Azathioprine-Induced Warfarin Resistance

PubMed Central

Vazquez, Sara R; Rondina, Matthew T; Pendleton, Robert C

2011-01-01

OBJECTIVE To describe a case of azathioprine-induced warfarin resistance, present a literature review on warfarin–azathioprine interactions, and provide recommendations on appropriate management of this clinically significant interaction. CASE SUMMARY A 29-year-old female with Cogan’s syndrome experienced thrombosis of the left internal carotid artery. She was treated with an average weekly warfarin dose of 39 mg (5.5 mg daily) prior to beginning azathioprine therapy. Three weeks following initiation of azathioprine 150 mg daily, the international normalized ratio (INR) decreased from 1.9 (prior to the medication change) to 1.0 without any change in the warfarin dose or other relevant factors. Over several weeks, the patient’s warfarin dose was titrated up to 112 mg weekly (16 mg daily) to achieve an INR of 2.5 (a 188%, or 2.9-fold dose increase). Because of elevated liver enzyme levels, the azathioprine dosage was decreased to 100 mg daily. Within 2 weeks following that decrease, warfarin requirements decreased to 105 mg weekly (15 mg daily). DISCUSSION Azathioprine was the probable causative agent of warfarin resistance according to the Naranjo probability scale, and a possible causative agent according to the Drug Interaction Probability Scale. A literature search (PubMed, 1966–December 2007) revealed 8 case reports of this drug interaction and 2 cases involving a similar effect with 6-mercaptopurine, the active metabolite of azathioprine. The exact mechanism of the interaction remains unknown. Previously published case reports point to a rapid onset and offset of the warfarin–azathioprine interaction and a dose-dependent increase of at least 2.5-fold in warfarin dose requirement with the initiation of azathioprine 75–200 mg daily. CONCLUSIONS This case report and several others point toward azathioprine as a clinically significant inducer of warfarin resistance. Providers should anticipate the need for higher warfarin doses, warfarin dose adjustment, and close INR monitoring in patients receiving azathioprine or its active metabolite, 6-mercaptopurine. PMID:18505911

Warfarin Dosing Algorithms Underpredict Dose Requirements in Patients Requiring ≥7 mg Daily: A Systematic Review and Meta-analysis.

PubMed

Saffian, S M; Duffull, S B; Wright, Dfb

2017-08-01

There is preliminary evidence to suggest that some published warfarin dosing algorithms produce biased maintenance dose predictions in patients who require higher than average doses. We conducted a meta-analysis of warfarin dosing algorithms to determine if there exists a systematic under- or overprediction of dose requirements for patients requiring ≥7 mg/day across published algorithms. Medline and Embase databases were searched up to September 2015. We quantified the proportion of over- and underpredicted doses in patients whose observed maintenance dose was ≥7 mg/day. The meta-analysis included 47 evaluations of 22 different warfarin dosing algorithms from 16 studies. The meta-analysis included data from 1,492 patients who required warfarin doses of ≥7 mg/day. All 22 algorithms were found to underpredict warfarin dosing requirements in patients who required ≥7 mg/day by an average of 2.3 mg/day with a pooled estimate of underpredicted doses of 92.3% (95% confidence interval 90.3-94.1, I 2 = 24%). © 2017 American Society for Clinical Pharmacology and Therapeutics.

Health risk assessment of inorganic arsenic intake of Ronphibun residents via duplicate diet study.

PubMed

Saipan, Piyawat; Ruangwises, Suthep

2009-06-01

To assess health risk from exposure to inorganic arsenic via duplicate portion sampling method in Ronphibun residents. A hundred and forty samples (140 subject-days) were collected from participants in Ronphibun sub-district. Inorganic arsenic in duplicate diet sample was determined by acid digestion and hydride generation-atomic absorption spectrometry. Deterministic risk assessment is referenced throughout the present paper using United States Environmental Protection Agency (U.S. EPA) guidelines. The average daily dose and lifetime average daily dose of inorganic arsenic via duplicate diet were 0.0021 mg/kg/d and 0.00084 mg/kg/d, respectively. The risk estimates in terms of hazard quotient was 6.98 and cancer risk was 1.26 x 10(-3). The results of deterministic risk characterization both hazard quotient and cancer risk from exposure inorganic arsenic in duplicate diets were greater than safety risk levels of hazard quotient (1) and cancer risk (1 x 10(-4)).

Oral and inhaled glucocorticoid use and risk of Achilles or biceps tendon rupture: a population-based case-control study.

PubMed

Spoendlin, Julia; Meier, Christian; Jick, Susan S; Meier, Christoph R

2015-01-01

Tendinotoxicity of glucocorticoids (GC) has been shown, but evidence on how this translates into clinical practice remains scarce. To explore the association between oral or inhaled GC use and the risk of Achilles or biceps tendon rupture (ATR/BTR). We identified patients aged 18 to 89 years with incident ATR or BTR (1995-2013) for a matched (1:4) case-control analysis using the UK-based Clinical Practice Research Datalink. We stratified oral GC use by indication, timing and duration of use, continuous versus intermittent use, cumulative dose, and average daily dose. We stratified inhaled GC use by timing and number of prescriptions. Among 8,202 cases, we observed increased odds ratios (ORs) around 3.0 for continuous oral GC use, which declined shortly after therapy cessation (similarly across indications). Odds ratios increased with average daily dose (≥ 10 mg/day, OR 4.05, 95% CI 2.32-7.08) and were elevated after one cycle of high-dose oral GC (≥ 20 mg/day). There was no effect of inhaled GC at any level of exposure. Our results provide evidence that oral GC therapy increases the risk of tendon rupture in a dose-response relationship. A single short-term high-dose GC treatment course may be sufficient transiently to increase the risk of tendon rupture.

Benefits of adaptive radiation therapy in lung cancer as a function of replanning frequency

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

Dial, Christian; Weiss, Elisabeth; Hugo, Geoffrey D., E-mail: gdhugo@vcu.edu

Purpose: To quantify the potential benefit associated with daily replanning in lung cancer in terms of normal tissue dose sparing and to characterize the tradeoff between adaptive benefit and replanning frequency. Methods: A set of synthetic images and contours, derived from weekly active breathing control images of 12 patients who underwent radiation therapy treatment for nonsmall cell lung cancer, is generated for each fraction of treatment using principal component analysis in a way that preserves temporal anatomical trends (e.g., tumor regression). Daily synthetic images and contours are used to simulate four different treatment scenarios: (1) a “no-adapt” scenario that simulatesmore » delivery of an initial plan throughout treatment, (2) a “midadapt” scenario that implements a single replan for fraction 18, (3) a “weekly adapt” scenario that simulates weekly adaptations, and (4) a “full-adapt” scenario that simulates daily replanning. An initial intensity modulated radiation therapy plan is created for each patient and replanning is carried out in an automated fashion by reoptimizing beam apertures and weights. Dose is calculated on each image and accumulated to the first in the series using deformable mappings utilized in synthetic image creation for comparison between simulated treatments. Results: Target coverage was maintained and cord tolerance was not exceeded for any of the adaptive simulations. Average reductions in mean lung dose (MLD) and volume of lung receiving 20 Gy or more (V20{sub lung}) were 65 ± 49 cGy (p = 0.000 01) and 1.1% ± 1.2% (p = 0.0006), respectively, for all patients. The largest reduction in MLD for a single patient was 162 cGy, which allowed an isotoxic escalation of the target dose of 1668 cGy. Average reductions in cord max dose, mean esophageal dose (MED), dose received by 66% of the heart (D66{sub heart}), and dose received by 33% of the heart (D33{sub heart}), were 158 ± 280, 117 ± 121, 37 ± 77, and 99 ± 120 cGy, respectively. Average incremental reductions in MLD for the midadapt, weekly adapt, and full-adapt treatments were 38, 18, and 8 cGy, respectively. Incremental reductions in MED for the same treatments were 57, 37, and 23 cGy. Reductions in MLD and MED for the full-adapt treatment were correlated with the absolute decrease in the planning target volume (r = 0.34 and r = 0.26). Conclusions: Adaptive radiation therapy for lung cancer yields clinically relevant reductions in normal tissue doses for frequencies of adaptation ranging from a single replan up to daily replanning. Increased frequencies of adaptation result in additional benefit while magnitude of benefit decreases.« less

SU-D-BRC-03: Development and Validation of an Online 2D Dose Verification System for Daily Patient Plan Delivery Accuracy Check

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

Zhao, J; Hu, W; Xing, Y

Purpose: All plan verification systems for particle therapy are designed to do plan verification before treatment. However, the actual dose distributions during patient treatment are not known. This study develops an online 2D dose verification tool to check the daily dose delivery accuracy. Methods: A Siemens particle treatment system with a modulated scanning spot beam is used in our center. In order to do online dose verification, we made a program to reconstruct the delivered 2D dose distributions based on the daily treatment log files and depth dose distributions. In the log files we can get the focus size, positionmore » and particle number for each spot. A gamma analysis is used to compare the reconstructed dose distributions with the dose distributions from the TPS to assess the daily dose delivery accuracy. To verify the dose reconstruction algorithm, we compared the reconstructed dose distributions to dose distributions measured using PTW 729XDR ion chamber matrix for 13 real patient plans. Then we analyzed 100 treatment beams (58 carbon and 42 proton) for prostate, lung, ACC, NPC and chordoma patients. Results: For algorithm verification, the gamma passing rate was 97.95% for the 3%/3mm and 92.36% for the 2%/2mm criteria. For patient treatment analysis,the results were 97.7%±1.1% and 91.7%±2.5% for carbon and 89.9%±4.8% and 79.7%±7.7% for proton using 3%/3mm and 2%/2mm criteria, respectively. The reason for the lower passing rate for the proton beam is that the focus size deviations were larger than for the carbon beam. The average focus size deviations were −14.27% and −6.73% for proton and −5.26% and −0.93% for carbon in the x and y direction respectively. Conclusion: The verification software meets our requirements to check for daily dose delivery discrepancies. Such tools can enhance the current treatment plan and delivery verification processes and improve safety of clinical treatments.« less

Daily radionuclide ingestion and internal radiation doses in Aomori prefecture, Japan.

PubMed

Ohtsuka, Yoshihito; Kakiuchi, Hideki; Akata, Naofumi; Takaku, Yuichi; Hisamatsu, Shun'ichi

2013-10-01

To assess internal annual dose in the general public in Aomori Prefecture, Japan, 80 duplicate cooked diet samples, equivalent to the food consumed over a 400-d period by one person, were collected from 100 volunteers in Aomori City and the village of Rokkasho during 2006–2010 and were analyzed for 11 radionuclides. To obtain average rates of ingestion of radionuclides, the volunteers were selected from among office, fisheries, agricultural, and livestock farm workers. Committed effective doses from ingestion of the diet over a 1-y period were calculated from the analytical results and from International Commission on Radiological Protection dose coefficients; for 40K, an internal effective dose rate from the literature was used. Fisheries workers had significantly higher combined internal annual dose than the other workers, possibly because of high rates of ingestion of marine products known to have high 210Po concentrations. The average internal dose rate, weighted by the numbers of households in each worker group in Aomori Prefecture, was estimated at 0.47 mSv y-1. Polonium-210 contributed 49% of this value. The sum of committed effective dose rates for 210Po, 210Pb, 228Ra, and 14C and the effective dose rate of 40K accounted for approximately 99% of the average internal dose rate.

Antimicrobial use in Belgian broiler production.

PubMed

Persoons, Davy; Dewulf, Jeroen; Smet, Annemieke; Herman, Lieve; Heyndrickx, Marc; Martel, An; Catry, Boudewijn; Butaye, Patrick; Haesebrouck, Freddy

2012-08-01

The use of antimicrobials in production animals has become a worldwide concern in the face of rising resistance levels in commensal, pathogenic and zoonotic bacteria. In the years 2007 and 2008 antimicrobial consumption records were collected during two non consecutive production cycles in 32 randomly selected Belgian broiler farms. Antimicrobials were used in 48 of the 64 monitored production cycles, 7 farms did not use any antimicrobials in both production cycles, 2 farms only administered antimicrobials in one of the two production cycles, the other 23 farms applied antimicrobial treatment in both production cycles. For the quantification of antimicrobial drug use, the treatment incidences (TI) based on the defined daily doses (the dose as it should be applied: DDD) and used daily doses (the actual dose applied: UDD) were calculated. A mean antimicrobial treatment incidence per 1000 animals of 131.8 (standard deviation 126.8) animals treated daily with one DDD and 121.4 (SD 106.7) animals treated daily with one UDD was found. The most frequently used compounds were amoxicillin, tylosin and trimethoprim-sulphonamide with a mean TI(UDD) of 37.9, 34.8, and 21.7, respectively. The ratio of the UDD/DDD gives an estimate on correctness of dosing. Tylosin was underdosed in most of the administrations whereas amoxicillin and trimethoprim-sulphonamide were slightly overdosed in the average flock. Copyright © 2012 Elsevier B.V. All rights reserved.

Documenting pharmacist interventions on an intranet.

PubMed

Simonian, Armen I

2003-01-15

The process of developing and implementing an intranet Web site for clinical intervention documentation is described. An inpatient pharmacy department initiated an organizationwide effort to improve documentation of interventions by pharmacists at its seven hospitals to achieve real-time capture of meaningful benchmarking data. Standardization of intervention types would allow the health system to contrast and compare medication use, process improvement, and patient care initiatives among its hospitals. After completing a needs assessment and reviewing current methodologies, a computerized tracking tool was developed in-house and integrated with the organization's intranet. Representatives from all hospitals agreed on content and functionality requirements for the Web site. The site was completed and activated in February 2002. Before this Web site was established, the most documented intervention types were Renal Adjustment and Clarify Dose, with a daily average of four and three, respectively. After site activation, daily averages for Renal Adjustment remained unchanged, but Clarify Dose is now documented nine times per day. Drug Information and i.v.-to-p.o. intervention types, which previously averaged less than one intervention per day, are now documented an average of four times daily. Approximately 91% of staff pharmacists are using this site. Future plans for this site include enhanced accessibility to the site with wireless personal digital assistants. The design and implementation of an intranet Web site to document pharmacists' interventions doubled the rate of intervention documentation and standardized the intervention types among hospitals in the health system.

[Risk factors for the oral use of antibiotics and animal treatment incidence of weaners in Switzerland].

PubMed

Hirsiger, P; Malik, J; Kommerlen, D; Vidondo, B; Arnold, C; Harisberger, M; Spring, P; Sidler, X

2015-12-01

In the present study, risk factors for the use of oral antibiotics in weaned piglets were collected on 112 pig farms by a personal questionaire. The most common indication for an antibiotic group therapy was diarrhoea, and the most frequently used antibiotic was Colistin. On average, 27.33 daily doses in the control farms and 387.21 daily doses in the problem farms per 1000 weaners were administered on a given day. The significant risk factors in the multivariate model were poor hygiene in the water supply of suckling piglets, less than two doses ofprestarter feed daily, lack of an all-in-and-all-out production system in weaners, no herd book performance data analysis, and less than two of the legally prescribed veterinary visits per year. Furthermore, the treatment incidence of weaners for oral antibiotics was calculated on the basis of the drug inventory. This study provides evidence that the use of oral antibiotics in weaners can be reduced by interventions in hygiene and management.

SU-F-J-57: Effectiveness of Daily CT-Based Three-Dimensional Image Guided and Adaptive Proton Therapy

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

Moriya, S; National Cancer Center, Kashiwa, Chiba; Tachibana, H

Purpose: Daily CT-based three-dimensional image-guided and adaptive (CTIGRT-ART) proton therapy system was designed and developed. We also evaluated the effectiveness of the CTIGRT-ART. Methods: Retrospective analysis was performed in three lung cancer patients: Proton treatment planning was performed using CT image datasets acquired by Toshiba Aquilion ONE. Planning target volume and surrounding organs were contoured by a well-trained radiation oncologist. Dose distribution was optimized using 180-deg. and 270-deg. two fields in passive scattering proton therapy. Well commissioned Simplified Monte Carlo algorithm was used as dose calculation engine. Daily consecutive CT image datasets was acquired by an in-room CT (Toshiba Aquilionmore » LB). In our in-house program, two image registrations for bone and tumor were performed to shift the isocenter using treatment CT image dataset. Subsequently, dose recalculation was performed after the shift of the isocenter. When the dose distribution after the tumor registration exhibits change of dosimetric parameter of CTV D90% compared to the initial plan, an additional process of was performed that the range shifter thickness was optimized. Dose distribution with CTV D90% for the bone registration, the tumor registration only and adaptive plan with the tumor registration was compared to the initial plan. Results: In the bone registration, tumor dose coverage was decreased by 16% on average (Maximum: 56%). The tumor registration shows better coverage than the bone registration, however the coverage was also decreased by 9% (Maximum: 22%) The adaptive plan shows similar dose coverage of the tumor (Average: 2%, Maximum: 7%). Conclusion: There is a high possibility that only image registration for bone and tumor may reduce tumor coverage. Thus, our proposed methodology of image guidance and adaptive planning using the range adaptation after tumor registration would be effective for proton therapy. This research is partially supported by Japan Agency for Medical Research and Development (AMED).« less

Association Between US State Medical Cannabis Laws and Opioid Prescribing in the Medicare Part D Population.

PubMed

Bradford, Ashley C; Bradford, W David; Abraham, Amanda; Bagwell Adams, Grace

2018-05-01

Opioid-related mortality increased by 15.6% from 2014 to 2015 and increased almost 320% between 2000 and 2015. Recent research finds that the use of all pain medications (opioid and nonopioid collectively) decreases in Medicare Part D and Medicaid populations when states approve medical cannabis laws (MCLs). The association between MCLs and opioid prescriptions is not well understood. To examine the association between prescribing patterns for opioids in Medicare Part D and the implementation of state MCLs. Longitudinal analysis of the daily doses of opioids filled in Medicare Part D for all opioids as a group and for categories of opioids by state and state-level MCLs from 2010 through 2015. Separate models were estimated first for whether the state had implemented any MCL and second for whether a state had implemented either a dispensary-based or a home cultivation only-based MCL. The primary outcome measure was the total number of daily opioid doses prescribed (in millions) in each US state for all opioids. The secondary analysis examined the association between MCLs separately by opioid class. From 2010 to 2015 there were 23.08 million daily doses of any opioid dispensed per year in the average state under Medicare Part D. Multiple regression analysis results found that patients filled fewer daily doses of any opioid in states with an MCL. The associations between MCLs and any opioid prescribing were statistically significant when we took the type of MCL into account: states with active dispensaries saw 3.742 million fewer daily doses filled (95% CI, -6.289 to -1.194); states with home cultivation only MCLs saw 1.792 million fewer filled daily doses (95% CI, -3.532 to -0.052). Results varied by type of opioid, with statistically significant estimated negative associations observed for hydrocodone and morphine. Hydrocodone use decreased by 2.320 million daily doses (or 17.4%) filled with dispensary-based MCLs (95% CI, -3.782 to -0.859; P = .002) and decreased by 1.256 million daily doses (or 9.4%) filled with home-cultivation-only-based MCLs (95% CI, -2.319 to -0.193; P = .02). Morphine use decreased by 0.361 million daily doses (or 20.7%) filled with dispensary-based MCLs (95% CI, -0.718 to -0.005; P = .047). Medical cannabis laws are associated with significant reductions in opioid prescribing in the Medicare Part D population. This finding was particularly strong in states that permit dispensaries, and for reductions in hydrocodone and morphine prescriptions.

Deformable Dose Reconstruction to Optimize the Planning and Delivery of Liver Cancer Radiotherapy

NASA Astrophysics Data System (ADS)

Velec, Michael

The precise delivery of radiation to liver cancer patients results in improved control with higher tumor doses and minimized normal tissues doses. A margin of normal tissue around the tumor requires irradiation however to account for treatment delivery uncertainties. Daily image-guidance allows targeting of the liver, a surrogate for the tumor, to reduce geometric errors. However poor direct tumor visualization, anatomical deformation and breathing motion introduce uncertainties between the planned dose, calculated on a single pre-treatment computed tomography image, and the dose that is delivered. A novel deformable image registration algorithm based on tissue biomechanics was applied to previous liver cancer patients to track targets and surrounding organs during radiotherapy. Modeling these daily anatomic variations permitted dose accumulation, thereby improving calculations of the delivered doses. The accuracy of the algorithm to track dose was validated using imaging from a deformable, 3-dimensional dosimeter able to optically track absorbed dose. Reconstructing the delivered dose revealed that 70% of patients had substantial deviations from the initial planned dose. An alternative image-guidance technique using respiratory-correlated imaging was simulated, which reduced both the residual tumor targeting errors and the magnitude of the delivered dose deviations. A planning and delivery strategy for liver radiotherapy was then developed that minimizes the impact of breathing motion, and applied a margin to account for the impact of liver deformation during treatment. This margin is 38% smaller on average than the margin used clinically, and permitted an average dose-escalation to liver tumors of 9% for the same risk of toxicity. Simulating the delivered dose with deformable dose reconstruction demonstrated the plans with smaller margins were robust as 90% of patients' tumors received the intended dose. This strategy can be readily implemented with widely available technologies and thus can potentially improve local control for liver cancer patients receiving radiotherapy.

Continuous transdermal nitroglycerin therapy for menopausal hot flashes: a single-arm, dose-escalation trial.

PubMed

Huang, Alison J; Cummings, Steven R; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

2016-03-01

To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Perimenopausal and postmenopausal women reporting at least seven hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hour nitroglycerin patch applied daily without patch-free periods. During 4 weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hour as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t tests examined change in outcomes between baseline and maximal-dose therapy and after discontinuation of nitroglycerin. Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hour, three to 0.4 mg/hour, two to 0.2 mg/hour, and one remained on 0.1 mg/hour nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P < 0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P = 0.041) and 96% increase in moderate-to-severe hot flashes (P < 0.001). Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel nonhormonal hot flash treatment.

Continuous Transdermal Nitroglycerin Therapy for Menopausal Hot Flashes: A Single-Arm Dose-Escalation Trial

PubMed Central

Huang, Alison J.; Cummings, Steven R.; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

2015-01-01

Objective To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Methods Peri- and postmenopausal women reporting at least 7 hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hr nitroglycerin patch applied daily without patch-free periods. Over four weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hr as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t-tests examined change in outcomes between baseline and maximal-dose therapy as well as after discontinuation of nitroglycerin. Results Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hr, three to 0.4 mg/hr, two to 0.2 mg/hr, and one remained on 0.1 mg/hr nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P<0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P=0.041) and 96% increase in moderate-to-severe hot flashes (P<0.001). Conclusions Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel non-hormonal hot flash treatment. PMID:26263283

Noise exposure levels for musicians during rehearsal and performance times.

PubMed

McIlvaine, Devon; Stewart, Michael; Anderson, Robert

2012-03-01

The purpose of this study was to determine daily noise doses and 8-hour time weighted averages for rock band musicians, crew members, and spectators during a typical rehearsal and performance using both Occupational Safety and Health Administration (OSHA) and National Institute of Occupational Safety and Health (NIOSH) measurement criteria. Personal noise dosimetry was completed on five members of a rock band during one 2-hr rehearsal and one 4-hr performance. Time-weighted averages (TWA) and daily dose values were calculated using both OSHA and NIOSH criteria and compared to industry guidelines for enrollment in hearing conservation programs and the use of hearing protection devices. TWA values ranged from 84.3 to 90.4 dBA (OSHA) and from 90.0 to 96.4 dBA (NIOSH) during the rehearsal. The same values ranged from 91.0 to 99.7 dBA (OSHA) and 94.0 to 102.8 dBA (NIOSH) for the performance. During the rehearsal, daily noise doses ranged from 45.54% to 106.7% (OSHA) and from 317.74% to 1396.07% (NIOSH). During the performance, doses ranged from 114.66% to 382.49% (OSHA) and from 793.31% to 5970.15% (NIOSH). The musicians in this study were exposed to dangerously high levels of noise and should be enrolled in a hearing conservation programs. Hearing protection devices should be worn, especially during performances. The OSHA measurement criteria yielded values significantly more conservative than those produced by NIOSH criteria. Audiologists should counsel musician-patients about the hazards of excessive noise (music) exposure and how to protect their hearing.

Association of Antidepressant Medications With Incident Type 2 Diabetes Among Medicaid-Insured Youths.

PubMed

Burcu, Mehmet; Zito, Julie M; Safer, Daniel J; Magder, Laurence S; dosReis, Susan; Shaya, Fadia T; Rosenthal, Geoffrey L

2017-12-01

Antidepressants are one of the most commonly prescribed classes of psychotropic medications among US youths. For adults, there is emerging evidence on the increased risk of type 2 diabetes in association with antidepressant use. However, little is known about the antidepressant treatment-emergent risk of type 2 diabetes among youths. To assess the association between antidepressant use and the risk of incident type 2 diabetes in youths by antidepressant subclass and according to duration of use, cumulative dose, and average daily dose. A retrospective cohort study was conducted using Medicaid claims data from 4 geographically diverse, large states of youths 5 to 20 years of age who initiated antidepressant treatment from January 1, 2005, to December 31, 2009. Antidepressant use (selective serotonin reuptake inhibitors [SSRIs] or serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic or other cyclic antidepressants, and other antidepressants) was assessed using the following 4 time-varying measures: current or former use, duration of use, cumulative dose, and average daily dose. Incident type 2 diabetes was assessed using discrete-time failure models, adjusting for disease risk score estimated using more than 125 baseline and time-dependent covariates. In this cohort of 119 608 youths aged 5 to 20 years who initiated antidepressant treatment (59 087 female youths and 60 521 male youths; 54.7% between 5 and 14 years of age) with a mean follow-up of 22.8 months, 79 285 [66.3%] had SSRI or SNRI exposure. The risk of type 2 diabetes was significantly greater during current use than former use of SSRIs or SNRIs (absolute risk, 1.29 per 10 000 person-months vs 0.64 per 10 000 person-months; adjusted relative risk [RR], 1.88; 95% CI, 1.34-2.64) and tricyclic or other cyclic antidepressants (absolute risk, 0.89 per 10 000 person-months vs 0.48 per 10 000 person-months; RR, 2.15; 95% CI, 1.06-4.36), but not of other antidepressants (absolute risk, 1.15 per 10 000 person-months vs 1.12 per 10 000 person-months; RR, 0.99; 95% CI, 0.66-1.50). Furthermore, for youths currently using SSRIs or SNRIs, the risk of type 2 diabetes increased with the duration of use (RR, 2.66; 95% CI, 1.45-4.88 for >210 days and RR, 2.56; 95% CI, 1.29-5.08 for 151-210 days compared with 1-90 days) and with the cumulative dose (RR, 2.44; 95% CI, 1.35-4.43 for >4500 mg and RR, 2.17; 95% CI, 1.07-4.40 for 3001-4500 mg compared with 1-1500 mg in fluoxetine hydrochloride dose equivalents). By contrast, neither the duration nor the cumulative dose of other antidepressants was associated with an increased risk of type 2 diabetes. The risk of type 2 diabetes increased significantly with the average daily dose among youths with more than 150 days of SSRI or SNRI use (RR, 2.39; 95% CI, 1.04-5.52 for >15.0 vs ≤15.0 mg/d) but not among youths with 1 to 150 days of SSRI or SNRI use. In a large cohort of youths insured by Medicaid, the use of SSRIs or SNRIs-the most commonly used antidepressant subclass-was associated with an increased risk of type 2 diabetes that intensified with increasing duration of use, cumulative dose, and average daily dose.

SU-F-T-584: Investigating Correction Methods for Ion Recombination Effects in OCTAVIUS 1000 SRS Measurements

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

Knill, C; Wayne State University School of Medicine, Detroit, MI; Snyder, M

Purpose: PTW’s Octavius 1000 SRS array performs IMRT QA measurements with liquid filled ionization chambers (LICs). Collection efficiencies of LICs have been shown to change during IMRT delivery as a function of LINAC pulse frequency and pulse dose, which affects QA results. In this study, two methods were developed to correct changes in collection efficiencies during IMRT QA measurements, and the effects of these corrections on QA pass rates were compared. Methods: For the first correction, Matlab software was developed that calculates pulse frequency and pulse dose for each detector, using measurement and DICOM RT Plan files. Pulse information ismore » converted to collection efficiency and measurements are corrected by multiplying detector dose by ratios of calibration to measured collection efficiencies. For the second correction, MU/min in daily 1000 SRS calibration was chosen to match average MU/min of the VMAT plan. Usefulness of derived corrections were evaluated using 6MV and 10FFF SBRT RapidArc plans delivered to the OCTAVIUS 4D system using a TrueBeam equipped with an HD- MLC. Effects of the two corrections on QA results were examined by performing 3D gamma analysis comparing predicted to measured dose, with and without corrections. Results: After complex Matlab corrections, average 3D gamma pass rates improved by [0.07%,0.40%,1.17%] for 6MV and [0.29%,1.40%,4.57%] for 10FFF using [3%/3mm,2%/2mm,1%/1mm] criteria. Maximum changes in gamma pass rates were [0.43%,1.63%,3.05%] for 6MV and [1.00%,4.80%,11.2%] for 10FFF using [3%/3mm,2%/2mm,1%/1mm] criteria. On average, pass rates of simple daily calibration corrections were within 1% of complex Matlab corrections. Conclusion: Ion recombination effects can potentially be clinically significant for OCTAVIUS 1000 SRS measurements, especially for higher pulse dose unflattened beams when using tighter gamma tolerances. Matching daily 1000 SRS calibration MU/min to average planned MU/min is a simple correction that greatly reduces ion recombination effects, improving measurements accuracy and gamma pass rates. This work was supported by PTW.« less

Analysis of nodal coverage utilizing image guided radiation therapy for primary gynecologic tumor volumes

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

Ahmed, Faisal; Loma Linda University Medical Center, Department of Radiation Oncology, Loma Linda, CA; Sarkar, Vikren

Purpose: To evaluate radiation dose delivered to pelvic lymph nodes, if daily Image Guided Radiation Therapy (IGRT) was implemented with treatment shifts based on the primary site (primary clinical target volume [CTV]). Our secondary goal was to compare dosimetric coverage with patient outcomes. Materials and methods: A total of 10 female patients with gynecologic malignancies were evaluated retrospectively after completion of definitive intensity-modulated radiation therapy (IMRT) to their pelvic lymph nodes and primary tumor site. IGRT consisted of daily kilovoltage computed tomography (CT)-on-rails imaging fused with initial planning scans for position verification. The initial plan was created using Varian's Eclipsemore » treatment planning software. Patients were treated with a median radiation dose of 45 Gy (range: 37.5 to 50 Gy) to the primary volume and 45 Gy (range: 45 to 64.8 Gy) to nodal structures. One IGRT scan per week was randomly selected from each patient's treatment course and re-planned on the Eclipse treatment planning station. CTVs were recreated by fusion on the IGRT image series, and the patient's treatment plan was applied to the new image set to calculate delivered dose. We evaluated the minimum, maximum, and 95% dose coverage for primary and nodal structures. Reconstructed primary tumor volumes were recreated within 4.7% of initial planning volume (0.9% to 8.6%), and reconstructed nodal volumes were recreated to within 2.9% of initial planning volume (0.01% to 5.5%). Results: Dosimetric parameters averaged less than 10% (range: 1% to 9%) of the original planned dose (45 Gy) for primary and nodal volumes on all patients (n = 10). For all patients, ≥99.3% of the primary tumor volume received ≥ 95% the prescribed dose (V95%) and the average minimum dose was 96.1% of the prescribed dose. In evaluating nodal CTV coverage, ≥ 99.8% of the volume received ≥ 95% the prescribed dose and the average minimum dose was 93%. In evaluating individual IGRT sessions, we found that 6 patients had an estimated minimal nodal CTV dose less than 90% (range: 78 to 99%) of that planned. With a median follow-up of 42.5 months, 2 patients experienced systemic disease progression at an average of 19.6 months. One patient was found to have a local or regional failure with an average follow-up of 42 months. Conclusion: Using only 3 dimensional IGRT corrections in gynecological radiation allows excellent coverage of the primary target volume and good average nodal CTV coverage. If IGRT corrections are based on alignment to the primary tumor volume, and is only able to be corrected in 3 degrees, this can create situations in which nodal volumes may be under dosed. Utilizing multiple IGRT sessions appears to average out dose discrepancies over the course of treatment. The implication of underdosing in a single IGRT session needs further evaluation in future studies. Based on the concern of minimum dose to a nodal target volume, these findings may signal caution when using IGRT and IMRT in gynecological radiation patients. Possible techniques to overcome this situation may include averaging shifts between tumor and nodal volume, use of a treatment couch with 6° of freedom, deformable registration, or adaptive planning.« less

Committed effective dose from naturally occuring radionuclides in shellfish

NASA Astrophysics Data System (ADS)

Khandaker, Mayeen Uddin; Wahib, Norfadira Binti; Amin, Yusoff Mohd.; Bradley, D. A.

2013-07-01

Recognizing their importance in the average Malaysian daily diet, the radioactivity concentrations in mollusc- and crustacean-based food have been determined for key naturally occuring radionuclides. Fresh samples collected from various maritime locations around peninsular Malaysia have been processed using standard procedures; the radionuclide concentrations being determined using an HPGe γ-ray spectrometer. For molluscs, assuming secular equilibrium, the range of activities of 238U (226Ra), 232Th (228Ra) and 40K were found to be 3.28±0.35 to 5.34±0.52, 1.20±0.21 to 2.44±0.21 and 118±6 to 281±14 Bq kg-1 dry weight, respectively. The respective values for crustaceans were 3.02±0.57 to 4.70±0.52, 1.38±0.21 to 2.40±0.35 and 216±11 to 316±15 Bq kg-1. The estimated average daily intake of radioactivity from consumption of molluscs are 0.37 Bq kg-1 for 238U (226Ra), 0.16 Bq kg-1 for 232Th (228Ra) and 18 Bq kg-1 for 40K; the respective daily intake values from crustaceans are 0.36 Bq kg-1, 0.16 Bq kg-1 and 23 Bq kg-1. Associated annual committed effective doses from molluscs are estimated to be in the range 21.3 to 34.7 μSv for 226Ra, 19.3 to 39.1 μSv for 228Ra and 17.0 to 40.4 μSv for 40K. For crustaceans, the respective dose ranges are 19.6 to 30.5 μSv, 22.0 to 38.4 μSv and 31.1 to 45.5 μSv, being some several times world average values.

Parotid Glands Dose–Effect Relationships Based on Their Actually Delivered Doses: Implications for Adaptive Replanning in Radiation Therapy of Head-and-Neck Cancer

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

Hunter, Klaudia U.; Fernandes, Laura L.; Vineberg, Karen A.

2013-11-15

Purpose: Doses actually delivered to the parotid glands during radiation therapy often exceed planned doses. We hypothesized that the delivered doses correlate better with parotid salivary output than the planned doses, used in all previous studies, and that determining these correlations will help make decisions regarding adaptive radiation therapy (ART) aimed at reducing the delivered doses. Methods and Materials: In this prospective study, oropharyngeal cancer patients treated definitively with chemoirradiation underwent daily cone-beam computed tomography (CBCT) with clinical setup alignment based on the C2 posterior edge. Parotid glands in the CBCTs were aligned by deformable registration to calculate cumulative deliveredmore » doses. Stimulated salivary flow rates were measured separately from each parotid gland pretherapy and periodically posttherapy. Results: Thirty-six parotid glands of 18 patients were analyzed. Average mean planned doses was 32 Gy, and differences from planned to delivered mean gland doses were −4.9 to +8.4 Gy, median difference +2.2 Gy in glands in which delivered doses increased relative to planned. Both planned and delivered mean doses were significantly correlated with posttreatment salivary outputs at almost all posttherapy time points, without statistically significant differences in the correlations. Large dispersions (on average, SD 3.6 Gy) characterized the dose–effect relationships for both. The differences between the cumulative delivered doses and planned doses were evident at first fraction (r=.92, P<.0001) because of complex setup deviations (eg, rotations and neck articulations), uncorrected by the translational clinical alignments. Conclusions: After daily translational setup corrections, differences between planned and delivered doses in most glands were small relative to the SDs of the dose–saliva data, suggesting that ART is not likely to gain measurable salivary output improvement in most cases. These differences were observed at first treatment, indicating potential benefit for more complex setup corrections or adaptive interventions in the minority of patients with large deviations detected early by CBCT.« less

[The role of chronic gastritis in past medical history with NSAID administration in patients with osteoarthrosis].

PubMed

Zak, M Iu

2014-11-01

122 patients with osteoarthrosis, who have in the past medical history verified chronic gastritis (50 males and 72 females) at the age from 42 to 64 have been examined. Control group was comprised of 40 patients with osteoarthrosis without gastroduodenal zone pathology in the past medical history. For arthralgia relief patients were prescribed meloxicam (average dose--12.5 - 1.39 mg daily) or nimesulide (average dose--150 ± 14.91 mg daily). As a result of this research it was determined that administration of selective NSAID (meloxicam and nimesulide) in patients with chronic gastritis in the past medical history raised the risk of NSAID gastropathy/dyspepsia 2.9 times (P < 0.03) than in patients without associated gastroduodenal zone pathology. Atrophy of gastric mucosa is associated with higher risks (P > 0.05) of erosive gastropathy. Patients with chronic gastritis in the past medical history when taking NSAID with the purpose of gastropathy prevention are recommended to undergo gastroprotective therapy.

Which metric of ambient ozone to predict daily mortality?

NASA Astrophysics Data System (ADS)

Moshammer, Hanns; Hutter, Hans-Peter; Kundi, Michael

2013-02-01

It is well known that ozone concentration is associated with daily cause specific mortality. But which ozone metric is the best predictor of the daily variability in mortality? We performed a time series analysis on daily deaths (all causes, respiratory and cardiovascular causes as well as death in elderly 65+) in Vienna for the years 1991-2009. We controlled for seasonal and long term trend, day of the week, temperature and humidity using the same basic model for all pollutant metrics. We found model fit was best for same day variability of ozone concentration (calculated as the difference between daily hourly maximum and minimum) and hourly maximum. Of these the variability displayed a more linear dose-response function. Maximum 8 h moving average and daily mean value performed not so well. Nitrogen dioxide (daily mean) in comparison performed better when previous day values were assessed. Same day ozone and previous day nitrogen dioxide effect estimates did not confound each other. Variability in daily ozone levels or peak ozone levels seem to be a better proxy of a complex reactive secondary pollutant mixture than daily average ozone levels in the Middle European setting. If this finding is confirmed this would have implications for the setting of legally binding limit values.

Evaluation of delivered dose for a clinical daily adaptive plan selection strategy for bladder cancer radiotherapy.

PubMed

Lutkenhaus, Lotte J; Visser, Jorrit; de Jong, Rianne; Hulshof, Maarten C C M; Bel, Arjan

2015-07-01

To account for variable bladder size during bladder cancer radiotherapy, a daily plan selection strategy was implemented. The aim of this study was to calculate the actually delivered dose using an adaptive strategy, compared to a non-adaptive approach. Ten patients were treated to the bladder and lymph nodes with an adaptive full bladder strategy. Interpolated delineations of bladder and tumor on a full and empty bladder CT scan resulted in five PTVs for which VMAT plans were created. Daily cone beam CT (CBCT) scans were used for plan selection. Bowel, rectum and target volumes were delineated on these CBCTs, and delivered dose for these was calculated using both the adaptive plan, and a non-adaptive plan. Target coverage for lymph nodes improved using an adaptive strategy. The full bladder strategy spared the healthy part of the bladder from a high dose. Average bowel cavity V30Gy and V40Gy significantly reduced with 60 and 69ml, respectively (p<0.01). Other parameters for bowel and rectum remained unchanged. Daily plan selection compared to a non-adaptive strategy yielded similar bladder coverage and improved coverage for lymph nodes, with a significant reduction in bowel cavity V30Gy and V40Gy only, while other sparing was limited. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

SU-E-J-181: Effect of Prostate Motion On Combined Brachytherapy and External Beam Dose Based On Daily Motion of the Prostate

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

Narayana, V; McLaughlin, P; University of Michigan, Ann Arbor, MI

2015-06-15

Purpose: In this study, the adequacy of target expansions on the combined external beam and implant dose was examined based on the measured daily motion of the prostate. Methods: Thirty patients received an I–125 prostate implant prescribed to dose of 90Gy. This was followed by external beam to deliver a dose of 90Gyeq (external beam equivalent) to the prostate over 25 to 30 fractions. An ideal IMRT plan was developed by optimizing the external beam dose based on the delivered implant dose. The implant dose was converted to an equivalent external beam dose using the linear quadratic model. Patients weremore » set up on the treatment table by daily orthogonal imaging and aligning the marker seeds in the prostate. Orthogonal images were obtained at the end of treatment to assess prostate intrafraction motion. Based on the observed motion of the markers between the initial and final images, 5 individual plans showing the actual dose delivered to the patient were calculated. A final true dose distribution was established based on summing the implant dose and the 5 external beam plans. Dose to the prostate, seminal vesicles, lymphnodes and normal tissues, rectal wall, urethra and lower sphincter were calculated and compared to ideal. On 18 patients who were sexually active, dose to the corpus cavernosum and internal pudendal artery was also calculated. Results: The average prostate motion in 3 orthogonal directions was less than 1 mm with a standard deviation of less than +2 mm. Dose and volume parameters showed that there was no decrease in dose to the targets and a marginal decrease in dose to in normal tissues. Conclusion: Dose delivered by seed implant moves with the prostate, decreasing the impact of intrafractions dose movement on actual dose delivered. Combined brachytherapy and external beam dose delivered to the prostate was not sensitive to prostate motion.« less

Primary hypothyroidism in the community: Lower daily dosages of levothyroxine replacement therapy for Asian patients.

PubMed

Tan, Ngiap Chuan; Chew, Rong Quan; Koh, Yi Ling Eileen; Subramanian, Reena Chandini; Sankari, Usha; Meyappan, Meykkumar; Cho, Li Wei

2017-02-01

The goal of treatment in patients with primary hypothyroidism is to attain euthyroidism guided by the stipulated thyroid-stimulating hormone (TSH) levels range so as to minimize any potential long-term adverse effects. However, various factors may result in their Levothyroxine (T4) under and over-replacement.Our study aimed to evaluate the mean daily dose of L-T4 replacement for Asian patients with primary hypothyroidism. The secondary aims were to determine the proportion of those who were either over or under-replaced, and the factors associated with their thyroid function status and replacement adherence.Data collected using questionnaire survey from targeted patients managed in a typical public primary care center in Singapore: socio-demographic characteristics, clinical parameters, laboratory investigations, mean daily L-T4-replacement doses, and replacement regimens. The thyroid status of patients was classified based on thyroid function investigations.Complete data of 229 patients were analyzed. A total of 59.8% of patients had TSH within the normal range, 27.5% and 12.7% were under and over-replaced, respectively. About 60% of Asian patients with primary hypothyroidism achieved normal TSH status requiring average of 1.1 μg of daily L-T4/kgBW (kg body weight). Subjects who were over-replaced had a higher daily L-T4 dose/kgBW when compared to the euthyroid and the under replaced groups. Those with L-T4 over-replacement were largely due to excessive dosage. Patients who were younger, from lower socioeconomic strata, and higher BMI were more likely to be over or under-replaced.Majority of Asian patients with hypothyroidism required replacement of 1.1 μg of daily L-T4/kgBW. Their thyroid status was influenced by demographic and dosing factors.

Technical Note: scuda: A software platform for cumulative dose assessment.

PubMed

Park, Seyoun; McNutt, Todd; Plishker, William; Quon, Harry; Wong, John; Shekhar, Raj; Lee, Junghoon

2016-10-01

Accurate tracking of anatomical changes and computation of actually delivered dose to the patient are critical for successful adaptive radiation therapy (ART). Additionally, efficient data management and fast processing are practically important for the adoption in clinic as ART involves a large amount of image and treatment data. The purpose of this study was to develop an accurate and efficient Software platform for CUmulative Dose Assessment (scuda) that can be seamlessly integrated into the clinical workflow. scuda consists of deformable image registration (DIR), segmentation, dose computation modules, and a graphical user interface. It is connected to our image PACS and radiotherapy informatics databases from which it automatically queries/retrieves patient images, radiotherapy plan, beam data, and daily treatment information, thus providing an efficient and unified workflow. For accurate registration of the planning CT and daily CBCTs, the authors iteratively correct CBCT intensities by matching local intensity histograms during the DIR process. Contours of the target tumor and critical structures are then propagated from the planning CT to daily CBCTs using the computed deformations. The actual delivered daily dose is computed using the registered CT and patient setup information by a superposition/convolution algorithm, and accumulated using the computed deformation fields. Both DIR and dose computation modules are accelerated by a graphics processing unit. The cumulative dose computation process has been validated on 30 head and neck (HN) cancer cases, showing 3.5 ± 5.0 Gy (mean±STD) absolute mean dose differences between the planned and the actually delivered doses in the parotid glands. On average, DIR, dose computation, and segmentation take 20 s/fraction and 17 min for a 35-fraction treatment including additional computation for dose accumulation. The authors developed a unified software platform that provides accurate and efficient monitoring of anatomical changes and computation of actually delivered dose to the patient, thus realizing an efficient cumulative dose computation workflow. Evaluation on HN cases demonstrated the utility of our platform for monitoring the treatment quality and detecting significant dosimetric variations that are keys to successful ART.

Technical Note: SCUDA: A software platform for cumulative dose assessment

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

Park, Seyoun; McNutt, Todd; Quon, Harry

Purpose: Accurate tracking of anatomical changes and computation of actually delivered dose to the patient are critical for successful adaptive radiation therapy (ART). Additionally, efficient data management and fast processing are practically important for the adoption in clinic as ART involves a large amount of image and treatment data. The purpose of this study was to develop an accurate and efficient Software platform for CUmulative Dose Assessment (SCUDA) that can be seamlessly integrated into the clinical workflow. Methods: SCUDA consists of deformable image registration (DIR), segmentation, dose computation modules, and a graphical user interface. It is connected to our imagemore » PACS and radiotherapy informatics databases from which it automatically queries/retrieves patient images, radiotherapy plan, beam data, and daily treatment information, thus providing an efficient and unified workflow. For accurate registration of the planning CT and daily CBCTs, the authors iteratively correct CBCT intensities by matching local intensity histograms during the DIR process. Contours of the target tumor and critical structures are then propagated from the planning CT to daily CBCTs using the computed deformations. The actual delivered daily dose is computed using the registered CT and patient setup information by a superposition/convolution algorithm, and accumulated using the computed deformation fields. Both DIR and dose computation modules are accelerated by a graphics processing unit. Results: The cumulative dose computation process has been validated on 30 head and neck (HN) cancer cases, showing 3.5 ± 5.0 Gy (mean±STD) absolute mean dose differences between the planned and the actually delivered doses in the parotid glands. On average, DIR, dose computation, and segmentation take 20 s/fraction and 17 min for a 35-fraction treatment including additional computation for dose accumulation. Conclusions: The authors developed a unified software platform that provides accurate and efficient monitoring of anatomical changes and computation of actually delivered dose to the patient, thus realizing an efficient cumulative dose computation workflow. Evaluation on HN cases demonstrated the utility of our platform for monitoring the treatment quality and detecting significant dosimetric variations that are keys to successful ART.« less

Phase 1b Study of New Posaconazole Tablet for Prevention of Invasive Fungal Infections in High-Risk Patients with Neutropenia

PubMed Central

López-Jiménez, Javier; Cornely, Oliver A.; Laverdiere, Michel; Helfgott, David; Haider, Shariq; Chandrasekar, Pranatharthi; Langston, Amelia; Perfect, John; Ma, Lei; van Iersel, Marlou L. P. S.; Connelly, Nancy; Kartsonis, Nicholas; Waskin, Hetty

2014-01-01

Posaconazole tablets, a new oral formulation of posaconazole, can be effective when given as antifungal prophylaxis to neutropenic patients at high risk for invasive fungal infection (e.g., those with acute myelogenous leukemia or myelodysplastic syndrome). Such effectiveness might be specifically important to patients with poor oral intake because of nausea, vomiting, or chemotherapy-associated mucositis. This was a prospective, global study in high-risk patients to characterize the pharmacokinetics and safety profile of posaconazole tablets and to identify the dose of posaconazole tablets that would provide exposure within a predefined range of exposures (steady-state average concentration [area under the concentration-time curve/24 h] of ≥500 ng/ml and ≤2,500 ng/ml in >90% of patients). The study evaluated two sequential dosing cohorts: 200 mg posaconazole once daily (n = 20) and 300 mg posaconazole once daily (n = 34) (both cohorts had a twice-daily loading dose on day 1) taken without regard to food intake during the neutropenic period for ≤28 days. The exposure target was reached (day 8) in 15 of 19 (79%) pharmacokinetic-evaluable patients taking 200 mg posaconazole once daily and in 31 of 32 (97%) patients taking 300 mg posaconazole once daily; 300 mg posaconazole once daily achieved the desired exposure target. Posaconazole tablets were generally well tolerated in high-risk neutropenic patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01777763.) PMID:25049247

Pitfalls associated with the therapeutic reference pricing practice of asthma medication

PubMed Central

2012-01-01

Background Therapeutic reference pricing (TRP) based on the WHO daily defined dose (DDD) is a method frequently employed for the cost-containment of pharmaceuticals. Our objective was to compare average drug use in the real world with DDD and to evaluate whether TRP based on DDD could result in cost savings on maintenance medication and the total direct health expenditures for asthma patients treated with Symbicort Turbuhaler (SYT) and Seretide Diskus (SED) in Hungary. Methods Real-world data were derived from the Hungarian National Health Insurance Fund database. Average doses and costs were compared between the high-dose and medium-dose SYT and SED groups. Multiple linear regressions were employed to adjust the data for differences in the gender and age distribution of patients. Results 27,779 patients with asthma were included in the analysis. Average drug use was lower than DDD in all groups, 1.38-1.95 inhalations in both SED groups, 1.28-1.97 and 1.74-2.49 inhalations in the medium and high-dose SYT groups, respectively. Although the cost of SED based on the DDD would be much lower than the cost of SYT in the medium-dose groups, no difference was found in the actual cost of the maintenance therapy. No significant differences were found between the groups in terms of total medical costs. Conclusions Cost-containment initiatives by payers may influence clinical decisions. TRP for inhalation asthma drugs raises special concern, because of differences in the therapeutic profile of pharmaceuticals and the lack of proven financial benefits after exclusion of the effect of generic price erosion. Our findings indicate that the presented TRP approach of asthma medications based on the daily therapeutic costs according to the WHO DDD does not result in reduced public healthcare spending in Hungary. Further analysis is required to show whether TRP generates additional expenditures by inducing switching costs and reducing patient compliance. Potential confounding factors may limit the generalisability of our conclusions. PMID:22818402

Pitfalls associated with the therapeutic reference pricing practice of asthma medication.

PubMed

Kalo, Zoltan; Abonyi-Toth, Zsolt; Bartfai, Zoltan; Voko, Zoltan

2012-07-20

Therapeutic reference pricing (TRP) based on the WHO daily defined dose (DDD) is a method frequently employed for the cost-containment of pharmaceuticals. Our objective was to compare average drug use in the real world with DDD and to evaluate whether TRP based on DDD could result in cost savings on maintenance medication and the total direct health expenditures for asthma patients treated with Symbicort Turbuhaler (SYT) and Seretide Diskus (SED) in Hungary. Real-world data were derived from the Hungarian National Health Insurance Fund database. Average doses and costs were compared between the high-dose and medium-dose SYT and SED groups. Multiple linear regressions were employed to adjust the data for differences in the gender and age distribution of patients. 27,779 patients with asthma were included in the analysis. Average drug use was lower than DDD in all groups, 1.38-1.95 inhalations in both SED groups, 1.28-1.97 and 1.74-2.49 inhalations in the medium and high-dose SYT groups, respectively. Although the cost of SED based on the DDD would be much lower than the cost of SYT in the medium-dose groups, no difference was found in the actual cost of the maintenance therapy. No significant differences were found between the groups in terms of total medical costs. Cost-containment initiatives by payers may influence clinical decisions. TRP for inhalation asthma drugs raises special concern, because of differences in the therapeutic profile of pharmaceuticals and the lack of proven financial benefits after exclusion of the effect of generic price erosion. Our findings indicate that the presented TRP approach of asthma medications based on the daily therapeutic costs according to the WHO DDD does not result in reduced public healthcare spending in Hungary. Further analysis is required to show whether TRP generates additional expenditures by inducing switching costs and reducing patient compliance. Potential confounding factors may limit the generalisability of our conclusions.

Brief communication: Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin.

PubMed

O'Donnell, Martin J; Kearon, Clive; Johnson, Judy; Robinson, Marlene; Zondag, Michelle; Turpie, Irene; Turpie, Alexander G

2007-02-06

Preoperative low-molecular-weight heparin (LMWH) is often used when warfarin therapy is interrupted for surgery. To determine the preoperative anticoagulant activity of LMWH following a standardized "bridging" regimen. Prospective cohort study. Single university hospital. Consecutive patients who had warfarin therapy interrupted before an invasive procedure. Enoxaparin, 1 mg/kg of body weight, twice daily. The last dose was administered the evening before surgery. Blood anti-factor Xa heparin levels measured shortly before surgery. Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels. The small sample size limits accurate estimates of the frequency of the clinical outcomes. A single regimen of LMWH was evaluated. Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.

High-dose nebulized budesonide is effective for mild asthma exacerbations in children under 3 years of age.

PubMed

Saito, M; Kikuchi, Y; Kawarai Lefor, A; Hoshina, M

2017-01-01

Background. High-dose inhaled steroid therapy has been shown to be effective in children and adults with asthma exacerbations. However, few reports are available regarding its efficacy for asthma exacerbations in younger children. Objective. In this study, we administered high-dose nebulized budesonide therapy for mild asthma exacerbations in children < 3 years of age and compared its efficacy and safety with systemic steroid therapy. Methods. This study included children < 3 years old with mild asthma exacerbations. Patients were randomly assigned to two groups: the BIS group was given 1 mg of nebulized budesonide twice daily, and the PSL group received prednisolone 0.5 mg/kg iv three times daily. Days to disappearance of wheezing, days of steroid use, days of oxygen use, serum cortisol level, and incidence of adverse events during treatment were compared between the groups. Result. Wheezing disappeared after an average of five days, and steroids were administered for an average of five days in both groups, with no significant difference in days of oxygen use. Serum cortisol levels at initiation and during the course of treatment remained unchanged in the BIS group, and were decreased in the PSL group; however, the decrease in the latter group was not pathologic. Conclusion. For children < 3 years old with mild asthma exacerbations, high-dose nebulized budesonide therapy is equally as effective as systemic steroid therapy.

Mammalian Toxicity of Munitions Compounds. Phase II. Effects of Multiple Doses Part II. 2,4-Dinitrotoluene

DTIC Science & Technology

1978-11-01

middle, or high levels of 2,4-DNT in the feed averaged 34, 93, or 266 mg/kg/day, respectively. The female rats consumed an average of 38, 108, or 145 mg...intake of males fed the low, middle or high levels of 2,4-DNT in the feed averaged 47, 137, or 413 mg/kg/day, respectively. The female mice consumed an...Experimental Procedures All dogs were observed daily for behavioral changes and toxic signs. Body weights of all dogs were recorded weekly. Blood

A randomised clinical trial on the efficacy of oxytetracycline dose through water medication of nursery pigs on diarrhoea, faecal shedding of Lawsonia intracellularis and average daily weight gain.

PubMed

Larsen, Inge; Hjulsager, Charlotte Kristiane; Holm, Anders; Olsen, John Elmerdahl; Nielsen, Søren Saxmose; Nielsen, Jens Peter

2016-01-01

Oral treatment with antimicrobials is widely used in pig production for the control of gastrointestinal infections. Lawsonia intracellularis (LI) causes enteritis in pigs older than six weeks of age and is commonly treated with antimicrobials. The objective of this study was to evaluate the efficacy of three oral dosage regimens (5, 10 and 20mg/kg body weight) of oxytetracycline (OTC) in drinking water over a five-day period on diarrhoea, faecal shedding of LI and average daily weight gain (ADG). A randomised clinical trial was carried out in four Danish pig herds. In total, 539 animals from 37 batches of nursery pigs were included in the study. The dosage regimens were randomly allocated to each batch and initiated at presence of assumed LI-related diarrhoea. In general, all OTC doses used for the treatment of LI infection resulted in reduced diarrhoea and LI shedding after treatment. Treatment with a low dose of 5mg/kg OTC per kg body weight, however, tended to cause more watery faeces and resulted in higher odds of pigs shedding LI above detection level when compared to medium and high doses (with odds ratios of 5.5 and 8.4, respectively). No association was found between the dose of OTC and the ADG. In conclusion, a dose of 5mg OTC per kg body weight was adequate for reducing the high-level LI shedding associated with enteropathy, but a dose of 10mg OTC per kg body weight was necessary to obtain a maximum reduction in LI shedding. Copyright © 2015 Elsevier B.V. All rights reserved.

Management of background pain and anxiety in critically burned children requiring protracted mechanical ventilation.

PubMed

Sheridan, R; Stoddard, F; Querzoli, E

2001-01-01

Optimal control of pain and anxiety is an elusive but important goal in children with protracted critical illness. This review represents an effort to document the doses of background medication required to achieve this goal in a group of children managed under a pain and anxiety protocol that adjusts background infusions to comfort. The course of children with wounds involving at least 10% of the body surface and coincident respiratory failure requiring mechanical ventilation for more than 7 days managed 1 Jan 97 to 31 Dec 98 was reviewed. A pain and anxiety protocol was used, including background infusions of morphine and midazolam adjusted to comfort. These 28 children had a mean (+/- standard deviation) age of 5.3 +/- 4.6 years, wound size of 48.3 +/- 28.4%, and were intubated for 25.0 +/- 23.9 days. Neuromuscular blocking drugs were administered for 65 of 447 (14.5%) ventilator days. To maintain comfort, drugs were required at doses substantially above standard dosing schemes. The highest daily background infusion of morphine sulfate averaged 0.40 mg/kg/hr +/- 0.24 mg/kg/hr (usual starting dose was 0.05 to 0.1 mg/kg/hr) and was reached 14.1 +/- 12.8 days after admission. The highest daily background infusion of midazolam averaged 0.15 +/- 0.07 mg/kg/hr (usual starting dose was 0.04 mg/kg/hr) and was reached 14.0 +/- 3.8 days after admission. Morphine infusions at extubation averaged 0.22 +/- 0.17 mg/kg/hr and midazolam infusions 0.10 +/- 0.12 mg/kg/hr. All children survived to discharge and there was no perceived morbidity related to these high doses of medication. Children with serious burns and respiratory failure will require high doses of background opiates and benzodiazepines to remain comfortable, because they develop drug tolerance during protracted critical illness. Infusions can be continued at a reduced dose through extubation, do not result in addiction or other apparent morbidity if adjusted to desired level of comfort, and may contribute to a reduced incidence of treatment-related stress disorders.

A Case of Severe, Prolonged, Refractory Hypophosphatemia After Zoledronic Acid Administration.

PubMed

Clark, Sarah L; Nystrom, Erin M

2016-04-01

Zoledronic acid (ZA) administration has been associated with electrolyte abnormalities, including hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia. We describe a case of severe, refractory hypophosphatemia in a patient who received ZA for hypercalcemia of malignancy (HCM). Little data are available that describe the incidence or degree of severity of hypophosphatemia that can occur following ZA administration. In addition, no formal recommendations exist to guide monitoring for or management of electrolyte derangements in the setting of bisphosphonate use. Our patient required daily, high-dose phosphorus replacement beginning day 4 following ZA administration. The average daily dose of phosphorus, including both intravenous and enteral administration, was highest in the first 2 weeks after ZA, averaging 77 mmol/d days 4 through 15, and does not include sources of phosphorus from the patient's nutrition support. Despite this high amount of supplementation, which was well beyond what meets normal daily requirements and the amount expected to treat "usual" hypophosphatemia, the patient did not achieve sustained normal serum phosphorus levels for over 30 days after ZA. ZA is a favorable option for treating HCM because of its longer duration of action, potent serum calcium-lowering effects, and favorable safety profile. The risk of hypophosphatemia with ZA use is reviewed. © The Author(s) 2016.

Factors Associated With Antidepressant Dosing in Asia: Findings From the Research on Asian Psychotropic Prescription Study.

PubMed

Rajaratnam, Kamini; Xiang, Yu-Tao; Tripathi, Adarsh; Chiu, Helen Fung Kum; Si, Tian-Mei; Chee, Kok-Yoon; Avasthi, Ajit; Grover, Sandeep; Chong, Mian-Yoon; Kuga, Hironori; Kanba, Shigenobu; He, Yan-Ling; Lee, Min-Soo; Yang, Shu-Yu; Udomratn, Pichet; Kallivayalil, Roy Abraham; Tanra, Andi J; Maramis, Margarita; Shen, Winston Wu-Dien; Sartorius, Norman; Kua, Ee-Heok; Tan, Chay-Hoon; Mahendran, Rathi; Shinfuku, Naotaka; Sum, Min Yi; Baldessarini, Ross J; Sim, Kang

2016-12-01

In this study, we sought to examine factors associated with dosing of antidepressants (ADs) in Asia. Based on reported data and clinical experience, we hypothesized that doses of ADs would be associated with demographic and clinical factors and would increase over time. This cross-sectional, pharmacoepidemiological study analyzed data collected within the Research Study on Asian Psychotropic Prescription Pattern for Antidepressants from 4164 participants in 10 Asian countries, using univariate and multivariate methods. The AD doses varied by twofold among countries (highest in PR China and RO Korea, lowest in Singapore and Indonesia), and averaged 124 (120-129) mg/d imipramine-equivalents. Average daily doses increased by 12% between 2004 and 2013. Doses were significantly higher among hospitalized patients and ranked by diagnosis: major depression > anxiety disorders > bipolar disorder, but were not associated with private/public or psychiatric/general-medical settings, nor with age, sex, or cotreatment with a mood stabilizer. In multivariate modeling, AD-dose remained significantly associated with major depressive disorder and being hospitalized. Doses of ADs have increased somewhat in Asia and were higher when used for major depression or anxiety disorders than for bipolar depression and for hospitalized psychiatric patients.

Transfer of Low Dose Aspirin Into Human Milk.

PubMed

Datta, Palika; Rewers-Felkins, Kathleen; Kallem, Raja Reddy; Baker, Teresa; Hale, Thomas W

2017-05-01

Aspirin has antipyretic and anti-inflammatory properties and is frequently used by pregnant and lactating women. However, its transfer in human milk when administered at low dose has not been reported. Research aim: This study aimed to evaluate the transfer of acetylsalicylic acid and its metabolite, salicylic acid, into human milk following the use of low dose aspirin. In this study, milk samples were collected at 0, 1, 2, 4, 8, 12, and 24 hours from seven breastfeeding women after a steady-state daily dose of 81 mg of aspirin. Milk levels of acetylsalicylic acid and salicylic acid were determined by liquid chromatography-tandem mass spectrometry. Acetylsalicylic acid levels were below the limit of quantification (0.61 ng/ml) in all the milk samples, whereas salicylic acid was detected at very low concentrations. The average concentration of salicylic acid observed was 24 ng/ml and the estimated relative infant dose was 0.4%. Acetylsalicylic acid transfer into milk is so low that it is undetectable even by highly sophisticated methodology. Salicylic acid does appear in the human milk in comparatively low amounts, which are probably subclinical in infants. Thus, the daily use of an 81-mg dose of aspirin should be considered safe during lactation.

Prophylactic and metaphylactic antimicrobial use in Belgian fattening pig herds.

PubMed

Callens, Bénédicte; Persoons, Davy; Maes, Dominiek; Laanen, Maria; Postma, Merel; Boyen, Filip; Haesebrouck, Freddy; Butaye, Patrick; Catry, Boudewijn; Dewulf, Jeroen

2012-09-01

The monitoring of antimicrobial use is an essential step to control the selection and spread of antimicrobial resistance. Between January and October 2010 data on prophylactic and metaphylactic antimicrobial use were collected retrospectively on 50 closed or semi-closed pig herds. Ninety-three percent of the group treatments were prophylactic whereas only 7% were methaphylactic. The most frequently used antimicrobials orally applied at group level were colistin (30.7%), amoxicillin (30.0%), trimethoprim-sulfonamides (13.1%), doxycycline (9.9%) and tylosin (8.1%). The most frequently applied injectable antimicrobials were tulathromycin (45.0%), long acting ceftiofur (40.1%) and long acting amoxicillin (8.4%). The treatment incidences (TI) based on the used daily dose pig (UDD(pig) or the actually administered dose per day per kg pig of a drug) for all oral and injectable antimicrobial drugs was on average 200.7 per 1000 pigs at risk per day (min=0, max=699.0), while the TI based on the animal daily dose pig (ADD(pig) or the national defined average maintenance dose per day per kg pig of a drug used for its main indication) was slightly higher (average=235.8, min=0, max=1322.1). This indicates that in reality fewer pigs were treated with the same amount of antimicrobials than theoretically possible. Injectable products were generally overdosed (79.5%), whereas oral treatments were often underdosed (47.3%). In conclusion, this study shows that prophylactic group treatment was applied in 98% of the visited herds and often includes the use of critically important and broad-spectrum antimicrobials. In Belgium, the guidelines for prudent use of antimicrobials are not yet implemented. Copyright © 2012 Elsevier B.V. All rights reserved.

Beneficial Effect of Higher Dietary Fiber Intake on Plasma HDL-C and TC/HDL-C Ratio among Chinese Rural-to-Urban Migrant Workers

PubMed Central

Zhou, Quan; Wu, Jiang; Tang, Jie; Wang, Jia-Ji; Lu, Chu-Hong; Wang, Pei-Xi

2015-01-01

Research has shown that high-dose supplemental dietary fiber intake has beneficial effects on cardiovascular risk factors. To clarify such a relationship, we examined the association between daily dietary fiber intake and plasma lipids using a cross-sectional design including 1034 (M 502, F 532) rural-to-urban workers in China. We found a dose-response relationship between increased dietary fiber intakes and increase of HDL cholesterol in male workers. There was also a dose-response relationship between increased dietary fiber intake and decreased total cholesterol to HDL cholesterol (TC/HDL-C) ratio in both male and female workers, after adjusting for potential confounders (p for trend, all p < 0.05). When the average dietary fiber intake increased from less than 18 g/day to over 30 g/day, the average HDL cholesterol level increased by 10.1%, and the TC/HDL-C ratio decreased by 14.4% for males (p = 0.020) and by 11.1% for females (p = 0.048). In conclusion, higher daily dietary fiber consumption is associated with beneficial effect on cholesterol for rural-to-urban workers in China, suggesting its potential beneficial effect on decreasing the risk of cardiovascular diseases. PMID:25938914

Beneficial Effect of Higher Dietary Fiber Intake on Plasma HDL-C and TC/HDL-C Ratio among Chinese Rural-to-Urban Migrant Workers.

PubMed

Zhou, Quan; Wu, Jiang; Tang, Jie; Wang, Jia-Ji; Lu, Chu-Hong; Wang, Pei-Xi

2015-04-29

Research has shown that high-dose supplemental dietary fiber intake has beneficial effects on cardiovascular risk factors. To clarify such a relationship, we examined the association between daily dietary fiber intake and plasma lipids using a cross-sectional design including 1034 (M 502, F 532) rural-to-urban workers in China. We found a dose-response relationship between increased dietary fiber intakes and increase of HDL cholesterol in male workers. There was also a dose-response relationship between increased dietary fiber intake and decreased total cholesterol to HDL cholesterol (TC/HDL-C) ratio in both male and female workers, after adjusting for potential confounders (p for trend, all p < 0.05). When the average dietary fiber intake increased from less than 18 g/day to over 30 g/day, the average HDL cholesterol level increased by 10.1%, and the TC/HDL-C ratio decreased by 14.4% for males (p = 0.020) and by 11.1% for females (p = 0.048). In conclusion, higher daily dietary fiber consumption is associated with beneficial effect on cholesterol for rural-to-urban workers in China, suggesting its potential beneficial effect on decreasing the risk of cardiovascular diseases.

Development of a Web-Based Clinical Decision Support System for Drug Prescription: Non-Interventional Naturalistic Description of the Antipsychotic Prescription Patterns in 4345 Outpatients and Future Applications.

PubMed

Berrouiguet, Sofian; Barrigón, Maria Luisa; Brandt, Sara A; Ovejero-García, Santiago; Álvarez-García, Raquel; Carballo, Juan Jose; Lenca, Philippe; Courtet, Philippe; Baca-García, Enrique

2016-01-01

The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web-application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system.

Development of a Web-Based Clinical Decision Support System for Drug Prescription: Non-Interventional Naturalistic Description of the Antipsychotic Prescription Patterns in 4345 Outpatients and Future Applications

PubMed Central

Berrouiguet, Sofian; Barrigón, Maria Luisa; Brandt, Sara A.; Ovejero-García, Santiago; Álvarez-García, Raquel; Carballo, Juan Jose; Lenca, Philippe; Courtet, Philippe; Baca-García, Enrique

2016-01-01

Purpose The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. Method A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web-application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. Results The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. Conclusions In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system. PMID:27764107

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

Huang, P; Gang, Y; Qin, S

Purpose: Many patients with hepatocellular carcinoma (HCC) had hepatic anatomy variations as a result of inter-fraction deformation during fractionated radiotherapy, which may result in difference from the planned dose. This study aimed to investigate the relationship between adjusted dose and radiation induced liver disease (RILD) in HCC patients receiving three dimensional conformal radiotherapy (3DCRT). Methods: Twenty-three HCC patients received conventional fractionated 3DCRT were enrolled in this retrospective investigation. Among them, seven patients had been diagnosed of RILD post-radiotherapy, including 4 cases of grade 2, 3 cases of grade 3 according to the CTCAE Version 3.0. Daily cone-beam CT (CBCT) scansmore » were acquired throughout the whole treatment course for each patient. To reconstruct the daily dose to a patient considering the interfraction anatomy variations, the planned beams from each patient’s treatment plan were firstly applied to each daily modified CBCT (mCBCT). The daily doses were then summed together with the help of deformable image registration (DIR) to obtain the adjusted dose (Dadjusted) of the patient. Finally, the dose changes in normal liver between planned dose (Dplan) and Dadjusted were evaluated by V20, V30, V40 and the mean dose to normal liver (MDTNL). Univariate analysis was performed to identify the significant dose changes. Results: Among the twenty-three patients, the adjusted liver V20, V30, V40 and MDTNL showed significant changes from the planned ones (p<0.05) and averagely increased by 4.1%, 4.7%, 4.5% and 3.9Gy, respectively. And the adjusted liver dose in twenty-one patients (91%) were higher than planned value, the adjusted dose of patients with RILD (6/7) exceeds to the hepatic radiation tolerance. Conclusion: The adjusted dose of all the studied patients significantly differs from planned dose, and mCBCT-based dose reconstruction can aid in evaluating the robustness of the planning solutions, and adjusted dose has the potential to reduce the risk of RILD. The author would like to express great thanks to Lei Xing, Daniel S Kapp and Yong Yang in the Stanford University School of Medicine for their valuable suggestions to this work.This work is supported by NSFC(61471226),China Postdoctoral Science Foundation (2015T80739, 2014M551949) and research funding from Shandong Province(JQ201516).« less

Comparison of therapy augmentation and deviation rates from the recommended once-daily dosing regimen between LDX and commonly prescribed long-acting stimulants for the treatment of ADHD in youth and adults.

PubMed

Setyawan, Juliana; Hodgkins, Paul; Guérin, Annie; Gauthier, Geneviève; Cloutier, Martin; Wu, Eric; Erder, M Haim

2013-10-01

To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated on lisdexamfetamine (LDX) vs other once-daily Food and Drug Administration (FDA) approved stimulants. ADHD patients initiated on a long-acting ADHD stimulant medication (index medication) in/after 2007 were selected from a large U.S. administrative claims database. Patients were required to be persistent for ≥90 days and continuously enrolled in their healthcare plan for ≥12 months following treatment initiation date. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (≥18 years old), and previously treated adults. Furthermore, patients were classified into four mutually exclusive treatment groups, based on index medication: lisdexamfetamine (LDX), osmotic release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate long-acting (MPH LA), and amphetamine/dextroamphetamine long-acting (AMPH LA). The average daily consumption was measured as the quantity of index medication supplied in the 12-month study period divided by the total number of days of supply. Therapy augmentation was defined as the use of another ADHD medication concomitantly with the index medication for ≥28 consecutive days. Therapy augmentation and deviation rates from the recommended once-daily dosing regimen were compared between treatment groups using multivariate logistic regression models. Compared to the other treatment groups, LDX patients were less likely to augment with another ADHD medication (range odds ratios [OR]; 1.28-3.30) and to deviate from the recommended once-daily dosing regimen (range OR; 1.73-4.55), except for previously treated adult patients, where therapy augmentation differences were not statistically significant when compared to OROS MPH and MPH LA patients. This study did not control for ADHD severity. Overall, compared to LDX-treated patients, patients initiated on other ADHD medications were equally or more likely to have a therapy augmentation and more likely to deviate from the recommended once-daily dosing regimen.

