriticum as proven parasitologically were successfully and safely treated with 2 capsules (300 mg each) on an empty stomach an hour before breakfast for four successive days. Cure (100%) was successfully achieved by stool analysis for seven days and macroscopically for detection of any adult worm after being slaughtered. The total dose required to treat infected sheep (2400 mg) was less than that required for human treatment (3600 mg).

The effect of Agaricus brasiliensis extract supplementation on honey bee colonies.

PubMed

Stevanovic, Jevrosima; Stanimirovic, Zoran; Simeunovic, Predrag; Lakic, Nada; Radovic, Ivica; Sokovic, Marina; Griensven, Leo J L D VAN

2018-01-01

This study was done to discover any beneficial effect of a medicinal mushroom Agaricus brasiliensis extract on the honey bee. Firstly, a laboratory experiment was conducted on 640 bees reared in 32 single-use plastic rearing cups. A. brasiliensis extract proved safe in all doses tested (50, 100 and 150 mg/kg/day) irrespective of feeding mode (sugar syrup or candy). Secondly, a three-year field experiment was conducted on 26 colonies treated with a single dose of A. brasiliensis extract (100 mg/kg/day) added to syrup. Each year the colonies were treated once in autumn and twice in spring. The treatments significantly increased colony strength parameters: brood rearing improvement and adult population growth were noticed more often than the increase in honey production and pollen reserves. These positive effects were mainly observed in April. In conclusion, A. brasiliensis extract is safe for the bees and helps maintaining strong colonies, especially in spring.

Nantenine alkaloid presents anticonvulsant effect on two classical animal models.

PubMed

Ribeiro, R A; Leite, J R

2003-01-01

The present study investigated the anticonvulsant and convulsant profiles of nantenine, an aporphine alkaloid found in several vegetal species. At lower doses (20-50 mg/kg, i.p.) the alkaloid proved to be effective in inhibiting pentylenotetrazol- (PTZ 100 mg/kg, s.c.) and maximal electroshock-induced seizures (80 mA, 50 pulses/s, 0.2 s), suggesting its potential as an anticonvulsant drug. However, at higher doses (> or = 75 mg/kg, i.p.) a convulsant activity was observed. Comparing the present in vivo nantenine effects on seizures with previous in vitro biphasic action on Na+, K+-ATPase activity, the convulsant effect appears to be related to inhibition of these phosphatase at high doses whereas anticonvulsant effect, observed at low doses, seems attributable to its stimulation and the resultant decrease of Ca2+-influx into the cell.

Age-specific radiation dose commitment factors for a one-year chronic intake

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

Hoenes, G.R.; Soldat, J.K.

1977-11-01

During the licensing process for nuclear facilities, radiation doses and dose commitments must be calculated for people in the environs of a nuclear facility. These radiation doses are determined by examining characteristics of population groups, pathways to people, and radionuclides found in those pathways. The pertinent characteristics, which are important in the sense of contributing a significant portion of the total dose, must then be analyzed in depth. Dose factors are generally available for adults, see Reference 1 for example, however numerous improvements in data on decay schemes and half-lives have been made in recent years. In addition, it ismore » advisable to define parameters for calculation of the radiation dose for ages other than adults since the population surrounding nuclear facilities will be composed of various age groups. Further, since infants, children, and teens may have higher rates of intake per unit body mass, it is conceivable that the maximally exposed individual may not be an adult. Thus, it was necessary to develop new radiation-dose commitment factors for various age groups. Dose commitment factors presented in this report have been calculated for a 50-year time period for four age groups.« less

Maximizing optical efficacy and color gamut in projection applications by combining four laser wavelengths

NASA Astrophysics Data System (ADS)

Wallhead, Ian; Ocaña, Roberto

2014-05-01

Laser projection devices should be designed to maximize their luminous efficacy and color gamut. This is for two main reasons. Firstly, being either stand alone devices or embedded in other products, they could be powered by battery, and lifetime is an important factor. Secondly, the increasing use of lasers to project images calls for a consideration of eye safety issues. The brightness of the projected image may be limited by the Class II accessible emission limit. There is reason to believe that current laser beam scanning projection technology is already close to the power ceiling based on eye safety limits. Consequently, it would be desirable to improve luminous efficacy to increase the output luminous flux whilst maintaining or improving color gamut for the same eye-safe optical power limit. Here we present a novel study about the combination of four laser wavelengths in order to maximize both color gamut and efficacy to produce the color white. Firstly, an analytic method to calculate efficacy as function of both four laser wavelengths and four laser powers is derived. Secondly we provide a new way to present the results by providing the diagram efficacy vs color gamut area that summarizes the performance of any wavelength combination for projection purposes. The results indicate that the maximal efficacy for the D65 white is only achievable by using a suitable combination of both laser power ratios and wavelengths.

High-intensity and resistance training and elite young athletes.

PubMed

Ratel, Sébastien

2011-01-01

Although in the past resistance and high-intensity exercise training among young children was the subject of numerous controversies, it is now well-documented that this training mode is a safe and effective means of developing maximal strength, maximal power output and athletic performance in youth, provided that exercises are performed with appropriate supervision and precautions. Muscular strength and power output values measured from vertical jump and Wingate anaerobic tests are higher in elite than in non-elite young athletes and normal children, and the specific training effects on maximal power output normalised for body size are clearly more distinct before puberty. At present, there is no scientific evidence to support the view that high-intensity and/or resistance training might hinder growth and maturation in young children. Pre-pubertal growth is not adversely affected by sport at a competitive level and anthropometric factors are of importance for choice of sport in children. However, coaches, teachers and parents should be aware that unsupervised high-intensity and resistance training programmes involving maximal loads or too frequently repeated resistance exercises increase the risk of injury. Resistance training alone is an effective additional means of developing athletic performance throughout planned youth sports training programmes. Strategies for enhancing the effectiveness and safety of youth resistance and high-intensity exercise training are discussed in this chapter. Copyright © 2011 S. Karger AG, Basel.

Laser speckle imaging to improve clinical outcomes for patients with trigeminal neuralgia undergoing radiofrequency thermocoagulation.

PubMed

Ringkamp, Matthias; Wooten, Matthew; Carson, Benjamin S; Lim, Michael; Hartke, Timothy; Guarnieri, Michael

2016-02-01

Percutaneous treatments for trigeminal neuralgia are safe, simple, and effective for achieving good pain control. Procedural risks could be minimized by using noninvasive imaging techniques to improve the placement of the radiofrequency thermocoagulation probe into the trigeminal ganglion. Positioning of a probe is crucial to maximize pain relief and to minimize unwanted side effects, such as denervation in unaffected areas. This investigation examined the use of laser speckle imaging during probe placement in an animal model. This preclinical safety study used nonhuman primates, Macaca nemestrina (pigtail monkeys), to examine whether real-time imaging of blood flow in the face during the positioning of a coagulation probe could monitor the location and guide the positioning of the probe within the trigeminal ganglion. Data from 6 experiments in 3 pigtail monkeys support the hypothesis that laser imaging is safe and improves the accuracy of probe placement. Noninvasive laser speckle imaging can be performed safely in nonhuman primates. Because improved probe placement may reduce morbidity associated with percutaneous rhizotomies, efficacy trials of laser speckle imaging should be conducted in humans.

FoodWiki: Ontology-Driven Mobile Safe Food Consumption System.

PubMed

Çelik, Duygu

2015-01-01

An ontology-driven safe food consumption mobile system is considered. Over 3,000 compounds are being added to processed food, with numerous effects on the food: to add color, stabilize, texturize, preserve, sweeten, thicken, add flavor, soften, emulsify, and so forth. According to World Health Organization, governments have lately focused on legislation to reduce such ingredients or compounds in manufactured foods as they may have side effects causing health risks such as heart disease, cancer, diabetes, allergens, and obesity. By supervising what and how much to eat as well as what not to eat, we can maximize a patient's life quality through avoidance of unhealthy ingredients. Smart e-health systems with powerful knowledge bases can provide suggestions of appropriate foods to individuals. Next-generation smart knowledgebase systems will not only include traditional syntactic-based search, which limits the utility of the search results, but will also provide semantics for rich searching. In this paper, performance of concept matching of food ingredients is semantic-based, meaning that it runs its own semantic based rule set to infer meaningful results through the proposed Ontology-Driven Mobile Safe Food Consumption System (FoodWiki).

Application of fire and evacuation models in evaluation of fire safety in railway tunnels

NASA Astrophysics Data System (ADS)

Cábová, Kamila; Apeltauer, Tomáš; Okřinová, Petra; Wald, František

2017-09-01

The paper describes an application of numerical simulation of fire dynamics and evacuation of people in a tunnel. The software tool Fire Dynamics Simulator is used to simulate temperature resolution and development of smoke in a railway tunnel. Comparing to temperature curves which are usually used in the design stage results of the model show that the numerical model gives lower temperature of hot smoke layer. Outputs of the numerical simulation of fire also enable to improve models of evacuation of people during fires in tunnels. In the presented study the calculated high of smoke layer in the tunnel is in 10 min after the fire ignition lower than the level of 2.2 m which is considered as the maximal limit for safe evacuation. Simulation of the evacuation process in bigger scale together with fire dynamics can provide very valuable information about important security conditions like Available Safe Evacuation Time (ASET) vs Required Safe Evacuation Time (RSET). On given example in software EXODUS the paper summarizes selected results of evacuation model which should be in mind of a designer when preparing an evacuation plan.

Preventing and Managing Toxicities of High-Dose Methotrexate.

PubMed

Howard, Scott C; McCormick, John; Pui, Ching-Hon; Buddington, Randall K; Harvey, R Donald

2016-12-01

: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m 2 , is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m 2 , is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity. ©AlphaMed Press.

Preventing and Managing Toxicities of High-Dose Methotrexate

PubMed Central

McCormick, John; Pui, Ching-Hon; Buddington, Randall K.; Harvey, R. Donald

2016-01-01

High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%–12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. Implications for Practice: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity. PMID:27496039

Optimal Physical Training During Military Basic Training Period.

PubMed

Santtila, Matti; Pihlainen, Kai; Viskari, Jarmo; Kyröläinen, Heikki

2015-11-01

The goal for military basic training (BT) is to create a foundation for physical fitness and military skills of soldiers. Thereafter, more advanced military training can safely take place. Large differences in the initial physical performance of conscripts or recruits have led military units to develop more safe and effective training programs. The purpose of this review article was to describe the limiting factors of optimal physical training during the BT period. This review revealed that the high volume of low-intensity physical activity combined with endurance-type military training (like combat training, prolonged physical activity, and field shooting) during BT interferes with optimal development of maximal oxygen uptake and muscle strength of the soldiers. Therefore, more progressive, periodized, and individualized training programs are needed. In conclusion, optimal training programs lead to higher training responses and lower risks for injuries and overloading.

Safe and Effective Use of the Once Weekly Dulaglutide Single-Dose Pen in Injection-Naïve Patients With Type 2 Diabetes.

PubMed

Matfin, Glenn; Van Brunt, Kate; Zimmermann, Alan G; Threlkeld, Rebecca; Ignaut, Debra A

2015-04-21

This 4-week, phase 3b, multicenter, open-label, single-arm, outpatient study demonstrated the safe and effective use of the dulaglutide single-dose pen containing 0.5 mL of placebo for subcutaneous injection in injection-naïve adult patients with type 2 diabetes (T2D), with A1C ≤ 8.5% (69 mmol/mol), BMI ≥ 23 kg/m2 and ≤ 45 kg/m(2). Patients completed a modified self-injecting subscale of the Diabetes Fear of Injecting and Self-Testing Questionnaire (mD-FISQ) and were trained to self-inject with the single-dose pen. Patients completed the initial self-injection at the site, injected at home for 2 subsequent weeks, and returned to the site for the final injection. The initial and final self-injections were evaluated for success; the final (initial) self-injection success rate was the primary (secondary) outcome measure, and the primary (secondary) objective was to demonstrate this success rate as being significantly greater than 80%. Patients recorded their level of pain after each injection. After the final injection, patients completed the mD-FISQ and the Medication Delivery Device Assessment Battery (MDDAB) to assess their perceptions of the single-dose pen, including ease of use and experience with the device. Among 211 patients (mean age: 61 years), the primary objective was met, with a final injection success rate of 99.1% (95% CI: 96.6% to 99.7%). Among 214 patients, the initial injection success rate was 97.2% (95% CI: 94.0% to 98.7%), meeting the key secondary objective. Overall, most patients (>96%) found the device easy to use, were satisfied with the device, and would be willing to continue to use the single-dose pen after the study. There was a significant reduction (P < .001) from baseline to study end in patients' fear of self-injecting, as measured by the mD-FISQ. The dulaglutide single-dose pen was found to be a safe and effective device for use by patients with T2D who were injection-naïve. A positive injection experience is an important factor for patients and providers when initiating injectable therapy. © 2015 Diabetes Technology Society.

Safe and Effective Use of the Once Weekly Dulaglutide Single-Dose Pen in Injection-Naïve Patients With Type 2 Diabetes

PubMed Central

Matfin, Glenn; Van Brunt, Kate; Zimmermann, Alan G.; Threlkeld, Rebecca; Ignaut, Debra A.

2015-01-01

Background: This 4-week, phase 3b, multicenter, open-label, single-arm, outpatient study demonstrated the safe and effective use of the dulaglutide single-dose pen containing 0.5 mL of placebo for subcutaneous injection in injection-naïve adult patients with type 2 diabetes (T2D), with A1C ≤ 8.5% (69 mmol/mol), BMI ≥ 23 kg/m2 and ≤ 45 kg/m2. Method: Patients completed a modified self-injecting subscale of the Diabetes Fear of Injecting and Self-Testing Questionnaire (mD-FISQ) and were trained to self-inject with the single-dose pen. Patients completed the initial self-injection at the site, injected at home for 2 subsequent weeks, and returned to the site for the final injection. The initial and final self-injections were evaluated for success; the final (initial) self-injection success rate was the primary (secondary) outcome measure, and the primary (secondary) objective was to demonstrate this success rate as being significantly greater than 80%. Patients recorded their level of pain after each injection. After the final injection, patients completed the mD-FISQ and the Medication Delivery Device Assessment Battery (MDDAB) to assess their perceptions of the single-dose pen, including ease of use and experience with the device. Results: Among 211 patients (mean age: 61 years), the primary objective was met, with a final injection success rate of 99.1% (95% CI: 96.6% to 99.7%). Among 214 patients, the initial injection success rate was 97.2% (95% CI: 94.0% to 98.7%), meeting the key secondary objective. Overall, most patients (>96%) found the device easy to use, were satisfied with the device, and would be willing to continue to use the single-dose pen after the study. There was a significant reduction (P < .001) from baseline to study end in patients’ fear of self-injecting, as measured by the mD-FISQ. Conclusions: The dulaglutide single-dose pen was found to be a safe and effective device for use by patients with T2D who were injection-naïve. A positive injection experience is an important factor for patients and providers when initiating injectable therapy. PMID:25901022

Ultrarush schedule of subcutaneous immunotherapy with modified allergen extracts is safe in paediatric age.

PubMed

Morais-Almeida, Mário; Arêde, Cristina; Sampaio, Graça; Borrego, Luis Miguel

2016-01-01

Traditional subcutaneous immunotherapy up dosing with allergenic extracts has been shown to be associated with frequent adverse reactions. In recent studies it has been demonstrated that using modified extracts, namely allergoids, it is a safe and effective procedure particularly on accelerated schedules. However data assessing its safety in paediatric age is scarce. To evaluate the safety profile in paediatric population of using modified allergen extracts, in an ultrarush schedule, to reach the maintenance dose in the first day. We included children undergoing treatment with subcutaneous immunotherapy during a five-year period, using modified aeroallergen extracts, depigmented, polymerized with glutaraldehyde and adsorbed on aluminium hydroxide using an ultrarush induction phase. The type of adverse reactions during the ultrarush protocol was recorded. We studied 100 paediatric patients (57 males) with a mean age of 11.6 years (5 to 18 years; standard deviation, 3.3), all with moderate to severe persistent rhinitis, with or without allergic conjunctivitis, asthma and atopic eczema, sensitized to mites and/or pollens. All reached the maintenance dose of 0.5 mL in the first day, except 1 child. During the ultrarush protocol the total number of injections was 199. There were 21 local adverse reactions in 11 patients, 11 immediate and 10 delayed; from those, had clinical relevance 1 immediate and 4 delayed. Systemic reactions were recorded in 2 cases, both immediate and mild. The ultrarush protocol, without premedication, was a safe alternative to be used in paediatric age during the induction phase of subcutaneous immunotherapy using allergoid depigmented extracts.