Post-mortem quetiapine concentrations in hair segments of psychiatric patients - Correlation between hair concentration, dose and concentration in blood.

PubMed

Günther, Kamilla Nyborg; Johansen, Sys Stybe; Nielsen, Marie Katrine Klose; Wicktor, Petra; Banner, Jytte; Linnet, Kristian

2018-04-01

Drug analysis in hair is useful when seeking to establish drug intake over a period of months to years. Segmental hair analysis can also document whether psychiatric patients are receiving a stable intake of antipsychotics. This study describes segmental analysis of the antipsychotic drug quetiapine in post-mortem hair samples from long-term quetiapine users by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. The aim was to obtain more knowledge on quetiapine concentrations in hair and to relate the concentration in hair to the administered dose and the post-mortem concentration in femoral blood. We analyzed hair samples from 22 deceased quetiapine-treated individuals, who were divided into two groups: natural hair colour and dyed/bleached hair. Two to six 1cm long segments were analyzed per individual, depending on the length of the hair, with 6cm corresponding to the last six months before death. The average daily quetiapine dose and average concentration in hair for the last six months prior to death were examined for potential correlation. Estimated doses ranged from 45 to 1040mg quetiapine daily over the period, and the average concentration in hair ranged from 0.18 to 13ng/mg. A significant positive correlation was observed between estimated daily dosage of quetiapine and average concentration in hair for individuals with natural hair colour (p=0.00005), but statistical significance was not reached for individuals with dyed/bleached hair (p=0.31). The individual coefficient of variation (CV) of the quetiapine concentrations between segments ranged from 3 to 34% for individuals with natural hair colour and 22-62% for individuals with dyed/bleached hair. Dose-adjusted concentrations in hair were significantly lower in females with dyed/bleached hair than in individuals with natural hair colour. The quetiapine concentrations in post-mortem femoral blood and in the proximal hair segment, segment 1 (S1), representing the last month before death were also investigated for correlation. A significant positive correlation was observed between quetiapine concentrations in blood at the time of death and concentrations in S1 for individuals with natural hair colour (p=0.003) but not for individuals with dyed/bleached hair (p=0.31). The blood concentrations of quetiapine ranged from 0.006 to 1.9mg/kg, and the quetiapine concentrations in S1 ranged from 0.22 to 24ng/mg. The results of this study suggest a positive correlation of quetiapine between both concentrations in hair and doses, and between proximal hair (S1) and blood concentrations, when conditions such as hair treatments are taken into consideration. Copyright © 2018 Elsevier B.V. All rights reserved.

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

Small, Katherine; Kelly, Chris; Beldham-Collins, Rachael

A comparative study was conducted comparing the difference between (1) conformal radiotherapy (CRT) to the whole breast with sequential boost excision cavity plans and (2) intensity-modulated radiation therapy (IMRT) to the whole breast with simultaneously integrated boost to the excision cavity. The computed tomography (CT) data sets of 25 breast cancer patients were used and the results analysed to determine if either planning method produced superior plans. CT data sets from 25 past breast cancer patients were planned using (1) CRT prescribed to 50 Gy in 25 fractions (Fx) to the whole-breast planning target volume (PTV) and 10 Gy inmore » 5Fx to the excision cavity and (2) IMRT prescribed to 60 Gy in 25Fx, with 60 Gy delivered to the excision cavity PTV and 50 Gy delivered to the whole-breast PTV, treated simultaneously. In total, 50 plans were created, with each plan evaluated by PTV coverage using conformity indices, plan maximum dose, lung dose, and heart maximum dose for patients with left-side lesions. CRT plans delivered the lowest plan maximum doses in 56% of cases (average CRT = 6314.34 cGy, IMRT = 6371.52 cGy). They also delivered the lowest mean lung dose in 68% of cases (average CRT = 1206.64 cGy, IMRT = 1288.37 cGy) and V20 in 88% of cases (average CRT = 20.03%, IMRT = 21.73%) and V30 doses in 92% of cases (average CRT = 16.82%, IMRT = 17.97%). IMRT created more conformal plans, using both conformity index and conformation number, in every instance, and lower heart maximum doses in 78.6% of cases (average CRT = 5295.26 cGy, IMRT = 5209.87 cGy). IMRT plans produced superior dose conformity and shorter treatment duration, but a slightly higher planning maximum and increased lung doses. IMRT plans are also faster to treat on a daily basis, with shorter fractionation.« less

SU-F-J-191: Dosimetric Evaluation of a Left Chestwall Patient Treated with a Compact Proton Pencil Beam Gantry Utilizing Daily Setup CBCT

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

Maynard, M; Chen, K; Rosen, L

Purpose: To evaluate the robustness of the gradient technique for treating a multi-isocenter left chest wall patient with a compact proton pencil beam gantry. Both CBCT and stereoscopic imaging are used to facilitate daily treatment setup. Methods: To treat the elongated chest wall planning target volume (PTV) with the compact PBS system, a 28 fraction (5040 CcGE) treatment plan was created using two fields with gradient matching technique. Daily table shifts between treatment field isocenters were obtained from the record and verify system for each treatment fraction. Copies of the initial treatment plan were made for each fraction and themore » field isocenter coordinates for each plan copy were adjusted to reflect daily table shifts. Doses were re-calculated for each fraction, summed, and compared against the initial plan. Results: The table shifts (average and range) were 2.2 (−5.1–+3.9), 3.0 (−6.0–+4.0) and 3.0 (−10.1–+1.9) millimeters in the anterior-posterior, superior-inferior and right-left directions, respectively. Dose difference to the PTV, heart and ipsilateral lung were evaluated. The percentage of the PTV receiving the prescription dose decreased from 94.6% to 89.1%. The D95 of the PTV increased from 99.6% to 99.9%. The maximum dose in PTV increased from 106.6% to 109.2% and V105 increased from 1.0% to 16.5%. The V20 of the ipsilateral lung increased from 18.5% to 21.0%. The mean heart dose difference was negligible. Conclusion: Observed dose differences to lung and heart tissues due to daily setup variations remained acceptably low while maintaining sufficient dose coverage to the PTV. This initial case study demonstrates the robustness of the gradient technique to treat a large target, multi-isocenter plan with a compact proton pencil beam gantry equipped with CBCT and stereoscopic imaging modalities.« less

SU-F-R-56: Early Assessment of Treatment Response During Radiation Therapy Delivery for Esophageal Cancer Using Quantitative CT

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

Li, D; Chen, X; Li, X

2016-06-15

Purpose: To investigate the feasibility of assessing treatment response using CTs during delivery of radiation therapy (RT) for esophageal cancer. Methods: Daily CTs acquired using a CT-on-Rails during the routine CT-guided RT for 20 patients with stage II to IV esophageal cancers were analyzed. All patients were treated with combined chemotherapy and IMRT of 45–50 Gy in 25 fractions, and were followed up for two years. Contours of GTV, spinal cord, and non-specified tissue (NST) irradiated with low dose were generated on each daily CT. A series of CT-texture metrics including Hounsfield Unit (HU) histogram, mean HU, standard derivation (STD),more » entropy, and energy were obtained in these contours on each daily CT. The changes of these metrics and GTV volume during RT delivery were calculated and correlated with treatment outcome. Results: Changes in CT texture (e.g., HU histogram) in GTV and spinal cord (but not in NST) were observed during RT delivery and were consistently increased with radiation dose. For the 20 cases studied, the mean HU in GTV was reduced on average by 4.0HU from the first to the last fractions, while 8 patients (responders) had larger reductions in GTV mean HU (average 7.8 HU) with an average GTV reduction of 51% and had increased consistently in GTV STD and entropy with radiation dose. The rest of 12 patients (non-responders) had lower reductions in GTV mean HU (average 1.5HU) and almost no change in STD and entropy. For the 8 responders, 2 experienced complete response, 7 (88%) survived and 1 died. In contrast, for the 12 non-responders, 4 (33%) survived and 8 died. Conclusion: Radiation can induce changes in CT texture in tumor (e.g., mean HU) during the delivery of RT for esophageal cancer. If validated with more data, such changes may be used for early prediction of RT response for esophageal cancer.« less

A Comparison of Glide Force Characteristics Between 2 Prefilled Insulin Lispro Pens

PubMed Central

Lennartz, Amanda H.; Ignaut, Debra A.

2015-01-01

Background: Glide force, average glide force, and glide force variability of the insulin lispro 200 units/mL pen (Eli Lilly and Company, Indianapolis, IN, USA) were compared to the Humalog® KwikPen® 100 units/mL pen (hereafter, KwikPen; Eli Lilly and Company, Indianapolis, IN, USA). Methods: Data were collected on 2 doses, 2 injection speeds, and 2 needle types. Results: Insulin lispro 200 units/mL pen showed significantly lower maximum glide force, average glide force, and glide force variability than the KwikPen across all combinations of dose size, dose speed, and needle type. Conclusions: The lower glide force observed with the insulin lispro 200 units/mL pen offers another treatment option for patients with type 1 or type 2 diabetes who require greater than 20 units of mealtime insulin daily. PMID:25591858

An analysis of collegiate band directors' exposure to sound pressure levels

NASA Astrophysics Data System (ADS)

Roebuck, Nikole Moore

Noise-induced hearing loss (NIHL) is a significant but unfortunate common occupational hazard. The purpose of the current study was to measure the magnitude of sound pressure levels generated within a collegiate band room and determine if those sound pressure levels are of a magnitude that exceeds the policy standards and recommendations of the Occupational Safety and Health Administration (OSHA), and the National Institute of Occupational Safety and Health (NIOSH). In addition, reverberation times were measured and analyzed in order to determine the appropriateness of acoustical conditions for the band rehearsal environment. Sound pressure measurements were taken from the rehearsal of seven collegiate marching bands. Single sample t test were conducted to compare the sound pressure levels of all bands to the noise exposure standards of OSHA and NIOSH. Multiple regression analysis were conducted and analyzed in order to determine the effect of the band room's conditions on the sound pressure levels and reverberation times. Time weighted averages (TWA), noise percentage doses, and peak levels were also collected. The mean Leq for all band directors was 90.5 dBA. The total accumulated noise percentage dose for all band directors was 77.6% of the maximum allowable daily noise dose under the OSHA standard. The total calculated TWA for all band directors was 88.2% of the maximum allowable daily noise dose under the OSHA standard. The total accumulated noise percentage dose for all band directors was 152.1% of the maximum allowable daily noise dose under the NIOSH standards, and the total calculated TWA for all band directors was 93dBA of the maximum allowable daily noise dose under the NIOSH standard. Multiple regression analysis revealed that the room volume, the level of acoustical treatment and the mean room reverberation time predicted 80% of the variance in sound pressure levels in this study.

Daily versus single-day offering of influenza vaccine in community pharmacies.

PubMed

Grabenstein, John D

2009-01-01

To assess the cumulative number of influenza vaccinations delivered per pharmacy in relation to number of days of offering vaccination per season. Automated records of pharmacies involved in a cohort study were queried for number of influenza vaccinations delivered in each of three influenza vaccination seasons between 1996 and 1998. Eleven pharmacies in Washington State were compared with 13 pharmacies in Oregon, contrasting years when nurses offered influenza vaccine 1 day per season with years when pharmacists offered influenza vaccine daily for several months. Pharmacies in which pharmacists offered influenza vaccination daily averaged 528 to 807 doses per pharmacy per season compared with 91 to 233 doses per pharmacy in seasons when nurses offered vaccination on a single day. Professionals dedicated to providing adult vaccination on any given day outperformed professionals who attended to both vaccination and other clinical duties, but the cumulative effect of offering vaccinations on multiple days can achieve a greater number of vaccinations over a several-month interval.

[Use of epsilon aminocaproic acid in abnormal hemorrhage using intrauterine contraceptive devices].

PubMed

Rueda González, R

1969-01-01

Epsilon-aminocaproic acid was tested in 50 women suffering from excessive bleeding as a result of the use of IUDs. The drug was administered daily in 500 mg tablets, in doses of 1-2 g, during the first 5 days of menstruation. All cases were kept under observation for 10 months. Results were good in 38 cases (76 percent) (bleeding returned to normal levels), average in 7 cases (14 percent) (considerably reduced bleeding but still above normal), and without effe ct in 5 cases (10 percent), using a dose of 1 g daily. In these 5 cases, the dose was doubled during the next cycle: results were acceptable in 3 cases (60 percent), while in the other 2 bleeding persisted and the IUD had to be removed. 28 cases (56 percent) required treatment for only 1 cycle, the remaining 9 cycles observed being normal. Treatment during all 10 cycles was necessary in only 5 cases (10 percent). It is concluded that the drug is highly effective, and the small doses used rule out the risk of toxicity or thromboembolic com plications.

Similarity of Bisphenol A Pharmacokinetics in Rhesus Monkeys and Mice: Relevance for Human Exposure

PubMed Central

Taylor, Julia A.; vom Saal, Frederick S.; Welshons, Wade V.; Drury, Bertram; Rottinghaus, George; Hunt, Patricia A.; Toutain, Pierre-Louis; Laffont, Céline M.; VandeVoort, Catherine A.

2011-01-01

Objective Daily adult human exposure to bisphenol A (BPA) has been estimated at < 1 μg/kg, with virtually complete first-pass conjugation in the liver in primates but not in mice. We measured unconjugated and conjugated BPA levels in serum from adult female rhesus monkeys and adult female mice after oral administration of BPA and compared findings in mice and monkeys with prior published data in women. Methods Eleven adult female rhesus macaques were fed 400 μg/kg deuterated BPA (dBPA) daily for 7 days. Levels of serum dBPA were analyzed by isotope-dilution liquid chromatography–mass spectrometry (0.2 ng/mL limit of quantitation) over 24 hr on day 1 and on day 7. The same dose of BPA was fed to adult female CD-1 mice; other female mice were administered 3H-BPA at doses ranging from 2 to 100,000 μg/kg. Results In monkeys, the maximum unconjugated serum dBPA concentration of 4 ng/mL was reached 1 hr after feeding and declined to low levels by 24 hr, with no significant bioaccumulation after seven daily doses. Mice and monkeys cleared unconjugated serum BPA at virtually identical rates. We observed a linear (proportional) relationship between administered dose and serum BPA in mice. Conclusions BPA pharmacokinetics in women, female monkeys, and mice is very similar. By comparison with approximately 2 ng/mL unconjugated serum BPA reported in multiple human studies, the average 24-hr unconjugated serum BPA concentration of 0.5 ng/mL in both monkeys and mice after a 400 μg/kg oral dose suggests that total daily human exposure is via multiple routes and is much higher than previously assumed. PMID:20855240

A travel mode comparison of commuters' exposures to air pollutants in Barcelona

NASA Astrophysics Data System (ADS)

de Nazelle, Audrey; Fruin, Scott; Westerdahl, Dane; Martinez, David; Ripoll, Anna; Kubesch, Nadine; Nieuwenhuijsen, Mark

2012-11-01

Daily commutes may contribute disproportionately to overall daily inhalations of urban air contaminants. Understanding factors that explain variability of exposures during travel, and especially differences across transportation modes, is essential to accurately assess health impacts of traffic emissions and to develop effective mitigating measures. We evaluated exposures and inhaled doses of air pollution and assessed factors that contributed to their variability in different travel modes in Barcelona. Black carbon (BC), ultrafine particles (UFP), carbon monoxide (CO), fine particle mass (PM2.5) and carbon dioxide (CO2) were measured and compared across walk, bike, bus, and car modes for a total of 172 trips made on two different round trip routes. On average, the car mode experienced highest concentrations for all contaminants. In pairwise t-tests between concurrent mode runs, statistically significant differences were found for cars compared to walking and biking. Car-to-walk or car-to-bike concentration ratios ranged from 1.3 for CO2 to 25 for CO and were 2-3 for PM2.5, BC, and UFP. In multivariate analyses, travel mode explained the greatest variability in travel exposures, from 8% for PM2.5 to 70% for CO. Different modal patterns emerged when estimating daily inhaled dose, with active commuters' two to three times greater total inhalation volume during travel producing about equal UFP and BC daily inhaled doses to car commuters and 33-50% higher UFP and BC doses compared to bus commuters. These findings, however, are specific to the bike and pedestrian lanes in this study being immediately adjacent to the roadways measured. Dedicated bike or pedestrian routes away from traffic would lead to lower active travel doses.

Characterization of opioid use in sickle cell disease.

PubMed

Han, Jin; Zhou, Jifang; Saraf, Santosh L; Gordeuk, Victor R; Calip, Gregory S

2018-05-01

Opioid analgesics are commonly used to treat vaso-occlusive pain episodes in sickle cell disease (SCD), but comprehensive evidence characterizing opioid use in this patient population is limited. Our objective was to characterize opioid use patterns among SCD patients using a large nationwide database. A large, US medical claims database was utilized to identify a cohort of 3882 SCD patients, and characteristics of opioid use were analyzed. Clinical variables including age, gender, medication use, health care utilization, and medical history were evaluated for correlations with opioid use. Forty percent of patients took opioid medications during a 12-month span, and the prevalence of any opioid use was highest for 20 to 29-year-old patients (58%). The median daily opioid dose was 1.85 mg (interquartile range: 0.62-10.68 mg) oral morphine equivalents (OME). While most opioid users took between 0 and 5 mg OME daily, 3% of pediatric patients and 23% of adult patients used more than 30-mg OME daily. High-dose opioid use was associated with older age, hydroxyurea therapy, nonsteroidal anti-inflammatory drug (NSAID) use, and frequent inpatient hospitalizations. In multivariable-adjusted analyses, patients with vaso-occlusive complications such as pain crisis (OR = 3.8, 95% CI 2.7-5.3) and avascular necrosis (AVN) (OR = 3.7, 95% CI 2.7-5.1) were associated with high-dose opioid use. Our study showed that only 40% SCD patients were on opioid analgesics during a 12-month span. However, a non-trivial number of patients used a much higher dose of opioids despite a relatively low average daily opioid dose among SCD patients, particularly with vaso-occlusive complications. Copyright © 2017 John Wiley & Sons, Ltd.

Effect of ketoconazole on cyclosporine dose in healthy dogs.

PubMed

Dahlinger, J; Gregory, C; Bea, J

1998-01-01

To determine the degree to which the dose of oral cyclosporine (CyA), in healthy dogs, can be decreased by concurrent oral administration of ketoconazole. Dogs in this study were observed for physical or biochemical side effects that might have been caused by the administration of CyA and ketoconazole. Prospective research study. Five healthy, intact female Beagle dogs. CyA was administered orally twice daily to achieve stable whole blood trough levels of 400 to 600 ng/mL. Ketoconazole was added at a low therapeutic dose (average dose: 13.6 mg/kg/d) then at a subtherapeutic dose (average dose: 4.7 mg/kg/d). CyA whole blood trough levels were monitored every 3 to 4 days and maintained at 400 to 600 ng/mL by adjusting CyA doses accordingly. Physical examination, CBC, biochemical profile, and urinalysis were performed at 2-week intervals throughout the study period. The initial mean dose of CyA required to achieve target blood levels was 14.5 mg/ kg/d. With concurrent ketoconazole (low therapeutic dose, average dose: 13.6 mg/kg/d) and CyA administration, the CyA dose declined to 3.4 mg/kg/day (range: 1.2 to 5.2 mg/kg/d), representing a 75% reduction in CyA dose and monetary savings of 57.8%. At a subtherapeutic dose of ketoconazole (average dose: 4.7 mg/kg/d), combination therapy resulted in a CyA dose of 10.1 mg/kg/day (4.9 to 10.6 mg/kg/d), representing a 38% reduction in CyA dose and monetary savings of 23.8%. Weight loss and transient hypoalbuminemia of unknown clinical significance were observed. Other physical and biochemical evaluations were unremarkable over the 12-week study period. The oral administration of ketoconazole can be used to reduce substantially the oral CyA dose needed to maintain selected blood levels in healthy dogs. The oral administration of ketoconazole can result in substantial cost savings to owners of dogs receiving CyA after renal allograft transplantation or for the treatment of autoimmune disease.

Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids.

PubMed

Bateman, Eric D; Guerreros, Alfredo G; Brockhaus, Florian; Holzhauer, Björn; Pethe, Abhijit; Kay, Richard A; Townley, Robert G

2017-08-01

Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP 2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS).Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d ) or twice-daily (2, 25, 75 or 150 mg b.i.d ) fevipiprant (n=782), montelukast 10 mg q.d (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.d Fevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d and 75 mg b.i.d groups, with no clinically meaningful differences between q.d and b.i.d Montelukast also demonstrated a significant improvement in this end-point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments.Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted. Copyright ©ERS 2017.

Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids

PubMed Central

Guerreros, Alfredo G.; Brockhaus, Florian; Pethe, Abhijit; Kay, Richard A.; Townley, Robert G.

2017-01-01

Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS). Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d.) or twice-daily (2, 25, 75 or 150 mg b.i.d.) fevipiprant (n=782), montelukast 10 mg q.d. (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.d. Fevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d. and 75 mg b.i.d. groups, with no clinically meaningful differences between q.d. and b.i.d. Montelukast also demonstrated a significant improvement in this end-point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments. Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted. PMID:28838980

No evidence found for an association between prednisone dose and FVC change in newly-treated pulmonary sarcoidosis.

PubMed

Broos, Caroline E; Poell, Linda H C; Looman, Caspar W N; In 't Veen, Johannes C C M; Grootenboers, Marco J J H; Heller, Roxane; van den Toorn, Leon M; Wapenaar, Monique; Hoogsteden, Henk C; Kool, Mirjam; Wijsenbeek, Marlies S; van den Blink, Bernt

2018-05-01

Prednisone is used as first-line therapy for pulmonary sarcoidosis. What dosing strategy has the best balance between effect and side-effects is largely unknown. We analyzed change in forced vital capacity (FVC) and weight during different prednisone doses used in daily practice for treatment naïve pulmonary sarcoidosis patients. Multilevel models were used to describe FVC and weight change over time. Correlations were calculated using linear regression models. Fifty-four patients were included. FVC changed over time (p < 0.001), with an average increase of 9.6% predicted (95% CI: 7.2 to 12.1) at 12 months. Weight changed significantly over time (p < 0.001), with an average increase of 4.3 kg (95% CI: 3.0 to 5.6) at 12 months. Although FVC and weight changed significantly over time, there was little correlation between prednisone dose and FVC change, while weight increase correlated significantly with cumulative prednisone dose at 24 months. In patients treated with a high cumulative prednisone dose, baseline FVC was on average lower (p = 0.001) compared to low dose treated patients, while no significant differences were observed in need for second/third-line therapy or number of exacerbations. A strategy leading to a low cumulative dose at 12 months was defined by rapid dose tapering to 10 mg/day within 3.5 months. These results suggest that prednisone therapy aimed at improving or preserving FVC in newly- treated pulmonary sarcoidosis can often be reduced in dose, using a treatment regimen that is characterized by early dose tapering. Copyright © 2017 Elsevier Ltd. All rights reserved.

Patient dose estimation from CT scans at the Mexican National Neurology and Neurosurgery Institute

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

Alva-Sánchez, Héctor, E-mail: halva@ciencias.unam.mx; Reynoso-Mejía, Alberto; Casares-Cruz, Katiuzka

In the radiology department of the Mexican National Institute of Neurology and Neurosurgery, a dedicated institute in Mexico City, on average 19.3 computed tomography (CT) examinations are performed daily on hospitalized patients for neurological disease diagnosis, control scans and follow-up imaging. The purpose of this work was to estimate the effective dose received by hospitalized patients who underwent a diagnostic CT scan using typical effective dose values for all CT types and to obtain the estimated effective dose distributions received by surgical and non-surgical patients. Effective patient doses were estimated from values per study type reported in the applications guidemore » provided by the scanner manufacturer. This retrospective study included all hospitalized patients who underwent a diagnostic CT scan between 1 January 2011 and 31 December 2012. A total of 8777 CT scans were performed in this two-year period. Simple brain scan was the CT type performed the most (74.3%) followed by contrasted brain scan (6.1%) and head angiotomography (5.7%). The average number of CT scans per patient was 2.83; the average effective dose per patient was 7.9 mSv; the mean estimated radiation dose was significantly higher for surgical (9.1 mSv) than non-surgical patients (6.0 mSv). Three percent of the patients had 10 or more brain CT scans and exceeded the organ radiation dose threshold set by the International Commission on Radiological Protection for deterministic effects of the eye-lens. Although radiation patient doses from CT scans were in general relatively low, 187 patients received a high effective dose (>20 mSv) and 3% might develop cataract from cumulative doses to the eye lens.« less

Patient dose estimation from CT scans at the Mexican National Neurology and Neurosurgery Institute

NASA Astrophysics Data System (ADS)

Alva-Sánchez, Héctor; Reynoso-Mejía, Alberto; Casares-Cruz, Katiuzka; Taboada-Barajas, Jesús

2014-11-01

In the radiology department of the Mexican National Institute of Neurology and Neurosurgery, a dedicated institute in Mexico City, on average 19.3 computed tomography (CT) examinations are performed daily on hospitalized patients for neurological disease diagnosis, control scans and follow-up imaging. The purpose of this work was to estimate the effective dose received by hospitalized patients who underwent a diagnostic CT scan using typical effective dose values for all CT types and to obtain the estimated effective dose distributions received by surgical and non-surgical patients. Effective patient doses were estimated from values per study type reported in the applications guide provided by the scanner manufacturer. This retrospective study included all hospitalized patients who underwent a diagnostic CT scan between 1 January 2011 and 31 December 2012. A total of 8777 CT scans were performed in this two-year period. Simple brain scan was the CT type performed the most (74.3%) followed by contrasted brain scan (6.1%) and head angiotomography (5.7%). The average number of CT scans per patient was 2.83; the average effective dose per patient was 7.9 mSv; the mean estimated radiation dose was significantly higher for surgical (9.1 mSv) than non-surgical patients (6.0 mSv). Three percent of the patients had 10 or more brain CT scans and exceeded the organ radiation dose threshold set by the International Commission on Radiological Protection for deterministic effects of the eye-lens. Although radiation patient doses from CT scans were in general relatively low, 187 patients received a high effective dose (>20 mSv) and 3% might develop cataract from cumulative doses to the eye lens.

[Dose-effect relationship of orally administered Pyritinol in the chronic organic brain syndrome (author's transl)].

PubMed

Glatzel, J

1978-08-04

161 patients with the chronic organic brain syndrome (average age 64 years) were treated with various oral doses of Pyritinol for various periods of time. Statistical analysis of the data by means of "Konfigurationsfrequenzanalyse" showed that the success rate of treatment increases significantly with increasing dose and duration of the treatment. This means that the recommended daily dose should be exceeded if - for example at the start of treatment and in severe cases or in hospitalized patients - there is no immediate clear improvement in the condition. From the point of view of method this study shows that a retrospective analysis of a group of patients treated in a clinic can also provide interesting results and appropriately supplement controlled studies.

A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis

PubMed Central

2011-01-01

Background Long-term immunosuppression is often required in myasthenia gravis (MG). There are no published trials using methotrexate (MTX) in MG. The steroid-sparing efficacy of azathioprine (AZA) has been demonstrated after 18-months of starting therapy. However, AZA is considered expensive in Africa. We evaluated the steroid-sparing efficacy of MTX (17.5 mg weekly) compared with AZA (2.5 mg/kg daily) in subjects recently diagnosed with generalized MG by assessing their average monthly prednisone requirements. Methods The primary outcome was the average daily prednisone requirement by month between the two groups. Prednisone was given at the lowest dose to manage MG symptoms and adjusted as required according to protocol. Single-blinded assessments were performed 3-monthly for 2-years to determine the quantitative MG score and the MG activities of daily living score in order to determine those with minimal manifestations of MG. Results Thirty-one subjects (AZA n = 15; MTX n = 16) satisfied the inclusion criteria but only 24 were randomized. Baseline characteristics were similar. There was no difference between the AZA- and MTX-groups in respect of prednisone dosing (apart from months 10 and 12), in quantitative MG Score improvement, proportions in sustained remission, frequencies of MG relapses, or adverse reactions and/or withdrawals. The MTX-group received lower prednisone doses between month 10 (p = 0.047) and month 12 (p = 0.039). At month 12 the prednisone dose per kilogram bodyweight in the MTX-group (0.15 mg/kg) was half that of the AZA-group (0.31 mg/kg)(p = 0.019). Conclusions This study provides evidence that in patients with generalized MG methotrexate is an effective steroid-sparing agent 10 months after treatment initiation. Our data suggests that in generalized MG methotrexate has similar efficacy and tolerability to azathioprine and may be the drug of choice in financially constrained health systems. Trial registration SANCTR:DOH-27-0411-2436 PMID:21819556

The effects of peritoneal dialysis on the single dose and steady state pharmacokinetics of valproic acid in a uremic epileptic child.

PubMed

Orr, J M; Farrell, K; Abbott, F S; Ferguson, S; Godolphin, W J

1983-01-01

The pharmacokinetics of valproic acid (VPA) have been studied during peritoneal dialysis in a uremic male epileptic child following a single 500 mg dose and after multiple doses over 5 months (700 mg daily) of valproic acid as the syrup. Serum level decline was biphasic in both instances with a terminal half-life of 27.2 after the single dose and 10.2 h at steady-state. Total serum clearance was 0.0236 l/h/kg after the single dose and increased to 0.0408 l/h/kg after 5 months. Free (intrinsic) serum clearances were 0.1489 and 0.1518 l/h/kg and serum free fractions were 0.224 and 0.272 respectively for the single dose and steady-state studies. Peritoneal dialysis for periods of 12 or 24 h removed an average of 4.5% of the VPA dose.

Efficacy of Pregabalin in Childhood Refractory Partial Seizure

PubMed Central

Zamani, Gholamreza; Tavasoli, Alireza; Zare-Shahabadi, Ameneh; Rezaei, Nima; Ahmadvand, Alireza

2014-01-01

Objective: About one third of partial seizures are refractory to treatment. Several anticonvulsant drugs have entered the market in recent decades but concerns about intolerance, drug interactions, and the safety of the drug are notable. One of these new anticonvulsants is pregabalin, a safe drug with almost no interaction with other antiepileptic drugs. Methods: In this open label clinical trial study, pregabalin was used for evaluation of its efficacy on reducing seizure frequency in 29 children suffering from refractory partial seizures. Average daily and weekly seizure frequency of the patients was recorded during a 6-week period (baseline period). Then, during a period of 2 weeks (titration period), pregabalin was started with a dose of 25-75 mg/d, using method of flexible dose, and was brought to maximum dose of drug that was intended in this study (450 mg/d) based on clinical response of the patients and seizure frequency. Then the patients were given the drug for 12 weeks and the average frequency of daily and weekly seizures were recorded again (treatment period). Findings : Reduction in seizure frequency in this study was 36% and the responder rate or number of patients who gained more than 50% reduction in seizure frequency was 51.7%. Conclusion: This study showed that pregabalin can be used with safety and an acceptable efficacy in treatment of childhood refractory partial seizures. PMID:25793053

Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine

PubMed Central

Lal, Ritu; Sukbuntherng, Juthamas; Luo, Wendy; Vicente, Virna; Blumenthal, Robin; Ho, Judy; Cundy, Kenneth C

2010-01-01

AIM Gabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose-proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug–drug interactions at these two transporters, the pharmacokinetics of gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT-1 substrate) or cimetidine (an OCT2 substrate). METHODS Subjects (n= 12 in each study) received doses of study drug until steady state was achieved; 1200 mg gabapentin enacarbil each day, followed by either naproxen (500 mg twice daily) or cimetidine (400 mg four times daily) followed by the combination. RESULTS When gabapentin enacarbil was co-administered with naproxen, gabapentin Css,max increased by, on average, 8% and AUC by, on average, 13%. When gabapentin enacarbil was co-administered with cimetidine, gabapentin AUCss increased by 24% and renal clearance of gabapentin decreased. Co-administration with gabapentin enacarbil did not affect naproxen or cimetidine exposure. Gabapentin enacarbil was generally well tolerated. CONCLUSIONS No gabapentin enacarbil dose adjustment is needed with co-administration of naproxen or cimetidine. PMID:20573085

Daily Physical Activity and Cognitive Function Variability in Older Adults.

PubMed

Phillips, Christine B; Edwards, Jerri D; Andel, Ross; Kilpatrick, Marcus

2016-04-01

Physical activity (PA) is believed to preserve cognitive function in older adulthood, though little is known about these relationships within the context of daily life. The present microlongitudinal pilot study explored within- and between-person relationships between daily PA and cognitive function and also examined within-person effect sizes in a sample of community-dwelling older adults. Fifty-one healthy participants (mean age = 70.1 years) wore an accelerometer and completed a cognitive assessment battery for five days. There were no significant associations between cognitive task performance and participants' daily or average PA over the study period. Effect size estimates indicated that PA explained 0-24% of within-person variability in cognitive function, depending on cognitive task and PA dose. Results indicate that PA may have near-term cognitive effects and should be explored as a possible strategy to enhance older adults' ability to perform cognitively complex activities within the context of daily living.

Rifaximin diminishes neutropenia following potentially lethal whole-body radiation.

PubMed

Jahraus, Christopher D; Schemera, Bettina; Rynders, Patricia; Ramos, Melissa; Powell, Charles; Faircloth, John; Brawner, William R

2010-07-01

Terrorist attacks involving radiological or nuclear weapons are a substantial geopolitical concern, given that large populations could be exposed to potentially lethal doses of radiation. Because of this, evaluating potential countermeasures against radiation-induced mortality is critical. Gut microflora are the most common source of systemic infection following exposure to lethal doses of whole-body radiation, suggesting that prophylactic antibiotic therapy may reduce mortality after radiation exposure. The chemical stability, easy administration and favorable tolerability profile of the non-systemic antibiotic, rifaximin, make it an ideal potential candidate for use as a countermeasure. This study evaluated the use of rifaximin as a countermeasure against low-to-intermediate-dose whole-body radiation in rodents. Female Wistar rats (8 weeks old) were irradiated with 550 cGy to the whole body and were evaluated for 30 d. Animals received methylcellulose, neomycin (179 mg/kg/d) or variably dosed rifaximin (150-2000 mg/kg/d) one hour after irradiation and daily throughout the study period. Clinical assessments (e.g. body weight) were made daily. On postirradiation day 30, blood samples were collected and a complete blood cell count was performed. Animals receiving high doses of rifaximin (i.e. 1000 or 2000 mg/kg/d) had a greater increase in weight from the day of irradiation to postirradiation day 30 compared with animals that received placebo or neomycin. For animals with an increase in average body weight from irradiation day within 80-110% of the group average, methylcellulose rendered an absolute neutrophil count (ANC) of 211, neomycin rendered an ANC of 334, rifaximin 300 mg/kg/d rendered an ANC of 582 and rifaximin 1000 mg/kg/d rendered an ANC of 854 (P = 0.05 for group comparison). Exposure to rifaximin after near-lethal whole-body radiation resulted in diminished levels of neutropenia.

Image guidance during head-and-neck cancer radiation therapy: analysis of alignment trends with in-room cone-beam computed tomography scans.

PubMed

Zumsteg, Zachary; DeMarco, John; Lee, Steve P; Steinberg, Michael L; Lin, Chun Shu; McBride, William; Lin, Kevin; Wang, Pin-Chieh; Kupelian, Patrick; Lee, Percy

2012-06-01

On-board cone-beam computed tomography (CBCT) is currently available for alignment of patients with head-and-neck cancer before radiotherapy. However, daily CBCT is time intensive and increases the overall radiation dose. We assessed the feasibility of using the average couch shifts from the first several CBCTs to estimate and correct for the presumed systematic setup error. 56 patients with head-and-neck cancer who received daily CBCT before intensity-modulated radiation therapy had recorded shift values in the medial-lateral, superior-inferior, and anterior-posterior dimensions. The average displacements in each direction were calculated for each patient based on the first five or 10 CBCT shifts and were presumed to represent the systematic setup error. The residual error after this correction was determined by subtracting the calculated shifts from the shifts obtained using daily CBCT. The magnitude of the average daily residual three-dimensional (3D) error was 4.8 ± 1.4 mm, 3.9 ± 1.3 mm, and 3.7 ± 1.1 mm for uncorrected, five CBCT corrected, and 10 CBCT corrected protocols, respectively. With no image guidance, 40.8% of fractions would have been >5 mm off target. Using the first five CBCT shifts to correct subsequent fractions, this percentage decreased to 19.0% of all fractions delivered and decreased the percentage of patients with average daily 3D errors >5 mm from 35.7% to 14.3% vs. no image guidance. Using an average of the first 10 CBCT shifts did not significantly improve this outcome. Using the first five CBCT shift measurements as an estimation of the systematic setup error improves daily setup accuracy for a subset of patients with head-and-neck cancer receiving intensity-modulated radiation therapy and primarily benefited those with large 3D correction vectors (>5 mm). Daily CBCT is still necessary until methods are developed that more accurately determine which patients may benefit from alternative imaging strategies. Copyright © 2012 Elsevier Inc. All rights reserved.

Investigating ion recombination effects in a liquid-filled ionization chamber array used for IMRT QA measurements

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

Knill, Cory, E-mail: knillcor@gmail.com; Snyder, Michael; Rakowski, Joseph T.

Purpose: PTW’s Octavius 1000 SRS array performs IMRT quality assurance (QA) measurements with liquid-filled ionization chambers (LICs) to allow closer detector spacing and higher resolution, compared to air-filled QA devices. However, reduced ion mobility in LICs relative to air leads to increased ion recombination effects and reduced collection efficiencies that are dependent on Linac pulse frequency and pulse dose. These pulse parameters are variable during an IMRT delivery, which affects QA results. In this study, (1) 1000 SRS collection efficiencies were measured as a function of pulse frequency and pulse dose, (2) two methods were developed to correct changes inmore » collection efficiencies during IMRT QA measurements, and the effects of these corrections on QA pass rates were compared. Methods: To obtain collection efficiencies, the OCTAVIUS 1000 SRS was used to measure open fields of varying pulse frequency, pulse dose, and beam energy with results normalized to air-filled chamber measurements. Changes in ratios of 1000 SRS to chamber measured dose were attributed to changing collection efficiencies, which were then correlated to pulse parameters using regression analysis. The usefulness of the derived corrections was then evaluated using 6 MV and 10FFF SBRT RapidArc plans delivered to the OCTAVIUS 4D system using a TrueBeam (Varian Medical Systems) linear accelerator equipped with a high definition multileaf collimator. For the first correction, MATLAB software was developed that calculates pulse frequency and pulse dose for each detector, using measurement and DICOM RT Plan files. Pulse information is converted to collection efficiency, and measurements are corrected by multiplying detector dose by ratios of calibration to measured collection efficiencies. For the second correction the MU/min in the daily 1000 SRS calibration was chosen to match the average MU/min of the volumetric modulated arc therapy plan. Effects of the two corrections on QA results were examined by performing 3D gamma analysis comparing predicted to measured dose, with and without corrections. Results: Collection efficiencies correlated linearly to pulse dose, while correlations with pulse frequency were less defined, generally increasing as pulse frequency decreased. After complex MATLAB corrections, average 3D gamma pass rates improved by [0.07%,0.40%,1.17%] for 6 MV and [0.29%,1.40%,4.57%] for 10FFF using [3%/3 mm,2%/2 mm,1%/1 mm] criteria. Maximum changes in gamma pass rates were [0.43%,1.63%,3.05%] for 6 MV and [1.00%,4.80%,11.2%] for 10FFF using [3%/3 mm,2%/2 mm,1%/1 mm] criteria. On average, pass rates of simple daily calibration corrections were within 1% of complex MATLAB corrections. Conclusions: OCTAVIUS 1000 SRS ion recombination effects have little effect on 6 MV measurements. However, the effect could potentially be clinically significant for higher pulse dose unflattened beams when using tighter gamma tolerances, especially when small aperture sizes are used, as is common for SRS/SBRT. In addition, ion recombination effects are strongly correlated to changing MU/min, therefore MU/min used in daily 1000 SRS calibrations should be matched to the expected average MU/min of the IMRT plan.« less

[Effectiveness of use in preventive nutrition the food ptoducts with contents of pectin and vitamins].

PubMed

Spiricheva, T V; Spirichev, V B; Kodentsova, V M; Beketova, N A; Pereverzeva, O G; Kosheleva, O V; Vrzhesinskaia, L A; Kharitonchik, L A; Shatniuk, L N; Mikheeva, G A; Iudin, A V; Ivanova, G S

2011-01-01

Daily inclusion in the diet of Pskov GRES workers the drinks or kissels containing 2 g pectin per daily serving (cup) during 6 months was accompanied by a statistically significant decline of their supply with vitamins C, B2, A and beta-carotene. This is reflected both in reducing the average vitamin concentration in blood serum and in the increase of the quota of people with deficiency of several vitamins. Additional inclusion of 13 vitamins in these drinks and kissels, in a dose about 80% of the RDA, has prevented the deterioration of vitamin status.

Dosimetric Evaluation Between Megavoltage Cone-Beam Computed Tomography and Body Mass Index for Intracranial, Thoracic, and Pelvic Localization

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

VanAntwerp, April E.; Raymond, Sarah M., E-mail: raymons9@ccf.org; Addington, Mark C.

2011-10-01

The aim of this study was to evaluate radiation dose for organs at risk (OAR) within the cranium, thorax, and pelvis from megavoltage cone-beam computed tomography (MV-CBCT). Using a clinical treatment planning system, CBCT doses were calculated from 60 patient datasets using 27.4 x 27.4 cm{sup 2} field size and 200{sup o} arc length. The body mass indices (BMIs) for these patients range from 17.2-48.4 kg/m{sup 2}. A total of 60 CBCT plans were created and calculated with heterogeneity corrections, with monitor units (MU) that varied from 8, 4, and 2 MU per plan. The isocenters of these plans weremore » placed at defined anatomical structures. The maximum dose, dose to the isocenter, and mean dose to the selected critical organs were analyzed. The study found that maximum and isocenter doses were weakly associated with BMI, but linearly associated with the total MU. Average maximum/isocenter doses in the cranium were 10.0 ({+-} 0.18)/7.0 ({+-} 0.08) cGy, 5.0 ({+-} 0.09)/3.5 ({+-} 0.05) cGy, and 2.5 ({+-} .04)/1.8 ({+-} 0.05) cGy for 8, 4, and 2 MU, respectively. Similar trends but slightly larger maximum/isocenter doses were found in the thoracic and pelvic regions. For the cranial region, the average mean doses with a total of 8 MU to the eye, lens, and brain were 9.7 ({+-} 0.12) cGy, 9.1 ({+-} 0.16) cGy, and 7.2 ({+-} 0.10) cGy, respectively. For the thoracic region, the average mean doses to the lung, heart, and spinal cord were 6.6 ({+-} 0.05) cGy, 6.9 ({+-} 1.2) cGy, and 4.7 ({+-} 0.8) cGy, respectively. For the pelvic region, the average mean dose to the femoral heads was 6.4 ({+-} 1.1) cGy. The MV-CBCT doses were linearly associated with the total MU but weakly dependent on patients' BMIs. Daily MV-CBCT has a cumulative effect on the total body dose and critical organs, which should be carefully considered for clinical impacts.« less

Impact of Bromocriptine-QR Therapy on Glycemic Control and Daily Insulin Requirement in Type 2 Diabetes Mellitus Subjects Whose Dysglycemia Is Poorly Controlled on High-Dose Insulin: A Pilot Study.

PubMed

Roe, Erin D; Chamarthi, Bindu; Raskin, Philip

2015-01-01

The concurrent use of a postprandial insulin sensitizing agent, such as bromocriptine-QR, a quick release formulation of bromocriptine, a dopamine D2 receptor agonist, may offer a strategy to improve glycemic control and limit/reduce insulin requirement in type 2 diabetes (T2DM) patients on high-dose insulin. This open label pilot study evaluated this potential utility of bromocriptine-QR. Ten T2DM subjects on metformin (1-2 gm/day) and high-dose (TDID ≥ 65 U/day) basal-bolus insulin were enrolled to receive once daily (morning) bromocriptine-QR (1.6-4.8 mg/day) for 24 weeks. Subjects with at least one postbaseline HbA1c measurement (N = 8) were analyzed for change from baseline HbA(1c), TDID, and postprandial glucose area under the curve of a four-hour mixed meal tolerance test (MMTT). Compared to the baseline, average HbA1c decreased 1.76% (9.74 ± 0.56 to 7.98 ± 0.36, P = 0.01), average TDID decreased 27% (199 ± 33 to 147 ± 31, P = 0.009), and MMTT AUC(60-240) decreased 32% (P = 0.04) over the treatment period. The decline in HbA(1c) and TDID was observed at 8 weeks and sustained over the remaining 16-week study duration. In this study, bromocriptine-QR therapy improved glycemic control and meal tolerance while reducing insulin requirement in T2DM subjects poorly controlled on high-dose insulin therapy.

Clinical radiobiology of stage T2-T3 bladder cancer.

PubMed

Majewski, Wojciech; Maciejewski, Boguslaw; Majewski, Stanislaw; Suwinski, Rafal; Miszczyk, Leszek; Tarnawski, Rafal

2004-09-01

To evaluate the relationship between total radiation dose and overall treatment time (OTT) with the treatment outcome, with adjustment for selected clinical factors, in patients with Stage T2-T3 bladder cancer treated with curative radiotherapy (RT). The analysis was based on 480 patients with Stage T2-T3 bladder cancer who were treated at the Center of Oncology in Gliwice between 1975 and 1995. The mean total radiation dose was 65.5 Gy, and the mean OTT was 51 days. In 261 patients (54%), planned and unplanned gaps occurred during RT. Four fractionation schedules were used: (1) conventional fractionation (once daily, 1.8-2.5 Gy/fraction); (2) protracted fractionation (pelvic RT, once daily, 1.6-1.7 Gy/fraction, boost RT, once daily, 2.0 Gy/fraction); (3) accelerated hyperfractionated boost (pelvic RT, once daily, 2.0 Gy/fraction; boost RT, twice daily, 1.3-1.4 Gy/fraction); and (4) accelerated hyperfractionation (pelvic and boost RT, twice daily, 1.2-1.5 Gy/fraction). In all fractionation schedules, the total radiation dose was similar (average 65.5 Gy), but the OTT was different (mean 53 days for conventional fractionation, 62 days for protracted fractionation, 45 days for accelerated hyperfractionated boost, and 41 days for accelerated hyperfractionation). A Cox proportional hazard model and maximum likelihood logistic model were used to evaluate the relationship between the treatment-related parameters (total radiation dose, dose per fraction, and OTT) and clinical factors (clinical T stage, hemoglobin level and bladder capacity before RT) and treatment outcome. With a median follow-up of 76 months, the actuarial 5-year local control rate was 47%, and the overall survival rate was 40%. The logistic analysis, which included the total dose, OTT, and T stage, revealed that all of these factors were significantly related to tumor control probability (p = 0.021 for total radiation dose, p = 0.038 for OTT, and p = 0.00068 for T stage). A multivariate Cox model, which included the treatment-related parameters and other clinical factors, revealed that the hemoglobin level and bladder capacity before RT and T-stage were statistically significant factors determining local control and overall survival. The total radiation dose was of borderline statistical significance for overall survival (p = 0.087), and OTT did not reach statistical significance. The results of our study showed that the treatment outcome after RT for bladder cancer depends mainly on clinical factors: hemoglobin level and bladder capacity before RT, and clinical T stage. An increase in the total radiation dose seemed to be associated with a better treatment outcome. The effect of the OTT was difficult to define, because it was influenced by other prognostic factors.

Study of UV radiation dose received by the Spanish population.

PubMed

Gurrea, Gonzalo; Cañada, Javier

2007-01-01

Excess exposure to UV radiation can affect our health by causing sunburn, skin cancer, etc. It is therefore useful to determine the UV dosage received by people as a way of protecting them from the possible negative effects that this kind of radiation can cause. In this work, the personal outdoor percentage, which shows the time spent in outdoor activities, as well as personal UV doses, has been calculated by means of global UV radiation on a horizontal plane. A database of average daily UVB radiation on the horizontal plane given by the National Institute of Meteorology has been used. In this work we evaluate the standard erythema dose of the Spanish population throughout the year.

Dose and Duration of Opioid Use in Patients with Cancer and Noncancer Pain at an Outpatient Hospital Setting in Malaysia.

PubMed

Zin, Che S; Rahman, Norny A; Ismail, Che R; Choy, Leong W

2017-07-01

There are currently limited data available on the patterns of opioid prescribing in Malaysia. This study investigated the patterns of opioid prescribing and characterized the dosing and duration of opioid use in patients with noncancer and cancer pain. This retrospective, cross-sectional study was conducted at an outpatient hospital setting in Malaysia. All prescriptions for opioids (dihydrocodeine, fentanyl, morphine, and oxycodone) issued between January 2013 and December 2014 were examined. The number of prescriptions and patients, the distribution of mean daily dose, annual total days covered with opioids, and annual total opioid dose at the individual level were calculated and stratified by noncancer and cancer groups. A total of 1015 opioid prescriptions were prescribed for 347 patients from 2013 to 2014. Approximately 41.5% of patients (N = 144/347) and 58.5% (N = 203/347) were associated with noncancer and cancer diagnosis, respectively. Oxycodone (38.0%) was the highest prescribed primarily for the noncancer group. The majority of patients in both noncancer (74.3%) and cancer (60.4%) groups were receiving mean daily doses of < 50 mg morphine equivalents. The chronic use of opioids (> 90 days per year) was associated with 21.8% of patients in the noncancer group and 17.5% in the cancer group. The finding from this study showed that 41.5% of opioid users at an outpatient hospital setting in Malaysia received opioids for noncancer pain and 21.8% of these users were using opioids for longer than 90 days. The average daily dose in the majority of patients in both groups of noncancer and cancer was modest. © 2016 World Institute of Pain.

Toxicological evaluation by in vitro and in vivo assays of an aqueous extract prepared from Echinodorus macrophyllus leaves.

PubMed

da Costa Lopes, L; Albano, F; Augusto Travassos Laranja, G; Marques Alves, L; Fernando Martins e Silva, L; Poubel de Souza, G; de Magalhães Araujo, I; Firmino Nogueira-Neto, J; Felzenszwalb, I; Kovary, K

2000-08-16

Toxicity of an aqueous extract prepared from Echinodorus macrophyllus dried leaves, a plant used in folk medicine to treat inflammation and kidney malfunctions, was estimated by different bioassays. Mutagenicity of the aqueous extract was evaluated in the Salmonella/microsome assay (TA97a, TA98, TA100 and TA102 strains), with or without metabolic activation. No mutagenic activity (lyophilized extract tested up to 50 mg/plate) could be detected to any of the tester strain. Furthermore, no cytotoxic effect has been observed when a crude extract of E. macrophyllus (up to 7.5 mg/ml) was tested on the exponential growth of hepatoma and normal kidney epithelial cells in culture. Toxicity of E. macrophyllus was also evaluated in male Swiss mice after 6 weeks of continuous ingestion of the aqueous extract in drinking water. Average daily ingested doses were 3, 23 and 297 mg/kg for a lyophilized extract, and 2200 mg/kg for a crude extract, with dose two being equivalent to the daily dose recommended to humans. At the end of the treatment, all animals revealed a deficit in final body weight ranging from 5 to 47%. Biochemical analysis of the plasma revealed some minor alterations indicating subclinical hepatic toxicity. Genotoxic effect on liver, kidney and blood cells has been also evaluated by the comet assay, being negative to liver and blood cells. However, DNA analyses of the kidney cells detected some genotoxic activity for the highest dose tested of E. macrophyllus extract, either lyophilized or crude. On the other hand, exposure dose of 23 mg/kg, equivalent to the daily dose recommended to humans, did not revealed any genotoxic effect and hence this herb seems to be safe to human organism.

Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

PubMed

Vučićević, Katarina; Jovanović, Marija; Golubović, Bojana; Kovačević, Sandra Vezmar; Miljković, Branislava; Martinović, Žarko; Prostran, Milica

2015-02-01

The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

TU-AB-303-01: A Feasibility Study for Dynamic Adaptive Therapy of Non-Small Cell Lung Cancer

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

Kim, M; Phillips, M

2015-06-15

Purpose: To compare plans for NSCLC optimized using Dynamic Adaptive Therapy (DAT) with conventional IMRT optimization. DAT adapts plans based on changes in the target volume by using dynamic programing techniques to consider expected changes into the optimization process. Information gathered during treatment, e.g. from CBCT, is incorporated into the optimization. Methods and materials: DAT is formulated using stochastic control formalism, which minimizes the total expected number of tumor cells at the end of a treatment course subject to uncertainty inherent in the tumor response and organs-at-risk (OAR) dose constraints. This formulation allows for non-stationary dose distribution as well asmore » non-stationary fractional dose as needed to achieve a series of optimal plans that are conformal to tumor over time. Sixteen phantom cases with various sizes and locations of tumors, and OAR geometries were generated. Each case was planned with DAT and conventional IMRT (60Gy/30fx). Tumor volume change over time was obtained by using, daily MVCT-based, two-level cell population model. Monte Carlo simulations have been performed for each treatment course to account for uncertainty in tumor response. Same OAR dose constraints were applied for both methods. The frequency of plan modification was varied to 1, 2, 5 (weekly), and 29 (daily). The final average tumor dose and OAR doses have been compared to quantify the potential benefit of DAT. Results: The average tumor max, min, mean, and D95 resulted from DAT were 124.0–125.2%, 102.1–114.7%, 113.7–123.4%, and 102.0–115.9% (range dependent on the frequency of plan modification) of those from conventional IMRT. Cord max, esophagus max, lung mean, heart mean, and unspecified tissue D05 resulted from AT were 84–102.4%, 99.8–106.9%, 66.9–85.6%, 58.2–78.8%, and 85.2–94.0% of those from conventional IMRT. Conclusions: Significant tumor dose increase and OAR dose reduction, especially with parallel OAR with mean or dose-volume constraints, can be achieved using DAT.« less

Open-label dose-finding trial of buprenorphine implants (Probuphine) for treatment of heroin dependence.

PubMed

White, Jason; Bell, James; Saunders, John B; Williamson, Paul; Makowska, Maria; Farquharson, Aaron; Beebe, Katherine L

2009-07-01

Buprenorphine, a mu-opioid receptor partial agonist, has been shown to be safe and effective for treatment of opioid dependence. A novel implantable formulation of buprenorphine (Probuphine), using a polymer matrix sustained-release technology, has been developed to offer treatment for opioid dependence while minimizing risks of patient noncompliance and illicit diversion. The goal of the current study was to conduct an initial, open-label, evaluation of the safety, pharmacokinetics, and efficacy of two doses of Probuphine in subjects with opioid dependence maintained on sublingual buprenorphine. Two doses of Probuphine were evaluated in 12 heroin-dependent volunteers switched from daily sublingual buprenorphine dosing to either two or four Probuphine implants based upon their buprenorphine daily maintenance dose of 8 mg or 16 mg respectively, and were monitored for 6 months. Probuphine implants provided continuous steady state delivery of buprenorphine until their removal at 6 months. Withdrawal symptoms and craving remained low throughout the 6 months. For the 12 subjects, an average of 59% of urines were opioid-negative across the 6 month treatment period. Injection site reactions were present in half of patients, but none were serious. No safety concerns were evident. These results suggest that Probuphine implants offer significant promise for enhancing delivery of effective opioid substitution treatment while minimizing risk for abuse of medication.

Effects of single and repeated doses of the calcium antagonist felodipine on blood pressure, renal function, electrolytes and water balance, and renin-angiotensin-aldosterone system in hypertensive patients.

PubMed

Leonetti, G; Gradnik, R; Terzoli, L; Fruscio, M; Rupoli, L; Cuspidi, C; Sampieri, L; Zanchetti, A

1986-01-01

Doses of 10 mg b.i.d. of the new dihydropyridine calcium antagonist, felodipine, were tested for seven consecutive days in 11 hospitalized hypertensive patients. A significant reduction of both systolic and diastolic blood pressures, with patients in both the supine and upright positions, occurred immediately after the first dose and was maintained (daily average 15%) throughout the following days. An increase in heart rate was observed after the first dose (15 and 23 beats/min, in supine and upright postures), and subsequently declined to average values of 8 and 14 beats/min on the seventh day. There was a marked natriuretic response during the first and second day, during which an average negative sodium balance of 95 mmol developed; on the following days sodium output was not significantly different from control, but a negative balance averaging 135 mmol was still present on the seventh day of felodipine administration. A moderate negative potassium balance also progressively developed and reached -48 mmol on the seventh day. Glomerular filtration rate was unchanged, but renal plasma flow increased significantly during administration of felodipine. Plasma renin activity and plasma aldosterone were also increased very moderately by felodipine. Compared with previous observations by our group with higher doses of felodipine (12.5, 25, and 50 mg t.i.d.), 10 mg b.i.d. of this new calcium antagonist appear to exert a marked and prolonged blood pressure reduction, accompanied by a definite natriuretic instead of an antinatriuretic effect.

Celecoxib and sulfasalazine had negative association with coronary artery diseases in patients with ankylosing spondylitis

PubMed Central

Wu, Li-Chih; Leong, Pui-Ying; Yeo, Kai-Jieh; Li, Ting-Yu; Wang, Yu-Hsun; Chiou, Jeng-Yuan; Wei, James Cheng-Chung

2016-01-01

Abstract The aim of the study is to assess the effects of celecoxib and sulfasalazine on the risk of coronary artery disease (CAD) in patients with ankylosing spondylitis (AS). Using the claims data of Taiwan National Health Insurance (NHI) database, a nationally representative data that contain the medical records of 23 million Taiwan residents, we randomly selected 1 million cohort from the database, and then we enrolled only patients who were newly diagnosed with AS (n = 4829) between year 2001 and 2010, excluding patients who had CAD (ICD-9- CM codes: 410–414) before the diagnosis of AS (n = 4112). According to propensity score matched 1:2 on age, gender, AS duration, Charlson comorbidity index, hypertension, and hyperlipidemia, 236 and 472 patients were included in the case (AS with CAD) and control (AS without CAD) groups, respectively. We used the WHO defined daily dose (DDD) as a tool to assess the dosage of sulfasalazine and celecoxib exposure. Conditional logistic regression was used to estimate the crude and adjusted odds ratios (ORs) and 95% confidence interval (CI) for the risk of CAD associated with use of sulfasalazine and celecoxib. Among 4112 AS patients, 8.4% (346/4112) developed CAD. CAD in AS patients were positively associated with age of 35 to 65, Charlson comorbidities index (CCI), hypertension, and hyperlipidemia. There was no gender difference between case and control groups. After adjustment for age, gender, CCI, hypertension, and hyperlipidemia, sulfasalazine users with an average daily dose ≥ 0.5 DDD (0.5 gm/day) had negative association with CAD events as compared to sulfasalazine nonusers (OR 0.63; 95% CI, 0.40–0.99, P < 0.05). NSAIDs, including celecoxib, etoricoxib, but no naproxen and diclofenac were negatively associated with CAD. Celecoxib users, with an average daily dose > 1.5 DDD, were negatively associated with CAD events, compared to celecoxib nonusers (OR 0.34; 95% CI, 0.13–0.89; P < 0.05). In this 10-year population-based case-control study, 8.4% of AS patients developed CAD. Sulfasalazine usage at an average dose of ≥ 0.5 gm/day demonstrated negative association with CAD events in patients with AS. PMID:27603385

Development of a Smartphone Application to Capture Carbohydrate, Lipid, and Protein Contents of Daily Food: Need for Integration in Artificial Pancreas for Patients With Type 1 Diabetes?

PubMed

Diouri, Omar; Place, Jerome; Traverso, Magali; Georgescu, Vera; Picot, Marie-Christine; Renard, Eric

2015-09-30

Meal lipids (LIP) and proteins (PRO) may influence the effect of insulin doses based on carbohydrate (CHO) counting in patients with type 1 diabetes (T1D). We developed a smartphone application for CHO, LIP, and PRO counting in daily food and assessed its usability in real-life conditions and potential usefulness. Ten T1D patients used the android application for 1 week to collect their food intakes. Data included meal composition, premeal and 2-hour postmeal blood glucose, corrections for hypo- or hyperglycemia after meals, and time for entering meals in the application. Meal insulin doses were based on patients' CHO counting (application in blinded mode). Linear mixed models were used to assess the statistical differences. In all, 187 meals were analyzed. Average computed CHO amount was 74.37 ± 31.78 grams; LIP amount: 20.26 ± 14.28 grams and PRO amount: 25.68 ± 16.68 grams. Average CHO, LIP, and PRO contents were significantly different between breakfast and lunch/dinner. The average time for meal entry in the application moved from 3-4 minutes to 2.5 minutes during the week. No significant impact of LIP and PRO was found on available blood glucose values. Our study shows CHO, LIP, and PRO intakes can be easily captured by an application on smartphone for meal entry used by T1D patients. Although LIP and PRO meal contents did not influence glucose levels when insulin doses were based on CHO in this pilot study, this application could be used for further investigation of this topic, including in closed-loop conditions. © 2015 Diabetes Technology Society.

SU-E-J-106: The Use of Deformable Image Registration with Cone-Beam CT for a Better Evaluation of Cumulative Dose to Organs

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

Fillion, O; Gingras, L; Archambault, L

2015-06-15

Purpose: The knowledge of dose accumulation in the patient tissues in radiotherapy helps in determining the treatment outcomes. This project aims at providing a workflow to map cumulative doses that takes into account interfraction organ motion without the need for manual re-contouring. Methods: Five prostate cancer patients were studied. Each patient had a planning CT (pCT) and 5 to 13 CBCT scans. On each series, a physician contoured the prostate, rectum, bladder, seminal vesicles and the intestine. First, a deformable image registration (DIR) of the pCTs onto the daily CBCTs yielded registered CTs (rCT) . This rCT combined the accuratemore » CT numbers of the pCT with the daily anatomy of the CBCT. Second, the original plans (220 cGy per fraction for 25 fractions) were copied on the rCT for dose re-calculation. Third, the DIR software Elastix was used to find the inverse transform from the rCT to the pCT. This transformation was then applied to the rCT dose grid to map the dose voxels back to their pCT location. Finally, the sum of these deformed dose grids for each patient was applied on the pCT to calculate the actual dose delivered to organs. Results: The discrepancy between the planned D98 and D2 and these indices re-calculated on the rCT, are, on average, of −1 ± 1 cGy and 1 ± 2 cGy per fraction, respectively. For fractions with large anatomical motion, the D98 discrepancy on the re-calculated dose grid mapped onto the pCT can raise to −17 ± 4 cGy. The obtained cumulative dose distributions illustrate the same behavior. Conclusion: This approach allowed the evaluation of cumulative doses to organs with the help of uncontoured daily CBCT scans. With this workflow, the easy evaluation of doses delivered for EBRT treatments could ultimately lead to a better follow-up of prostate cancer patients.« less

Comparison of the effectiveness of brand-name and generic antipsychotic drugs for treating patients with schizophrenia in Taiwan.

PubMed

Hsu, Chih-Wei; Lee, Sheng-Yu; Wang, Liang-Jen

2018-03-01

The purpose of this nationwide population-based study is to compare the long-term effectiveness of brand-name antipsychotics with generic antipsychotics for treating schizophrenia. We identified patients with schizophrenia who were prescribed antipsychotics from a random sample of one million records from Taiwan's National Health Insurance database, observed between January 1, 2000 and December 31, 2012. Only those with no prior use of antipsychotics for at least 180days were included. We selected patients who were prescribed brand-name risperidone (N=404), generic risperidone (N=145), brand-name sulpiride (N=334), or generic sulpiride (N=991). The effectiveness of the treatments researched in this study consisted of average daily doses, rates of treatment discontinuation, augmentation therapy, and psychiatric hospitalization. We found that compared to patients treated with generic risperidone, those treated with brand-name risperidone required lower daily doses (2.14mg vs. 2.61mg). However, the two groups demonstrated similar rates of treatment discontinuation, augmentation, and psychiatric hospitalization. On the other hand, in comparison with patients prescribed generic sulpiride, those treated with brand-name sulpiride not only required lower daily doses (302.72mg vs. 340.71mg) but also had lower psychiatric admission rates (adjusted hazard ratio: 0.24, 95% confidence interval: 0.10-0.56). In conclusion, for both risperidone and sulpiride, higher daily doses of the respective generic drugs were prescribed than with brand-name drugs in clinical settings. Furthermore, the brand-name sulpiride is more effective at preventing patients from hospitalization than generic sulpiride. These findings can serve as an important reference for clinical practices and healthcare economics for treating schizophrenic patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Measurement of natural radionuclides in U.K. diet.

PubMed

Smith-Briggs, J L; Bradley, E J

1984-05-01

The levels of radium-226, lead-210 and polonium-210 in the U.K. diet have been determined. The important food groups contributing to the intake of these radionuclides have been identified. Seventy-five percent of the daily intake of radium-226 is derived from beverages, cereals, other vegetables, bread, sugars and preserves. Seventy-five percent of the intake of lead-210 and polonium-210 is derived from bread, milk, cereals, beverages, other vegetables, sugars and preserves, and meat products. The average daily intakes of these radionuclides are tentatively calculated to be 30 mBq for radium-226 and 82 mBq for both lead-210 and polonium-210. These levels are compared with data from other countries. The annual effective dose equivalents resulting from the intakes are approximately 3 muSv for radium-226 and 54 muSv from lead-210 and polonium-210 together. The differences between these doses and other current estimates are discussed.

SU-F-J-55: Feasibility of Supraclavicular Field Treatment by Investigating Variation of Junction Position Between Breast Tangential and Supraclavicular Fields for Deep Inspiration Breath Hold (DIBH) Left Breast Radiation

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

Zhao, H; Sarkar, V; Paxton, A

Purpose: To explore the feasibility of supraclavicular field treatment by investigating the variation of junction position between tangential and supraclavicular fields during left breast radiation using DIBH technique. Methods: Six patients with left breast cancer treated using DIBH technique were included in this study. AlignRT system was used to track patient’s breast surface. During daily treatment, when the patient’s DIBH reached preset AlignRT tolerance of ±3mm for all principle directions (vertical, longitudinal, and lateral), the remaining longitudinal offset was recorded. The average with standard-deviation and the range of daily longitudinal offset for the entire treatment course were calculated for allmore » six patients (93 fractions totally). The ranges of average ± 1σ and 2σ were calculated, and they represent longitudinal field edge error with the confidence level of 68% and 95%. Based on these longitudinal errors, dose at junction between breast tangential and supraclavicular fields with variable gap/overlap sizes was calculated as a percentage of prescription (on a representative patient treatment plan). Results: The average of longitudinal offset for all patients is 0.16±1.32mm, and the range of longitudinal offset is −2.6 to 2.6mm. The range of longitudinal field edge error at 68% confidence level is −1.48 to 1.16mm, and at 95% confidence level is −2.80 to 2.48mm. With a 5mm and 1mm gap, the junction dose could be as low as 37.5% and 84.9% of prescription dose; with a 5mm and 1mm overlap, the junction dose could be as high as 169.3% and 117.6%. Conclusion: We observed longitudinal field edge error at 95% confidence level is about ±2.5mm, and the junction dose could reach 70% hot/cold between different DIBH. However, over the entire course of treatment, the average junction variation for all patients is within 0.2mm. The results from our study shows it is potentially feasible to treat supraclavicular field with breast tangents.« less

Chitin Oligosaccharide (COS) Reduces Antibiotics Dose and Prevents Antibiotics-Caused Side Effects in Adolescent Idiopathic Scoliosis (AIS) Patients with Spinal Fusion Surgery.

PubMed

Qu, Yang; Xu, Jinyu; Zhou, Haohan; Dong, Rongpeng; Kang, Mingyang; Zhao, Jianwu

2017-03-14

Antibiotics are always considered for surgical site infection (SSI) in adolescent idiopathic scoliosis (AIS) surgery. However, the use of antibiotics often causes the antibiotic resistance of pathogens and side effects. Thus, it is necessary to explore natural products as drug candidates. Chitin Oligosaccharide (COS) has anti-inflammation and anti-bacteria functions. The effects of COS on surgical infection in AIS surgery were investigated. A total of 312 AIS patients were evenly and randomly assigned into control group (CG, each patient took one-gram alternative Azithromycin/Erythromycin/Cloxacillin/Aztreonam/Ceftazidime or combined daily), experiment group (EG, each patient took 20 mg COS and half-dose antibiotics daily), and placebo group (PG, each patient took 20 mg placebo and half-dose antibiotics daily). The average follow-up was one month, and infection severity and side effects were analyzed. The effects of COS on isolated pathogens were analyzed. SSI rates were 2%, 3% and 8% for spine wounds and 1%, 2% and 7% for iliac wound in CG, EG and PG ( p < 0.05), respectively. COS reduces the side effects caused by antibiotics ( p < 0.05). COS improved biochemical indexes and reduced the levels of interleukin (IL)-6 and tumor necrosis factor (TNF) alpha. COS reduced the antibiotics dose and antibiotics-caused side effects in AIS patients with spinal fusion surgery by improving antioxidant and anti-inflammatory activities. COS should be developed as potential adjuvant for antibiotics therapies.

[A study of variability in glycaemia in children and adolescents with diabetes mellitus type 1 on treatment with insulin glargine].

PubMed

Rodríguez Pérez, C; Lizondo Escuder, A; López García, M J; Escrivá Cholbi, L; Alpera Lacruz, R; Collado Pérez, C

2008-11-01

To determine the usefulness of insulin glargine (IG) to reduce hipoglycaemias and hyperglycaemic events in children and adolescents with type 1 diabetes. In a retrospective/prospective study, 29 patients with a high number of non-severe hypoglycaemias, aged 3-18, and an average HbA1c of 8+/-0.7, received IG once daily plus regular insulin or rapid analogue before meals. Inclusion criteria were: a) previous treatment with NPH insulin; b) diagnosis of type 1 diabetes for at least 1 year before starting IG, and c) >3 blood glucose controls within a day. Incidence of severe and non-severe hypoglycaemic events, hyperglycaemic events, HbA1c values, body mass index, daily insulin dose before and after the institution of glargine therapy, were collected. Additionally, family were asked to complete a diabetes quality of life survey. 1,294+/-411 glycaemias/subject were obtained. Hypoglycaemic episodes were not reduced (5.9% vs 6.2%) and hyperglycaemic events remained unchanged. Fasting blood glucose levels decreased from 195.3+/-36.6 to 162.8+/-25.8 in all patients (p<0.05) and a tendency a decrease in nocturnal hypoglycaemias was observed. The average HbA1c and total daily insulin doses also remained unchanged (0.8+/-0.2 UI/Kg/day). Using IG achieves a glycaemic control similar to NPH, with a tendency to decrease the frequency of nocturnal hypoglycaemias and an improvement in fasting glycaemia values.

Great horned owl (Bubo virginianus) dietary exposure to PCDD/DF in the Tittabawassee River floodplain in Midland, Michigan, USA.

PubMed

Coefield, Sarah J; Zwiernik, Matthew J; Fredricks, Timothy B; Seston, Rita M; Nadeau, Michael W; Tazelaar, Dustin L; Moore, Jeremy N; Kay, Denise P; Roark, Shaun A; Giesy, John P

2010-10-01

Soils and sediments in the floodplain of the Tittabawassee River downstream of Midland, Michigan, USA contain elevated concentrations of polychlorinated dibenzofurans (PCDF) and polychlorinated dibenzo-p-dioxins (PCDD). As a long-lived, resident top predator, the great horned owl (Bubo virginianus; GHO) has the potential to be exposed to bioaccumulative compounds such as PCDD/DF. Site-specific components of the GHO diet were collected along 115 km of the Tittabawassee, Pine, Chippewa, and Saginaw Rivers during 2005 and 2006. The site-specific GHO biomass-based diet was dominated by cottontail rabbits (Sylvilagus floridanus) and muskrats (Ondatra zibethicus). Incidental soil ingestion and cottontail rabbits were the primary contributors of PCDD/DF to the GHO diet. The great horned owl daily dietary exposure estimates were greater in the study area (SA) (3.3 to 5.0 ng 2,3,7,8-TCDD equivalents (TEQ(WHO-avian))/kg body wt/d) than the reference area (RA) (0.07 ng TEQ(WHO-Avian)/kg body wt/d). Hazard quotients (HQs) based on central tendency estimates of the average daily dose and no-observable-adverse effect level (NOAEL) for the screech owl and uncertainty factors were <1.0 for both the RA and the SA. Hazard quotients based on upper end estimates of the average daily dose and NOAEL were <1.0 in the RA and up to 3.4 in the SA. Environ. Toxicol. Chem. 2010;29:2350-2362. © 2010 SETAC.

Characteristics of refractory gastroesophageal reflux disease (GERD) symptoms -is switching proton pump inhibitors based on the patient's CYP2C19 genotype an effective management strategy?

PubMed

Takeuchi, Toshihisa; Oota, Kazuhiro; Harada, Satoshi; Edogawa, Shoko; Kojima, Yuichi; Sanomura, Makoto; Sakaguchi, Masahiro; Hayashi, Katsuyoshi; Hongoh, Yasushi; Itabashi, Tsukasa; Kitae, Hidehiro; Hoshimoto, Masahiro; Takeuchi, Nozomi; Higuchi, Kazuhide

2015-01-01

We investigated factors related to proton pump inhibitor (PPI) -refractory gastroesophageal reflux disease (GERD) symptoms, particularly with respect to acid, the CYP2C19 genotype and psychological aspects. Patients with an Frequency Scale for the Symptoms of GERD (FSSG) score of ≥8 after the initial treatment were switched to therapy with rabeprazole at a dose of 20 mg once daily for eight weeks. We investigated the rate of improvement in PPI-refractory GERD symptoms, background factors, the Hospital Anxiety and Depression Scale (HADS) score and the CYP2C19 genotype. Patients Sixty patients endoscopically diagnosed with reflux esophagitis within the past six months who had received omeprazole at a dose of 20 mg once daily for eight weeks or longer were enrolled. In 71.6% of the patients, the FSSG score decreased to <8 after treatment with omeprazole at a dose of 20 mg once daily for ≥8 weeks, resulting in improvements in their GERD symptoms. Significant factors related to omeprazole-refractory GERD symptoms included a longer disease duration (p=0.0004) and higher HADS score (p=0.01). Among the omeprazole-refractory cases, only 23.5% of the patients showed symptom improvement after switching to rabeprazole. There were no significant differences in the average scores for FSSG (p=0.089) or HADS (p=0.182), before or after the drug change. A total of 92% of the rabeprazole poor responders were homo/hetero extensive metabolizers for the CYP2C19 genotype. Our findings suggest that switching the PPI from omeprazole (20 mg once daily) to rabeprazole (20 mg once daily) is not a significant effective therapeutic strategy for improving PPI-refractory GERD symptoms, taking into consideration possible psychometric factors and patients who require stronger acid suppression than that achieved with a double dose of PPIs for PPI-refractory GERD symptoms.

[Do poor-responder patients benefit from increasing the daily gonadotropin dose from 300 to 450 IU during controlled ovarian hyperstimulation for IVF?].

PubMed

Haas, Jigal; Zilberberg, Eran; Kedem, Alon; Dar, Shir; Orvieto, Raoul

2015-02-01

We aim to evaluate the IVF-ET outcome in patients receiving a high daily dose (300 IU) of gonadotropins during controlled ovarian hyperstimulation (COH) for IVF and to assess the role of increasing the daily dose to 450 IU on improving outcome. All consecutive women admitted to our IVF unit during an 11 year period who underwent COH consisting of daily gonadotropin dose of 300 IU were included in the study. The ovarian stimulation characteristics, number of oocytes retrieved, number of embryo transferred and pregnancy rate were assessed. We also evaluated the subsequent cycle, using daily gonadotropin doses of 450 IU, among those patients who did not conceive using the 300 IU daily gonadotropin dose. Nine hundred and forty-nine consecutive IVF cycles were evaluated. Patients who conceived using the daily gonadotropin dose of 300 IU (n = 133, 14% pregnancy rate) had significantly longer stimulation, yielded higher numbers of oocytes retrieved, fertilization rate and number of embryos transferred, compared to those who did not conceive. Moreover, while comparing IVF cycles using daily gonadotropin doses of 300 IU to 450 IU (n = 117), no in-between group differences were observed, except for significantly higher yields of oocytes retrieved. Moreover, cycles using daily gonadotropin doses of 450 IU resulted in a 7.7 live-birth rate. In poor responders undergoing COH with a daily gonadotropin dose of 300 IU, increasing the dose to 450 IU resulted in significantly higher oocyte yields and a reasonable live birth rate.

Onychopharmacokinetics of terbinafine hydrochloride penetration from a novel topical formulation into the human nail in vitro.

PubMed

Hui, Xiaoying; Lindahl, Åke; Lamel, Sonia; Maibach, Howard I

2013-09-01

This study determined the onychopharmacokinetics, nail absorption, distribution, and penetration of [¹⁴C]-terbinafine HCl in a new topical formulation into/through the human finger nail using the in vitro finite dose model. This study determined the penetration rate of terbinafine HCl from multiple doses of topical formulation applied daily for 14 days. Results showed that the total dose recovery (mass balance) was almost 100%. The concentration of terbinafine HCl in the deeper nail plate (ventral/intermediate layers) and the cotton-pad nail bed samples after the 14-day treatment were 613 ± 145 and (±S.D.) and 27 ± 1.2 µg/cm³ (or 1.9 ± 0.6 µg/cm³ daily) on average, respectively. In comparison with nail concentration data from the literature for other topical terbinatine formulations, our results show that higher amounts of terbinafine HCl reached the deep nail plate and/or the nail bed after a 14-day topical treatment with this topical formulation in vitro.

Internal exposure to (210)Po and (40)K from ingestion of cooked daily foodstuffs for adults in Japanese cities.

PubMed

Sugiyama, Hideo; Terada, Hiroshi; Isomura, Kimio; Iijima, Ikuyo; Kobayashi, Jun; Kitamura, Kiyoshi

2009-10-01

The isotope (210)Po was suspected of being involved in the death of a former Russian intelligence agent in 2006 in the UK. Although human exposure to this natural radionuclide in foods is estimated to be high, few studies are available. UNSCEAR Report 2000 does not contain data on (210)Po concentrations of foodstuffs in Japan. We analyzed samples of the everyday Japanese diet cooked with foodstuffs purchased at supermarkets in 7 major domestic cities in 2007-2008. (210)Po was quantified by alpha spectrometry and natural radionuclides such as (40)K by gamma spectrometry. The daily intake and committed effective dose of (210)Po, (40)K, and other natural radionuclides for Japanese adults were calculated. Daily intake was 0.34-1.84 (mean +/- sigma : 0.66 +/- 0.53) and 68.5-94.2 (81.5 +/- 8.5) Bq/d and the committed effective dose was 0.15-0.81 (0.29 +/- 0.24) and 0.16-0.21 (0.18 +/- 0.02) mSv for (210)Po and (40)K, respectively, comprising a high percentage of the total exposure. The total of the mean committed effective dose for the two nuclides (0.47 mSv) was higher than the annual effective dose from ingestion of foods reported by UNSCEAR 2000 (0.29 mSv). The mean committed effective dose of (40)K in the 7 major Japanese cities was comparable to the global average (0.17 mSv). The dietary exposure of Japanese adults can be characterized by a higher (210)Po contribution than in other countries. Of the total daily dietary (210)Po exposure (13 food categories excluding water) for adults in Yokohama, about 70% was from fish/shellfish and 20% from vegetables/mushrooms/seaweeds, reflecting preferences of Japanese to eat a considerable amount of fish/shellfish containing high (210)Po concentrations.

Using Six Sigma to improve once daily gentamicin dosing and therapeutic drug monitoring performance.

PubMed

Egan, Sean; Murphy, Philip G; Fennell, Jerome P; Kelly, Sinead; Hickey, Mary; McLean, Carolyn; Pate, Muriel; Kirke, Ciara; Whiriskey, Annette; Wall, Niall; McCullagh, Eddie; Murphy, Joan; Delaney, Tim

2012-12-01

Safe, effective therapy with the antimicrobial gentamicin requires good practice in dose selection and monitoring of serum levels. Suboptimal therapy occurs with breakdown in the process of drug dosing, serum blood sampling, laboratory processing and level interpretation. Unintentional underdosing may result. This improvement effort aimed to optimise this process in an academic teaching hospital using Six Sigma process improvement methodology. A multidisciplinary project team was formed. Process measures considered critical to quality were defined, and baseline practice was examined through process mapping and audit. Root cause analysis informed improvement measures. These included a new dosing and monitoring schedule, and standardised assay sampling and drug administration timing which maximised local capabilities. Three iterations of the improvement cycle were conducted over a 24-month period. The attainment of serum level sampling in the required time window improved by 85% (p≤0.0001). A 66% improvement in accuracy of dosing was observed (p≤0.0001). Unnecessary dose omission while awaiting level results and inadvertent disruption to therapy due to dosing and monitoring process breakdown were eliminated. Average daily dose administered increased from 3.39 mg/kg to 4.78 mg/kg/day. Using Six Sigma methodology enhanced gentamicin usage process performance. Local process related factors may adversely affect adherence to practice guidelines for gentamicin, a drug which is complex to use. It is vital to adapt dosing guidance and monitoring requirements so that they are capable of being implemented in the clinical environment as a matter of routine. Improvement may be achieved through a structured localised approach with multidisciplinary stakeholder involvement.

Assessment of female breast dose for thoracic cone-beam CT using MOSFET dosimeters.

PubMed

Sun, Wenzhao; Wang, Bin; Qiu, Bo; Liang, Jian; Xie, Weihao; Deng, Xiaowu; Qi, Zhenyu

2017-03-21

To assess the breast dose during a routine thoracic cone-beam CT (CBCT) check with the efforts to explore the possible dose reduction strategy. Metal oxide semiconductor field-effect transistor (MOSFET) dosimeters were used to measure breast surface doses during a thorax kV CBCT scan in an anthropomorphic phantom. Breast doses for different scanning protocols and breast sizes were compared. Dose reduction was attempted by using partial arc CBCT scan with bowtie filter. The impact of this dose reduction strategy on image registration accuracy was investigated. The average breast surface doses were 20.02 mGy and 11.65 mGy for thoracic CBCT without filtration and with filtration, respectively. This indicates a dose reduction of 41.8% by use of bowtie filter. It was found 220° partial arc scanning significantly reduced the dose to contralateral breast (44.4% lower than ipsilateral breast), while the image registration accuracy was not compromised. Breast dose reduction can be achieved by using ipsilateral 220° partial arc scan with bowtie filter. This strategy also provides sufficient image quality for thorax image registration in daily patient positioning verification.

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.

Conversion from thrice- to twice-daily pregabalin dosing for pain: Economic and clinical outcomes in a veteran population.

PubMed

Okolo, Chike; Malmstrom, Robert; Duncan, Karsten; Lopez, Julio

2015-09-01

Results of a study analyzing economic and clinical outcomes one year after conversion from thrice- to twice-daily pregabalin dosing for pain are presented. A retrospective chart review was conducted at two Veterans Affairs facilities. The analyzed population included all patients receiving pregabalin for pain whose dosing was converted from thrice- to twice-daily pregabalin dosing during a one-year period. The primary endpoint was the economic impact of the conversion. Secondary endpoints included reversion to thrice-daily pregabalin dosing, pregabalin discontinuation, addition of medications for pain, and unscheduled neuropathy-related visits. Among the 57 patients included in the data analysis, 41 continued to take pregabalin twice daily, 10 had pregabalin discontinued, and 6 had dosing reverted to thrice daily. The mean age of patients and the distribution of add-on pain medications did not differ significantly between patients whose pregabalin dosing frequency remained at twice daily and patients whose frequency reverted to thrice daily. The costs associated with pregabalin therapy differed significantly between the preconversion and postconversion periods. A savings of $115,867 was realized from this conversion for both facilities combined over the course of one year. In patients receiving pregabalin for pain, conversion from thrice- to twice-daily pregabalin dosing-while maintaining the same daily dose-resulted in substantial cost savings while having little effect on clinical outcomes. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Radiation exposure of ventilated trauma patients in intensive care: a retrospective study comparing two time periods.

PubMed

Yee, Micaela V; Barron, Rochelle A; Knobloch, Tom A; Pandey, Umesh; Twyford, Catherine; Freebairn, Ross C

2012-08-01

To describe the cumulative effective dose of radiation that was received during the initial Emergency Department assessment and ICU stay of patients admitted with trauma, who required mechanical ventilation, during two time periods. A retrospective analysis of radiological and clinical data, set in a regional nonurban ICU. Two cohorts (starting 1 January 2004 and 1 January 2009), each comprising 45 adult patients admitted with trauma who were mechanically ventilated in intensive care, were studied. Frequency and type of radiological examinations, demographic information, and clinical data were collated from the radiological database, hospital admission record and Australian Outcomes Research Tool for Intensive Care database. Cumulative effective doses were calculated and expressed as a total dose and average daily dose for each cohort. The median cumulative effective dose per patient (in milliSieverts) increased from 34.59 [interquartile range (IQR) 9.08-43.91] in 2004 to 40.51 (IQR 22.01-48.87) in 2009, P=0.045. An increased number of computed tomography examinations per patient was also observed over the same interval from an average of 2.11 (median 2, IQR 1-3) in 2004 to an average of 2.62 (2, 2-4) in 2009, P=0.046. The radiation exposure of mechanically ventilated trauma patients in intensive care has increased over time. Radiation exposure should be prospectively monitored and staff should be aware of the increased risk resulting from this change in practice.

Maternal and developmental toxicity of the hallucinogenic plant-based beverage ayahuasca in rats.

PubMed

da Motta, Luciana Gueiros; de Morais, Juliana Alves; Tavares, Ana Carolina A M; Vianna, Leonora Maciel Sousa; Mortari, Marcia Renata; Amorim, Rivadávio Fernandes Batista; Carvalho, Rosângela R; Paumgartten, Francisco José R; Pic-Taylor, Aline; Caldas, Eloisa Dutra

2018-04-01

Rats were treated orally with ayahuasca (AYA) on gestation days (GD) 6-20 at doses corresponding to one-(1X) to eight-fold (8X) the average dose taken by a human adult in a religious ritual, and the pregnancy outcome evaluated on GD21. Rats treated with 4X and 8X doses died during the treatment period (44 and 52%), and those that survived showed kidney injury. Rats surviving the 8X dose showed neuronal loss in hippocampal regions and in the raphe nuclei, and those from the 2X dose neuronal loss in CA1. Delayed intrauterine growth, induced embryo deaths and increased occurrence of foetal anomalies were observed at the 8X dose. At non-lethal doses, AYA enhanced embryolethality and the incidence of foetal soft-tissue and skeleton anomalies. This study suggested that AYA is developmentally toxic and that its daily use by pregnant women may pose risks for the conceptus. Copyright © 2018 Elsevier Inc. All rights reserved.

Measurement of natural radionuclides in Malaysian bottled mineral water and consequent health risk estimation

NASA Astrophysics Data System (ADS)

Priharti, W.; Samat, S. B.; Yasir, M. S.

2015-09-01

The radionuclides of 226Ra, 232Th and 40K were measured in ten mineral water samples, of which from the radioactivity obtained, the ingestion doses for infants, children and adults were calculated and the cancer risk for the adult was estimated. Results showed that the calculated ingestion doses for the three age categories are much lower than the average worldwide ingestion exposure of 0.29 mSv/y and the estimated cancer risk is much lower than the cancer risk of 8.40 × 10-3 (estimated from the total natural radiation dose of 2.40 mSv/y). The present study concludes that the bottled mineral water produced in Malaysia is safe for daily human consumption.

Pharmacokinetics of Modified Slow-Release Oral Testosterone Over 9 Days in Normal Men With Experimental Hypogonadism

PubMed Central

Lee, Ada; Rubinow, Katya; Clark, Richard V.; Caricofe, Ralph B.; Bush, Mark A.; Zhi, Hui; Roth, Mara Y; Page, Stephanie T.; Bremner, William J.; Amory, John K.

2014-01-01

Oral administration of testosterone has potential use for the treatment of hypogonadism. We have recently demonstrated that a novel formulation of oral testosterone transiently normalized serum testosterone in a single-dose pharmacokinetic study. In this report, we present the steady-state pharmacokinetics of this formulation. Twelve healthy young men were rendered hypogonadal with the gonadotropin-releasing hormone antagonist acyline (300 µg/kg subcutaneously) and administered 300 mg of oral testosterone 3 times daily for 9 days. Serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone–binding globulin (SHBG) were measured before and 1, 2, 4, 5, 6, 8, 10, 11, 12, 14, 16, and 24 hours on the first and ninth day of dosing. Before testosterone administration, all men had serum testosterone under 75 ng/dL. Over day 1, the 24-hour average (geometric mean [%CV]) serum total testosterone was 378 (45) ng/dL. This decreased to 315 (41) ng/dL after 9 days of continuous treatment (P = .1 compared with day 1). The 24-hour average serum SHBG was 27 (46) nmol/L on day 1 and was significantly reduced to 19 (47) nmol/L by day 9 (P > .01). As a result, the calculated free testosterone values were similar between day 1 and day 9: 8.7 (43) and 8.3 (37) ng/dL, respectively. DHT was in the reference range and estradiol was slightly below on day 9. Oral testosterone (300 mg) dosed 3 times daily normalized serum testosterone in men with experimentally induced hypogonadism after 9 days of dosing and significantly suppressed SHBG. This formulation of oral testosterone may have efficacy for the treatment of testosterone deficiency. PMID:21868746

Impact of Bromocriptine-QR Therapy on Glycemic Control and Daily Insulin Requirement in Type 2 Diabetes Mellitus Subjects Whose Dysglycemia Is Poorly Controlled on High-Dose Insulin: A Pilot Study

PubMed Central

Roe, Erin D.; Chamarthi, Bindu; Raskin, Philip

2015-01-01

Background. The concurrent use of a postprandial insulin sensitizing agent, such as bromocriptine-QR, a quick release formulation of bromocriptine, a dopamine D2 receptor agonist, may offer a strategy to improve glycemic control and limit/reduce insulin requirement in type 2 diabetes (T2DM) patients on high-dose insulin. This open label pilot study evaluated this potential utility of bromocriptine-QR. Methods. Ten T2DM subjects on metformin (1-2 gm/day) and high-dose (TDID ≥ 65 U/day) basal-bolus insulin were enrolled to receive once daily (morning) bromocriptine-QR (1.6–4.8 mg/day) for 24 weeks. Subjects with at least one postbaseline HbA1c measurement (N = 8) were analyzed for change from baseline HbA1c, TDID, and postprandial glucose area under the curve of a four-hour mixed meal tolerance test (MMTT). Results. Compared to the baseline, average HbA1c decreased 1.76% (9.74 ± 0.56 to 7.98 ± 0.36, P = 0.01), average TDID decreased 27% (199 ± 33 to 147 ± 31, P = 0.009), and MMTT AUC60–240 decreased 32% (P = 0.04) over the treatment period. The decline in HbA1c and TDID was observed at 8 weeks and sustained over the remaining 16-week study duration. Conclusion. In this study, bromocriptine-QR therapy improved glycemic control and meal tolerance while reducing insulin requirement in T2DM subjects poorly controlled on high-dose insulin therapy. PMID:26060825

Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis.

PubMed

Ford, Alexander C; Khan, Khurram J; Sandborn, William J; Kane, Sunanda V; Moayyedi, Paul

2011-12-01

Maintenance therapy with 5-aminosalicylates (5-ASAs) is recommended in patients with quiescent ulcerative colitis (UC), but compliance rates are low. Once-daily dosing may improve adherence, but impact on the relapse of disease activity is unclear as no previous meta-analysis has studied this issue. MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through April 2011). Eligible randomized controlled trials (RCTs) recruited adults with quiescent UC, and compared once-daily dosing of 5-ASAs with a more frequent dosing schedule of an identical total daily dose of the same 5-ASA drug. Minimum treatment duration was 6 months. Trials reported a dichotomous assessment of relapse of disease activity at last point of follow-up. Data concerning non-compliance and adverse events were extracted, where reported. Effect of once-daily vs. more frequent dosing schedule was reported as relative risk (RR) of relapse with a 95% confidence interval (CI). The search identified 3,061 citations, and seven RCTs containing 2,745 patients were eligible. All RCTs used mesalamine. Relapse rates were not significantly different between once-daily and conventional dosing schedules for mesalamine (RR of relapse=0.94; 95% CI: 0.82-1.08). Non-compliance (RR=0.87; 95% CI: 0.46-1.66) and adverse events were no more likely with once-daily dosing (RR=1.08; 95% CI: 0.97-1.20). Once-daily dosing with mesalamine is as effective as conventional dosing schedules for the prevention of relapse of quiescent UC, although there is no definitive evidence that compliance with once-daily dosing is better. Adverse events occur at a similar frequency.

Comparison of the effects of the antiestrogens EM-800 and tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice.

PubMed

Couillard, S; Gutman, M; Labrie, C; Bélanger, A; Candas, B; Labrie, F

1998-01-01

Although estrone supplementation in ovariectomized (OVX) nude mice bearing ZR-75-1 xenografts caused a 365% increase in average tumor size during the 4-month treatment period, administration of the antiestrogen EM-800 at the daily oral doses of 50, 150, or 400 microg completely prevented estrogen-stimulated tumor growth. At the same doses of tamoxifen, tumor size was inhibited to 189, 117, and 120% above pretreatment values. However, when EM-800 (150 microg/day) was added to the daily 150- and 400-microg doses of tamoxifen, final tumor size was decreased further to 12 and 38% above pretreatment values, respectively. EM-800 (400 microg daily) administered to estrone-supplemented OVX mice caused complete, partial, and stable responses in 11, 22, and 49% of estrone-stimulated tumors, respectively, whereas 19% (7 of 37) progressed. At the same dose of tamoxifen, the corresponding responses were 3% (complete response), 3% (partial response), and 25% (no change), whereas 69% (22 of 32) of tumors progressed. In the absence of estrone supplementation, tamoxifen (400 microg) alone administered to OVX mice stimulated tumor growth to 161% compared with initial size whereas the same dose of EM-800 reduced tumor size by 55%, a value superimposable to that observed in OVX control animals. The agonistic effect of tamoxifen is thus illustrated by the observation that 73% of tumors progressed when tamoxifen was administered alone to OVX animals whereas no tumor progressed with EM-800. The present data strongly suggest that at least part of the initial lack of response and resistance to tamoxifen during tamoxifen treatment in women is due to the estrogenic activity of this compound, whereas the new antiestrogen EM-800 exerts pure antagonistic action.

Effects of low-dose IV ketamine on peripheral and central pain from major limb injuries sustained in combat.

PubMed

Polomano, Rosemary C; Buckenmaier, Chester C; Kwon, Kyung H; Hanlon, Alexandra L; Rupprecht, Christine; Goldberg, Cynthia; Gallagher, Rollin M

2013-07-01

Examine response patterns to low-dose intravenous (IV) ketamine continuous infusions on multiple pain outcomes, and demonstrate effectiveness, safety, and tolerability of ketamine administration on general wards. Retrospective case series of consecutive patients given low-dose IV ketamine continuous infusions. Walter Reed Army Medical Center, Washington, DC. Nineteen eligible inpatients with neuropathic pain from major limb injuries sustained in combat with inadequate pain control from multimodal analgesia. A 3-day IV infusion of ketamine at doses ≤ 120 μg/kg/h. Daily present (PPI), average (API), and worst (WPI) pain intensity (0-10), global pain relief (GPR) (1 "no relief" to 5 "complete relief"), daily assessments of adverse events, and daily opioid requirements measured during therapy. A significant reduction in PPI (P < 0.001) and improvement in GPR (P = 0.031) was noted over time. Higher baseline WPI (≥ 7; N = 4) was associated with a significant decrease in WPI (P = 0.0388), but lower baseline WPI (N = 5) was not. Significant mean percent decreases in PPI with higher baseline PPI (N = 8; P = 0.0078) and WPI with no phantom limb pain (PLP) (N = 10; P = 0.0436) were observed. Mean percent increase in overall GPR was better for those reporting GPR scores ≤ 3 (N = 13) in the first 24 hours of therapy (P = 0.0153). While not significant, mean opioid requirement (IV morphine equivalents) decreased from 129.9 mgs ± 137.3 on day 1 to 112.14 ± 86.3 24 hours after therapy. Low-dose ketamine infusions for complex combat injury pain were safe and effective, and demonstrated response patterns over time and by baseline pain score stratification and presence or absence of PLP. Wiley Periodicals, Inc.

Relationship between Individual External Doses, Ambient Dose Rates and Individuals' Activity-Patterns in Affected Areas in Fukushima following the Fukushima Daiichi Nuclear Power Plant Accident.

PubMed

Naito, Wataru; Uesaka, Motoki; Yamada, Chie; Kurosawa, Tadahiro; Yasutaka, Tetsuo; Ishii, Hideki

2016-01-01

The accident at Fukushima Daiichi Nuclear Power Plant on March 11, 2011, released radioactive material into the atmosphere and contaminated the land in Fukushima and several neighboring prefectures. Five years after the nuclear disaster, the radiation levels have greatly decreased due to physical decay, weathering, and decontamination operations in Fukushima. The populations of 12 communities were forced to evacuate after the accident; as of March 2016, the evacuation order has been lifted in only a limited area, and permanent habitation is still prohibited in most of the areas. In order for the government to lift the evacuation order and for individuals to return to their original residential areas, it is important to assess current and future realistic individual external doses. Here, we used personal dosimeters along with the Global Positioning System and Geographic Information System to understand realistic individual external doses and to relate individual external doses, ambient doses, and activity-patterns of individuals in the affected areas in Fukushima. The results showed that the additional individual external doses were well correlated to the additional ambient doses based on the airborne monitoring survey. The results of linear regression analysis suggested that the additional individual external doses were on average about one-fifth that of the additional ambient doses. The reduction factors, which are defined as the ratios of the additional individual external doses to the additional ambient doses, were calculated to be on average 0.14 and 0.32 for time spent at home and outdoors, respectively. Analysis of the contribution of various activity patterns to the total individual external dose demonstrated good agreement with the average fraction of time spent daily in each activity, but the contribution due to being outdoors varied widely. These results are a valuable contribution to understanding realistic individual external doses and the corresponding airborne monitoring-based ambient doses and time-activity patterns of individuals. Moreover, the results provide important information for predicting future cumulative doses after the return of residents to evacuation order areas in Fukushima.

Relationship between Individual External Doses, Ambient Dose Rates and Individuals’ Activity-Patterns in Affected Areas in Fukushima following the Fukushima Daiichi Nuclear Power Plant Accident

PubMed Central

Kurosawa, Tadahiro; Yasutaka, Tetsuo; Ishii, Hideki

2016-01-01

The accident at Fukushima Daiichi Nuclear Power Plant on March 11, 2011, released radioactive material into the atmosphere and contaminated the land in Fukushima and several neighboring prefectures. Five years after the nuclear disaster, the radiation levels have greatly decreased due to physical decay, weathering, and decontamination operations in Fukushima. The populations of 12 communities were forced to evacuate after the accident; as of March 2016, the evacuation order has been lifted in only a limited area, and permanent habitation is still prohibited in most of the areas. In order for the government to lift the evacuation order and for individuals to return to their original residential areas, it is important to assess current and future realistic individual external doses. Here, we used personal dosimeters along with the Global Positioning System and Geographic Information System to understand realistic individual external doses and to relate individual external doses, ambient doses, and activity-patterns of individuals in the affected areas in Fukushima. The results showed that the additional individual external doses were well correlated to the additional ambient doses based on the airborne monitoring survey. The results of linear regression analysis suggested that the additional individual external doses were on average about one-fifth that of the additional ambient doses. The reduction factors, which are defined as the ratios of the additional individual external doses to the additional ambient doses, were calculated to be on average 0.14 and 0.32 for time spent at home and outdoors, respectively. Analysis of the contribution of various activity patterns to the total individual external dose demonstrated good agreement with the average fraction of time spent daily in each activity, but the contribution due to being outdoors varied widely. These results are a valuable contribution to understanding realistic individual external doses and the corresponding airborne monitoring-based ambient doses and time-activity patterns of individuals. Moreover, the results provide important information for predicting future cumulative doses after the return of residents to evacuation order areas in Fukushima. PMID:27494021

Fast online replanning for interfraction rotation correction in prostate radiotherapy.

PubMed

Kontaxis, Charis; Bol, Gijsbert H; Kerkmeijer, Linda G W; Lagendijk, Jan J W; Raaymakers, Bas W

2017-10-01

To enable fast online replanning for prostate radiotherapy with the inclusion of interfraction rotations and translations and investigate the possibility for margin reduction via this regime. Online daily replanning for a 35-fraction treatment for five prostate cases is simulated while accounting for anatomical transformations derived from fiducial marker data available in our clinic. Two online replanning strategies were simulated, compensating for: (a) rotation-only in combination with a couch shift and (b) both translation and rotation without a couch shift. They were compared against our current clinical protocol consisting of a single offline plan used over all fractions with daily couch repositioning (translations only). For every patient, the above methods were generated for several planning margins (0-8 mm with 2 mm increments) in order to assess the performance of online replanning in terms of target coverage and investigate the possible dosimetric benefit for the organs at risk. The daily DVHs for each treatment strategy were used for evaluation and the non tumor integral dose (NTID) for the different margins was calculated in order to quantify the overall reduction of the delivered energy to the patient. Our system is able to generate a daily automated prostate plan in less than 2 min. For every patient, the daily treatment plans produce similar dose distributions to the original approved plan (average CTV D99 relative difference: 0.2%). The inclusion of both shifts and rotations can be effectively compensated via replanning among all planning margins (average CTV D99 difference: 0.01 Gy between the two replanning regimes). Online replanning is able to maintain target coverage among all margins, while - as expected - the conventional treatment plan is increasingly affected by the interfraction rotations as the margins shrink (average CTV D99 decrease: 0.2 Gy at 8 mm to 2.9 Gy at 0 mm margin). The possible gain in total delivered energy to the patient was quantified by the decreased NTID ranging from 12.6% at 6 mm to 32.9% at 0 mm. We demonstrate that fast daily replanning can be utilized to account for daily rotations and translations based on the daily positioning protocol. A daily plan can be generated from scratch in less than 2 min making it suitable for online application. Given the large magnitude of prostate rotation around the LR axis, online correction for daily rotations can be beneficial even for the clinical 8 mm margin and could be utilized for treatments with small margin reduction mainly limited then by anatomical deformations and intrafraction motion. Our online replanning pipeline can be used in future treatments with online MR guidance that can lead to further safe reduction of the planning margins. © 2017 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Effect of pill burden on dosing preferences, willingness to pay, and likely adherence among patients with type 2 diabetes

PubMed Central

Hauber, A Brett; Han, Steven; Yang, Jui-Chen; Gantz, Ira; Tunceli, Kaan; Gonzalez, Juan Marcos; Brodovicz, Kimberly; Alexander, Charles M; Davies, Michael; Iglay, Kristy; Zhang, Qiaoyi; Radican, Larry

2013-01-01

Purpose To quantify willingness-to-pay (WTP) for reducing pill burden and dosing frequency among patients with type 2 diabetes mellitus (T2DM), and to examine the effect of dosing frequency and pill burden on likely medication adherence. Patients and methods Participants were US adults with T2DM on oral antihyperglycemic therapy. Each patient completed an online discrete-choice experiment (DCE) with eight choice questions, each including a pair of hypothetical medication profiles. Each profile was defined by reduction in average glucose (AG), daily dosing, chance of mild-to-moderate stomach problems, frequency of hypoglycemia, weight change, incremental risk of congestive heart failure (CHF), and cost. Patients were asked to rate their likely adherence to the profiles presented in each question. Choice questions were based on a predetermined experimental design. Choice data were analyzed using random-parameters logit. Likely treatment adherence was analyzed using a Heckman two-stage model. Results Of the 1,114 patients who completed the survey, 90 had lower dosing burden (<5 pills/day taken once/day or as needed) for all medications, and 1,024 had higher dosing burden (≥5 pills/day or more than once/day). Reduction in AG was valued most highly by patients. Hypoglycemia, chance of mild-to-moderate stomach problems, weight change, incremental risk of CHF, and daily dosing were less valued. Patients with higher current dosing burden had lower WTP for more convenient dosing schedules than patients with lower current dosing burden. Changes in dosing and cost impacted likely adherence. The magnitude of the impact of dosing on likely adherence was higher for patients with lower current dosing burden than for patients with higher current dosing burden. Conclusion Patients with T2DM were willing to pay for improvements in efficacy, side effects, and dosing. Patients’ WTP for more convenient dosing depended on current dosing burden, as did the effect of these attributes on likely adherence. PMID:24086104

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

PubMed

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

2001-04-01

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

Comparison of twice-daily vs once-daily deferasirox dosing in a gerbil model of iron cardiomyopathy

PubMed Central

Otto-Duessel, Maya; Aguilar, Michelle; Nick, Hanspeter; Moats, Rex; Wood, John C.

2010-01-01

Objective Despite the availability of deferoxamine chelation therapy for more than 20 years, iron cardiomyopathy remains the leading cause of death in thalassemia major patients. Effective chelation of cardiac iron is difficult; cardiac iron stores respond more slowly to chelation therapy and require a constant gradient of labile iron species between serum and myocytes. We have previously demonstrated the efficacy of once-daily deferasirox in removing previously stored cardiac iron in the gerbil, but changes in cardiac iron were relatively modest compared with hepatic iron. We postulated that daily divided dosing, by sustaining a longer labile iron gradient from myocytes to serum, would produce better cardiac iron chelation than a comparable daily dose. Methods Twenty-four 8- to 10-week-old female gerbils underwent iron dextran—loading for 10 weeks, followed by a 1-week iron equilibration period. Animals were divided into three treatment groups of eight animals each and were treated with deferasirox 100 mg/kg/day as a single dose, deferasirox 100 mg/kg/day daily divided dose, or sham chelation for a total of 12 weeks. Following euthanasia, organs were harvested for quantitative iron and tissue histology. Results Hepatic and cardiac iron contents were not statistically different between the daily single-dose and daily divided-dose groups. However, the ratio of cardiac to hepatic iron content was lower in the divided-dose group (0.78% vs 1.11%, p = 0.0007). Conclusion Daily divided dosing of deferasirox changes the relative cardiac and liver iron chelation profile compared with daily single dosing, trading improvements in cardiac iron elimination for less-effective hepatic chelation. PMID:17588475

IMATINIB 800MG DAILY INDUCES DEEPER MOLECULAR RESPONSES THAN IMATINIB 400MG DAILY: RESULTS OF SWOG S0325, AN INTERGROUP RANDOMIZED PHASE II TRIAL IN NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOID LEUKAEMIA

PubMed Central

Deininger, Michael W.; Kopecky, Kenneth J.; Radich, Jerald P.; Kamel-Reid, Suzanne; Stock, Wendy; Paietta, Elisabeth; Emanuel, Peter D.; Tallman, Martin; Wadleigh, Martha; Larson, Richard A.; Lipton, Jeffrey H.; Slovak, Marilyn L.; Appelbaum, Frederick R.; Druker, Brian J.

2014-01-01

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukemia (CP-CML) is 400mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematologic and cytogenetic response to IM400 vs. imatinib 400mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P=0.038; 3-log reduction: 53% vs. 35%, P=0.049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2.9-fold lower than in the IM400 arm (P=0.010). Complete haematologic response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P=0.040). Grade 3–4 toxicities were more common for IM800 (58% vs. 31%, P=0.0007), and were most commonly haematologic. Few patients have relapsed, progressed or died, but progression-free (P=0.048) and relapse-free (P=0.031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper molecular responses than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity. PMID:24383843

Effects of chronic methamphetamine on psychomotor and cognitive functions and dopamine signaling in the brain.

PubMed

Thanos, Panayotis K; Kim, Ronald; Delis, Foteini; Rocco, Mark J; Cho, Jacob; Volkow, Nora D

2017-03-01

Methamphetamine (MA) studies in animals usually involve acute, binge, or short-term exposure to the drug. However, addicts take substantial amounts of MA for extended periods of time. Here we wished to study the effects of MA exposure on brain and behavior, using an animal model analogous to this pattern of MA intake. MA doses, 4 and 8mg/kg/day, were based on previously reported average daily freely available MA self-administration levels. We examined the effects of 16 week MA treatment on psychomotor and cognitive function in the rat using open field and novel object recognition tests and we studied the adaptations of the dopaminergic system, using in vitro and in vivo receptor imaging. We show that chronic MA treatment, at doses that correspond to the average daily freely available self-administration levels in the rat, disorganizes open field activity, impairs alert exploratory behavior and anxiety-like state, and downregulates dopamine transporter in the striatum. Under these treatment conditions, dopamine terminal functional integrity in the nucleus accumbens is also affected. In addition, lower dopamine D1 receptor binding density, and, to a smaller degree, lower dopamine D2 receptor binding density were observed. Potential mechanisms related to these alterations are discussed. Copyright © 2016. Published by Elsevier B.V.

Effects of Lactobacillus acidophilus supplementation on growth performance, nutrient digestibility, fecal microbial and noxious gas emission in weaning pigs.

PubMed

Lan, Ruixia; Koo, Jinmo; Kim, Inho

2017-03-01

Antibiotics used as growth promoters in livestock have been banned in the European Union since 2006. Antibiotics alternatives have focused on probiotics, such as Lactobacillus acidophilus. The concentration of L. acidophilus is considered crucial for obtaining the desired effects. However, limited studies have been conducted to test the dose-dependent effects of L. acidophilus. Therefore, the present study aimed to test the dose-dependent effects of L. acidophilus on growth performance, nutrient digestibility, fecal microbial flora and fecal noxious gas emission in weaning pigs. Lactobacillus acidophilus supplementation increased (P < 0.05) average daily gain, average daily feed intake, apparent nutrient digestibility of dry matter, nitrogen and gross energy, and Lactobacillus counts compared to the basal diet treatment, and a linear effect (P < 0.05) was observed on those criteria. Escherichia coli counts and NH 3 emission were decreased (P < 0.05) by L. acidophilus supplementation, and a linear effect (P < 0.05) was observed on E. coli counts. These results suggest that L. acidophilus could be used as an antibiotic alternative by improving growth performance, nutrient digestibility and gut balance (i.e. increased Lactobacillus counts and decreased E. coli counts), and decreasing NH3 emission, of weaning pigs. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

SU-F-J-68: Deformable Dose Accumulation for Voxel-Based Dose Tracking of PTV Cold Spots for Adaptive Radiotherapy of the Head and Neck

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

Liu, C; Chetty, I; Mao, W

Purpose: To utilize deformable dose accumulation (DDA) to determine how cold spots within the PTV change over the course of fractionated head and neck (H&N) radiotherapy. Methods: Voxel-based dose was tracked using a DDA platform. The DDA process consisted of B-spline-based deformable image registration (DIR) and dose accumulation between planning CT’s and daily cone-beam CT’s for 10 H&N cancer patients. Cold spots within the PTV (regions receiving less than the prescription, 70 Gy) were contoured on the cumulative dose distribution. These cold spots were mapped to each fraction, starting from the first fraction to determine how they changed. Spatial correlationmore » between cold spot regions over each fraction, relative to the last fraction, was computed using the Jaccard index Jk (Mk,N), where N is the cold spot within the PTV at the end of the treatment, and Mk the same region for fraction k. Results: Figure 1 shows good spatial correlation between cold spots, and highlights expansion of the cold spot region over the course of treatment, as a result of setup uncertainties, and anatomical changes. Figure 2 shows a plot of Jk versus fraction number k averaged over 10 patients. This confirms the good spatial correlation between cold spots over the course of treatment. On average, Jk reaches ∼90% at fraction 22, suggesting that possible intervention (e.g. reoptimization) may mitigate the cold spot region. The cold spot, D99, averaged over 10 patients corresponded to a dose of ∼65 Gy, relative to the prescription dose of 70 Gy. Conclusion: DDA-based tracking provides spatial dose information, which can be used to monitor dose in different regions of the treatment plan, thereby enabling appropriate mid-treatment interventions. This work is supported in part by Varian Medical Systems, Palo Alto, CA.« less

High-dose N-acetylcysteine in the prevention of COPD exacerbations: rationale and design of the PANTHEON Study.

PubMed

Zheng, Jin-Ping; Wen, Fu-Qiang; Bai, Chun-Xue; Wan, Huan-Ying; Kang, Jian; Chen, Ping; Yao, Wan-Zhen; Ma, Li-Jun; Xia, Qi-Kui; Gao, Yi; Zhong, Nan-Shan

2013-04-01

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation; from a pathophysiological point of view it involves many components, including mucus hypersecretion, oxidative stress and inflammation. N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. Long-term efficacy of NAC 600mg/d in COPD is controversial; a dose-effect relationship has been demonstrated, but at present it is not known whether a higher dose provides clinical benefits. The PANTHEON Study is a prospective, ICS stratified, randomized, double-blind, placebo-controlled, parallel-group, multi-center trial designed to assess the efficacy and safety of high-dose (1200 mg/daily) NAC treatment for one year in moderate-to-severe COPD patients. The primary endpoint is the annual exacerbation rate. Secondary endpoints include recurrent exacerbations hazard ratio, time to first exacerbation, as well as quality of life and pulmonary function. The hypothesis, design and methodology are described and baseline characteristics of recruited patients are presented. 1006 COPD patients (444 treated with maintenance ICS, 562 ICS naive, aged 66.27±8.76 yrs, average post-bronchodilator FEV1 48.95±11.80 of predicted) have been randomized at 34 hospitals in China. Final results of this study will provide objective data on the effects of high-dose (1200 mg/daily) long-term NAC treatment in the prevention of COPD exacerbations and other outcome variables.

Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive

PubMed Central

Hofmann, Birte; Reinecke, Isabel; Schuett, Barbara; Merz, Martin; Zurth, Christian

2014-01-01

Objective: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). Materials: Participants were healthy, non-obese women aged 18 – 45 years (study 1) or 18 – 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). Methods: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P–M–E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M–P–E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval). Results: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 – 1.16), indicating average daily delivery similar to oral administration of 0.019 – 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 – 0.885), indicating average daily delivery from the patch of 0.057 – 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0–168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 – 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. Conclusions: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives. PMID:25295716

The Concomitant Consumption of Cod Liver Oil Causes a Reduction in the Daily Diclofenac Sodium Usage in Rheumatoid Arthritis Patients: A Pilot Study

PubMed Central

Gupta, Vinay Kumar; Khan, Z. Y. Zafer; Ahmad, Mushtaq

2013-01-01

Objective: To evaluate whether the concomitant consumption of Cod liver oil can reduce the daily dose of Diclofenac Sodium and probably the risk of the side effects which are associated with it in Rheumatoid Arthritis patients. Material and Methods: This longitudinal, prospective, open label study was conducted from April to September 2012 at Mahatma Gandhi Medical College and Hospital, Jaipur, India. 30 Rheumatoid Arthritis patients who were aged between 19 to 60 years, who fulfilled the inclusion criteria, were enrolled. Each patient was given five Cod liver oil capsules twice a day, for a period of 24 weeks. Each capsule which contained 300 mg of Cod liver oil had Eicosapentaenoic acid-20 mg and Docosahexaenoic acid-30 mg. The patients who took different Nonsteroidal anti-inflammatory drugs daily were switched over to Diclofenac Sodium 50 mg as a single dose, up to a maximum dose of 200 mg per day. The dose of Diclofenac Sodium which was consumed per day and the average daily requirement at different visits were recorded in each patient and they were compared. The patients were assessed for their pain scores by using the Visual Analogue Scale (VAS) at different weeks. In addition, the ‘Subjective Response’ to the pain was evaluated in each patient at the respective visits. The Student’s “t”-test was applied for the analysis of the VAS pain score and for the evaluation of the reduction in the mean daily dose of the Diclofenac Sodium consumption. A probability value of less than 0.05 (p< 0.05) was considered to be statistically significant. Moreover, the results of the ‘Subjective Response’ to the pain were expressed as percentage. Results: A significant decrease (p< 0.05) in the mean VAS pain score from 80.38 ± 6.4 at week 0 to 67.30 ± 5.3 at week 24 was noted in the patients. There was a significant reduction (p<0.05) in mean dose of Diclofenac Sodium consumed from 115.04 ± 24.56 at week 4 to 98.83 ± 22.32 at week 24. Moreover, the percentage of the patients who experienced a ‘Better’ Subjective Response increased from 15.38% at week 4 to 61.53% at week 24 of the treatment follow up. Conclusion: This study revealed that the concurrent use of Cod liver oil which contained n-3 Essential Fatty Acid in Rheumatoid Arthritis patients reduced the mean daily dose of Diclofenac Sodium consumed and probably the incidence of the side effects which were associated with it. PMID:23998063

Associations of daily pediatric asthma emergency department visits with air pollution in Newark, NJ: utilizing time-series and case-crossover study designs.

PubMed

Gleason, Jessie A; Fagliano, Jerald A

2015-10-01

Asthma is one of the most common chronic diseases affecting children. This study assesses the associations of ozone and fine particulate matter (PM2.5) with pediatric emergency department visits in the urban environment of Newark, NJ. Two study designs were utilized and evaluated for usability. We obtained daily emergency department visits among children aged 3-17 years with a primary diagnosis of asthma during April to September for 2004-2007. Both a time-stratified case-crossover study design with bi-directional control sampling and a time-series study design were utilized. Lagged effects (1-d through 5-d lag, 3-d average, and 5-d average) of ozone and PM2.5 were explored and a dose-response analysis comparing the bottom 5th percentile of 3-d average lag ozone with each 5 percentile increase was performed. Associations of interquartile range increase in same-day ozone were similar between the time-series and case-crossover study designs (RR = 1.08, 95% CI 1.04-1.12) and (OR = 1.10, 95% CI 1.06-1.14), respectively. Similar associations were seen for 1-day lag and 3-day average lag ozone levels. PM2.5 was not associated with the outcome in either study design. Dose-response assessment indicated a statistically significant and increasing association around 50-55 ppb consistent for both study designs. Ozone was statistically positively associated with pediatric asthma ED visits in Newark, NJ. Our results were generally comparable across the time-series and case-crossover study designs, indicating both are useful to assess local air pollution impacts.

The addition of tramadol as a second opioid may improve pain relief in severe osteoarthritis: a prospective study.

PubMed

Di Lorenzo, Luigi; Foti, Calogero; Forte, Alfonso Maria; Palmieri, Enzo; Formisano, Rita; Vatakencherry, Abraham; Pappagallo, Marco

2010-01-01

Opioid combination has been shown to reduce the need for escalating doses for the treatment of cancer pain. A prospective study was planned to evaluate the addition of tramadol to a stronger opioid for the treatment of severe pain as a result of osteoarthritis, previously uncontrolled by non-opioid analgesics or weak opioids. All subjects received tramadol 200 mg and tizanidine 2 mg. At 2 weeks, tramadol was discontinued for patients still reporting poor pain relief (effectiveness ≤50%), and a stronger opioid was titrated to a morphine equivalent amount (MEA) of 40-60 mg orally. After two additional weeks, patients were then divided into two groups: the Strong Opioid Group (SO) and the Tramadol plus the Strong Opioid Group (TSO). The SO group was allowed to escalate opioid dose for lack of effectiveness; the TSO group received tramadol 150 mg daily, thereafter additional strong opioid titration was allowed. A total of 74 patients were studied: SO (n = 40) and TSOG (n = 34). All patients eventually achieved pain relief quality, with both groups reporting similar Karnofsky Performance Scale effectiveness. The SO group achieved satisfactory pain relief (>50%) at an average daily oral MEA of 120 mg. TSO subjects achieved satisfactory pain relief (>50%) at an average daily oral MEA of 95 mg. The addition of tramadol provided a synergistic effect resulting in a 30-mg decrease in necessary morphine equivalents with fewer opioid-related adverse effects. © 2010 The Authors. Pain Practice © 2010 World Institute of Pain.

Drinking water as a proportion of total human exposure to volatile N-nitrosamines.

PubMed

Hrudey, Steve E; Bull, Richard J; Cotruvo, Joseph A; Paoli, Greg; Wilson, Margaret

2013-12-01

Some volatile N-nitrosamines, primarily N-nitrosodimethylamine (NDMA), are recognized as products of drinking water treatment at ng/L levels and as known carcinogens. The U.S. EPA has identified the N-nitrosamines as contaminants being considered for regulation as a group under the Safe Drinking Water Act. Nitrosamines are common dietary components, and a major database (over 18,000 drinking water samples) has recently been created under the Unregulated Contaminant Monitoring Rule. A Monte Carlo modeling analysis in 2007 found that drinking water contributed less than 2.8% of ingested NDMA and less than 0.02% of total NDMA exposure when estimated endogenous formation was considered. Our analysis, based upon human blood concentrations, indicates that endogenous NDMA production is larger than expected. The blood-based estimates are within the range that would be calculated from estimates based on daily urinary NDMA excretion and an estimate based on methylated guanine in DNA of lymphocytes from human volunteers. Our analysis of ingested NDMA from food and water based on Monte Carlo modeling with more complete data input shows that drinking water contributes a mean proportion of the lifetime average daily NDMA dose ranging from between 0.0002% and 0.001% for surface water systems using free chlorine or between 0.001% and 0.01% for surface water systems using chloramines. The proportions of average daily dose are higher for infants (zero to six months) than other age cohorts, with the highest mean up to 0.09% (upper 95th percentile of 0.3%). © 2013 Society for Risk Analysis.

[Clinical trial on treatment of Parkinson's disease of Gan-Shen yin deficiency type by recipe for nourishing Gan-Shen].

PubMed

Zhao, Hong; Li, Wen-Wei; Gao, Jun-Peng

2007-09-01

To observe the curative effect of the recipe for nourishing Gan-Shen on Parkinson's disease (PD) of Gan-Shen yin deficiency type. One hundred and twenty-one PD patients were ran-domly assigned by blocking design to the control group and the treated group in the ratio of 1:1. All were treated according to the international medication guiding principle for PD treatment, but the treated group was ad-ministered with the recipe for nourishing Gan-Shen additionally. The treatment course lasted for 12 consecutive months, and the end point was the end of the 12th month. The unified Parkinson's disease rating scale (UP-DRS) score, TCM primary and secondary symptom scores were evaluated before treatment, every 3 months of treatment and at the end point. The average daily levodopa dose and the Hoehn & Yahr grading were assessed before treatment and at the end point. After treatment, UPDRS score in both groups showed an ascending trend at a slower rate in the treated groups than in the control group. At the 9th and 12th month of medication, a significant difference was found in UPDRS score between the two groups (P < 0.05), and the TCM symptom score was obviously lower in the treated group than in the control group (P < 0.05). At the end point of the trial, the average daily levodopa dose used was lower in the treated group than in the control group (P < 0.05) and there was no significant difference in the Hoehn & Yahr score between the two groups (P > 0.05). The recipe for norishing Gan-Shen can slow the ascending trend of UPDRS score in the PD patients, improve the symptoms of Gan-Shen yin deficiency, and decrease the daily levodopa dose used, showing a curative effect on PD of Gan-Shen yin deficiency type.

Screening-Level Risk Assessment for Styrene-Acrylonitrile (SAN) Trimer Detected in Soil and Groundwater

PubMed Central

Kirman, C. R.; Gargas, M. L.; Collins, J. J.; Rowlands, J. C.

2012-01-01

A screening-level risk assessment was conducted for styrene-acrylonitrile (SAN) Trimer detected at the Reich Farm Superfund site in Toms River, NJ. Consistent with a screening-level approach, on-site and off-site exposure scenarios were evaluated using assumptions that are expected to overestimate actual exposures and hazards at the site. Environmental sampling data collected for soil and groundwater were used to estimate exposure point concentrations. Several exposure scenarios were evaluated to assess potential on-site and off-site exposures, using parameter values for exposures to soil (oral, inhalation of particulates, and dermal contact) and groundwater (oral, dermal contact) to reflect central tendency exposure (CTE) and reasonable maximum exposure (RME) conditions. Three reference dose (RfD) values were derived for SAN Trimer for short-term, subchronic, and chronic exposures, based upon its effects on the liver in exposed rats. Benchmark (BMD) methods were used to assess the relationship between exposure and response, and to characterize appropriate points of departure (POD) for each RfD. An uncertainty factor of 300 was applied to each POD to yield RfD values of 0.1, 0.04, and 0.03 mg/kg-d for short-term, subchronic, and chronic exposures, respectively. Because a chronic cancer bioassay for SAN Trimer in rats (NTP 2011a) does not provide evidence of carcinogenicity, a cancer risk assessment is not appropriate for this chemical. Potential health hazards to human health were assessed using a hazard index (HI) approach, which considers the ratio of exposure dose (i.e., average daily dose, mg/kg-d) to toxicity dose (RfD, mg/kg-d) for each scenario. All CTE and RME HI values are well below 1 (where the average daily dose is equivalent to the RfD), indicating that there is no concern for potential noncancer effects in exposed populations even under the conservative assumptions of this screening-level assessment. PMID:23030654

TU-H-CAMPUS-JeP3-02: Automated Dose Accumulation and Dose Accuracy Assessment for Online Or Offline Adaptive Replanning

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

Chen, G; Ahunbay, E; Li, X

Purpose: With introduction of high-quality treatment imaging during radiation therapy (RT) delivery, e.g., MR-Linac, adaptive replanning of either online or offline becomes appealing. Dose accumulation of delivered fractions, a prerequisite for the adaptive replanning, can be cumbersome and inaccurate. The purpose of this work is to develop an automated process to accumulate daily doses and to assess the dose accumulation accuracy voxel-by-voxel for adaptive replanning. Methods: The process includes the following main steps: 1) reconstructing daily dose for each delivered fraction with a treatment planning system (Monaco, Elekta) based on the daily images using machine delivery log file and consideringmore » patient repositioning if applicable, 2) overlaying the daily dose to the planning image based on deformable image registering (DIR) (ADMIRE, Elekta), 3) assessing voxel dose deformation accuracy based on deformation field using predetermined criteria, and 4) outputting accumulated dose and dose-accuracy volume histograms and parameters. Daily CTs acquired using a CT-on-rails during routine CT-guided RT for sample patients with head and neck and prostate cancers were used to test the process. Results: Daily and accumulated doses (dose-volume histograms, etc) along with their accuracies (dose-accuracy volume histogram) can be robustly generated using the proposed process. The test data for a head and neck cancer case shows that the gross tumor volume decreased by 20% towards the end of treatment course, and the parotid gland mean dose increased by 10%. Such information would trigger adaptive replanning for the subsequent fractions. The voxel-based accuracy in the accumulated dose showed that errors in accumulated dose near rigid structures were small. Conclusion: A procedure as well as necessary tools to automatically accumulate daily dose and assess dose accumulation accuracy is developed and is useful for adaptive replanning. Partially supported by Elekta, Inc.« less

Measurement of natural radionuclides in Malaysian bottled mineral water and consequent health risk estimation

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

Priharti, W.; Samat, S. B.; Yasir, M. S.

2015-09-25

The radionuclides of {sup 226}Ra, {sup 232}Th and {sup 40}K were measured in ten mineral water samples, of which from the radioactivity obtained, the ingestion doses for infants, children and adults were calculated and the cancer risk for the adult was estimated. Results showed that the calculated ingestion doses for the three age categories are much lower than the average worldwide ingestion exposure of 0.29 mSv/y and the estimated cancer risk is much lower than the cancer risk of 8.40 × 10{sup −3} (estimated from the total natural radiation dose of 2.40 mSv/y). The present study concludes that the bottledmore » mineral water produced in Malaysia is safe for daily human consumption.« less

Model‐Informed Development and Registration of a Once‐Daily Regimen of Extended‐Release Tofacitinib

PubMed Central

Lamba, M; Hutmacher, MM; Furst, DE; Dikranian, A; Dowty, ME; Conrado, D; Stock, T; Nduaka, C; Cook, J

2017-01-01

Extended‐release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model‐informed, exposure–response (E‐R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E‐R analyses were conducted using validated clinical endpoints from phase II dose–response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration. PMID:27859030

Deconvolution analysis of 24-h serum cortisol profiles informs the amount and distribution of hydrocortisone replacement therapy.

PubMed

Peters, Catherine J; Hill, Nathan; Dattani, Mehul T; Charmandari, Evangelia; Matthews, David R; Hindmarsh, Peter C

2013-03-01

Hydrocortisone therapy is based on a dosing regimen derived from estimates of cortisol secretion, but little is known of how the dose should be distributed throughout the 24 h. We have used deconvolution analysis of 24-h serum cortisol profiles to determine 24-h cortisol secretion and distribution to inform hydrocortisone dosing schedules in young children and older adults. Twenty four hour serum cortisol profiles from 80 adults (41 men, aged 60-74 years) and 29 children (24 boys, aged 5-9 years) were subject to deconvolution analysis using an 80-min half-life to ascertain total cortisol secretion and distribution throughout the 24-h period. Mean daily cortisol secretion was similar between adults (6.3 mg/m(2) body surface area/day, range 5.1-9.3) and children (8.0 mg/m(2) body surface area/day, range 5.3-12.0). Peak serum cortisol concentration was higher in children compared with adults, whereas nadir serum cortisol concentrations were similar. Timing of the peak serum cortisol concentration was similar (07.05-07.25), whereas that of the nadir concentration occurred later in adults (midnight) compared with children (22.48) (P = 0.003). Children had the highest percentage of cortisol secretion between 06.00 and 12.00 (38.4%), whereas in adults this took place between midnight and 06.00 (45.2%). These observations suggest that the daily hydrocortisone replacement dose should be equivalent on average to 6.3 mg/m(2) body surface area/day in adults and 8.0 mg/m(2) body surface area/day in children. Differences in distribution of the total daily dose between older adults and young children need to be taken into account when using a three or four times per day dosing regimen. © 2012 Blackwell Publishing Ltd.

Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis.

PubMed

Shiue, Harn J; Taylor, Maria; Sands, Kara A

2017-10-01

Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. To compare two LEV dosing regimens, daily versus twice-daily (BID), in ESRD patients undergoing HD. Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 ± 6.3, 19.4 ± 5.2, 34.9 ± 4.3 vs 21.1 ± 3.9, 6.9 ± 1.5, 11.9 ± 1.7 µg/mL; P < 0.05). BID post-HD levels were 41.9 ± 4.6% of predialysis levels versus 36.9 ± 7.3% with daily dosing ( P = 0.275). Post-HD dose levels were 81.4±4.3% of predialysis on LEV BID versus 65.7 ± 8.8% on LEV daily ( P = 0.045). No seizures were reported during hospital admission in either group. Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected.

Assessment of female breast dose for thoracic cone-beam CT using MOSFET dosimeters

PubMed Central

Qiu, Bo; Liang, Jian; Xie, Weihao; Deng, Xiaowu; Qi, Zhenyu

2017-01-01

Objective: To assess the breast dose during a routine thoracic cone-beam CT (CBCT) check with the efforts to explore the possible dose reduction strategy. Materials and Methods: Metal oxide semiconductor field-effect transistor (MOSFET) dosimeters were used to measure breast surface doses during a thorax kV CBCT scan in an anthropomorphic phantom. Breast doses for different scanning protocols and breast sizes were compared. Dose reduction was attempted by using partial arc CBCT scan with bowtie filter. The impact of this dose reduction strategy on image registration accuracy was investigated. Results: The average breast surface doses were 20.02 mGy and 11.65 mGy for thoracic CBCT without filtration and with filtration, respectively. This indicates a dose reduction of 41.8% by use of bowtie filter. It was found 220° partial arc scanning significantly reduced the dose to contralateral breast (44.4% lower than ipsilateral breast), while the image registration accuracy was not compromised. Conclusions: Breast dose reduction can be achieved by using ipsilateral 220° partial arc scan with bowtie filter. This strategy also provides sufficient image quality for thorax image registration in daily patient positioning verification. PMID:28423624

V-Go Insulin Delivery System Versus Multiple Daily Insulin Injections for Patients With Uncontrolled Type 2 Diabetes Mellitus.

PubMed

Winter, Abigail; Lintner, Michaela; Knezevich, Emily

2015-04-21

Type 2 diabetes mellitus affects over 29.1 million Americans, diagnosed and undiagnosed. Achieving and maintaining glycemic control for these patients is of extreme importance when working to prevent complications and improve quality of life for patients. The V-Go is a newly developed insulin delivery system. The push of a button inserts a needle into the patient once daily and remains attached for 24 hours. The V-Go is designed to release a set basal rate throughout the day, while allowing patients to provide up to 36 units of on-demand bolus insulin with the manual click of 2 buttons. It is a spring-loaded device filled daily with rapid-acting insulin that runs without the use of batteries or computer software. The main objective of this prospective active comparator study was to observe the A1C lowering effects of multiple daily insulin injections (MDII) versus the use of the V-Go insulin delivery system for patients with uncontrolled type 2 diabetes mellitus over a 3-month period. In addition, the effect on insulin requirement for these patients was assessed with secondary comparisons of weight, blood pressure, prevalence of hypoglycemic events, and quality of life before and after 3 months of intensified insulin therapy with regular monitoring by a clinical pharmacist at an internal medicine clinic. The average A1C lowering experienced by the 3 patients in the V-Go group was 1.5%, while the average A1C change in the 3 patients in the MDII group was an increase of 0.2%. All patients in the V-Go group experienced a decrease in insulin total daily dose (TDD), with an average decrease of 26.3 units. All patients in the MDII group experienced an increase in insulin TDD with an average of 15 units daily to achieve therapeutic goals individualized for each patient. All patients who underwent intensification of insulin therapy experienced an increase in subjective quality of life (QOL) as determined using the Diabetes-39 (D-39) questionnaire, though QOL results lacked statistical significance. © 2015 Diabetes Technology Society.

Comparison of once-daily versus twice-daily combination of ropinirole prolonged release in Parkinson's disease.

PubMed

Yun, Ji Young; Kim, Han-Joon; Lee, Jee-Young; Kim, Young Eun; Kim, Ji Seon; Kim, Jong-Min; Jeon, Beom S

2013-09-02

Ropinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson's disease. This study was an open-label crossover study. We enrolled Parkinson's disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson's Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI). A total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen. RPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.

On-pump Cardiac Surgery Enhances Platelet Renewal and Impairs Aspirin Pharmacodynamics: Effects of Improved Dosing Regimens.

PubMed

Cavalca, V; Rocca, B; Veglia, F; Petrucci, G; Porro, B; Myasoedova, V; De Cristofaro, R; Turnu, L; Bonomi, A; Songia, P; Cavallotti, L; Zanobini, M; Camera, M; Alamanni, F; Parolari, A; Patrono, C; Tremoli, E

2017-11-01

On-pump cardiac surgery may trigger inflammation and accelerate platelet cyclooxygenase-1 renewal, thereby modifying low-dose aspirin pharmacodynamics. Thirty-seven patients on standard aspirin 100 mg once-daily were studied before surgery and randomized within 36 hours postsurgery to 100 mg once-daily, 100 mg twice-daily, or 200 mg once-daily for 90 days. On day 7 postsurgery, immature and mature platelets, platelet mass, thrombopoietin, glycocalicin, leukocytes, C-reactive protein, and interleukin-6 significantly increased. Interleukin-6 significantly correlated with immature platelets. At day 7, patients randomized to 100 mg once-daily showed a significant increase in serum thromboxane (TX)B 2 within the 24-hour dosing interval and urinary TXA 2 metabolite (TXM) excretion. Aspirin 100 mg twice-daily lowered serum TXB 2 and prevented postsurgery TXM increase (P < 0.01), without affecting prostacyclin metabolite excretion. After cardiac surgery, shortening the dosing interval, but not doubling the once-daily dose, rescues the impaired antiplatelet effect of low-dose aspirin and prevents platelet activation associated with acute inflammation and enhanced platelet turnover. © 2017 American Society for Clinical Pharmacology and Therapeutics.

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

PubMed

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

2018-01-01

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

Retrospective cross-sectional pilot study of rifaximin dosing for the prevention of recurrent hepatic encephalopathy.

PubMed

Lyon, Kelsey C; Likar, Eric; Martello, Jay L; Regier, Michael

2017-09-01

Standard treatment for hepatic encephalopathy (HE) includes medications that reduce ammonia and bacterial translocation in the gut. Rifaximin can be used off-label for the reduction of overt HE. The study purpose was to determine efficacy of traditional rifaximin dosing (400 mg three times daily) compared with newer dosing (550 mg twice daily) via readmission rates for the prevention of recurrent HE. This was a retrospective, observational, cross-sectional pilot study conducted in a tertiary medical center. A total of 226 patients 18-89 years of age with documentation of HE via ICD-9 code who started rifaximin therapy while inpatient between April 2009 and June 2014 were evaluated. Data collected included rifaximin dosing, other medications used to treat HE, duration of therapy, time to readmission, and various laboratory values. There were no differences in readmission rates at 30 days, 60 days, or 6 months between treatment groups. Additionally, there was no difference in the odds of readmission between the treatment groups (OR = 0.77, 95% CI: [0.201, 4.365], P = 0.718). Patients had a low overall probability of readmission over the observational period. Based on average wholesale price data, the cost for a 9-day supply of rifaximin for the 400-mg dosing regimen is $952.56 versus $605.16 for the 550-mg dosing regimen. The rifaximin 550-mg dosing strategy should be utilized in hospitalized patients for the prevention of recurrent HE as there was no difference in readmission rate or time to readmission between dosing groups. The 550-mg regimen had a lower acquisition cost for a 9-day duration of treatment in the studied institution. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Reviewing long-term antidepressants can reduce drug burden: a prospective observational cohort study

PubMed Central

Johnson, Chris F; Macdonald, Hector J; Atkinson, Pauline; Buchanan, Alasdair I; Downes, Noreen; Dougall, Nadine

2012-01-01

Background Antidepressant prescribing continues to rise. Contributing factors are increased long-term prescribing and possibly the use of higher selective serotonin re-uptake inhibitor (SSRI) doses. Aim To review general practice patients prescribed the same antidepressant long-term (≥2 years) and evaluate prescribing and management pre and post-review. Design and setting Prospective observational cohort study using routine data from 78 urban general practices, Scotland. Method All patients prescribed antidepressants (excluding amitriptyline) for ≥2 years were identified from records November 2009 to March 2010. GPs selected patients for face-to-face review of clinical condition and medication, December 2009 to September 2010. Pre- and post-review data were collected; average antidepressant doses and changes in prescribed daily doses were calculated. Onward referral to support services was recorded. Results 8.6% (33 312/388 656) of all registered patients were prescribed an antidepressant, 47.1% (15 689) were defined as long-term users and 2849 (18.2%) were reviewed. 811 (28.5%) patients reviewed had a change in antidepressant therapy: 7.0% stopped, 12.8% reduced dose, 5.3% increased dose, and 3.4% changed antidepressant, resulting in 9.5% (95% CI = 9.1% to 9.8% P<0.001) reduction in prescribed daily dose and 8.1% reduction in prescribing costs. 6.3% were referred onwards, half to NHS Mental Health Services. Pre-review SSRI doses were 10–30% higher than previously reported. Conclusion Almost half of all people prescribed antidepressants were long-term users. Appropriate reductions in prescribing can be achieved by reviewing patients. Higher SSRI doses may be contributing to current antidepressant growth. PMID:23211181

The effects of hypervitaminosis A in sheep following intramuscular administrations of vitamin A.

PubMed

Raoofi, Afshin; Asadi, Farzad; Mardjanmehr, Seyed Hossein; Kazempoor, Reza

2010-01-01

Ten ewe lambs (median age 11 months and average weight 29.2+/-2.5 kg) were used in the present study. They were divided into two groups: test (n=5) and control (n=5). Housing and all diets were identical. In the test group vitamin A was injected into the thigh muscle at a daily dose of 5000 IU/kg body weight for 16 days. The average final body weight of sheep in the test group was significantly (P<0.05) less than the control group. All animals were slaughtered at day 17. The lambs' feet were X-rayed to evaluate any difference for radiographic signs between test and control groups. No significant differences were seen for PCV, WBC, differential leukocyte count, and total serum protein between groups. There were no significant differences for serum AST, ALT, and ALP activities and serum calcium, inorganic phosphate, and magnesium concentrations between groups. Histological examination revealed an increased number of lipid droplets in the cytoplasm of the stellate cells of the liver in the test group. The results showed that daily administrations of vitamin A approximately 150 times greater than the daily requirement were well tolerated by sheep. Copyright 2009 Elsevier Ltd. All rights reserved.

Twice-Daily versus Once-Daily Pramipexole Extended Release Dosage Regimens in Parkinson's Disease.

PubMed

Yun, Ji Young; Kim, Young Eun; Yang, Hui-Jun; Kim, Han-Joon; Jeon, Beomseok

2017-01-01

This open-label study aimed to compare once-daily and twice-daily pramipexole extended release (PER) treatment in Parkinson's disease (PD). PD patients on dopamine agonist therapy, but with unsatisfactory control, were enrolled. Existing agonist doses were switched into equivalent PER doses. Subjects were consecutively enrolled into either once-daily-first or twice-daily-first groups and received the prescribed amount in one or two, respectively, daily doses for 8 weeks. For the second period, subjects switched regimens in a crossover manner. The forty-four patients completed a questionnaire requesting preference during their last visit. We measured the UPDRS-III, Hoehn and Yahr stages (H&Y) in medication-on state, Parkinson's disease sleep scale (PDSS), and Epworth Sleepiness Scale. Eighteen patients preferred a twice-daily regimen, 12 preferred a once-daily regimen, and 14 had no preference. After the trial, 14 subjects wanted to be on a once-daily regimen, 25 chose a twice-daily regimen, and 5 wanted to maintain the prestudy regimen. Main reasons for choosing the twice-daily regimen were decreased off-duration, more tolerable off-symptoms, and psychological stability. The mean UPDRS-III, H&Y, and PDSS were not different. Daytime sleepiness was significantly high in the once-daily regimen, whereas nocturnal hallucinations were more common in the twice-daily. Multiple dosing should be considered if once-daily dosing is unsatisfactory. This study is registered as NCT01515774 at ClinicalTrials.gov.

Postmastectomy radiotherapy with integrated scar boost using helical tomotherapy.

PubMed

Rong, Yi; Yadav, Poonam; Welsh, James S; Fahner, Tasha; Paliwal, Bhudatt

2012-01-01

The purpose of this study was to evaluate helical tomotherapy dosimetry in postmastectomy patients undergoing treatment for chest wall and positive nodal regions with simultaneous integrated boost (SIB) in the scar region using strip bolus. Six postmastectomy patients were scanned with a 5-mm-thick strip bolus covering the scar planning target volume (PTV) plus 2-cm margin. For all 6 cases, the chest wall received a total cumulative dose of 49.3-50.4 Gy with daily fraction size of 1.7-2.0 Gy. Total dose to the scar PTV was prescribed to 58.0-60.2 Gy at 2.0-2.5 Gy per fraction. The supraclavicular PTV and mammary nodal PTV received 1.7-1.9 dose per fraction. Two plans (with and without bolus) were generated for all 6 cases. To generate no-bolus plans, strip bolus was contoured and overrode to air density before planning. The setup reproducibility and delivered dose accuracy were evaluated for all 6 cases. Dose-volume histograms were used to evaluate dose-volume coverage of targets and critical structures. We observed reduced air cavities with the strip bolus setup compared with what we normally see with the full bolus. The thermoluminescence dosimeters (TLD) in vivo dosimetry confirmed accurate dose delivery beneath the bolus. The verification plans performed on the first day megavoltage computed tomography (MVCT) image verified that the daily setup and overall dose delivery was within 2% accuracy compared with the planned dose. The hotspot of the scar PTV in no-bolus plans was 111.4% of the prescribed dose averaged over 6 cases compared with 106.6% with strip bolus. With a strip bolus only covering the postmastectomy scar region, we observed increased dose uniformity to the scar PTV, higher setup reproducibility, and accurate dose delivered beneath the bolus. This study demonstrates the feasibility of using a strip bolus over the scar using tomotherapy for SIB dosimetry in postmastectomy treatments. Published by Elsevier Inc.