Ultrarush schedule of subcutaneous immunotherapy with modified allergen extracts is safe in paediatric age

PubMed Central

Arêde, Cristina; Sampaio, Graça; Borrego, Luis Miguel

2016-01-01

Background Traditional subcutaneous immunotherapy up dosing with allergenic extracts has been shown to be associated with frequent adverse reactions. In recent studies it has been demonstrated that using modified extracts, namely allergoids, it is a safe and effective procedure particularly on accelerated schedules. However data assessing its safety in paediatric age is scarce. Objective To evaluate the safety profile in paediatric population of using modified allergen extracts, in an ultrarush schedule, to reach the maintenance dose in the first day. Methods We included children undergoing treatment with subcutaneous immunotherapy during a five-year period, using modified aeroallergen extracts, depigmented, polymerized with glutaraldehyde and adsorbed on aluminium hydroxide using an ultrarush induction phase. The type of adverse reactions during the ultrarush protocol was recorded. Results We studied 100 paediatric patients (57 males) with a mean age of 11.6 years (5 to 18 years; standard deviation, 3.3), all with moderate to severe persistent rhinitis, with or without allergic conjunctivitis, asthma and atopic eczema, sensitized to mites and/or pollens. All reached the maintenance dose of 0.5 mL in the first day, except 1 child. During the ultrarush protocol the total number of injections was 199. There were 21 local adverse reactions in 11 patients, 11 immediate and 10 delayed; from those, had clinical relevance 1 immediate and 4 delayed. Systemic reactions were recorded in 2 cases, both immediate and mild. Conclusion The ultrarush protocol, without premedication, was a safe alternative to be used in paediatric age during the induction phase of subcutaneous immunotherapy using allergoid depigmented extracts. PMID:26844218

Spectral reconstruction of dental X-ray tubes using laplace inverse transform of the attenuation curve

NASA Astrophysics Data System (ADS)

Malezan, A.; Tomal, A.; Antoniassi, M.; Watanabe, P. C. A.; Albino, L. D.; Poletti, M. E.

2015-11-01

In this work, a spectral reconstruction methodology for diagnostic X-ray, using Laplace inverse transform of the attenuation, was successfully applied to dental X-ray equipments. The attenuation curves of 8 commercially available dental X-ray equipment, from 3 different manufactures (Siemens, Gnatus and Dabi Atlante), were obtained by using an ionization chamber and high purity aluminium filters, while the kVp was obtained with a specific meter. A computational routine was implemented in order to adjust a model function, whose inverse Laplace transform is analytically known, to the attenuation curve. This methodology was validated by comparing the reconstructed and the measured (using semiconductor detector of cadmium telluride) spectra of a given dental X-ray unit. The spectral reconstruction showed the Dabi Atlante equipments generating similar shape spectra. This is a desirable feature from clinic standpoint because it produces similar levels of image quality and dose. We observed that equipments from Siemens and Gnatus generate significantly different spectra, suggesting that, for a given operating protocol, these units will present different levels of image quality and dose. This fact claims for the necessity of individualized operating protocols that maximize image quality and dose. The proposed methodology is suitable to perform a spectral reconstruction of dental X-ray equipments from the simple measurements of attenuation curve and kVp. The simplified experimental apparatus and the low level of technical difficulty make this methodology accessible to a broad range of users. The knowledge of the spectral distribution can help in the development of operating protocols that maximize image quality and dose.

Influence of adipocyte size and adipose depot on the in vitro lipolytic activity and insulin sensitivity of adipose tissue in dairy cows at the end of the dry period.

PubMed

De Koster, J; Van den Broeck, W; Hulpio, L; Claeys, E; Van Eetvelde, M; Hermans, K; Hostens, M; Fievez, V; Opsomer, G

2016-03-01

The aim of the present research was to describe characteristics of adipose tissue lipolysis in dairy cows with a variable body condition score (BCS). Ten clinically healthy Holstein Friesian cows were selected based on BCS and euthanized 10 to 13 d before the expected parturition date. Immediately after euthanasia, adipose tissue samples were collected from subcutaneous and omental fat depots. In both depots, we observed an increase in adipocyte size with increasing BCS. Using an in vitro explant culture of subcutaneous and omental adipose tissue, we aimed to determine the influence of adipocyte size and localization of adipose depot on the lipolytic activity in basal conditions and after addition of isoproterenol (nonselective β-agonist) and insulin in different concentrations. Glycerol release in the medium was used as a measure for lipolytic activity. We observed that the basal lipolytic activity of subcutaneous and omental adipose tissue increased with adipocyte volume, meaning that larger fat cells have higher basal lipolytic activity independent of the location of the adipose depot. Dose-response curves were created between the concentration of isoproterenol or insulin and the amount of glycerol released. The shape of the dose-response curves is determined by the concentration of isoproterenol and insulin needed to elicit the half-maximal effect and the maximal amount of stimulated glycerol release or the maximal inhibitory effect of insulin. We observed that larger fat cells released more glycerol upon maximal stimulation with isoproterenol and this was more pronounced in subcutaneous adipose tissue. Additionally, larger fat cells had a higher sensitivity toward lipolytic signals. We observed a trend for larger adipocytes to be more resistant to the maximal antilipolytic effect of insulin. The insulin concentration needed to elicit the half-maximal inhibitory effect of insulin was within the physiological range of insulin and was not influenced by adipocyte size or adipose depot. We conclude that overconditioned cows have larger adipocytes and are predisposed to excessive mobilization of body fat due to a higher basal and stimulated lipolytic activity of large adipocytes while the antilipolytic effect of insulin is preserved. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Conditioning of the 4 Curies Radium-226 Sealed Radiation Source in Thailand

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

Punnachaiya, M.; Sawangsri, T.; Wanabongse, P.

This paper describes the conditioning of the 4 curies Radium-226 (Ra-226) sealed radiation source using as a teletherapy unit for cancer treatment in Thailand. The conditioning was under the International Atomic Energy Agency (IAEA) supervision and budgetary supports, comprised of 6 operational steps: the surface dose rate and actual dimension of radium unit measurements, the appropriate lead shielding design with IAEA approval, confirmation of radioactive contamination before conditioning (smear test and radon gas leakage test), transfer of radium source unit into the designed shielding, confirmation of radioactive contamination and dose rate measurement after conditioning, and transportation of Ra-226 conditioning wastemore » package to OAP interim waste storage. The Ra-226 unit was taken out of OAP temporary waste storage for the surface dose rate and the actual dimension measurements behind the 12 inches thick heavy concrete shielding. The maximum measured surface dose rate was 70 R/hr. The special lead container was designed according to its surface dose rate along the source unit which the maximum permissible dose limit for surface dose rate of waste package after conditioning at 2 mSv/hr was applied. The IAEA approved container had total weight of 2.4 ton. After the confirmation of radioactive contamination, Ra-226 source unit was transferred and loaded in the designed lead shielding within 2 minutes. The results of smear test before and after conditioning including radon gas leakage test revealed that there was no radioactive contamination. After conditioning, the surface dose rate measured on the top, bottom were 15,10 mR/hr and varied from 6 - 50 mR/hr around lead container. The Ra-226 conditioning waste package was safely transported to store in OAP interim waste storage. Total working time including the time consumed for radon gas leakage test was 3.5 hours. The total radiation dose received by 16 operators, were ranged from 1 - 69.84 {mu}Sv and the operational team completed the conditioning safely within the effective dose limit for occupational exposure of 50 mSv/year (200 {mu}Sv/day). (authors)« less

Inactivated polio vaccines from three different manufacturers have equivalent safety and immunogenicity when given as 1 or 2 additional doses after bivalent OPV: Results from a randomized controlled trial in Latin America.

PubMed

Lopez-Medina, Eduardo; Melgar, Mario; Gaensbauer, James T; Bandyopadhyay, Ananda S; Borate, Bhavesh R; Weldon, William C; Rüttimann, Ricardo; Ward, Joel; Clemens, Ralf; Asturias, Edwin J

2017-06-16

Since April 2016 inactivated poliovirus vaccine (IPV) has been the only routine source of polio type 2 protection worldwide. With IPV supply constraints, data on comparability of immunogenicity and safety will be important to optimally utilize available supplies from different manufacturers. In this multicenter phase IV study, 900 Latin American infants randomly assigned to six study groups received three doses of bOPV at 6, 10 and 14weeks and either one IPV dose at 14weeks (groups SP-1, GSK-1 and BBio-1) or two IPV doses at 14 and 36weeks (groups SP-2, GSK-2 and BBio-2) from three different manufacturers. Children were challenged with mOPV2 at either 18 (one IPV dose) or 40weeks (two IPV doses) and stools were collected weekly for 4weeks to assess viral shedding. Serum neutralizing antibodies were measured at various time points pre and post vaccination. Serious adverse events and important medical events (SAE and IME) were monitored for 6months after last study vaccine. At week 18, 4weeks after one dose of IPV, overall type 2 seroconversion rates were 80.4%, 80.4% and 73.3% for SP-1, GSK-1 and BBio-1 groups, respectively; and 92.6%, 96.8% and 88.0% in those who were seronegative before IPV administration. At 40weeks, 4weeks after a second IPV dose, type 2 seroconversion rates were ≥99% for any of the three manufacturers. There were no significant differences in fecal shedding index endpoint (SIE) after one or two IPV doses (SP: 2.3 [95% CI: 2.1-2.6]); GSK: 2.2 [1.7-2.5]; BBio 1.8 [1.5-2.3]. All vaccines appeared safe, with no vaccine-related SAE or IME. Current WHO prequalified IPV vaccines are safe and induce similar humoral and intestinal immunity after one or two doses. The parent study was registered with ClinicalTrials.gov, number NCT01831050. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination.

PubMed

Paller, Channing J; Rudek, Michelle A; Zhou, Xian C; Wagner, William D; Hudson, Tamaro S; Anders, Nicole; Hammers, Hans J; Dowling, Donna; King, Serina; Antonarakis, Emmanuel S; Drake, Charles G; Eisenberger, Mario A; Denmeade, Samuel R; Rosner, Gary L; Carducci, Michael A

2015-10-01

New therapies are being explored as therapeutic options for men with biochemically recurrent prostate cancer (BRPC) who wish to defer androgen deprivation therapy. MPX is pulverized muscadine grape (Vitis rotundifolia) skin that contains ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro. In the phase I portion of this phase I/II study, non-metastatic BRPC patients were assigned to increasing doses of MPX (Muscadine Naturals. Inc., Clemmons, NC) in cohorts of two patients, with six patients at the highest dose, using a modified continual reassessment method. Initial dose selection was based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. The primary endpoint was the recommended phase II dosing regimen. The cohort (n = 14, 71% Caucasian, 29% black) had a median follow-up of 19.2 (6.2-29.7) months, median age of 61 years, and median Gleason score of 7. Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 eructation. No other related adverse events were reported and one patient reported improvement of chronic constipation. Six of 14 patients came off study for disease progression (five metastatic, one rising PSA) after exposure for a median of 15 months. One patient came off for myasthenia gravis that was unrelated to treatment. Seven patients remain on study. The lack of dose-limiting toxicities led to the selection of 4,000 mg/d as the highest dose for further study. Median within-patient PSADT increased by 5.3 months (non-significant, P = 0.17). No patients experienced a maintained decline in serum PSA from baseline. These data suggest that 4,000 mg of MPX is safe, and exploratory review of a lengthening in PSADT of a median of 5.3 months supports further exploration of MPX. Both low-dose (500 mg) and high-dose (4,000 mg) MPX are being further investigated in a randomized, multicenter, placebo-controlled, dose-evaluating phase II trial. © 2015 Wiley Periodicals, Inc.

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.

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).

Outpatient radioiodine therapy for thyroid cancer: a safe nuclear medicine procedure.

PubMed

Willegaignon, José; Sapienza, Marcelo; Ono, Carla; Watanabe, Tomoco; Guimarães, Maria Inês; Gutterres, Ricardo; Marechal, Maria Helena; Buchpiguel, Carlos

2011-06-01

To evaluate the dosimetric effect of outpatient radioiodine therapy for thyroid cancer in members of a patient's family and their living environment, when using iodine-131 doses reaching 7.4 GBq. The following parameters were thus defined: (a) whole-body radiation doses to caregivers, (b) the production of contaminated solid waste, and (c) radiation potential and surface contamination within patients' living quarters. In total, 100 patients were treated on an outpatient basis, taking into consideration their acceptable living conditions, interests, and willingness to comply with medical and radiation safety guidelines. Both the caregivers and the radiation dose potentiality inside patients' residences were monitored by using thermoluminescent dosimeters. Surface contamination and contaminated solid wastes were identified and measured with a Geiger-Müller detector. A total of 90 monitored individuals received a mean dose of 0.27 (±0.28) mSv, and the maximum dose registered was 1.6 mSv. The mean value for the potential dose within all living quarters was 0.31 (±0.34) mSv, and the mean value per monitored surface was 5.58 Bq/cm(2) for all the 1659 points measured. The overall production of contaminated solid wastes was at a low level, being about 3 times less than the exemption level indicated by the International Atomic Energy Agency. This study indicates that the treatment of thyroid cancer by applying radioiodine activities up to 7.4 GBq, on an outpatient basis, is a safe procedure, especially when supervised by qualified professionals. This alternative therapy should be a topic for careful discussion considering the high potential for reducing costs in healthcare and improving patient acceptance.

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

Clinical review: Treatment of neurohypophyseal diabetes insipidus.

PubMed

Oiso, Yutaka; Robertson, Gary L; Nørgaard, Jens Peter; Juul, Kristian Vinter

2013-10-01

In recent years, there have been several improvements in the treatment of neurohypophyseal diabetes insipidus (DI). They include new formulations of the vasopressin analog, desmopressin; a better understanding of the effect of fluid intake on dosing; and more information about treatments of infants, children, and pregnant women who present special challenges. This review aims to summarize past and current information relative to the safety and efficacy of treatments for the types of DI caused by a primary deficiency of vasopressin. The review is based on publications identified primarily by a PubMed search of the international literature without limitations of date. In acute settings where fluid intake is determined by factors other than thirst, desmopressin should be given iv in doses that have a short duration of action and can be adjusted quickly in accordance with changes in hydration as indicated by plasma sodium. In ambulatory patients, the oral formulations (tablet or melt) are preferred for their convenience. If fluid intake is regulated normally by the thirst mechanism, the tablets or melt can be taken safely 1 to 3 times a day in doses sufficient to completely eliminate the polyuria. However, if fluid intake consistently exceeds replacement needs as evidenced by the development of hyponatremia, the dose should be reduced to allow higher than normal rates of urine output or intermittent breakthrough diuresis. This regimen is often indicated in infants or children because their rate of fluid intake tends to be greater than in adults. In all cases, the appropriate dose should be determined by titration, owing to considerable interindividual differences in bioavailability and antidiuretic effect. Desmopressin can provide effective and safe therapy for all patients with neurohypophyseal or gestational DI if given in doses and by a route that takes into account the determinants of fluid intake.

Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial.