Postmastectomy radiotherapy with integrated scar boost using helical tomotherapy

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

Rong Yi, E-mail: rong@humonc.wisc.edu; University of Wisconsin Riverview Cancer Center, Wisconsin Rapids, WI; Yadav, Poonam

2012-10-01

The purpose of this study was to evaluate helical tomotherapy dosimetry in postmastectomy patients undergoing treatment for chest wall and positive nodal regions with simultaneous integrated boost (SIB) in the scar region using strip bolus. Six postmastectomy patients were scanned with a 5-mm-thick strip bolus covering the scar planning target volume (PTV) plus 2-cm margin. For all 6 cases, the chest wall received a total cumulative dose of 49.3-50.4 Gy with daily fraction size of 1.7-2.0 Gy. Total dose to the scar PTV was prescribed to 58.0-60.2 Gy at 2.0-2.5 Gy per fraction. The supraclavicular PTV and mammary nodal PTVmore » received 1.7-1.9 dose per fraction. Two plans (with and without bolus) were generated for all 6 cases. To generate no-bolus plans, strip bolus was contoured and overrode to air density before planning. The setup reproducibility and delivered dose accuracy were evaluated for all 6 cases. Dose-volume histograms were used to evaluate dose-volume coverage of targets and critical structures. We observed reduced air cavities with the strip bolus setup compared with what we normally see with the full bolus. The thermoluminescence dosimeters (TLD) in vivo dosimetry confirmed accurate dose delivery beneath the bolus. The verification plans performed on the first day megavoltage computed tomography (MVCT) image verified that the daily setup and overall dose delivery was within 2% accuracy compared with the planned dose. The hotspot of the scar PTV in no-bolus plans was 111.4% of the prescribed dose averaged over 6 cases compared with 106.6% with strip bolus. With a strip bolus only covering the postmastectomy scar region, we observed increased dose uniformity to the scar PTV, higher setup reproducibility, and accurate dose delivered beneath the bolus. This study demonstrates the feasibility of using a strip bolus over the scar using tomotherapy for SIB dosimetry in postmastectomy treatments.« less

Assessment of four methods to estimate surface UV radiation using satellite data, by comparison with ground measurements from four stations in Europe

NASA Astrophysics Data System (ADS)

Arola, Antti; Kalliskota, S.; den Outer, P. N.; Edvardsen, K.; Hansen, G.; Koskela, T.; Martin, T. J.; Matthijsen, J.; Meerkoetter, R.; Peeters, P.; Seckmeyer, G.; Simon, P. C.; Slaper, H.; Taalas, P.; Verdebout, J.

2002-08-01

Four different satellite-UV mapping methods are assessed by comparing them against ground-based measurements. The study includes most of the variability found in geographical, meteorological and atmospheric conditions. Three of the methods did not show any significant systematic bias, except during snow cover. The mean difference (bias) in daily doses for the Rijksinstituut voor Volksgezondheid en Milieu (RIVM) and Joint Research Centre (JRC) methods was found to be less than 10% with a RMS difference of the order of 30%. The Deutsches Zentrum für Luft- und Raumfahrt (DLR) method was assessed for a few selected months, and the accuracy was similar to the RIVM and JRC methods. It was additionally used to demonstrate how spatial averaging of high-resolution cloud data improves the estimation of UV daily doses. For the Institut d'Aéronomie Spatiale de Belgique (IASB) method the differences were somewhat higher, because of their original cloud algorithm. The mean difference in daily doses for IASB was about 30% or more, depending on the station, while the RMS difference was about 60%. The cloud algorithm of IASB has been replaced recently, and as a result the accuracy of the IASB method has improved. Evidence is found that further research and development should focus on the improvement of the cloud parameterization. Estimation of daily exposures is likely to be improved if additional time-resolved cloudiness information is available for the satellite-based methods. It is also demonstrated that further development work should be carried out on the treatment of albedo of snow-covered surfaces.

Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia.

PubMed

Deininger, Michael W; Kopecky, Kenneth J; Radich, Jerald P; Kamel-Reid, Suzanne; Stock, Wendy; Paietta, Elisabeth; Emanuel, Peter D; Tallman, Martin; Wadleigh, Martha; Larson, Richard A; Lipton, Jeffrey H; Slovak, Marilyn L; Appelbaum, Frederick R; Druker, Brian J

2014-01-01

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP-CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3-log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2·9-fold lower than in the IM400 arm (P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3-4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression-free (P = 0·048) and relapse-free (P = 0·031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity. © 2013 John Wiley & Sons Ltd.

Trends in erythemal doses at the Polish Polar Station, Hornsund, Svalbard based on the homogenized measurements (1996-2016) and reconstructed data (1983-1995)

NASA Astrophysics Data System (ADS)

Krzyścin, Janusz W.; Sobolewski, Piotr S.

2018-01-01

Erythemal daily doses measured at the Polish Polar Station, Hornsund (77°00' N, 15°33' E), for the periods 1996-2001 and 2005-2016 are homogenized using yearly calibration constants derived from the comparison of observed doses for cloudless conditions with the corresponding doses calculated by radiative transfer (RT) simulations. Modeled all-sky doses are calculated by the multiplication of cloudless RT doses by the empirical cloud modification factor dependent on the daily sunshine duration. An all-sky model is built using daily erythemal doses measured in the period 2005-2006-2007. The model is verified by comparisons with the 1996-1997-1998 and 2009-2010-2011 measured data. The daily doses since 1983 (beginning of the proxy data) are reconstructed using the all-sky model with the historical data of the column ozone from satellite measurements (SBUV merged ozone data set), the snow depth (for ground albedo estimation), and the observed daily sunshine duration at the site. Trend analyses of the monthly and yearly time series comprised of the reconstructed and observed doses do not reveal a statistically significant trend in the period 1983-2016. The trends based on the observed data only (1996-2001 and 2005-2016) show declining tendency (about -1 % per year) in the monthly mean of daily erythemal doses in May and June, and in the yearly sum of daily erythemal doses. An analysis of sources of the yearly dose variability since 1983 shows that cloud cover changes are a basic driver of the long-term UV changes at the site.

Biological Monitoring of Human Exposure to Neonicotinoids Using Urine Samples, and Neonicotinoid Excretion Kinetics

PubMed Central

Harada, Kouji H.; Tanaka, Keiko; Sakamoto, Hiroko; Imanaka, Mie; Niisoe, Tamon; Hitomi, Toshiaki; Kobayashi, Hatasu; Okuda, Hiroko; Inoue, Sumiko; Kusakawa, Koichi; Oshima, Masayo; Watanabe, Kiyohiko; Yasojima, Makoto; Takasuga, Takumi; Koizumi, Akio

2016-01-01

Background Neonicotinoids, which are novel pesticides, have entered into usage around the world because they are selectively toxic to arthropods and relatively non-toxic to vertebrates. It has been suggested that several neonicotinoids cause neurodevelopmental toxicity in mammals. The aim was to establish the relationship between oral intake and urinary excretion of neonicotinoids by humans to facilitate biological monitoring, and to estimate dietary neonicotinoid intakes by Japanese adults. Methodology/Principal Findings Deuterium-labeled neonicotinoid (acetamiprid, clothianidin, dinotefuran, and imidacloprid) microdoses were orally ingested by nine healthy adults, and 24 h pooled urine samples were collected for 4 consecutive days after dosing. The excretion kinetics were modeled using one- and two-compartment models, then validated in a non-deuterium-labeled neonicotinoid microdose study involving 12 healthy adults. Increased urinary concentrations of labeled neonicotinoids were observed after dosing. Clothianidin was recovered unchanged within 3 days, and most dinotefuran was recovered unchanged within 1 day. Around 10% of the imidacloprid dose was excreted unchanged. Most of the acetamiprid was metabolized to desmethyl-acetamiprid. Spot urine samples from 373 Japanese adults were analyzed for neonicotinoids, and daily intakes were estimated. The estimated average daily intake of these neonicotinoids was 0.53–3.66 μg/day. The highest intake of any of the neonicotinoids in the study population was 64.5 μg/day for dinotefuran, and this was <1% of the acceptable daily intake. PMID:26731104

Image-guided radiotherapy using megavoltage cone-beam computed tomography for treatment of paraspinous tumors in the presence of orthopedic hardware

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

Hansen, Eric K.; Larson, David A.; Aubin, Michele

Purpose: This report describes a new image-guided radiotherapy (IGRT) technique using megavoltage cone-beam computed tomography (MV-CBCT) to treat paraspinous tumors in the presence of orthopedic hardware. Methods and Materials: A patient with a resected paraspinous high-grade sarcoma was treated to 59.4 Gy with an IMRT plan. Daily MV-CBCT imaging was used to ensure accurate positioning. The displacement between MV-CBCT and planning CT images were determined daily and applied remotely to the treatment couch. The dose-volume histograms of the original and a hypothetical IMRT plan (shifted by the average daily setup errors) were compared to estimate the impact on dosimetry. Results:more » The mean setup corrections in the lateral, longitudinal, and vertical directions were 3.6 mm (95% CI, 2.6-4.6 mm), 4.1 mm (95% CI, 3.2-5.0 mm), and 1.0 mm (95% CI, 0.6-1.3 mm), respectively. Without corrected positioning, the dose to 0.1 cc of the spinal cord increased by 9.4 Gy, and the doses to 95% of clinical target volumes 1 and 2 were reduced by 4 Gy and 4.8 Gy, respectively. Conclusions: Megavoltage-CBCT provides a new alternative image-guided radiotherapy approach for treatment of paraspinous tumors in the presence of orthopedic hardware by providing 3D anatomic information in the treatment position, with clear imaging of metallic objects and without compromising soft-tissue information.« less

Antimicrobial drug use in Austrian pig farms: plausibility check of electronic on-farm records and estimation of consumption.

PubMed

Trauffler, M; Griesbacher, A; Fuchs, K; Köfer, J

2014-10-25

Electronic drug application records from farmers from 75 conventional pig farms were revised and checked for their plausibility. The registered drug amounts were verified by comparing the farmers' records with veterinarians' dispensary records. The antimicrobial consumption was evaluated from 2008 to 2011 and expressed in weight of active substance(s), number of used daily doses (nUDD), number of animal daily doses (nADD) and number of product-related daily doses (nPrDD). All results were referred to one year and animal bodyweight (kg biomass). The data plausibility proof revealed about 14 per cent of unrealistic drug amount entries in the farmers' records. The annual antimicrobial consumption was 33.9 mg/kg/year, 4.9 UDDkg/kg/year, 1.9 ADDkg/kg/year and 2.5 PrDDkg/kg/year (average). Most of the antimicrobials were applied orally (86 per cent) and at group-level. Main therapy indications were metaphylactic/prophylactic measures (farrow-to-finish and fattening farms) or digestive tract diseases (breeding farms). The proportion of the 'highest priority critically important antimicrobials' was low (12 per cent). After determination of a threshold value, farms with a high antimicrobial use could be detected. Statistical tests showed that the veterinarian had an influence on the dosage, the therapy indication and the active substance. Orally administered antimicrobials were mostly underdosed, parenterally administered antimicrobials rather correctly or overdosed. British Veterinary Association.

Quality and efficiency of statin prescribing across countries with a special focus on South Africa: findings and future implications.

PubMed

Godman, Brian; Bishop, Iain; Campbell, Stephen M; Malmström, Rickard E; Truter, Ilse

2015-04-01

Statins are recommended first-line treatment for hyperlipidemia, with published studies suggesting limited differences between them. However, there are reports of under-dosing. South Africa has introduced measures to enhance generic utilization. Part one documents prescribed doses of statins in 2011. Part two determines the extent of generics versus originator and single-sourced statins in 2011 and their costs. Underdosing of simvastatin in 2011 with average prescribed dose of 23.7 mg; however, not for atorvastatin (20.91 mg) or rosuvastatin (15.02 mg). High utilization of generics versus originators at 93-99% for atorvastatin and simvastatin, with limited utilization of single-sourced statins (22% of total statins - defined daily dose basis), mirroring Netherlands, Sweden and UK. Generics priced 33-51% below originator prices. Opportunity to increase simvastatin dosing through education, prescribing targets and incentives. Opportunity to lower generic prices with generic simvastatin 96-98% below single-sourced prices in some European countries.

Depth dose measurements with the Liulin-5 experiment inside the spherical phantom of the MATROSHKA-R project onboard the International Space Station

NASA Astrophysics Data System (ADS)

Semkova, J.; Koleva, R.; Maltchev, St.; Bankov, N.; Benghin, V.; Chernykh, I.; Shurshakov, V.; Petrov, V.; Drobyshev, S.; Nikolaev, I.

2012-02-01

The Liulin-5 experiment is a part of the international project MATROSHKA-R on the Russian segment of the ISS, which uses a tissue-equivalent spherical phantom equipped with a set of radiation detectors. The objective of the MATROSHKA-R project is to provide depth dose distribution of the radiation field inside the sphere in order to get more information on the distribution of dose in a human body. Liulin-5 is a charged particle telescope using three silicon detectors. It measures time resolved energy deposition spectra, linear energy transfer (LET) spectra, particle flux, and absorbed doses of electrons, protons and heavy ions, simultaneously at three depths along the radius of the phantom. Measurements during the minimum of the solar activity in cycle 23 show that the average absorbed daily doses at 40 mm depth in the phantom are between 180 μGy/day and 220 μGy/day. The absorbed doses at 165 mm depth in the phantom decrease by a factor of 1.6-1.8 compared to the doses at 40 mm depth due to the self-shielding of the phantom from trapped protons. The average dose equivalent at 40 mm depth is 590 ± 32 μSV/day and the galactic cosmic rays (GCR) contribute at least 70% of the total dose equivalent at that depth. Shown is that due to the South Atlantic Anomaly (SAA) trapped protons asymmetry and the direction of Liulin-5 lowest shielding zone the dose rates on ascending and descending nodes in SAA are different. The data obtained are compared to data from other radiation detectors on ISS.

Modeling Of In-Vehicle Human Exposure to Ambient Fine Particulate Matter

PubMed Central

Liu, Xiaozhen; Frey, H. Christopher

2012-01-01

A method for estimating in-vehicle PM2.5 exposure as part of a scenario-based population simulation model is developed and assessed. In existing models, such as the Stochastic Exposure and Dose Simulation model for Particulate Matter (SHEDS-PM), in-vehicle exposure is estimated using linear regression based on area-wide ambient PM2.5 concentration. An alternative modeling approach is explored based on estimation of near-road PM2.5 concentration and an in-vehicle mass balance. Near-road PM2.5 concentration is estimated using a dispersion model and fixed site monitor (FSM) data. In-vehicle concentration is estimated based on air exchange rate and filter efficiency. In-vehicle concentration varies with road type, traffic flow, windspeed, stability class, and ventilation. Average in-vehicle exposure is estimated to contribute 10 to 20 percent of average daily exposure. The contribution of in-vehicle exposure to total daily exposure can be higher for some individuals. Recommendations are made for updating exposure models and implementation of the alternative approach. PMID:23101000

Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily.

PubMed

Riha, Gordon M; Van, Philbert Y; Differding, Jerome A; Schreiber, Martin A

2012-05-01

The purpose of this study was to analyze whether 2 standard dosing regimens of enoxaparin (30 mg twice daily vs 40 mg once daily) would result in different deep vein thrombosis (DVT) rates and anti-factor Xa activity (anti-Xa) in surgical patients. Patients who required enoxaparin for prophylaxis were followed prospectively. Demographics were recorded. Patients underwent standardized duplex screening. Peak anti-Xa levels were drawn on 4 consecutive days. Sixty-three patients were followed up (28 patients on 30 mg twice daily, 35 patients on 40 mg once daily). There was no significant difference in demographics between groups. Twenty-five percent of patients on 30 mg twice daily developed a DVT, whereas 2.9% of patients on 40 mg once daily developed a DVT. Patients on 30 mg twice daily had significantly lower anti-Xa levels. The incidence of DVT is increased in surgical patients who receive 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Dosing of 40 mg once daily results in significantly higher peak anti-Xa levels compared with 30 mg twice daily. Copyright © 2012 Elsevier Inc. All rights reserved.

Radiation-induced CT number changes in GTV and parotid glands during the course of radiation therapy for nasopharyngeal cancer

PubMed Central

Xu, Shouping; Wu, Zhaoxia; Yang, Cungeng; Ma, Lin; Qu, Baolin; Chen, Guangpei; Yao, Weirong; Wang, Shi; Liu, Yaqiang

2016-01-01

Objective: To investigate the changes in CT number (CTN) in gross tumour volume (GTV) and organs at risk (OARs) during the course of radiation therapy (RT) for nasopharyngeal cancer (NPC). Methods: Daily megavoltage CT (MVCT) data collected from 30 patients with NPC treated with a prescription dose of 70 Gy in 30–33 fractions using helical tomotherapy were retrospectively analyzed. The contours of GTV and OARs on daily MVCTs were obtained by populating the planning contours from planning CT to daily MVCTs with manual editing, if necessary. The changes of GTV and OAR volumes and the histograms of CTN in the GTV and OARs during the course of RT delivery were analyzed. Results: Volumes of GTV and parotid glands were reduced during the course of radiation treatment, with an average shrinkage rate of 0.23% per day (range, 0.02–0.8%) and 1.2% per day (range, 0.2–2.3%), respectively. The mean CTN changes in GTV and ipsilateral and contralateral parotid glands were reduced by 52 ± 35 HU, 18 ± 20 HU and 17 ± 22 HU, respectively. For GTV, the CTN and GTV volume decreases were found to be correlated with each other (p < 0.0001). No noticeable CTN change was found in the spinal cord and non-specified tissue irradiated with low doses. Conclusion: The CTN changes in GTV and parotids are measurable during the delivery of fractionated radiotherapy for NPC, were associated with the doses received (the number of fractions delivered) and were patient specific. Advances in knowledge: The CTN change during radiotherapy is dose dependent and is measurable for NPC. PMID:27033059

Confirmatory field study for the evaluation of ciclosporin at a target dose of 7.0 mg/kg (3.2 mg/lb) in the control of feline hypersensitivity dermatitis.

PubMed

Roberts, Elizabeth S; Speranza, Cindy; Friberg, Cecilia; Griffin, Craig; Steffan, Jean; Roycroft, Linda; King, Stephen

2016-11-01

Objectives This study was designed to confirm the efficacy and tolerability of a daily dose of 7.0 mg/kg (3.2 mg/lb) ciclosporin (CsA) in the treatment of feline hypersensitivity dermatitis (HD), as this includes some of the most frequently suspected skin diseases in cats and recent publications have reported the successful use of CsA in the treatment of feline HD. Methods In total, 217 cats with feline HD were treated daily for 42 days with a target dose of 7 mg/kg CsA (n = 144) or a placebo control (n = 73) administered either in the food or directly in the mouth following feeding. Clinical and dermatological evaluations were conducted on days 0, 21 and 42, or study exit. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results Administration of CsA at 7.0 mg/kg produced a significant improvement in the total lesion score ( P <0.0001). The average reduction from visit 1 to visit 3 was 65.1% in the CsA group (9.2% for the placebo). In addition, owners assessed 78.3% of the cases in the CsA group as a success. Statistically significant recoveries were also seen in extent of lesions, investigator assessment of overall improvement, and mean improvement in both the investigators' and owners' assessment of pruritus. Mild gastrointestinal disorders were the most common AEs but did not require cessation of therapy. Conclusions and relevance Results confirm that 7.0 mg/kg CsA dosed daily in food or orally for up to 6 weeks is effective and well tolerated by cats with feline HD.

Radiation dose-dependent risk on individuals due to ingestion of uranium and radon concentration in drinking water samples of four districts of Haryana, India

NASA Astrophysics Data System (ADS)

Panghal, Amanjeet; Kumar, Ajay; Kumar, Suneel; Singh, Joga; Sharma, Sumit; Singh, Parminder; Mehra, Rohit; Bajwa, B. S.

2017-06-01

Uranium gets into drinking water when the minerals containing uranium are dissolved in groundwater. Uranium and radon concentrations have been measured in drinking water samples from different water sources such as hand pumps, tube wells and bore wells at different depths from various locations of four districts (Jind, Rohtak, Panipat and Sonipat) of Haryana, India, using the LED flourimetry technique and RAD7, electronic silicon solid state detector. The uranium (238U) and radon (222Rn) concentrations in water samples have been found to vary from 1.07 to 40.25 µg L-1 with an average of 17.91 µg L-1 and 16.06 ± 0.97 to 57.35 ± 1.28 Bq L-1 with an average of 32.98 ± 2.45 Bq L-1, respectively. The observed value of radon concentration in 43 samples exceeded the recommended limits of 11 Bq L-1 (USEPA) and all the values are within the European Commission recommended limit of 100 Bq L-1. The average value of uranium concentration is observed to be within the safe limit recommended by World Health Organization (WHO) and Atomic Energy Regulatory Board. The annual effective dose has also been measured in all the water samples and is found to be below the prescribed dose limit of 100 µSv y-1 recommended by WHO. Risk assessment of uranium in water is also calculated using life time cancer risk, life time average daily dose and hazard quotient. The high uranium concentration observed in certain areas is due to interaction of ground water with the soil formation of this region and the local subsurface geology of the region.

a Comparison of Evaluations and Assessments Obtained Using Alternative Standards for Predicting the Hazards of Whole-Body Vibration and Repeated Shocks

NASA Astrophysics Data System (ADS)

Lewis, C. H.; Griffin, M. J.

1998-08-01

There are three current standards that might be used to assess the vibration and shock transmitted by a vehicle seat with respect to possible effects on human health: ISO 2631/1 (1985), BS 6841 (1987) and ISO 2631-1 (1997). Evaluations have been performed on the seat accelerations measured in nine different transport environments (bus, car, mobile crane, fork-lift truck, tank, ambulance, power boat, inflatable boat, mountain bike) in conditions that might be considered severe. For each environment, limiting daily exposure durations were estimated by comparing the frequency weighted root mean square (i.e., r.m.s.) accelerations and the vibration dose values (i.e.,VDV), calculated according to each standard with the relevant exposure limits, action level and health guidance caution zones. Very different estimates of the limiting daily exposure duration can be obtained using the methods described in the three standards. Differences were observed due to variations in the shapes of the frequency weightings, the phase responses of the frequency weighting filters, the method of combining multi-axis vibration, the averaging method, and the assessment method. With the evaluated motions, differences in the shapes of the weighting filters results in up to about 31% difference in r.m.s. acceleration between the “old” and the “new” ISO standard and up to about 14% difference between BS 6841 and the “new” ISO 2631. There were correspondingly greater differences in the estimates of safe daily exposure durations. With three of the more severe motions there was a difference of more than 250% between estimated safe daily exposure durations based on r.m.s. acceleration and those based on fourth power vibration dose values. The vibration dose values provided the more cautious assessments of the limiting daily exposure duration.

Pimozide versus fluphenazine in ambulatory schizophrenics: A 12-month comparison study.

PubMed

Donlon, P T; Swaback, D O; Osborne, M L

1977-02-01

In this study, chronic schizophrenic outpatients who had been maintained on various neuroleptics for an average of about 4 years had their previous medications (approximately equivalent to 695 mg of chlorpromazine per day) changed abruptly to either pimozide or fluphenazine given in single daily oral doses on a double-blind basis for a period of 52 weeks. Average daily doses were pimozide 9.6 mg and fluphenazine 12.5 mg. Measurements of the therapeutic effects of the two drugs were made immediately prior to starting the study, at the end of the 2nd and 4th weeks, and thereafter every 4th week to the end of the study. Three psychometric scales were used for evaluation: Brief Psychiatric Rating Scale (BPRS); Evaluation of Social Functioning (ESFR); and Clinical Global Impressions (CGI). In addition, patients participated in a Social Adjustment Inventory (SAI) evaluation. Statistical analysis with the use of several statistical techniques for between- and within-drug group comparisons revealed that pimozide and fluphenazine were equally effective in maintaining control of symptomatology of chronic schizophrenics at a level commensurate with or better than that provided by their previous medication. Side effects were characteristic of marketed neuroleptics, similar in severity and occurrence between study-drug groups, mainly extrapyramidal symptoms, and readily controlled with antiparkinsonian medication. Pimozide, slightly more potent than fluphenazine, proved to be equally effective for the long-term management of chronic schizophrenic patients.

Idiopathic constipation: A challenging but manageable problem.

PubMed

Bischoff, Andrea; Brisighelli, Giulia; Dickie, Belinda; Frischer, Jason; Levitt, Marc A; Peña, Alberto

2017-10-10

A protocol to treat idiopathic constipation is presented. A contrast enema is performed in every patient and, when indicated, patients are initially submitted to a "clean out" protocol. All patients are started on a Senna-based laxative. The initial dosage is empirically determined and adjusted daily, during a one week period, based on history and abdominal radiographs, until the amount of Senna that empties the colon is reached. The management is considered successful when patients empty their colon daily and stop soiling. If the laxatives dose provokes abdominal cramping, distension, and vomiting, without producing bowel movements, patients are considered nonmanageable. From 2005 to 2012, 215 patients were treated. 121 (56%) were males. The average age was 8.2years (range: 1-20). 160 patients (74%) presented encopresis. 67 patients (32%) needed a clean out. After one week, 181 patients (84%) achieved successful management, with an average Senna dose of 67mg (range: 5-175mg). In 34 patients (16%) the treatment was unsuccessful: 19 were nonmanageable, 3 noncompliant, and 12 continued soiling. At a later follow-up (median: 329days) the success rate for 174 patients was 81%. We designed a successful protocol to manage idiopathic constipation. The key points are clean out before starting laxatives, individual adjustments of laxative, and radiological monitoring of colonic emptying. Level IV. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of organ motion on proton prostate treatments, as determined from analysis of daily CT imaging for patient positioning.

PubMed

Maeda, Yoshikazu; Sato, Yoshitaka; Shibata, Satoshi; Bou, Sayuri; Yamamoto, Kazutaka; Tamamura, Hiroyasu; Fuwa, Nobukazu; Takamatsu, Shigeyuki; Sasaki, Makoto; Tameshige, Yuji; Kume, Kyo; Minami, Hiroki; Saga, Yusuke; Saito, Makoto

2018-05-01

We quantified interfractional movements of the prostate, seminal vesicles (SVs), and rectum during computed tomography (CT) image-guided proton therapy for prostate cancer and studied the range variation in opposed lateral proton beams. We analyzed 375 sets of daily CT images acquired throughout the proton therapy treatment of ten patients. We analyzed daily movements of the prostate, SVs, and rectum by simulating three image-matching strategies: bone matching, prostate center (PC) matching, and prostate-rectum boundary (PRB) matching. In the PC matching, translational movements of the prostate center were corrected after bone matching. In the PRB matching, we performed PC matching and correction along the anterior-posterior direction to match the boundary between the prostate and the rectum's anterior region. In each strategy, we evaluated systematic errors (Σ) and random errors (σ) by measuring the daily movements of certain points on each anatomic structure. The average positional deviations in millimeter of each point were determined by the Van Herk formula of 2.5Σ + 0.7σ. Using these positional deviations, we created planning target volumes of the prostate and SVs and analyzed the daily variation in the water equivalent length (WEL) from the skin surface to the target along the lateral beam directions using the density converted from the daily CT number. Based on this analysis, we designed prostate cancer treatment planning and evaluated the dose volume histograms (DVHs) for these strategies. The SVs' daily movements showed large variations over the superior-inferior direction, as did the rectum's anterior region. The average positional deviations of the prostate in the anterior, posterior, superior, inferior, and lateral sides (mm) in bone matching, PC matching, and PRB matching were (8.9, 9.8, 7.5, 3.6, 1.6), (5.6, 6.1, 3.5, 4.5, 1.9), and (8.6, 3.2, 3.5, 4.5, 1.9) (mm), respectively. Moreover, the ones of the SV tip were similarly (22.5, 15.5, 11.0, 7.6, 6.0), (11.8, 8.4, 7.8, 5.2, 6.3), and (9.9, 7.5, 7.8, 5.2, 6.3). PRB matching showed the smallest positional deviations at all portions except for the anterior portion of the prostate and was able to markedly reduce the positional deviations at the posterior portion. The averaged WEL variations at the distal and proximal sides of planning target volumes were estimated 7-9 mm and 4-6 mm, respectively, and showed the increasing of a few millimeters in PC and PRB matching compared to bone matching. In the treatment planning simulation, the DVH values of the rectum in PRB matching were reduced compared to those obtained with other matching strategies. The positional deviations for the prostate on the posterior side and the SVs were smaller by PRB matching than the other strategies and effectively reduced the rectal dose. 3D dose calculations indicate that PRB matching with CT image guidance may do a better job relative to other positioning methods to effectively reduce the rectal complications. The WEL variation was quite large, and the appropriate margin (approx. 10 mm) must be adapted to the proton range in an initial planning to maintain the coverage of target volumes throughout entire treatment. © 2018 American Association of Physicists in Medicine.

SU-F-J-194: Development of Dose-Based Image Guided Proton Therapy Workflow

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

Pham, R; Sun, B; Zhao, T

Purpose: To implement image-guided proton therapy (IGPT) based on daily proton dose distribution. Methods: Unlike x-ray therapy, simple alignment based on anatomy cannot ensure proper dose coverage in proton therapy. Anatomy changes along the beam path may lead to underdosing the target, or overdosing the organ-at-risk (OAR). With an in-room mobile computed tomography (CT) system, we are developing a dose-based IGPT software tool that allows patient positioning and treatment adaption based on daily dose distributions. During an IGPT treatment, daily CT images are acquired in treatment position. After initial positioning based on rigid image registration, proton dose distribution is calculatedmore » on daily CT images. The target and OARs are automatically delineated via deformable image registration. Dose distributions are evaluated to decide if repositioning or plan adaptation is necessary in order to achieve proper coverage of the target and sparing of OARs. Besides online dose-based image guidance, the software tool can also map daily treatment doses to the treatment planning CT images for offline adaptive treatment. Results: An in-room helical CT system is commissioned for IGPT purposes. It produces accurate CT numbers that allow proton dose calculation. GPU-based deformable image registration algorithms are developed and evaluated for automatic ROI-delineation and dose mapping. The online and offline IGPT functionalities are evaluated with daily CT images of the proton patients. Conclusion: The online and offline IGPT software tool may improve the safety and quality of proton treatment by allowing dose-based IGPT and adaptive proton treatments. Research is partially supported by Mevion Medical Systems.« less

Control of hypertension with single daily doses of sotalol hydrochloride.

PubMed

Gabriel, R

A study was carried out in 12 previously untreated hypertensive patients to assess the efficacy of sotalol given in a once-daily dosage regimen. After an initial dosage titration period (mean 3 weeks) during which diastolic pressure was stabilized at less than 100 mmHg, all patients were satisfactorily maintained on a constant once-daily dose of sotalol for 3 months. Eight of the 12 patients required 320 mg or less daily (mean dose 190 mg). Whilst blood pressure remained controlled for at least 26 hours after daily doses the pulse rate, counted at the same time, showed escape from beta-blockade. Side-effects (vivid dreams) were reported in only 1 patient.

The use of megavoltage CT (MVCT) images for dose recomputations

NASA Astrophysics Data System (ADS)

Langen, K. M.; Meeks, S. L.; Poole, D. O.; Wagner, T. H.; Willoughby, T. R.; Kupelian, P. A.; Ruchala, K. J.; Haimerl, J.; Olivera, G. H.

2005-09-01

Megavoltage CT (MVCT) images of patients are acquired daily on a helical tomotherapy unit (TomoTherapy, Inc., Madison, WI). While these images are used primarily for patient alignment, they can also be used to recalculate the treatment plan for the patient anatomy of the day. The use of MVCT images for dose computations requires a reliable CT number to electron density calibration curve. In this work, we tested the stability of the MVCT numbers by determining the variation of this calibration with spatial arrangement of the phantom, time and MVCT acquisition parameters. The two calibration curves that represent the largest variations were applied to six clinical MVCT images for recalculations to test for dosimetric uncertainties. Among the six cases tested, the largest difference in any of the dosimetric endpoints was 3.1% but more typically the dosimetric endpoints varied by less than 2%. Using an average CT to electron density calibration and a thorax phantom, a series of end-to-end tests were run. Using a rigid phantom, recalculated dose volume histograms (DVHs) were compared with plan DVHs. Using a deformed phantom, recalculated point dose variations were compared with measurements. The MVCT field of view is limited and the image space outside this field of view can be filled in with information from the planning kVCT. This merging technique was tested for a rigid phantom. Finally, the influence of the MVCT slice thickness on the dose recalculation was investigated. The dosimetric differences observed in all phantom tests were within the range of dosimetric uncertainties observed due to variations in the calibration curve. The use of MVCT images allows the assessment of daily dose distributions with an accuracy that is similar to that of the initial kVCT dose calculation.

With adaptation, the WHO guidelines on calcium supplementation for prevention of pre-eclampsia are adopted by pregnant women.

PubMed

Omotayo, Moshood O; Martin, Stephanie L; Stoltzfus, Rebecca J; Ortolano, Stephanie E; Mwanga, Erick; Dickin, Katherine L

2018-04-01

The World Health Organization (WHO) recommends calcium supplementation for prevention of pre-eclampsia, but factors affecting adoption and acceptability of the recommendations among pregnant women have not been examined. We explored adoption of the WHO guidelines in Kenya, using the trials of improved practices. We recruited 38 pregnant women and assigned participants to three regimens representing potential trade-offs among daily dose, bioavailability, and acceptability. Participants were provided with supplements, requested to select preferred product type, counselled on how to take them, and interviewed 4 times over 6 weeks to assess their experiences. We tracked bottle opening with electronic monitors, as proxy for supplement consumption. We analysed interview transcripts thematically. All participants were willing to try the supplements. Average daily consumption ranged from 77 to 1,577 mg/d. Most participants (74%) chose the chewable product. Participants preferred its "sweet taste" and liked the ability to consume it without water. Women in the 2-dose regimen were least likely to switch; however, women assigned to the 3-dose regimen, or who switched to the 3-dose regimen, consumed the most calcium per day. Difficulties with the 4-dose regimen included afternoon doses when women were likely to forget and having to wait hours after supper for last dose. Use of an illustrated calendar, keeping supplements in conspicuous locations and requesting support from relatives were strategies that supported adherence. Pregnant women are likely to adopt Ca supplementation, with appropriate programmatic adaptations. Careful attention to product attributes, regimen complexity, and strategies for reassuring and reminding women are needed to adapt the WHO guidelines. © 2017 John Wiley & Sons Ltd.

Evaluation of indoramin added to oxprenolol and bendrofluazide as a third agent in severe hypertension.

PubMed

Marshall, A J; Kettle, M A; Barritt, D W

1980-09-01

1 Indoramin, an alpha-adrenoreceptor blocking agent has been given as a third agent to patients with severe hypertension treated with adequate doses of a beta-adrenoceptor blocking drug and a thiazide diuretic. 2 A further fall in blood pressure followed the addition of indoramin. With 75 mg twice daily this was on average a fall of 12% of mean arterial pressure in the supine position, 16% standing an 17% after exercise. 3 The rise in blood pressure caused by isometric exercise was not altered by indoramin. 4 Indoramin slowed the heart rate. On 75 mg twice daily the reduction was 14% at rest and 19% after exercise. 5 Side effects of indoramin were sedation, sleep disturbance and vivid dreams.

Case series in patients with zoster-associated pain using Mangifera indica L. extract.

PubMed

Garrido-Suárez, Beatriz; Garrido, Gabino; Delgado, Rene; Bosch, Fe; del C Rabí, María

2011-01-01

Neuroimmune activation has been proposed as a source of new targets for therapeutic intervention in neuropathic pain. Vimang® is an aqueous extract from Mangifera indica L. (common mango) that is traditionally used in Cuba for its antioxidant, anti-inflammatory, analgesic, and immunomodulatory properties. In the present case report, we determine its potential effects in patients with zoster-associated pain. 12 patients with zoster-associated pain (6 with subacute herpetic neuralgia and 6 with post-herpetic neuralgia) received a daily dose of 1,800 mg of extract (2 coated 300 mg tablets, 3 times daily before meals) together with low doses of amitriptyline (10-25 mg/day) for 120 days. In addition to the tablets, patients used Vimang® cream 1.2% as a topical agent. The average daily pain score using the Likert scale, area and rate of dynamic allodynia, rate of thermal allodynia, and frequency of burning spontaneous pain were evaluated. Pain scores and sensory abnormalities decreased significantly (p < 0.05) with respect to baseline data from week 4. No adverse events were reported. These results suggest that Vimang® could be beneficial in the treatment of neuropathic pain. However, a controlled clinical trial is necessary to confirm this hypothesis. Copyright © 2011 S. Karger AG, Basel.

Assessment of toxicity and potential risk of the anticoagulant rodenticide diphacinone using Eastern screech-owls (Megascops asio).

PubMed

Rattner, Barnett A; Horak, Katherine E; Lazarus, Rebecca S; Eisenreich, Karen M; Meteyer, Carol U; Volker, Steven F; Campton, Christopher M; Eisemann, John D; Johnston, John J

2012-04-01

In the United States, new regulatory restrictions have been placed on the use of some second-generation anticoagulant rodenticides. This action may be offset by expanded use of first-generation compounds (e.g., diphacinone; DPN). Single-day acute oral exposure of adult Eastern screech-owls (Megascops asio) to DPN evoked overt signs of intoxication, coagulopathy, histopathological lesions (e.g., hemorrhage, hepatocellular vacuolation), and/or lethality at doses as low as 130 mg/kg body weight, although there was no dose-response relation. However, this single-day exposure protocol does not mimic the multiple-day field exposures required to cause mortality in rodent pest species and non-target birds and mammals. In 7-day feeding trials, similar toxic effects were observed in owls fed diets containing 2.15, 9.55 or 22.6 ppm DPN, but at a small fraction (<5%) of the acute oral dose. In the dietary trial, the average lowest-observed-adverse-effect-level for prolonged clotting time was 1.68 mg DPN/kg owl/week (0.24 mg/kg owl/day; 0.049 mg/owl/day) and the lowest lethal dose was 5.75 mg DPN/kg owl/week (0.82 mg/kg owl/day). In this feeding trial, DPN concentration in liver ranged from 0.473 to 2.21 μg/g wet weight, and was directly related to the daily and cumulative dose consumed by each owl. A probabilistic risk assessment indicated that daily exposure to as little as 3-5 g of liver from DPN-poisoned rodents for 7 days could result in prolonged clotting time in the endangered Hawaiian short-eared owl (Asio flammeus sandwichensis) and Hawaiian hawk (Buteo solitarius), and daily exposure to greater quantities (9-13 g of liver) could result in low-level mortality. These findings can assist natural resource managers in weighing the costs and benefits of anticoagulant rodenticide use in pest control and eradication programs.

Assessment of toxicity and potential risk of the anticoagulant rodenticide diphacinone using Eastern screech-owls (Megascops asio)

USGS Publications Warehouse

Rattner, Barnett A.; Horak, Katherine E.; Lazarus, Rebecca S.; Eisenreich, Karen M.; Meteyer, Carol U.; Volker, Steven F.; Campton, Christopher M.; Eisemann, John D.; Johnston, John J.

2012-01-01

In the United States, new regulatory restrictions have been placed on the use of some second-generation anticoagulant rodenticides. This action may be offset by expanded use of first-generation compounds (e.g., diphacinone; DPN). Single-day acute oral exposure of adult Eastern screech-owls (Megascops asio) to DPN evoked overt signs of intoxication, coagulopathy, histopathological lesions (e.g., hemorrhage, hepatocellular vacuolation), and/ or lethality at doses as low as 130 mg/kg body weight, although there was no dose-response relation. However, this single-day exposure protocol does not mimic the multiple-day field exposures required to cause mortality in rodent pest species and non-target birds and mammals. In 7-day feeding trials, similar toxic effects were observed in owls fed diets containing 2.15, 9.55 or 22.6 ppm DPN, but at a small fraction (<5%) of the acute oral dose. In the dietary trial, the average lowest-observed-adverse-effect-level for prolonged clotting time was 1.68 mg DPN/kg owl/week (0.24 mg/kg owl/day; 0.049 mg/owl/day) and the lowest lethal dose was 5.75 mg DPN/kg owl/week (0.82 mg/kg owl/day). In this feeding trial, DPN concentration in liver ranged from 0.473 to 2.21 μg/g wet weight, and was directly related to the daily and cumulative dose consumed by each owl. A probabilistic risk assessment indicated that daily exposure to as little as 3-5 g of liver from DPN-poisoned rodents for 7 days could result in prolonged clotting time in the endangered Hawaiian shorteared owl (Asio flammeus sandwichensis) and Hawaiian hawk (Buteo solitarius), and daily exposure to greater quantities (9-13 g of liver) could result in low-level mortality. These findings can assist natural resource managers in weighing the costs and benefits of anticoagulant rodenticide use in pest control and eradication programs.

Prescription patterns of diuretics in Dutch community-dwelling elderly patients

PubMed Central

Van Kraaij, Dave J W; Jansen, René W M M; De Gier, Johan J; Gribnau, Frank W J; Hoefnagels, Willibrord H L

1998-01-01

Aims To describe age-and gender-related prescription patterns of diuretics in community-dwelling elderly, and to compare diuretics to other cardiovascular (CV) medications. Methods Cross-sectional study of patient-specific prescription data derived from a panel of 10 Dutch community pharmacies. Determination of proportional prescription rates and prescribed daily dose (PDD) of diuretics, cardiac glycosides, nitrates, angiotensin converting enzyme (ACE) inhibitors, β-adrenoceptor blockers, and calcium channel blockers in all 5326 patients aged 65 years or older dispensed CV medications between August 1st, 1995 and February 1st, 1996. Results Diuretics were prescribed to 2677 of 5326 patients (50.3%), 1325 patients (24.9%) using thiazides and 1198 patients (22.5%) using loop diuretics. Prescription rates of loop diuretics increased from 15.1% in patients aged 65–74 years to 37.2% in patients aged 85 years or older. Rates also increased for digoxin and nitrates. Rates for thiazide diuretics remained unchanged with age; rates for β-adrenoceptor blockers, ACE inhibitors and calcium channel blockers declined with age. Thiazides were prescribed to 30.1% of women compared with 16% of men (P<0.001). Average PDD was 135±117% of defined daily dose (DDD) for loop diuretics, and highest for bumetanide (245±2.01% of DDD, equivalent to 2.5±2.0 mg). Average PDD was 74±40% of DDD for thiazides, and highest for chlorthalidone (100±49% of DDD, equivalent to 25±12 mg). Conclusions Important characteristics of diuretic usage patterns in this elderly population were a steep increase in loop diuretic use in the oldest old, a large gender difference for thiazide use, and high prescribed doses for thiazides. PMID:9803990

Development and evaluation of a multidisciplinary controlled substances committee within a patient-centered medical home.

PubMed

Gernant, Stephanie A; Bastien, Rachel; Lai, Andrea

2015-01-01

To present the development of a multidisciplinary controlled substances committee and describe its effectiveness in relation to prescribers' acceptance of committee recommendations, the number of premature deaths associated with controlled substances, and prescribers' need for education on controlled substances. A patient-centered medical home and accountable care organization in Maine that serves more than 60,000 patients across a large rural area, 70% of whom are classified as lower income. A multidisciplinary group of prescribers and PharmD residents created a committee to influence organizational culture regarding controlled substances. The Controlled Substances Initiative Committee (CSIC) updated institutional policies, developed provider education, and made personalized patient recommendations to prescribers. The primary outcome was average change in daily morphine equivalent dose (MED) in patients for whom CSIC recommended a dose reduction to the patient's prescriber. Secondary outcomes included the proportion of patients who died of a known overdose or suspected drug-related death during 2012-2013 or 2013-2014. In addition, prescriber beliefs about controlled substances were measured via a needs assessment. The average daily MED for patients whom CSIC recommended dose reduction was lower after 3 months compared with at baseline (175.5 ± 344.3 mg vs. 292.7 ± 466.5 mg; P <0.05). The proportion of patients who died of a known overdose did not differ between 2012-2013 and 2013-2014 (11.8% vs. 11.1%; P = 1.00). However, a greater number of patients had a suspected drug-related death during 2013-2014 compared with during 2012-2013 (0% vs. 27.3%; P = 0.05). A multidisciplinary controlled substances committee may improve patient safety and outcomes by offering prescriber support and helping alter prescribing culture.

A Randomized Controlled Study of an Insulin Dosing Application That Uses Recognition and Meal Bolus Estimations

PubMed Central

Pańkowska, Ewa; Ładyżyński, Piotr; Foltyński, Piotr; Mazurczak, Karolina

2016-01-01

Background: Throughout the insulin pump therapy, decisions of prandial boluses programming are taken by patients individually a few times every day, and, moreover, this complex process requires numerical skills and knowledge in nutrition components estimation. The aim of the study was to determine the impact of the expert system, supporting the patient’s decision on meal bolus programming, on the time in range of diurnal glucose excursion in patients treated with continuous subcutaneous insulin infusion (CSII). Methods: The crossover, randomized study included 12 adults, aged 19 to 53, with type 1 diabetes mellitus, duration ranging from 7 to 30 years. Patients were educated in complex food counting, including carbohydrate units (CU) and fat-protein units (FPU). Subsequently, they were randomly allocated to the experimental group (A), which used the expert software named VoiceDiab, and the control group (B), using a manual method of meal-bolus estimation. Results: It was found that 66.7% of patients within the A group statistically reported a relevant increase in the percentage (%) of sensor glucose (SG) in range (TIR 70-180 mg/dl), compared to the B group. TIR (median) reached 53.9% in the experimental group (A) versus 44% within the control group (B), P < .05. The average difference in the number of hypoglycemia episodes was not statistically significant (–0.2%, SD 11.6%, P = .93). The daily insulin requirement in both groups was comparable—the average difference in total daily insulin dose between two groups was 0.26 (SD 7.06 IU, P = .9). Conclusion: The expert system in meal insulin dosing allows improvement in glucose control without increasing the rates of hypoglycemia or the insulin requirement. PMID:28264177

National adherence to evidence-based guidelines for the prescription of nonsteroidal anti-inflammatory drugs.

PubMed

Abraham, Neena S; El-Serag, Hashem B; Johnson, Michael L; Hartman, Christine; Richardson, Peter; Ray, Wayne A; Smalley, Walter

2005-10-01

Our objective was to assess adherence to evidence-based guidelines by providers of the Department of Veterans Affairs nationwide. This was a cross-sectional study among veterans prescribed a nonsteroidal anti-inflammatory drug (NSAID) from January 1, 2002, to December 31, 2002. Prescription data were linked to inpatient and outpatient medical records and death files. The population was characterized as high risk based on the following: age 65 years or older, concurrent corticosteroid or anticoagulant use, history of peptic ulcer, and high average daily dose of NSAIDs. Adherence was defined as the prescription of a traditional NSAID with gastroprotection or a coxib in high-risk NSAID users. Univariate and multivariate analyses assessed the potential predictors of adherence. Three hundred three thousand seven hundred eighty-seven met our definition of high risk. Most (97.3%) were male; 55.6% were white, 9.6% black, and 34.8% of other/unknown race. Age 65 years or older was the largest high-risk subset (87.1%). Overall, only 27.2% of high-risk veterans (n = 82,766) were prescribed an adherent strategy. Among veterans with at least 2 risk factors, adherence was 39.7%; among those with 3 risk factors, adherence was 41.8%. Predictors of adherence included history of upper gastrointestinal events, anticoagulant use, rheumatologic disease, high Deyo comorbidity index score, use of low-dose salicylates, and concurrent corticosteroid use. Predictors of nonadherence included prescriptions > or =90 days and high average daily dose of NSAIDs. Adherence to evidence-based guidelines for safe prescription of NSAIDs in the Department of Veterans Affairs is low (27.2%). The likelihood of adherence is further decreased if veterans are prescribed NSAIDs for > or=90 days.

Acemannan-containing wound dressing gel reduces radiation-induced skin reactions in C3H mice

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

Roberts, D.B.; Travis, E.L.

To determine (a) whether a wound dressing gel that contains acemannan extracted from aloe leaves affects the severity of radiation-induced acute skin reactions in C3H mice; (b) if so, whether other commercially available gels such as a personal lubricating jelly and a healing ointment have similar effects; and (c) when the wound dressing gel should be applied for maximum effect. Male C3H mice received graded single doses of gamma radiation ranging from 30 to 47.5 Gy to the right leg. In most experiments, the gel was applied daily beginning immediately after irradiation. Dose-response curves were obtained by plotting the percentagemore » of mice that reached or exceeded a given peak skin reaction as a function of dose. Curves were fitted by logit analysis and ED{sub 50} values, and 95% confidence limits were obtained. The average peak skin reactions of the wound dressing gel-treated mice were lower than those of the untreated mice at all radiation doses tested. The ED{sub 50} values for skin reactions of 2.0-2.75 were approximately 7 Gy higher in the wound dressing gel-treated mice. The average peak skin reactions and the ED{sub 50} values for mice treated with personal lubricating jelly or healing ointment were similar to irradiated control values. Reduction in the percentage of mice with skin reactions of 2.5 or more was greatest in the groups that received wound dressing gel for at least 2 weeks beginning immediately after irradiation. There was no effect if gel was applied only before irradiation or beginning 1 week after irradiation. Wound dressing gel, but not personal lubricating jelly or healing ointment, reduces acute radiation-induced skin reactions in C3H mice if applied daily for at least 2 weeks beginning immediately after irradiation. 31 refs., 4 figs., 1 tab.« less

Sensitivity of Daily Doses of Biologically Active Radiation, To Ozone Changes In Southern French Alps

NASA Astrophysics Data System (ADS)

de La Casinière, A.; Touré, M. L.; Masserot, D.; Lenoble, J.; Cabot, T.; Pinedo Vega, J. L.

Global UV irradiance spectra we re recorded each half an hour between sunrise and sunset, along the year 2000 in Briançon (1300m asl) at the CEMBREU (Centre Européen Médical Bioclimatique de Recherche et d'Enseignement Universitaire), a site of the French spectral UV network in Southern Alps. From these spectra are retrieved atmospheric transmissivities corresponding to daily doses of various biologically active radiation. A transmissivity is defined as the ratio of the ground level value of a daily dose to the extra -atmospheric value of this daily dose. The daily doses studied relate to UVB, erythema, DNA damage, and plant damage. Multiple linear correlations of the various transmissivities with the three predictors (daily sunshine fraction), µmin (cosine of the daily minimum SZA), and (daily total ozone column) assumed to be independent variables, are done for year 2000. These correlations permit to assess the mean sensitivities of the various transmissivities, to changes in for different cloud cover conditions in Briançon. The variations of each sensitivity is studied as a function of , µmin and . Comparing the results obtained with those given in the literature, we find for = 1 (that is for a strong probability of clear sky conditions) and SZA min = 45°, a radiation amplification factor (RAF) of the erythemal daily dose equal to 1.1 when = 285 DU, and to 1.4 when = 315 DU.

TU-H-CAMPUS-JeP2-04: Deriving Delivered Doses to Assess the Viability of 2.5 Mm Margins in Head and Neck SBRT

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

Lin, S; Shang, Q; Godley, A

Purpose: To calculate the delivered dose for head and neck SBRT patients using pre-treatment images. This delivered dose was then used to determine the viability of 2.5 mm margins. Methods: Daily cone beam CTs (CBCTs) were collected for 20 patients along with a planning CT, planned dose, and planning structures. The day 1 CBCT was aligned to the planning CT using the treatment shifts (six degrees of freedom) and then the dose and contours were transferred to the CBCT. The day 1 CBCT becomes the reference image for days 2–5. The day 2–5 CBCTs were also aligned to the planningmore » CT using the treatment shifts given and the dose transferred. The day 2–5 CBCTs were then deformably registered to the day 1 CBCT. The doses delivered on days 2–5 were then deformed to the day 1 CBCT where they could be accumulated. This was achieved with MIM 6.5.1 (MIM Software, Cleveland OH). The accumulated doses for the 20 patients were evaluated against the planned doses using the initial planning criteria as points of comparison. Results: The delivered CTV dose conformed to the planned 98.6% coverage, with an average decrease of 2.6% between planned and delivered coverage. This implies the 2.5 mm margin was sufficient. Larger CTVs correlated to smaller differences between planned and delivered coverage. Delivered dose to critical structures including the spinal cord, mandible, brain, brainstem, and larynx was acceptable, with differences between planned and delivered max dose <5% on average. Similarly for the parotid glands, globes, cochlear, optic nerve, lens, and submandibular glands, differences between planned and delivered doses were generally <5%. Conclusion: The 2.5 mm margin provided acceptable CTV coverage, adequately accounting for setup errors. Organ at risk sparing was also satisfactory. Small tumor volumes (<20 cc) may require a larger margin to treat effectively.« less

[Risk assessment of carcinogenic and non-carcinogenic effects in the use of food].

PubMed

Frolova, O A; Karpova, M V

2012-01-01

Application of methodology for assessing the risk of diseases associated with consumption of contaminated foods, is aimed at predicting possible changes in the future and helps to create a framework for the prevention of negative effects on public health. The purpose of the study is assessment of health risks formed under the influence of chemical contaminants that pollute the food. Exponential average daily dose of receipt of chemicals in the body, non-carcinogenic and carcinogenic risks were calculated.

A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors.

PubMed

Fakih, Marwan G; Fetterly, Gerald; Egorin, Merrill J; Muindi, Josephia R; Espinoza-Delgado, Igor; Zwiebel, James A; Litwin, Alan; Holleran, Julianne L; Wang, Kangsheng; Diasio, Robert B

2010-07-15

We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2). Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. Copyrighth 2010 AACR.

A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Two Schedules of Vorinostat in Combination with 5-Fluorouracil and Leucovorin in Patients with Refractory Solid Tumors

PubMed Central

Fakih, Marwan G.; Fetterly, Gerald; Egorin, Merrill J.; Muindi, Josephia R.; Espinoza-Delgado, Igor; Zwiebel, James A.; Litwin, Alan; Holleran, Julianne L.; Wang, Kangsheng; Diasio, Robert B.

2010-01-01

Purpose We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat × 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Experimental Design Vorinostat doses were escalated in a standard 3 × 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hours followed by FU 400 mg/m2 i.v. bolus and 2,400 mg/m2 over 46 hours (sLV5FU2). Results Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. Conclusions The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily × 3 or 600 mg orally twice daily × 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. PMID:20463088

Analysis of clinical efficacy, side effects, and laboratory changes among patients with acne vulgaris receiving single versus twice daily dose of oral isotretinoin.

PubMed

Ahmad, Hesham M

2015-01-01

Acne vulgaris is a debilitating disorder and requires proper treatment. This work evaluates the clinical efficacy, side effects, and laboratory changes of serum lipids and liver function during oral isotretinoin therapy for acne vulgaris, comparing single versus twice daily dose. Fifty-eight patients with acne vulgaris were included and randomized into group I (26 patients), who received once daily dose, and group II (32 patients), who received twice daily dose of oral isotretinoin. Global acne scoring system was used to evaluate acne severity and post-treatment improvement. Both regimens resulted in highly significant clinical improvement of acne with no significant difference. However, side effects were significantly more common among patients of group I. Both regimens caused mild rise of serum cholesterol, alanine transaminase (ALT), and aspartate aminotransferase (AST) with more prominent rise of triglycerides especially with twice daily dose. Oral isotretinoin is a very effective treatment for acne vulgaris with no statistically significant difference in clinical efficacy between once and twice daily doses. However, dividing dose to twice per day might cause fewer incidence of side effects without reducing clinical efficacy. The drug causes mild clinically insignificant rise of serum cholesterol, triglycerides, AST, and ALT. © 2015 Wiley Periodicals, Inc.

Impact of a planned dose interruption of dacomitinib in the treatment of advanced non-small-cell lung cancer (ARCHER 1042)

PubMed Central

Kim, Dong-Wan; Garon, Edward B.; Jatoi, Aminah; Keefe, Dorothy M.; Lacouture, Mario E.; Sonis, Stephen; Gernhardt, Diana; Wang, Tao; Giri, Nagdeep; Doherty, Jim P.; Nadanaciva, Sashi; O’Connell, Joseph; Sbar, Eric; Cho, Byoung Chul

2017-01-01

Objectives Dacomitinib is a pan-HER inhibitor for advanced non-small-cell lung cancer (NSCLC). We explored the impact of a planned 4-day dacomitinib dose interruption on plasma exposure of dacomitinib and adverse events (AEs) of interest in Cohort III of the ARCHER 1042 study. Materials and methods Patients, treatment-naïve for advanced NSCLC with EGFR activating mutations, received oral dacomitinib 45 mg QD (once daily). A planned dose interruption occurred in Cycle 1 from Days 11 through 14. The primary endpoint was the pharmacokinetic (PK) characteristics of dacomitinib in Cycle 1 Day 10 and during dose interruption. Secondary endpoints included safety and concomitant medications used to treat AEs of interest. Results Cohort III enrolled 25 patients. Median plasma Cmax of dacomitinib in Cycle 1 Day 10 was 83.40 ng/mL. Average median plasma dacomitinib concentration during the 4-day dose interruption was 42.63 ng/mL. In the first 8 weeks of treatment 1) 80% of patients used concomitant medications for dermatologic AEs, 76% for diarrhea, and 44% for stomatitis, and 2) all patients experienced treatment-emergent AEs and 28% had all-causality Grade 3 AEs. Conclusion At 45 mg QD dosing, PK parameters of plasma dacomitinib in Cycle 1 Day 10 were comparable to that obtained in Cycle 1 Day 14 from other dacomitinib studies. Average median plasma dacomitinib concentration during the 4-day dose interruption was approximately half of the median plasma Cmax of dacomitinib observed prior to dose interruption. The toxicity profile was consistent with that from other studies of dacomitinib. PMID:28285698

The Hypertension Optimal Treatment (HOT) Study--patient characteristics: randomization, risk profiles, and early blood pressure results.

PubMed

Hansson, L; Zanchetti, A

1994-09-01

The Hypertension Optimal Treatment (HOT) Study is a prospective, randomized, multicenter trial being conducted in 26 countries. Its main aim is to evaluate the relationship between three levels of target diastolic blood pressure (< or = 90, < or = 85 or < or = 80 mmHg) and cardiovascular morbidity and mortality in hypertensive patients. In addition, the study will examine the effects on morbidity and mortality of a low dose, 75 mg daily, of acetylsalicylic acid (ASA, aspirin) or placebo. In the HOT Study, basic antihypertensive treatment is initiated with the calcium antagonist felodipine at a dose of 5 mg daily. If target blood pressure is not reached, additional antihypertensive therapy with either an angiotensin converting enzyme (ACE) inhibitor or a beta-adrenoceptor blocking agent is given. Further dosage adjustments are made in accordance with a set protocol. As a fifth and final step, a diuretic may be added. Inclusion of patients was stopped on April 30, 1994. At that time 19,196 patients had been randomized. There were 9,055 (47%) women and 10,141 (53%) men with an average age of 61.5 +/- 7.5 (SD) years. At enrollment, 52% of patients were receiving antihypertensive treatment. These patients entered a wash-out period of at least 2 weeks before randomization. The average randomization blood pressure in untreated patients was 169 +/- 14/106 +/- 3 mmHg and in the treated patients 170 +/- 14/105 +/- 3 mmHg. On August 15, 1994, blood pressure data were available for 14,710 and 10,275 patients, who had completed 3 and 6 months treatment, respectively. The average reduction in diastolic blood pressure was 22 mmHg after 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency of Acute Kidney Injury Caused by Tazobactam/Piperacillin in Patients with Pneumonia and Chronic Kidney Disease: A Retrospective Observational Study.

PubMed

Morimoto, Takeyori; Nagashima, Hiroki; Morimoto, Yasuko; Tokuyama, Shogo

2017-01-01

 Tazobactam/piperacillin (TAZ/PIPC) is a combination antibiotic frequently used to treat pneumonia. It has recently been reported that TAZ/PIPC worsens renal function in patients with existing renal impairment. Creatinine clearance is generally between 10 and 40 mL/min in Japanese patients, so TAZ/PIPC is given at a dose of 2.25 g three times daily or 4.5 g twice daily. If pneumonia is severe or intractable, the dose frequency may be increased to 2.25 g four times daily and 4.5 g three times daily. We examined the effect of these different dosing regimens on renal function. We studied a cohort of 57 patients with impaired renal function hospitalized with pneumonia and treated with TAZ/PIPC between January 2015 and November 2016. Patients were classified into four groups according to TAZ/PIPC dose: 2.25 g three times daily (Group A); 2.25 g four times daily (B); 4.5 g twice daily (C) and 4.5 g three times daily (D). We examined the frequency of acute kidney injury (AKI) and treatment effectiveness. In Groups A, B, C and D, AKI occurred in 5.6%, 0.0%, 25.0% and 38.5% of patient. In groups C and D, hydration and dose reduction were required to address early signs of impending AKI. Our findings suggest that the higher TAZ/PIPC dose of 4.5 g was responsible for the decline in renal function, even if the dose frequency was reduced.

One and three doses of propranolol a day in hypertension.

PubMed

van den Brink, G; Boer, P; van Asten, P; Dorhout Mees, E J; Geyskes, G G

1980-01-01

In 26 patients with essential hypertension who were on continuous chlorthalidone therapy, 1 and 3 daily doses of propranolol were compared in a crossover study. Plasma propranolol levels and heart rates had larger daily fluctuations on single-dose therapy than on 3 times daily; plasma renin activity was more constant. There was no significant difference in blood pressures. Once-daily propranolol dosage was well tolerated and possibly gave less rise to the troublesome side effect of vivid dreaming.

Risk of Radiation Retinopathy in Patients With Orbital and Ocular Lymphoma

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

Kaushik, Megha; Pulido, Jose S.; Schild, Steven E.

2012-12-01

Purpose: Radiation retinopathy is a potential long-term complication of radiation therapy to the orbit. The risk of developing this adverse effect is dose dependent; however, the threshold is unclear. The aim of this study was to identify the risk of developing radiation retinopathy at increasing radiation doses. Methods and Materials: A 40-year retrospective review was performed of patients who received external beam radiation therapy for ocular/orbital non-Hodgkin lymphoma (NHL). Results: Sixty-seven patients who had at least one ophthalmic follow-up examination were included in this study. Most patients (52%) were diagnosed with NHL involving the orbit. Patients received external beam radiationmore » therapy at doses between 1886 and 5400 cGy (mean, 3033 {+-} 782 cGy). Radiation retinopathy developed in 12% of patients, and the median time to diagnosis was 27 months (range, 15-241months). The mean prescribed radiation dose in patients with retinopathy was 3309 {+-} 585 cGy, and the estimated retinal dose (derived by reviewing the dosimetry) was 3087 {+-} 1030 cGy. The incidence of retinopathy increased with dose. The average prescribed daily fractionated dose was higher in patients who developed retinopathy than in patients who did not (mean, 202 cGy vs 180 cGy, respectively; P = .04). More patients with radiation retinopathy had comorbid diabetes mellitus type 2 than patients without retinopathy (P = .015). In our study, the mean visual acuity of the eyes that received radiation was worse than that of the eyes that did not (P = .027). Other postradiotherapy ocular findings included keratitis (6%), dry eyes (39%), and cataract (33%). Conclusions: Radiation retinopathy, a known complication of radiotherapy for orbital tumors, relates to vascular comorbidities and dose. Higher total doses and larger daily fractions (>180 cGy) appear to be related to higher rates of retinopathy. Future larger studies are required to identify a statistically significant threshold for the development of retinopathy.« less

Range of therapeutic metformin concentrations in clinical blood samples and comparison to a forensic case with death due to lactic acidosis.

PubMed

Hess, C; Unger, M; Madea, B; Stratmann, B; Tschoepe, D

2018-05-01

Due to a lack of reference values for blood concentration of metformin in the literature, the forensic evaluation of metformin findings in blood samples is difficult. Interpretations with regard to the assessment of blood concentrations as well as an estimation of the ingested metformin amounts are often vague. Furthermore, post mortem evaluation of death due to lactic acidosis because of metformin is difficult since renal performance or lactate concentrations can not always reliably be determined after death. To describe a concentration range in clinical samples after chronic use of metformin, metformin serum concentrations were determined in serum samples of 95 diabetic patients receiving daily doses of 500mg-3000mg of metformin. The analyses of metformin was carried out using a validated high performance liquid chromatograph coupled to triple quadrupole mass spectrometry (LC-QQQ-MS). On average, metformin concentrations were 1846ng/mL (

Graduate student voice use and vocal efficiency in an opera rehearsal week: a case study.

PubMed

Schloneger, Matthew J

2011-11-01

The purpose of this case study was to document graduate voice students' (N=2) voice use before, during, and after an intense week of opera rehearsals through (1) acquired Ambulatory Phonation Monitor (APM) data, (2) daily surveys, (3) participant activity logs, (4) three administrations of the Singing Voice Handicap Index (SVHI), and (5) pre- and post-stroboscopic laryngeal examinations. Two female graduate students, both of whom were cast in a university production of Stravinsky's The Rake's Progress (stage names Anne and Baba) and both of whom served as graduate teaching assistants in voice, wore APMs during waking hours for 9 days, including two pretest baseline days, a 5-day intensive rehearsal week just before the opera production week, and 2 baseline days after opera performances were completed. Mean phonation time dose percentages (Dt) and daily distance dose averages (Dd) were similar between the pre- and posttest periods and the intensive week. Disaggregation of acquired data by four types of activities (opera rehearsals, personal practice time, voice teaching time, and nonrehearsal or teaching time) indicated that the highest mean Dts and Dds were acquired during personal practice time and voice teaching time. Daily surveys and SVHI data as well as the pre- and post-stroboscopies indicated no notable changes occurring in vocal health. Results indicated that these singers were conscious about their voice use during periods of extensive performance demands. However, high vocal doses during voice teaching times suggest that these individuals might benefit from teacher voice care education. Copyright © 2011 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Efficacy, Safety, and Tolerability of an Extended-Release Orally Disintegrating Methylphenidate Tablet in Children 6-12 Years of Age with Attention-Deficit/Hyperactivity Disorder in the Laboratory Classroom Setting.

PubMed

Childress, Ann C; Kollins, Scott H; Cutler, Andrew J; Marraffino, Andrea; Sikes, Carolyn R

2017-02-01

Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) represent a new technology for MPH delivery. ODTs disintegrate in the mouth without water and provide a pharmacokinetic profile that is consistent with once-daily dosing. This study sought to determine the efficacy, safety, and tolerability of this novel MPH XR-ODT formulation in school-age children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. Children aged 6-12 years with ADHD (n = 87) were enrolled in this randomized, multicenter, double-blind, placebo-controlled, parallel, laboratory classroom study. The MPH XR-ODT dose was titrated to an optimized dose during a 4-week open-label period and maintained on that dose for 1 week. Participants (n = 85) were then randomized to receive their optimized dose of MPH XR-ODT or placebo once daily for 1 week (double blind), culminating in a laboratory classroom testing day. Efficacy was evaluated using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Attention, Deportment, and Combined scores along with Permanent Product Measure of Performance (PERMP; Attempted and Correct) assessments. Onset and duration of drug action were also evaluated as key secondary endpoints. Safety assessments included adverse events (AEs), physical examinations, electrocardiograms (ECGs), and the Columbia Suicide Severity Rating Scale (C-SSRS). The average SKAMP-Combined score on the classroom study day was significantly better for the MPH XR-ODT group (n = 43) than for the placebo group (n = 39; p < 0.0001). The effect was evident at 1 hour and lasted through 12 hours postdose. The average SKAMP-Attention, SKAMP-Deportment, PERMP-A, and PERMP-C scores were indicative of significantly greater ADHD symptom control for the MPH XR-ODT group. The most common AEs reported were decreased appetite, upper abdominal pain, headache, insomnia, upper respiratory tract infection, affect lability, irritability, cough, and vomiting. MPH XR-ODT was effective and well tolerated for the treatment of children with ADHD in a laboratory classroom setting. Clinical Trial Registry: NCT01835548 ( ClinicalTrials.gov ).

Increased medication compliance of liver transplant patients switched from a twice-daily to a once-daily tacrolimus-based immunosuppressive regimen.

PubMed

Eberlin, M; Otto, G; Krämer, I

2013-01-01

Compliance with immunosuppressive therapy plays a major role in the long-term success of liver transplantation. Thus, the development of strategies to promote compliance of liver transplant patients and its evaluation over time are of particular interest. The main objective of this study was to compare medication compliance rates among liver transplant patients over time after transplantation where switched from a twice- to once-daily tacrolimus-based regimen. Sixty-five liver transplant patients being administered tacrolimus-based therapy were classified into three subgroups with regard to time posttransplantation. Medication compliance with tacrolimus-based therapy was measured using an electronic medication event monitoring system over a 12-month period: for 6 months tacrolimus was administered twice-daily and for 6 months, once-daily. Dosing, taking, and timing compliance as well as drug holidays were compared intra-individually between twice- and once-daily intake and among the three subgroups. In addition, patient compliance and quality of life were evaluated using questionnaires. A per protocol analysis of electronically obtained data showed 63 patients to be eligible. The resulting dosing, taking, and timing compliance rates of the patients were higher during the once-daily dosing period. No significant differences in compliance rates with tacrolimus therapy were observed among three subgroups independent of the dosing regimen. More patients failed the correct timing of the evening compared to the morning dose. Missing doses occurred particularly during weekends. Compliance variables measured by questionnaires (Morisky score, self-report, Medication Experience Scale for Immunosuppressants (MESI) score) and the Hospital Anxiety and Depression Scale score were similar in the two dosing periods. The short-form health survey (SF-36) score was higher with once-daily intake. The high measured compliance rates did not vary significantly dependent upon the time after transplantation. Nevertheless, compliance rates were greater using once-daily tacrolimus dosing. Copyright © 2013 Elsevier Inc. All rights reserved.

Assessing health risk due to exposure to arsenic in drinking water in Hanam Province, Vietnam.

PubMed

Huy, Tung Bui; Tuyet-Hanh, Tran Thi; Johnston, Richard; Nguyen-Viet, Hung

2014-07-24

We assessed health risks related to Arsenic (As) in contaminated drinking water in Hanam, applying the Australian Environmental Health Risk Assessment Framework, which promotes stakeholder involvement in risk assessments. As concentrations in 300 tube-well water samples, before and after filtration, were analyzed and the water consumption levels in 150 households were estimated. Skin cancer risk was characterized using Cancer Slope Factor index and lifetime average daily dose with a probabilistic approach. The results showed that arsenic concentrations in tube-well water ranged from 8-579 ppb (mean 301 ppb) before filtration and current sand filters used by the households did not meet the standard for As removal. Arsenic daily consumption of 40% of the adults exceeded the level of TDI (Tolerable Daily Intake) at 1 µg/kg/day. The average skin cancer risk in adults due to consuming filtered tube-well water for drinking purpose were 25.3 × 10-5 (using only well water) and 7.6 × 10-5 (using both well and rain water). The skin cancer risk would be 11.5 times higher if the water was not filtered. Improvement of filtration measures or the replacement of the current drinking water sources to minimize the health risks to the local population is urgently needed.

Assessing Health Risk due to Exposure to Arsenic in Drinking Water in Hanam Province, Vietnam

PubMed Central

Bui Huy, Tung; Tuyet-Hanh, Tran Thi; Johnston, Richard; Nguyen-Viet, Hung

2014-01-01

We assessed health risks related to Arsenic (As) in contaminated drinking water in Hanam, applying the Australian Environmental Health Risk Assessment Framework, which promotes stakeholder involvement in risk assessments. As concentrations in 300 tube-well water samples, before and after filtration, were analyzed and the water consumption levels in 150 households were estimated. Skin cancer risk was characterized using Cancer Slope Factor index and lifetime average daily dose with a probabilistic approach. The results showed that arsenic concentrations in tube-well water ranged from 8–579 ppb (mean 301 ppb) before filtration and current sand filters used by the households did not meet the standard for As removal. Arsenic daily consumption of 40% of the adults exceeded the level of TDI (Tolerable Daily Intake) at 1 µg/kg/day. The average skin cancer risk in adults due to consuming filtered tube-well water for drinking purpose were 25.3 × 10−5 (using only well water) and 7.6 × 10−5 (using both well and rain water). The skin cancer risk would be 11.5 times higher if the water was not filtered. Improvement of filtration measures or the replacement of the current drinking water sources to minimize the health risks to the local population is urgently needed. PMID:25062276

Effect of glyphosate on reproductive organs in male rat.

PubMed

Dai, Pengyuan; Hu, Ping; Tang, Juan; Li, Yansen; Li, Chunmei

2016-06-01

Glyphosate as an active ingredient of Roundup(®) which is thought to be one of the most popular herbicide was used worldwide. Many studies have focused on reproductive toxicity on glyphosate-based herbicide, but few evidence exists to imply the male reproductive toxicity of glyphosate alone in vivo. In this study SD rats were Lavaged with glyphosate at doses of 5, 50, 500mg/kg to detect the toxicity of glyphosate on rat testis. Glyphosate significantly decreased the average daily feed intake at dose of 50mg/kg, and the weight of seminal vesicle gland, coagulating gland as well as the total sperm count at dose of 500mg/kg. Immunohistochemistry of androgen receptor (AR) has no difference among all groups. As to testosterone, estradiol, progesterone and oxidative stress parameters, the level of them has no differences amidst all doses. Taken together, we conclude that glyphosate alone has low toxicity on male rats reproductive system. Copyright © 2016 Elsevier GmbH. All rights reserved.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

PubMed

Senni, Michele; McMurray, John J V; Wachter, Rolf; McIntyre, Hugh F; Reyes, Antonio; Majercak, Ivan; Andreka, Peter; Shehova-Yankova, Nina; Anand, Inder; Yilmaz, Mehmet B; Gogia, Harinder; Martinez-Selles, Manuel; Fischer, Steffen; Zilahi, Zsolt; Cosmi, Franco; Gelev, Valeri; Galve, Enrique; Gómez-Doblas, Juanjo J; Nociar, Jan; Radomska, Maria; Sokolova, Beata; Volterrani, Maurizio; Sarkar, Arnab; Reimund, Bernard; Chen, Fabian; Charney, Alan

2016-09-01

To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group. © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

A 5-year follow-up study of users of benzodiazepine: starting with diazepam versus oxazepam.

PubMed

Tvete, Ingunn Fride; Bjørner, Trine; Skomedal, Tor

2016-04-01

Drug dependency may develop during long-term benzodiazepine use, indicated, for example, by dose escalation. The first benzodiazepine chosen may affect the risk of dose escalation. To detect possible differences in benzodiazepine use between new users of diazepam and oxazepam over time. This 5-year prescription database study included 19 747 new benzodiazepine users, inhabitants of Norway, aged 30-60 years, with first redemption for diazepam or oxazepam. Individuals starting on diazepam versus oxazepam were analysed by logistic regression with sex, age, other drug redemptions, prescriber's specialty, household income, education level, type of work, and vocational rehabilitation support as background variables. Time to reach a daily average intake of ≥1 defined daily doses (DDD) over a 3-month period was analysed using a Cox proportional hazard regression model. New users of oxazepam had a higher risk for dose escalation compared with new users of diazepam. This was true even when accounting for differences in sociodemographic status and previous drug use (hazard ratio [HR] 1.33, 95% confidence interval = 1.17 to 1.51). Most doctors prescribed, according to recommendations, oxazepam to individuals they may have regarded as prone to and at risk of dependency. However, these individuals were at higher risk for dose escalation even when accounting for differences in sociodemographic status and previous drug use. Differences between the two user groups could be explained by different preferences for starting drug, DDD for oxazepam being possibly too low, and some unaccounted differences in illness. © British Journal of General Practice 2016.

Pharmacokinetic/pharmacodynamic integration and modelling of oxytetracycline for the porcine pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida.

PubMed

Dorey, L; Pelligand, L; Cheng, Z; Lees, P

2017-10-01

Pharmacokinetic-pharmacodynamic (PK/PD) integration and modelling were used to predict dosage schedules of oxytetracycline for two pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in broth and porcine serum. PK/PD integration established ratios of average concentration over 48 h (C av0-48 h )/MIC of 5.87 and 0.27 μg/mL (P. multocida) and 0.70 and 0.85 μg/mL (A. pleuropneumoniae) for broth and serum MICs, respectively. PK/PD modelling of in vitro time-kill curves established broth and serum breakpoint values for area under curve (AUC 0-24 h )/MIC for three levels of inhibition of growth, bacteriostasis and 3 and 4 log 10 reductions in bacterial count. Doses were then predicted for each pathogen, based on Monte Carlo simulations, for: (i) bacteriostatic and bactericidal levels of kill; (ii) 50% and 90% target attainment rates (TAR); and (iii) single dosing and daily dosing at steady-state. For 90% TAR, predicted daily doses at steady-state for bactericidal actions were 1123 mg/kg (P. multocida) and 43 mg/kg (A. pleuropneumoniae) based on serum MICs. Lower TARs were predicted from broth MIC data; corresponding dose estimates were 95 mg/kg (P. multocida) and 34 mg/kg (A. pleuropneumoniae). © 2017 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial.

PubMed

Bunnapradist, S; Ciechanowski, K; West-Thielke, P; Mulgaonkar, S; Rostaing, L; Vasudev, B; Budde, K

2013-03-01

Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice-daily tacrolimus to a novel extended-release once-daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection [BPAR], or loss to follow-up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4-15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once-daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

TU-AB-BRA-11: Indications for Online Adaptive Radiotherapy Based On Dosimetric Consequences of Interfractional Pancreas-To-Duodenum Motion in MRI-Guided Pancreatic Radiotherapy

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

Mittauer, K; Rosenberg, S; Geurts, M

Purpose: Dose limiting structures, such as the duodenum, render the treatment of pancreatic cancer challenging. In this multi-institutional study, we assess dosimetric differences caused by interfraction pancreas-to-duodenum motion using MR-IGRT to determine the potential impact of adaptive replanning. Methods: Ten patients from two institutions undergoing MRI-guided radiotherapy with conventional fractionation (n=5) or SBRT (n=5) for pancreatic cancer were included. Initial plans were limited by duodenal dose constraints of 50 Gy (0.5 cc)/31 Gy (0.1 cc) for conventional/SBRT with prescriptions of 30 Gy/5 fractions (SBRT) and 40–50 Gy/25 fractions (conventional). Daily volumetric MR images were acquired under treatment conditions on amore » clinical MR-IGRT system. The correlation was assessed between interfractional GTV-to-duodenum positional variation and daily recalculations of duodenal dose metrics. Positional variation was quantified as the interfraction difference in Hausdorff distance from simulation baseline (ΔHD) between the GTV and proximal duodenal surface, or volume overlap between GTV and duodenum for cases with HD{sub 0}=0 (GTV abutting duodenum). Adaptation was considered indicated when daily positional variations enabled dose escalation to the target while maintaining duodenal constraints. Results: For fractions with ΔHD>0 (n=14, SBRT only), the mean interfraction duodenum dose decrease from simulation to treatment was 44±53 cGy (maximum 136 cGy). A correlation was found between ΔHD and dosimetric difference (R{sup 2}=0.82). No correlation was found between volume of overlap and dosimetric difference (R{sup 2}=0.31). For 89% of fractions, the duodenum remained overlapped with the target and the duodenal dose difference was negligible. The maximum observed indication for adaptation was for interfraction ΔHD=11.6 mm with potential for adaptive dose escalation of 136 cGy. Conclusion: This assessment showed that Hausdorff distance was a reasonable metric to use to determine the indication for adaptation. Adaptation was potentially indicated in 11% of the treatments (fractions where GTV-to-duodenum distance increased from simulation), with a feasible average dose escalation of 7.0%. MB, LH, JO, RK, PP: research and/or travel funding from ViewRay Inc. PP: research grant from Varian Medical Systems and Philips Healthcare.« less

Conversion From Twice-Daily Tacrolimus Capsules to Once-Daily Extended-Release Tacrolimus (LCPT): A Phase 2 Trial of Stable Renal Transplant Recipients

PubMed Central

Gaber, A. Osama; Alloway, Rita R.; Bodziak, Kenneth; Kaplan, Bruce; Bunnapradist, Suphamai

2013-01-01

Background LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Phase 1 studies demonstrated greater bioavailability to twice-daily tacrolimus capsules and no new safety concerns. Methods In this phase 2 study, adult stable kidney transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8 to 21; trough levels were to be maintained between 5 and 15 ng/mL; 24-hr pharmacokinetic assessments were done on days 7 (baseline pre-switch), 14, and 21. Results Forty-seven patients completed LCP-Tacro dosing per protocol. The mean conversion ratio was 0.71. Pharmacokinetic data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax (P=0.0001), Cmax/Cmin ratio (P<0.001), percent fluctuation (P<0.0001), and swing (P=0.0004) were significantly lower and Tmax significantly (P<0.001) longer for LCP-Tacro versus Prograf. AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy were 0.86 or more, demonstrating a robust correlation between LCP-Tacro tacrolimus exposure and trough levels. There were three serious adverse events; none were related to study drug and all were resolved. Conclusions Stable kidney transplant patients can be safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allows for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displays flatter kinetics characterized by significantly lower peak-trough fluctuations. PMID:23715050

A novel method of estimating cost of therapy by using patient population characteristics: analysis of fluoroquinolones in various populations with different distributions of renal function.

PubMed

Enzweiler, Kevin A; Bosso, John A; White, Roger L

2003-07-01

Formulary decisions regarding a given drug class are often made in the absence of patient outcome and/or sophisticated pharmacoeconomic data. Analyses that consider factors beyond simple acquisition costs may be useful in such situations. For example, the cost implications of using manufacturers' recommendations for dosing in patients with renal dysfunction may be important, depending on the distribution of various levels of renal function within a patient population. Using four 1000-patient populations representing different renal function distributions and a fifth population of our medical center's distribution, we determined the costs of therapy for intravenous and oral levofloxacin, gatifloxacin, and moxifloxacin for a 10-day course of therapy for community-acquired pneumonia. Costs considered were average wholesale prices (AWPs), 50% of AWP, or same daily price, plus intravenous dose preparation and administration costs when applicable. Costs for each renal function distribution were examined for significant differences with an analysis-of-variance test. Also, costs of failing to adjust dosing regimens for decreased renal function were determined. Differences in fluoroquinolone costs (AWP, 50% AWP, or when matched as the same daily price) among the populations were found. When considering same daily prices, differences among populations ranged from about 35,000 dollars with intravenous gatifloxacin to more than 51,000 dollars for intravenous levofloxacin (all fluoroquinolones, p>0.05). Within a population, differences in costs among the intravenous fluoroquinolones ranged from 47,000-99,000 dollars. Rank orders of the drugs and population costs of therapy were affected by the pricing structure used and varied by the specific population and drug. Differences among the fluoroquinolones or populations were much smaller (<2100 dollars) when considering oral regimens. Costs potentially incurred by failing to adjust dosing for renal function were substantial. Formulary decisions can be facilitated by considering factors such as patient characteristics and related dosing in addition to simple acquisition costs. In our example, consideration of the distribution of renal function within a given patient population and related dosing for these fluoroquinolones revealed potentially important differences within the class.

Understanding Adherence to Daily and Intermittent Regimens of Oral HIV Pre-exposure Prophylaxis Among Men Who Have Sex with Men in Kenya.

PubMed

Mugo, Peter Mwangi; Sanders, Eduard J; Mutua, Gaudensia; van der Elst, Elisabeth; Anzala, Omu; Barin, Burc; Bangsberg, David R; Priddy, Frances H; Haberer, Jessica E

2015-05-01

A qualitative assessment of Kenyan men who have sex with men taking daily and intermittent oral HIV pre-exposure prophylaxis (PrEP) found stigma, sex work, mobility, and alcohol impacted adherence. We analyzed quantitative data from the same cohort to explore different definitions of intermittent adherence. Volunteers were randomized to daily emtricitabine/tenofovir or placebo, or intermittent (prescription: Mondays/Fridays/after sex, maximum 1 dose/day) emtricitabine/tenofovir or placebo (2:1:2:1), and followed for 4 months. By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a "relaxed" definition (accounting for off-prescription dosing) and 40 % per a "strict" definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP.

Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers.

PubMed

Mutua, Gaudensia; Sanders, Eduard; Mugo, Peter; Anzala, Omu; Haberer, Jessica E; Bangsberg, David; Barin, Burc; Rooney, James F; Mark, David; Chetty, Paramesh; Fast, Patricia; Priddy, Frances H

2012-01-01

Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63-92] for daily dosing and 55% [IQR:28-78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14-50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens. ClinicalTrials.gov NCT00971230.

Long-term erythemal UV doses at Sodankylä estimated using total ozone, sunshine duration and snow depth

NASA Astrophysics Data System (ADS)

Lindfors, A. V.; Arola, A.; Kaurola, J.; Taalas, P.; Svenøe, T.

2003-04-01

A method for estimating daily erythemal UV doses using total ozone, sunshine duration and snow depth has been developed. The method consists of three steps: (1) daily clear-sky UV doses were simulated using the UVSPEC radiative transfer program, with daily values of total ozone as input data, (2) an empirical relationship was sought between the simulated clear-sky UV doses, the measured UV doses and the duration of bright sunshine, (3) daily erythemal UV doses were estimated using this relationship. The method accounts for the varying surface albedo by dividing the period of interest into winter and summer days, depending on the snow depth. Using this method, the daily erythemal UV doses at Sodankylä were estimated for the period 1950--99. This was done using Tromsø's total ozone together with Sodankylä's own sunshine duration and snow depth as input data. Although the method is fairly simple, the results are in good agreement, even on the daily scale, with the UV radiation measured with the Brewer spectrophotometer at Sodankylä. Statistically significant increasing trends in erythemal UV doses of a few percents per decade over the period 1950--99 were found for March and April, suggesting a connection to the stratospheric ozone depletion. For July, on the other hand, a significant decreasing trend of about 3% per decade, supported by the changes in both total ozone and sunshine duration, was found. The produced data set of erythemal UV doses is the longest time series of estimated UV known to the authors.

Clinical practice variations in prescribing antipsychotics for patients with schizophrenia.

PubMed

Owen, Richard R; Fischer, Ellen P; Kirchner, JoAnn E; Thrush, Carol R; Williams, D Keith; Cuffel, Brian J; Elliott, Carl E; Booth, Brenda M

2003-01-01

Few studies have examined the variations among individual physicians in prescribing antipsychotics for schizophrenia. This study examined clinical practice variations in the route and dosage of antipsychotic medication prescribed for inpatients with schizophrenia by 11 different psychiatrists. The sample consisted of 130 patients with a DSM-III-R diagnosis of schizophrenia who had received inpatient care at a state hospital or Veterans Affairs medical center in the southeastern United States in 1992-1993. Mixed-effects regression models were developed to explore the influence of individual physicians and hospitals on route of antipsychotic administration (oral or depot) and daily antipsychotic dose, controlling for patient case-mix variables (age, race, sex, duration of illness, symptom severity, and substance-abuse diagnosis). The average daily antipsychotic dose was 1092 +/- 892 chlorpromazine mg equivalents. Almost half of the patients (48%) were prescribed doses above or below the range recommended by current practice guidelines. The proportion of patients prescribed depot antipsychotics was significantly different at the 2 hospitals, as was the antipsychotic dose prescribed at discharge. Individual physicians and patient characteristics were not significantly associated with prescribing practices. These data, which were obtained before clinical practice guidelines were widely disseminated, provide a benchmark against which to examine more current practice variations in antipsychotic prescribing. The results raise several questions about deviations from practice guidelines in the pharmacological treatment of schizophrenia. To adequately assess quality and inform and possibly further develop clinical practice guideline recommendations for schizophrenia, well-designed research studies conducted in routine clinical settings are needed.

Impact of early human milk on sepsis and health-care costs in very low birth weight infants.

PubMed

Patel, A L; Johnson, T J; Engstrom, J L; Fogg, L F; Jegier, B J; Bigger, H R; Meier, P P

2013-07-01

To study the incidence of sepsis and neonatal intensive care unit (NICU) costs as a function of the human milk (HM) dose received during the first 28 days post birth for very low birth weight (VLBW) infants. Prospective cohort study of 175 VLBW infants. The average daily dose of HM (ADDHM) was calculated from daily nutritional data for the first 28 days post birth (ADDHM-Days 1-28). Other covariates associated with sepsis were used to create a propensity score, combining multiple risk factors into a single metric. The mean gestational age and birth weight were 28.1 ± 2.4 weeks and 1087 ± 252 g, respectively. The mean ADDHM-Days 1-28 was 54 ± 39 ml kg(-1) day(-1) (range 0-135). Binary logistic regression analysis controlling for propensity score revealed that increasing ADDHM-Days 1-28 was associated with lower odds of sepsis (odds ratio 0.981, 95% confidence interval 0.967-0.995, P=0.008). Increasing ADDHM-Days 1-28 was associated with significantly lower NICU costs. A dose-response relationship was demonstrated between ADDHM-Days 1-28 and a reduction in the odds of sepsis and associated NICU costs after controlling for propensity score. For every HM dose increase of 10 ml kg(-1) day(-1), the odds of sepsis decreased by 19%. NICU costs were lowest in the VLBW infants who received the highest ADDHM-Days 1-28.

Impact of Early Human Milk on Sepsis and Health Care Costs in Very Low Birth Weight Infants

PubMed Central

Patel, Aloka L.; Johnson, Tricia J.; Engstrom, Janet L.; Fogg, Louis F.; Jegier, Briana J.; Bigger, Harold R.; Meier, Paula P.

2013-01-01

Objective To study the incidence of sepsis and neonatal intensive care unit (NICU) costs as a function of the human milk (HM) dose received during the first 28 days post-birth for very low birth weight (VLBW) infants. Study Design Prospective cohort study of 175 VLBW infants. Average daily dose of HM (ADDHM) was calculated from daily nutritional data for the first 28 days post-birth (ADDHM-Days1-28). Other covariates associated with sepsis were used to create a propensity score, combining multiple risk factors into a single metric. Result The mean gestational age and birth weight were 28.1 ± 2.4 wk and 1087 ± 252 g, respectively. The mean ADDHM-Days1-28 was 54 ± 39 mL/kg/d (range 0-135). Binary logistic regression analysis controlling for propensity score revealed that increasing ADDHM-Days1-28 was associated with lower odds of sepsis (OR .981, 95%CI .967-.995, p=.008). Increasing ADDHM-Days1-28 was associated with significantly lower NICU costs. Conclusion A dose-response relationship was demonstrated between ADDHM-Days1-28 and a reduction in the odds of sepsis and associated NICU costs after controlling for propensity score. For every HM dose increase of 10 mL/kg/d, the odds of sepsis decreased by 19%. NICU costs were lowest in the VLBW infants who received the highest ADDHM-Days1-28. PMID:23370606

Daily and Nondaily Oral Preexposure Prophylaxis in Men and Transgender Women Who Have Sex With Men: The Human Immunodeficiency Virus Prevention Trials Network 067/ADAPT Study.

PubMed

Grant, Robert M; Mannheimer, Sharon; Hughes, James P; Hirsch-Moverman, Yael; Loquere, Avelino; Chitwarakorn, Anupong; Curlin, Marcel E; Li, Maoji; Amico, K Rivet; Hendrix, Craig W; Anderson, Peter L; Dye, Bonnie J; Marzinke, Mark A; Piwowar-Manning, Estelle; McKinstry, Laura; Elharrar, Vanessa; Stirratt, Michael; Rooney, James F; Eshleman, Susan H; McNicholl, Janet M; van Griensven, Frits; Holtz, Timothy H

2018-05-17

Nondaily dosing of oral preexposure prophylaxis (PrEP) may provide equivalent coverage of sex events compared with daily dosing. At-risk men and transgender women who have sex with men were randomly assigned to 1 of 3 dosing regimens: 1 tablet daily, 1 tablet twice weekly with a postsex dose (time-driven), or 1 tablet before and after sex (event-driven), and were followed for coverage of sex events with pre- and postsex dosing measured by weekly self-report, drug concentrations, and electronic drug monitoring. From July 2012 to May 2014, 357 participants were randomized. In Bangkok, the coverage of sex events was 85% for the daily arm compared with 84% for the time-driven arm (P = .79) and 74% for the event-driven arm (P = .02). In Harlem, coverage was 66%, 47% (P = .01), and 52% (P = .01) for these groups. In Bangkok, PrEP medication concentrations in blood were consistent with use of ≥2 tablets per week in >95% of visits when sex was reported in the prior week, while in Harlem, such medication concentrations occurred in 48.5% in the daily arm, 30.9% in the time-driven arm, and 16.7% in the event-driven arm (P < .0001). Creatinine elevations were more common in the daily arm (P = .050), although they were not dose limiting. Daily dosing recommendations increased coverage and protective drug concentrations in the Harlem cohort, while daily and nondaily regimens led to comparably favorable outcomes in Bangkok, where participants had higher levels of education and employment. NCT01327651.

Action spectrum for phototherapy of psoriasis

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

Parrish, J.A.; Jaenicke, K.F.

1981-05-01

Using a monochromator the action spectrum for ultraviolet phototherapy of psoriasis was determined for radiation between 254 and 313 nm and compared to the action spectrum for erythema of uninvolved adjacent skin. Daily exposures of different doses of 254, 280, 290, 296, 300, 304 and 313 nm radiation were observed. Wavelengths of 254, 280, 290 nm were erythemogenic but not therapeutic even at 10 to 50 times the minimal erythema dose. At the other wavelengths studied, the 2 action spectra were similar. In general, fixed daily doses cleared at lower cumulative dose than did incrementally increased daily doses. The smallmore » number of suberythemogenic exposure doses required suggests that monochromatic radiation may have advantages over broadband sources.« less

Successful treatment of chronic severe neutropenia with weekly recombinant granulocyte-colony stimulating factor.

PubMed

Fine, K D; Byrd, T D; Stone, M J

1997-04-01

Daily treatment for symptomatic chronic neutropenia with recombinant granulocyte-colony stimulating factor (rhG-CSF) filgrastim is costly and sometimes causes neutrophillia. We report the use of weekly filgrastim in a 40-year-old man with life-long symptomatic neutropenia. Baseline neutrophil counts were < 1 x 10(9)/l 60% of the time, and fell below 0.5 x 10(9)/l for 7d periods every 22 d. Following 1 year of weekly filgrastim treatment, the absolute neutrophil count was maintained > 1 x 10(9)/l (averaging 2 x 10(9)/l) and the frequency and severity of symptoms were reduced by 85%. Therefore the benefits of filgrastim for the treatment of at least one form of chronic severe neutropenia can be derived from weekly rather than daily doses.

Therapeutic Response to Twice-daily Rabeprazole on Health-related Quality of Life and Symptoms in Patients with Refractory Reflux Esophagitis: A Multicenter Observational Study

PubMed Central

Kinoshita, Yoshikazu; Hongo, Michio; Kusano, Motoyasu; Furuhata, Yoshinori; Miyagishi, Hideaki; Ikeuchi, Satoshi

2017-01-01

Objective To investigate the effect of twice-daily rabeprazole doses on health-related quality of life in refractory patients. Methods and Patients Reflux esophagitis patients with an insufficient response to once-daily proton pump inhibitor therapy (Los Angeles Classification grade A-D) received rabeprazole 10 mg or 20 mg twice daily for 8 weeks. The health-related quality of life (SF-8™) and symptoms, using the Frequency Scale for the Symptoms of Gastroesophageal reflux disease, were evaluated before treatment and at weeks 4 and 8. Endoscopy was performed at baseline and at weeks 8 and 32 where possible. The rabeprazole dose was determined by the attending physician. Results There were 1,796 patients analyzed for the efficacy of the twice-daily treatment. Of these cases, 1,462 were treated with rabeprazole 10 mg twice daily, and 334 were treated with rabeprazole 20 mg twice daily. The factors that affected the selection of the twice-daily rabeprazole dose by physicians were evaluated, and as expected, “endoscopic findings when treatment was started” had a strong effect on the selection of the rabeprazole dose. With both regimens, health-related quality of life and subjective symptoms were significantly improved at weeks 4 and 8 compared to baseline (p<0.001). The recurrence rate of erosive esophagitis at week 32 was 9.7% in rabeprazole twice daily-treated patients and 28.4% in proton pump inhibitor (PPI) once daily-treated patients. Both regimens were well tolerated. Conclusion Twice-daily treatment with rabeprazole improved the subjective symptoms and health-related quality of life in patients with refractory reflux esophagitis more effectively than the standard once-daily dose. PMID:28502925

Effectiveness of Switch to Erythropoiesis-Stimulating Agent (ESA) Biosimilars versus Maintenance of ESA Originators in the Real-Life Setting: Matched-Control Study in Hemodialysis Patients.

PubMed

Minutolo, Roberto; Bolasco, Piergiorgio; Chiodini, Paolo; Sposini, Stefano; Borzumati, Maurizio; Abaterusso, Cataldo; Mele, Alessandra A; Santoro, Domenico; Canale, Valeria; Santoboni, Alberto; Filiberti, Oliviero; Fiorini, Fulvio; Mura, Carlo; Imperiali, Patrizio; Borrelli, Silvio; Russo, Luigi; De Nicola, Luca; Russo, Domenico

2017-10-01

In hemodialysis (HD), switching from erythropoiesis-stimulating agent (ESA) originators to biosimilars is associated with the need for doses approximately 10% higher, according to industry-driven studies. The aim of this study was to evaluate the efficacy on anemia control of switching from ESA originators to biosimilars in daily clinical practice. We retrospectively selected consecutive HD patients receiving stable intravenous ESA doses, and who had not been transfused in the previous 6 months, from 12 non-profit Italian centers. Patients switched from originators to biosimilars (n = 163) were matched with those maintained on ESA originators (n = 163) using a propensity score approach. The study duration was 24 weeks, and the primary endpoint was the mean dose difference (MDD), defined as the difference between the switch and control groups of ESA dose changes during the study (time-weighted average ESA dose minus baseline ESA dose). Age (70 ± 13 years), male sex (63%), diabetes (29%), history of cardiovascular disease (40%), body weight (68 ± 14 kg), vascular access (86% arteriovenous fistula), hemoglobin [Hb] (11.2 ± 0.9 g/dL) and ESA dose (8504 ± 6370 IU/week) were similar in the two groups. Hb remained unchanged during the study in both groups. Conversely, ESA dose remained unchanged in the control group and progressively increased in the switch group from week 8 to 24. The time-weighted average of the ESA dose was higher in the switch group than in the control group (10,503 ± 7389 vs. 7981 ± 5858 IU/week; p = 0.001), leading to a significant MDD of 2423 IU/week (95% confidence interval [CI] 1615-3321), corresponding to a 39.6% (95% CI 24.7-54.6) higher dose of biosimilars compared with originators. The time-weighted average of Hb was 0.2 g/dL lower in the switch group, with a more frequent ESA hyporesponsiveness (14.7 vs. 2.5%). Iron parameters and other resistance factors remained unchanged. In stable dialysis patients, switching from ESA originators to biosimilars requires 40% higher doses to maintain anemia control.

Analyzing U.S. prescription lists with RxNorm and the ATC/DDD Index.

PubMed

Bodenreider, Olivier; Rodriguez, Laritza M

2014-01-01

To evaluate the suitability of the ATC/DDD Index (Anatomical Therapeutic Chemical (ATC) Classification System/Defined Daily Dose) for analyzing prescription lists in the U.S. We mapped RxNorm clinical drugs to ATC. We used this mapping to classify a large set of prescription drugs with ATC and compared the prescribed daily dose to the defined daily dose (DDD) in ATC. 64% of the 11,422 clinical drugs could be precisely mapped to ATC. 97% of the 87,001 RxNorm codes from the prescription dataset could be classified with ATC, and 97% of the prescribed daily doses could be assessed. Although the mapping of RxNorm ingredients to ATC appears to be largely incomplete, the most frequently prescribed drugs in the prescription dataset we analyzed were covered. This study demonstrates the feasibility of using ATC in conjunction with RxNorm for analyzing U.S. prescription datasets for drug classification and assessment of the prescribed daily doses.

Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial.

PubMed

Singer, Daniel E; Hellkamp, Anne S; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R; Piccini, Jonathan P; Hankey, Graeme J; Breithardt, Günter; Halperin, Jonathan L; Becker, Richard C; Hacke, Werner; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M

2015-03-03

In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted. TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported. URL: ClinicalTrials.gov. Unique identifier: NCT00403767. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial

PubMed Central

Singer, Daniel E.; Hellkamp, Anne S.; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R.; Piccini, Jonathan P.; Hankey, Graeme J.; Breithardt, Günter; Halperin, Jonathan L.; Becker, Richard C.; Hacke, Werner; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.

2015-01-01

Background In the ROCKET AF (Rivaroxaban–Once‐daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter‐INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow‐up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. Methods and Results We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change–based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in‐range INRs (“corrections”) versus INRs that were out of range in the opposite direction (“overshoots”). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change–based approach, depending on assumptions. However, large inter‐regional differences in anticoagulation control persisted. Conclusions TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow‐up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change–based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter‐regional differences previously reported. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00403767. PMID:25736441

Reconstruction of the erythemal UV radiation data in Novi Sad (Serbia) using the NEOPLANTA parametric model

NASA Astrophysics Data System (ADS)

Malinovic-Milicevic, S.; Mihailovic, D. T.; Radovanovic, M. M.

2015-07-01

This paper focuses on the development and application of a technique for filling the daily erythemal UV dose data gaps and the reconstruction of the past daily erythemal UV doses in Novi Sad, Serbia. The technique implies developing the empirical equation for estimation of daily erythemal UV doses by means of relative daily sunshine duration under all sky conditions. A good agreement was found between modeled and measured values of erythemal UV doses. This technique was used for filling the short gaps in the erythemal UV dose measurement series (2003-2009) as well as for the reconstruction of the past time-series values (1981-2002). Statistically significant positive erythemal UV dose trend of 6.9 J m-2 per year was found during the period 1981-2009. In relation to the reference period 1981-1989, an increase in the erythemal UV dose of 6.92 % is visible in the period 1990-1999 and the increase of 9.67 % can be seen in the period 2000-2009. The strongest increase in erythemal UV doses has been found for winter and spring seasons.

Efficacy of alternate day versus daily dosing of rosuvastatin

PubMed Central

Dulay, Daisy; LaHaye, Stephen A; Lahey, Karen A; Day, Andrew G

2009-01-01

BACKGROUND: Compared with other statins, rosuvastatin has a relatively long half-life, which may allow for the administration of this medication on an alternate day basis. OBJECTIVE: To compare the efficacy of administering rosuvastatin on a daily basis versus on an alternate day basis for the treatment of dyslipidemia. METHODS: In the present crossover study, 45 patients with documented hypercholesterolemia requiring pharmacotherapy were administered either 20 mg of rosuvastatin on alternate days or 10 mg of rosuvastatin daily for six weeks. After a four-week washout period, patients were then switched to the other regimen for another six weeks. The primary end point was the percentage reduction of low-density lipoprotein cholesterol (LDL-C). RESULTS: LDL-C decreased by 48.5% versus 40.9% with daily and alternate day dosing, respectively. This represented an additional absolute reduction of LDL-C of 7.6% (95% CI 1.8% to 13.4%, P=0.012) with the daily dosing regimen. Both dosing regimens provided similar improvements in high-density lipoprotein cholesterol and triglycerides. CONCLUSIONS: Compared with alternate day dosing, daily dosing of rosuvastatin provides a statistically significant advantage in LDL-C reduction. However, the alternate day regimen may be a viable option for those patients in whom cost is a limitation to compliance. PMID:19214297

Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints.

PubMed

de Velde, Femke; de Winter, Brenda C M; Koch, Birgit C P; van Gelder, Teun; Mouton, Johan W

2016-10-01

To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens. Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens. AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily). The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Plasma pharmacokinetics of once-daily abacavir- and lamivudine-containing regimens and week 96 efficacy in HIV-infected Thai children.

PubMed

Bunupuradah, Torsak; Punyahotra, Passorn; Cressey, Tim R; Srimuan, Amornrat; Thammajaruk, Narukjaporn; Sophonphan, Jiratchaya; Sriheara, Chulalak; Burger, David M; Puthanakit, Thanyawee; Ananworanich, Jintanat

2015-07-01

Abacavir and lamivudine are approved for once-daily use in HIV-infected adults. Limited pharmacokinetic (PK) data for abacavir and lamivudine in children are available. A crossover study to compare PK of once- versus twice-daily abacavir and lamivudine was conducted in virologically suppressed HIV-infected Thai children aged <18years, with bodyweight of at least 14 kg, HIV RNA <50 copies/mL and HLA-B*5701 negative. Abacavir and lamivudine daily doses by bodyweight were 300 and 150 mg for 14-<20 kg, 450 and 300 mg for 20-<25 kg, and 600 and 300 mg for ≥25 kg, respectively. Originator abacavir and lamivudine scored tablets were administered. Intensive PK sampling was performed after 14 days of each dose. PK parameters were determined using non-compartmental analysis. Thirty children (57% male) were enrolled, 10 per weight band. Median (IQR) age was 8.8 (6.6-11.3) years and bodyweight was 21.9 (19.2-30.6) kg. The geometric means (GM) AUC0-24 of once- and twice-daily abacavir were 14.43 and 10.65 mg.h/L, respectively. The geometric mean ratio (GMR) of AUC0-24 for once- versus twice-daily abacavir dosing was 1.36 [90% confidence interval (CI) 1.11-1.66]. The GM AUC0-24 of once- and twice-daily lamivudine were 17.70 and 18.11 mg.h/L, respectively. The GMR of AUC0-24 for once- versus twice-daily lamivudine dosing was 0.98 (90% CI 0.84-1.14). At 96 weeks, 90% had HIV RNA <50 copies/mL and there were no serious adverse events. Abacavir exposure was greater with once-daily dosing, while lamivudine once- and twice-daily exposures were bioequivalent. Once-daily abacavir and lamivudine using weight-band dosing is a treatment option for children.

Randomized controlled trial comparing impact on platelet reactivity of twice-daily with once-daily aspirin in people with Type 2 diabetes.

PubMed

Bethel, M A; Harrison, P; Sourij, H; Sun, Y; Tucker, L; Kennedy, I; White, S; Hill, L; Oulhaj, A; Coleman, R L; Holman, R R

2016-02-01

Reduced aspirin efficacy has been demonstrated in people with Type 2 diabetes. Because increased platelet reactivity and/or turnover are postulated mechanisms, we examined whether higher and/or more frequent aspirin dosing might reduce platelet reactivity more effectively. Participants with Type 2 diabetes (n = 24) but without known cardiovascular disease were randomized in a three-way crossover design to 2-week treatment periods with aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily. The primary outcome was platelet reactivity, assessed using the VerifyNow(™) ASA method. Relationships between platelet reactivity and aspirin dosing were examined using generalized linear mixed models with random subject effects. Platelet reactivity decreased from baseline with all doses of aspirin. Modelled platelet reactivity was more effectively reduced with aspirin 100 mg twice daily vs. 100 mg once daily, but not vs. 200 mg once daily. Aspirin 200 mg once daily did not differ from 100 mg once daily. Aspirin 100 mg twice daily was also more effective than once daily as measured by collagen/epinephrine-stimulated platelet aggregation and urinary thromboxane levels, with a similar trend measured by serum thromboxane levels. No episodes of bleeding occurred. In Type 2 diabetes, aspirin 100 mg twice daily reduced platelet reactivity more effectively than 100 mg once daily, and numerically more than 200 mg once daily. Clinical outcome trials evaluating primary cardiovascular disease prevention with aspirin in Type 2 diabetes may need to consider using a more frequent dosing schedule. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2013-05-01

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

Using Quality of Life Measures in a Phase I Clinical Trial of Noni in Patients with Advanced Cancer to Select a Phase II Dose

PubMed Central

Issell, Brian F.; Gotay, Carolyn C.; Pagano, Ian; Franke, A. Adrian

2015-01-01

Purpose We conducted a Phase I study of noni in patients with advanced cancer. Quality of life measures were examined as an alternate way to select a Phase II dose of this popular dietary supplement. Patients and Methods Starting at two capsules twice daily (2 grams), the dose suggested for marketed products, dose levels were escalated by 2 grams daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed QLQ-C30 Quality of Life, and the Brief Fatigue Inventory (BFI), questionnaires at baseline and at four week intervals. Scopoletin was measured in blood and urine collected at baseline and at approximately four week intervals. Results Fifty-one patients were enrolled at seven dose levels. Seven capsules four times daily (14 grams) was the maximum tolerated dose. No dose limiting toxicity was found but four of eight patients at this level withdrew from the study due to the challenges of ingesting so many capsules. There was a dose response for self reported physical functioning and the control of pain and fatigue. Patients taking four capsules four times daily experienced less fatigue than patients taking lower or higher doses. A relationship between noni dose and blood and urinary scopoletin concentrations was found. Conclusion Measuring quality of life to determine a dose for subsequent Phase II testing is feasible. A noni dose of four capsules four times daily (8 grams) is recommended for Phase II testing where controlling fatigue and maintaining physical function is the efficacy of interest. Scopoletin is a measurable noni ingredient for pharmacokinetic studies in patients with cancer. PMID:22435516

A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer.

PubMed

Fakih, Marwan G; Pendyala, Lakshmi; Fetterly, Gerald; Toth, Karoli; Zwiebel, James A; Espinoza-Delgado, Igor; Litwin, Alan; Rustum, Youcef M; Ross, Mary Ellen; Holleran, Julianne L; Egorin, Merrill J

2009-05-01

We conducted a phase I study to determine the maximum tolerated dose of vorinostat in combination with fixed doses of 5-fluorouracil (FU), leucovorin, and oxaliplatin (FOLFOX). Vorinostat was given orally twice daily for 1 week every 2 weeks. FOLFOX was given on days 4 and 5 of vorinostat. The vorinostat starting dose was 100 mg twice daily. Escalation occurred in cohorts of three to six patients. Pharmacokinetics of vorinostat, FU, and oxaliplatin were studied. Twenty-one patients were enrolled. Thrombocytopenia, neutropenia, gastrointestinal toxicities, and fatigue increased in frequency and severity at higher dose levels of vorinostat. Two of 4 evaluable patients at dose level 4 (vorinostat 400 mg orally twice daily) developed dose-limiting fatigue. One of 10 evaluable patients at dose level 3 (vorinostat 300 mg orally twice daily) had dose-limiting fatigue, anorexia, and dehydration. There were significant relationships between vorinostat dose and the area under the curve on days 1 and 5 (Pearson, < 0.001). The vorinostat area under the curve increased (P = 0.005) and clearance decreased (P = 0.003) on day 5 compared with day 1. The median C(max) of FU at each dose level increased significantly with increasing doses of vorinostat, suggesting a pharmacokinetic interaction between FU and vorinostat. Vorinostat-induced thymidylate synthase (TS) modulation was not consistent; only two of six patients had a decrease in intratumoral TS expression by reverse transcription-PCR. The maximum tolerated dose of vorinostat in combination with FOLFOX is 300 mg orally twice daily x 1 week every 2 weeks. Alternative vorinostat dosing schedules may be needed for optimal down-regulation of TS expression.

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

PubMed Central

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

2011-01-01

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

SU-E-T-784: Using MLC Log Files for Daily IMRT Delivery Verification

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

Stathakis, S; Defoor, D; Linden, P

2015-06-15

Purpose: To verify daily intensity modulated radiation therapy (IMRT) treatments using multi-leaf collimator (MLC) log files. Methods: The MLC log files from a NovalisTX Varian linear accelerator were used in this study. The MLC files were recorded daily for all patients undergoing IMRT or volumetric modulated arc therapy (VMAT). The first record of each patient was used as reference and all records for subsequent days were compared against the reference. An in house MATLAB software code was used for the comparisons. Each MLC log file was converted to a fluence map (FM) and a gamma index (γ) analysis was usedmore » for the evaluation of each daily delivery for every patient. The tolerance for the gamma index was set to 2% dose difference and 2mm distance to agreement while points with signal of 10% or lower of the maximum value were excluded from the comparisons. Results: The γ between each of the reference FMs and the consecutive daily fraction FMs had an average value of 99.1% (ranged from 98.2 to 100.0%). The FM images were reconstructed at various resolutions in order to study the effect of the resolution on the γ and at the same time reduce the time for processing the images. We found that the comparison of images with the highest resolution (768×1024) yielded on average a lower γ (99.1%) than the ones with low resolution (192×256) (γ 99.5%). Conclusion: We developed an in-house software that allows us to monitor the quality of daily IMRT and VMAT treatment deliveries using information from the MLC log files of the linear accelerator. The information can be analyzed and evaluated as early as after the completion of each daily treatment. Such tool can be valuable to assess the effect of MLC positioning on plan quality, especially in the context of adaptive radiotherapy.« less

Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials.

PubMed

Stoffel, Nicole U; Cercamondi, Colin I; Brittenham, Gary; Zeder, Christophe; Geurts-Moespot, Anneke J; Swinkels, Dorine W; Moretti, Diego; Zimmermann, Michael B

2017-11-01

Current guidelines to treat iron deficiency recommend daily provision of ferrous iron divided through the day to increase absorption. However, daily dosing and split dosing might increase serum hepcidin and decrease iron absorption from subsequent doses. Our study aim was to compare iron absorption from oral iron supplements given on consecutive versus alternate days and given as single morning doses versus twice-daily split dosing. We did two prospective, open-label, randomised controlled trials assessing iron absorption using ( 54 Fe)-labelled, ( 57 Fe)-labelled, or ( 58 Fe)-labelled ferrous sulfate in iron-depleted (serum ferritin ≤25 μg/L) women aged 18-40 years recruited from ETH Zurich and the University of Zurich, Switzerland. In study 1, women were randomly assigned (1:1) to two groups. One group was given 60 mg iron at 0800 h (±1 h) on consecutive days for 14 days, and the other group was given the same doses on alternate days for 28 days. In study 2, women were assigned to two groups, stratified by serum ferritin so that two groups with similar iron statuses could be formed. One group was given 120 mg iron at 0800 h (±1 h) and the other was given the dose split into two divided doses of 60 mg at 0800 h (±1 h) and 1700 h (±1 h) for three consecutive days. 14 days after the final dose, the groups were each crossed over to the other regimen. Within-individual comparisons were done. The co-primary outcomes in both studies were iron bioavailability (total and fractional iron absorption), assessed by measuring the isotopic label abundance in erythrocytes 14 days after administration, and serum hepcidin. Group allocations in both studies were not masked and primary and safety analyses were done on an intention-to-treat basis. The studies were registered at ClinicalTrials.gov, numbers NCT02175888 (study 1) and NCT02177851 (study 2) and are complete. For study 1, 40 women were enrolled on Oct 15-29, 2015. 21 women were assigned to the consecutive-day group and 19 to the alternate-day group. At the end of treatment (14 days for the consecutive-day group and 28 days for the alternate-day group), geometric mean (-SD, +SD) cumulative fractional iron absorptions were 16·3% (9·3, 28·8) in the consecutive-day group versus 21·8% (13·7, 34·6) in the alternate-day group (p=0·0013), and cumulative total iron absorption was 131·0 mg (71·4, 240·5) versus 175·3 mg (110·3, 278·5; p=0·0010). During the first 14 days of supplementation in both groups, serum hepcidin was higher in the consecutive-day group than the alternate-day group (p=0·0031). In study 2, 20 women were enrolled between Aug 13 and 18, 2015. Ten women were assigned to receive once-daily dosing and ten were assigned to receive twice-daily divided dosing. No significant differences were seen in fractional (day 1-3 geometric mean: 11·8% [7·1, 19·4] once daily vs 13·1% [8·2, 20·7] twice daily; p=0·33) or total iron absorption (day 1-3: 44·3 mg [29·4, 66·7] once daily vs 49·4 [35·2, 69·4] twice daily; p=0·33) between the two dosing regimens. Twice-daily divided doses resulted in a higher serum hepcidin concentration than once-daily dosing (p=0·013). No grade 3 or 4 adverse events were reported in either study. In iron-depleted women, providing iron supplements daily as divided doses increases serum hepcidin and reduces iron absorption. Providing iron supplements on alternate days and in single doses optimises iron absorption and might be a preferable dosing regimen. These findings should be confirmed in iron-deficient anaemic patients. Swiss National Science Foundation, Bern, Switzerland. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pseudoephedrine: effects on milk production in women and estimation of infant exposure via breastmilk

PubMed Central

Aljazaf, Khalidah; Hale, Thomas W; Ilett, Kenneth F; Hartmann, Peter E; Mitoulas, Leon R; Kristensen, Judith H; Hackett, L Peter

2003-01-01

Aims To assess the effects of pseudoephedrine on breast blood flow, temperature and milk production, and to estimate the likely infant dose during breastfeeding. Methods Eight lactating women (mean age 35 years and weight 69 kg) participated in a single-blind randomized crossover study of 60 mg pseudoephedrine hydrochloride vs placebo. Breast blood flow and surface temperature were measured from 0 to 4 h following the dose, and change in plasma prolactin was measured as the difference between predose and 1 h postdose concentrations. Milk production was measured for 24 h following placebo and pseudoephedrine. Infant dose of pseudoephedrine for a 60-mg dose administered four times daily to the mother was quantified as the product of average steady-state drug concentration in milk and an estimated milk production rate of 0.15 l kg−1 day−1 and expressed relative to the maternal weight-adjusted dose. Results There were no physiologically significant changes in breast blood flow or temperature between the placebo and pseudoephedrine periods. The mean change in plasma prolactin was slightly (13.5%), but not significantly lower (t = 1.245, P = 0.253) after pseudoephedrine (1775 mU l−1) compared with placebo (2014 mU l−1). However, the mean milk volume was reduced by 24% from 784 ml day−1 in the placebo period to 623 ml day−1 in the pseudoephedrine period (difference between means 161 ml day−1 (95% CI: 63, 259 ml day−1); t = 3.9, P = 0.006). Assuming maternal intake of 60 mg pseudoephedrine hydrochloride four times daily, the estimated infant dose of pseudoephedrine was 4.3% (95% CI, 3.2, 5.4%) of the weight-adjusted maternal dose. Conclusions A single dose of pseudoephedrine significantly reduced milk production. This effect was not attributable to changes in blood flow, but depression of prolactin secretion may be a contributing factor. At the maximum recommended pseudoephedrine doses, the calculated infant dose delivered via milk was < 10% of the maternal dose, and is unlikely to affect the infant adversely. The ability of pseudoephedrine to suppress lactation suggests a novel use for the drug. PMID:12848771

Effect of ractopamine hydrochloride (Optaflexx) dose and duration on growth performance and carcass characteristics of finishing steers.

PubMed

Bittner, C J; Crawford, G I; Berger, L L; Holt, S; Pritchard, R R; Platter, W J; Van Koevering, M T; Pyatt, N A; Erickson, G E

2016-12-01

Three experiments evaluated the effects of ractopamine hydrochloride (RAC) dose and duration on growth performance and carcass characteristics of feedlot steers. In total, 1,509 crossbred steers (530 kg initial BW [SD 22]) were used in a randomized complete block design using a 3 × 3 factorial treatment structure. Treatments consisted of RAC dose (0, 100, or 200 mg/steer daily) and duration (28, 35, or 42 d) of RAC feeding prior to harvest. Initiation of RAC dose was staggered (7 d apart) based on RAC duration, which resulted in common days on feed among treatments. Data from the 3 experiments were combined for statistical analyses. There were no RAC dose × duration interactions ( ≥ 0.85) for growth performance. Live final BW was not different ( ≥ 0.24) as RAC dose increased. Dry matter intake linearly decreased ( < 0.01) as RAC dose increased. Live ADG and G:F linearly increased ( ≤ 0.01) as RAC dose increased. Carcass-adjusted ADG and G:F linearly increased ( ≤ 0.02) as RAC dose increased. Compared with steers fed 0 mg RAC/steer daily, G:F was improved by 5.0 and 13.0% when steers were fed 100 ( = 0.31) and 200 ( = 0.01) mg RAC/steer daily, respectively. Hot carcass weight tended ( = 0.10) to linearly increase as RAC dose increased, with carcasses from steers fed 100 ( = 0.38) and 200 ( = 0.10) mg RAC/steer daily being 2.2 and 4.1 kg heavier, respectively, than carcasses from steers fed 0 mg RAC/steer daily. Increasing RAC dose linearly ( < 0.01) increased LM area and linearly ( = 0.02) decreased marbling score. Live final BW was not different ( ≥ 0.60) among RAC durations. Carcass-adjusted final BW, ADG, and G:F were not different ( ≥ 0.41) as RAC duration increased. Carcass traits did not differ ( ≥ 0.18) among RAC duration. Feeding 200 mg RAC/steer daily improved ADG, feed efficiency, and HCW. Increasing the feeding duration of RAC had no effect of growth performance or carcass characteristics. These data indicate that feeding 200 mg RAC/steer daily for 28 d improves steer growth performance.

Long-term erythemal UV doses at Sodankylä estimated using total ozone, sunshine duration, and snow depth

NASA Astrophysics Data System (ADS)

Lindfors, A. V.; Arola, A.; Kaurola, J.; Taalas, P.; SvenøE, T.

2003-08-01

A method for estimating daily erythemal UV doses using total ozone, sunshine duration, and snow depth has been developed. The method consists of three steps: (1) daily clear-sky UV doses were simulated using the UVSPEC radiative transfer program, with daily values of total ozone as input data, (2) an empirical relationship was sought between the simulated clear-sky UV doses, the measured UV doses, and the duration of bright sunshine, and (3) daily erythemal UV doses were estimated using this relationship. The method accounts for the varying surface albedo by dividing the period of interest into winter and summer days, depending on the snow depth. Using this method, the daily erythemal UV doses at Sodankylä were estimated for the period 1950-1999. This was done using Tromsø's total ozone together with Sodankylä's own sunshine duration and snow depth as input data. Although the method is fairly simple, the results are in good agreement, even on the daily scale, with the UV radiation measured with the Brewer spectrophotometer at Sodankylä. Over the period 1950-1999 a statistically significant increasing trend of 3.9% per decade in erythemal UV doses was found for March. The fact that this trend is much more pronounced during the latter part of the period, which is also the case for April, suggests a connection to the stratospheric ozone depletion. For July, on the other hand, a significant decreasing trend of 3.3% per decade, supported by the changes in both total ozone and sunshine duration, was found.

SU-E-J-39: Dosimetric Benefit of Implanted Marker-Based CBCT Setup for Definitive Prostatic Radiotherapy

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

Zhen, H; Wu, Z; Bluemenfeld, P

Purpose Daily setup for definitive prostatic radiotherapy is challenged by suboptimal visibility of the prostate boundary and daily variation of rectum shape and position. For patients with improved bowel preparation, we conducted a dosimetric comparison between prostate implanted marker (IM)-based daily setup and anterior rectal wall (ARW)-based setup, with the hypothesis that the former leads to adequate target coverage with better rectal sparing. Methods Five IMRT/VMAT prostate cases with implanted markers were selected for analysis. Daily CBCT showed improvement of the rectal volume compared to planning CT. For each patient, the prostate and rectum were contoured on three CBCT imagesmore » (fraction 5/15/25) with subsequent physician review. The CBCTs were then registered to a planning CT using IM-based registration. The deviation of ARW positions from planning CT to CBCT were analyzed at various sup-inf levels (−1.8 cm to 1.8 cm from level of prostate center). To estimate the potential dosimetric impact from ARW-based setup, the treatment plans were recalculated using A-P shifts ranging from −1mm to +6mm. Clinically important rectum DVH values including Dmax, D3cc and Dmean were computed. Results For the studied patients, we observed on average 32% rectum volume reduction from planning CT to CBCT. As a Results, the ARW on average shifts posteriorly by −1mm to +5mm, depending on the sup-inf level of observation, with larger shifts observed at more superior levels. Recalculation shows that when ARW shifts 1mm posteriorly, ARW-based CBCT setup leads to a 1.0%, 4.2%, and 3.2% increase in rectum Dmax, D3cc, and Dmean, respectively, compared to IM-based setup. The dosimetric deviations increase to 4.7%, 25.8% and 24.7% when ARW shifts 6mm posteriorly. No significant prostate-only dose difference was observed. Conclusion For patients with improved bowel preparation, IM-based CBCT setup leads to accurate prostate coverage along with significantly lower rectal dose, compared to ARW-based setup.« less

A review of ropinirole prolonged release in Parkinson’s disease

PubMed Central

Nashatizadeh, Muhammad M; Lyons, Kelly E; Pahwa, Rajesh

2009-01-01

Ropinirole prolonged release is a once-daily, 24-hour formulation of ropinirole, a non-ergot dopamine agonist. It is approved as monotherapy and as an adjunct to levodopa in the treatment of Parkinson’s disease (PD). Several potential advantages of ropinirole prolonged release compared to the immediate release formulation include maintaining more consistent dopaminergic activity with steadier plasma levels, increased tolerability, greater compliance from a simpler once-daily dosing regimen and ease in dose titration. In a randomized, double-blind, non-inferiority, crossover study, ropinirole prolonged release was shown to have comparable efficacy and tolerability to immediate release ropinirole in early PD patients, with significantly greater compliance. Subjects were converted overnight between ropinirole formulations without loss of efficacy and with good tolerability. In a randomized, double-blind, placebo-controlled study in advanced PD, daily “off” time was reduced by an average of 2.1 hours with ropinirole prolonged release compared to 0.4 hours with placebo. Patients on ropinirole prolonged release were also more likely to require less daily levodopa. Ropinirole prolonged release is well tolerated with a similar adverse effect profile to other non-ergot dopamine agonists. The most common adverse effects include dyskinesia, nausea, dizziness, hallucinations, somnolence, abdominal pain or discomfort and orthostatic hypotension. Ropinirole prolonged release is a safe and effective treatment option for both early and advanced PD. This manuscript briefly reviews the current pharmacological treatment options for PD and provides a more detailed review of the currently available data regarding ropinirole prolonged release as a treatment option for PD. PMID:19503779

Monitoring of perchlorate in diverse foods and its estimated dietary exposure for Korea populations.

PubMed

Lee, Ji-Woo; Oh, Sung-Hee; Oh, Jeong-Eun

2012-12-01

The perchlorate concentrations in various Korean food samples were monitored, and 663 samples belonging to 39 kinds of food were analyzed. The analysis results revealed that dairy products contain the highest average concentration of 6.34 μg/kg and high detection frequency of over 85%. Fruit and vegetables showed the next highest perchlorate concentration with an average of 6.17 μg/kg. Especially, with its average concentration of 39.9 μg/kg, spinach showed the highest perchlorate level among all target food samples studied. Tomato was followed by spinach, which showed a high perchlorate average concentration of 19.8 μg/kg, and over 7 μg/kg was detected in ham and sausage (avg. 7.31 μg/kg) and in instant noodles (avg. 7.58 μg/kg). Less than 2 μg/kg was detected in fishes, meats and beverages. The exposure dose of perchlorate in Korean by food intake was calculated on the basis of the analyzed perchlorate levels in this study. The daily perchlorate dose to which Korean adults are exposed is 0.04 μg/kg bw/day, which is lower than the RfD (0.7 μg/kg bw/day) value suggested by US NAS. This result indicates that Korean people's current exposure to perchlorate from domestic food consumption is evaluated as safe. Copyright © 2012 Elsevier B.V. All rights reserved.

Clinical efficacy and safety following dose tapering of ciclosporin in cats with hypersensitivity dermatitis.

PubMed

Roberts, Elizabeth S; Tapp, Tiffany; Trimmer, Ann; Roycroft, Linda; King, Stephen

2016-11-01

Objectives This study was designed to evaluate the efficacy and safety of reducing ciclosporin (CsA) dosing frequency from daily to every other day (EOD) or twice a week (TW) according to clinical response in cats with hypersensitivity dermatitis (HD) and treated with CsA. Methods One hundred and ninety-one cats with HD were given 7 mg/kg CsA daily for at least 4 weeks. Depending on clinical response, the dosing frequency was tapered from daily to EOD over the next 4 weeks and further to TW for an additional 4 weeks. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results The majority of cats were able to have their dose of CsA tapered to either EOD (15.5%) or TW (62.9%) according to the clinical response. Observed AEs were most frequently mild and self-limiting vomiting and diarrhea. A higher percentage of AEs occurred with daily administration (73%) compared with other dosing regimens (27%). Conclusions and relevance Following 4 weeks of daily dosing at 7 mg/kg, CsA may be tapered to EOD or TW while maintaining the desired therapeutic response in cats with HD. Additionally, CsA appears to be well tolerated with fewer AEs at EOD or TW dosing. Establishing the lowest effective dosing frequency of CsA improves the drug's safety profile.

Understanding the gap between cognitive abilities and daily living skills in adolescents with autism spectrum disorders with average intelligence.

PubMed

Duncan, Amie W; Bishop, Somer L

2015-01-01

Daily living skills standard scores on the Vineland Adaptive Behavior Scales-2nd edition were examined in 417 adolescents from the Simons Simplex Collection. All participants had at least average intelligence and a diagnosis of autism spectrum disorder. Descriptive statistics and binary logistic regressions were used to examine the prevalence and predictors of a "daily living skills deficit," defined as below average daily living skills in the context of average intelligence quotient. Approximately half of the adolescents were identified as having a daily living skills deficit. Autism symptomatology, intelligence quotient, maternal education, age, and sex accounted for only 10% of the variance in predicting a daily living skills deficit. Identifying factors associated with better or worse daily living skills may help shed light on the variability in adult outcome in individuals with autism spectrum disorder with average intelligence. © The Author(s) 2013.

Short-term mechanisms of toxic action of airborne particulates underlie dose-rate dependent health risks and support control of one-hour airborne particle levels

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

Michaels, R.A.; Kleinman, M.T.

1999-07-01

Twenty-four-hour airborne particle mass levels permissible under the NAAQS have been associated with mortality and morbidity in communities, motivating reconsideration of the standard. Reports of shorter-term mechanisms of toxic action exerted by airborne PM and PM constituents are emerging. The mechanisms are diverse, but have in common a short time frame of toxic action, from minutes to hours. In view of documented PM excursions also lasting minutes to hours, this study inquires whether such short-term mechanisms might contribute to explaining daily morbidity and mortality. Toxicology experiments have demonstrated the harmfulness of brief exposure to PM levels in the range ofmore » observed excursions. This suggests that toxicological processes initiated by short-term inhalation of PM may exert clinically important effects, and that weak associations of 24-hour-average particle mass with mortality and morbidity may represent artifacts of stronger, shorter-term associations whose full magnitude remains to be quantified. In one study, the area of lung surface developing lesions was elevated in rats breathing the same four-hour dose of aerosols, when the four-hour average rate of aerosol delivery included a short-term (five-minute) burst fifty percent above the average dose rate. Elevations were observed with each of two aerosols tested. The magnitude of the effect was higher with one of the two aerosols, whose dose rate included four excursions rather than just one excursion. Particulate matter inhaled or instilled intratracheally has produced morbidity in animals, including apnea and electrophysiological effects in dogs. Other studies reveal that PM can kill rats via electrophysiological and possibly other mechanisms. PM has also adversely affected asthmatic people in controlled clinical settings during exercise or, in one study, at rest.« less

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

Saleh, H; Ferjani, S; Masssey, V

Purpose: Perform dosimetric comparison between planned and delivered dose in the junction area, measure daily dose variation in the arc junction area for pediatric patients treated for medulloblastoma using Craniospinal axis irradiation(CSI) Material and methods Dose comparison in the junction area, daily dose variation in the arc junction area for a Rando Phantom and 5 pediatric patients treated using CSI technique were analyzed. Plans were created using the Eclipse treatment planning system. Two arcs for cranium and 1 arc for spine region were used. Planar dose matrix was created by projecting phantom and patient plan into the ArcCheck phantom. EBT3more » film was placed in the middle of ArcCheck plug to measure dose distribution in the junction areaDuring patient treatment, strip of EBT3 film was placed daily at each junction area for verification. EBT3 films were scanned using a flatbed scanner, Epson Expression 10000 XL. Film QA pro software was used to analyze film. Scanning and analysis was performed according to vendor recommendations and AAPM TG-55 report. Films were scanned and analyzed daily after each treatment and at the end of treatment course. Planar dose distributions from films were compared with planar dose distribution from treatment planning system. Results: Comparison of planned vs. measured dose distributions for patients have passing rates of 90%–100% with 3% and 3 mm gamma analysis. In some of the treatment fractions, daily setup film showed variation in dose distribution in the junction area. Conclusion: It is critical to measure dose distribution in the arc junction area and use additional quality assurance measures to verify daily setup for CSI patient where one or more junctions are present. EBT3 film prove to be a good tool to achieve this task considering flexibility associated with the film such as symmetry, self-developing and ease of use.« less

Obesity/Overweight in Persons With Early and Chronic SCI: A Randomized, Multicenter, Controlled Lifestyle Intervention

DTIC Science & Technology

2014-10-01

profile Drug Class Candidate Drugs TG %D LDL-C %D HDL-C %D HMG-CoA reductase inhibitors: “Statins” Atorvastatin (Lipitor) Lovastatin (Mevacor...30% Medium Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20–40 mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg...Fluvastatin 40 mg bid Pitavastatin 2–4 mg Daily dose lowers LDL-C on average, by approximately 30% to អ% High Atorvastatin (40–80 mg) Rosuvastatin 29 (40) mg

On the impacts of computing daily temperatures as the average of the daily minimum and maximum temperatures

NASA Astrophysics Data System (ADS)

Villarini, Gabriele; Khouakhi, Abdou; Cunningham, Evan

2017-12-01

Daily temperature values are generally computed as the average of the daily minimum and maximum observations, which can lead to biases in the estimation of daily averaged values. This study examines the impacts of these biases on the calculation of climatology and trends in temperature extremes at 409 sites in North America with at least 25 years of complete hourly records. Our results show that the calculation of daily temperature based on the average of minimum and maximum daily readings leads to an overestimation of the daily values of 10+ % when focusing on extremes and values above (below) high (low) thresholds. Moreover, the effects of the data processing method on trend estimation are generally small, even though the use of the daily minimum and maximum readings reduces the power of trend detection ( 5-10% fewer trends detected in comparison with the reference data).

Long-term safety and effectiveness of once-daily, single-entity, extended-release hydrocodone over 76 weeks of an open-label study in patients with chronic noncancer and nonneuropathic pain.

PubMed

Taber, Louise; Lynch, Shau Yu; He, Ellie; Ripa, Steven R

2016-01-01

To evaluate long-term use of Hysingla(®) ER (HYD), a single-entity, extended-release, once-daily hydrocodone bitartrate tablet with abuse-deterrent properties in patients with moderate-to-severe chronic noncancer and nonneuropathic pain. This open-label study consisted of a dose-titration period (up to 45 days), a 52-week maintenance period and a 24-week extension period. Opioid-naïve or opioid-experienced patients with controlled or uncontrolled chronic pain conditions were treated with HYD 20-120 mg daily. Supplemental nonopioid and short-acting opioid analgesics were permitted. This paper presents the results of 106 patients who continued HYD treatment for up to 76 weeks. Primary safety measures included the incidence of adverse events, as well as audiologic, clinical laboratory and electrocardiogram measurements. Effectiveness was measured by the change between baseline and the overall 76-week treatment period in "average pain over the last 24 h" (0 = no pain, 10 = pain as bad as you can imagine), Brief Pain Inventory-Short Form survey, Medical Outcomes Study 36-Item Short Form Health Survey, Medical Outcomes Study Sleep Scale-Revised and concomitant nonstudy opioid analgesic use. Among 410 patients who completed the maintenance period, 106 continued into the extension. Of these, 83 (78%) completed the entire 76-week treatment period. Treatment-emergent adverse events were typical of those observed with μ-opioid agonists. No study drug abuse or diversion was reported. Clinically important analgesia and functional improvement were achieved during the dose-titration period and were maintained in most patients throughout 76 weeks without the need for continued HYD dose increases or changes in concomitant nonstudy opioid analgesics. The mean pain score was 6.1 at baseline, 3.8 at the end of the dose titration period and 3.8 through 76 weeks. HYD was generally well tolerated. No unexpected safety concerns emerged. Pain control was sustained throughout 76 weeks of treatment.

Impact of antimicrobial stewardship programme on hospitalized patients at the intensive care unit: a prospective audit and feedback study.

PubMed

Khdour, Maher R; Hallak, Hussein O; Aldeyab, Mamoon A; Nasif, Mowaffaq A; Khalili, Aliaa M; Dallashi, Ahamad A; Khofash, Mohammad B; Scott, Michael G

2018-04-01

Inappropriate use of antibiotics is one of the most important factors contributing to the emergence of drug resistant pathogens. The purpose of this study was to measure the clinical impact of antimicrobial stewardship programme (ASP) interventions on hospitalized patients at the Intensive care unit at Palestinian Medical Complex. A prospective audit with intervention and feedback by ASP team within 48-72 h of antibiotic administration began in September 2015. Four months of pre-ASP data were compared with 4 months of post-ASP data. Data collected included clinical and demographic data; use of antimicrobials measured by defined daily doses, duration of therapy, length of stay, readmission and all-cause mortality. Overall, 176 interventions were made the ASP team with an average acceptance rate of 78.4%. The most accepted interventions were dose optimization (87.0%) followed by de-escalation based on culture results with an acceptance rate of 84.4%. ASP interventions significantly reduces antimicrobial use by 24.3% (87.3 defined daily doses/100 beds vs. 66.1 defined daily doses/100 beds P < 0.001). The median (interquartile range) of length of stay was significantly reduced post ASP [11 (3-21) vs. 7 (4-19) days; P < 0.01]. Also, the median (interquartile range) of duration of therapy was significantly reduced post-ASP [8 (5-12) days vs. 5 (3-9); P = 0.01]. There was no significant difference in overall 30-day mortality or readmission between the pre-ASP and post-ASP groups (26.9% vs. 23.9%; P = 0.1) and (26.1% vs. 24.6%; P = 0.54) respectively. Our prospective audit and feedback programme was associated with positive impact on antimicrobial use, duration of therapy and length of stay. © 2017 The British Pharmacological Society.

Efficacy of two low-dose oral tylosin regimens in controlling the relapse of diarrhea in dogs with tylosin-responsive diarrhea: a prospective, single-blinded, two-arm parallel, clinical field trial.

PubMed

Kilpinen, Susanne; Spillmann, Thomas; Westermarck, Elias

2014-08-06

Despite its wide acceptance as a treatment for canine chronic enteropathies, the macrolide antibiotic tylosin lacks official oral dosage recommendations. Not even textbooks share consensus about the dose; daily recommendations vary from 25 to 80 mg/kg and dosing intervals from one to three times daily. All eight dogs responded to the 5 mg/kg dose, and six of seven dogs responded to the 15 mg/kg dose. The mean fecal consistency scores at the 25 mg/kg tylosin dosage were no significantly different from scores at the 5 mg/kg or 15 mg/kg tylosin dosages (P=0.672, P=0.345). Interestingly, 14/15 (93%) of the dogs responding to a dose of 25 mg/kg tylosin once daily for seven days also responded to the lower dosages at diarrhea relapse. The data indicate that a suitable dose of tylosin for treating diarrhea relapse in canine TRD could be as low as 5 mg/kg once daily for seven days.

Patient doses and occupational exposure in a hybrid operating room.

PubMed

Andrés, C; Pérez-García, H; Agulla, M; Torres, R; Miguel, D; Del Castillo, A; Flota, C M; Alonso, D; de Frutos, J; Vaquero, C

2017-05-01

This study aimed to characterize the radiation exposure to patients and workers in a new vascular hybrid operating room during X-ray-guided procedures. During one year, data from 260 interventions performed in a hybrid operating room equipped with a Siemens Artis Zeego angiography system were monitored. The patient doses were analysed using the following parameters: radiation time, kerma-area product, patient entrance reference point dose and peak skin dose. Staff radiation exposure and ambient dose equivalent were also measured using direct reading dosimeters and thermoluminescent dosimeters. The radiation time, kerma-area product, patient entrance reference point dose and peak skin dose were, on average, 19:15min, 67Gy·cm 2 , 0.41Gy and 0.23Gy, respectively. Although the contribution of the acquisition mode was smaller than 5% in terms of the radiation time, this mode accounted for more than 60% of the effective dose per patient. All of the worker dose measurements remained below the limits established by law. The working conditions in the hybrid operating room HOR are safe in terms of patient and staff radiation protection. Nevertheless, doses are highly dependent on the workload; thus, further research is necessary to evaluate any possible radiological deviation of the daily working conditions in the HOR. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Prospective study on quantitative and qualitative antimicrobial and anti-inflammatory drug use in white veal calves.

PubMed

Pardon, Bart; Catry, Boudewijn; Dewulf, Jeroen; Persoons, Davy; Hostens, Miel; De Bleecker, Koen; Deprez, Piet

2012-04-01

To document and quantify drug use in white veal calves, an intensive livestock production system where multidrug resistance is abundantly present. Drug consumption data were prospectively collected on 15 white veal production cohorts (n = 5853 calves) in Belgium (2007-09). Treatment incidences (TIs) based on animal defined daily dose (ADD), prescribed daily dose (PDD) and used daily dose (UDD) were calculated. Risk factors were identified by linear regression. The average TI(ADD) of antimicrobial treatments was 416.8 ADD per 1000 animals at risk. Predominantly, oral group antimicrobial treatments were used (95.8%). Of the oral group antimicrobial treatments, 12% and 88% were used for prophylactic or metaphylactic indications, respectively. The main indication for group and individual drug use was respiratory disease. The most frequently used antimicrobials (group treatments) were oxytetracycline (23.7%), amoxicillin (18.5%), tylosin (17.2%) and colistin (15.2%). Deviations from the leaflet dosage recommendations were frequently encountered, with 43.7% of the group treatments underdosed (often oxytetracycline and tylosin to treat dysbacteriosis). In 33.3% of the oral antimicrobial group treatments a combination of two antimicrobial preparations was used. Smaller integrations used more antimicrobials in group treatments than larger ones (P < 0.05); an integration is defined as a company that combines all steps of the production chain by having its own feed plant and slaughterhouse and by placing its calves in veal herds owned by producers that fatten these calves for this integration on contract. Producers used higher dosages than prescribed by the veterinarian in cohorts with a single caretaker (P < 0.01). The present study provided detailed information on the intensive antimicrobial use in the white veal industry. Reduction can only be achieved by reducing the number of oral group treatments.

Successful pharmacogenetics-based optimization of unboosted atazanavir plasma exposure in HIV-positive patients: a randomized, controlled, pilot study (the REYAGEN study).

PubMed

Bonora, S; Rusconi, S; Calcagno, A; Bracchi, M; Viganò, O; Cusato, J; Lanzafame, M; Trentalange, A; Marinaro, L; Siccardi, M; D'Avolio, A; Galli, M; Di Perri, G

2015-11-01

Atazanavir without ritonavir, despite efficacy and tolerability, shows low plasma concentrations that warrant optimization. In a randomized, controlled, pilot trial, stable HIV-positive patients on atazanavir/ritonavir (with tenofovir/emtricitabine) were switched to atazanavir. In the standard-dose arm, atazanavir was administered as 400 mg once daily, while according to patients' genetics (PXR, ABCB1 and SLCO1B1), in the pharmacogenetic arm: patients with unfavourable genotypes received 200 mg of atazanavir twice daily. EudraCT number: 2009-014216-35. Eighty patients were enrolled with balanced baseline characteristics. The average atazanavir exposure was 253 ng/mL (150-542) in the pharmacogenetic arm versus 111 ng/mL (64-190) in the standard-dose arm (P < 0.001); 28 patients in the pharmacogenetic arm (75.7%) had atazanavir exposure >150 ng/mL versus 14 patients (38.9%) in the standard-dose arm (P = 0.001). Immunovirological and laboratory parameters had a favourable outcome throughout the study with non-significant differences between study arms. Atazanavir plasma exposure is higher when the schedule is chosen according to the patient's genetic profile. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Variations in total ozone column and biologically effective solar UV exposure doses in Bologna, Italy during the period 2005-2010

NASA Astrophysics Data System (ADS)

Petkov, Boyan; Vitale, Vito; Tomasi, Claudio; Mazzola, Mauro; Lanconelli, Christian; Lupi, Angelo; Busetto, Maurizio

2014-01-01

Variations in total ozone column and sun exposures able to cause erythema and damage the DNA molecules were observed by the narrow-band filter radiometer UV-RAD in Bologna, Italy from 2005 to 2010. The ozone columns determined from the UV-RAD measurements were found to be close to those provided by the satellite Ozone Monitoring Instrument (OMI) showing an average discrepancy of 1 % with standard deviation of ± 6 %. Analysis of the data highlights a well-marked annual cycle of the ozone column variations while the oscillations with periods of 8, 18 and 34 months present much smaller amplitudes. The influence of the frequency of solar irradiance measurements on the accuracy of the evaluated daily exposure dose has been studied and it was found that time intervals no longer than 5-10 min between the measurements of erythema and DNA damage effective UV irradiances provide a satisfactory assessment of the corresponding daily exposures. The latter do not present significant year-to-year variations for the period under study, while their annual distributions show slight changes likely due to the specific cloud cover and ozone column variability for different years. The annual erythemal exposure dose for 2007-2010 varied between 603.7 and 638.1 kJ m-2, while the corresponding sun exposure affecting DNA changed from 6.38 to 7.91 kJ m-2.

Review of Utilization of Cardiovascular Medicines by Daily Defined Dose in the Czech Republic and Slovak Republic.