PubMed

Mannelli, Paolo; Wu, Li-Tzy; Peindl, Kathleen S; Swartz, Marvin S; Woody, George E

2014-05-01

The approval of extended release injectable naltrexone (XR-NTX; Vivitrol(®)) has introduced a new option for treating opioid addiction, but studies are needed to identify its place within the spectrum of available therapies. The absence of physiological opioid dependence is a necessary and challenging first step for starting XR-NTX. Outpatient detoxification gives poor results and inpatient detoxification is either unavailable or too brief for the physiological effects of opioids to resolve. Here we present findings from an open label study that tested whether the transition from opioid addiction to XR-NTX can be safely and effectively performed in an outpatient setting using very low dose naltrexone and buprenorphine. Twenty treatment seeking opioid addicted individuals were given increasing doses of naltrexone starting at 0.25mg with decreasing doses of buprenorphine starting at 4 mg during a 7-day outpatient XR-NTX induction procedure. Withdrawal discomfort, craving, drug use, and adverse events were assessed daily until the XR-NTX injection, then weekly over the next month. Fourteen of the 20 participants received XR-NTX and 13 completed weekly assessments. Withdrawal, craving, and opioid or other drug use were significantly lower during induction and after XR-NTX administration compared with baseline, and no serious adverse events were recorded. Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with downward titration of low dose buprenorphine was safe, well tolerated, and completed by most participants. Further studies with larger numbers of subjects are needed to see if this approach is useful for naltrexone induction. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

PubMed Central

Trippett, Tanya M.; Herzog, Cynthia; Whitlock, James A.; Wolff, Johannes; Kuttesch, John; Bagatell, Rochelle; Hunger, Stephen P.; Boklan, Jessica; Smith, Amy A.; Arceci, Robert J.; Katzenstein, Howard M.; Harbison, Christopher; Zhou, Xiaofei; Lu, Haolan; Langer, Christiane; Weber, Martin; Gore, Lia

2009-01-01

Purpose To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and Methods This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m2) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m2/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. Results Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m2 weekly plus irinotecan 16 mg/m2/d (pediatric) or 20 mg/m2/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). Conclusion The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen. PMID:19770383

Is Daily Low-Dose Aspirin Safe to Take Following Laparoscopic Roux-en-Y Gastric Bypass for Obesity Surgery?

PubMed

Kang, Xian; Hong, Dennis; Anvari, Mehran; Tiboni, Maria; Amin, Nalin; Gmora, Scott

2017-05-01

Laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery is a safe and effective procedure for patients with severe obesity. One potential complication of LRYGB is the development of marginal ulcers (MUs). Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to significantly increase the likelihood of developing marginal ulcers after surgery. However, the risk associated with low-dose aspirin consumption is not well defined. We examined the impact of daily low-dose aspirin (81 mg) on the development of marginal ulcers following LRYGB. A retrospective cohort design studied patients undergoing LRYGB surgery, between January 2009 and January 2013, at a single, high-volume bariatric center in Ontario, Canada. The marginal ulcer rate of patients taking low-dose aspirin after surgery was compared to that of the control patients who did not take any NSAID. Diagnosis of MU was confirmed by upper endoscopy in patients presenting with symptoms and a history indicative of marginal ulceration. A chi-square test of independence was performed to examine the difference in marginal ulcer rates. A total of 1016 patients underwent LRYGB. Patients taking aspirin were more likely to be male, older, and have diabetes than patients not taking NSAIDs. Of the 1016 patients, 145 (14.3%) took low-dose aspirin following LRYGB and the rest did not (n = 871, 85.7%). The incidence of marginal ulceration was not significantly different between the two treatment groups (12/145, 8.3% versus 90/871, 10.3%; p = 0.45). Patients treated with LRYGB at our institution were not at increased risk of marginal ulcer formation when taking low-dose aspirin after surgery.

Design and Laboratory Implementation of Autonomous Optimal Motion Planning for Non-Holonomic Planetary Rovers

DTIC Science & Technology

2012-12-01

autonomy helped to maximize a Mars day journey, because humans could only plan the first portion of the journey based on images sent from the rover...safe trajectory based on its sensors [1]. The distance between Mars and Earth ranges from 100-200 million miles [1] and at this distance, the time...This feature worked for the pre- planned maneuvers, which were planned by humans the day before based on available sensory and visual inputs. Once the

Effects of external electrical and magnetic fields on pacemakers and defibrillators: from engineering principles to clinical practice.

PubMed

Beinart, Roy; Nazarian, Saman

2013-12-24

The overall risk of clinically significant adverse events related to EMI in recipients of CIEDs is very low. Therefore, no special precautions are needed when household appliances are used. Environmental and industrial sources of EMI are relatively safe when the exposure time is limited and distance from the CIEDs is maximized. The risk of EMI-induced events is highest within the hospital environment. Physician awareness of the possible interactions and methods to minimize them is warranted.

The practicality of employee empowerment: supporting a psychologically safe culture.

PubMed

Valadares, Kevin J

2004-01-01

In times of workforce shortages and increasing pressures to compete, health care organizations need to advance and ameliorate their resources to ensure organizational success. Other industries have maximized empowerment initiatives as a strategy to retain and develop employees as primary stakeholders of its mission. While the notion of employee empowerment is by itself noble, for it to succeed, health care organizations must promote a culture of psychological safety to ensure a genuine commitment exists in its mission and strategies.

Metabolic Energy Costs of USAF Explosive Ordnance Disposal Render Safe Procedures: Field Determinations

DTIC Science & Technology

1991-05-01

work requirement in the moderate to hard work category. This level of energy expenditure should be within the capacity of the average EOD technician...Review of the component tasks of the RSP indicates that peak, short-term work expenditure did not approach the estimated maximal work category (1.9 1 min...hazard which would significantly increase the total energy cost of the RSP. The majority of the expected increase in energy expenditure would result from

Cardiorespiratory assessment of decongestant-antihistamine effects of altitude, +Gz, and fatigue tolerances.

DOT National Transportation Integrated Search

1978-04-01

Decongestants and antihistamines are known to produce effects capable of adversely modifying physiological function and psychomotor task performance. Because of relevance to safe pilot performance, the effects of single doses of two decongestant-anti...

SU-D-19A-06: The Effect of Beam Parameters On Very High-Energy Electron Radiotherapy: A Planning Study

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

Palma, B; Bazalova, M; Qu, B

Purpose: We evaluated the effect of very high-energy electron (VHEE) beam parameters on the planning of a lung cancer case by means of Monte Carlo simulations. Methods: We simulated VHEE radiotherapy plans using the EGSnrc/BEAMnrc-DOSXYZnrc code. We selected a lung cancer case that was treated with 6MV photon VMAT to be planned with VHEE. We studied the effect of beam energy (80 MeV, 100 MeV, and 120 MeV), number of equidistant beams (16 or 32), and beamlets sizes (3 mm, 5 mm or 7 mm) on PTV coverage, sparing of organs at risk (OARs) and dose conformity. Inverse-planning optimization wasmore » performed in a research version of RayStation (RaySearch Laboratories AB) using identical objective functions and constraints for all VHEE plans. Results: Similar PTV coverage and dose conformity was achieved by all the VHEE plans. The 100 MeV and 120 MeV VHEE plans were equivalent amongst them and were superior to the 80 MeV plan in terms of OARs sparing. The effect of using 16 or 32 equidistant beams was a mean difference in average dose of 2.4% (0%–7.7%) between the two plans. The use of 3 mm beamlet size systematically reduced the dose to all the OARs. Based on these results we selected the 100MeV-16beams-3mm-beamlet-size plan to compare it against VMAT. The selected VHEE plan was more conformal than VMAT and improved OAR sparing (heart and trachea received 125% and 177% lower dose, respectively) especially in the low-dose region. Conclusion: We determined the VHEE beam parameters that maximized the OAR dose sparing and dose conformity of the actually delivered VMAT plan of a lung cancer case. The selected parameters could be used for the planning of other treatment sites with similar size, shape, and location. For larger targets, a larger beamlet size might be used without significantly increasing the dose. B Palma: None. M Bazalova: None. B Hardemark: Employee, RaySearch Americas. E Hynning: Employee, RaySearch Americas. B Qu: None. B Loo Jr.: Research support, RaySearch, Varian. P Maxim: Research support, RaySearch, Varian.« less

Aspirin, lysine, mifepristone and doxycycline combined can effectively and safely prevent and treat cancer metastasis: prevent seeds from gemmating on soil

PubMed Central

Xu, Huo; Ma, Ji; Zhu, Yewei; Lu, Yusheng; Wang, Jichuang; Zhang, Ting; Li, Tao; Xie, Jingjing; Xu, Bo; Xie, Fangwei; Gao, Yu; Shao, Jingwei; Tu, Xiaohuang; Jia, Lee

2015-01-01

Recent scientific advances have increased our understanding of the cancer metastatic complexities and provided further impetus for new combination therapies to prevent cancer metastasis. Here, we demonstrated that a combination (HAMPT) of aspirin, lysine, mifepristone and doxycycline can effectively and safely prevent cancer metastasis. The pharmaceutically-formulated HAMPT inhibited adhesion of cancer cells to either endothelial cells or extracellular matrix via down-regulating cell adhesion molecules ICAM-1 and α4-integrin. HAMPT inhibited the cloak effect by activated platelets on cancer cells, thereby interfering adhesion and invasion of cancer cells to the underlying stroma. At the effective concentration, HAMPT induced cancer cells into dormancy with minor inhibition on cell viability. Four-day pretreatment followed by 30-day oral administration of HAMPT (33.5-134 mg/kg) to the mice inoculated with cancer cells produced significant inhibition on cancer metastasis dose-dependently without marked side effects. Fifty-day rat toxicity study with HAMPT at doses (335-1340 mg/kg) 20-fold higher than its therapeutic dose produced no significant toxicity. Interestingly, the acute toxic death could not be reached at the maximum administrable dose (5 g/kg). This proof-of-concept study provides the first conceptual evidence that cancer metastasis can be controlled by using affordable old drugs to restrain circulating tumor cells from gemmating on the metastatic soil without the need for cytotoxicity. PMID:26459390

The Effect of Variant Dosages of Amphetamine Upon Endurance.

ERIC Educational Resources Information Center

Williams, Melvin H.; Thompson, John

The purpose of this study was to provide basic information concerning the acute effects of a small, moderate, and large dose of d-amphetamine sulfate upon muscular endurance; a secondary purpose involved the effect upon resting (R), and submaximal, and maximal (MAX) heart rate (HR). Twelve male university students underwent four separate trials of…

Pharmacological activity and toxicity of some neurotropic agents under conditions of experimental hypodynamia

NASA Technical Reports Server (NTRS)

Kirichek, L. T.

1980-01-01

The indices of pharmacological range, risk coefficients, ED50, LD50, the size of the area of toxic activity, and maximal tolerated and absolute lethal doses were compared in hypodynamic mice. The pharmacological activity of the test neurotropic agents exhibiting a central action underwent change, but their toxicity remained unchanged.

Effects of intensive atorvastatin and rosuvastatin treatment on apolipoprotein B-48 and remnant lipoprotein cholesterol levels

USDA-ARS?s Scientific Manuscript database

Atorvastatin and rosuvastatin at maximal doses are both highly effective in lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Rosuvastatin has been shown to be more effective than atorvastatin in lowering LDL-C, small dense LDL-C and in raising high-density lipoprote...

Vitamin D supplementation increases calcium absorption without a threshold effect

USDA-ARS?s Scientific Manuscript database

The maximal calcium absorption in response to vitamin D has been proposed as a biomarker for vitamin D sufficiency. Our objective was to determine whether there is a threshold beyond which increasing doses of vitamin D, or concentrations of serum 25-hydroxyvitamin D [25(OH)D], no longer increase cal...

Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study's primary analysis of 2573 patients.

PubMed

Gligorov, J; Ataseven, B; Verrill, M; De Laurentiis, M; Jung, K H; Azim, H A; Al-Sakaff, N; Lauer, S; Shing, M; Pivot, X

2017-09-01

To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety Evaluation of Turmeric Polysaccharide Extract: Assessment of Mutagenicity and Acute Oral Toxicity

PubMed Central

Velusami, Chandrasekaran Chinampudur; Boddapati, Srinivasa Rao; Hongasandra Srinivasa, Srikanth; Richard, Edwin Jothie; Balasubramanian, Murali

2013-01-01

Curcuma longa Linn. (Zingiberaceae) commonly known as turmeric has long been used for centuries as a spice and household remedy. The present study was carried out to assess the possible mutagenic potential and acute oral toxicity of polysaccharide extract of turmeric rhizome (NR-INF-02) using standard tests. The standard battery of in vitro genotoxicity tests, bacterial reverse mutation test (BRMT), chromosome aberration (CA), and micronucleus (MN) tests were employed to assess the possible mutagenic activity of NR-INF-02 (Turmacin). The results showed no mutagenic effect with NR-INF-02 up to a dose of 5000 µg/mL in BRMT. The results on CA and MN tests revealed the non clastogenic activity of NR-INF-02 in a dose range of 250.36 to 2500 µg/mL with and without metabolic activation (S9). In acute oral toxicity study, NR-INF-02 was found to be safe up to 5 g/kg body weight in Wistar rats. Overall, results indicated that polysaccharide extract of C. longa was found to be genotoxically safe and also exhibited maximum tolerable dose of more than 5 g/kg rat body weight. PMID:24455673

RADIATION DOSE DUE TO RADON AND HEAVY METAL ANALYSIS IN DRINKING WATER SAMPLES OF JAMMU DISTRICT, JAMMU & KASHMIR, INDIA.

PubMed

Kumar, A; Kaur, M; Sharma, S; Mehra, R; Sharma, D K; Mishra, R

2016-10-01

In the present investigation, radon concentration and heavy metal analysis were carried out in drinking water samples in Jammu district, Jammu & Kashmir, India. The radon concentration was measured by using RAD-7, portable alpha particle detector. The values of radon concentration in drinking water samples were also compared within the safe limit recommended by different health agencies. The total annual effective dose ranged from 53.04 to 197.29 µSv y -1 The annual effective dose from few locations from the studied area was found to be greater than the safe limit (100 µSv y -1 ) suggested by World Health Organisation (WHO) and EU Council. Heavy metal concentration was determined by atomic absorption spectrophotometer. A total of eight elements were analysed, viz. arsenic, mercury, zinc, iron, copper, chromium, manganese and cadmium. Heavy metals are considered to be the major pollutants of water sources. The results were compared with the limits of WHO, EU and Indian organisations. The trace metal analysis is not on the exceeding side of the permissible limit in all the samples. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Dismantling of Radium-226 Coal Level Gauges: Encountered Problems and How to Solve

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

Punnachaiya, M.; Nuanjan, P.; Moombansao, K.

2006-07-01

This paper describes the techniques for dismantling of disused-sealed Radium-226 (Ra-226) coal level gauges which the source specifications and documents were not available, including problems occurred during dismantling stage and the decision making in solving all those obstacles. The 2 mCi (20 pieces), 6 mCi (20 pieces) and 6.6 mCi (30 pieces) of Ra-226 hemi-spherically-shaped with lead-filled coal level gauges were used in industrial applications for electric power generation. All sources needed to be dismantled for further conditioning as requested by the International Atomic Energy Agency (IAEA). One of the 2 mCi Ra-226 source was dismantled under the supervision ofmore » IAEA expert. Before conditioning period, each of the 6 mCi and 6.6 mCi sources were dismantled and inspected. It was found that coal level gauges had two different source types: the sealed cylindrical source (diameter 2 cm x 2 cm length) locked with spring in lead housing for 2 mCi and 6.6 mCi; while the 6 mCi was an embedded capsule inside source holder stud assembly in lead-filled housing. Dismantling Ra-226 coal level gauges comprised of 6 operational steps: confirmation of the surface dose rate on each source activity, calculation of working time within the effective occupational dose limit, cutting the weld of lead container by electrical blade, confirmation of the Ra-226 embedded capsule size using radiation scanning technique and gamma radiography, automatic sawing of the source holder stud assembly, and transferring the source to store in lead safe box. The embedded length of 6 mCi Ra-226 capsule in its diameter 2 cm x 14.7 cm length stud assembly was identified, the results from scanning technique and radiographic film revealed the embedded source length of about 2 cm, therefore all the 6 mCi sources were safely cut at 3 cm using the automatic saw. Another occurring problem was one of the 6.6 mCi spring type source stuck inside its housing because the spring was deformed and there was previously a leakage on inner source housing. Thus, during manufacturing the filled-lead for shielding passed through this small hole and fixed the deformed spring together with the source. The circular surface of inner hole was measured and slowly drilled at a diameter 2.2 cm behind shielding, till the spring and the fixed lead sheet were cut, therefore the source could be finally hammered out. The surface dose rate of coal level gauges before weld cutting was 10-15 mR/hr and the highest dose rate at the position of the weld cutter was 2.5 mR/hr. The total time for each weld cutting and automatic sawing was 2-3 minutes and 1 minute, respectively. The source was individually and safely transferred to store in lead safe box using a 1-meter length tong and a light container with 1 meter length handle. The total time for Ra-226 (70 pieces) dismantling, including the encountered problems and their troubles shooting took 4 days operation in which the total dose obtained by 18 operators were ranged from 1-38 {mu}Sv. The dismantling team safely completed the activities within the effective dose limit for occupational exposure of 20 mSv/year (80 {mu}Sv/day). (authors)« less

Exposure-response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes.