PubMed

Szilágyiová, Petra; Slušná, Jana; Babela, Robert

2017-11-01

To the Editor, Drug utilization is an important field of drug policy and an integral part of public health internationally. This area of research attracts increasing interest but the pioneering work was done 50 years ago when the first drug consumption report from six European countries for the period of 1966-1967 showed great differences in drug utilization between population groups (WHO, 1968). These results gave important stimulus for creation of Anatomical Therapeutic Chemical (ATC) classification and technical unit of measurement called the Defined Daily Dose (DDD) which is specified as "the assumed average maintenance dose per day for a drug used for its main indication in adults" that dealt with the objections against traditional units of measurement in drug utilization studies (WHO, 2016). The ATC/DDD methodology has in the meantime proved its suitability in drug utilization monitoring and research. As mentioned previously, consumption of pharmaceuticals is often used as a basis for comparison between countries. Based on our professional expertise, we decided to analyze the consumption of cardiovascular medicines by DDD in the Czech Republic and Slovak Republic within all ATC groups reported to OECD (OECD, 2016a). According to OECD indicator results, the Slovak Republic showed in 2014 a higher pharmaceutical consumption by DDD in ATC group C (cardiovascular system) compared to the Czech Republic (OECD, 2016a).

Analysis of the solar radiation data for Beer Sheva, Israel, and its environs

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

Kudish, A.I.; Ianetz, A.

The solar radiation climate of Beer Sheva, Israel, is reported upon in detail. The database utilized in this analysis consisted of global radiation on a horizontal surface, normal incidence beam radiation, and global radiation on a south-facing surface tilted at 40{degree}. Monthly-average hourly and daily values are reported for each of these three types of measured radiations, together with the calculated monthly-average daily values for the components of the global radiation, viz. the horizontal beam and diffuse radiations. The monthly-average hourly and daily clearness index values have also been calculated and analyzed. Monthly-average daily frequency distributions of the clearness indexmore » values are reported for each month. The solar radiation climate of Beer Sheva has also been compared to those reported for a number of countries in this region. The annual-average daily global radiation incident on a horizontal surface is 18.91 MG/m{sup 2} and that for normal incidence beam radiation is 21.17 MG/m{sup 2}. The annual-average daily fraction of the horizontal global radiation that is beam is 0.72. The annual-average daily value for the clearness index is 0.587 and the average frequency of clear days annually is 58.6%. The authors conclude, based upon the above analysis, that Beer Sheva and its environs are characterized by relatively high, average-daily irradiation rates, both global and beam, and a relatively high frequency of clear days.« less

Short- and Long-Term Outcomes of Deep Brain Stimulation in Patients 70 Years and Older with Parkinson Disease.

PubMed

Mathkour, Mansour; Garces, Juanita; Scullen, Tyler; Hanna, Joshua; Valle-Giler, Edison; Kahn, Lora; Arrington, Teresa; Houghton, David; Lea, Georgia; Biro, Erin; Bui, Cuong J; Sulaiman, Olawale A R; Smith, Roger D

2017-01-01

Parkinson disease (PD) is a common neurodegenerative disease in elderly patients that may be treated with deep brain stimulation (DBS). DBS is an accepted surgical treatment in PD patients <70 years that demonstrates marked improvement in disease symptomology. Patients ≥70 years historically have been excluded from DBS therapy. Our objective is to evaluate the short- and long-term outcomes in patients with PD ≥70 years who underwent DBS at our center. In our single-center study, we retrospectively assessed a prospective registry of patients with PD treated with DBS who were ≥70 years old at the time of their procedure. Univariate analyses and 1-sample paired t test were used to evaluate data. Motor scores were evaluated with the Unified Parkinson's Disease Rating Scale III, and the effects on medication requirements were evaluated with levodopa equivalence daily doses (LEDD). Thirty-seven patients were followed for an average of 42.2 months post-DBS. The average ages at diagnosis and at the time of DBS surgery were 63.05 years and 72.45 years, respectively. Significant reductions in the average Unified Parkinson's Disease Rating Scale III score were observed (preoperative 31.8; postoperative 15.6; P < 0.0001). Significant reductions in the average LEDD (preoperative 891.94 mg; postoperative 559.6 mg; P = 0.0008) and medication doses per day (preoperative 11.54; postoperative 7.97; P = 0.0112) also were present. DBS is effective in treating elderly patients with PD. Patients experienced improvement in motor function, LEDD, and medication doses per day after DBS. Our results suggest that DBS is an effective treatment modality in elderly patients with PD. Copyright © 2016 Elsevier Inc. All rights reserved.

Intussusception after monovalent rotavirus vaccine-United States, Vaccine Adverse Event Reporting System (VAERS), 2008-2014.

PubMed

Haber, Penina; Parashar, Umesh D; Haber, Michael; DeStefano, Frank

2015-09-11

In 2006 and 2008, two new rotavirus vaccines (RotaTeq [RV5] and Rotarix [RV1]) were introduced in the United States. US data on intussusception have been mostly related to RV5, with limited data on RV1. We assessed intussusception events following RV1 reported to the Vaccine Adverse Event Reporting System (VAERS), a US national passive surveillance system, during February 2008-December 2014. We conducted a self-controlled risk interval analysis using Poisson regression to estimate the daily reporting ratio (DRR) of intussusception after the first 2 doses of RV1 comparing average daily reports 3-6 versus 0-2 days after vaccination. We calculated the excess risk of intussusception per 100,000 vaccinations based on DRRs and background rates of intussusception. Sensitivity analyses were conducted to assess effects of differential reporting completeness and inaccuracy of baseline rates. VAERS received 108 confirmed insusceptible reports after RV1. A significant clustering was observed on days 3-8 after does1 (p=0.001) and days 2-7 after dose 2 (p=0.001). The DRR comparing the 3-6 day and the 0-2 day periods after RV1 dose 1 was 7.5 (95% CI=2.3, 24.6), translating to an excess risk of 1.6 (95% CI=0.3, 5.8) per 100,000 vaccinations. The DRR was elevated but not significant after dose 2 (2.4 [95% CI=0.8,7.5]). The excess risk ranged from 1.2 to 2.8 per 100,000 in sensitivity analysis. We observed a significant increased risk of intussusception 3-6 days after dose 1 of RV1. The estimated small number of intussusception cases attributable to RV1 is outweighed by the benefits of rotavirus vaccination. Published by Elsevier Ltd.

Once-weekly exenatide as adjunct treatment of type 1 diabetes mellitus in patients receiving continuous subcutaneous insulin infusion therapy.

PubMed

Traina, Andrea N; Lull, Melinda E; Hui, Adrian C; Zahorian, Toni M; Lyons-Patterson, Jane

2014-08-01

The use of once-weekly exenatide in type 2 diabetes mellitus is well supported, but little is known about its effectiveness in type 1 diabetes. The objective of this study was to determine the clinical efficacy of once-weekly exenatide on glycemic control in patients with type 1 diabetes when added to basal-bolus insulin therapy. For this retrospective study, patients with type 1 diabetes, aged 18 years and older, receiving continuous subcutaneous insulin infusion, using a continuous glucose monitoring device or regularly measuring blood glucose levels and receiving 2 mg of exenatide once weekly for at least 3 months were included. Demographic information, glycated hemoglobin (A1C), body weight, body mass index, systolic and diastolic blood pressures, total daily insulin dose, basal and bolus insulin doses, 28-day continuous subcutaneous insulin infusion glucose average and incidence of hypoglycemia were collected at baseline and 3 months after beginning therapy with once-weekly exenatide. An electronic medical record search identified 11 patients with type 1 diabetes who met the inclusion criteria. Comparing baseline and 3 months after initiation of once-weekly exenatide revealed reductions of 0.6% in A1C (p=0.013), 3.7% in body weight (p=0.008), 1.7 kg/m(2) in body mass index (p=0.003), 13% in total daily insulin dose (p=0.011) and 9.3 units in bolus insulin dose (p=0.015). This study revealed that the addition of once-weekly exenatide to insulin therapy for type 1 diabetes patients leads to significant improvements in A1C, body weight, body mass index and insulin doses. Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

The effects of missed doses of amlodipine and losartan on blood pressure in older hypertensive patients.

PubMed

de Leeuw, Peter W; Fagard, Robert; Kroon, Abraham A

2017-06-01

This randomized, double-blind, parallel-group, multicenter study compared the efficacy of amlodipine and losartan in an older hypertensive population, focusing on therapeutic coverage in the case of missed doses. Following a 4-week, single-blind, placebo washout period, 211 patients were randomly assigned to receive either 5 mg of amlodipine once daily or 50 mg of losartan once daily. Doses were doubled after 6 weeks of treatment if the diastolic blood pressure exceeded 90 mm Hg. After the 12-week treatment period, patients received the placebo for 2 days (drug holiday) to simulate two missed doses of antihypertensive medication. Twenty-four-hour ambulatory blood pressure monitoring was conducted at the end of the placebo washout period (baseline), upon completion of the 12-week treatment period (steady state), and after the 2-day drug holiday. Amlodipine was more effective than losartan in reducing patients' 24-h ambulatory blood pressure at the steady-state sampling time. The increases in 24-h blood pressure during the drug holiday averaged 6±2/2±1 mm Hg (P<0.0001) in the amlodipine group and 3±2/2±1 mm Hg (P<0.0001) in the losartan group. The rise in systolic pressure was greater in patients on amlodipine than in those on losartan (P<0.0001). For diastolic pressure, the changes did not differ. Owing to the lower pressure during treatment, patients in the amlodipine group remained at a significantly lower blood pressure level after the 2-day drug holiday. Amlodipine was more effective than losartan in lowering blood pressure and in maintaining blood pressure control after two missed doses, and the difference was most significant for systolic blood pressure.

Improving maraviroc oral bioavailability by formation of solid drug nanoparticles.

PubMed

Savage, Alison C; Tatham, Lee M; Siccardi, Marco; Scott, Trevor; Vourvahis, Manoli; Clark, Andrew; Rannard, Steve P; Owen, Andrew

2018-05-17

Oral drug administration remains the preferred approach for treatment of HIV in most patients. Maraviroc (MVC) is the first in class co-receptor antagonist, which blocks HIV entry into host cells. MVC has an oral bioavailability of approximately 33%, which is limited by poor permeability as well as affinity for CYP3A and several drug transporters. While once-daily doses are now the favoured option for HIV therapy, dose-limiting postural hypotension has been of theoretical concern when administering doses high enough to achieve this for MVC (particularly during coadministration of enzyme inhibitors). To overcome low bioavailability and modify the pharmacokinetic profile, a series of 70 wt% MVC solid drug nanoparticle (SDN) formulations (containing 30 wt% of various polymer/surfactant excipients) were generated using emulsion templated freeze-drying. The lead formulation contained PVA and AOT excipients ( MVC SDN PVA/AOT ), and was demonstrated to be fully water-dispersible to release drug nanoparticles with z-average diameter of 728 nm and polydispersity index of 0.3. In vitro and in vivo studies of MVC SDN PVA/AOT showed increased apparent permeability of MVC, compared to a conventional MVC preparation, with in vivo studies in rats showing a 2.5-fold increase in AUC (145.33 vs. 58.71 ng h ml -1 ). MVC tissue distribution was similar or slightly increased in tissues examined compared to the conventional MVC preparation, with the exception of the liver, spleen and kidneys, which showed statistically significant increases in MVC for MVC SDN PVA/AOT . These data support a novel oral format with the potential for dose reduction while maintaining therapeutic MVC exposure and potentially enabling a once-daily fixed dose combination product. Copyright © 2018. Published by Elsevier B.V.

[Combination of tricyclic antidepressants and MAOI in the depressions].

PubMed

Abdala, E N

1975-03-01

This study was aimed at the assessment of therapeutic and side effects of simultaneous administration of tricyclic antidepressants and MAOI. The sample consisted of 122 patients with depressive syndromes, treated at the "Centro de Psicología Médica San Martín de Tours" (period 1970/1973), with Isocarboxazide and Trimiprimine. All patients received both drugs three times a day. The average daily dose was 20 mg of Isocarboxazide together with 125 mg of Trimiprimine. The average treatment was 70 days long. The study lead to the following conclusions: 1. There were no serious side effects. 2. The scarce side effects registered were not very different from those of the other anti-depressants. 3. The therapeutic doses were lower than those required when each drug is used alone. 4. The speed of action was higher than for each drug separately. 5. The overall percentage of improvement in patients was higher than the percentage obtained for each drug alone. 6. The lack of side effects for a theoretically risky combination of drugs is likely to be attributed to the neuroleptic action of Trimipramine.

SU-F-T-519: Is Geometry Based Setup Sufficient for All of the Head and Neck Treatment Cases?: A Feasibility Study Towards the Dose Based Setup

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

Lee, S; Chen, S; Zhang, B

Purpose: This study compares the geometric-based setup (GBS) which is currently used in the clinic to a novel concept of dose-based setup (DBS) of head and neck (H&N) patients using cone beam CT (CBCT) of the day; and evaluates the clinical advantages. Methods: Ten H&N patients who underwent re-simulation and re-plan due to noticeable anatomic changes during the course of the treatments were retrospectively reviewed on dosimetric changes in the assumption of no plan modification was performed. RayStation planning system (RaySearch Laboratories AB, Sweden) was used to match (ROI fusion module) between prescribed isodoseline (IDL) in the CBCT imported alongmore » with ROIs from re-planned CT and the IDL of original plan (Dose-based setup: DBS). Then, the CBCT plan based on daily setup using the GBS (previously used for a patient) and the DBS CBCT plan recalculated in RayStation compared against the original CT-sim plan. Results: Most of patients’ tumor coverage and OAR doses got generally worsen when the CBCT plans were compared with original CT-sim plan with GBS. However, when DBS intervened, the OAR dose and tumor coverage was better than the GBS. For example, one of patients’ daily average doses of right parotid and oral cavity increased to 26% and 36%, respectively from the original plan to the GBS planning. However, it only increased by 13% and 24%, respectively with DBS. GTV D95 coverage also decreased by 16% with GBS, but only 2% decreased with DBS. Conclusion: DBS method is superior to GBS to prevent any abrupt dose changes to OARs as well as PTV/CTV or GTV at least for some H&N cases. Since it is not known when the DBS is beneficial to the GBS, a system which enables the on-line DBS may be helpful for better treatment of H&N.« less

Opioid analgesia in mechanically ventilated children: results from the multicenter Measuring Opioid Tolerance Induced by Fentanyl study.

PubMed

Anand, Kanwaljeet J S; Clark, Amy E; Willson, Douglas F; Berger, John; Meert, Kathleen L; Zimmerman, Jerry J; Harrison, Rick; Carcillo, Joseph A; Newth, Christopher J L; Bisping, Stephanie; Holubkov, Richard; Dean, J Michael; Nicholson, Carol E

2013-01-01

To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit. Prospective, observational study with 100% accrual of eligible patients. Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network. Four hundred nineteen children treated with morphine or fentanyl infusions. None. Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03). Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy.

Intrathecal Baclofen Dosing Regimens: A Retrospective Chart Review.

PubMed

Clearfield, Jacob S; Nelson, Mary Elizabeth S; McGuire, John; Rein, Lisa E; Tarima, Sergey

2016-08-01

To examine dosing patterns in patients receiving baclofen via intrathecal baclofen pumps to assess for common patterns by diagnosis, ambulation ability, and affected limbs distribution. This trial study included 25 patients with baclofen pumps selected from the 356 patients enrolled in our center's baclofen pump program. Selection was done by splitting all patients into diagnostic categories of stroke, multiple sclerosis, traumatic/anoxic brain injury, cerebral palsy, and spinal cord injury, and then, five patients were randomly selected from each diagnosis.A systematic chart review was then conducted for each patient from Jan 1, 2008, through September 16, 2013, to look at factors including mean daily dose at end of study, and among those implanted during the study mean initial stable dose and time to initial stable dose. Analysis of mean daily dose across diagnoses found significant differences, with brain injury, cerebral palsy, and spinal cord injury patients having higher doses while multiple sclerosis and stroke patients required lower doses. Nonambulatory patients strongly trended to have higher daily doses than ambulatory patients. Similar trends of mean initial stable dose being higher in a similar pattern as that of end mean daily dose were seen according to diagnoses and ambulatory status, although statistical significance could not be achieved with the small sample size. Significant differences in dosing were found between diagnoses and trended to differ by ambulatory status at the end of the study, and similar trends could be observed in achieving initial stable dose. © 2015 International Neuromodulation Society.

SU-F-J-13: Choosing An IMRT Technique in the Treatment of Head and Neck Cancer with Daily Localization Uncertainties

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

Lin, T; Wang, L; Galloway, T

Purpose: Head and Neck cancer treatment with IMRT/VMAT has two choices: split-filed IMRT(SFI), in which the LAN is treated with a separate anterior field and the extended whole-field IMRT(WFI) in which LAN is included with the IMRT/VMAT field. This study shows that under the same dose limit criteria, choosing the technique becomes a critical issue if daily localization and immobilization altered the dose distribution. Methods: Nine common head-and-neck cancer cases were chosen to illustrate how the daily localization and immobilization uncertainties affect to choose between SFI and WFI. Both SFI and WFI at upper target coverage were generated with VMAT.more » For each case, the same planning criteria were applied to the target and critical structures; therefore, similar target coverage and dose falloff can be observed in both techniques. Thirty days of kV cone beam CT(CBCT) images on each case were also delineated with contralateral and ipsilateral target as well as larynx as critical structure. About 300 CBCT images with daily delivered doses were analyzed and compared in a form of dose-volume histograms. Results: While both plans for SFI and WFI with VMAT planning utilized and meet the criteria of D95>prescription dose and for not-involved larynx with mean dose <35Gy and V55<10%, the daily localization and immobilization has a great contribution to the resulted dose delivery. With WFI, the better daily contralateral and ipsilateral neck target coverage can reflect a simpler or shorter localization; however, a much superior avoidance (WFI: mean dose a 42.5Gy; SFI: mean dose a 18.9Gy) of the non-involved larynx from the SFI is preferred. Conclusion: Dosimetrically, SFI and WFI are equally well for head and Neck cancer treatment with VMAT technique; however, if considering the contribution of daily localization(CBCT) method uncertainties, SFI is better with sparing non-involved larynx and WFI has better target coverage.« less

Using quality of life measures in a Phase I clinical trial of noni in patients with advanced cancer to select a Phase II dose.

PubMed

Issell, Brian F; Gotay, Carolyn C; Pagano, Ian; Franke, Adrian A

2009-01-01

ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.

Personal radiofrequency electromagnetic field exposure measurements in Swiss adolescents.

PubMed

Roser, Katharina; Schoeni, Anna; Struchen, Benjamin; Zahner, Marco; Eeftens, Marloes; Fröhlich, Jürg; Röösli, Martin

2017-02-01

Adolescents belong to the heaviest users of wireless communication devices, but little is known about their personal exposure to radiofrequency electromagnetic fields (RF-EMF). The aim of this paper is to describe personal RF-EMF exposure of Swiss adolescents and evaluate exposure relevant factors. Furthermore, personal measurements were used to estimate average contributions of various sources to the total absorbed RF-EMF dose of the brain and the whole body. Personal exposure was measured using a portable RF-EMF measurement device (ExpoM-RF) measuring 13 frequency bands ranging from 470 to 3600MHz. The participants carried the device for three consecutive days and kept a time-activity diary. In total, 90 adolescents aged 13 to 17years participated in the study conducted between May 2013 and April 2014. In addition, personal measurement values were combined with dose calculations for the use of wireless communication devices to quantify the contribution of various RF-EMF sources to the daily RF-EMF dose of adolescents. Main contributors to the total personal RF-EMF measurements of 63.2μW/m 2 (0.15V/m) were exposures from mobile phones (67.2%) and from mobile phone base stations (19.8%). WLAN at school and at home had little impact on the personal measurements (WLAN accounted for 3.5% of total personal measurements). According to the dose calculations, exposure from environmental sources (broadcast transmitters, mobile phone base stations, cordless phone base stations, WLAN access points, and mobile phones in the surroundings) contributed on average 6.0% to the brain dose and 9.0% to the whole-body dose. RF-EMF exposure of adolescents is dominated by their own mobile phone use. Environmental sources such as mobile phone base stations play a minor role. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dosimetric evaluation of three adaptive strategies for prostate cancer treatment including pelvic lymph nodes irradiation.

PubMed

Cantin, Audrey; Gingras, Luc; Lachance, Bernard; Foster, William; Goudreault, Julie; Archambault, Louis

2015-12-01

The movements of the prostate relative to the pelvic lymph nodes during intensity-modulated radiation therapy treatment can limit margin reduction and affect the protection of the organs at risk (OAR). In this study, the authors performed an analysis of three adaptive treatment strategies that combine information from both bony and gold marker registrations. The robustness of those treatments against the interfraction prostate movements was evaluated. A retrospective study was conducted on five prostate cancer patients with 7-13 daily cone-beam CTs (CBCTs). The clinical target volumes (CTVs) consisting of pelvic lymph nodes, prostate, and seminal vesicles as well as the OARs were delineated on each CBCT and the initial CT. Three adaptive strategies were analyzed. Two of these methods relied on a two-step patient positioning at each fraction. First step: a bony registration was used to deliver the nodal CTV prescription. Second step: a gold marker registration was then used either to (1) complete the dose delivered to the prostate (complement); (2) or give almost the entire prescription to the prostate with a weak dose gradient between the targets to compensate for possible motions (gradient). The third method (COR) used a pool of precalculated plans based on images acquired at previous treatment fractions. At each new fraction, a plan is selected from that pool based on the daily position of prostate center-of-mass. The dosimetric comparison was conducted and results are presented with and without the systematic shift in the prostate position on the CT planning. The adaptive strategies were compared to the current clinical standard where all fractions are treated with the initial nonadaptive plan. The minimum daily prostate D95% is improved by 2%, 9%, and 6% for the complement, the gradient, and the COR approaches, respectively, compared to the nonadaptive method. The average nodal CTV D95% remains constant across the strategies, except for the gradient approach where a reduction of 7% is observed. However, a correction of the systematic shift reduced the problem, and the adaptive strategies remain robust against the prostate movement across the fraction. The bladder V55Gy is reduced by 35% on average for the adaptive strategies. Because they offer increased CTV coverage and OAR sparing, adaptive methods may be suitable candidates for simple and efficient adaptive treatment strategies for prostate cancer. Margin reduction and systematic error correction in the prostate position improve the protection of the OAR and the dose coverage. A cumulative dose to simulate a complete treatment would show real effects and allow a better comparison between each method.

210-Polonium studies in some environmental and biological matrices of Domiasiat uranium deposit area, West Khasi Hills, Meghalaya, India.

PubMed

Marbaniang, Deswyn G; Poddar, Raj K; Nongkynrih, Phlis; Khathing, Darlando T

2010-03-01

The study was performed using a silicon surface barrier alpha spectrometer at Bhabha Atomic Research Centre, Mumbai, India. Through the study, the observed (210)Po activity in water sample from different locations in the Domiasiat area ranges from 0.04 to 0.69 Bq/l. The daily and annual intake of (210)Po through water was also estimated and the mean value of 0.72 and 263.61 Bq, respectively, were observed. It is observed that the effective doses through water were higher than the World Health Organization recommended dose of 0.05 mSv/year. The total annual effective doses through terrestrial ingestion for all the locations was studied and the mean annual effective dose was observed to be 0.315 mSv, which, when compared to the worldwide and the Indian values, was observed to be slightly higher. The mean activity in soil is found to be 124.8 +/-5.7 Bq/kg and in meat the activity is 0.43 +/-0.05 Bq/kg. In fishes, an activity of 0.48 +/-0.07 Bq/kg in Garra lamta, 0.29 +/-0.02 Bq/kg in Neolissocheilus hexaganolepis, and 3.3 +/-0.1 Bq/kg in Macrobrachium sp. is observed. Activity concentration in plant samples was analyzed and the activity ranges from 0.020 +/-0.002 to 9.69 +/-0.35 Bq/kg. Committed effective dose by the adult population of the Domiasiat area through intake of (210)Po through these food items was also determined and compared with the Indian average value and the worldwide average value.

Gender, Emotion Work, and Relationship Quality: A Daily Diary Study

PubMed Central

Curran, Melissa A.; McDaniel, Brandon T.; Pollitt, Amanda M.; Totenhagen, Casey J.

2015-01-01

We use the gender relations perspective from feminist theorizing to investigate how gender and daily emotion work predict daily relationship quality in 74 couples (148 individuals in dating, cohabiting, or married relationships) primarily from the southwest U.S. Emotion work is characterized by activities that enhance others’ emotional well-being. We examined emotion work two ways: trait (individuals’ average levels) and state (individuals’ daily fluctuations). We examined actor and partner effects of emotion work and tested for gender differences. As outcome variables, we included six types of daily relationship quality: love, commitment, satisfaction, closeness, ambivalence, and conflict. This approach allowed us to predict three aspects of relationship quality: average levels, daily fluctuations, and volatility (overall daily variability across a week). Three patterns emerged. First, emotion work predicted relationship quality in this diverse set of couples. Second, gender differences were minimal for fixed effects: Trait and state emotion work predicted higher average scores on, and positive daily increases in, individuals’ own positive relationship quality and lower average ambivalence. Third, gender differences were more robust for volatility: For partner effects, having a partner who reported higher average emotion work predicted lower volatility in love, satisfaction, and closeness for women versus greater volatility in love and commitment for men. Neither gender nor emotion work predicted average levels, daily fluctuations, or volatility in conflict. We discuss implications and future directions pertaining to the unique role of gender in understanding the associations between daily emotion work and volatility in daily relationship quality for relational partners. PMID:26508808

Gender, Emotion Work, and Relationship Quality: A Daily Diary Study.

PubMed

Curran, Melissa A; McDaniel, Brandon T; Pollitt, Amanda M; Totenhagen, Casey J

2015-08-01

We use the gender relations perspective from feminist theorizing to investigate how gender and daily emotion work predict daily relationship quality in 74 couples (148 individuals in dating, cohabiting, or married relationships) primarily from the southwest U.S. Emotion work is characterized by activities that enhance others' emotional well-being. We examined emotion work two ways: trait (individuals' average levels) and state (individuals' daily fluctuations). We examined actor and partner effects of emotion work and tested for gender differences. As outcome variables, we included six types of daily relationship quality: love, commitment, satisfaction, closeness, ambivalence, and conflict. This approach allowed us to predict three aspects of relationship quality: average levels, daily fluctuations, and volatility (overall daily variability across a week). Three patterns emerged. First, emotion work predicted relationship quality in this diverse set of couples. Second, gender differences were minimal for fixed effects: Trait and state emotion work predicted higher average scores on, and positive daily increases in, individuals' own positive relationship quality and lower average ambivalence. Third, gender differences were more robust for volatility: For partner effects, having a partner who reported higher average emotion work predicted lower volatility in love, satisfaction, and closeness for women versus greater volatility in love and commitment for men. Neither gender nor emotion work predicted average levels, daily fluctuations, or volatility in conflict. We discuss implications and future directions pertaining to the unique role of gender in understanding the associations between daily emotion work and volatility in daily relationship quality for relational partners.

Clinical experience with image-guided radiotherapy in an accelerated partial breast intensity-modulated radiotherapy protocol.

PubMed

Leonard, Charles E; Tallhamer, Michael; Johnson, Tim; Hunter, Kari; Howell, Kathryn; Kercher, Jane; Widener, Jodi; Kaske, Terese; Paul, Devchand; Sedlacek, Scot; Carter, Dennis L

2010-02-01

To explore the feasibility of fiducial markers for the use of image-guided radiotherapy (IGRT) in an accelerated partial breast intensity modulated radiotherapy protocol. Nineteen patients consented to an institutional review board approved protocol of accelerated partial breast intensity-modulated radiotherapy with fiducial marker placement and treatment with IGRT. Patients (1 patient with bilateral breast cancer; 20 total breasts) underwent ultrasound guided implantation of three 1.2- x 3-mm gold markers placed around the surgical cavity. For each patient, table shifts (inferior/superior, right/left lateral, and anterior/posterior) and minimum, maximum, mean error with standard deviation were recorded for each of the 10 BID treatments. The dose contribution of daily orthogonal films was also examined. All IGRT patients underwent successful marker placement. In all, 200 IGRT treatment sessions were performed. The average vector displacement was 4 mm (range, 2-7 mm). The average superior/inferior shift was 2 mm (range, 0-5 mm), the average lateral shift was 2 mm (range, 1-4 mm), and the average anterior/posterior shift was 3 mm (range, 1 5 mm). This study shows that the use of IGRT can be successfully used in an accelerated partial breast intensity-modulated radiotherapy protocol. The authors believe that this technique has increased daily treatment accuracy and permitted reduction in the margin added to the clinical target volume to form the planning target volume. Copyright 2010 Elsevier Inc. All rights reserved.

The dose-effect relationship of baclofen in alcohol dependence: A 1-year cohort study.

PubMed

Pignon, Baptiste; Labreuche, Julien; Auffret, Marine; Gautier, Sophie; Deheul, Sylvie; Simioni, Nicolas; Cottencin, Olivier; Bordet, Régis; Duhamel, Alain; Rolland, Benjamin

2017-07-01

Our aim is to study the relationship between dose of baclofen and effectiveness in alcohol dependence. Two hundred two patients with alcohol dependence, who received baclofen treatment for drinking reduction, were followed up for 1 year. For each patient-month of treatment, the maximum daily dose of baclofen (DDB) and average weekly alcohol consumption (AWAC) were calculated. We defined a favorable drinking outcome as an AWAC under 200 g/w for at least 2 consecutive months. We divided the DDB of each patient-month into 3 categories (low dose: <90 mg/d, medium dose: 90-150 mg/d, and high dose: >150 mg/d) and investigated the relationship between reaching a favorable outcome and the concurrent DDB category in a time-varying Cox regression analysis. Hazard ratios (HRs) were adjusted based on age, sex, and initial AWAC. One hundred forty subjects were followed during at least 1 month. Of these patients, 58 (41%) had a favorable drinking outcome. In comparison to low dose, medium dose was associated with a decreased rate of favorable drinking outcome (HR = 0.42; 95% CI [0.20, 0.88]), whereas no difference was found with high dose (HR = 1.31; 95% CI [0.65, 2.64]). The relationship between dose of baclofen and favorable drinking outcome was U-shaped, that is, was increased at low and high doses compared to medium doses. Copyright © 2017 John Wiley & Sons, Ltd.

Organochlorines in urban soils from Central India: probabilistic health hazard and risk implications to human population.

PubMed

Kumar, Bhupander; Mishra, Meenu; Verma, V K; Rai, Premanjali; Kumar, Sanjay

2018-04-21

This study presents distribution of organochlorines (OCs) including HCH, DDT and PCBs in urban soils, and their environmental and human health risk. Forty-eight soil samples were extracted using ultrasonication, cleaned with modified silica gel chromatography and analyzed by GC-ECD. The observed concentrations of ∑HCH, ∑DDT and ∑PCBs in soils ranged between < 0.01-2.54, 1.30-27.41 and < 0.01-62.8 µg kg -1 , respectively, which were lower than the recommended soil quality guidelines. Human health risk was estimated following recommended guidelines. Lifetime average daily dose (LADD), non-cancer risk or hazard quotient (HQ) and incremental lifetime cancer risk (ILCR) for humans due to individual and total OCs were estimated and presented. Estimated LADD were lower than acceptable daily intake and reference dose. Human health risk estimates were lower than safe limit of non-cancer risk (HQ < 1.0) and the acceptable distribution range of ILCR (10 -6 -10 -4 ). Therefore, this study concluded that present levels of OCs (HCH, DDT and PCBs) in studied soils were low, and subsequently posed low health risk to human population in the study area.

Time profile of cosmic radiation exposure during the EXPOSE-E mission: the R3DE instrument.

PubMed

Dachev, Tsvetan; Horneck, Gerda; Häder, Donat-Peter; Schuster, Martin; Richter, Peter; Lebert, Michael; Demets, Rene

2012-05-01

The aim of this paper is to present the time profile of cosmic radiation exposure obtained by the Radiation Risk Radiometer-Dosimeter during the EXPOSE-E mission in the European Technology Exposure Facility on the International Space Station's Columbus module. Another aim is to make the obtained results available to other EXPOSE-E teams for use in their data analysis. Radiation Risk Radiometer-Dosimeter is a low-mass and small-dimension automatic device that measures solar radiation in four channels and cosmic ionizing radiation as well. The main results of the present study include the following: (1) three different radiation sources were detected and quantified-galactic cosmic rays (GCR), energetic protons from the South Atlantic Anomaly (SAA) region of the inner radiation belt, and energetic electrons from the outer radiation belt (ORB); (2) the highest daily averaged absorbed dose rate of 426 μGy d(-1) came from SAA protons; (3) GCR delivered a much smaller daily absorbed dose rate of 91.1 μGy d(-1), and the ORB source delivered only 8.6 μGy d(-1). The analysis of the UV and temperature data is a subject of another article (Schuster et al., 2012 ).

Preclinical toxicologic evaluation of 5-isoxazoleacetic acid, alpha-amino-3-chloro-4,5-dihydro-(nsc 163501), in dogs, monkeys, and cdf1 mice. Final report 24 Apr-13 Sep 78

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

Denine, E.P.; Stout, L.D.; Peckham, J.C.

1978-11-10

Dose-limiting gastrointestinal toxicosis was qualitatively similar in dogs, monkeys, and mice. In dogs and monkeys, anorexia and/or oligodipsia were cardinal signs. Severity of intoxication was indicated by progression to a diarrheal syndrome. Intoxication of the erythron was indicated in the dog and monkey studies. Quantitatively, mice were the most resistant to toxicity, and monkeys were more resistant than dogs. In dogs, fractionation of a single dose to five daily doses resulted in marked cumulative toxicity. Further fractionation to 10 daily doses produced only additive intoxication. Fractionation of a single dose to weekly doses offered some protection from additive toxicity. Similarmore » results were obtained when 5 daily doses were fractionated to three 5-day courses of treatment separated by 9-day rest periods.« less

Efficacy of two low-dose oral tylosin regimens in controlling the relapse of diarrhea in dogs with tylosin-responsive diarrhea: a prospective, single-blinded, two-arm parallel, clinical field trial

PubMed Central

2014-01-01

Background Despite its wide acceptance as a treatment for canine chronic enteropathies, the macrolide antibiotic tylosin lacks official oral dosage recommendations. Not even textbooks share consensus about the dose; daily recommendations vary from 25 to 80 mg/kg and dosing intervals from one to three times daily. The objective of this prospective, single-blinded, two-arm parallel, clinical field trial was to determine whether doses of 5 mg/kg or 15 mg/kg tylosin administered orally once daily for seven days would have a similar effect on fecal consistency in diarrhea relapses to that of a 25 mg/kg dose of tylosin administered once daily for seven days, a dosage that has proved effective in controlling canine tylosin-responsive diarrhea (TRD). A further objective was to compare the efficacy of the 5 mg/kg and 15 mg/kg tylosin dosages. Fifteen client-owned dogs diagnosed with TRD that had responded to a dose of 25 mg/kg tylosin once daily for seven days were enrolled in the study. After a relapse of diarrhea the dogs were allocated into two groups receiving tylosin orally in doses of either 5 mg/kg or 15 mg/kg once daily for seven days. The owners were blinded to the dosage. The elimination of diarrhea was the main criterion in assessing treatment success. The mean fecal consistency score of the last three treatment days for all dosages, including 25 mg/kg, as evaluated by the owners according to a standardized fecal scoring system, served as the primary outcome measures. Results All eight dogs responded to the 5 mg/kg dose, and six of seven dogs responded to the 15 mg/kg dose. The mean fecal consistency scores at the 25 mg/kg tylosin dosage were no significantly different from scores at the 5 mg/kg or 15 mg/kg tylosin dosages (P = 0.672, P = 0.345). Conclusions Interestingly, 14/15 (93%) of the dogs responding to a dose of 25 mg/kg tylosin once daily for seven days also responded to the lower dosages at diarrhea relapse. The data indicate that a suitable dose of tylosin for treating diarrhea relapse in canine TRD could be as low as 5 mg/kg once daily for seven days. PMID:25096196

SU-E-T-27: A Dosimetric Evaluation of Boney Anatomy Versus Fiducial Marker Alignment for the Treatment of Prostate Cancer Using Scanned Beam Proton Therapy

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

Freund, D; Ding, X; Zhang, J

Purpose: In prostate proton radiotherapy, three fiducial markers are used for patient daily alignment. However fiducial alignment can change beamline heterogeneity in proton therapy. The purpose of this study is to determine the difference in fiducial and boney anatomy alignment for patient treatment. Methods and materials: Prostate cancer patients who received proton treatment were included in this study. 3 fiducial markers were implanted before the initial CT. All the patients were re-CT’d every 2 weeks to check the fiducial marker position reproducibility as well as dosimetric consistence of target coverage. In geometry study, re-CT were fused to the initial CTmore » base on the boney anatomy and the average fiducial marker displacement was measured the centers of the fiducials. Dosimetrically, the initial plan was recalculated directly to re-CT image set based on the boney alignment and fiducial alignment to determine the difference from daily treatment. Prostate coverage and hotspots were evaluated using the dose to 98% of the CTV (D98) and dose to 2% (D2), respectively. Results: The shift from the initial 6 patient CT image sets resulted in an average change in the fiducial location of 5.70 +/− 3 mm. Dosimetric comparison from a single patient revealed that differences from the planned dose resulted from both boney and fiducial alignment. Planned clinical treatment volume coverage resulted in a D98 of 70.44Gy and D2 of 70.84Gy compared to a D98 of 70.13Gy and D2 70.94Gy for boney alignment and a D98 of 70.08Gy and D2 71.18Gy for fiducial alignment respectively. Conclusion: This study demonstrates that with boney anatomy alignment there is little change to CTV coverage and only slightly worse CTV coverage and hotspot production with fiducial alignment. An increase patient cohort and further investigation is necessary to determine the whether boney alignment can help better control dose heterogeneity.« less

Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea.

PubMed

Thiboutot, Diane M; Fleischer, Alan B; Del Rosso, James Q; Graupe, Klaus

2008-06-01

Twice-daily azelaic acid (AzA) is the conventional regimen for papulopustular rosacea, but once-daily AzA may be equally effective, with greater convenience and dosing flexibility. In order to test this hypothesis, an exploratory study was conducted. The evaluable efficacy population of this 12-week double-blind, parallel-group study included 72 patients and the population that was used to report safety results included 92 patients. Baseline characteristics were comparable between the once-daily and twice-daily study groups. Evaluations were performed at baseline and at weeks 4, 8, and 12. No significant difference was found between the once-daily and twice-daily groups at the end of study therapy in mean investigator global assessment (IGA) scores, treatment success, or treatment response. The mean number of inflammatory lesions, the intensity of erythema intensity, and the intensity of telangiectasia at treatment end were likewise not significantly different (P>.205 for all). More than 90% of subjects in each group rated cosmetic acceptability of this AzA gel as satisfactory or better. Based on these findings and those of prior studies, once-daily AzA 15% gel can therefore be utilized as a safe, effective, and economical dosing option for the treatment of mild-to-moderate papulopustular rosacea. Once-daily dosing of AzA 15% gel was well accepted by patients and can offer considerable dosing flexibility and convenience for the patient as well as for the dermatologist.

Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications

PubMed Central

Shen, Jie; Goodkin, Margot L; Tong, Warren; Attar, Mayssa

2017-01-01

Purpose Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed. Methods New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve. Results Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6–8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation. Conclusion Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties), formulations of bimatoprost 0.01% can be administered once or twice daily. These findings support development of bimatoprost 0.01%-based fixed-dose combination therapies administered twice daily for patients who require multiple adjunctive medications to control their IOP. PMID:29026287

Higher pain scores, similar opioid doses and side effects associated with antipyretic analgesics in specialised tertiary pain care.

PubMed

Lötsch, Jörn; Freynhagen, Rainer; von Hentig, Nils; Griessinger, Norbert; Zimmermann, Michael; Sittl, Reinhard; Geisslinger, Gerd

2010-11-01

To evaluate whether non-opioid antipyretic analgesics are associated with lower pain scores, opioid doses and side effects in pain patients in tertiary care. In a cross-sectional observational study, data from 519 Caucasians (197 men, 322 women; mean age 55.6 ± 15 years) who had undertaken pain therapy for various causes for 77.5 ± 90.8 months, obtained in three separate study centres, was analysed for actual 24-h pain scores, daily opioid doses and the occurrence of side effects. Of the 519 patients, 352 received opioids and 260 antipyretic analgesics, from whom 154 received both classes and 304 only either class. The administration of non-opioid antipyretic analgesics was associated with higher average pain scores (4.6 ± 2.5 vs 3.9 ± 2.6; P = 0.01), tendentially higher average oral morphine equivalent doses (121.8 ± 162.2 vs 146.7 ± 242.4 mg/d; P = 0.25) and a similar incidence of side effects (P = 0.21). These results were correspondingly seen when analysing the three study centres separately as independent cohorts. With the caution advised for cross-sectional data, the results dispute a clinical benefit of non-opioid antipyretic analgesics for most chronic pain patients in tertiary care and draw attention towards prospectively re-evaluating the utility of non-opioid antipyretic analgesics in tertiary pain care in a randomised placebo controlled trial.

Reconstruction of erythemal UV irradiance at Hohenpeissenberg (1968-2001) considering trends of total ozone, cloudiness, and turbidity

NASA Astrophysics Data System (ADS)

Trepte, S.; Winkler, P.

2003-04-01

The global mean total column ozone amount for the period 1997-2001 was approximately 3% below the 1964-1980 average. The largest ozone decreases in the northern hemisphere midlatitudes are observed during winter-spring (˜4%), with summer-autumn decreases approximately half as large. Total ozone measured at Hohenpeissenberg, Germany (48^oN, 11^oE) shows a strong decrease by about 10% since 1968, representing the long-term downward trend over Central Europe. The main consequence of this phenomenon is the expected increase of solar ultraviolet irradiation (UV-B) reaching the Earth's surface with the known harmful effects on the biosphere. Global data records of reliable routine observations of UV irradiance are still too short for accurate estimation of long-term UV variations and trends. While direct UV mesaurements at Hohenpeissenberg are available only since 1990, the long-term development of UV-B have to be reconstructed. Besides on the amount of total ozone the UV irradiation at the ground depends also on atmospheric turbidity and cloudiness. The reconstruction method is based on statistical correlations of measured UV-B data with the influencing parameters total ozone, turbidity and cloud modification factors derived from eye-observations in connection with total solar irradiance data. These observed data allow a realistic reconstruction of the UV-B time series, since no assumption on these influencing data have to be made. A model is presented, using hourly observed spectral UV-B irradiance (1990-1998), total solar irradiance, total ozone amount (daily mean) and clouds to derive erythemal UV irradiance and daily doses at Hohenpeissenberg in the period 1968-2001. A comparison with recorded UV data shows good agreement. Due to long-term total ozone loss, peak values of erythemal UV irradiance in spring and summer at clear-sky conditions have strongly increased (+4.2%/decade in June). Mean daily doses have also increased in this season (+5.4%/decade in May) but meteorological changes like reduced sunshine duration and increased cloudiness lead to a partly compensation of the ozone-loss effect in spring and to an overcompensation in autumn, where we found a long-term decrease of the daily dose (-3.0%/decade in September). Model calculations also demonstrate large year-to-year fluctuations of UV doses induced by meteorological variability, which exceed the long-term trend of the various months significantly. Nevertheless, this investigation has shown that on a long-term time scale the daily doses develop in a different way as compared to the peak values because the reasons for ozone decline (anthropogenic CFC's) and the cloud cover (hydrological cycle changes due to greenhouse effect) are caused by different phenomena.

Adherence to Biobehavioral Recommendations in Pediatric Migraine as Measured by Electronic Monitoring: The Adherence in Migraine (AIM) Study.

PubMed

Kroon Van Diest, Ashley M; Ramsey, Rachelle; Aylward, Brandon; Kroner, John W; Sullivan, Stephanie M; Nause, Katie; Allen, Janelle R; Chamberlin, Leigh A; Slater, Shalonda; Hommel, Kevin; LeCates, Susan L; Kabbouche, Marielle A; O'Brien, Hope L; Kacperski, Joanne; Hershey, Andrew D; Powers, Scott W

2016-07-01

The purpose of this investigation was to examine treatment adherence to medication and lifestyle recommendations among pediatric migraine patients using electronic monitoring systems. Nonadherence to medical treatment is a significant public health concern, and can result in poorer treatment outcomes, decreased cost-effectiveness of medical care, and increased morbidity. No studies have systematically examined adherence to medication and lifestyle recommendations in adolescents with migraine outside of a clinical trial. Participants included 56 adolescents ages 11-17 who were presenting for clinical care. All were diagnosed with migraine with or without aura or chronic migraine and had at least 4 headache days per month. Medication adherence was objectively measured using electronic monitoring systems (Medication Event Monitoring Systems technology) and daily, prospective self-report via personal electronic devices. Adherence to lifestyle recommendations of regular exercise, eating, and fluid intake were also assessed using daily self-report on personal electronic devices. Electronic monitoring indicates that adolescents adhere to their medication 75% of the time, which was significantly higher than self-reported rates of medication adherence (64%). Use of electronic monitoring of medication detected rates of adherence that were significantly higher for participants taking once daily medication (85%) versus participants taking twice daily medication (59%). Average reported adherence to lifestyle recommendations of consistent noncaffeinated fluid intake (M = 5 cups per day) was below recommended levels of a minimum of 8 cups per day. Participants on average also reported skipping 1 meal per week despite recommendations of consistently eating three meals per day. Results suggest that intervention focused on adherence to preventive treatments (such as medication) and lifestyle recommendations may provide more optimal outcomes for children and adolescents with migraine and their families. Once daily dosing of medication may be preferred to twice daily medication for increased medication adherence among children and adolescents. © 2016 American Headache Society.

Treatment of Hypertension: Favourable Effect of the Twice-Daily Compared to the Once-Daily (Evening) Administration of Perindopril and Losartan.

PubMed

Szauder, Ipoly; Csajági, Eszter; Major, Zsuzsanna; Pavlik, Gabor; Ujhelyi, Gabriella

2015-01-01

Little is known about the effect of twice daily administration of same dose of ACE inhibitor and ARB on the diurnal/nocturnal blood pressure (BP) ratio. We aimed to assess the effect of two widely used long-acting drugs: perindopril and losartan in the treatment of hypertension comparing the once-daily (evening) vs. twice-daily (morning and evening) administration with the same daily doses. Untreated primary hypertensive patients without complaints (a total of 164: 65 men, 99 women, 55.7 ± 13.7 years of age, 41-41 patients per treated groups) were selected with non-dipper phenomenon, estimated by diurnal index (DI) <10%. The effect of evening (8 mg perindopril or 100 mg losartan) vs morning and evening (4-4 mg perindopril or 50-50 mg losartan) administration was determined on a 14-day treatment by ABPM. The mean BP, the percent time elevation index, and the hyperbaric impact decreased in both drug groups. Significant difference was observed in the DI in the case of twice-daily administration vs once-daily evening dosing. The twice-daily administration with the same daily dose of perindopril or losartan seems to be more effective compared to the once daily evening administration in eliminating the non-dipper phenomenon. According to some authors the non-dipping phenomenon increases cardiovascular risk, while others are of the opinion that the association of non-dipping with cardiovascular events does not necessarily mean that selective treatment of non-dipping improves cardiovascular outcomes. © 2015 S. Karger AG, Basel.

Best Practices for Intrathecal Baclofen Therapy: Dosing and Long-Term Management.

PubMed

Boster, Aaron L; Adair, Roy L; Gooch, Judith L; Nelson, Mary Elizabeth S; Toomer, Andrea; Urquidez, Joe; Saulino, Michael

2016-08-01

Intrathecal baclofen (ITB) therapy aims to reduce spasticity and provide functional control. An expert panel consulted on best practices. Pump fill and drug delivery can be started intraoperatively, with monitoring for at least eight hours. Initiate with the 500 mcg/mL concentration. The starting daily dose should be twice the effective bolus screening dose, or the screening dose if the patient had a prolonged response (greater than eight hours) or negative reactions. Oral antispasmodics can be weaned, one drug at a time beginning with oral baclofen after ITB begins. Assessment should occur within 24 hours of a dose change. For adults, daily dose increases may be 5% to 15% once every 24 hours for cerebral-origin spasticity and 10% to 30% once every 24 hours for spinal-origin spasticity. Daily dose increases can be 5% to 15% once every 24 hours for children. Inpatients should be assessed at least every 24 hours and receive rehabilitation. Step dosing can be used for outpatients who cannot return daily. Dosing options include simple continuous dosing, variable 24-hour flex dosing, or regularly scheduled boluses. Patients/caregivers should understand the care plan, responsibilities, and possible side-effects. Low-reservoir alarm dates and refill schedules should be written down, along with emergency contact information. A higher concentration at refill can extend refill intervals, and a bridge bolus must be programmed. Time changes may affect flex dosing. Pump replacement should be scheduled at least three months in advance. ITB dosing is multistep and individualized. © 2016 International Neuromodulation Society.

26 CFR 1.142(a)(5)-1 - Exempt facility bonds: Sewage facilities.

Code of Federal Regulations, 2011 CFR

2011-04-01

...; however, for property treating wastewater reasonably expected to have an average daily raw wasteload... the extent the treatment is for wastewater having an average daily raw wasteload concentration of BOD...—(i) Exception to BOD limit. A facility treating wastewater with an average daily raw wasteload...

26 CFR 1.142(a)(5)-1 - Exempt facility bonds: Sewage facilities.

Code of Federal Regulations, 2012 CFR

2012-04-01

...; however, for property treating wastewater reasonably expected to have an average daily raw wasteload... the extent the treatment is for wastewater having an average daily raw wasteload concentration of BOD...—(i) Exception to BOD limit. A facility treating wastewater with an average daily raw wasteload...

26 CFR 1.142(a)(5)-1 - Exempt facility bonds: Sewage facilities.

Code of Federal Regulations, 2014 CFR

2014-04-01

...; however, for property treating wastewater reasonably expected to have an average daily raw wasteload... the extent the treatment is for wastewater having an average daily raw wasteload concentration of BOD...—(i) Exception to BOD limit. A facility treating wastewater with an average daily raw wasteload...

26 CFR 1.142(a)(5)-1 - Exempt facility bonds: Sewage facilities.

Code of Federal Regulations, 2013 CFR

2013-04-01

...; however, for property treating wastewater reasonably expected to have an average daily raw wasteload... the extent the treatment is for wastewater having an average daily raw wasteload concentration of BOD...—(i) Exception to BOD limit. A facility treating wastewater with an average daily raw wasteload...

26 CFR 1.142(a)(5)-1 - Exempt facility bonds: Sewage facilities.

Code of Federal Regulations, 2010 CFR

2010-04-01

...; however, for property treating wastewater reasonably expected to have an average daily raw wasteload... the extent the treatment is for wastewater having an average daily raw wasteload concentration of BOD...—(i) Exception to BOD limit. A facility treating wastewater with an average daily raw wasteload...

Thalidomide treatment in cutaneous lesions of systemic lupus erythematosus: a multicenter study in China.

PubMed

Wang, Dandan; Chen, Haifeng; Wang, Shiying; Zou, Yaohong; Li, Jing; Pan, Jieping; Wang, Xiangdang; Ren, Tianli; Zhang, Yu; Chen, Zhiwei; Feng, Xuebing; Sun, Lingyun

2016-06-01

Thalidomide is effective for treating severe cutaneous lupus patients. The aim of this study was to observe the optimum effective and maintenance doses of thalidomide to maximize clinical benefit and minimize side effects for patients with cutaneous lupus in China. Sixty-nine patients with lupus rash from eight hospitals in China were enrolled and treated with different doses of thalidomide. We started the dose of thalidomide at 25 mg daily and gradually increased administration dose once a week until erythema was markedly improved. The effective and maintenance doses were documented. The size of skin lesions was noted once a week. Systemic lupus erythematosus disease activity index (SLEDAI) score, levels of erythrocyte sedimentation rate (ESR), and serum TNF-α were measured before and after treatment. The remission rates were evaluated weekly until 8 weeks. Sixty-eight percent of patients showed an effective dose of 50 mg daily; another 13, 10, and 9 % of patients had an effective dose of 100, 75, and 25 mg daily, respectively. The maintenance dose was 50 mg daily for 71 % of the patients, and 100, 75, and 25 mg daily for 9, 14, and 6 % of the patients. SLEDAI score and serum ESR levels significantly decreased 4 weeks after thalidomide treatment. At the end of the fourth week, the rates of complete remission, partial remission, and no response were 56 % (n = 39), 41 % (n = 28), and 3 % (n = 2). At the eighth week, the rate of total remission rose up to 100 %. The most common side effects were drowsiness and constipation. No peripheral neuropathy was observed in these patients. Thalidomide at a dose of 50 mg daily may offer a better benefit to risk ratio in the treatment of Chinese cutaneous lupus patients.

40 CFR 439.22 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2013 CFR

2013-07-01

... average limitation for BOD5 that is less than the equivalent of 45 mg/L. (1) The long-term average daily... subject to this subpart, calculation of the long-term average daily BOD5 load in the influent to the... this section is higher than a concentration value reflecting a reduction in the long-term average daily...

40 CFR 439.22 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2014 CFR

2014-07-01

... average limitation for BOD5 that is less than the equivalent of 45 mg/L. (1) The long-term average daily... subject to this subpart, calculation of the long-term average daily BOD5 load in the influent to the... this section is higher than a concentration value reflecting a reduction in the long-term average daily...

40 CFR 439.22 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2012 CFR

2012-07-01

... average limitation for BOD5 that is less than the equivalent of 45 mg/L. (1) The long-term average daily... subject to this subpart, calculation of the long-term average daily BOD5 load in the influent to the... this section is higher than a concentration value reflecting a reduction in the long-term average daily...

Optimizing drug-dose alerts using commercial software throughout an integrated health care system.

PubMed

Saiyed, Salim M; Greco, Peter J; Fernandes, Glenn; Kaelber, David C

2017-11-01

All default electronic health record and drug reference database vendor drug-dose alerting recommendations (single dose, daily dose, dose frequency, and dose duration) were silently turned on in inpatient, outpatient, and emergency department areas for pediatric-only and nonpediatric-only populations. Drug-dose alerts were evaluated during a 3-month period. Drug-dose alerts fired on 12% of orders (104 098/834 911). System-level and drug-specific strategies to decrease drug-dose alerts were analyzed. System-level strategies included: (1) turning off all minimum drug-dosing alerts, (2) turning off all incomplete information drug-dosing alerts, (3) increasing the maximum single-dose drug-dose alert threshold to 125%, (4) increasing the daily dose maximum drug-dose alert threshold to 125%, and (5) increasing the dose frequency drug-dose alert threshold to more than 2 doses per day above initial threshold. Drug-specific strategies included changing drug-specific maximum single and maximum daily drug-dose alerting parameters for the top 22 drug categories by alert frequency. System-level approaches decreased alerting to 5% (46 988/834 911) and drug-specific approaches decreased alerts to 3% (25 455/834 911). Drug-dose alerts varied between care settings and patient populations. © The Author 2017. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A feasibility study of dynamic adaptive radiotherapy for nonsmall cell lung cancer

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

Kim, Minsun, E-mail: mk688@uw.edu; Phillips, Mark H.

2016-05-15

Purpose: The final state of the tumor at the end of a radiotherapy course is dependent on the doses given in each fraction during the treatment course. This study investigates the feasibility of using dynamic adaptive radiotherapy (DART) in treating lung cancers assuming CBCT is available to observe midtreatment tumor states. DART adapts treatment plans using a dynamic programming technique to consider the expected changes of the tumor in the optimization process. Methods: DART is constructed using a stochastic control formalism framework. It minimizes the total expected number of tumor cells at the end of a treatment course, which ismore » equivalent to maximizing tumor control probability, subject to the uncertainty inherent in the tumor response. This formulation allows for nonstationary dose distributions as well as nonstationary fractional doses as needed to achieve a series of optimal plans that are conformal to the tumor over time, i.e., spatiotemporally optimal plans. Sixteen phantom cases with various sizes and locations of tumors and organs-at-risk (OAR) were generated using in-house software. Each case was planned with DART and conventional IMRT prescribing 60 Gy in 30 fractions. The observations of the change in the tumor volume over a treatment course were simulated using a two-level cell population model. Monte Carlo simulations of the treatment course for each case were run to account for uncertainty in the tumor response. The same OAR dose constraints were applied for both methods. The frequency of replanning was varied between 1, 2, 5 (weekly), and 29 times (daily). The final average tumor dose and OAR doses have been compared to quantify the potential dosimetric benefits of DART. Results: The average tumor max, min, mean, and D95 doses using DART relative to these using conventional IMRT were 124.0%–125.2%, 102.1%–114.7%, 113.7%–123.4%, and 102.0%–115.9% (range dependent on the frequency of replanning). The average relative maximum doses for the cord and esophagus, mean doses for the heart and lungs, and D05 for the unspecified tissue resulting 84%–102.4%, 99.8%–106.9%, 66.9%–85.6%, 58.2%–78.8%, and 85.2%–94.0%, respectively. Conclusions: It is feasible to apply DART to the treatment of NSCLC using CBCT to observe the midtreatment tumor state. Potential increases in the tumor dose and reductions in the OAR dose, particularly for parallel OARs with mean or dose–volume constraints, could be achieved using DART compared to nonadaptive IMRT.« less

The effect of flow data resolution on sediment yield estimation and channel design

NASA Astrophysics Data System (ADS)

Rosburg, Tyler T.; Nelson, Peter A.; Sholtes, Joel S.; Bledsoe, Brian P.

2016-07-01

The decision to use either daily-averaged or sub-daily streamflow records has the potential to impact the calculation of sediment transport metrics and stream channel design. Using bedload and suspended load sediment transport measurements collected at 138 sites across the United States, we calculated the effective discharge, sediment yield, and half-load discharge using sediment rating curves over long time periods (median record length = 24 years) with both daily-averaged and sub-daily streamflow records. A comparison of sediment transport metrics calculated with both daily-average and sub-daily stream flow data at each site showed that daily-averaged flow data do not adequately represent the magnitude of high stream flows at hydrologically flashy sites. Daily-average stream flow data cause an underestimation of sediment transport and sediment yield (including the half-load discharge) at flashy sites. The degree of underestimation was correlated with the level of flashiness and the exponent of the sediment rating curve. No consistent relationship between the use of either daily-average or sub-daily streamflow data and the resultant effective discharge was found. When used in channel design, computed sediment transport metrics may have errors due to flow data resolution, which can propagate into design slope calculations which, if implemented, could lead to unwanted aggradation or degradation in the design channel. This analysis illustrates the importance of using sub-daily flow data in the calculation of sediment yield in urbanizing or otherwise flashy watersheds. Furthermore, this analysis provides practical charts for estimating and correcting these types of underestimation errors commonly incurred in sediment yield calculations.

Daily Fluctuation in Negative Affect for Family Caregivers of Individuals With Dementia

PubMed Central

Liu, Yin; Kim, Kyungmin; Almeida, David M.; Zarit, Steven H.

2017-01-01

Objective The study examined associations of intrinsic fluctuation in daily negative affect (i.e., depression and anger) with adult day service (ADS) use, daily experiences, and other caregiving characteristics. Methods This was an 8-day diary of 173 family caregivers of individuals with dementia. Multilevel models with common within-person variance were fit first to show average associations between daily stressors and mean level of daily affect. Then multilevel models with heterogeneous within-person variance were fit to test the hypotheses on associations between ADS use, daily experiences, and intrinsic fluctuation in daily affect. Results The study showed that, when the sum of ADS days was greater than average, there was a stabilizing effect of ADS use on caregivers’ within-person fluctuation in negative affect. Moreover, fewer daily stressors and greater-than-average daily care-related stressors, more positive events, not being a spouse, greater-than-average duration of caregiving, and less-than-average dependency of individuals with dementia on activities of daily living were associated with less fluctuation. Better sleep quality was associated with less intrinsic fluctuation in anger; and younger age and more years of education were associated with less intrinsic fluctuation in daily depression. Conclusions Because emotional stability has been argued as an aspect of emotional well-being in the general populations, intrinsic fluctuation of emotional experience was suggested as an outcome of evidence-based interventions for family caregivers. PMID:25365414

Dosimetric benefit of adaptive re-planning in pancreatic cancer stereotactic body radiotherapy

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

Li, Yongbao; Center for Advanced Radiotherapy Technologies University of California San Diego, La Jolla, CA; Department of Radiation Oncology, University of California San Diego, La Jolla, CA

Stereotactic body radiotherapy (SBRT) shows promise in unresectable pancreatic cancer, though this treatment modality has high rates of normal tissue toxicity. This study explores the dosimetric utility of daily adaptive re-planning with pancreas SBRT. We used a previously developed supercomputing online re-planning environment (SCORE) to re-plan 10 patients with pancreas SBRT. Tumor and normal tissue contours were deformed from treatment planning computed tomographies (CTs) and transferred to daily cone-beam CT (CBCT) scans before re-optimizing each daily treatment plan. We compared the intended radiation dose, the actual radiation dose, and the optimized radiation dose for the pancreas tumor planning target volumemore » (PTV) and the duodenum. Treatment re-optimization improved coverage of the PTV and reduced dose to the duodenum. Within the PTV, the actual hot spot (volume receiving 110% of the prescription dose) decreased from 4.5% to 0.5% after daily adaptive re-planning. Within the duodenum, the volume receiving the prescription dose decreased from 0.9% to 0.3% after re-planning. It is noteworthy that variation in the amount of air within a patient's stomach substantially changed dose to the PTV. Adaptive re-planning with pancreas SBRT has the ability to improve dose to the tumor and decrease dose to the nearby duodenum, thereby reducing the risk of toxicity.« less

A decade of Australian methotrexate dosing errors.

PubMed

Cairns, Rose; Brown, Jared A; Lynch, Ann-Maree; Robinson, Jeff; Wylie, Carol; Buckley, Nicholas A

2016-06-06

Accidental daily dosing of methotrexate can result in life-threatening toxicity. We investigated methotrexate dosing errors reported to the National Coronial Information System (NCIS), the Therapeutic Goods Administration Database of Adverse Event Notifications (TGA DAEN) and Australian Poisons Information Centres (PICs). A retrospective review of coronial cases in the NCIS (2000-2014), and of reports to the TGA DAEN (2004-2014) and Australian PICs (2004-2015). Cases were included if dosing errors were accidental, with evidence of daily dosing on at least 3 consecutive days. Events per year, dose, consecutive days of methotrexate administration, reasons for the error, clinical features. Twenty-two deaths linked with methotrexate were identified in the NCIS, including seven cases in which erroneous daily dosing was documented. Methotrexate medication error was listed in ten cases in the DAEN, including two deaths. Australian PIC databases contained 92 cases, with a worrying increase seen during 2014-2015. Reasons for the errors included patient misunderstanding and incorrect packaging of dosette packs by pharmacists. The recorded clinical effects of daily dosage were consistent with those previously reported for methotrexate toxicity. Dosing errors with methotrexate can be lethal and continue to occur despite a number of safety initiatives in the past decade. Further strategies to reduce these preventable harms need to be implemented and evaluated. Recent suggestions include further changes in packet size, mandatory weekly dosing labelling on packaging, improving education, and including alerts in prescribing and dispensing software.

Daily oral iron supplementation during pregnancy

PubMed Central

Peña-Rosas, Juan Pablo; De-Regil, Luz Maria; Dowswell, Therese; Viteri, Fernando E

2014-01-01

Background Iron and folic acid supplementation has been the preferred intervention to improve iron stores and prevent anaemia among pregnant women, and it may also improve other maternal and birth outcomes. Objectives To assess the effects of daily oral iron supplements for pregnant women, either alone or in conjunction with folic acid, or with other vitamins and minerals as a public health intervention. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (2 July 2012). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) (2 July 2012) and contacted relevant organisations for the identification of ongoing and unpublished studies. Selection criteria Randomised or quasi-randomised trials evaluating the effects of oral preventive supplementation with daily iron, iron + folic acid or iron + other vitamins and minerals during pregnancy. Data collection and analysis We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. Main results We included 60 trials. Forty-three trials, involving more than 27,402 women, contributed data and compared the effects of daily oral supplements containing iron versus no iron or placebo. Overall, women taking iron supplements were less likely to have low birthweight newborns (below 2500 g) compared with controls (8.4% versus 10.2%, average risk ratio (RR) 0.81; 95% confidence interval (CI) 0.68 to 0.97, 11 trials, 8480 women) and mean birthweight was 30.81 g greater for those infants whose mothers received iron during pregnancy (average mean difference (MD) 30.81; 95% CI 5.94 to 55.68, 14 trials, 9385 women). Preventive iron supplementation reduced the risk of maternal anaemia at term by 70% (RR 0.30; 95% CI 0.19 to 0.46, 14 trials, 2199 women) and iron deficiency at term by 57% (RR 0.43; 95% CI 0.27 to 0.66, seven trials, 1256 women). Although the difference between groups did not reach statistical significance, women who received iron supplements were more likely than controls to report side effects (25.3% versus 9.91%) (RR 2.36; 95% CI 0.96 to 5.82, 11 trials, 4418 women), particularly at doses 60 mg of elemental iron or higher. Women receiving iron were on average more likely to have higher haemoglobin (Hb) concentrations at term and in the postpartum period, but were at increased risk of Hb concentrations greater than 130g/L during pregnancy and at term. Twenty-three studies were conducted in countries that in 2011 had some malaria risk in parts of the country. In some of these countries/territories, malaria is present only in certain areas or up to a particular altitude. Only two of these reported malaria outcomes. There is no evidence that iron supplementation increases placental malaria. For some outcomes heterogeneity was higher than 50%. Authors’ conclusions Prenatal supplementation with daily iron are effective to reduce the risk of low birthweight, and to prevent maternal anaemia and iron deficiency in pregnancy. Associated maternal side effects and particularly high Hb concentrations during pregnancy at currently used doses suggest the need to update recommendations on doses and regimens for routine iron supplementation. PMID:23235616

Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain

PubMed Central

Wasan, Ajay, D.; Michna, Edward; Edwards, Robert, R.; Katz, Jeff, N.; Nedeljkovic, Srdjan, S.; Dolman, Andrew, J.; Janfaza, David; Isaac, Zach; Jamison, Robert, N.

2015-01-01

Background Opioids are frequently prescribed for chronic low back pain (CLBP), but there is little prospective data on which patient subgroups may benefit. Psychiatric comorbidity, such as high levels of depression and anxiety symptoms (termed, comorbid negative affect [NA]) is a common presentation and may predict diminished opioid analgesia and/or increased opioid misuse. Methods We conducted a 6½-month prospective cohort study of oral opioid therapy, with an active drug/placebo run-in period, in 81 CLBP patients with low, moderate, and high levels of NA. Treatment included an opioid titration phase with a prescribing physician blinded to NA group assignment, and a 4-month continuation phase, during which subjects recorded daily pain levels using an electronic diary. The primary outcome was the percent improvement in average daily pain, summarized weekly. Results There was an overall 25% drop out rate. Despite the high NA group being prescribed a higher average daily dose of morphine equivalents, linear mixed model analysis revealed that the 24 study completers in each of the high and low NA groups had an average 21% vs. 39% improvement in pain, respectively (p<.01). The high NA group also had a significantly greater rate of opioid misuse (39% vs. 8%, p<.05), and significantly more and intense opioid side effects (p<.01). Conclusions These results indicate that the benefit and risk considerations in CLBP patients with high vs. low NA are distinctly different. Thus, negative affect is an important phenotypic variable to characterize at baseline, prior to deciding whether to prescribe opioids for CLBP. PMID:26375824

Positioning accuracy during VMAT of gynecologic malignancies and the resulting dosimetric impact by a 6-degree-of-freedom couch in combination with daily kilovoltage cone beam computed tomography.

PubMed

Yao, Lihong; Zhu, Lihong; Wang, Junjie; Liu, Lu; Zhou, Shun; Jiang, ShuKun; Cao, Qianqian; Qu, Ang; Tian, Suqing

2015-04-26

To improve the delivery of radiotherapy in gynecologic malignancies and to minimize the irradiation of unaffected tissues by using daily kilovoltage cone beam computed tomography (kV-CBCT) to reduce setup errors. Thirteen patients with gynecologic cancers were treated with postoperative volumetric-modulated arc therapy (VMAT). All patients had a planning CT scan and daily CBCT during treatment. Automatic bone anatomy matching was used to determine initial inter-fraction positioning error. Positional correction on a six-degrees-of-freedom (6DoF) couch was followed by a second scan to calculate the residual inter-fraction error, and a post-treatment scan assessed intra-fraction motion. The margins of the planning target volume (MPTV) were calculated from these setup variations and the effect of margin size on normal tissue sparing was evaluated. In total, 573 CBCT scans were acquired. Mean absolute pre-/post-correction errors were obtained in all six planes. With 6DoF couch correction, the MPTV accounting for intra-fraction errors was reduced by 3.8-5.6 mm. This permitted a reduction in the maximum dose to the small intestine, bladder and femoral head (P=0.001, 0.035 and 0.032, respectively), the average dose to the rectum, small intestine, bladder and pelvic marrow (P=0.003, 0.000, 0.001 and 0.000, respectively) and markedly reduced irradiated normal tissue volumes. A 6DoF couch in combination with daily kV-CBCT can considerably improve positioning accuracy during VMAT treatment in gynecologic malignancies, reducing the MPTV. The reduced margin size permits improved normal tissue sparing and a smaller total irradiated volume.

Magnitude of Interfractional Vaginal Cuff Movement: Implications for External Irradiation

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

Ma, Daniel J.; Michaletz-Lorenz, Martha; Goddu, S. Murty

2012-03-15

Purpose: To quantify the extent of interfractional vaginal cuff movement in patients receiving postoperative irradiation for cervical or endometrial cancer in the absence of bowel/bladder instruction. Methods and Materials: Eleven consecutive patients with cervical or endometrial cancer underwent placement of three gold seed fiducial markers in the vaginal cuff apex as part of standard of care before simulation. Patients subsequently underwent external irradiation and brachytherapy treatment based on institutional guidelines. Daily megavoltage CT imaging was performed during each external radiation treatment fraction. The daily positions of the vaginal apex fiducial markers were subsequently compared with the original position of themore » fiducial markers on the simulation CT. Composite dose-volume histograms were also created by summing daily target positions. Results: The average ({+-} standard deviation) vaginal cuff movement throughout daily pelvic external radiotherapy when referenced to the simulation position was 16.2 {+-} 8.3 mm. The maximum vaginal cuff movement for any patient during treatment was 34.5 mm. In the axial plane the mean vaginal cuff movement was 12.9 {+-} 6.7 mm. The maximum vaginal cuff axial movement was 30.7 mm. In the craniocaudal axis the mean movement was 10.3 {+-} 7.6 mm, with a maximum movement of 27.0 mm. Probability of cuff excursion outside of the clinical target volume steadily dropped as margin size increased (53%, 26%, 4.2%, and 1.4% for 1.0, 1.5, 2.0, and 2.5 cm, respectively.) However, rectal and bladder doses steadily increased with larger margin sizes. Conclusions: The magnitude of vaginal cuff movement is highly patient specific and can impact target coverage in patients without bowel/bladder instructions at simulation. The use of vaginal cuff fiducials can help identify patients at risk for target volume excursion.« less

Dosimetric impact of daily setup variations during treatment of canine nasal tumors using intensity-modulated radiation therapy.

PubMed

Deveau, Michael A; Gutiérrez, Alonso N; Mackie, Thomas R; Tomé, Wolfgang A; Forrest, Lisa J

2010-01-01

Intensity-modulated radiation therapy (IMRT) can be employed to yield precise dose distributions that tightly conform to targets and reduce high doses to normal structures by generating steep dose gradients. Because of these sharp gradients, daily setup variations may have an adverse effect on clinical outcome such that an adjacent normal structure may be overdosed and/or the target may be underdosed. This study provides a detailed analysis of the impact of daily setup variations on optimized IMRT canine nasal tumor treatment plans when variations are not accounted for due to the lack of image guidance. Setup histories of ten patients with nasal tumors previously treated using helical tomotherapy were replanned retrospectively to study the impact of daily setup variations on IMRT dose distributions. Daily setup shifts were applied to IMRT plans on a fraction-by-fraction basis. Using mattress immobilization and laser alignment, mean setup error magnitude in any single dimension was at least 2.5 mm (0-10.0 mm). With inclusions of all three translational coordinates, mean composite offset vector was 5.9 +/- 3.3 mm. Due to variations, a loss of equivalent uniform dose for target volumes of up to 5.6% was noted which corresponded to a potential loss in tumor control probability of 39.5%. Overdosing of eyes and brain was noted by increases in mean normalized total dose and highest normalized dose given to 2% of the volume. Findings suggest that successful implementation of canine nasal IMRT requires daily image guidance to ensure accurate delivery of precise IMRT distributions when non-rigid immobilization techniques are utilized. Unrecognized geographical misses may result in tumor recurrence and/or radiation toxicities to the eyes and brain.

DOSIMETRIC IMPACT OF DAILY SETUP VARIATIONS DURING TREATMENT OF CANINE NASAL TUMORS USING INTENSITY-MODULATED RADIATION THERAPY

PubMed Central

Deveau, Michael A.; Gutiérrez, Alonso N.; Mackie, Thomas R.; Tomé, Wolfgang A.; Forrest, Lisa J.

2009-01-01

Intensity-modulated radiation therapy (IMRT) can be employed to yield precise dose distributions that tightly conform to targets and reduce high doses to normal structures by generating steep dose gradients. Because of these sharp gradients, daily setup variations may have an adverse effect on clinical outcome such that an adjacent normal structure may be overdosed and/or the target may be underdosed. This study provides a detailed analysis of the impact of daily setup variations on optimized IMRT canine nasal tumor treatment plans when variations are not accounted for due to the lack of image guidance. Setup histories of ten patients with nasal tumors previously treated using helical tomotherapy were replanned retrospectively to study the impact of daily setup variations on IMRT dose distributions. Daily setup shifts were applied to IMRT plans on a fraction-by-fraction basis. Using mattress immobilization and laser alignment, mean setup error magnitude in any single dimension was at least 2.5mm (0-10.0mm). With inclusions of all three translational coordinates, mean composite offset vector was 5.9±3.3mm. Due to variations, a loss of equivalent uniform dose (EUD) for target volumes of up to 5.6% was noted which corresponded to a potential loss in TCP of 39.5%. Overdosing of eyes and brain was noted by increases in mean normalized total dose (NTDmean) and highest normalized dose given to 2% of the volume (NTD2%). Findings suggest that successful implementation of canine nasal IMRT requires daily image guidance to ensure accurate delivery of precise IMRT distributions when non-rigid immobilization techniques are utilized. Unrecognized geographical misses may result in tumor recurrence and/or radiation toxicities to the eyes and brain. PMID:20166402

The effectiveness of crude papain enzyme supplement for tilapia’s (Oreochromis niloticus) growth at the floating nets of Cirata Reservoir

NASA Astrophysics Data System (ADS)

Rostika, R.; Sunarto; Sugiyanto, H. N.; Dewanti, L. P.

2018-03-01

Papain is an enzyme capable of hydrolyzing protease into a more simple elements i.e. the peptide to amino acids. The enzyme in the feed can increase the absorption of protein and digestion rate in the digestive tract of fish. This research examined the effective level of enzyme papain to increase the Feed Utilization Efficiency (FUE), Protein Efficiency Ratio (PER) and Average Daily Gain (ADG). This research used Completely Randomized Design (CRD) with five treatments i.e. treatment A (control), treatment B (1.5 %), treatment C (2.25 %), treatment D (3 %) and treatment E (3.75 %) in triplicate. Tilapia (Oreochromis niloticus) with the average initial weight of 17 g, and initial total lenght of 8–10 cm was fed three times daily at feeding rate of 5 % of the total body weight. The results showed that supplementation of papain in the feed significantly increased the activity of protease, FUE, PER and ADG. The optimal dose of the enzyme papain at 3.75 % was able to increase 48.31 % of FUE, 2.13 % of PER and 2.07 % of ADG.

Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.

PubMed

Mehta, Shamir R; Bassand, Jean-Pierre; Chrolavicius, Susan; Diaz, Rafael; Eikelboom, John W; Fox, Keith A A; Granger, Christopher B; Jolly, Sanjit; Joyner, Campbell D; Rupprecht, Hans-Jurgen; Widimsky, Petr; Afzal, Rizwan; Pogue, Janice; Yusuf, Salim

2010-09-02

Clopidogrel and aspirin are widely used for patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI). However, evidence-based guidelines for dosing have not been established for either agent. We randomly assigned, in a 2-by-2 factorial design, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% confidence interval [CI], 0.83 to 1.06; P=0.30). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; hazard ratio, 0.68; 95% CI, 0.55 to 0.85; P=0.001). There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs. 4.4%; hazard ratio, 0.97; 95% CI, 0.86 to 1.09; P=0.61) or major bleeding (2.3% vs. 2.3%; hazard ratio, 0.99; 95% CI, 0.84 to 1.17; P=0.90). In patients with an acute coronary syndrome who were referred for an invasive strategy, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00335452.)

Impact of High-Dose Vitamin D3 Supplementation in Patients with Crohn's Disease in Remission: A Pilot Randomized Double-Blind Controlled Study.

PubMed

Narula, Neeraj; Cooray, Mohan; Anglin, Rebecca; Muqtadir, Zack; Narula, Alisha; Marshall, John K

2017-02-01

To assess the tolerability and efficacy of high-dose vitamin D3 in patients with Crohn's disease (CD). This was a randomized, double-blind placebo-controlled trial of high-dose vitamin D3 at 10,000 IU daily (n = 18) compared to 1000 IU daily (n = 16) for 12 months in patients with CD in remission. The primary outcome was change in serum 25-hydroxy-vitamin D levels. Secondary outcomes included clinical relapse rates and changes in mood scores. High-dose vitamin D3 at 10,000 IU daily significantly improved 25-hydroxy-vitamin D levels from a mean of 73.5 nmol/L [standard deviation (SD) 11.7 nmol/L] to 160.8 nmol/L (SD 43.2 nmol/L) (p = 0.02). On an intention-to-treat basis, the rate of relapse was not significantly different between patients receiving low- and high-dose vitamin D3 (68.8 vs 33.3%, p = 0.0844). In per-protocol analysis, clinical relapse of Crohn's disease was less frequently observed in patients receiving a high dose (0/12 or 0%) compared to those receiving a low dose of 1000 IU daily (3/8 or 37.5%) (p = 0.049). Improvement in anxiety and depression scores and a good safety profile were observed in both groups treated with vitamin D3. Oral supplementation with high-dose vitamin D3 at 10,000 IU daily significantly improved serum 25-hydroxy-vitamin D levels. Rates of clinical relapse were similar between both groups. Larger studies using high-dose vitamin D3 for treatment of inflammatory bowel diseases are warranted. CLINICALTRIALS. NCT02615288.

Conversion from intravenous to oral medications: assessment of a computerized intervention for hospitalized patients.

PubMed

Fischer, Michael A; Solomon, Daniel H; Teich, Jonathan M; Avorn, Jerry

2003-11-24

Many hospitalized patients continue to receive intravenous medications longer than necessary. Earlier conversion from the intravenous to the oral route could increase patient safety and comfort, reduce costs, and facilitate earlier discharge from the hospital without compromising clinical care. We examined the effect of a computer-based intervention to prompt physicians to switch appropriate patients from intravenous to oral medications. This study was performed at Brigham and Women's Hospital, an academic tertiary care hospital at which all medications are ordered online. We targeted 5 medications with equal oral and intravenous bioavailability: fluconazole, levofloxacin, metronidazole, ranitidine, and amiodarone. We used the hospital's computerized order entry system to prompt physicians to convert appropriate intravenous medications to the oral route. We measured the total use of the targeted medications via each route in the 4 months before and after the implementation of the intervention. We also measured the rate at which physicians responded to the intervention when prompted. The average intravenous defined daily dose declined by 11.1% (P =.002) from the preintervention to the postintervention period, while the average oral defined daily dose increased by 3.7% (P =.002). Length of stay, case-mix index, and total drug use at the hospital increased during the study period. The average total monthly use of the intravenous preparation of all of the targeted medications declined in the 4 months after the intervention began, compared with the 4 months before. In 35.6% of 1045 orders for which a prompt was generated, the physician either made a conversion from the intravenous to the oral version or canceled the order altogether. Computer-generated reminders can produce a substantial reduction in excessive use of targeted intravenous medications. As online prescribing becomes more common, this approach can be used to reduce excess use of intravenous medications, with potential benefits in patient comfort, safety, and cost.

GOSPEL 2 - Colchicine for the treatment of gout flares in France - a GOSPEL survey subgroup analysis. Doses used in common practices regardless of renal impairment and age.

PubMed

Pascart, Tristan; Lancrenon, Sylvie; Lanz, Sabine; Delva, Catherine; Guggenbuhl, Pascal; Lambert, Charles; Aubert, Jean-Pierre; Saraux, Alain; Ea, Hang-Korng; Lioté, Frédéric

2016-12-01

The objective of this sub-study was to assess the use of colchicine for the treatment of gout flares in real life conditions in the GOSPEL cohort following the 2006 EULAR recommendations for gout management. This national cross-sectional epidemiologic survey included outpatients with gout suffering from acute flare followed by randomly selected primary care physicians (n=398) and private practice rheumatologists (n=109) between October 2008 and September 2009 in France. Data regarding patient characteristics and treatment prescription was collected by each physician. Glomerular filtration rate (eGFR) was estimated using the Cockroft-Gault formula. Patients included in the survey for a gout flare filled in a specific self-questionnaire including colchicine effective intake and pain relief (numeric scale). This analysis focused on the 349 patients presenting with gout flare and treated with colchicine. Mean (±SD) prescribed dose of colchicine was 2.8 (±0.7) mg within the first 24hours and the cumulative dose over the first three days of treatment was 6.9 (±1.8) mg. Patients with mild decline in eGFR (eDFG 60-80mL/min) were prescribed an average initial dose of 2.8mg (±0.8) mg (n=58), 2.7 (±0.8) mg in chronic kidney disease (CKD) stage 3 (n=43) and 2.5 (±0.7) mg in CKD stage 4 (n=2). Cumulative doses of colchicine did not take into account either renal impairment or age. This study draws attention to some misuse of colchicine in daily practice and the prescription of excessive doses especially in case of renal impairment. eGFR should be enforced in daily practice. Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Role of self-caught fish in total fish consumption rates for recreational fishermen: Average consumption for some species exceeds allowable intake.

PubMed

Burger, Joanna

2013-01-01

Studies of fish consumption focus on recreational or subsistence fishing, on awareness and adherence to advisories, consumption patterns, and contaminants in fish. Yet the general public obtains their fish from commercial sources. In this paper I examine fish consumption patterns of recreational fishermen in New Jersey to determine: 1) consumption rates for self-caught fish and for other fish, 2) meals consumed per year, 3) average meal size, and average daily intake of mercury, and 4) variations in these parameters for commonly-consumed fish, and different methods of computing intake. Over 300 people were interviewed at fishing sites and fishing clubs along the New Jersey shore. Consumption patterns of anglers varied by species of fish. From 2 to 90 % of the anglers ate the different fish species, and between 9 and 75 % gave fish away to family or friends. Self-caught fish made up 7 to 92 % of fish diets. On average, self-caught fish were eaten for only 2 to 6 months of the year, whereas other fish (commercial or restaurant) were eaten up to 10 months a year. Anglers consumed from 5 to 36 meals of different fish a year, which resulted in intake of mercury ranging from 0.01 to 0.22 ug/kg/day. Average intake of Mako shark, swordfish, and tuna (sushi, canned tuna, self-caught tuna) exceeded the U.S. Environmental Protection Agency's oral, chronic reference dose for mercury of 0.1 ug/kg/day. However, computing intake using consumption for the highest month results in average mercury intake exceeding the reference dose for striped bass and bluefish as well. These data, and the variability in consumption patterns, have implications for risk assessors, risk managers, and health professionals.

Role of self-caught fish in total fish consumption rates for recreational fishermen: Average consumption for some species exceeds allowable intake

PubMed Central

Burger, Joanna

2013-01-01

Studies of fish consumption focus on recreational or subsistence fishing, on awareness and adherence to advisories, consumption patterns, and contaminants in fish. Yet the general public obtains their fish from commercial sources. In this paper I examine fish consumption patterns of recreational fishermen in New Jersey to determine: 1) consumption rates for self-caught fish and for other fish, 2) meals consumed per year, 3) average meal size, and average daily intake of mercury, and 4) variations in these parameters for commonly-consumed fish, and different methods of computing intake. Over 300 people were interviewed at fishing sites and fishing clubs along the New Jersey shore. Consumption patterns of anglers varied by species of fish. From 2 to 90 % of the anglers ate the different fish species, and between 9 and 75 % gave fish away to family or friends. Self-caught fish made up 7 to 92 % of fish diets. On average, self-caught fish were eaten for only 2 to 6 months of the year, whereas other fish (commercial or restaurant) were eaten up to 10 months a year. Anglers consumed from 5 to 36 meals of different fish a year, which resulted in intake of mercury ranging from 0.01 to 0.22 ug/kg/day. Average intake of Mako shark, swordfish, and tuna (sushi, canned tuna, self-caught tuna) exceeded the U.S. Environmental Protection Agency’s oral, chronic reference dose for mercury of 0.1 ug/kg/day. However, computing intake using consumption for the highest month results in average mercury intake exceeding the reference dose for striped bass and bluefish as well. These data, and the variability in consumption patterns, have implications for risk assessors, risk managers, and health professionals. PMID:23914136

The effectiveness of reducing the daily dose of finasteride in men with benign prostatic hyperplasia

PubMed Central

Sullivan, Michael J; Geller, Jack

2002-01-01

Background Finasteride, a 5 alpha reductase inhibitor, is an established treatment for benign prostatic hyperplasia. The recommended dosage is 5 mg a day, however case reports have show effectiveness with lower doses. The objective of the current study was to determine in men with benign prostatic hyperplasia, previously treated for at least one year with finasteride 5 mg daily, if they will maintain subjective and objective improvements in urinary obstruction when treated with 2.5 mg of finasteride daily for one year. Methods In an open label, prospective study, 40 men with benign prostatic hyperplasia, previously treated for at least one year with 5 mg of finasteride, took 2.5 mg of finasteride daily for one year. Measurements included AUA symptom score, maximum flow rate, voided volume and PSA. Results There were no significant changes in maximum flow rate, voided volume, or AUA symptom score after one year of finasteride 2.5 mg daily therapy. PSA increased significantly, p < .01, after one year of finasteride 2.5 mg daily, 2.0 +1.4 ng/ml, when compared to finasteride 5 mg daily, 1.4+ 1.0 ng/ml. Conclusions The daily dose of finasteride can be reduced to 2.5 mg daily without significant effect on subjective and objective measures of urinary obstruction. Although statistically significant increases in PSA are noted when reducing the daily finasteride dose from 5 mg to 2.5 mg, the clinical significance of a mean .6 ng/ml increase in PSA is questionable. PMID:11818031

Evaluation of the Environmental Bias on Accelerometer-Measured Total Daily Activity Counts and Owner Survey Responses in Dogs with Osteoarthritis.

PubMed

Katz, Erin M; Scott, Ruth M; Thomson, Christopher B; Mesa, Eileen; Evans, Richard; Conzemius, Michael G

2017-11-01

Objective  To determine if environmental variables affect the average daily activity counts (AC) of dogs with osteoarthritis (OA) and/or owners' perception of their dog's clinical signs or quality of life. Methods  The AC and Canine Brief Pain Inventory (CBPI) owner questionnaires of 62 dogs with OA were compared with daily environmental variables including the following: average temperature (°C), high temperature (°C), low temperature (°C), relative humidity (%), total precipitation (mm), average barometric pressure (hPa) and total daylight hours. Results  Daily AC significantly correlated with average temperature and total daylight hours, but average temperature and total daylight hours accounted for less than 1% of variation in AC. No other significant relationships were found between daily AC and daily high temperature, low temperature, relative humidity, total precipitation or average barometric pressure. No statistical relationship was found between daily AC and the CBPI, nor between environmental variables and the CBPI. Canine Brief Pain Inventory scores for pain severity and pain interference decreased significantly over the test period. Clinical Significance  The relationship between daily AC and average temperature and total daylight hours was significant, but unlikely to be clinically significant. Thus, environmental variables do not appear to have a clinically relevant bias on AC or owner CBPI questionnaires. The decrease over time in CBPI pain severity and pain interference values suggests owners completing the CBPI in this study were influenced by a caregiver placebo effect. Schattauer GmbH Stuttgart.

Emergency department patient knowledge concerning acetaminophen (paracetamol) in over-the-counter and prescription analgesics.

PubMed

Fosnocht, D; Taylor, J R; Caravati, E M

2008-04-01

This study was designed to evaluate patient knowledge of the acetaminophen (paracetamol) content of commonly used pain medications and the maximum daily recommended dose of acetaminophen. A prospective, convenience sample of emergency department patients were enrolled. Data were recorded using a standardised questionnaire over 4 months. 1009 patients were enrolled. 492 patients (49%) did not know if Tylenol contained acetaminophen (paracetamol). The majority (66-90%) of patients did not know if Lortab, Vicodin, Percocet, non-aspirin pain reliever, ibuprofen, Motrin, or Advil contained acetaminophen. 568 patients (56%) reported not knowing the maximum daily dose of acetaminophen and only 71 patients (7%) reported the correct daily dose. Patient knowledge of the acetaminophen content of commonly used analgesic medications and its maximum recommended daily dose is limited. This may contribute to unintentional repeated supratherapeutic ingestion (RSTI) of acetaminophen, or overdose.

Influence of daily dosage and frequency of administration of rifampicin-levofloxacin therapy on tolerance and effectiveness in 154 patients treated for prosthetic joint infections.

PubMed

Nguyen, S; Robineau, O; Titecat, M; Blondiaux, N; Valette, M; Loiez, C; Beltrand, E; Migaud, H; Senneville, E

2015-08-01

Data on the tolerance and effectiveness of rifampicin-levofloxacin combination therapy (RLCT) in patients treated for prosthetic joint infections (PJIs) according to daily dosage are lacking. A review of the clinical data from patients treated with RLCT for PJIs in a French referent center for PJIs was conducted. A total of 154 patients (75 F/79 M), with a median age of 64.1 years and median body weight of 83.1 kg, were included. The median daily dosages of rifampicin and levofloxacin were, respectively, 1,200 mg (range 300-2,100) and 750 mg (range 500-1,500), corresponding to a mean daily dose per kg of, respectively, 16.2 ± 4.3 mg/kg and 10.1 ± 3.0 mg/kg. After a mean follow-up period of 55.6 ± 27.1 months (range 24-236), 127 patients (82.5 %) were in remission. Adverse events attributable to rifampicin and levofloxacin were reported in 48 (31.2 %) and 13 (8.4 %) patients (p < 0.001), respectively. Patients who experienced rifampicin-related adverse events had been given higher rifampicin daily doses than the other patients (p = 0.04). The rifampicin daily dosage did not influence patient outcome and nor did the levofloxacin daily dosage on both tolerance and patient outcome. Our results suggest that adjusting rifampicin daily doses to the patient total body weight when combined with levofloxacin for the treatment of PJIs is associated with a poor tolerance. High daily doses of rifampicin (>600 mg) and levofloxacin (750 mg) do not improve patient outcome when compared to lower daily doses in this setting.

SU-F-T-224: Importance of Timely Review of Daily Cone-Beam CTs: Dosimetric Evaluation of Rejected CBCTs for Head and Neck Patients

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

Andrews, M; Yu, N; Joshi, N

Purpose: To dosimetrically evaluate the importance of timely reviewing daily CBCTs for patients with head and neck cancer. Methods: After each fraction daily cone-beam CT (CBCT) for head and neck patients are reviewed by physicians prior to next treatment. Physician rejected image registrations of CBCT were identified and analyzed for 17 patients. These CBCT images were rigidly fused with planning CT images and the contours from the planning CT were transferred to CBCTs. Because of limited extension in the superior-inferior dimension contours with partial volumes in CBCTs were discarded. The treatment isocenter was placed by applying the clinically recorded shiftsmore » to the volume isocenter of the CBCT. Dose was recalculated at the shifted isocenter using a homogeneous dose calculation algorithm. Dosimetrically relevant changes defined as greater than 5% deviation from the clinically accepted plans but with homogeneous dose calculation were evaluated for the high dose (HD), intermediate dose (ID), and low dose (LD) CTVs, spinal cord, larynx, oropharynx, parotids, and submandibular glands. Results: Among seventeen rejected CBCTS, HD-CTVs, ID-CTVs, and LD-CTVs were completely included in the CBCTs for 17, 1, and 15 patients, respectively. The prescription doses to the HD-CTV, ID-CTV, and LD-CTV were received by < 95% of the CTV volumes in 5/17, 1/1, and 5/15 patients respectively. For the spinal cord, the maximum doses (D0.03cc) were increased > 5% in 13 of 17 patients. For the oropharynx, larynx, parotid, and submandibular glands, the mean dose of these organs at risk was increased > 5% in 7/17, 8/12, 11/16 and 6/16 patients, respectively. Conclusion: Timely review daily CBCTs for head and neck patients under daily CBCT guidance is important, and uncorrected setup errors can translate to dosimetrically relevant dose increases in organsat- risk and dose decreases in the clinical target volumes.« less

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

PubMed

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

2018-05-30

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

Efficacy of two once-daily methylphenidate formulations compared across dose levels at different times of the day: preliminary indications from a secondary analysis of the COMACS study data.

PubMed

Sonuga-Barke, Edmund J S; Swanson, James M; Coghill, David; DeCory, Heleen H; Hatch, Simon J

2004-09-30

Methylphenidate (MPH) is commonly prescribed in the treatment of Attention-Deficit/Hyperactivity Disorder or ADHD. Concerta and Metadate CD are once-daily formulations of MPH using different delivery mechanisms resulting in different pharmacokinetic profiles. A recent study (COMACS) showed that for near-milligram (mg) equivalent daily doses, Metadate CD provides greater symptom control in the morning (1.5 through 4.5 hours post-dose), while Concerta provides greater control in the early evening (12 hours post-dose). Non-inferential comparison of effects for different dose levels of the two formulations suggested that equivalent levels of morning symptom control could be obtained with lower daily doses of Metadate CD than Concerta; the situation being reversed in the evening. The current paper presents a secondary analysis that provides a statistical test of these observations. The COMACS study was a multi-center, double-blind crossover study of Metadate CD, Concerta and placebo with each treatment administered for 1 week. Children were assigned on the basis of their pre-trial dosage to either high (Metadate CD 60 mg; Concerta 54 mg), medium (Metadate CD 40 mg; Concerta 36 mg) or low doses (Metadate CD 20 mg; Concerta 18 mg) of MPH, and attended a laboratory school on the 7th day for assessment at 7 sessions across the day. For the post-hoc comparisons across dose levels presented here, total SKAMP scores with the active treatments (adjusted for placebo response) were analyzed using an analysis of covariance, with a combined measure modeling placebo response across all time period as the covariate. Symptom control from 1.5 through 6.0 hours post-dose was as good with lower doses of Metadate CD (20 and 40 mg) as with higher doses of Concerta (36 and 54 mg, respectively). Lower daily doses of Concerta (18 and 36 mg) and higher doses of Metadate CD (40 and 60 mg, respectively) gave equivalent control at 7.5 and 12 hours with Metadate CD giving better control from1.5 through 6.0 hours post-dose. Different delivery profiles of Metadate CD and Concerta can be exploited to limit total daily exposure to MPH while at the same targeting a specific, especially clinically significant, period of the day. These results need to be confirmed in a study in which children are randomly allocated to different dose levels of the two formulations and plasma MPH concentrations are assessed simultaneously.

Bioequivalence and Safety of Twice-Daily Sustained-Release Paracetamol (Acetaminophen) Compared With 3- and 4-Times-Daily Paracetamol: A Repeat-Dose, Crossover Pharmacokinetic Study in Healthy Volunteers.

PubMed

Liu, Dongzhou J; Collaku, Agron

2018-01-01

Twice-daily sustained-release (SR) paracetamol (acetaminophen) offers convenient administration to chronic users. This study investigated at steady state (during the last 24 hours of a 3-day dosing period) the pharmacokinetics, bioequivalence, and safety of twice-daily SR paracetamol compared with extended-release (ER) and immediate-release (IR) paracetamol. In this open-label, randomized, multidose, 3-way crossover study, 28 healthy subjects received paracetamol SR (2 × 1000 mg twice daily), ER (2 × 665 mg 3 times daily), and IR (2 × 500 mg 4 times daily). At steady state, twice-daily SR paracetamol was bioequivalent to ER and IR paracetamol. The 90% confidence intervals for the ratios of geometric means were within the acceptance interval for SR/ER paracetamol (AUC 0-t , 0.973-1.033; AUC 0-24 , 0.974-1.034; AUC 0-∞ , 0.948-1.011; C max , 1.082-1.212; C av , 1.011-1.106) and SR/IR paracetamol (AUC 0-t , 0.969-1.029; AUC 0-24 , 0.968-1.027; AUC 0-∞ , 0.963-1.026; C max , 0.902-1.010; C av , 1.004-1.098). Given twice daily, the SR formulation demonstrated SR properties as expected. Mean time at or above a 4 μg/mL plasma concentration of paracetamol from 2 daily doses of the SR formulation was significantly longer than that from 4 daily doses of IR paracetamol. SR formulation also had a greater T max , a longer half-life, and lower C min compared with ER and IR paracetamol. All formulations were well tolerated. © 2017, The American College of Clinical Pharmacology.

Antiplatelet regimens in the long-term secondary prevention of transient ischaemic attack and ischaemic stroke: an updated network meta-analysis

PubMed Central

Niu, Peng-Peng; Guo, Zhen-Ni; Jin, Hang; Xing, Ying-Qi; Yang, Yi

2016-01-01

Objective To examine the comparative efficacy and safety of different antiplatelet regimens in patients with prior non-cardioembolic ischaemic stroke or transient ischaemic attack. Design Systematic review and network meta-analysis. Data sources As on 31 March 2015, all randomised controlled trials that investigated the effects of antiplatelet agents in the long-term (≥3 months) secondary prevention of non-cardioembolic transient ischaemic attack or ischaemic stroke were searched and identified. Outcome measures The primary outcome measure of efficacy was serious vascular events (non-fatal stroke, non-fatal myocardial infarction and vascular death). The outcome measure of safety was any bleeding. Results A total of 36 randomised controlled trials (82 144 patients) were included. Network meta-analysis showed that cilostazol was significantly more effective than clopidogrel (OR 0.77, 95% credible interval 0.60–0.98) and low-dose (75–162 mg daily) aspirin (0.69, 0.55–0.86) in the prevention of serious vascular events. Aspirin (50 mg daily) plus dipyridamole (400 mg daily) and clopidogrel reduced the risk of serious vascular events compared with low-dose aspirin; however, the difference was not statistically significant. Furthermore, low-dose aspirin was as effective as higher daily doses. Cilostazol was associated with a significantly lower bleeding risk than most of the other regimens. Moreover, aspirin plus clopidogrel was associated with significantly more haemorrhagic events than other regimens. Direct comparisons showed similar results as the network meta-analysis. Conclusions Cilostazol was significantly more effective than aspirin and clopidogrel alone in the long-term prevention of serious vascular events in patients with prior non-cardioembolic ischaemic stroke or transient ischaemic attack. Cilostazol was associated with a significantly lower bleeding risk than low-dose aspirin (75–162 mg daily) and aspirin (50 mg daily) plus dipyridamole (400 mg daily). Low-dose aspirin was as effective as higher daily doses. However, further large, randomised, controlled, head-to-head trials are needed, especially in non-Asian ethnic groups. PMID:26988347

Safety, Adherence and Acceptability of Intermittent Tenofovir/Emtricitabine as HIV Pre-Exposure Prophylaxis (PrEP) among HIV-Uninfected Ugandan Volunteers Living in HIV-Serodiscordant Relationships: A Randomized, Clinical Trial

PubMed Central

Kibengo, Freddie M.; Ruzagira, Eugene; Katende, David; Bwanika, Agnes N.; Bahemuka, Ubaldo; Haberer, Jessica E.; Bangsberg, David R.; Barin, Burc; Rooney, James F.; Mark, David; Chetty, Paramesh; Fast, Patricia; Kamali, Anatoli; Priddy, Frances H.

2013-01-01

Background Efficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens. Design Seventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment. Methods Volunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT. Results Both daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen. Conclusions Both daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing. Registration Clinicaltrials.gov number NCT00931346 PMID:24086333

Phase I dose-finding study of sorafenib with FOLFOX4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer.

PubMed

Chi, Yihebali; Yang, Jianliang; Yang, Sheng; Sun, Yongkun; Jia, Bo; Shi, Yuankai

2015-06-01

To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and efficacy of sorafenib in combination with FOLFOX4 (oxaliplatin/leucovorin (LV)/5-fluorouracil) as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level (from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily). If the patient achieved complete response (CR), partial response (PR) or stable disease (SD) after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9 (77.8%) evaluable patients achieved PR, with a median overall survival (OS) of 11.8 [95% confidence interval (CI): 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea. Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies.

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

PubMed

Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Astex Pharmaceuticals, Stand Up To Cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of cost, dosage and clinical preference for risperidone and olanzapine.

PubMed

Rabinowitz, J; Lichtenberg, P; Kaplan, Z

2000-12-15

Because risperidone and olanzapine have similar efficacy and tolerability in the treatment of schizophrenia, costs, physician experience, and preference become relevant considerations in making treatment decisions. The purpose of this paper is to compare daily treatment costs of risperidone and olanzapine, and to examine psychiatrists' clinical preferences. Dosage information was obtained from a national Ministry of Health registry and a national survey of psychiatrists. In addition, psychiatrists' clinical preference of antipsychotic medication and dosage for patient subtypes were examined by the national survey. Data from the registry and national survey estimated the mean daily dose of risperidone to be one-third that of olanzapine, irrespective of patient subtype. Taking into account drug costs and dosage requirements, the average daily retail price was US $6.85 for risperidone and US $13.60 for olanzapine. Psychiatrists preferred risperidone for first-episode psychosis and elderly psychosis, and olanzapine for patients sensitive to EPS. They rated the drugs equally effective on positive and negative symptoms, for chronic patients, for treatment-refractory patients and relapse prevention. Risperidone has a substantial cost advantage over olanzapine, and was preferred by psychiatrists for more indications.

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

Park, J; Kim, J; Park, S

Purpose: To investigate exposure outside the treatment field when treating breast cancer with tri-Co-60 magnetic resonance (MR) image guided radiation therapy (IGRT) system. Methods: A total of 7 patients who treated with accelerated partial breast irradiation (APBI) technique were selected prospectively for this study (prescription dose = 38.5 Gy in 10 fractions). Every patient treated with two plans, one was an initial plan and the other was an adaptive plan generated after finishing 5 fractions (a total of 14 plans). Every plan was calculated with and without magnetic field in the treatment planning system. The EBT3 films were attached onmore » the front and the back of 1 cm bolus, and then it was placed on the patient body vertically to cover patient’s jaw and shoulder. After measurements, the maximum point dose and the mean dose of whole area of EBT3 film were acquired. Results: In the treatment plan with magnetic field, low dose stream outside the patient body was observed, almost reaching the patient’s jaw or shoulder, while it was not observed without magnetic field. The average values of the measured maximum and mean doses at the front of bolus were 30.1 ± 11.1 cGy (7.8% of the daily dose) and 14.7 ± 3.3 cGy (3.8%), respectively. At the back of bolus, those values were 6.0 ± 1.9 cGy (1.6%) and 5.1 ± 1.6 cGy (1.3%), respectively. The largest maximum dose at the front was 54.2 cGy (14.1%) while it was 20.7 cGy (5.4%) at the back. The average decrease of the maximum dose by the bolus was 24.0 ± 11.0 cGy. Conclusion: Due to magnetic field, dose stream outside the patient body can be generated during breast cancer treatment with the tri-Co-60 MR-IGRT system. Since this dose stream irradiated skin outside the treatment field, it should be shielded. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015R1C1A1A01054192).« less

40 CFR Table 2 to Subpart Mmmmm of... - Operating Limits for New or Reconstructed Flame Lamination Affected Sources

Code of Federal Regulations, 2010 CFR

2010-07-01

... scrubber, maintain the daily average pressure drop across the venturi within the operating range value... . . . You must . . . 1. Scrubber a. Maintain the daily average scrubber inlet liquid flow rate above the minimum value established during the performance test. b. Maintain the daily average scrubber effluent pH...

40 CFR Table 2 to Subpart Mmmmm of... - Operating Limits for New or Reconstructed Flame Lamination Affected Sources

Code of Federal Regulations, 2011 CFR

2011-07-01

... . . . You must . . . 1. Scrubber a. Maintain the daily average scrubber inlet liquid flow rate above the minimum value established during the performance test. b. Maintain the daily average scrubber effluent pH... scrubber, maintain the daily average pressure drop across the venturi within the operating range value...

Optimization of tomotherapy treatment planning for patients with bilateral hip prostheses.

PubMed

Chapman, David; Smith, Shaun; Barnett, Rob; Bauman, Glenn; Yartsev, Slav

2014-02-04

To determine the effect of different imaging options and the most efficient imaging strategy for treatment planning of patients with hip prostheses. The planning kilovoltage CT (kVCT) and daily megavoltage CT (MVCT) studies for three prostate cancer patients with bilateral hip prostheses were used for creating hybrid kVCT/MVCT image sets. Treatment plans were created for kVCT images alone, hybrid kVCT/MVCT images, and MVCT images alone using the same dose prescription and planning parameters. The resulting dose volume histograms were compared. The orthopedic metal artifact reduction (O-MAR) reconstruction tool for kVCT images and different MVCT options were investigated with a water tank fit with double hip prostheses. Treatment plans were created for all imaging options and calculated dose was compared with the one measured by a pin-point ion chamber. On average for three patients, the D35% for the bladder was 8% higher in plans based on MVCT images and 7% higher in plans based on hybrid images, compared to the plans based on kVCT images alone. Likewise, the D35% for the rectum was 3% higher than the kVCT based plan for both hybrid and MVCT plans. The average difference in planned D99% in the PTV compared to kVCT plans was 0.9% and 0.1% for MVCT and hybrid plans, respectively. For the water tank with hip prostheses phantom, the kVCT plan with O-MAR correction applied showed better agreement between the measured and calculated dose than the original image set, with a difference of -1.9% compared to 3.3%. The measured doses for the MVCT plans were lower than the calculated dose due to image size limitations. The best agreement was for the kVCT/MVCT hybrid plans with the difference between calculated and measured dose around 1%. MVCT image provides better visualization of patient anatomy and hybrid kVCT/MVCT study enables more accurate calculations using updated MVCT relative electron density calibration.

SU-C-207-02: A Method to Estimate the Average Planar Dose From a C-Arm CBCT Acquisition

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

Supanich, MP

2015-06-15

Purpose: The planar average dose in a C-arm Cone Beam CT (CBCT) acquisition had been estimated in the past by averaging the four peripheral dose measurements in a CTDI phantom and then using the standard 2/3rds peripheral and 1/3 central CTDIw method (hereafter referred to as Dw). The accuracy of this assumption has not been investigated and the purpose of this work is to test the presumed relationship. Methods: Dose measurements were made in the central plane of two consecutively placed 16cm CTDI phantoms using a 0.6cc ionization chamber at each of the 4 peripheral dose bores and in themore » central dose bore for a C-arm CBCT protocol. The same setup was scanned with a circular cut-out of radiosensitive gafchromic film positioned between the two phantoms to capture the planar dose distribution. Calibration curves for color pixel value after scanning were generated from film strips irradiated at different known dose levels. The planar average dose for red and green pixel values was calculated by summing the dose values in the irradiated circular film cut out. Dw was calculated using the ionization chamber measurements and film dose values at the location of each of the dose bores. Results: The planar average dose using both the red and green pixel color calibration curves were within 10% agreement of the planar average dose estimated using the Dw method of film dose values at the bore locations. Additionally, an average of the planar average doses calculated using the red and green calibration curves differed from the ionization chamber Dw estimate by only 5%. Conclusion: The method of calculating the planar average dose at the central plane of a C-arm CBCT non-360 rotation by calculating Dw from peripheral and central dose bore measurements is a reasonable approach to estimating the planar average dose. Research Grant, Siemens AG.« less

The real-world dose-relativity of sevelamer hydrochloride and lanthanum carbonate monotherapy in patients with end-stage renal disease.

PubMed

Wilson, Rosamund J; Keith, Michael S; Preston, Peter; Copley, J Brian

2013-12-01

Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used for the management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to evaluate the real-world dose-relativity between SH and LC monotherapy in US patients with ESRD. This was a post hoc analysis of a 16-week, real-world study (Vemuri et al. in BMC Nephrol 12:49, 2011) of the efficacy of conversion to LC monotherapy from other phosphate binders. The SH:LC dose-relativity ratio, based on the mean daily dose, was calculated in the subset of patients from the Vemuri study who converted from SH to LC monotherapy and had available SH and LC dose data. A total of 950 patients converted from SH to LC monotherapy and had recorded dose data. The post hoc analysis population comprised 691 patients with available dose data for both SH at baseline and LC at week 16. The mean (SD) serum phosphate level at baseline was 5.91 (1.66) mg/dL. After conversion to LC monotherapy for 16 weeks, the mean (SD) serum phosphate level was 5.93 (1.85) mg/dL. The mean (SD) daily baseline SH dose was 7,703 (3,642) mg and the mean (SD) daily LC dose at week 16 was 2,800 (939) mg (9.6 versus 2.8 tablets, respectively; P < 0.0001), resulting in a SH:LC dose-relativity ratio of 2.8. The median individual patient SH:LC dose-relativity ratio was 2.6 (95% CI 2.6-2.8). Across baseline SH dose subgroups (2,400-4,800, >4,800-7,200, >7,200-9,600, and >9,600 mg/day), the mean daily SH dose was 4,051, 7,047, 9,253, and 13,150 mg, respectively. In comparison, the mean daily LC dose was 2,445-3,156 mg. Thus, patients requiring baseline SH doses >7,200 mg/day (41% of the analysis population) had higher SH:LC dose-relativity ratios of 3.1-4.2 (median individual patient ratios 3.1-4.0). In this post hoc analysis of real-world dose-relativity, the overall SH:LC dose-relativity ratio was 2.8 (median individual patient ratio 2.6 (95% CI 2.6-2.8). These findings are consistent with the World Health Organization-defined daily dose and previous studies of the relative phosphate binding capacity of the two drugs. Patients requiring SH doses >7,200 mg/day had higher SH:LC dose-relativities of 3.1-4.2 (median individual patient ratios 3.1-4.0). These findings have implications for the tablet burden and cost-effectiveness of SH and LC in the treatment of hyperphosphatemia.

Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet
.

PubMed

Scheidel, Bernhard; Maritz, Martina A; Gschwind, Yves J; Steigerwald, Kerstin; Guth, Volker; Kovacs, Peter; Rey, Helene

2017-11-01

To evaluate and to compare the bioavailability, the influence of food intake on the bioavailability, and the safety and tolerability of a newly-developed oxycodone once-daily (OOD) prolonged-release tablet with an established oxycodone twice-daily (OTD) prolonged-release tablet after single-dose administration under fasting or fed conditions as well as after multiple-dose administration. Three single-center, open-label, randomized, balanced, two-treatment, two-period, two-sequence crossover studies were conducted. In each study, 36 healthy volunteers were randomized to receive 10 mg oxycodone daily as OOD (oxycodone HCL 10-mg PR tablets XL (Develco Pharma Schweiz AG, Pratteln, Switzerland); administration of 1 tablet in the morning) or as OTD (reference formulation: oxygesic 5-mg tablets (Mundipharma GmbH, Limburg an der Lahn, Germany); administration of 1 tablet in the morning and 1 tablet in the evening). Tablets were administered once daily or twice daily under fasting conditions (study 1) or under fed conditions (study 2) as well as after multiple-dose administration (study 3). A sufficient number of blood samples were taken for describing plasma profiles and for calculation of pharmacokinetic parameters. Plasma concentrations of oxycodone were determined by LC-MS/MS. Safety and tolerability were monitored and assessed in all three studies. Plasma profiles of OOD reveal sustained concentrations of oxycodone over the complete dosing interval of 24 hours. In comparison to the OTD reference formulation, the OOD test formulation showed a slightly slower increase of concentrations within the absorption phase and similar plasma concentrations at the maximum and at the end of the dosing interval (24 hours). Extent of bioavailability (AUC), maximum plasma concentrations (C_max), and plasma concentrations at the end of the dosing interval (C_τ,ss,24h) of OOD could be classified as comparable to OTD considering 90% confidence intervals (CIs) and acceptance limits of 80.00 - 125.00%. Bioavailability of OOD was not influenced by concomitant food intake. OOD and OTD were generally well tolerated, a difference between the two products could not be observed. The new 10-mg OOD formulation provides sustained oxycodone plasma concentrations over the dosing interval of 24 hours and is suitable for once-daily administration. Bioavailability of OOD could be classified as comparable to the twice-daily administration of the OTD reference formulation. The new formulation widens and optimizes the range of strong opioid drug products in patient-centered therapy of chronic pain with simplified dosing and better compliance.
.

Instantaneous-to-daily GPP upscaling schemes based on a coupled photosynthesis-stomatal conductance model: correcting the overestimation of GPP by directly using daily average meteorological inputs.

PubMed

Wang, Fumin; Gonsamo, Alemu; Chen, Jing M; Black, T Andrew; Zhou, Bin

2014-11-01

Daily canopy photosynthesis is usually temporally upscaled from instantaneous (i.e., seconds) photosynthesis rate. The nonlinear response of photosynthesis to meteorological variables makes the temporal scaling a significant challenge. In this study, two temporal upscaling schemes of daily photosynthesis, the integrated daily model (IDM) and the segmented daily model (SDM), are presented by considering the diurnal variations of meteorological variables based on a coupled photosynthesis-stomatal conductance model. The two models, as well as a simple average daily model (SADM) with daily average meteorological inputs, were validated using the tower-derived gross primary production (GPP) to assess their abilities in simulating daily photosynthesis. The results showed IDM closely followed the seasonal trend of the tower-derived GPP with an average RMSE of 1.63 g C m(-2) day(-1), and an average Nash-Sutcliffe model efficiency coefficient (E) of 0.87. SDM performed similarly to IDM in GPP simulation but decreased the computation time by >66%. SADM overestimated daily GPP by about 15% during the growing season compared to IDM. Both IDM and SDM greatly decreased the overestimation by SADM, and improved the simulation of daily GPP by reducing the RMSE by 34 and 30%, respectively. The results indicated that IDM and SDM are useful temporal upscaling approaches, and both are superior to SADM in daily GPP simulation because they take into account the diurnally varying responses of photosynthesis to meteorological variables. SDM is computationally more efficient, and therefore more suitable for long-term and large-scale GPP simulations.

Donepezil dosing strategies: pharmacokinetic considerations.

PubMed

Gomolin, Irving H; Smith, Candace; Jeitner, Thomas M

2011-10-01

Donepezil (Aricept) is a cholinesterase inhibitor approved for the treatment of Alzheimer's disease. Immediate release formulations of 5- and 10-mg tablets were approved by the Food and Drug Administration in the United States in 1996. In July 2010, the Food and Drug Administration approved a 23-mg sustained release (SR) formulation. The SR formulation may provide additional benefit to patients receiving 10 mg daily but the incidence of adverse reactions is increased. We derived plasma concentration profiles for higher dose immediate-release formulations (15 mg once daily, 10 mg twice daily, and 20 mg once daily) and for the profile anticipated to result from the 23-mg SR formulation. Our model predicts similar steady-state concentration profiles for 10 mg twice daily, 20 mg once daily, and 23 mg SR once daily. This provides the theoretical basis for incremental immediate release dose escalation to minimize the emergence of adverse reactions and the potential to offer a cost-effective alternative to the SR formulation with currently approved generic immediate release formulations. Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.

Patterns of prednisone use during pregnancy in women with rheumatoid arthritis: Daily and cumulative dose.

PubMed

Palmsten, Kristin; Rolland, Matthieu; Hebert, Mary F; Clowse, Megan E B; Schatz, Michael; Xu, Ronghui; Chambers, Christina D

2018-04-01

To characterize prednisone use in pregnant women with rheumatoid arthritis using individual-level heat-maps and clustering individual trajectories of prednisone dose, and to evaluate the association between prednisone dose trajectory groups and gestational length. This study included pregnant women with rheumatoid arthritis who enrolled in the MotherToBaby Autoimmune Diseases in Pregnancy Study (2003-2014) before gestational week 20 and reported prednisone use without another oral glucocorticoid during pregnancy (n = 254). Information on medication use and pregnancy outcomes was collected by telephone interview plus by medical record review. Prednisone daily dose and cumulative dose were plotted by gestational day using a heat map for each individual. K-means clustering was used to cluster individual trajectories of prednisone dose into groups. The associations between trajectory group and demographics, disease severity measured by the Health Assessment Questionnaire at enrollment, and gestational length were evaluated. Women used prednisone 3 to 292 days during pregnancy, with daily doses ranging from <1 to 60 mg. Total cumulative dose ranged from 8 to 6225 mg. Disease severity, non-biologic disease modifying anti-rheumatic drug use, and gestational length varied significantly by trajectory group. After adjusting for disease severity, non-biologic disease modifying anti-rheumatic drug use, and other covariates, the highest vs lowest daily dose trajectory group was associated with reduced gestational age at delivery (β: -2.3 weeks (95%: -3.4, -1.3)), as was the highest vs lowest cumulative dose trajectory group (β: -2.6 weeks (95%: -3.6, -1.5)). In pregnant women with rheumatoid arthritis, patterns of higher prednisone dose were associated with shorter gestational length compared with lower dose. Copyright © 2018 John Wiley & Sons, Ltd.

Contribution of tap water to chlorate and perchlorate intake: a market basket study.

PubMed

Asami, Mari; Yoshida, Nobue; Kosaka, Koji; Ohno, Koichi; Matsui, Yoshihiko

2013-10-01

The contributions of water to total levels of chlorate and perchlorate intake were determined using food and water samples from a market basket study from 10 locations in Japan between 2008 and 2009. Foods were categorized into 13 groups and analyzed along with tap water. The average total chlorate intake was 333 (min. 193-max. 486) μg/day for samples cooked with tap water. The contribution of tap water to total chlorate intake was as high as 47%-58%, although total chlorate intake was less than 32% of the tolerable daily intake, 1500 μg/day for body weight of 50 kg. For perchlorate, daily intake from water was 0.7 (0.1-4.4) μg/day, which is not high compared to the average total intake of 14 (2.5-84) μg/day, while the reference dose (RfD) is 35 μg/day and the provisional maximum tolerable daily intake (PMTDI) is 500 μg/day for body weight of 50 kg. The highest intake of perchlorate was 84 μg/day, where concentrations in foods were high, but not in water. The contribution of water to total perchlorate intake ranged from 0.5% to 22%, while the ratio of highest daily intake to RfD was 240% and that to PMTDI was 17%. Eight baby formulas were also tested--total chlorate and perchlorate intakes were 147 (42-332) μg/day and 1.11 (0.05-4.5) μg/day, respectively, for an ingestion volume of 1 L/day if prepared with tap water. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Sex, PrEP, and Stigma: Experiences with HIV Pre-exposure Prophylaxis Among New York City MSM Participating in the HPTN 067/ADAPT Study.

PubMed

Franks, Julie; Hirsch-Moverman, Yael; Loquere, Avelino S; Amico, K Rivet; Grant, Robert M; Dye, Bonnie J; Rivera, Yan; Gamboa, Robert; Mannheimer, Sharon B

2018-04-01

The HPTN 067/Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking (ADAPT) study evaluated daily and non-daily dosing schedules for oral pre-exposure prophylaxis (PrEP) to prevent HIV. A qualitative sub-study including focus groups and in-depth interviews was conducted among men who have sex with men participating in New York City to understand their experience with PrEP and study dosing schedules. The 37 sub-study participants were 68% black, 11% white, and 8% Asian; 27% were of Hispanic/Latino ethnicity. Mean age was 34 years. Themes resulting from qualitative analysis include: PrEP is a significant advance for HIV prevention; non-daily dosing of PrEP is congruent with HIV risk; and pervasive stigma connected to HIV and risk behavior is a barrier to PrEP adherence, especially for non-daily dosing schedules. The findings underscore how PrEP intersects with other HIV prevention practices and highlight the need to understand and address multidimensional stigma related to PrEP use.

Development of a twice daily dosing regimen of amoxicillin/clavulanate.

PubMed

Bax, Richard

2007-12-01

Amoxicillin/clavulanate was first launched as a three times daily dosage for the treatment of a range of community-acquired infections. A decade later, it became necessary to introduce a twice daily dosage for reasons of convenience, compliance and to remain competitive with other recently launched antibacterials. Twice daily formulations of amoxicillin/clavulanate were developed in which the amount of amoxicillin was increased relative to clavulanate to provide equivalent bacteriological and clinical efficacy with no change in the safety profile. Equivalence of the two dosing regimens was confirmed by randomised clinical trials in adults (in skin and soft tissue, urinary tract and lower respiratory tract infections, sinusitis and recurrent tonsillitis) and paediatrics (in lower respiratory tract infections, otitis media and recurrent tonsillitis). An improvement in the safety profile, specifically gastrointestinal effects, due to the reduced daily dose of clavulanate, was noted for all patients, but particularly in children.

Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

PubMed

Christoph, Annette; Eerdekens, Marie-Henriette; Kok, Maurits; Volkers, Gisela; Freynhagen, Rainer

2017-09-01

Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double-blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerability of cebranopadol in patients with moderate-to-severe chronic LBP with and without neuropathic pain component. Patients were treated for 14 weeks with cebranopadol 200, 400, or 600 μg once daily, tapentadol 200 mg twice daily, or placebo. The primary efficacy endpoints were the change from baseline pain to the weekly average 24-hour pain during the entire 12 weeks and during week 12 of the maintenance phase. Cebranopadol demonstrated analgesic efficacy, with statistically significant and clinically relevant improvements over placebo for all doses as did tapentadol. The responder analysis (≥30% or ≥50% pain reduction) confirmed these results. Cebranopadol and tapentadol displayed beneficial effects on sleep and functionality. Cebranopadol treatment was safe, with higher doses leading to higher treatment discontinuations because of treatment-emergent adverse events occurring mostly during titration. Those patients reaching the target doses had an acceptable tolerability profile. The incidence rate of most frequently reported treatment-emergent adverse events during maintenance phase was ≤10%. Although further optimizing the titration scheme to the optimal dose for individual patients is essential, cebranopadol is a new drug candidate with a novel mechanistic approach for potential chronic LBP treatment.

An investigation of the predictors of photoprotection and UVR dose to the face in patients with XP: a protocol using observational mixed methods

PubMed Central

Walburn, Jessica; Sarkany, Robert; Norton, Sam; Foster, Lesley; Morgan, Myfanwy; Sainsbury, Kirby; Araújo-Soares, Vera; Anderson, Rebecca; Garrood, Isabel; Heydenreich, Jakob; Sniehotta, Falko F; Vieira, Rute; Wulf, Hans Christian; Weinman, John

2017-01-01

Introduction Xeroderma pigmentosum (XP) is a rare genetic condition caused by defective nucleotide excision repair and characterised by skin cancer, ocular and neurological involvement. Stringent ultraviolet protection is the only way to prevent skin cancer. Despite the risks, some patients’ photoprotection is poor, with a potentially devastating impact on their prognosis. The aim of this research is to identify disease-specific and psychosocial predictors of photoprotection behaviour and ultraviolet radiation (UVR) dose to the face. Methods and analysis Mixed methods research based on 45 UK patients will involve qualitative interviews to identify individuals’ experience of XP and the influences on their photoprotection behaviours and a cross-sectional quantitative survey to assess biopsychosocial correlates of these behaviours at baseline. This will be followed by objective measurement of UVR exposure for 21 days by wrist-worn dosimeter and daily recording of photoprotection behaviours and psychological variables for up to 50 days in the summer months. This novel methodology will enable UVR dose reaching the face to be calculated and analysed as a clinically relevant endpoint. A range of qualitative and quantitative analytical approaches will be used, reflecting the mixed methods (eg, cross-sectional qualitative interviews, n-of-1 studies). Framework analysis will be used to analyse the qualitative interviews; mixed-effects longitudinal models will be used to examine the association of clinical and psychosocial factors with the average daily UVR dose; dynamic logistic regression models will be used to investigate participant-specific psychosocial factors associated with photoprotection behaviours. Ethics and dissemination This research has been approved by Camden and King’s Cross Research Ethics Committee 15/LO/1395. The findings will be published in peer-reviewed journals and presented at national and international scientific conferences. PMID:28827277

Baseline Preferences for Daily, Event-Driven, or Periodic HIV Pre-Exposure Prophylaxis among Gay and Bisexual Men in the PRELUDE Demonstration Project.

PubMed

Vaccher, Stefanie J; Gianacas, Christopher; Templeton, David J; Poynten, Isobel M; Haire, Bridget G; Ooi, Catriona; Foster, Rosalind; McNulty, Anna; Grulich, Andrew E; Zablotska, Iryna B

2017-01-01

The effectiveness of daily pre-exposure prophylaxis (PrEP) is well established. However, there has been increasing interest in non-daily dosing schedules among gay and bisexual men (GBM). This paper explores preferences for PrEP dosing schedules among GBM at baseline in the PRELUDE demonstration project. Individuals at high-risk of HIV were enrolled in a free PrEP demonstration project in New South Wales, Australia, between November 2014 and April 2016. At baseline, they completed an online survey containing detailed behavioural, demographic, and attitudinal questions, including their ideal way to take PrEP: daily (one pill taken every day), event-driven (pills taken only around specific risk events), or periodic (daily dosing during periods of increased risk). Overall, 315 GBM (98% of study sample) provided a preferred PrEP dosing schedule at baseline. One-third of GBM expressed a preference for non-daily PrEP dosing: 20% for event-driven PrEP, and 14% for periodic PrEP. Individuals with a trade/vocational qualification were more likely to prefer periodic to daily PrEP [adjusted odds ratio (aOR) = 4.58, 95% confidence intervals (95% CI): (1.68, 12.49)], compared to individuals whose highest level of education was high school. Having an HIV-positive main regular partner was associated with strong preference for daily, compared to event-driven PrEP [aOR = 0.20, 95% CI: (0.04, 0.87)]. Participants who rated themselves better at taking medications were more likely to prefer daily over periodic PrEP [aOR = 0.39, 95% CI: (0.20, 0.76)]. Individuals' preferences for PrEP schedules are associated with demographic and behavioural factors that may impact on their ability to access health services and information about PrEP and patterns of HIV risk. At the time of data collection, there were limited data available about the efficacy of non-daily PrEP schedules, and clinicians only recommended daily PrEP to study participants. Further research investigating how behaviours and PrEP preferences change correspondingly over time is needed. ClinicalTrials.gov NCT02206555. Registered 28 July 2014.

40 CFR 439.12 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2011 CFR

2011-07-01

... percent reduction in the long-term average daily BOD5 load of the raw (untreated) process wastewater, multiplied by a variability factor of 3.0. (1) The long-term average daily BOD5 load of the raw process... concentration value reflecting a reduction in the long-term average daily COD load in the raw (untreated...

40 CFR 439.12 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2010 CFR

2010-07-01

... percent reduction in the long-term average daily BOD5 load of the raw (untreated) process wastewater, multiplied by a variability factor of 3.0. (1) The long-term average daily BOD5 load of the raw process... concentration value reflecting a reduction in the long-term average daily COD load in the raw (untreated...

A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

PubMed

Deming, Dustin A; Ninan, Jacob; Bailey, Howard H; Kolesar, Jill M; Eickhoff, Jens; Reid, Joel M; Ames, Matthew M; McGovern, Renee M; Alberti, Dona; Marnocha, Rebecca; Espinoza-Delgado, Igor; Wright, John; Wilding, George; Schelman, William R

2014-04-01

Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial.

PubMed

Bakris, George L; Pitt, Bertram; Weir, Matthew R; Freeman, Mason W; Mayo, Martha R; Garza, Dahlia; Stasiv, Yuri; Zawadzki, Rezi; Berman, Lance; Bushinsky, David A

2015-07-14

Hyperkalemia is a potentially life-threatening condition predominantly seen in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or greater chronic kidney disease (CKD) who may also have diabetes, heart failure, or both. To select starting doses for a phase 3 study and to evaluate the long-term safety and efficacy of a potassium-binding polymer, patiromer, in outpatients with hyperkalemia. Phase 2, multicenter, open-label, dose-ranging, randomized clinical trial (AMETHYST-DN), conducted at 48 sites in Europe from June 2011 to June 2013 evaluating patiromer in 306 outpatients with type 2 diabetes (estimated glomerular filtration rate, 15 to <60 mL/min/1.73 m2 and serum potassium level >5.0 mEq/L). All patients received RAAS inhibitors prior to and during study treatment. Patients were stratified by baseline serum potassium level into mild or moderate hyperkalemia groups and received 1 of 3 randomized starting doses of patiromer (4.2 g [n = 74], 8.4 g [n = 74], or 12.6 g [n = 74] twice daily [mild hyperkalemia] or 8.4 g [n = 26], 12.6 g [n = 28], or 16.8 g [n = 30] twice daily [moderate hyperkalemia]). Patiromer was titrated to achieve and maintain serum potassium level 5.0 mEq/L or lower. The primary efficacy end point was mean change in serum potassium level from baseline to week 4 or prior to initiation of dose titration. The primary safety end point was adverse events through 52 weeks. Secondary efficacy end points included mean change in serum potassium level through 52 weeks. A total of 306 patients were randomized. The least squares mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35 (95% CI, 0.22-0.48) mEq/L for the 4.2 g twice daily starting-dose group, 0.51 (95% CI, 0.38-0.64) mEq/L for the 8.4 g twice daily starting-dose group, and 0.55 (95% CI, 0.42-0.68) mEq/L for the 12.6 g twice daily starting-dose group. In those with moderate hyperkalemia, the reduction was 0.87 (95% CI, 0.60-1.14) mEq/L for the 8.4 g twice daily starting-dose group, 0.97 (95% CI, 0.70-1.23) mEq/L for the 12.6 g twice daily starting-dose group, and 0.92 (95% CI, 0.67-1.17) mEq/L for the 16.8 g twice daily starting-dose group (P < .001 for all changes vs baseline by hyperkalemia starting-dose groups within strata). From week 4 through week 52, statistically significant mean decreases in serum potassium levels were observed at each monthly point in patients with mild and moderate hyperkalemia. Over the 52 weeks, hypomagnesemia (7.2%) was the most common treatment-related adverse event, mild to moderate constipation (6.3%) was the most common gastrointestinal adverse event, and hypokalemia (<3.5 mEq/L) occurred in 5.6% of patients. Among patients with hyperkalemia and diabetic kidney disease, patiromer starting doses of 4.2 to 16.8 g twice daily resulted in statistically significant decreases in serum potassium level after 4 weeks of treatment, lasting through 52 weeks. clinicaltrials.gov Identifier:NCT01371747.

Pharmacokinetic Study of Intravenous Acetaminophen Administered to Critically Ill Multiple-Trauma Patients at the Usual Dosage and a New Proposal for Administration.

PubMed

Fuster-Lluch, Oscar; Zapater-Hernández, Pedro; Gerónimo-Pardo, Manuel

2017-10-01

The pharmacokinetic profile of intravenous acetaminophen administered to critically ill multiple-trauma patients was studied after 4 consecutive doses of 1 g every 6 hours. Eleven blood samples were taken (predose and 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 minutes postdose), and urine was collected (during 6-hour intervals between doses) to determine serum and urine acetaminophen concentrations. These were used to calculate the following pharmacokinetic parameters: maximum and minimum concentrations, terminal half-life, area under serum concentration-time curve from 0 to 6 hours, mean residence time, volume of distribution, and serum and renal clearance of acetaminophen. Daily doses of acetaminophen required to obtain steady-state minimum (bolus dosing) and average plasma concentrations (continuous infusion) of 10 μg/mL were calculated (10 μg/mL is the presumed lower limit of the analgesic range). Data are expressed as median [interquartile range]. Twenty-two patients were studied, mostly young (age 44 [34-64] years) males (68%), not obese (weight 78 [70-84] kg). Acetaminophen concentrations and pharmacokinetic parameters were these: maximum concentration 33.6 [25.7-38.7] μg/mL and minimum concentration 0.5 [0.2-2.3] μg/mL, all values below 10 μg/mL and 8 below the detection limit; half-life 1.2 [1.0-1.9] hours; area under the curve for 6 hours 34.7 [29.7-52.7] μg·h/mL; mean residence time 1.8 [1.3-2.6] hours; steady-state volume of distribution 50.8 [42.5-66.5] L; and serum and renal clearance 28.8 [18.9-33.7] L/h and 15 [11-19] mL/min, respectively. Theoretically, daily doses for a steady-state minimum concentration of 10 μg/mL would be 12.2 [7.8-16.4] g/day (166 [112-202] mg/[kg·day]); for an average steady-state concentration of 10 μg/mL, they would be 6.9 [4.5-8.1] g/day (91 [59-111] mg/[kg·day]). In conclusion, administration of acetaminophen at the recommended dosage of 1 g per 6 hours to critically ill multiple-trauma patients yields serum concentrations below 10 μg/mL due to increased elimination. To reach the 10 μg/mL target, and from a strictly pharmacokinetic point of view, continuous infusion may be more feasible than bolus dosing. Such a change in dosing strategy requires appropriate, pharmacokinetic-pharmacodynamic and specific safety study. © 2017, The American College of Clinical Pharmacology.

Randomized clinical trial to comparing efficacy of daily, weekly and monthly administration of vitamin D3.

PubMed

Takács, István; Tóth, Béla E; Szekeres, László; Szabó, Boglárka; Bakos, Bence; Lakatos, Péter

2017-01-01

The comparative efficacy and safety profiles of selected daily 1000 IU, weekly 7000 IU and monthly 30,000 IU vitamin D 3 -not previously investigated-will be evaluated. Here, a prospective, randomized clinical trial, comparing efficacy and safety of a daily single dose of 1000 IU (group A) to a once-weekly 7000 IU dose (group B), or monthly 30,000 IU dose (group C) of vitamin D 3 . The present study is a controlled, randomized, open-label, multicenter clinical trial, 3  months in duration. Sixty-four adult subjects with vitamin D deficiency (25OHD<20 ng/ml), were included according to the inclusion and exclusion criteria. Dose-responses for increases in serum vitamin 25OHD were statistically equivalent for each of the three groups: A, B and C. Outcomes were 13.0 ± 1.5; 12.6 ± 1.1 and 12.9 ± 0.9 ng/ml increases in serum 25OHD per 1000 IU, daily, weekly and monthly, respectively. The treatment of subjects with selected doses restored 25OHD values to levels above 20 ng/ml in all groups. Treatment with distinct administration frequency of vitamin D 3 did not exhibit any differences in safety parameters. The daily, weekly and monthly administrations of daily equivalent of 1000 IU of vitamin D 3 provide equal efficacy and safety profiles.

Poster - Thur Eve - 26: Interfraction reproducibility of heart position during breast irradiation using Active Breathing Control.

PubMed

Comsa, D; Zhang, B; Mosely, D; Yeung, I

2012-07-01

The moderate deep-inspiration breath hold (mDIBH) technique using the Active Breathing Coordinator (ABC) from Elekta is used in our clinic to lower the heart dose during left breast irradiations. The purpose of this work was to investigate the interfraction reproducibility of the heart to chest distance during these treatments and to evaluate the dosimetric effect of any changes in the heart position. Daily CBCT images were available for 5 patients who had been treated with ABC tangents and a cavity boost. On these images, one-dimensional measurements of the distance between the heart and the chest wall were taken at two anatomical locations corresponding roughly with the location where the radiation field most likely intercepts the heart. The average change in this distance was interpreted as a shift of the heart position. To assess the effect of this shift on the delivered heart dose, the heart contours in the clinical plans of the corresponding patients were shifted towards the treatment field using standard Pinnacle tools. Although the ABC device allows good reproducibility of the volume of air held, this does not warrant reproducibility of heart position for all patients during treatment. The largest average heart shift extracted from CBCT images in this study was 6.2mm. The heart dose reconstructed using this shift for the corresponding patient also showed the largest effect. However, even in the presence of a systematic heart shift of this magnitude, the ABC plan still showed superior heart dose reduction compared to the free-breathing plan. © 2012 American Association of Physicists in Medicine.

[BIOLOGICAL EFFECTIVENESS OF FISSION SPECTRUM NEUTRONS AND PROTONS WITH ENERGIES OF 60-126 MEV DURING ACUTE AND PROLONGED IRRADIATION].

PubMed

Shafirkin, A V

2015-01-01

Neutrons of the fission spectrum are characterized by relatively high values of linear energy transfer (LET). Data about their effects on biological objects are used to evaluate the risk of delayed effects of accelerated ions within the same LET range that serve as an experimental model of the nuclei component of galactic cosmic rays (GCR). Additionally, risks of delayed consequences to cosmonaut's health and average lifetime from certain GCR fluxes and secondary neutrons can be also prognosticated. The article deals with comparative analysis of the literature on reduction of average lifespan (ALS) of animals exposed to neutron reactor spectrum, 60-126 MeV protons, and X- and γ-rays in a broad range of radiation intensity and duration. It was shown that a minimal lifespan reduction by 5% occurs due to a brief exposure to neutrons with the absorbed dose of 5 cGy, whereas same lifespan reduction due to hard X- and γ-radiation occurs after absorption of a minimal dose of 100 cGy. Therefore, according to the estimated minimal ALS reduction in mice, neutron effectiveness is 20-fold higher. Biological effectiveness of protons as regards ALS reduction is virtually equal to that of standard types of radiation. Exposure to X- and γ-radiation with decreasing daily doses, and increasing number of fractions and duration gives rise to an apparent trend toward a less dramatic ALS reduction in mice; on the contrary, exposure to neutrons of varying duration had no effect on threshold doses for the specified ALS reductions. Factors of relative biological effectiveness of neutrons reached 40.

Particulate matter exposure of bicycle path users in a high-altitude city

NASA Astrophysics Data System (ADS)

Fajardo, Oscar A.; Rojas, Nestor Y.

2012-01-01

It is necessary to evaluate cyclists' exposure to particulate matter and if they are at a higher risk due to their increased breathing rate and their exposure to freshly emitted pollutants. The aim of this pilot study was to determine cyclists' exposure to PM 10 in a highly-polluted, high-altitude city such as Bogotá, and comment on the appropriateness of building bicycle paths alongside roads with heavy traffic in third world cities. A total of 29 particulate matter (PM 10) measurements, taken at two sampling sites using Harvard impactors, were used for estimating the exposure of users of the 80th street bicycle path to this pollutant. PM 10 dose could be considered as being high, especially due to high concentrations and cyclists' increased inhalation rates. A random survey was conducted over 73 bicycle path users to determine cyclists' time, distance and speed on the bicycle path on a daily and weekly basis, their level of effort when cycling and general characteristics, such as this population's gender and age. Based on this information, the PM 10 average daily dose (ADD c) for different bicycle path users and the ratio between ADD c and a reference ADD for people at rest exposed to an indoor concentration of 25 μg m -3 were estimated. The average increase in ADD was 6%-9% when riding with light effort and by 12%-18% when riding with moderate effort. The most enthusiastic bicycle path users showed ADD c/ADD r ratios as high as 1.30 when riding with light effort and 1.64 when riding with moderate effort, thereby significantly increasing their PM 10 exposure-associated health risks.

Consistent, high-level ethanol consumption in pig-tailed macaques via a multiple-session, limited-intake, oral self-dosing procedure.

PubMed

Weed, Michael R; Wilcox, Kristin M; Ator, Nancy A; Hienz, Robert D

2008-06-01

Alcohol abuse is a major public health burden that can lead to many adverse health effects such as impaired hepatic, gastrointestinal, central nervous system and immune system function. Preclinical animal models of alcohol abuse allow for experimental control over variables often difficult to control in human clinical studies (e.g., ethanol exposure before or during the study, history of other drug use, access to medical care, nutritional status, etc). Nonhuman primate models in particular provide increased genetic, anatomic and physiologic similarity to humans, relative to rodent models. A small percentage of macaques will spontaneously consume large quantities of ethanol; however, most nonhuman primate models of "voluntary" ethanol intake produce relatively low daily ethanol intake in the majority of monkeys. To facilitate study of chronic exposure to high levels of ethanol intake, a macaque model has been developed that induces consistent, daily high-level ethanol consumption. This multiple-session procedure employed 4 drinking sessions per day, with sessions occurring once every 6 hours. The group average alcohol consumption was 4.6 g/kg/d (SEM 0.4), roughly twice the group average consumption of previous reports. Ethanol drinking sessions produced group mean blood ethanol levels of 95 mg/dl after 60 minutes, and fine motor control was impaired up to 90 minutes after a drinking session. This model of multiple-session, limited access, oral ethanol self-dosing produced consistent, high-level ethanol consumption with each session qualifying as a "binge" drinking session using the definition of "binge" provided by the NIAAA (>80 mg/dl/session). This model of ethanol drinking in macaques will be of great utility in the study of immunological, physiological and behavioral effects of ethanol in nonhuman primates.

NSAIDs utilization for musculoskeletal indications in elderly patients with cerebro/cardiovascular disease.

PubMed

Roberto, Giuseppe; Bartolini, Claudia; Rea, Federico; Onder, Graziano; Vitale, Cristiana; Trifirò, Gianluca; Kirchmayer, Ursula; Chinellato, Alessandro; Lucenteforte, Ersilia; Corrao, Giovanni; Mugelli, Alessandro; Lapi, Francesco; Gini, Rosa

2018-05-01

To describe NSAID utilization for musculoskeletal conditions in a large cohort of Italian elderly with cerebro/cardiovascular disease, a population in which NSAIDs should be generally avoided due to the prothrombotic potential. Administrative data from five Italian geographic areas were analyzed. Patients aged ≥ 65 with a cerebro/cardiovascular event recorded between 2008 and 2011 (cohort entry) were selected. Prescription NSAIDs reimbursed for musculoskeletal conditions and dispensed during 1 year follow-up were retrieved to describe (i) prevalence of use, (ii) average amount of defined daily doses of NSAIDs claimed by users per day of follow-up, and (iii) distribution of the received daily dose (RDD) among patients with ≥ 2 dispensings. Among new users, i.e., patients without NSAID dispensings during 2 years before cohort entry, the first dispensed NSAID molecule was observed. Overall, 511,989 patients were selected. Across the five geographic areas, prevalence of use ranged from 48 to 21% and average consumption ranged between 30 and 67 DDD/1000 users/day. Around 10% of patients in the overall cohort had a RDD > 1. Nimesulide (9.6%) and diclofenac (7.5%) had the highest prevalence of use. The most consumed NSAIDs were nimesulide and coxibs with 10.6 and 7.5 DDD/1000 users/day, respectively. Among new users recruited in 2011, 30% had diclofenac or a coxibs as the first prescription. NSAID use was common in the study cohort, particularly in central-southern areas. In contrast with current recommendations, coxibs and diclofenac were among the most prescribed active principles, even in new users. Interventions to promote appropriateness of use are warranted.

5-Aminosalicylates Reduce the Risk of Colorectal Neoplasia in Patients with Ulcerative Colitis: An Updated Meta-Analysis

PubMed Central

Zhao, Li-Na; Li, Jie-Yao; Yu, Tao; Chen, Guang-Cheng; Yuan, Yu-Hong; Chen, Qi-Kui

2014-01-01

Background Although the chemopreventive effect of 5-aminosalicylates on patients with ulcerative colitis has been extensively studied, the results remain controversial. This updated review included more recent studies and evaluated the effectiveness of 5-aminosalicylates use on colorectal neoplasia prevention in patients with ulcerative colitis. Methods Up to July 2013, we searched Medline, Embase, Web of Science, Cochrane CENTRAL, and SinoMed of China for all relevant observational studies (case-control and cohort) about the effect of 5-aminosalicylates on the risk of colorectal neoplasia among patients with ulcerative colitis. The Newcastle-Ottawa Scale was used to assess the quality of studies. Adjusted odds ratios (ORs) were extracted from each study. A random-effects model was used to generate pooled ORs and 95% confidence intervals (95%CI). Publication bias and heterogeneity were assessed. Results Seventeen studies containing 1,508 cases of colorectal neoplasia and a total of 20,193 subjects published from 1994 to 2012 were analyzed. 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis (OR 0.63; 95%CI 0.48–0.84). Pooled OR of a higher average daily dose of 5-aminosalicylates (sulfasalazine ≥ 2.0 g/d, mesalamine ≥ 1.2 g/d) was 0.51 [0.35–0.75]. Pooled OR of 5-aminosalicylates use in patients with extensive ulcerative colitis was 1.00 [0.53–1.89]. Conclusion Our pooled results indicated that 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis, especially in the cases with a higher average daily dose of 5-aminosalicylates use. However, the chemopreventive benefit of 5-aminosalicylates use in patients with extensive ulcerative colitis was limited. PMID:24710620

5-Aminosalicylates reduce the risk of colorectal neoplasia in patients with ulcerative colitis: an updated meta-analysis.