PubMed

Riggs, Matthew M; Seman, Leo J; Staab, Alexander; MacGregor, Thomas R; Gillespie, William; Gastonguay, Marc R; Woerle, Hans J; Macha, Sreeraj

2014-12-01

To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure-response (E-R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM). Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1-100 mg once daily, duration ≤12 weeks) were used to develop E-R models for efficacy (glycosylated haemoglobin [HbA1c ], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E-R. The efficacy model predicted maximal decreases in FPG and HbA1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl(-1) ) and 10-25 mg every day empagliflozin targeted 80-90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation. E-R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy. © 2014 The British Pharmacological Society.

Exposure−response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes

PubMed Central

Riggs, Matthew M; Seman, Leo J; Staab, Alexander; MacGregor, Thomas R; Gillespie, William; Gastonguay, Marc R; Woerle, Hans J; Macha, Sreeraj

2014-01-01

Aims To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure−response (E−R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM). Methods Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1–100 mg once daily, duration ≤12 weeks) were used to develop E−R models for efficacy (glycosylated haemoglobin [HbA1c], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E−R. Results The efficacy model predicted maximal decreases in FPG and HbA1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl−1) and 10–25 mg every day empagliflozin targeted 80–90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation. Conclusions E−R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy. PMID:24964723

SU-F-T-147: An Alternative Parameterization of Scatter Behavior Allows Significant Reduction of Beam Characterization for Pencil Beam Proton Therapy

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

Van den Heuvel, F; Fiorini, F; George, B

2016-06-15

Purpose: 1) To describe the characteristics of pencil beam proton dose deposition kernels in a homogenous medium using a novel parameterization. 2) To propose a method utilizing this novel parametrization to reduce the measurements and pre-computation required in commissioning a pencil beam proton therapy system. Methods: Using beam data from a clinical, pencil beam proton therapy center, Monte Carlo simulations were performed to characterize the dose depositions at a range of energies from 100.32 to 226.08 MeV in 3.6MeV steps. At each energy, the beam is defined at the surface of the phantom by a two-dimensional Normal distribution. Using FLUKA,more » the in-medium dose distribution is calculated in 200×200×350 mm cube with 1 mm{sup 3} tally volumes. The calculated dose distribution in each 200×200 slice perpendicular to the beam axis is then characterized using a symmetric alpha-stable distribution centered on the beam axis. This results in two parameters, α and γ, that completely describe shape of the distribution. In addition, the total dose deposited on each slice is calculated. The alpha-stable parameters are plotted as function of the depth in-medium, providing a representation of dose deposition along the pencil beam. We observed that these graphs are isometric through a scaling of both abscissa and ordinate map the curves. Results: Using interpolation of the scaling factors of two source curves representative of different beam energies, we predicted the parameters of a third curve at an intermediate energy. The errors are quantified by the maximal difference and provide a fit better than previous methods. The maximal energy difference between the source curves generating identical curves was 21.14MeV. Conclusion: We have introduced a novel method to parameterize the in-phantom properties of pencil beam proton dose depositions. For the case of the Knoxville IBA system, no more than nine pencil beams have to be fully characterized.« less

Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline

PubMed Central

Arrossi, Silvina; Temin, Sarah; Garland, Suzanne; Eckert, Linda O’Neal; Bhatla, Neerja; Castellsagué, Xavier; Alkaff, Sharifa Ezat; Felder, Tamika; Hammouda, Doudja; Konno, Ryo; Lopes, Gilberto; Mugisha, Emmanuel; Murillo, Rául; Scarinci, Isabel C.; Stanley, Margaret; Tsu, Vivien; Wheeler, Cosette M.; Adewole, Isaac Folorunso; de Sanjosé, Silvia

2017-01-01

Purpose To provide resource-stratified (four tiers), evidence-based recommendations on the primary prevention of cervical cancer globally. Methods The American Society of Clinical Oncology convened a multidisciplinary, multinational panel of oncology, obstetrics/gynecology, public health, cancer control, epidemiology/biostatistics, health economics, behavioral/implementation science, and patient advocacy experts. The Expert Panel reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus-based process with additional experts (consensus ratings group) for one round of formal ratings. Results Existing sets of guidelines from five guideline developers were identified and reviewed; adapted recommendations formed the evidence base. Five systematic reviews, along with cost-effectiveness analyses, provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75%. Recommendations In all resource settings, two doses of human papillomavirus vaccine are recommended for girls age 9 to 14 years, with an interval of at least 6 months and possibly up to 12 to 15 months. Individuals with HIV positivity should receive three doses. Maximal and enhanced settings: if girls are age ≥ 15 years and received their first dose before age 15 years, they may complete the series; if no doses were received before age 15 years, three doses should be administered; in both scenarios, vaccination may be through age 26 years. Limited and basic settings: if sufficient resources remain after vaccinating girls age 9 to 14 years, girls who received one dose may receive additional doses between age 15 and 26 years. Maximal, enhanced, and limited settings: if ≥ 50% coverage in the priority female target population, sufficient resources, and cost effectiveness, boys may be vaccinated to prevent other noncervical human papillomavirus–related cancers and diseases. Basic settings: vaccinating boys is not recommended. It is the view of the American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines. PMID:29094100

[Myocardial electrogenesis in laboratory rats under conditions of acute nitrite intoxication].

PubMed

Shumilova, T E; Shereshkov, V I; Ianvareva, I N; Nozdrachev, A D

2010-01-01

In anesthetized male rats the arterial blood pressure in femoral artery and electrocardiogram in standard leads were recorded uninterruptedly for 1-1.5 h under conditions of acute nitrite intoxication produced by a subcutaneous injection of water solution of sodium nitrite (donor of nitric oxide) at concentrations of 10, 30, and 50 mg/kg body mass. Results of the study have shown dose-dependent changes of arterial pressure as well as of time and amplitude characteristics of electrocardiogram under effect of NaNO2. At the threshold hypoxic dose, an increase of amplitude of R and S waves was observed by the 30-45th min, while at the maximal NaNO2 dose, amplitude of all waves rose by the 15th min of intoxication. High nitric doses often caused an increase of the ST segment above the isoelectric line and a rise of the amplitude of the T wave, on which a notch appeared in some cases. The change of the ECG time parameters was expressed in the dose-dependent development of bradycardia for the first 4-7 min; its level correlated with the progressively decreasing arterial pressure in the beginning (the 2-4th min) of nitrite intoxication. Variation analysis of heart rate spectral characteristics by Baevskii has revealed a rise of the total spectral power of pulse oscillations. Under effect of nitrite, in the spectrum of cardiointervals, quent recovery of the normal ECG spectrum in the end of the experimental period. The maximal nitrite dose produced more pronounced shifts of the heart rate spectrum towards the LF and VLF diapasons that were not restored for 1 h of experiment. Transitory processes of readjustment of the cardiac rhythm had discrete character. The nitrite dose of 50 mg/kg body mass increased the RR-interval after 4-7 min with amplitude steps of 3-5 imp/s and the time constant of 20-40 s. The revealed ECG changes had the reflex (enhancement of parasympathetic tonus) and metabolic (the hypoxic and histotoxic damage of myocardium) nature.

A theoretical framework to predict the most likely ion path in particle imaging.

PubMed

Collins-Fekete, Charles-Antoine; Volz, Lennart; Portillo, Stephen K N; Beaulieu, Luc; Seco, Joao

2017-03-07

In this work, a generic rigorous Bayesian formalism is introduced to predict the most likely path of any ion crossing a medium between two detection points. The path is predicted based on a combination of the particle scattering in the material and measurements of its initial and final position, direction and energy. The path estimate's precision is compared to the Monte Carlo simulated path. Every ion from hydrogen to carbon is simulated in two scenarios, (1) where the range is fixed and (2) where the initial velocity is fixed. In the scenario where the range is kept constant, the maximal root-mean-square error between the estimated path and the Monte Carlo path drops significantly between the proton path estimate (0.50 mm) and the helium path estimate (0.18 mm), but less so up to the carbon path estimate (0.09 mm). However, this scenario is identified as the configuration that maximizes the dose while minimizing the path resolution. In the scenario where the initial velocity is fixed, the maximal root-mean-square error between the estimated path and the Monte Carlo path drops significantly between the proton path estimate (0.29 mm) and the helium path estimate (0.09 mm) but increases for heavier ions up to carbon (0.12 mm). As a result, helium is found to be the particle with the most accurate path estimate for the lowest dose, potentially leading to tomographic images of higher spatial resolution.

In vivo dose perturbation effects of metallic dental alloys during head and neck irradiation with intensity modulated radiation therapy.

PubMed

Fuller, Clifton D; Diaz, Irma; Cavanaugh, Sean X; Eng, Tony Y

2004-07-01

A patient with base of tongue squamous sell carcinoma, with significant CT artifact-inducing metallic alloy, non-removable dental restorations in both the mandible and maxilla was identified. Simultaneous with IMRT treatment, thermoluminescent dosimeters (TLDs) were placed in the oral cavity. After a series of three treatments, the data from the TLDs and software calculations were analyzed. Analysis of mean in vivo TLD dosimetry reveals differentials from software predicted dose calculation that fall within acceptable dose variation limits. IMRT dose calculation software is a relatively accurate predictor of dose attenuation and augmentation due to dental alloys within the treatment volume, as measured by intra-oral thermoluminescent dosimetry. IMRT represents a safe and effective methodology to treat patients with non-removable metallic dental work who have head and neck cancer.

Acellular pertussis vaccine boosters combined with diphtheria and tetanus toxoid boosters for adolescents: safety and immunogenicity assessment when preceded by different 5-dose DTaP/DTwP schedules.

PubMed

Pichichero, Michael E; Casey, Janet R; Francis, Anne B; Marsocci, Steven M; Murphy, Marie; Hoeger, William; Cleary, Carolyn

2006-09-01

A sixth dose of tetanus, diphtheria, acellular pertussis (Tdap) vaccine in adolescents might produce a differing reactogenicity and/or immunogenicity response depending on the composition of the 5 prior doses of DTaP or DT-whole cell pertussis (DTwP) vaccine. Reactions and immune responses following receipt of the Sanofi Pasteur (Adacel) and GlaxoSmithKline (Boostrix) Tdap vaccines were assessed in 229 adolescents. No differences were observed for reactions to either Tdap vaccine regardless of the prior DTaP/DTwP vaccination history. Seroprotective levels and antibody concentrations were comparable regardless of prior DTaP/DTwP vaccine history. A sixth sequential dose of Tdap after 5 doses of DTaP appears safe and immunogenic.

Acute administration of high doses of taurine does not substantially improve high-intensity running performance and the effect on maximal accumulated oxygen deficit is unclear.

PubMed

Milioni, Fabio; Malta, Elvis de Souza; Rocha, Leandro George Spinola do Amaral; Mesquita, Camila Angélica Asahi; de Freitas, Ellen Cristini; Zagatto, Alessandro Moura

2016-05-01

The aim of the present study was to investigate the effects of acute administration of taurine overload on time to exhaustion (TTE) of high-intensity running performance and alternative maximal accumulated oxygen deficit (MAODALT). The study design was a randomized, placebo-controlled, crossover design. Seventeen healthy male volunteers (age: 25 ± 6 years; maximal oxygen uptake: 50.5 ± 7.6 mL·kg(-1)·min(-1)) performed an incremental treadmill-running test until voluntary exhaustion to determine maximal oxygen uptake and exercise intensity at maximal oxygen uptake. Subsequently, participants completed randomly 2 bouts of supramaximal treadmill-running at 110% exercise intensity at maximal oxygen uptake until exhaustion (placebo (6 g dextrose) or taurine (6 g) supplementation), separated by 1 week. MAODALT was determined using a single supramaximal effort by summating the contribution of the phosphagen and glycolytic pathways. When comparing the results of the supramaximal trials (i.e., placebo and taurine conditions) no differences were observed for high-intensity running TTE (237.70 ± 66.00 and 277.30 ± 40.64 s; p = 0.44) and MAODALT (55.77 ± 8.22 and 55.06 ± 7.89 mL·kg(-1); p = 0.61), which seem to indicate trivial and unclear differences using the magnitude-based inferences approach, respectively. In conclusion, acute 6 g taurine supplementation before exercise did not substantially improve high-intensity running performance and showed an unclear effect on MAODALT.

Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression.

PubMed

Rush, A John; Trivedi, Madhukar H; Wisniewski, Stephen R; Stewart, Jonathan W; Nierenberg, Andrew A; Thase, Michael E; Ritz, Louise; Biggs, Melanie M; Warden, Diane; Luther, James F; Shores-Wilson, Kathy; Niederehe, George; Fava, Maurizio

2006-03-23

After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor (SSRI), it is not known whether switching to one antidepressant is more effective than switching to another. We randomly assigned 727 adult outpatients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram to receive one of the following drugs for up to 14 weeks: sustained-release bupropion (239 patients) at a maximal daily dose of 400 mg, sertraline (238 patients) at a maximal daily dose of 200 mg, or extended-release venlafaxine (250 patients) at a maximal daily dose of 375 mg. The study was conducted in 18 primary and 23 psychiatric care settings. The primary outcome was symptom remission, defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of the study. Scores on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR-16), obtained at treatment visits, determined secondary outcomes, including remission (a score of 5 or less at exit) and response (a reduction of 50 percent or more on baseline scores). Remission rates as assessed by the HRSD-17 and the QIDS-SR-16, respectively, were 21.3 percent and 25.5 percent for sustained-release bupropion, 17.6 percent and 26.6 percent for sertraline, and 24.8 percent and 25.0 percent for extended-release venlafaxine. QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion, 26.7 percent for sertraline, and 28.2 percent for extended-release venlafaxine. These treatments did not differ significantly with respect to outcomes, tolerability, or adverse events. After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant. Any one of the medications in the study provided a reasonable second-step choice for patients with depression. (ClinicalTrials.gov number, NCT00021528.). Copyright 2006 Massachusetts Medical Society.

Assessment of the anticonvulsant potency of various benzylamide derivatives in the mouse maximal electroshock-induced seizure threshold model.

PubMed

Świąder, Mariusz J; Paruszewski, Ryszard; Łuszczki, Jarogniew J

2016-04-01

The aim of this study was to assess the anticonvulsant potency of 6 various benzylamide derivatives [i.e., nicotinic acid benzylamide (Nic-BZA), picolinic acid 2-fluoro-benzylamide (2F-Pic-BZA), picolinic acid benzylamide (Pic-BZA), (RS)-methyl-alanine-benzylamide (Me-Ala-BZA), isonicotinic acid benzylamide (Iso-Nic-BZA), and (R)-N-methyl-proline-benzylamide (Me-Pro-BZA)] in the threshold for maximal electroshock (MEST)-induced seizures in mice. Electroconvulsions (seizure activity) were produced in mice by means of a current (sine-wave, 50Hz, 500V, strength from 4 to 18mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Nic-BZA, 2F-Pic-BZA, Pic-BZA, Me-Ala-BZA, Iso-Nic-BZA, and Me-Pro-BZA administered systemically (ip) in a dose-dependent manner increase the threshold for maximal electroconvulsions in mice. Linear regression analysis of Nic-BZA, 2F-Pic-BZA, Pic-BZA, MeAla-BZA, IsoNic-BZA, and Me-Pro-BZA doses and their corresponding threshold increases allowed determining threshold increasing doses by 20% (TID20 values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 values in the MEST test for Nic-BZA, 2F-Pic-BZA, Pic-BZA, Me-Ala-BZA, Iso-Nic-BZA, and Me-Pro-BZA were 7.45mg/kg, 7.72mg/kg, 8.74mg/kg, 15.11mg/kg, 21.95mg/kg and 28.06mg/kg, respectively. The studied benzylamide derivatives can be arranged with respect to their anticonvulsant potency in the MEST test as follows: Nic-BZA>2F-Pic-BZA>Pic-BZA>Me-Ala-BZA>Iso-Nic-BZA>Me-Pro-BZA. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Improving birth dose coverage of hepatitis B vaccine.

PubMed Central

Hipgrave, David B.; Maynard, James E.; Biggs, Beverley-Ann

2006-01-01

Administration of a birth dose of hepatitis B vaccine (HepB vaccine) to neonates is recommended to prevent mother-to-infant transmission and chronic infection with the hepatitis B virus (HBV). Although manufacturers recommend HepB vaccine distribution and storage at 2-8 degrees C, recognition of the heat stability of hepatitis B surface antigen stimulated research into its use after storage at, or exposure to, ambient or high temperatures. Storage of HepB vaccine at ambient temperatures would enable birth dosing for neonates delivered at home in remote areas or at health posts lacking refrigeration. This article reviews the current evidence on the thermostability of HepB vaccine when stored outside the cold chain (OCC). The reports reviewed show that the vaccines studied were safe and effective whether stored cold or OCC. Field and laboratory data also verifies the retained potency of the vaccine after exposure to heat. The attachment of a highly stable variety of a vaccine vial monitor (measuring cumulative exposure to heat) on many HepB vaccines strongly supports policies allowing their storage OCC, when this will benefit birth dose coverage. We recommend that this strategy be introduced to improve birth dose coverage, especially in rural and remote areas. Concurrent monitoring and evaluation should be undertaken to affirm the safe implementation of this strategy, and assess its cost, feasibility and effect on reducing HBV infection rates. Meanwhile, release of manufacturer data verifying the potency of currently available HepB vaccines after exposure to heat will increase confidence in the use of vaccine vial monitors as a managerial tool during storage of HepB vaccine OCC. PMID:16501717

Ultrasound-guided corticosteroid injection therapy for juvenile idiopathic arthritis: 12-year care experience.

PubMed

Young, Cody M; Shiels, William E; Coley, Brian D; Hogan, Mark J; Murakami, James W; Jones, Karla; Higgins, Gloria C; Rennebohm, Robert M

2012-12-01

Intra-articular corticosteroid injections are a safe and effective treatment for patients with juvenile idiopathic arthritis. The potential scope of care in ultrasound-guided corticosteroid therapy in children and a joint-based corticosteroid dose protocol designed to optimize interdisciplinary care are not found in the current literature. The purpose of this study was to report the spectrum of care, technique and safety of ultrasound-guided corticosteroid injection therapy in patients with juvenile idiopathic arthritis and to propose an age-weight-joint-based corticosteroid dose protocol. A retrospective analysis was performed of 198 patients (ages 21 months to 28 years) referred for treatment of juvenile idiopathic arthritis with corticosteroid therapy. Symptomatic joints and tendon sheaths were treated as prescribed by the referring rheumatologist. An age-weight-joint-based dose protocol was developed and utilized for corticosteroid dose prescription. A total of 1,444 corticosteroid injections (1,340 joints, 104 tendon sheaths) were performed under US guidance. Injection sites included small, medium and large appendicular skeletal joints (upper extremity 497, lower extremity 837) and six temporomandibular joints. For patients with recurrent symptoms, 414 repeat injections were performed, with an average time interval of 17.7 months (range, 0.5-101.5 months) between injections. Complications occurred in 2.6% of injections and included subcutaneous tissue atrophy, skin hypopigmentation, erythema and pruritis. US-guided corticosteroid injection therapy provides dynamic, precise and safe treatment of a broad spectrum of joints and tendon sheaths throughout the entire pediatric musculoskeletal system. An age-weight-joint-based corticosteroid dose protocol is effective and integral to interdisciplinary care of patients with juvenile idiopathic arthritis.

Research on Ratio of Dosage of Drugs in Traditional Chinese Prescriptions by Data Mining.

PubMed

Yu, Xing-Wen; Gong, Qing-Yue; Hu, Kong-Fa; Mao, Wen-Jing; Zhang, Wei-Ming

2017-01-01

Maximizing the effectiveness of prescriptions and minimizing adverse effects of drugs is a key component of the health care of patients. In the practice of traditional Chinese medicine (TCM), it is important to provide clinicians a reference for dosing of prescribed drugs. The traditional Cheng-Church biclustering algorithm (CC) is optimized and the data of TCM prescription dose is analyzed by using the optimization algorithm. Based on an analysis of 212 prescriptions related to TCM treatment of kidney diseases, the study generated 87 prescription dose quantum matrices and each sub-matrix represents the referential value of the doses of drugs in different recipes. The optimized CC algorithm can effectively eliminate the interference of zero in the original dose matrix of TCM prescriptions and avoid zero appearing in output sub-matrix. This results in the ability to effectively analyze the reference value of drugs in different prescriptions related to kidney diseases, so as to provide valuable reference for clinicians to use drugs rationally.

Pharmacokinetic evaluation of losartan.

PubMed

Burnier, Michel; Wuerzner, Grégoire

2011-05-01

Blockade of the renin-angiotensin system is one of the major therapeutic strategies in the management of patients with essential hypertension, congestive heart failure and diabetic as well as non-diabetic renal diseases. As the first angiotensin II receptor blocker (ARB) on the market, losartan belongs to the most frequently prescribed ARB. The present review examines the pharmacokinetics of losartan with a special discussion on the dose of losartan that should be used in clinical practice to obtain the maximal benefits of the drug. Readers are provided with arguments suggesting that the dose of 50 mg losartan is probably too low and that losartan should preferably be prescribed at the dose of 100 mg/day or higher. Losartan is an effective antagonist of angiotensin II AT(1) receptors which has been shown to provide important clinical benefits in patients with hypertension, congestive heart failure and renal diseases. Losartan should be prescribed at the dose of 100 mg/day and the use of higher doses should be reconsidered in future studies to improve its clinical efficacy.

Phase I/II adaptive design for drug combination oncology trials

PubMed Central

Wages, Nolan A.; Conaway, Mark R.

2014-01-01

Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose–toxicity and dose–efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents. PMID:24470329

Automated detection of irradiated food with the comet assay.

PubMed

Verbeek, F; Koppen, G; Schaeken, B; Verschaeve, L

2008-01-01

Food irradiation is the process of exposing food to ionising radiation in order to disinfect, sanitise, sterilise and preserve food or to provide insect disinfestation. Irradiated food should be adequately labelled according to international and national guidelines. In many countries, there are furthermore restrictions to the product-specific maximal dose that can be administered. Therefore, there is a need for methods that allow detection of irradiated food, as well as for methods that provide a reliable dose estimate. In recent years, the comet assay was proposed as a simple, rapid and inexpensive method to fulfil these goals, but further research is required to explore the full potential of this method. In this paper we describe the use of an automated image analysing system to measure DNA comets which allow the discrimination between irradiated and non-irradiated food as well as the set-up of standard dose-response curves, and hence a sufficiently accurate dose estimation.

[Mefenamic acid and other non-steroidal anti-inflammatory agents in dental practice. A review of the literature].

PubMed

Künzel, André Rätzer; Haschke, Manuel; Surber, Christian; Lambrecht, J Thomas

2007-01-01

There are no studies verifying that mefenamic acid is more effective than other NSAID (= non-steroidal anti-inflammatory drugs). However, there are several notions in the literature that this drug is less well-tolerated than other NSAID because over a prolonged period of application more lesions of the upper gastro-intestinal tract are induced as well as occasionally renal insufficiency. Compared to other NSAID the systemic toxicity starts already with relatively low doses above the maximal daily dose. Considering current knowledge there is no reason to prefer mefenamic acid to other NSAID.

The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis

PubMed Central

Patterson, Stephen; Wyllie, Susan; Norval, Suzanne; Stojanovski, Laste; Simeons, Frederick RC; Auer, Jennifer L; Osuna-Cabello, Maria; Read, Kevin D; Fairlamb, Alan H

2016-01-01

There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg-1 for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg-1 than at 3 mg kg-1 (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL. DOI: http://dx.doi.org/10.7554/eLife.09744.001 PMID:27215734

Aqueous ethanol extract of the fruit of Xylopia aethiopica (Annonaceae) exhibits anti-anaphylactic and anti-inflammatory actions in mice.

PubMed

Obiri, David D; Osafo, Newman

2013-07-30

Xylopia aethiopica has been traditionally used in the form of the dried fruit decoction to treat bronchitis, asthma, arthritis and rheumatism in Ghana, Nigeria and Cameroon. Aim of the study is to evaluate the anti-anaphylactic and anti-inflammatory effects of a 70% aqueous ethanol extract of the fruits of Xylopia aethiopica. Systemic anaphylaxis was induced by the injection of either compound 48/80 or lipopolysaccharide, LPS and survival rates of mice monitored for 1 h or 7 days respectively while IgE-mediated anaphylaxis in a local allergic reaction was studied in the pinnal inflammation model in mice. Clonidine-induced catalepsy in mice was used to evaluate the indirect antihistamine effect of Xylopia aethiopica, XAE. The effects of XAE assessed on the maximal and total oedema responses in the carrageenan-induced paw oedema in mice was used to evaluate the anti-inflammatory action of the extract. Administered at 30, 100, 300 and 1000 mg kg(-1) p.o., XAE dose dependently suppressed compound 48/80-induced mouse systemic anaphylactic shock and offered 63% protection to mice against LPS-induced endotoxic shock at a dose of 300 mg kg(-1). In addition, the extract (30-300 mg kg(-1)) in a dose dependent manner significantly inhibited by 23-62% the mouse pinnal inflammation. Clonidine-induced catalepsy in mice was significantly suppressed in a dose and time dependent manner when administered both prophylactically and therapeutically. In the same doses, when administered before the induction of the mouse carrageenan-induced paw oedema, the mean maximal swelling attained during 6 h was reduced to 41.02±6.94%, 35.61±4.30%, and 29.09±4.90% of the inflamed control response respectively and total paw swellings induced over the 6 h were also dose-dependently and significantly suppressed to 74.84±14.84%, 63.95±9.37%, and 48.13±10.90% of the inflamed control response respectively. Administered after the induction of the carrageenan paw oedema the mean maximal swelling attained during 6 h was suppressed to 49.84±3.95%, 43.62±1.01%, and 35.97±1.34% of the inflamed control response respectively while the total paw swellings induced over the 6 h were also dose-dependently and significantly suppressed at 100 and 300 mg kg(-1) to 72.39±4.38% and 60.81±3.25% of the inflamed control response respectively. These findings suggest that XAE inhibits mast cell-dependent immediate allergic reactions and exhibit anti-inflammatory actions through the inhibition of histamine release from mast cells via stabilizing the cell membrane. Our results contribute towards validation of the traditional use of Xylopia aethiopica in the treatment of bronchitis, asthma, arthritis and rheumatism. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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

Intrathecal morphine for postoperative analgesia in patients with idiopathic scoliosis undergoing posterior spinal fusion.

PubMed

Tripi, Paul A; Poe-Kochert, Connie; Potzman, Jennifer; Son-Hing, Jochen P; Thompson, George H

2008-09-15

A retrospective study of postoperative pain management with intrathecal morphine. Identify the dosing regimen of intrathecal morphine that safely and effectively provides postoperative analgesia with minimal complications in patients with idiopathic scoliosis undergoing posterior spinal fusion (PSF) and segmental spinal instrumentation (SSI). Postoperative pain after surgery for idiopathic scoliosis is a concern. Intrathecal morphine has been used to decrease pain. However, the most appropriate dose has not been determined. We retrospectively analyzed 407 consecutive patients with idiopathic scoliosis who underwent PSF and SSI at our institution from 1992 through 2006. Patients were divided into 3 groups based on the intrathecal morphine dose: no dose (n = 68); moderate dose of 9 to 19 microg/kg, mean 14 microg/kg (n = 293); and high dose of 20 microg/kg or greater, mean 24 microg/kg (n = 46). Data included demographics, Wong-Baker visual analog scale postoperative pain scores, postoperative intravenous morphine requirements, time to first rescue dose of intravenous morphine, and postoperative complications of pruritus, nausea/vomiting, respiratory depression, and pediatric intensive care unit (PICU) admission. The demographics of the 3 study groups showed no statistical differences. The mean Wong-Baker visual analog scale pain score in the post anesthesia care unit was 5.2, 0.5, and 0.2, and the mean time to first morphine rescue was 6.6, 16.7, and 22.9 hours, respectively. In the first 48 postoperative hours, respiratory depression occurred in 1 (1.5%), 8 (2.7%), and 7 (15.2%) patients, whereas PICU admission occurred in 0 (0%), 6 (2%), and 8 (17.4%) patients, respectively. The majority of PICU admissions were the result of respiratory depression. Frequency of pruritus and nausea/vomiting was similar in all 3 groups. Intrathecal morphine in the moderate dose range of 9 to 19 microg/kg (mean 14 microg/kg), provides safe and effective postoperative analgesia in the immediate postoperative period for patients with idiopathic scoliosis undergoing PSF and SSI. Higher doses did not result in significantly better analgesia and had a greater frequency of respiratory depression requiring PICU admission.

Epidermal Growth Factor Receptor Overexpression as a Target for Auger Electron Radiotherapy of Breast Cancer

DTIC Science & Technology

2002-08-01

treatment of mice with 92.5 MBq (2.5 mCi) of ..In-DTPA-hEGF in five divided weekly doses. * Cumulative Radioactivity in Source Compartment (,s, Bq x...equiv- nalization of the radiopharmaceutical resulted in selective alent to a human dose of 14,208 MBq /m 2) can be safely and enhanced cytotoxicity in... be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. " ROIForm Approved

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.

Hemodynamic effects of IV sodium nitrite in hospitalized comatose survivors of out of hospital cardiac arrest.

PubMed

Dezfulian, Cameron; Olsufka, Michele; Fly, Deborah; Scruggs, Sue; Do, Rose; Maynard, Charles; Nichol, Graham; Kim, Francis

2018-01-01

Patients resuscitated from cardiac arrest have brain and cardiac injury. Recent animal studies suggest that the administration of sodium nitrite after resuscitation from 12min of asystole limits acute cardiac dysfunction and improves survival and neurologic outcomes. It has been hypothesized that low doses of IV sodium nitrite given during resuscitation of out of hospital cardiac arrest (OHCA) will improve survival. Low doses of sodium nitrite (e.g., 9.6mg of sodium nitrite) are safe in healthy individuals, however the effect of nitrite on blood pressure in resuscitated cardiac arrest patients is unknown. We performed a single-center, pilot trial of low dose sodium nitrite (1 or 9.6mg dose) vs. placebo in hospitalized out-of-hospital cardiac arrest patient to determine whether nitrite administration reduced blood pressure and whether whole blood nitrite levels increased in response to nitrite administration. This is the first reported study of sodium nitrite in cardiac arrest patients. Infusion of low doses of sodium nitrite in comatose survivors of OHCA (n=7) compared to placebo (n=4) had no significant effects on heart rate within 30min after infusion (70±20 vs. 78±3 beats per minute, p=0.18), systolic blood pressure (103±20 vs 108±15mmHg, p=0.3), or methemoglobin levels (0.92±0.33 vs. 0.70±0.26, p=0.45). Serum nitrite levels of 2-4μM were achieved within 15min of a 9.6mg nitrite infusion. Low dose sodium nitrite does not cause significant hemodynamic effect in patients with OHCA, which suggests that nitrite can be delivered safely in this critically ill patient population. Higher doses of sodium nitrite are necessary in order to achieve target serum level of 10μM. Copyright © 2017 Elsevier B.V. All rights reserved.

Pediatric tuberculous meningitis: model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children

PubMed Central

Savic, Radojka M.; Ruslami, Rovina; Hibma, Jennifer E.; Hesseling, Anneke; Ramachandran, Geetha; Ganiem, A. Rizal; Swaminathan, Soumya; McIlleron, Helen; Gupta, Amita; Thakur, Kiran; van Crevel, Reinout; Aarnoutse, Rob; Dooley, Kelly E.

2016-01-01

Pediatric TB meningitis (TBM) is a highly-morbid, oft-fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic and outcomes data from adult TBM trials plus plasma pharmacokinetic data from children. A population pharmacokinetic/pharmacodynamic model using adult data defined rifampin target exposures (plasma AUC0–24=92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously. From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19–33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results. PMID:26260983

Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin's dose-dependent inhibition of fasting growth hormone secretion.

PubMed

Bray, M J; Vick, T M; Shah, N; Anderson, S M; Rice, L W; Iranmanesh, A; Evans, W S; Veldhuis, J D

2001-07-01

How estradiol stimulates pulsatile GH secretion in the human is not well understood. Here, we test the clinical hypothesis that estradiol stimulates GH secretion, in part, by opposing somatostatin's inhibition of GH release. To this end, 13 estrogen-withdrawn postmenopausal women received placebo or 1 mg micronized estradiol-17beta orally, twice daily for 14 days, in a prospectively randomized, patient-blinded, within-subject cross-over design. For each intervention, the dose-dependent suppressive actions of somatostatin were evaluated by infusing 0 (saline), 3, 10, 30, 100, or 300 microg/1.73 m(2).h somatostatin-14 continuously, iv, for 3 h, on separate mornings, in the fasting state, 48 h apart. Blood was sampled at 10-min intervals for 2 h before, for 3 h concurrently with, and for 1 h after each infusion. Serum GH concentrations were quantitated in an ultrasensitive chemiluminescence-based assay (detection threshold, 0.005 microg/L). In the estrogen-deficient milieu, constant iv somatostatin infusions inhibited steady-state serum GH concentrations (valley mean during the last 60 min of the infusion interval) in a dose-dependent manner (P < 10(-4) interventional effect). Maximally effective doses of somatostatin reduced the latter by 89 +/- 6.1% (mean +/- SEM) below the subject-specific preinfusion baseline. Estrogen administration increased the serum estradiol concentration from 12 +/- 1 to 245 +/- 35 pg/mL [42 +/- 4 to 920 +/- 110 pmol/L] (P < 10(-4)); decreased serum concentrations of LH (P = 0.018), FSH (P < 10(-4)), and insulin-like growth factor-I (P = 0.003); and elevated the fasting (6-h mean) serum GH concentration from 0.41 +/- 0.07 to 0.87 +/- 0.27 (P = 0.011). Estradiol supplementation did not alter somatostatin's maximal suppression of GH by 89 +/- 4.7% (P < 10(-4) below subject-specific preinfusion baseline), thus signifying unchanging somatostatin efficacy. In contrast, estradiol replacement significantly elevated the half-maximally inhibitory dose of infused somatostatin by 13.5-fold, from 0.43 (0.38-0.48, 95% group statistical confidence intervals) (placebo) to 6.0 (5.2-7.0) (estradiol) microg/1.73 m(2)/h (P < 10(-4)), denoting muting of somatostatin's inhibitory potency. The latter inference was confirmed by a concomitant 4-fold decrease in the exponential steepness of the somatostatin inhibitory dose-response function; viz., mean 1.42 (1.49 to 1.33) (placebo) vs. 0.34 (0.62 to 0.26) (estradiol) slope units (P < 10(-4)). The foregoing effects were specific, because estrogen did not alter somatostatin's dose-dependent enhancement (P < 10(-4)) of the orderliness of GH release patterns, as quantitated via the approximate entropy regularity statistic. In summary, short-term replacement of estradiol to midfollicular phase levels in postmenopausal women selectively reduces the potency, but not the efficacy, of somatostatin's dose-dependent inhibition of GH release. Estrogen supplementation does not modify somatostatin's reciprocal enhancement of the quantifiable orderliness (approximate entropy) of the GH secretory process. Accordingly, we postulate that estradiol can facilitate pulsatile GH secretion, in part, by opposing the repressive actions of somatostatin.

"The Actualized Neurosurgeon": A Proposed Model of Surgical Resident Development.

PubMed

Lipsman, Nir; Khan, Osaama; Kulkarni, Abhaya V

2017-03-01

Modern neurosurgical training is both physically and emotionally demanding, posing significant challenges, new and old, to residents as well as programs attempting to train safe, competent surgeons. Models to describe resident development, such as the Accreditation Council for Graduate Medical Education competencies and milestones, address the acquisition of specific skills but largely ignore the stresses and pressures unique to each stage of resident training. We propose an alternative model of resident development adapted from the developmental psychology literature. Our model identifies the challenges that must be met at each stage of junior, intermediate, and senior and chief residency, leading ultimately to an "actualized" neurosurgeon (i.e., one who has maximized his or her potential). Failure to overcome any 1 of these challenges can lead to specific long-lasting consequences, including regret, identity crisis, incompetence, and bitterness. In contrast, the actualized surgeon is one who has successfully acquired the virtues of hope, will, purpose, fidelity, productivity, leadership, competence, and wisdom. The actualized surgeon not only functions safely, confidently, and professionally, but also successfully navigates the challenges of residency and emerges from them having fulfilled his or her maximal potential. This developmental perspective provides an individualized description of healthy surgical development. Our model allows programs to identify the basis for residents who fail to progress, counsel residents during their training, and perhaps help identify resident candidates who are better prepared to meet the developmental challenges of residency training. Copyright © 2016 Elsevier Inc. All rights reserved.

Maximizing Efficiency and Reducing Robotic Surgery Costs Using the NASA Task Load Index.

PubMed

Walters, Carrie; Webb, Paula J

2017-10-01

Perioperative leaders at our facility were struggling to meet efficiency targets for robotic surgery procedures while also maintaining the satisfaction of the surgical team. We developed a human resources time and motion study tool and used it in conjunction with the NASA Task Load Index to observe and analyze the required workload of personnel assigned to 25 robotic surgery procedures. The time and motion study identified opportunities to enlist the help of nonlicensed support personnel to ensure safe patient care and improve OR efficiency. Using the NASA Task Load Index demonstrated that high temporal, effort, and physical demands existed for personnel assisting with and performing robotic surgery. We believe that this process could be used to develop cost-effective staffing models, resulting in safe and efficient care for all surgical patients. Copyright © 2017 AORN, Inc. Published by Elsevier Inc. All rights reserved.

Reduction in fluoride-induced genotoxicity in mouse bone marrow cells after substituting high fluoride-containing water with safe drinking water.

PubMed

Podder, Santosh; Chattopadhyay, Ansuman; Bhattacharya, Shelley

2011-10-01

Treatment of mice with 15 mg l(-1) sodium fluoride (NaF) for 30 days increased the number of cell death, chromosomal aberrations (CAs) and 'cells with chromatid breaks' (aberrant cells) compared with control. The present study was intended to determine whether the fluoride (F)-induced genotoxicity could be reduced by substituting high F-containing water after 30 days with safe drinking water, containing 0.1 mg F ions l(-1). A significant fall in percentage of CAs and aberrant cells after withdrawal of F-treatment following 30 days of safe water treatment in mice was observed which was highest after 90 days, although their levels still remained significantly high compared with the control group. This observation suggests that F-induced genotoxicity could be reduced by substituting high F-containing water with safe drinking water. Further study is warranted with different doses and extended treatment of safe water to determine whether the induced damages could be completely reduced or not. Copyright © 2011 John Wiley & Sons, Ltd.

Radioactive Iodine Treatment for Hyperthyroidism

MedlinePlus

... other parts of the body. RAI, also called iodine 131 (I-131), is given as a single-dose capsule or liquid. Most often, you will not need a hospital stay. It can take 6 to ... Know? Radioactive iodine is a generally safe treatment that can cure ...

Population dose commitments due to radioactive releases from nuclear power plant sites in 1987

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

Baker, D.A.

Population radiation dose commitments have been estimated from reported radionuclide releases from commercial power reactors operating during 1987. Fifty-year dose commitments for a one-year exposure from both liquid and atmospheric releases were calculated for four population groups (infant, child, teen-ager and adult) residing between 2 and 80 km from each of 70 reactor sites. This report tabulates the results of these calculations, showing the dose commitments for both water and airborne pathways for each age group and organ. Also included for reach of the sites is a histogram showing the fraction of the total population within 2 to 80 kmmore » around each site receiving various average dose commitments from the airborne pathways. The site average individual dose commitment from all pathways ranged from a low of 2 {times} 10{sup {minus}6} mrem to a high of 0.009 mrem. No attempt was made in this study to determine the maximum dose commitment received by any one individual from the radionuclides released at any of the sites. However, licensee calculation of doses to the maximally exposed individual at some sites indicated values of up to approximately 100 times average individual doses (on the order of a few millirem per year). 2 refs., 2 figs., 7 tabs.« less

Efficacy and tolerability of high-dose phenobarbital in children with focal seizures.

PubMed

Okumura, Akihisa; Nakahara, Eri; Ikeno, Mitsuru; Abe, Shinpei; Igarashi, Ayuko; Nakazawa, Mika; Takasu, Michihiko; Shimizu, Toshiaki

2016-04-01

We retrospectively reviewed the outcomes of children with focal epilepsy treated with oral high-dose phenobarbital. We reviewed data on children (aged<15 years) with focal seizures treated with high-dose phenobarbital (>5 mg/kg/day to maintain a target serum level >40 μg/mL) for at least 6 months. Seizure frequency was evaluated after phenobarbital titration, and 1 and 2 years after high-dose phenobarbital treatment commenced. Treatment was judged effective when seizure frequencies fell by ⩾75%. Seven boys and eight girls were treated. The median age at commencement of high-dose phenobarbital therapy was 30 months. The maximal serum phenobarbital level ranged from 36.5 to 62.9 μg/mL. High-dose PB was effective in seven. In two patients, treatment was transiently effective, but seizure frequency later returned to the baseline. High-dose PB was ineffective in six. No significant association between effectiveness and any clinical variable was evident. Drowsiness was recorded in nine patients, but no patient developed a behavioral problem or hypersensitivity. Oral high-dose phenobarbital was effective in 7 of 15 patients with focal epilepsy and well tolerated. High-dose PB may be useful when surgical treatment is difficult. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

In vitro comparison of the antiproliferative effects of rhenium-186 and rhenium-188 on human aortic endothelial cells.

PubMed

Sauter, Alexander; Arthasana, Daniel; Dittmann, Helmut; Pritzkow, Maren; Wiesinger, Benjamin; Schmehl, Joerg; Brechtel, Klaus; Bantleon, Rüdiger; Claussen, Claus; Kehlbach, Rainer

2011-08-01

Rhenium-186 ((186)Re) and rhenium-188 ((188)Re) are promising radionuclides for the inhibition of restenosis after percutaneous transluminal angioplasty or other vascular interventions. Until now the maximal dose tolerance of endothelial cells has not been clearly known. To characterize the effects of local irradiation treatment, human aortic endothelial cells (ECs) were incubated with different doses of (186)Re and (188)Re. Two days after plating, ECs received treatment for a period of 5 days. The total radiation doses applied were 1, 4, 8, 16, and 32 Gy. On days 1, 3, 5, 7, and 12 after initial rhenium incubation, cell growth, clonogenic activity, cell-cycle distribution, and cytoskeletal architecture were evaluated. From the first day on, a dose-dependent growth inhibition was observed. Cumulative doses of ≥32 Gy caused a weak colony formation and significant alterations in the cytoskeletal architecture. An increased fraction of cells in G2/M phase was seen for cumulative radiation doses of ≥16 Gy. Interestingly, there were no significant differences between (186)Re and (188)Re. Even for low dose rates of β particles a dose-dependent proliferation inhibition of ECs is seen. Doses beyond 32 Gy alter the cytoskeletal architecture with possibly endothelial dysfunction and late thrombosis.

THE EFFECTS OF ATRAZINE AND ITS METABOLITE DACT ON HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACTIVATION IN ADULT MALE WISTAR RATS

EPA Science Inventory

Previous work in our laboratory has shown that a single administration of atrazine (ATR), a chloro-s-triazine herbicide that is used extensively throughout the USA and world, is able to induce a dose-dependent increase in plasma ACTH, with maximal concentrations observed at 15 mi...

Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma

PubMed Central

Wicks, Robert T.; Azadi, Javad; Mangraviti, Antonella; Zhang, Irma; Hwang, Lee; Joshi, Avadhut; Bow, Hansen; Hutt-Cabezas, Marianne; Martin, Kristin L.; Rudek, Michelle A.; Zhao, Ming; Brem, Henry; Tyler, Betty M.

2015-01-01

Background 3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPA's inability to cross the blood-brain-barrier and DCA's dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed. Methods Cytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT). Results 3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%. Conclusion Intracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect. PMID:25053853

Safety and Efficacy of a Progressively Prolonged Maintenance Interval of Venom Immunotherapy.

PubMed

Kontou-Fili, Kalliopi; Pitsios, Constantinos; Kompoti, Evangelia; Giannakopoulos, Dionysios; Kouridakis, Spyros

2018-01-01

The long-term protection provided by venom immunotherapy (VIT) is related to the dose administered and to its long duration; the latter, however, becomes inconvenient for patients in countries like Greece, with many islanders or inhabitants of distant mountainous areas. Maintenance interval prolongation reduces the number of office visits - saving time and money - and as a consequence contributes to the patients' compliance. The aim of this prospective study was to evaluate the safety and efficacy of VIT on a progressively prolonged maintenance interval (PPMI). 450 venom-allergic patients were reviewed for participation in our study; all of them were initially treated with a modified rush or an ultrarush protocol using freshly reconstituted, pure venoms. Upon reaching the maintenance dose, the VIT interval was scheduled to be gradually prolonged - by 1 week each time - aiming at a maximal interval of 26 weeks. 267/450 patients consented to participate in our VIT PPMI protocol: 98 were treated with vespid(s) venom, 142 with honeybee venom, and 27 with both. The mean duration of patient follow-up was 9.1 ± 4.2 years. The majority of systemic reactions due to VIT injections occurred up to the 8-weeks PPMI; few additional reactions were documented in a small fraction (2.9%) of our patient population beyond 9 weeks and up to 16 weeks; all were caused by honeybee VIT. No reactions were observed during VIT administration at the 26-week interval. Ninety-six patients reported 204 field sting occurrences by the culprit insect. Ten systemic reactions (8 mild and 2 moderate in severity) were registered between the 9- and 18-week PPMI; the honeybee was the culprit insect in all cases. 108 field stings by the offending insect were sustained beyond the 20- and up to the 26-week PPMI; there were no reactions at all. Progressively prolonging the VIT maintenance interval up to 26 weeks appears to be safe and efficacious. © 2018 S. Karger AG, Basel.

Use of intradermal dilutional testing and skin prick testing: clinical relevance and cost efficiency.

PubMed

Seshul, Merritt; Pillsbury, Harold; Eby, Thomas

2006-09-01

The objective was to determine the agreement of the positive results from a multiple skin prick test (SPT) device with the ability to determine a definable endpoint through intradermal dilutional testing (IDT) to compare semiquantitatively the degree of positivity of SPT results with quantitative results from IDT and to analyze the cost of immunotherapy based on SPT compared with IDT guided by SPT. Retrospective review of clinical data (random accrual). One hundred thirty-four patients underwent allergy screening using a multiple SPT device. Antigens testing positive by skin prick device were tested using IDT on a separate day. Antigens testing negative by SPT were not evaluated by IDT. Regional allergy testing practice patterns were determined, and a cost analysis using Medicare rates was performed There was good agreement between an antigen testing positive by SPT and the determination of a definable endpoint (93.33%, n = 1,334 antigens). The degree of positivity from the SPT correlated poorly with the final endpoint concentration (r = 0.40, P < .0001). Blended testing techniques were similar in cost when compared with several commonly used allergy testing protocols. Antigens which show reactivity to a multiple SPT device usually have a treatable endpoint that is independent of the degree of positivity of the SPT result. IDT is an important step in the determination of the strongest starting dose of immunotherapy that may be safely administered. Initiating immunotherapy in this manner may potentially create significant health care savings by shortening the time required for a patient to reach their individual maximally tolerated dose. The use of a relatively large screening panel is cost effective and does not increase the average number of antigens treated by immunotherapy. Blended allergy testing techniques that include IDT in their protocol are comparable in cost with commonly used allergy testing protocols.

The Effect of Total Tumor Volume on the Biologically Effective Dose to Tumor and Kidneys for 177Lu-Labeled PSMA Peptides.

PubMed

Begum, Nusrat J; Thieme, Anne; Eberhardt, Nina; Tauber, Robert; D'Alessandria, Calogero; Beer, Ambros J; Glatting, Gerhard; Eiber, Matthias; Kletting, Peter

2018-06-01

The aim of this work was to simulate the effect of prostate-specific membrane antigen (PSMA)-positive total tumor volume (TTV) on the biologically effective doses (BEDs) to tumors and organs at risk in patients with metastatic castration-resistant prostate cancer who are undergoing 177 Lu-PSMA radioligand therapy. Methods: A physiologically based pharmacokinetic model was fitted to the data of 13 patients treated with 177 Lu-PSMA I&T (a PSMA inhibitor for imaging and therapy). The tumor, kidney, and salivary gland BEDs were simulated for TTVs of 0.1-10 L. The activity and peptide amounts leading to an optimal tumor-to-kidneys BED ratio were also investigated. Results: When the TTV was increased from 0.3 to 3 L, the simulated BEDs to tumors, kidneys, parotid glands, and submandibular glands decreased from 22 ± 15 to 11.0 ± 6.0 Gy 1.49 , 6.5 ± 2.3 to 3.7 ± 1.4 Gy 2.5 , 11.0 ± 2.7 to 6.4 ± 1.9 Gy 4.5 , and 10.9 ± 2.7 to 6.3 ± 1.9 Gy 4.5 , respectively (where the subscripts denote that an α/β of 1.49, 2.5, or 4.5 Gy was used to calculate the BED). The BED to the red marrow increased from 0.17 ± 0.05 to 0.32 ± 0.11 Gy 15 For patients with a TTV of more than 0.3 L, the optimal amount of peptide was 273 ± 136 nmol and the optimal activity was 10.4 ± 4.4 GBq. Conclusion: This simulation study suggests that in patients with large PSMA-positive tumor volumes, higher activities and peptide amounts can be safely administered to maximize tumor BEDs without exceeding the tolerable BED to the organs at risk. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Acute respiratory syndrome after inhalation of waterproofing sprays: a posteriori exposure-response assessment in 102 cases.

PubMed

Vernez, David; Bruzzi, Raffaella; Kupferschmidt, Hugo; De-Batz, Alice; Droz, Pierre; Lazor, Romain

2006-05-01

Waterproofing agents are widely used to protect leather and textiles in both domestic and occupational activities. An outbreak of acute respiratory syndrome following exposure to waterproofing sprays occurred during the winter 2002-2003 in Switzerland. About 180 cases were reported by the Swiss Toxicological Information Centre between October 2002 and March 2003, whereas fewer than 10 cases per year had been recorded previously. The reported cases involved three brands of sprays containing a common waterproofing mixture, that had undergone a formulation change in the months preceding the outbreak. A retrospective analysis was undertaken in collaboration with the Swiss Toxicological Information Centre and the Swiss Registries for Interstitial and Orphan Lung Diseases to clarify the circumstances and possible causes of the observed health effects. Individual exposure data were generated with questionnaires and experimental emission measurements. The collected data was used to conduct numeric simulation for 102 cases of exposure. A classical two-zone model was used to assess the aerosol dispersion in the near- and far-field during spraying. The resulting assessed dose and exposure levels obtained were spread on large scales, of several orders of magnitude. No dose-response relationship was found between exposure indicators and health effects indicators (perceived severity and clinical indicators). Weak relationships were found between unspecific inflammatory response indicators (leukocytes, C-reactive protein) and the maximal exposure concentration. The results obtained disclose a high interindividual response variability and suggest that some indirect mechanism(s) predominates in the respiratory disease occurrence. Furthermore, no threshold could be found to define a safe level of exposure. These findings suggest that the improvement of environmental exposure conditions during spraying alone does not constitute a sufficient measure to prevent future outbreaks of waterproofing spray toxicity. More efficient preventive measures are needed prior to the marketing and distribution of new waterproofing agents.

Ultra-low dose naltrexone enhances cannabinoid-induced antinociception.

PubMed

Paquette, Jay; Olmstead, Mary C; Olmstead, Mary

2005-12-01

Both opioids and cannabinoids have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to Gi/o-proteins. Surprisingly, the analgesic effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist, naltrexone. As opioid and cannabinoid systems interact, this study investigated whether ultra-low dose naltrexone also influences cannabinoid-induced antinociception. Separate groups of Long-Evans rats were tested for antinociception following an injection of vehicle, a sub-maximal dose of the cannabinoid agonist WIN 55 212-2, naltrexone (an ultra-low or a high dose) or a combination of WIN 55 212-2 and naltrexone doses. Tail-flick latencies were recorded for 3 h, at 10-min intervals for the first hour, and at 15-min intervals thereafter. Ultra-low dose naltrexone elevated WIN 55 212-2-induced tail flick thresholds without extending its duration of action. This enhancement was replicated in animals receiving intraperitoneal or intravenous injections. A high dose of naltrexone had no effect on WIN 55 212-2-induced tail flick latencies, but a high dose of the cannabinoid 1 receptor antagonist SR 141716 blocked the elevated tail-flick thresholds produced by WIN 55 212-2+ultra-low dose naltrexone. These data suggest a mechanism of cannabinoid-opioid interaction whereby activated opioid receptors that couple to Gs-proteins may attenuate cannabinoid-induced antinociception and/or motor functioning.

Tools for placing the radiological health hazard in perspective following a severe emergency at a light water reactor (LWR) or its spent fuel pool.

PubMed

McKenna, Thomas; Welter, Phillip Vilar; Callen, Jessica; Martincic, Rafael; Dodd, Brian; Kutkov, Vladimir

2015-01-01

Experience from past nuclear and radiological emergencies shows that placing the radiological health hazard in perspective and having a definition of "safe" are required in order to prevent members of the public, those responsible for protecting the public (i.e., decision makers), and others from taking inappropriate and damaging actions that are not justified based on the radiological health hazard. The principle concerns of the public during a severe nuclear power plant or spent fuel pool emergency are "Am I safe?" and "What should I do to be safe?" However, these questions have not been answered to the satisfaction of the public, despite various protective actions being implemented to ensure their safety. Instead, calculated doses or various measured quantities (e.g., ambient dose rate or radionuclide concentrations) are used to describe the situation to the public without placing them into perspective in terms of the possible radiological health hazard, or if they have, it has been done incorrectly. This has contributed to members of the public taking actions that do more harm than good in the belief that they are protecting themselves. Based on established international guidance, this paper provides a definition of "safe" for the radiological health hazard for use in nuclear or radiological emergencies and a system for putting the radiological health hazard in perspective for quantities most commonly measured after a release resulting from a severe emergency at a light water reactor or its spent fuel pool.

Newcastle disease virus-vectored rabies vaccine is safe, highly immunogenic, and provides long-lasting protection in dogs and cats.

PubMed

Ge, Jinying; Wang, Xijun; Tao, Lihong; Wen, Zhiyuan; Feng, Na; Yang, Songtao; Xia, Xianzhu; Yang, Chinglai; Chen, Hualan; Bu, Zhigao

2011-08-01

Effective, safe, and affordable rabies vaccines are still being sought. Newcastle disease virus (NDV), an avian paramyxovirus, has shown promise as a vaccine vector for mammals. Here, we generated a recombinant avirulent NDV La Sota strain expressing the rabies virus glycoprotein (RVG) and evaluated its potential to serve as a vaccine against rabies. The recombinant virus, rL-RVG, retained its high-growth property in chicken eggs, with titers of up to 10⁹·⁸ 50% egg infective doses (EID₅₀)/ml of allantoic fluid. RVG expression enabled rL-RVG to spread from cell to cell in a rabies virus-like manner, and RVG was incorporated on the surface of the rL-RVG viral particle. RVG incorporation did not alter the trypsin-dependent infectivity of the NDV vector in mammalian cells. rL-RVG and La Sota NDV showed similar levels of sensitivity to a neutralization antibody against NDV and similar levels of resistance to a neutralization antibody against rabies virus. Animal studies demonstrated that rL-RVG is safe in several species, including cats and dogs, when administered as multiple high doses of recombinant vaccine. Intramuscular vaccination with rL-RVG induced a substantial rabies virus neutralization antibody response and provided complete protection from challenge with circulating rabies virus strains. Most importantly, rL-RVG induced strong and long-lasting protective neutralization antibody responses to rabies virus in dogs and cats. A low vaccine dose of 10⁸·³ EID₅₀ completely protected dogs from challenge with a circulating strain of rabies virus for more than a year. This is the first study to demonstrate that immunization with an NDV-vectored vaccine can induce long-lasting, systemic protective immunity against rabies.

Effective and Safe Anesthesia for Yorkshire and Yucatan Swine with and without Cardiovascular Injury and Intervention

PubMed Central

Linkenhoker, Jan R; Burkholder, Tanya H; Linton, CG Garry; Walden, April; Abusakran-Monday, Kim A; Rosero, Ana P; Foltz, Charmaine J

2010-01-01

The goal of this study was to identify an injectable anesthetic protocol that provides sedation sufficient for peripheral vascular catheterization, intubation, and transport while minimizing cardiovascular changes in Yorkshire and Yucatan pigs with and without cardiovascular injury and intervention (CI). Phase 1 examined the safety and efficacy of acepromazine–ketamine, diazepam–ketamine, midazolam–ketamine, and medetomidine–ketamine in 5 healthy Yorkshire pigs. For each drug combination, we obtained multiple measurements of heart rate, blood pressure, respiratory rate, temperature, sedation score, ability to catheterize and intubate, and recovery score. Phase 2 evaluated and refined the dose of the most effective Phase 1 anesthetic combination (midazolam–ketamine) in healthy and CI Yorkshire pigs (n = 53 trials). Phase 3 mirrored Phase 2 but tested midazolam–ketamine in healthy and CI Yucatan pigs (n = 34 trials). Midazolam (0.5 mg/kg)–ketamine (25 to 27 mg/kg) was the most effective anesthetic combination in healthy Yorkshire pigs, but this dose was less effective in healthy Yucatan pigs and CI Yorkshire and Yucatan pigs. Midazolam–ketamine resulted in tachycardia and apnea more frequently in CI pigs than healthy pigs. This combination also caused vomiting in one CI Yucatan pig. Overall, midazolam–ketamine provided safe and effective sedation for catheterization and intubation of both healthy and CI pigs. This study suggests Yucatan pigs may require a higher dose midazolam–ketamine to achieve the same level of sedation as that in Yorkshire pigs. Although anesthetic complication rates were higher in CI pigs, our results indicate that midazolam–ketamine can be safely used for sedation of both pig breeds with and without CI. PMID:20587167

Peru-15 (Choleragarde(®)), a live attenuated oral cholera vaccine, is safe and immunogenic in human immunodeficiency virus (HIV)-seropositive adults in Thailand.

PubMed

Ratanasuwan, W; Kim, Y H; Sah, B K; Suwanagool, S; Kim, D R; Anekthananon, A; Lopez, A L; Techasathit, W; Grahek, S L; Clemens, J D; Wierzba, T F

2015-09-11

Many areas with endemic and epidemic cholera report significant levels of HIV transmission. According to the World Health Organization (WHO), over 95% of reported cholera cases occur in Africa, which also accounts for nearly 70% of people living with HIV/AIDS globally. Peru-15, a promising single dose live attenuated oral cholera vaccine (LA-OCV), was previously found to be safe and immunogenic in cholera endemic areas. However, no data on the vaccine's safety among HIV-seropositive adults had been collected. This study was a double-blinded, individually randomized, placebo-controlled trial enrolling HIV-seropositive adults, 18-45 years of age, conducted in Bangkok, Thailand, to assess the safety of Peru-15 in a HIV-seropositive cohort. 32 HIV infected subjects were randomized to receive either a single oral dose of the Peru-15 vaccine with a buffer or a placebo (buffer only). No serious adverse events were reported during the follow-up period in either group. The geometric mean fold (GMF) rise in V. cholerae O1 El Tor specific antibody titers between baseline and 7 days after dosing was 32.0 (p<0.001) in the vaccine group compared to 1.6 (p<0.14) in the placebo group. Among the 16 vaccinees,14 vaccinees (87.5%) had seroconversion compared to 1 of 16 placebo recipients (6.3%). V. cholerae was isolated from the stool of one vaccinee, and found to be genetically identical to the Peru-15 vaccine strain. There were no significant changes in HIV viral load or CD4 T-cell counts between vaccine and placebo groups. Peru-15 was shown to be safe and immunogenic in HIV-seropositive Thai adults. Copyright © 2015 Elsevier Ltd. All rights reserved.

SU-E-T-649: Quality Assurances for Proton Therapy Delivery Equipment

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

Arjomandy, B; Kase, Y; Flanz, J

2015-06-15

Purpose: The number of proton therapy centers has increased dramatically over the past decade. Currently, there is no comprehensive set of guidelines that addresses quality assurance (QA) procedures for the different technologies used for proton therapy. The AAPM has charged task group 224 (TG-224) to provide recommendations for QA required for accurate and safe dose delivery, using existing and next generation proton therapy delivery equipment. Methods: A database comprised of QA procedures and tolerance limits was generated from many existing proton therapy centers in and outside of the US. These consist of proton therapy centers that possessed double scattering, uniformmore » scanning, and pencil beams delivery systems. The diversity in beam delivery systems as well as the existing devices to perform QA checks for different beam parameters is the main subject of TG-224. Based on current practice at the clinically active proton centers participating in this task group, consensus QA recommendations were developed. The methodologies and requirements of the parameters that must be verified for consistency of the performance of the proton beam delivery systems are discussed. Results: TG-224 provides procedures and QA checks for mechanical, imaging, safety and dosimetry requirements for different proton equipment. These procedures are categorized based on their importance and their required frequencies in order to deliver a safe and consistent dose. The task group provides daily, weekly, monthly, and annual QA check procedures with their tolerance limits. Conclusions: The procedures outlined in this protocol provide sufficient information to qualified medical physicists to perform QA checks for any proton delivery system. Execution of these procedures should provide confidence that proton therapy equipment is functioning as commissioned for patient treatment and delivers dose safely and accurately within the established tolerance limits. The report will be published in late 2015.« less

United States Department of Energy National Nuclear Security Administration Sandia Field Office NESHAP Annual Report CY2014 for Sandia National Laboratories New Mexico

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

evelo, stacie; Miller, Mark L.

2015-05-01

This report provides a summary of the radionuclide releases from the United States (U.S.) Department of Energy (DOE) National Nuclear Security Administration facilities at Sandia National Laboratories, New Mexico (SNL/NM) during Calendar Year (CY) 2014, including the data, calculations, and supporting documentation for demonstrating compliance with 40 Code of Federal Regulation (CFR) 61, Subpart H--NATIONAL EMISSION STANDARDS FOR EMISSIONS OF RADIONUCLIDES OTHER THAN RADON FROM DEPARTMENT OF ENERGY FACILITIES. A description is given of the sources and their contributions to the overall dose assessment. In addition, the maximally exposed individual (MEI) radiological dose calculation and the population dose to localmore » and regional residents are discussed.« less

Prolonged head-down tilt exposure reduces maximal cutaneous vasodilator and sweating capacity in humans

NASA Technical Reports Server (NTRS)

Crandall, C. G.; Shibasaki, M.; Wilson, T. E.; Cui, J.; Levine, B. D.

2003-01-01

Cutaneous vasodilation and sweat rate are reduced during a thermal challenge after simulated and actual microgravity exposure. The effects of microgravity exposure on cutaneous vasodilator capacity and on sweat gland function are unknown. The purpose of this study was to test the hypothesis that simulated microgravity exposure, using the 6 degrees head-down tilt (HDT) bed rest model, reduces maximal forearm cutaneous vascular conductance (FVC) and sweat gland function and that exercise during HDT preserves these responses. To test these hypotheses, 20 subjects were exposed to 14 days of strict HDT bed rest. Twelve of those subjects exercised (supine cycle ergometry) at 75% of pre-bed rest heart rate maximum for 90 min/day throughout HDT bed rest. Before and after HDT bed rest, maximal FVC was measured, via plethysmography, by heating the entire forearm to 42 degrees C for 45 min. Sweat gland function was assessed by administering 1 x 10(-6) to 2 M acetylcholine (9 doses) via intradermal microdialysis while simultaneously monitoring sweat rate over the microdialysis membranes. In the nonexercise group, maximal FVC and maximal stimulated sweat rate were significantly reduced after HDT bed rest. In contrast, these responses were unchanged in the exercise group. These data suggest that 14 days of simulated microgravity exposure, using the HDT bed rest model, reduces cutaneous vasodilator and sweating capacity, whereas aerobic exercise training during HDT bed rest preserves these responses.

Randomised, double blind trial of two loading dose regimens of diamorphine in ventilated newborn infants.

PubMed

Barker, D P; Simpson, J; Pawula, M; Barrett, D A; Shaw, P N; Rutter, N

1995-07-01

To compare the safety and efficacy of two loading doses of diamorphine in 27 ventilated newborn infants in a randomised double blind trial. Fifty or 200 mcg/kg were infused intravenously over 30 minutes, followed by a 15 mcg/kg/hour continuous infusion. Serial measurements were made of physiology, behaviour, and stress hormones. Both loading doses produced small but significant falls in blood pressure. The 200 mcg/kg dose produced greater respiratory depression, and two infants deteriorated clinically, requiring resuscitation. Loading reduced respiratory effort in most of the infants, but had little effect on behavioural activity. Stress hormone concentrations were reduced at six hours in both dosage groups; differences between loading doses were not significant. Morphine, morphine-3-glucuronide, and morphine-6-glucuronide were detected in the plasma of all patients. No significant differences in concentrations between loading doses were found. Diamorphine reduces the stress response in ventilated newborn infants. A high loading dose confers no benefit, and may produce undesirable physiological effects. A 50 mcg/kg loading dose seems to be safe and effective.

Randomised, double blind trial of two loading dose regimens of diamorphine in ventilated newborn infants.

PubMed Central

Barker, D. P.; Simpson, J.; Pawula, M.; Barrett, D. A.; Shaw, P. N.; Rutter, N.

1995-01-01

AIMS--To compare the safety and efficacy of two loading doses of diamorphine in 27 ventilated newborn infants in a randomised double blind trial. METHODS--Fifty or 200 mcg/kg were infused intravenously over 30 minutes, followed by a 15 mcg/kg/hour continuous infusion. Serial measurements were made of physiology, behaviour, and stress hormones. RESULTS--Both loading doses produced small but significant falls in blood pressure. The 200 mcg/kg dose produced greater respiratory depression, and two infants deteriorated clinically, requiring resuscitation. Loading reduced respiratory effort in most of the infants, but had little effect on behavioural activity. Stress hormone concentrations were reduced at six hours in both dosage groups; differences between loading doses were not significant. Morphine, morphine-3-glucuronide, and morphine-6-glucuronide were detected in the plasma of all patients. No significant differences in concentrations between loading doses were found. CONCLUSIONS--Diamorphine reduces the stress response in ventilated newborn infants. A high loading dose confers no benefit, and may produce undesirable physiological effects. A 50 mcg/kg loading dose seems to be safe and effective. PMID:7552591

Anticonvulsant effects of Senna spectabilis on seizures induced by chemicals and maximal electroshock.

PubMed

Nkamguie Nkantchoua, Gisele Claudine; Kameni Njapdounke, Jacqueline Stephanie; Jules Fifen, Jean; Sotoing Taiwe, Germain; Josiane Ojong, Lucie; Kavaye Kandeda, Antoine; Ngo Bum, Elisabeth

2018-02-15

Senna spectabilis (Fabaceae) is one of the medicinal plants used in Cameroon by traditional healers to treat epilepsy, constipation, insomnia, anxiety. The present study aimed to investigate the anticonvulsant effects of Senna spectabilis decoction on seizures induced by maximal electroshock (MES), pentylenetetrazole (PTZ), pilocarpine (PC) and its possible action mechanisms in animal models using flumazenil (FLU), methyl-ß-carboline-3-carboxylate (BC) and bicuculline (BIC). Senna spectabilis decoction (106.5 and 213.0mg/kg) antagonized completely tonic-clonic hind limbs of mice induced by MES. The lowest plant dose (42.6mg/kg) provided 100% of protection against seizures induced by PTZ (70mg/kg). Administration of different doses of the plant decoction antagonized seizures induced by PC up to 75%, causing a dose dependent protection and reduced significantly the mortality rate induced by this convulsant. Both FLU and BC antagonize strongly the anticonvulsant effects of this plant and are unable to reverse totally diazepam or the plant decoction effects on inhibiting seizures. The animals did not present any sign of acute toxicity even at higher doses of the plant decoction. In conclusion, Senna spectabilis possesses an anticonvulsant activity. We showed that its decoction protects significantly mice against seizures induced by chemicals and MES, delays the onset time and reduces mortality rate in seizures-induced. It also appears that the oral administration of the decoction of S. spectabilis is more active than the intraperitoneal administration of the ethanolic extract on inhibiting seizures induced by MES and PTZ. Moreover, the plant decoction could interact with GABA A complex receptor probably on the GABA and benzodiazepines sites. Copyright © 2017 Elsevier B.V. All rights reserved.

Gastrokinetic activity of Morinda citrifolia aqueous fruit extract and its possible mechanism of action in human and rat models.

PubMed

Nima, Sawpheeyah; Kasiwong, Srirat; Ridtitid, Wibool; Thaenmanee, Niwan; Mahattanadul, Sirima

2012-07-13

This study was to investigate the gastrokinetic activity of Morinda citrifolia aqueous fruit extract (AFE) in human subjects by examining the GI absorption of ranitidine, a putative indicator of GI motility and to elucidate its possible gastrokinetic mechanism of action in rats. The single-dose, randomized, open-label and 2-period crossover study was performed on 20 Thai healthy volunteers with a washout period of 14 day between the doses. AFE or drinking water was administered orally 30 min prior to a single oral administration of ranitidine (300 mg). Blood samples were collected over a 12 h period after drug administration and the pharmacokinetic parameters of ranitidine were calculated. The gastrokinetic mechanism of action of AFE was elucidated by measurement of its contractile response on the isolated rat gastric fundus strip. The area under the plasma ranitidine concentration-time curve and the maximal plasma ranitidine concentration were significantly increased after pretreatment with AFE (p=0.001). The plasma ranitidine concentrations were significantly greater at 30-120 min after its administration. AFE produced a definite contractile response of a rat gastric fundus strip with a dose dependency. Scopoletin at the same equivalent dose present in AFE elicited a concentration-dependent contraction that amounted to 45% of the maximal response to AFE. The contractile response of both AFE and scopoletin was mediated through the 5-HT(4) receptor. AFE has a unique gastrokinetic activity in enhancement of the rate and the extent of ranitidine absorption. The underlying mechanism can be attributed, at least in part, to the ability of its active component: scopoletin to stimulate the 5-HT(4) receptor. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting.

PubMed

Howell, Julian; Smeets, Jean; Drenth, Henk-Jan; Gill, David

2009-12-01

To determine the pharmacokinetic (PK) profile of granisetron transdermal formulation and examine its possible relationship with age, gender, and renal function. This article describes a Phase I PK study and a post hoc pooled population PK analysis. The Phase I study was a randomized, cross-over study that assessed PK parameters of three granisetron patch sizes and oral granisetron. The pooled population PK analysis included data from three trials in healthy subjects (n = 48) and from Phase II and III studies in patients with cancer (n = 793). The population PK model was used to investigate granisetron exposure and its possible relationship with age, gender, and renal function. Following oral dosing, plasma granisetron concentration was quantifiable at 1 h, and maximal mean concentration (4.7 ng/mL) was reached 2 h after administration. With transdermal application, maximal concentration was reached 48 h post-application; t(1/2) was 36 h. With oral dosing, overall exposure after 5 days was 306 ng/mL.h, and C(avg) 2.6 ng/mL. This corresponded to an AUC(0-infinity) for the 52 cm(2) patch of 420 ng/mL.h and C(avg) 2.2 ng/mL over 6 days. Clearance was not affected by age, gender, weight, or renal function. The 52 cm( 2) granisetron patch achieves a similar exposure to that of a 2 mg oral dose and provides continuous delivery of granisetron over 6 days. The patch may have utility in treating chemotherapy-induced nausea and vomiting where prolonged drug delivery is advantageous. No dose adjustments would be needed based on age or renal function.

In vivo interaction of ketoconazole and sucralfate in healthy volunteers.

PubMed Central

Carver, P L; Berardi, R R; Knapp, M J; Rider, J M; Kauffman, C A; Bradley, S F; Atassi, M

1994-01-01

Absorption of ketoconazole is impaired in subjects with an increased gastric pH due to administration of antacids, H2-receptor antagonists, proton pump inhibitors, or the presence of hypochlorhydria. Sucralfate could provide an attractive alternative in patients receiving ketoconazole who require therapy for acid-peptic disorders. Twelve healthy human volunteers were administered a single 400-mg oral dose of ketoconazole in each of three randomized treatment phases. In phase A, ketoconazole was administered orally with 240 ml of water. In phase B, ketoconazole and sucralfate (1.0 g) were administered simultaneously with 240 ml of water. In phase C, ketoconazole was administered with 240 ml of water 2 h after administration of sucralfate (1.0 g) orally with 240 ml of water. A 680-mg oral dose of glutamic acid hydrochloride was administered 10 min prior to and with each dose of ketoconazole, sucralfate, or ketoconazole plus sucralfate. Simultaneous administration of ketoconazole and sucralfate led to a significant reduction in the area under the concentration-time curve and maximal concentration of ketoconazole in serum (78.12 +/- 12.20 versus 59.32 +/- 13.61 micrograms.h/ml and 12.34 +/- 3.07 versus 8.92 +/- 2.57 micrograms/ml, respectively; P < 0.05). When ketoconazole was administered 2 h after sucralfate, the observed ketoconazole area under the concentration-time curve was not significantly decreased compared with that of ketoconazole alone. The time to maximal concentrations in serum and the ketoconazole elimination rate constant were not significantly different in any of the three treatment phases. In patients receiving concurrent administration of ketoconazole and sucralfate, doses should be separated by at least 2 h. PMID:7910724

Influence of WIN 55,212-2 on the anticonvulsant and acute neurotoxic potential of clobazam and lacosamide in the maximal electroshock-induced seizure model and chimney test in mice.

PubMed

Florek-Luszczki, Magdalena; Zagaja, Miroslaw; Luszczki, Jarogniew J

2014-12-01

The influence of WIN 55,212-2 mesylate (WIN) on the anticonvulsant activity and acute neurotoxic potential of clobazam (CLB) and lacosamide (LCM) was studied in the maximal electroshock-induced seizure (MES) model and chimney test in mice. indicate that WIN administered intraperitoneally, at doses of 2.5 and 5 mg/kg significantly enhanced the anticonvulsant action of CLB in the MES test by reducing its median effective dose (ED50) from 20.80 mg/kg to 12.05 mg/kg (P<0.05), and 8.22 mg/kg (P<0.001), respectively. In contrast, WIN (1.25 mg/kg) did not significantly potentiate the anticonvulsant activity of CLB against MES-induced seizures. Similarly, WIN at doses of 1.25, 2.5 and 5 mg/kg had no significant impact on the anticonvulsant action of LCM in the MES test. On the other hand, WIN (5 mg/kg) had no impact on the acute neurotoxic effects of CLB and LCM in the chimney test and the median toxic doses (TD50) for CLB and LCM were almost unchanged. Thus, WIN (5 mg/kg) elevated the protective index values for CLB (from 1.41 to 3.07) and LCM (from 3.60 to 4.91). In conclusion, WIN potentiates suppression of tonic-clonic seizures produced by CLB in the mouse MES model, without affecting acute neurotoxic adverse effects of CLB in the chimney test in mice, which is favorable from a preclinical point of view. Copyright © 2014 Elsevier B.V. All rights reserved.

Feasibility and Association of Neurohumoral Blocker Up-titration After Cardiac Resynchronization Therapy.

PubMed

Martens, Pieter; Verbrugge, Frederik H; Nijst, Petra; Bertrand, Philippe B; Dupont, Matthias; Tang, Wilson H; Mullens, Wilfried

2017-08-01

Cardiac resynchronization therapy (CRT) improves mortality and morbidity on top of optimal medical therapy in heart failure with reduced ejection fraction (HFrEF). This study aimed to elucidate the association between neurohumoral blocker up-titration after CRT implantation and clinical outcomes. Doses of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and beta-blockers were retrospectively evaluated in 650 consecutive CRT patients implanted from October 2008 to August 2015 and followed in a tertiary multidisciplinary CRT clinic. All 650 CRT patients were on a maximal tolerable dose of ACE-I/ARB and beta-blocker at the time of CRT implantation. However, further up-titration was successful in 45.4% for ACE-I/ARB and in 56.8% for beta-blocker after CRT-implantation. During a mean follow-up of 37 ± 22 months, a total of 139 events occurred for the combined end point of heart failure admission and all-cause mortality. Successful, versus unsuccessful, up-titration was associated with adjusted hazard ratios of 0.537 (95% confidence interval 0.316-0.913; P = .022) for ACE-I/ARB and 0.633 (0.406-0.988; P = .044) for beta-blocker on the combined end point heart failure admission and all-cause mortality. Patients in the up-titration group exhibited a similar risk for death or heart failure admission as patients treated with the maximal dose (ACE-I/ARB: P = .133; beta-blockers: P = .709). After CRT, a majority of patients are capable of tolerating higher dosages of neurohumoral blockers. Up-titration of neurohumoral blockers after CRT implantation is associated with improved clinical outcomes, similarly to patients treated with the guideline-recommended target dose at the time of CRT implantation. Copyright © 2017 Elsevier Inc. All rights reserved.

Frameless Stereotactic Radiosurgery for Treatment of Multiple Sclerosis-Related Trigeminal Neuralgia.

PubMed

Conti, Alfredo; Pontoriero, Antonio; Iatì, Giuseppe; Esposito, Felice; Siniscalchi, Enrico Nastro; Crimi, Salvatore; Vinci, Sergio; Brogna, Anna; De Ponte, Francesco; Germanò, Antonino; Pergolizzi, Stefano; Tomasello, Francesco

2017-07-01

Trigeminal neuralgia (TN) affects 7% of patients with multiple sclerosis (MS). In such patients, TN is difficult to manage either pharmacologically and surgically. Radiosurgical rhizotomy is an effective treatment option. The nonisocentric geometry of radiation beams of CyberKnife introduces new concepts in the treatment of TN. Its efficacy for MS-related TN has not yet been demonstrated. Twenty-seven patients with refractory TN and MS were treated. A nonisocentric beams distribution was chosen; the maximal target dose was 72.5 Gy. The maximal dose to the brainstem was <12 Gy. Effects on pain, medications, sensory disturbance, rate, and time of pain recurrence were analyzed. Median follow-up was 37 (18-72) months. Barrow Neurological Institute pain scale score I-III was achieved in 23/27 patients (85%) within 45 days. Prescription isodose line (80%) accounting for a dose of 58 Gy incorporated an average of 4.85 mm (4-6 mm) of the nerve and mean nerve volume of 26.4 mm 3 (range 20-38 mm 3 ). Seven out of 27 patients (26%) had mild, not bothersome, facial numbness (Barrow Neurological Institute numbness score II). The rate of pain control decreased progressively after the first year, and only 44% of patients retained pain control 4 years later. Frameless radiosurgery can be effectively used to perform retrogasserian rhizotomy. Pain relief was satisfactory and, with our dose/volume constraints, no sensory complications were recorded. Nonetheless, long-term pain control was possible in less than half of the patients. This is a limitation that CyberKnife radiosurgery shares with other techniques in MS patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension.

PubMed

White, William B; Weber, Michael A; Sica, Domenic; Bakris, George L; Perez, Alfonso; Cao, Charlie; Kupfer, Stuart

2011-03-01

Azilsartan medoxomil is an angiotensin receptor blocker (ARB) being developed for hypertension treatment. To compare this ARB with others in the class, we studied the effects of 2 doses of azilsartan medoxomil, with valsartan 320 mg and olmesartan medoxomil (olmesartan) 40 mg, in a randomized, double-blind, placebo-controlled trial using ambulatory blood pressure (BP) monitoring and clinic BP measurements. The primary efficacy end point was the change from baseline in 24-hour mean systolic BP. Hierarchical analysis testing for superiority over placebo was followed by noninferiority analysis and then superiority testing of azilsartan medoxomil (80 mg and then 40 mg) versus the comparator ARBs. For 1291 randomized patients, mean age was 56 years, 54% were men, and baseline 24-hour mean systolic BP was 145 mm Hg. Azilsartan medoxomil at 80 mg had superior efficacy to both valsartan at 320 mg and olmesartan at 40 mg: placebo-adjusted 24-hour systolic BP was lowered (-14.3 mm Hg) more than 320 mg of valsartan (-10.0 mm Hg; P<0.001) and 40 mg of olmesartan (-11.7 mm Hg; P=0.009). Azilsartan medoxomil at 40 mg was noninferior to 40 mg of olmesartan (difference: -1.4 mm Hg [95% CI: -3.3 to 0.5]). For clinic systolic BP, both doses of azilsartan medoxomil were superior to the comparator ARBs. Safety and tolerability were similar among the placebo and 4 active treatments. These data demonstrate that azilsartan medoxomil at its maximal dose has superior efficacy to both olmesartan and valsartan at their maximal, approved doses without increasing adverse events. Azilsartan medoxomil could provide higher rates of hypertension control within the ARB class.