PubMed

Zhao, Li-Na; Li, Jie-Yao; Yu, Tao; Chen, Guang-Cheng; Yuan, Yu-Hong; Chen, Qi-Kui

2014-01-01

Although the chemopreventive effect of 5-aminosalicylates on patients with ulcerative colitis has been extensively studied, the results remain controversial. This updated review included more recent studies and evaluated the effectiveness of 5-aminosalicylates use on colorectal neoplasia prevention in patients with ulcerative colitis. Up to July 2013, we searched Medline, Embase, Web of Science, Cochrane CENTRAL, and SinoMed of China for all relevant observational studies (case-control and cohort) about the effect of 5-aminosalicylates on the risk of colorectal neoplasia among patients with ulcerative colitis. The Newcastle-Ottawa Scale was used to assess the quality of studies. Adjusted odds ratios (ORs) were extracted from each study. A random-effects model was used to generate pooled ORs and 95% confidence intervals (95%CI). Publication bias and heterogeneity were assessed. Seventeen studies containing 1,508 cases of colorectal neoplasia and a total of 20,193 subjects published from 1994 to 2012 were analyzed. 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis (OR 0.63; 95%CI 0.48-0.84). Pooled OR of a higher average daily dose of 5-aminosalicylates (sulfasalazine ≥ 2.0 g/d, mesalamine ≥ 1.2 g/d) was 0.51 [0.35-0.75]. Pooled OR of 5-aminosalicylates use in patients with extensive ulcerative colitis was 1.00 [0.53-1.89]. Our pooled results indicated that 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis, especially in the cases with a higher average daily dose of 5-aminosalicylates use. However, the chemopreventive benefit of 5-aminosalicylates use in patients with extensive ulcerative colitis was limited.

Patterns of antibacterials use in intensive care units.

PubMed

Santos, Edilson Floriano Dos; Lauria-Pires, Liana

2010-06-01

To know and compare the patterns of antimicrobials use in intensive care units (ICUs) based on the Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) system. a prospective cohort study was conducted in three medical-surgical intensive care units, two of them in public hospitals and one in a private hospital. Simple random, independent samples of patients admitted from 10/2004 to 09/2005 to the selected intensive care units were used. The antibiotics use was assessed using the ATC/DDD system. The amount of antibacterials used in each intensive care unit, in grams, was transformed in daily defined dose (DDD). The number of DDDs was divided by the number of patient-days, multiplied by one thousand, to obtain the average density of consumption (DC) per thousand patient-days (DDD1000). 1,728 patients-days and 2,918.6 DDDs were examined in the three intensive care units, corresponding to an average density of consumption of 1,689.0 DDD1000. The median number of DDDs of antibiotics use in the public hospitals’ intensive care units was significantly higher (p=0.002) versus the private hospital’s intensive care unit. The consumption of antibiotics in the private hospital’s intensive care unit (DC=2,191.7 DDD1000) was significantly higher (p<0.001) versus the intensive care units of public hospitals (1,499.5 DDD1000). The most used antibiotics groups in the three intensive care units were 3rd generation cephalosporins, penicillins/betalactamases inhibitors, carbapenems and fluorquinolones. The pattern of antibiotics use in the three examined intensive care units was not uniform. The private hospital’s intensive care unit used a significantly larger amount versus the public hospitals’ intensive care units. Nevertheless, the most used antibiotics groups were similar in the three intensive care units.

A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor

PubMed Central

Bendell, Johanna C; Javle, Milind; Bekaii-Saab, Tanios S; Finn, Richard S; Wainberg, Zev A; Laheru, Daniel A; Weekes, Colin D; Tan, Benjamin R; Khan, Gazala N; Zalupski, Mark M; Infante, Jeffrey R; Jones, Suzanne; Papadopoulos, Kyriakos P; Tolcher, Anthony W; Chavira, Renae E; Christy-Bittel, Janna L; Barrett, Emma; Patnaik, Amita

2017-01-01

Background: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer. Methods: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples. Results: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial). Conclusions: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population. PMID:28152546

[Solar exposure time for sunburn in Mexican population].

PubMed

Castanedo Cázares, Juan Pablo; Torres Álvarez, Bertha; Sobrevilla Ondarza, Salvador; Ehnis Pérez, Adriana; Gordillo Moscoso, Antonio

2012-01-01

THe minimal erythemal dose (MED) quantifies an individual's sensitivity to UV radiation (UVR). To estimate it in our population and establish the time of exposure inducing it during daily activities would allow us to calculate risk intervals. From 2005-2012, the UV solar radiation was measured with terrestrial radiometry and compared to public UV index (UVI). We determined the MED in 90 individuals with the prevalent phototypes in Mexico (III, IV, V), and estimated the time needed for the development of sunburn. The average MED for phototype III was 39 (IC 95%: 35-42) mJ/cm2, for IV 48 (IC 95%:42-53) mJ/cm2, and for V was 84 (IC 95%:75-92) mJ/cm2 (ANOVA, p ≤ 0.001). Approximately, 80% of the daily UVR was accumulated between 10:00-16:00 h, and 77% of the annual UV dose is received between March-October. The public UVI had a high correlation with the one quantified at terrestrial level (r = 0.89; p ≤ 0.001). Mexico receives continuously high levels of UVR. Phototype III will present sunburn after 22-33 min in a summer day, while phototype V will require over one hour of exposure. This last group is at risk of chronic exposure without considering consequences.

Time Profile of Cosmic Radiation Exposure During the EXPOSE-E Mission: The R3DE Instrument

PubMed Central

Horneck, Gerda; Häder, Donat-Peter; Schuster, Martin; Richter, Peter; Lebert, Michael; Demets, Rene

2012-01-01

Abstract The aim of this paper is to present the time profile of cosmic radiation exposure obtained by the Radiation Risk Radiometer-Dosimeter during the EXPOSE-E mission in the European Technology Exposure Facility on the International Space Station's Columbus module. Another aim is to make the obtained results available to other EXPOSE-E teams for use in their data analysis. Radiation Risk Radiometer-Dosimeter is a low-mass and small-dimension automatic device that measures solar radiation in four channels and cosmic ionizing radiation as well. The main results of the present study include the following: (1) three different radiation sources were detected and quantified—galactic cosmic rays (GCR), energetic protons from the South Atlantic Anomaly (SAA) region of the inner radiation belt, and energetic electrons from the outer radiation belt (ORB); (2) the highest daily averaged absorbed dose rate of 426 μGy d−1 came from SAA protons; (3) GCR delivered a much smaller daily absorbed dose rate of 91.1 μGy d−1, and the ORB source delivered only 8.6 μGy d−1. The analysis of the UV and temperature data is a subject of another article (Schuster et al., 2012). Key Words: Ionizing radiation—R3D—ISS. Astrobiology 12, 403–411. PMID:22680687

Association of drinking-water source and use characteristics with urinary antimony concentrations.

PubMed

Makris, Konstantinos C; Andra, Syam S; Herrick, Lisa; Christophi, Costas A; Snyder, Shane A; Hauser, Russ

2013-03-01

Environmental factors, such as storage time, frequency of bottle reuse and temperature, have been shown to facilitate antimony (Sb) leaching from water- and food-packaging materials. The globally escalating consumption of water packaged in Sb-containing bottles, such as that of polyethylene terephthalate (PET), could increase human daily Sb doses. This study set out to investigate the relationship between drinking-water source, use characteristics, and urinary Sb concentrations (U-Sb) accompanied with survey responses of a healthy (n=35) Cypriot participant pool. One spot urine sample was collected during administration of questionnaire, while a second spot urine sample was collected from the same individual about 7 days later. Urinary and water Sb concentrations were measured with an inductively coupled plasma mass spectrometer. Survey responses showed that bottled water summed over various volumes and plastic types, such as polycarbonate and PET contributed to an average 61% of daily water consumption. Water sources such as tap, mobile stations (explained in a following section), and well water contributed to 24%, 14%, and 2% of an individual's daily water consumption pattern, respectively. Average daily potable water use of both bottled and tap water by individuals consisted of 65% drinking-water, while the remaining 35% was water used for preparing cold and hot beverages, such as, tea, coffee, and juices. A significant (P=0.02) association between per capita water consumption from PET bottles and urinary creatinine-unadjusted concentrations was observed, but this relationship did not remain after inclusion of covariates in a multivariate regression model. In the creatinine-adjusted regression model, only gender (female) was a significant (P<0.01) predictor of U-Sb, after adjusting for several covariates. It is proposed that consumption data collection on various water uses and sources among individuals could perhaps decrease the uncertainty associated with derivations of acceptable daily Sb intakes.

Dosimetric evaluation of three adaptive strategies for prostate cancer treatment including pelvic lymph nodes irradiation

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

Cantin, Audrey; Gingras, Luc; Archambault, Louis, E-mail: louis.archambault@phy.ulaval.ca

Purpose: The movements of the prostate relative to the pelvic lymph nodes during intensity-modulated radiation therapy treatment can limit margin reduction and affect the protection of the organs at risk (OAR). In this study, the authors performed an analysis of three adaptive treatment strategies that combine information from both bony and gold marker registrations. The robustness of those treatments against the interfraction prostate movements was evaluated. Methods: A retrospective study was conducted on five prostate cancer patients with 7–13 daily cone-beam CTs (CBCTs). The clinical target volumes (CTVs) consisting of pelvic lymph nodes, prostate, and seminal vesicles as well asmore » the OARs were delineated on each CBCT and the initial CT. Three adaptive strategies were analyzed. Two of these methods relied on a two-step patient positioning at each fraction. First step: a bony registration was used to deliver the nodal CTV prescription. Second step: a gold marker registration was then used either to (1) complete the dose delivered to the prostate (complement); (2) or give almost the entire prescription to the prostate with a weak dose gradient between the targets to compensate for possible motions (gradient). The third method (COR) used a pool of precalculated plans based on images acquired at previous treatment fractions. At each new fraction, a plan is selected from that pool based on the daily position of prostate center-of-mass. The dosimetric comparison was conducted and results are presented with and without the systematic shift in the prostate position on the CT planning. The adaptive strategies were compared to the current clinical standard where all fractions are treated with the initial nonadaptive plan. Results: The minimum daily prostate D{sub 95%} is improved by 2%, 9%, and 6% for the complement, the gradient, and the COR approaches, respectively, compared to the nonadaptive method. The average nodal CTV D{sub 95%} remains constant across the strategies, except for the gradient approach where a reduction of 7% is observed. However, a correction of the systematic shift reduced the problem, and the adaptive strategies remain robust against the prostate movement across the fraction. The bladder V{sub 55Gy} is reduced by 35% on average for the adaptive strategies. Conclusions: Because they offer increased CTV coverage and OAR sparing, adaptive methods may be suitable candidates for simple and efficient adaptive treatment strategies for prostate cancer. Margin reduction and systematic error correction in the prostate position improve the protection of the OAR and the dose coverage. A cumulative dose to simulate a complete treatment would show real effects and allow a better comparison between each method.« less

Short-term digestive tolerance of different doses of NUTRIOSE FB, a food dextrin, in adult men.

PubMed

van den Heuvel, E G H M; Wils, D; Pasman, W J; Bakker, M; Saniez, M-H; Kardinaal, A F M

2004-07-01

To determine the tolerance of increasing dosages of an incompletely hydrolysed and/or incompletely absorbed food dextrin coming from wheat starch, NUTRIOSE FB, at daily levels of 10 and 15 g up to 60 and 80 g, respectively. A randomized, double-blind, multiple dose, placebo-controlled, combined crossover and parallel trial. The metabolic ward of TNO Nutrition and Food Research. A total of 20 healthy men (age 31.7 +/- 9.1 y; BMI 24.5 +/- 2.9 kg/m2). One group of 10 subjects consumed on top of their diet 10, 30 and 60 g of NUTRIOSE FB or maltodextrin (placebo) daily. The other group of 10 subjects consumed 15, 45 and 80 g daily. Each dose was consumed for 7 days. Compared with placebo, flatulence occurred more frequently over the last 6 days on 30, 60 or 80 g/day of NUTRIOSE FB (P < 0.05). During the last 24 h, that is, days 6-7, of 60 and 80 g/day of NUTRIOSE FB, the frequency of flatulence was even higher (P < 0.05). During the last 24 h on a daily dose of 60 g NUTRIOSE FB, the frequency of defecation decreased (P < 0.05). Bloating occurred more often during the last 24 h on 80 g/day of NUTRIOSE FB (P < 0.05). None of the doses of NUTRIOSE FB resulted in diarrhoea. Compared to baseline levels, breath H2 excretion, which was only measured after a week with 10 and 15 g of NUTRIOSE FB daily, increased (P < 0.05). However, no difference in area under the curve was found. NUTRIOSE FB is a fermentable carbohydrate and is well tolerated up to a dose of 45 g daily. Higher daily dosages (60 and 80 g) may result in flatulence, but does not result in diarrhoea. TNO Nutrition and Food Research was assigned by Roquette Frères to perform the study.

Oral glucocorticoid use and osteonecrosis in children and adults with chronic inflammatory diseases: a population-based cohort study

PubMed Central

Haynes, Kevin; Denburg, Michelle R; Thacker, Mihir M; Rose, Carlos D; Putt, Mary E; Leonard, Mary B; Strom, Brian L

2017-01-01

Objectives We studied oral glucocorticoids and osteonecrosis, a rare but serious bone disease, in individuals with various chronic inflammatory diseases. We hypothesised that we would find stronger associations in adults versus children and in people with autoimmune diseases. Design Retrospective cohort study. Setting Population-representative data (1994–2013) from general practices in the UK. Participants Children and adults diagnosed with asthma; inflammatory bowel disease; juvenile, psoriatic or rheumatoid arthritis; psoriasis; or systemic lupus. Exposures Oral glucocorticoid patterns. Primary and secondary outcome measures Diagnosed osteonecrosis (primary) and osteonecrosis plus clinical features (eg, symptoms, pain medication, surgical repair) (secondary). Discrete time failure models estimated the adjusted hazard ratio (aHR) of incident osteonecrosis following oral glucocorticoid exposure. Hypothesis testing was one sided (with corresponding 90% CI) since glucocorticoids were unlikely protective. Results After adjusting for demographic, disease-related and health utilisation factors, glucocorticoid exposure was associated with osteonecrosis in adults (ages 18–49, aHR 2.1 (90% CI 1.5 to 2.9); ages ≥50, aHR 1.3 (90% CI 1.01 to 1.7)). However, low-dose glucocorticoids, corresponding to average doses <7.5 mg prednisolone daily and maximum doses <30 mg daily, were not associated with osteonecrosis in adults. Furthermore, even at high glucocorticoid doses, there was no evidence of increased osteonecrosis among glucocorticoid-exposed children (p=0.04 for interaction by age) (any glucocorticoid exposure, ages 2–9: aHR 1.1 (90% CI 0.7 to 1.7); ages 10–17: aHR 0.6 (90% CI 0.3 to 1.6)). Arthritis, inflammatory bowel disease and lupus were independently associated with osteonecrosis, but there was a similar dose relationship between glucocorticoids and osteonecrosis among adults with low-risk and high-risk diseases. Conclusions Glucocorticoid use was clearly associated with osteonecrosis in a dose-related fashion in adults, especially young adults, but this risk was not detectable in children. The absolute risk of glucocorticoid-associated osteonecrosis in the general paediatric population and in adults taking low glucocorticoid doses is at most extremely small. PMID:28733303

Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization

PubMed Central

Cao, G; Zhang, J; Wu, X; Yu, J; Chen, Y; Ye, X; Zhu, D; Zhang, Y; Guo, B; Shi, Y

2013-01-01

What is known and objective The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen. Methods The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fCmax/MIC ≥5 and fAUC24 h/MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated. Results and discussion The results of PK study showed that the Cmax and AUC0–∞ of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean Css,max, Css,min and AUC0–τ of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fCmax/MIC and fAUC/MIC targets. What is new and conclusion The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results. PMID:23701411

Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization.

PubMed

Cao, G; Zhang, J; Wu, X; Yu, J; Chen, Y; Ye, X; Zhu, D; Zhang, Y; Guo, B; Shi, Y

2013-10-01

The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen. The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fC(max) /MIC ≥5 and fAUC(24 h) /MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated. The results of PK study showed that the C(max) and AUC(0-∞) of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean C(ss,max), C(ss,min) and AUC(0-τ) of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fC(max) /MIC and fAUC/MIC targets. The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results. © 2013 John Wiley & Sons Ltd.

Poster — Thur Eve — 15: Improvements in the stability of the tomotherapy imaging beam

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

Belec, J

2014-08-15

Use of helical TomoTherapy based MVCT imaging for adaptive planning requires the image values (HU) to remain stable over the course of treatment. In the past, the image value stability was suboptimal, which required frequent change to the image value to density calibration curve to avoid dose errors on the order of 2–4%. The stability of the image values at our center was recently improved by stabilizing the dose rate of the machine (dose control servo) and performing daily MVCT calibration corrections. In this work, we quantify the stability of the image values over treatment time by comparing patient treatmentmore » image density derived using MVCT and KVCT. The analysis includes 1) MVCT - KVCT density difference histogram, 2) MVCT vs KVCT density spectrum, 3) multiple average profile density comparison and 4) density difference in homogeneous locations. Over two months, the imaging beam stability was compromised several times due to a combination of target wobbling, spectral calibration, target change and magnetron issues. The stability of the image values were analyzed over the same period. Results show that the impact on the patient dose calculation is 0.7% +− 0.6%.« less

40 CFR 439.22 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2011 CFR

2011-07-01

... limitation for BOD5 that is less than the equivalent of 45 mg/L. (1) The long-term average daily BOD5 load of... to this subpart, calculation of the long-term average daily BOD5 load in the influent to the... this section is higher than a concentration value reflecting a reduction in the long-term average daily...

40 CFR 439.52 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2012 CFR

2012-07-01

..., kg) per day, must reflect not less than 74 percent reduction in the long-term average daily COD load... long-term average daily BOD5 or COD mass loading of the raw process wastewater (i.e., the base number..., calculation of the long-term average daily BOD5 or COD load in the influent to the wastewater treatment system...

40 CFR 439.22 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2010 CFR

2010-07-01

... limitation for BOD5 that is less than the equivalent of 45 mg/L. (1) The long-term average daily BOD5 load of... to this subpart, calculation of the long-term average daily BOD5 load in the influent to the... this section is higher than a concentration value reflecting a reduction in the long-term average daily...

40 CFR 439.52 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2014 CFR

2014-07-01

..., kg) per day, must reflect not less than 74 percent reduction in the long-term average daily COD load... long-term average daily BOD5 or COD mass loading of the raw process wastewater (i.e., the base number..., calculation of the long-term average daily BOD5 or COD load in the influent to the wastewater treatment system...

40 CFR 439.52 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2013 CFR

2013-07-01

..., kg) per day, must reflect not less than 74 percent reduction in the long-term average daily COD load... long-term average daily BOD5 or COD mass loading of the raw process wastewater (i.e., the base number..., calculation of the long-term average daily BOD5 or COD load in the influent to the wastewater treatment system...

40 CFR 439.12 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2013 CFR

2013-07-01

... than 90 percent reduction in the long-term average daily BOD5 load of the raw (untreated) process wastewater, multiplied by a variability factor of 3.0. (1) The long-term average daily BOD5 load of the raw..., calculation of the long-term average daily BOD5 load in the influent to the wastewater treatment system must...

40 CFR 439.12 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2012 CFR

2012-07-01

... than 90 percent reduction in the long-term average daily BOD5 load of the raw (untreated) process wastewater, multiplied by a variability factor of 3.0. (1) The long-term average daily BOD5 load of the raw..., calculation of the long-term average daily BOD5 load in the influent to the wastewater treatment system must...

40 CFR 439.12 - Effluent limitations attainable by the application of the best practicable control technology...

Code of Federal Regulations, 2014 CFR

2014-07-01

... than 90 percent reduction in the long-term average daily BOD5 load of the raw (untreated) process wastewater, multiplied by a variability factor of 3.0. (1) The long-term average daily BOD5 load of the raw..., calculation of the long-term average daily BOD5 load in the influent to the wastewater treatment system must...

Impact of dose reductions on efficacy outcome in heart transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil at 12 months post-transplantation.

PubMed

Segovia, Javier; Gerosa, Gino; Almenar, Luis; Livi, Ugolino; Viganò, Mario; Arizón, Jose Maria; Yonan, Nizar; Di Salvo, Thomas G; Renlund, Dale G; Kobashigawa, Jon A

2008-01-01

Mycophenolic acid (MPA) dose reduction is associated with increased risk of rejection and graft loss in renal transplantation. This analysis investigated the impact of MPA dose changes with enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) in de novo heart transplant recipients. In a 12-month, single-blind trial, 154 patients (EC-MPS, 78; MMF, 76) were randomized to either EC-MPS (1080 mg bid) or MMF (1500 mg bid) in combination with cyclosporine and steroids. The primary efficacy variable was the incidence of treatment failure, comprising a composite of biopsy-proven (BPAR) and treated acute rejection, graft loss or death. Significantly fewer patients receiving EC-MPS required > or =2 dose reductions than patients on MMF (26.9% vs. 42.1% of patients, p = 0.048). Accordingly, the average daily dose of EC-MPS as a percentage of the recommended dose was significantly higher than for MMF (88.4% vs. 79.0%, p = 0.016). Among patients requiring > or =1 dose reduction, the incidence of treated BPAR grade > or =3A was significantly lower with EC-MPS compared with MMF (23.4% vs. 44.0%, p = 0.032). These data suggest that EC-MPS-treated heart transplant patients are less likely to require multiple dose reductions than those on MMF which may be associated with a significantly lower risk of treated BPAR > or =3A.

Effects of isoflavone supplements vs. soy foods on blood concentrations of genistein and daidzein in adults

PubMed Central

Gardner, Christopher D.; Chatterjee, Lorraine M.; Franke, Adrian A.

2012-01-01

The objective of this investigation was to examine the pharmacokinetics of isoflavone concentrations over a 24-hour period among healthy adults consuming either soy foods or soy isoflavone tablets at different doses. This randomized, cross-over trial was conducted with twelve generally healthy adults. The three phases of the intervention included: isoflavone tablets at 1) 144 mg/day or 2) 288 mg/day, and 3) soy foods designed to provide a calculated 96 mg isoflavones/day (doses in aglycone equivalents). Doses were spread out over three meals/day. After 6 days on each study phase, plasma isoflavone concentrations were determined on the seventh day at 0, 4, 8, 10, 12 and 24 hours. Average levels of total isoflavone concentrations at 8, 10 and 12 hours were >4 μmol/L for the soy food phase and for the higher dose tablet phase. Genistein concentrations were higher overall in the soy food vs. both the lower and the higher dose supplement phases of the study (p≤0.05). When comparing plasma concentrations for the two doses of tablets, saturation appeared more evident for genistein than daidzein at the higher dose level. In conclusion, we observed important differences in the pharmacokinetics of genistein and daidzein contrasting the sources and doses of isoflavones when administered three times daily, including a possible advantage for increasing serum concentrations of isoflavones from consuming soy foods relative to isoflavone supplements. PMID:18602820

Effects of isoflavone supplements vs. soy foods on blood concentrations of genistein and daidzein in adults.

PubMed

Gardner, Christopher D; Chatterjee, Lorraine M; Franke, Adrian A

2009-03-01

The objective of this investigation was to examine the pharmacokinetics of isoflavone concentrations over a 24-h period among healthy adults consuming either soy foods or soy isoflavone tablets at different doses. This randomized, cross-over trial was conducted with 12 generally healthy adults. The three phases of the intervention included isoflavone tablets at (1) 144 mg/day or (2) 288 mg/day and (3) soy foods designed to provide a calculated 96 mg isoflavones/day (doses in aglycone equivalents). Doses were spread out over three meals per day. After 6 days on each study phase, plasma isoflavone concentrations were determined on the seventh day at 0, 4, 8, 10, 12 and 24 h. Average levels of total isoflavone concentrations at 8, 10 and 12 h were >4 micromol/L for the soy food phase and for the higher dose tablet phase. Genistein concentrations were higher overall in the soy food vs. both the lower and the higher dose supplement phases of the study (P<.05). When comparing plasma concentrations for the two doses of tablets, saturation appeared more evident for genistein than for daidzein at the higher dose level. In conclusion, we observed important differences in the pharmacokinetics of genistein and daidzein contrasting the sources and doses of isoflavones when administered three times daily, including a possible advantage for increasing serum concentrations of isoflavones from consuming soy foods relative to isoflavone supplements.

An examination of the treatment of iron-dosed waste activated sludge by anaerobic digestion.

PubMed

Johnson, D K; Carliell-Marquet, C M; Forster, C F

2003-08-01

Anaerobic digestion is an important sludge treatment process enabling stabilisation of the organic fraction of sewage sludge prior to land application. Any practice which might retard the anaerobic digestion process will jeopardize the stability of the resulting digested sludge. This paper reports on an investigation into the relative digestibility of iron-dosed waste activated sludge (WAS) from a sewage treatment works (STW) with chemical phosphorus removal (CPR), in comparison to WAS from a works without phosphorus removal. Two laboratory scale anaerobic digesters (51) were fed initially with non iron-dosed WAS (Works M) at a solids retention time of 19 days. After 2 months the iron-dosed CPR sludge (Works R) was introduced into the second digester, resulting in a 32% decrease in biogas production and an increase in the methane content of the biogas from an average of 74% to 81%. Pre-treatment of the CPR sludge with sodium sulphide and shear, both alone and in combination, caused the gas production to deteriorate further. Pre-acidification and pre-treatment with EDTA did result in an enhanced gas production but it was still not comparable with that of the digester being fed with non-iron-dosed sludge. The daily gas production was found to be linearly related to the amount of bound iron in the sludge.

Low-Dose Daily Intake of Vitamin K(2) (Menaquinone-7) Improves Osteocalcin γ-Carboxylation: A Double-Blind, Randomized Controlled Trials.

PubMed

Inaba, Naoko; Sato, Toshiro; Yamashita, Takatoshi

2015-01-01

Vitamin K is essential for bone health, but the effects of low-dose vitamin K intake in Japanese subjects remain unclear. We investigated the effective minimum daily menaquinone-7 dose for improving osteocalcin γ-carboxylation. Study 1 was a double-blind, randomized controlled dose-finding trial; 60 postmenopausal women aged 50-69 y were allocated to one of four dosage group and consumed 0, 50, 100, or 200 μg menaquinone-7 daily for 4 wk, respectively, with a controlled diet in accordance with recommended daily intakes for 2010 in Japan. Study 2 was a double-blind, randomized placebo-controlled trial based on the results of Study 1; 120 subjects aged 20-69 y were allocated to the placebo or MK-7 group and consumed 0 or 100 μg menaquinone-7 daily for 12 wk, respectively. In both studies, circulating carboxylated osteocalcin and undercarboxylated osteocalcin were measured. The carboxylated osteocalcin/undercarboxylated osteocalcin ratio decreased significantly from baseline in the 0 μg menaquinone-7 group, in which subjects consumed the recommended daily intake of vitamin K with vitamin K1 and menaquinone-4 (Study 1). Menaquinone-7 increased the carboxylated osteocalcin/undercarboxylated osteocalcin ratio dose dependently, and significant effects were observed in both the 100 and 200 μg groups compared with the 0 μg group. Undercarboxylated osteocalcin concentrations decreased significantly, and the carboxylated osteocalcin/undercarboxylated osteocalcin ratio increased significantly in the 100 μg menaquinone-7 group compared with the placebo group (Study 2). Daily menaquinone-7 intake ≥100 μg was suggested to improve osteocalcin γ-carboxylation.

Tamoxifen-DNA adduct formation in monkey and human reproductive organs.

PubMed

Hernandez-Ramon, Elena E; Sandoval, Nicole A; John, Kaarthik; Cline, J Mark; Wood, Charles E; Woodward, Ruth A; Poirier, Miriam C

2014-05-01

The estrogen analog tamoxifen (TAM), used for adjuvant therapy of breast cancer, induces endometrial and uterine tumors in breast cancer patients. Proliferation stimulus of the uterine endometrium is likely involved in tumor induction, but genotoxicity may also play a role. Formation of TAM-DNA adducts in human tissues has been reported but remains controversial. To address this issue, we examined TAM-DNA adducts in uteri from two species of monkeys, Erythrocebus patas (patas) and Macaca fascicularis (macaque), and in human endometrium and myometrium. Monkeys were given 3-4 months of chronic TAM dosing scaled to be equivalent to the daily human dose. In the uteri, livers and brains from the patas (n = 3), and endometrium from the macaques (n = 4), TAM-DNA adducts were measurable by TAM-DNA chemiluminescence immunoassay. Average TAM-DNA adduct values for the patas uteri (23 adducts/10(8) nucleotides) were similar to those found in endometrium of the macaques (19 adducts/10(8) nucleotides). Endometrium of macaques exposed to both TAM and low-dose estradiol (n = 5) averaged 34 adducts/10(8) nucleotides. To examine TAM-DNA persistence in the patas, females (n = 3) were exposed to TAM for 3 months and to no drug for an additional month, resulting in low or non-detectable TAM-DNA in livers and uteri. Human endometrial and myometrial samples from women receiving (n = 8) and not receiving (n = 8) TAM therapy were also evaluated. Women receiving TAM therapy averaged 10.3 TAM-DNA adducts/10(8) nucleotides, whereas unexposed women showed no detectable TAM-DNA. The data indicate that genotoxicity, in addition to estrogen agonist effects, may contribute to TAM-induced human endometrial cancer.

Vitamin D in newborns. A randomised controlled trial comparing daily and single oral bolus vitamin D in infants.

PubMed

Huynh, Julie; Lu, Thao; Liew, Danny; Doery, James Cg; Tudball, Ronald; Jona, Madeleine; Bhamjee, Roisin; Rodda, Christine P

2017-02-01

There are no published data to demonstrate the efficacy of bolus dose vitamin D in newborn infants. The study sought to evaluate this alternative approach of supplementation. This single centre, open randomised controlled trial was conducted from August 2013 to May 2014. It compared the efficacy and safety of daily (400 IU) versus a bolus dose (50 000 IU) of cholecalciferol in newborn infants of vitamin D deficient mothers. The primary outcome measure was the rate of 25 hydroxyvitamin D (25OHD) repletion-defined as 25OHD greater than 50 nmol/L. The secondary objective was determining safety using adjusted total serum calcium. Of 70 eligible infants, 36 received a daily dose and 34 received a single high-dose cholecalciferol. Mean 25OHD in the bolus group (154 nmol/L, 95% confidence interval (CI) 131-177) was higher than the daily group (48 nmol/L, 95% CI 42-54) at 1-2 weeks of age. This was reversed at 3-4 months, (65 nmol/L, 95% CI 59-71) compared with the daily group (81 nmol/L, 95% CI 77-85). More infants in the single bolus group achieved vitamin D repletion (100 vs. 31%) at 1-2 weeks. By 3-4 months, both groups achieved similar vitamin D repletion rates (91 vs. 89%). Mean adjusted total serum calcium in the bolus group were normal at 1-2 weeks (2.73 mmol/L) and 3-4 months (2.55 mmol/L). Single bolus dosing of 50 000 IU cholecalciferol achieves higher 25OHD repletion rates at 1-2 weeks of age compared with daily dosing, but repletion rates were similar by 3-4 months. There was no hypercalcaemia documented with single bolus dosing in this study. © 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors.

PubMed

Lewin, Jeremy; Soria, Jean-Charles; Stathis, Anastasios; Delord, Jean-Pierre; Peters, Solange; Awada, Ahmad; Aftimos, Philippe G; Bekradda, Mohamed; Rezai, Keyvan; Zeng, Zhen; Hussain, Azher; Perez, Susan; Siu, Lillian L; Massard, Christophe

2018-05-07

Purpose Birabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer in this phase Ib study. Patients and Methods Forty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design. The primary objective was occurrence of dose-limiting toxicities (DLTs) and determination of the recommended phase II dose. Results Of 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non-small-cell lung cancer. For cohort A, four of 19 (21%) evaluable patients had DLTs at 80 mg once daily (grade 3 thrombocytopenia [n = 3], ALT/hyperbilirubinemia [n = 1]) and two of three had DLTs at 100 mg once daily (grade 2 anorexia and nausea with treatment delay > 7 days [n = 1], grade 4 thrombocytopenia [n = 1]). No DLTs occurred in cohort B. Of 46 patients, 38 (83%) had treatment-related adverse events (diarrhea, 17 [37%]; nausea, 17 [37%]; anorexia, 14 [30%]; vomiting, 12 [26%]; thrombocytopenia 10 [22%]). Three patients with NMC (80 mg once daily) had a partial response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) with duration of 1.4 to 8.4 months. Pharmacokinetic analysis indicated a dose-proportional increase in birabresib exposure and rapid absorption. Conclusion The recommended phase II dose of birabresib in patients with select solid tumors is 80 mg once daily with continuous dosing. Birabresib has dose-proportional exposure and a favorable safety profile, with clinical activity observed in NMC. Future studies of birabresib must consider intermittent scheduling to possibly mitigate the toxicities of chronic dosing.

Fluctuation Dynamics of Exchange Rates on Indian Financial Market

NASA Astrophysics Data System (ADS)

Sarkar, A.; Barat, P.

Here we investigate the scaling behavior and the complexity of the average daily exchange rate returns of the Indian Rupee against four foreign currencies namely US Dollar, Euro, Great Britain Pound and Japanese Yen. Our analysis revealed that the average daily exchange rate return of the Indian Rupee against the US Dollar exhibits a persistent scaling behavior and follow Levy stable distribution. On the contrary the average daily exchange rate returns of the other three foreign currencies show randomness and follow Gaussian distribution. Moreover, it is seen that the complexity of the average daily exchange rate return of the Indian Rupee against US Dollar is less than the other three exchange rate returns.

The use of paracetamol (acetaminophen) among a community sample of people with chronic non-cancer pain prescribed opioids.

PubMed

Hoban, B; Larance, B; Gisev, N; Nielsen, S; Cohen, M; Bruno, R; Shand, F; Lintzeris, N; Hall, W; Farrell, M; Degenhardt, L

2015-11-01

The regular use of simple analgesics in addition to opioids such as paracetamol (or acetaminophen) is recommended for persistent pain to enhance analgesia. Few studies have examined the frequency and doses of paracetamol among people with chronic non-cancer pain including use above the recommended maximum daily dose. To assess (i) the prevalence of paracetamol use among people with chronic non-cancer pain prescribed opioids, (ii) assess the prevalence of paracetamol use above the recommended maximum daily dose and (iii) assess correlates of people who used paracetamol above the recommended maximum daily dose including: age, gender, income, education, pain severity and interference, use of paracetamol/opioid combination analgesics, total opioid dose, depression, anxiety, pain self-efficacy or comorbid substance use, among people prescribed opioids for chronic non-cancer pain. This study draws on baseline data collected for the Pain and Opioids IN Treatment (POINT) study and utilises data from 962 interviews and medication diaries. The POINT study is national prospective cohort of people with chronic non-cancer pain prescribed opioids. Participants were recruited from randomly selected pharmacies across Australia. Sixty-three per cent of the participants had used paracetamol in the past week (95% CI = 59.7-65.8). Among the paracetamol users 22% (95% CI = 19.3-24.6) had used paracetamol/opioid combination analgesics and 4.8% (95% CI = 3.6-6.3) had used paracetamol above the recommended maximum daily dose (i.e. > 4000 mg/day). Following binomial logistic regression (χ(2) = 25.98, df = 10, p = 0.004), people who had taken above the recommended maximum daily dose were less likely to have low income (AOR = 0.52, 95% CI = 0.27-0.99), more likely to use paracetamol/opioid combination analgesics (AOR = 2.01, 95% CI = 1.02-3.98) and more likely to take a higher opioid dose (AOR = 1.00, 95% CI = 1.00-1.01). The majority of people with chronic non-cancer pain prescribed opioids report using paracetamol appropriately. High income, use of paracetamol/opioid combination analgesics and higher opioid dose were independently associated with paracetamol use above the recommended maximum daily dose. © 2015 John Wiley & Sons Ltd.

Twice-daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice-daily omeprazole, rabeprazole or lansoprazole.

PubMed

Sahara, S; Sugimoto, M; Uotani, T; Ichikawa, H; Yamade, M; Iwaizumi, M; Yamada, T; Osawa, S; Sugimoto, K; Umemura, K; Miyajima, H; Furuta, T

2013-11-01

Twice-daily dosing of proton pump inhibitors (PPIs) is used to treat Helicobacter pylori or acid-related diseases, such as gastro-oesophageal reflux disease (GERD) refractory to standard dose of a PPI. Genetic polymorphisms of CYP2C19 are involved to different extents in the metabolism of four kinds of PPIs (omeprazole, lansoprazole, rabeprazole and esomeprazole) available in Japan. To compare acid-inhibitory effects of the four PPIs dosed twice daily in relation to CYP2C19 genotype. We performed 24-h pH monitoring studies on Day 7 of PPI treatment for 40 Japanese H. pylori-negative volunteers [15 CYP2C19 rapid metabolisers (RMs), 15 intermediate metabolisers (IMs) and 10 poor metabolisers (PMs)] using a randomised four-way crossover design: omeprazole 20 mg, esomeprazole 20 mg, lansoprazole 30 mg and rabeprazole 10 mg twice daily. Although median pH values with esomeprazole, omeprazole, lansoprazole and rabeprazole were 5.7 (3.5-7.2), 5.5 (2.4-7.2), 5.5 (3.7-7.3) and 5.2 (2.5-7.3), respectively (no statistically significant differences), CYP2C19 genotype-dependent differences were smaller for esomeprazole and rabeprazole compared with values for omeprazole and lansoprazole. In CYP2C19 RMs, the median pH with esomeprazole [5.4 (3.5-6.8)] was significantly higher than those with omeprazole [5.0 (2.4-5.9), P = 0.018], lansoprazole [4.7 (3.7-5.5), P = 0.017] or rabeprazole [4.8 (2.5-6.4), P = 0.002]. In IMs and PMs, the median pH was >5.0 independent of the PPI. In intermediate and rapid metabolisers of CYP2C19, PPIs dosed twice daily could attain sufficient acid suppression, while in CYP2C19 RMs, esomeprazole 20 mg twice daily caused the strongest inhibition of the four PPIs. Therefore, esomeprazole may be effective in Japanese population when dosed twice daily. © 2013 John Wiley & Sons Ltd.

A Randomized Double-Blind, Placebo Controlled, Four-Arm Parallel Study Investigating the Effect of a Broad-Spectrum Wellness Beverage on Mood State in Healthy, Moderately Stressed Adults.

PubMed

Evans, Malkanthi; Antony, Joseph; Guthrie, Najla; Landes, Bernie; Aruoma, Okezie I

2018-01-01

The objective of this study was to investigate the effect of a broad-spectrum wellness beverage (Zeal Wellness [ZW]) on standardized measures of mood states, including overall feelings of vitality, in healthy, moderately stressed adults. A randomized, double-blind, placebo-controlled clinical trial was conducted among 99 eligible participants prescreened for moderate stress. Participants were randomized to one of four groups and received ZW once daily (1-dose-ZW; 14 g), ZW twice daily (2-dose-ZW; 28 g), placebo once daily (1-dose-placebo), or placebo twice daily (2-dose-placebo) for 4 weeks. A stress/vitality questionnaire assessed stress and the Profile of Moods (POMS) Questionnaire assessed vigor via mental/physical energy and global mood state. Safety was assessed by clinical chemistry, liver, kidney function, and anthropometric measures and adverse event reporting. Participants receiving 2-dose-ZW reported a 6.6% decrease in scores on POMS-Total Mood Disturbance (TMD; p < 0.05) and a 6.8% decrease in the anger-hostility mood state (p < 0.022) compared to the combined placebo group at day 29. The 2-dose-ZW provided a 12.8% greater improvement in POMS-TMD scores when compared to participants receiving 1-dose-ZW after 28 days of supplementation (p = 0.014). Within groups, there was a 22.4% and a 9.6% decrease in POMS-TMD scores in participants with 2-dose-ZW and 1-dose-ZW, respectively. In addition, participants receiving 2-dose-ZW showed significant improvements (p = 0.001) in the POMS t-score iceberg profile, which represented a shift to a more healthy profile. These data show that daily supplementation with 2-dose-ZW significantly decreased POMS-TMD scores and anger-hostility mood state and shifted the POMS iceberg profile to a healthy profile compared to the combined placebo, reflecting the functional benefit of rice-bran-fruit-vegetable extracts based beverage on health.

The efficacy and safety of weekly 35-mg risedronate dosing regimen for Chinese postmenopausal women with osteoporosis or osteopenia: 1-year data.

PubMed

Gu, Jie-mei; Wang, Li; Lin, Hua; Chen, De-cai; Tang, Hai; Jin, Xiao-lan; Xia, Wei-bo; Hu, Yun-qiu; Fu, Wen-zhen; He, Jin-wei; Zhang, Hao; Wang, Chun; Yue, Hua; Hu, Wei-wei; Liu, Yu-juan; Zhang, Zhen-lin

2015-07-01

Oral risedronate is effective in the treatment of postmenopausal osteoporosis when administered daily, weekly, or monthly. In this 1-year, randomized, double-blind, multicenter study we compared the weekly 35-mg and daily 5-mg risedronate dosing regimens in the treatment of Chinese postmenopausal women with osteoporosis or osteopenia. Postmenopausal women with primary osteoporosis or osteopenia were randomly assigned to the weekly group or daily group (n=145 for each) that received oral risedronate 35 mg once a week or 5 mg daily, respectively, for 1 year. The subjects' bone mineral densities (BMDs), bone turnover markers (P1NP and β-CTX), new vertebral fractures, and adverse events were assessed at baseline and during the treatments. All subjects in the weekly group and 144 subjects in the daily group completed the study. The primary efficacy endpoint after 1 year, ie the mean percent changes in the lumbar spine BMD (95% CI) were 4.87% (3.92% to 5.81%) for the weekly group and 4.35% (3.31% to 5.39%) for the daily group. The incidences of clinical adverse events were 48.3% in the weekly group and 54.2% in the daily group. The weekly 35-mg and daily 5-mg risedronate dosing regimens during 1 year of follow-up show similar efficacy in improving BMDs and biochemical markers of bone turnover in Chinese postmenopausal women with osteoporosis or osteopenia. Moreover, the two dosing regimens exhibit similar safety and tolerability.

Efficacy and safety of the CRTh2 antagonist AZD1981 as add-on therapy to inhaled corticosteroids and long-acting β2-agonists in patients with atopic asthma.

PubMed

Bateman, Eric D; O'Brien, Christopher; Rugman, Paul; Luke, Sally; Ivanov, Stefan; Uddin, Mohib

2018-01-01

To evaluate the efficacy and safety of AZD1981, a potent, specific antagonist of the CRTh2 receptor, as add-on therapy to inhaled corticosteroids (ICS) and long-acting β 2 -agonists (LABA), in patients with persistent asthma with an allergic component. In this placebo-controlled, parallel-group Phase IIb study, patients with persistent atopic asthma on ICS and LABA were randomized to receive 12 weeks of treatment with placebo or AZD1981 (80 mg daily, 200 mg daily, and 10 mg, 40 mg, 100 mg, or 400 mg twice daily [BID]). The primary end point was the mean change from baseline in predose, prebronchodilator forced expiratory volume in 1 second (FEV 1 ) averaged over weeks 2, 4, 8, and 12 in the AZD1981-treatment group vs the placebo group. Secondary end points included other measures of lung function, symptoms, and asthma control, as well as standard measures of safety. In total, 1,140 patients (99.7%) received study treatment. There were improvements in the primary end point across all treatment groups over 12 weeks of treatment. However, the improvement for the highest AZD1981 dose (400 mg BID) vs placebo was not statistically significant (0.02 L, P =0.58), preventing interpretation of statistical testing for the lower doses. AZD1981 was well tolerated, and the incidence of adverse events was comparable across placebo and treatment groups. In patients with allergic asthma receiving ICS and LABA therapy, the addition of AZD1981 at doses up to 400 mg BID failed to produce a clinically relevant improvement in lung function or any other measured end point, but appeared to have an acceptable safety profile. This clinical study is registered with ClinicalTrials.gov (NCT01197794).

Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal.

PubMed

Chapman, Kenneth R; Barnes, Neil C; Greening, Andrew P; Jones, Paul W; Pedersen, S

2010-08-01

The use of a combination inhaler containing budesonide and formoterol as both maintenance and quick relief therapy (SMART) has been recommended as an improved method of using inhaled corticosteroid/long-acting beta agonist (ICS/LABA) therapy. Published double-blind trials show that budesonide/formoterol therapy delivered in SMART fashion achieves better asthma outcomes than budesonide monotherapy or lower doses of budesonide/formoterol therapy delivered in constant dosage. Attempts to compare budesonide/formoterol SMART therapy with regular combination ICS/LABA dosing using other compounds have been confounded by a lack of blinding and unspecified dose adjustment strategies. The asthma control outcomes in SMART-treated patients are poor; it has been reported that only 17.1% of SMART-treated patients are controlled. In seven trials of 6-12 months duration, patients using SMART have used quick reliever daily (weighted average 0.92 inhalations/day), have awakened with asthma symptoms once every 7-10 days (weighted average 11.5% of nights), have suffered asthma symptoms more than half of days (weighted average 54.0% of days) and have had a severe exacerbation rate of one in five patients per year (weighted average 0.22 severe exacerbations/patient/year). These poor outcomes may reflect the recruitment of a skewed patient population. Although improvement from baseline has been attributed to these patients receiving additional ICS therapy at pivotal times, electronic monitoring has not been used to test this hypothesis nor the equally plausible hypothesis that patients who are non-compliant with maintenance medication have used budesonide/formoterol as needed for self-treatment of exacerbations. Although the long-term consequences of SMART therapy have not been studied, its use over 1 year has been associated with significant increases in sputum and biopsy eosinophilia. At present, there is no evidence that better asthma treatment outcomes can be obtained by moment-to-moment symptom-driven use of ICS/LABA therapy than conventional physician-monitored and adjusted ICS/LABA therapy.

Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study.

PubMed

Collaku, Agron; Yue, Yong; Reed, Kenneth

2017-01-01

Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

PubMed Central

Collaku, Agron; Yue, Yong; Reed, Kenneth

2017-01-01

Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

Baclofen for alcohol dependence: Relationships between baclofen and alcohol dosing and the occurrence of major sedation.

PubMed

Rolland, Benjamin; Labreuche, Julien; Duhamel, Alain; Deheul, Sylvie; Gautier, Sophie; Auffret, Marine; Pignon, Baptiste; Valin, Thomas; Bordet, Régis; Cottencin, Olivier

2015-10-01

High-dose baclofen, i.e., 300 mg/d or more, has recently emerged as a strategy for treating alcohol dependence. The impact that the co-exposure of large amounts of alcohol and baclofen has on sedation is unclear. In a prospective cohort of 253 subjects with alcohol dependence, we collected daily alcohol and baclofen doses across the first year of baclofen treatment and the monthly maximum subjective sedation experienced by each patient (0-10 visual analog scale). For each patient-month, we determined the average weekly alcohol consumption (AWAC; standard-drinks/week) and the maximum daily dose of baclofen (DDB; mg/d). The occurrence of an episode of major sedation (EMS) during a patient-month was defined as a sedation score ≥7. The relationship between the EMS occurrence and the concurrent AWAC and DDB was investigated using a generalized estimating equation model. In total, 1528 patient-months were compiled (70 with an EMS). Univariate analyses demonstrated that the rate of patient-month to EMS increased gradually with AWAC (p<0.001), from 0.9% for AWAC=0 to 9.4% for AWAC >35. There was also a significant gradual risk for EMS associated with DDB (<0.001). Multivariate analysis demonstrated a significant interaction between DDB and AWAC on EMS risk (p=0.047). Each 20mg/d increase in DDB was associated with an OR of EMS in AWAC >35 of 1.22 (95%CI, 1.08-1.38) versus 1.11 (95%CI, 0.96-1.29) in AWAC=1-35, and 0.95 (95%CI, 0.76-1.19) in AWAC=0. The level of sedation observed in patients using baclofen for alcohol dependence appears to directly depend on the immediate doses of both the baclofen and the alcohol. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Impact of aspartame and saccharin on the rat liver: Biochemical, molecular, and histological approach.

PubMed

Alkafafy, Mohamed El-Sayed; Ibrahim, Zein Shaban; Ahmed, Mohamed Mohamed; El-Shazly, Samir Ahmed

2015-06-01

The current work was undertaken to settle the debate about the toxicity of artificial sweeteners (AS), particularly aspartame and saccharin. Twenty-five, 7-week-old male Wistar albino rats with an average body weight of 101 ± 4.8 g were divided into a control group and four experimental groups (n = 5 rats). The first and second experimental groups received daily doses equivalent to the acceptable daily intake (ADI) of aspartame (250 mg/Kg BW) and four-fold ADI of aspartame (1000 mg/Kg BW). The third and fourth experimental groups received daily doses equivalent to ADI of saccharin (25 mg/Kg BW) and four-fold ADI of saccharin (100 mg/Kg BW). The experimental groups received the corresponding sweetener dissolved in water by oral route for 8 weeks. The activities of enzymes relevant to liver functions and antioxidants were measured in the blood plasma. Histological studies were used for the evaluation of the changes in the hepatic tissues. The gene expression levels of the key oncogene (h-Ras) and the tumor suppressor gene (P27) were also evaluated. In addition to a significant reduction in the body weight, the AS-treated groups displayed elevated enzymes activities, lowered antioxidants values, and histological changes reflecting the hepatotoxic effect of aspartame and saccharin. Moreover, the overexpression of the key oncogene (h-Ras) and the downregulation of the tumor suppressor gene (P27) in all treated rat groups may indicate a potential risk of liver carcinogenesis, particularly on long-term exposure. © The Author(s) 2015.

Fatigue Moderates the Relationship Between Perceived Stress and Suicidal Ideation: Evidence From Two High-Resolution Studies.

PubMed

Kleiman, Evan M; Turner, Brianna J; Chapman, Alexander L; Nock, Matthew K

2018-01-01

Theoretical models of self-harm suggest that high perceived stress and high fatigue (which might affect the ability to cope with stress) may interact to predict the short-term occurrence of suicidal ideation and nonsuicidal self-injury (NSSI). We tested 3 approaches to examining this interaction, each of which provided a different understanding of the specific nature of these associations: comparing each individual's daily stress/fatigue to the entire sample's overall average (i.e., grand-mean centering), comparing each individual's daily perceived stress/fatigue to his or her overall average (i.e., group- or participant-mean centering), and comparing each individual's average perceived stress/fatigue to the sample's overall average (i.e., centering participant means on overall grand mean). In 2 studies, adolescents (n = 30; 574 daily reports, M age = 17.3 years, range = 12-19; 87.6% female) and young adults (n = 60; 698 daily reports; M age = 23.25 years, range = 18-35; 85% female) completed daily measures of perceived stress, fatigue, suicidal ideation, and NSSI. In both samples, the interaction between high daily perceived stress and high daily fatigue predicted greater odds of daily suicidal ideation (but not NSSI). Only the model comparing each individual's daily stress/fatigue to the entire sample's overall average was consistently significant across the two studies. Participants were most likely to experience suicidal ideation on days when both perceived stress and fatigue were elevated relative to the average level experienced across people and time points. Studies should build upon these findings with more in-depth examination of the temporal nature of stability and change in these factors as they relate to sustained suicidal ideation.

Rivaroxaban in patients with a recent acute coronary syndrome.

PubMed

Mega, Jessica L; Braunwald, Eugene; Wiviott, Stephen D; Bassand, Jean-Pierre; Bhatt, Deepak L; Bode, Christoph; Burton, Paul; Cohen, Marc; Cook-Bruns, Nancy; Fox, Keith A A; Goto, Shinya; Murphy, Sabina A; Plotnikov, Alexei N; Schneider, David; Sun, Xiang; Verheugt, Freek W A; Gibson, C Michael

2012-01-05

Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).

Head and Neck Margin Reduction With Adaptive Radiation Therapy: Robustness of Treatment Plans Against Anatomy Changes

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

Kranen, Simon van; Hamming-Vrieze, Olga; Wolf, Annelisa

Purpose: We set out to investigate loss of target coverage from anatomy changes in head and neck cancer patients as a function of applied safety margins and to verify a cone beam computed tomography (CBCT)–based adaptive strategy with an average patient anatomy to overcome possible target underdosage. Methods and Materials: For 19 oropharyngeal cancer patients, volumetric modulated arc therapy treatment plans (2 arcs; simultaneous integrated boost, 70 and 54.25 Gy; 35 fractions) were automatically optimized with uniform clinical target volume (CTV)–to–planning target volume margins of 5, 3, and 0 mm. We applied b-spline CBCT–to–computed tomography (CT) deformable registration to allow recalculation ofmore » the dose on modified CT scans (planning CT deformed to daily CBCT following online positioning) and dose accumulation in the planning CT scan. Patients with deviations in primary or elective CTV coverage >2 Gy were identified as candidates for adaptive replanning. For these patients, a single adaptive intervention was simulated with an average anatomy from the first 10 fractions. Results: Margin reduction from 5 mm to 3 mm to 0 mm generally led to an organ-at-risk (OAR) mean dose (D{sub mean}) sparing of approximately 1 Gy/mm. CTV shrinkage was mainly seen in the elective volumes (up to 10%), likely related to weight loss. Despite online repositioning, substantial systematic errors were present (>3 mm) in lymph node CTV, the parotid glands, and the larynx. Nevertheless, the average increase in OAR dose was small: maximum of 1.2 Gy (parotid glands, D{sub mean}) for all applied margins. Loss of CTV coverage >2 Gy was found in 1, 3, and 7 of 73 CTVs, respectively. Adaptive intervention in 0-mm plans substantially improved coverage: in 5 of 7 CTVs (in 6 patients) to <2 Gy of initially planned. Conclusions: Volumetric modulated arc therapy head and neck cancer treatment plans with 5-mm margins are robust for anatomy changes and show a modest increase in OAR dose. Margin reduction improves OAR sparing with approximately 1 Gy/mm at the expense of target coverage in a subgroup of patients. Patients at risk of CTV underdosage >2 Gy in 0-mm plans may be identified early in treatment using dose accumulation. A single intervention with an average anatomy derived from CBCT effectively mitigates discrepancies.« less

Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC.

PubMed

Karschner, Erin L; Schwope, David M; Schwilke, Eugene W; Goodwin, Robert S; Kelly, Deanna L; Gorelick, David A; Huestis, Marilyn A

2012-10-01

Determining time since last cannabis/Δ9-tetrahydrocannabinol (THC) exposure is important in clinical, workplace, and forensic settings. Mathematical models calculating time of last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing. Ten male chronic, daily cannabis smokers received escalating around-the-clock oral THC (40-120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by two-dimensional gas chromatography-mass spectrometry. Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5h (4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n=196), 11-hydroxy-THC 0.60 (n=189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n=200). Predictive models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100% of specimens collected within 1-5h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5h after the last THC dose, respectively. Predictive models estimating time since last cannabis intake from whole blood and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate during active THC dosing. THC redistribution from large cannabinoid body stores and high circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less than daily cannabis smokers that were used to derive the models. Thus, the models do not accurately predict time of last THC intake in individuals consuming THC daily. Published by Elsevier Ireland Ltd.

Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population.

PubMed

Stumpf, Janice L; Skyles, Amy J; Alaniz, Cesar; Erickson, Steven R

2007-01-01

To evaluate the knowledge of appropriate doses and potential toxicities of acetaminophen and assess the ability to recognize products containing acetaminophen in an adult outpatient setting. Cross-sectional, prospective study. University adult general internal medicine (AGIM) clinic. 104 adult patients presenting to the clinic over consecutive weekdays in December 2003. Three-page, written questionnaire. Ability of patients to identify maximum daily doses and potential toxicities of acetaminophen and recognize products that contain acetaminophen. A large percentage of participants (68.3%) reported pain on a daily or weekly basis, and 78.9% reported use of acetaminophen in the past 6 months. Only 2 patients correctly identified the maximum daily dose of regular acetaminophen, and just 3 correctly identified the maximum dose of extra-strength acetaminophen. Furthermore, 28 patients were unsure of the maximum dose of either product. Approximately 63% of participants either had not received or were unsure whether information on the possible danger of high doses of acetaminophen had been previously provided to them. When asked to identify potential problems associated with high doses of acetaminophen, 43.3% of patients noted the liver would be affected. The majority of the patients (71.2%) recognized Tylenol as containing acetaminophen, but fewer than 15% correctly identified Vicodin, Darvocet, Tylox, Percocet, and Lorcet as containing acetaminophen. Although nearly 80% of this AGIM population reported recent acetaminophen use, their knowledge of the maximum daily acetaminophen doses and potential toxicities associated with higher doses was poor and appeared to be independent of education level, age, and race. This indicates a need for educational efforts to all patients receiving acetaminophen-containing products, especially since the ability to recognize multi-ingredient products containing acetaminophen was likewise poor.

Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects

PubMed Central

Frost, Charles; Nepal, Sunil; Wang, Jessie; Schuster, Alan; Byon, Wonkyung; Boyd, Rebecca A; Yu, Zhigang; Shenker, Andrew; Barrett, Yu Chen; Mosqueda-Garcia, Rogelio; LaCreta, Frank

2013-01-01

Aim Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. Method This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily– with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). Results Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3–1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile. Conclusion Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures. PMID:23451769

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection.

PubMed

Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van't Klooster, Gerben

2015-08-01

Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.

Compliance, clinical outcome, and quality of life of patients with stable angina pectoris receiving once-daily betaxolol versus twice daily metoprolol: a randomized controlled trial

PubMed Central

Kardas, Przemyslaw

2007-01-01

Background A randomized, controlled trial was conducted in an outpatient setting to examine the effect of beta-blocker dosing frequency on patient compliance, clinical outcome, and health-related quality of life in patients with stable angina pectoris. Methods One hundred and twelve beta-blockers-naive outpatients with stable angina pectoris were randomized to receive betaxolol, 20 mg once daily or metoprolol tartrate, 50 mg twice daily for 8 weeks. The principal outcome measure was overall compliance measured electronically, whereas secondary outcome measures were drug effectiveness and health-related quality of life. Results The overall compliance was 86.5 ± 21.3% in the betaxolol group versus 76.1 ± 26.3% in the metoprolol group (p < 0.01), and the correct number of doses was taken on 84.4 ± 21.6% and 64.0 ± 31.7% of treatment days, respectively (p < 0.0001). The percentage of missed doses was 14.5 ± 21.5% in the once-daily group and 24.8 ± 26.4% in the twice-daily group (p < 0.01). The percentage of doses taken in the correct time window (58.6% vs 42.0%, p = 0.01), correct interdose intervals (77.4% v 53.1%, p < 0.0001), and therapeutic coverage (85.6% vs 73.7%, p < 0.001) were significantly higher in the once-daily group. Both studied drugs had similar antianginal effectiveness. Health-related quality of life improved in both groups, but this increase was more pronounced in the betaxolol arm in some dimensions. Conclusions The study demonstrates that patient compliance with once-daily betaxolol is significantly better than with twice daily metoprolol. Similarly, this treatment provides better quality of life. These results demonstrate possible therapeutic advantages of once-daily over twice-daily beta-blockers in the treatment of stable angina pectoris. PMID:17580734

A phase I study of LY317615 (enzastaurin) and temozolomide in patients with gliomas (EORTC trial 26054)

PubMed Central

Rampling, Roy; Sanson, Marc; Gorlia, Thiery; Lacombe, Denis; Lai, Christina; Gharib, Myriam; Taal, Walter; Stoffregen, Clemens; Decker, Rodney; van den Bent, Martin J.

2012-01-01

We report a phase 1 study to examine the safety and recommended dose of the oral protein kinase C-beta inhibitor (anti-angiogenic) enzastaurin in combination with single-agent temozolomide. The study was conducted in patients with recurrent glioblastoma or newly diagnosed disease that was not treatable with standard (chemo)radiotherapy. Patients were treated with standard dose temozolomide (200 mg/m2 for 5 days every 4 weeks) together with daily oral enzastaurin. Three dose levels of enzastaurin were investigated: 250 mg daily (OD), 500 mg OD, and 250 mg twice daily (BID). Dose-limiting toxicity was determined in the first 2 cycles, but treatment continued until limiting toxicity or disease progression was identified. Twenty-eight patients were enrolled. No dose-limiting toxicity was noted at 250 mg OD or 500 mg OD. However, at 250 mg BID, 2 dose-limiting episodes of thrombocytopenia were noted. The recommended dose for enzastaurin in combination with standard 4-weekly temozolomide is therefore 500 mg OD. The pharmacokinetics of enzastaurin in combination with temozolomide was evaluated. Temozolomide did not appear to effect enzastaurin exposures at the 250 mg or 500 mg OD dose levels. PMID:22291006

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

PubMed

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

2018-06-01

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

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

Brock, K; Lee, C; Samuels, S

Purpose: Tools are now available to perform daily dose assessment in radiotherapy, however, guidance is lacking as to when to replan to limit increase in normal tissue dose. This work performs statistical analysis to provide guidance for when adaptive replanning may be necessary for head/neck (HN) patients. Methods: Planning CT and daily kVCBCT images for 50 HN patients treated with VMAT were retrospectively evaluated. Twelve of 50 patients were replanned due to anatomical changes noted over their RT course. Daily dose assessment was performed to calculate the variation between the planned and delivered dose for the 38 patients not replannedmore » and the patients replanned using their delivered plan. In addition, for the replanned patients, the dose that would have been delivered if the plan was not modified was also quantified. Deviations in dose were analyzed before and after replanning, the daily variations in patients who were not replanned assessed, and the predictive power of the deviation after 1, 5, and 15 fractions determined. Results: Dose deviations were significantly reduced following replanning, compared to if the original plan would have been delivered for the entire course. Early deviations were significantly correlated with total deviations (p<0.01). Using the criteria that a 10% increase in the final delivered dose indicates a replan may be needed earlier in the treatment course, the following guidelines can be made with a 90% specificity after the first 5 fractions: deviations of 7% in the mean dose to the inferior constrictors and 5% in the mean dose to the parotid glands and submandibular glands. No significant dose deviations were observed in any patients for the CTV -70Gy (max deviation 4%). Conclusions: A 5–7% increase in mean dose to normal tissues within the first 5 fractions strongly correlate to an overall deviatios in the delivered dose for HN patients. This work is funded in part by NIH 2P01CA059827-16.« less

Dosimetric and radiobiological consequences of computed tomography-guided adaptive strategies for intensity modulated radiation therapy of the prostate.

PubMed

Battista, Jerry J; Johnson, Carol; Turnbull, David; Kempe, Jeff; Bzdusek, Karl; Van Dyk, Jacob; Bauman, Glenn

2013-12-01

To examine a range of scenarios for image-guided adaptive radiation therapy of prostate cancer, including different schedules for megavoltage CT imaging, patient repositioning, and dose replanning. We simulated multifraction dose distributions with deformable registration using 35 sets of megavoltage CT scans of 13 patients. We computed cumulative dose-volume histograms, from which tumor control probabilities and normal tissue complication probabilities (NTCPs) for rectum were calculated. Five-field intensity modulated radiation therapy (IMRT) with 18-MV x-rays was planned to achieve an isocentric dose of 76 Gy to the clinical target volume (CTV). The differences between D95, tumor control probability, V70Gy, and NTCP for rectum, for accumulated versus planned dose distributions, were compared for different target volume sizes, margins, and adaptive strategies. The CTV D95 for IMRT treatment plans, averaged over 13 patients, was 75.2 Gy. Using the largest CTV margins (10/7 mm), the D95 values accumulated over 35 fractions were within 2% of the planned value, regardless of the adaptive strategy used. For tighter margins (5 mm), the average D95 values dropped to approximately 73.0 Gy even with frequent repositioning, and daily replanning was necessary to correct this deficit. When personalized margins were applied to an adaptive CTV derived from the first 6 treatment fractions using the STAPLE (Simultaneous Truth and Performance Level Estimation) algorithm, target coverage could be maintained using a single replan 1 week into therapy. For all approaches, normal tissue parameters (rectum V(70Gy) and NTCP) remained within acceptable limits. The frequency of adaptive interventions depends on the size of the CTV combined with target margins used during IMRT optimization. The application of adaptive target margins (<5 mm) to an adaptive CTV determined 1 week into therapy minimizes the need for subsequent dose replanning. Copyright © 2013 Elsevier Inc. All rights reserved.

Safety of prolonged high-dose levofloxacin therapy for bone infections.

PubMed

Senneville, E; Poissy, J; Legout, L; Dehecq, C; Loïez, C; Valette, M; Beltrand, E; Caillaux, M; Mouton, Y; Migaud, H; Yazdanpanah, Y

2007-12-01

The records of 84 patients with bone infections treated with high-dose levofloxacin (i.e. 0.75-1g daily) for more than 4 weeks were reviewed. Patients were given either 500 mg b.i.d. throughout the treatment period [Group 1 (n=41)], 500 mg b.i.d. for 3 weeks and then 750 mg q.d. [Group 2 (n=21)] or 750 mg q.d. for the whole treatment period [Group 3 (n=22)]. All patients had combined therapy, including levofloxacin-rifampin in 62 cases (73.8%), for an average duration of 13.7 weeks. Muscular pain and/or tendonitis were reported in 19 patients (22.6%) which affected more patients in Groups 1 and 2 than in Group 3 (14/41 and 5/21 vs. 0/22; p=0.01 and 0.001, respectively). A dosage of 750 mg q.d. may be warranted for prolonged high-dose levofloxacin treatment in patients with bone infections rather than 500 mg b.i.d. for the entire duration of treatment, or for the first 3 weeks.

Methylenetetrahydrofolate reductase gene haplotypes affect toxicity during maintenance therapy for childhood acute lymphoblastic leukemia in Japanese patients.

PubMed

Tanaka, Yoichi; Manabe, Atsushi; Nakadate, Hisaya; Kondoh, Kensuke; Nakamura, Kozue; Koh, Katsuyoshi; Kikuchi, Akira; Komiyama, Takako

2014-05-01

Abstract The aim of this study was to investigate the influence of daily 6-mercaptopurine (6-MP) and low-dose weekly methotrexate (MTX) combination treatment and methylenetetrahydrofolate reductase (MTHFR) haplotypes on toxicity during maintenance therapy in Japanese childhood acute lymphoblastic leukemia (ALL). We retrospectively analyzed the MTHFR C677T and A1298C polymorphisms and influence of haplotypes on toxicity in 73 patients. Patients with the MTHFR 677TT and 677CT + 1298AC were associated with severe liver toxicity (p = 0.014, odds ratio [OR] = 3.82, 95% confidence interval [CI] = 1.27-11.46) and more rapid onset of liver toxicity (p = 0.010). Patients with MTHFR 677TT and 677CT + 1298AC were associated with lower frequency of 6-MP and MTX dose reduction due to leukopenia (p < 0.05). No difference was observed in average drug doses in the MTHFR genotypes. In conclusion, the MTHFR C677T and A1298C haplotypes might be useful for monitoring adverse effects in childhood ALL maintenance therapy in Japanese patients.

Intermittent minodronic acid treatment with sufficient bone resorption inhibition prevents reduction in bone mass and strength in ovariectomized rats with established osteopenia comparable with daily treatment.

PubMed

Kimoto, Aishi; Tanaka, Makoto; Nozaki, Kazutoshi; Mori, Masamichi; Fukushima, Shinji; Mori, Hiroshi; Shiroya, Tsutomu; Nakamura, Toshitaka

2013-07-01

This study examined and compared the effects of four-week intermittent and daily administrations of minodronic acid, a highly potent nitrogen-containing bisphosphonate, on bone mineral density (BMD), bone strength, bone turnover, and histomorphometry on established osteopenia in ovariectomized (OVX) rats. Fourteen-week-old female F344 rats were OVX or sham-operated. At 12 weeks post surgery, minodronic acid was orally administered once every 4 weeks at 0.2, 1, and 5 mg/kg and once daily at 0.006, 0.03, and 0.15 mg/kg for 12 months. The total dosing amount was comparable between the two dosing regimens. The levels of urinary deoxypyridinoline and serum osteocalcin were measured to assess bone turnover. BMD as assessed via dual-energy X-ray absorptiometry, bone structure and dynamical changes in vertebral trabecula and biomechanical properties were measured ex vivo at 12 months to assess bone content and material properties. Minodronic acid dose-dependently ameliorated the decrease in BMD of lumbar vertebrae and the femur in both treatment regimens similarly. Minodronic acid suppressed elevated urinary levels of deoxypyridinoline, a bone resorption marker, and reduced the serum levels of osteocalcin, a bone formation marker. In the mechanical test at 12 months of treatment, minodronic acid dose-dependently ameliorated the reduction in bone strength in femur and vertebral body. There is no significant difference in parameters between the two regimens except maximal load of lower doses in lumbar vertebral body and absorption energy of middle doses in femur. With these parameters with significant differences, values of the intermittent regimen were significantly lower than that of daily repeated regimen. Bone histomorphometric analysis of the lumbar vertebral body showed that minodronic acid significantly ameliorated the decrease in bone mass, trabecular thickness and number, and the increase in trabecular separation, bone resorption indices (Oc.S/BS and N.Oc/BS), and bone formation indices (BFR/BS, MAR and OV/BV) in both regimens. Minodronic acid suppressed OVX-induced increases in bone turnover at the tissue level and ameliorated all structural indices, thereby improving the deterioration of bone quality under osteoporotic disease conditions regardless of the regimen. In conclusion, a four-week intermittent treatment of minodronic acid suppressed increased bone resorption as daily treatment when considering the total administered dose in OVX rats with established osteopenia. The improvement of microarchitectural destruction in low dose of intermittent treatment was weaker than that observed in a daily repeated regimen; however the effects of high and middle doses of intermittent treatment were equivalent to that observed in daily repeated regimen accompanied by sufficient bone resorption inhibition in rats. These findings suggest that minodronic acid at an appropriate dose in an intermittent regimen may be as clinically useful in osteoporosis therapy as in daily treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

SU-C-202-05: Pilot Study of Online Treatment Evaluation and Adaptive Re-Planning for Laryngeal SBRT

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

Mao, W; Henry Ford Health System, Detroit, MI; Liu, C

Purpose: We have instigated a phase I trial of 5-fraction stereotactic body radiotherapy (SBRT) for advanced-stage laryngeal cancer. We conducted this pilot dosimetric study to confirm the potential utility of online adaptive re-planning to preserve treatment quality. Methods: Ten cases of larynx cancer were evaluated. Baseline and daily SBRT treatment plans were generated per trial protocol. Daily volumetric images were acquired prior to every fraction of treatment. Reference simulation CT images were deformably registered to daily volumetric images using Eclipse. Planning contours were then deformably propagated to daily images. Reference SBRT plans were directly copied to calculate delivered dose distributionsmore » on deformed reference CT images. In-house software platform has been developed to calculate cumulative dose over a course of treatment in four steps: 1) deforming delivered dose grid to reference CT images using deformation information exported from Eclipse; 2) generating tetrahedrons using deformed dose grid as vertices; 3) resampling dose to a high resolution within every tetrahedron; 4) calculating dose-volume histograms. Our inhouse software was benchmarked with a commercial software, Mirada. Results: In all ten cases including 49 fractions of treatments, delivered daily doses were completely evaluated and treatment could be re-planned within 10 minutes. Prescription dose coverage of PTV was less than intended in 53% of fractions of treatment (mean: 94%, range: 84%–98%) while minimum coverage of CTV and GTV was 94% and 97%, respectively. Maximum bystander point dose limits to arytenoids, parotids, and spinal cord remained respected in all cases, although variances in carotid artery doses were observed in a minority of cases. Conclusion: Although GTV and CTV coverage is preserved by in-room 3D image guidance of larynx SBRT, PTV coverage can vary significantly from intended plans. Online adaptive treatment evaluation and re-planning is potentially necessary and our procedure is clinically applicable to fully preserve treatment quality. This project is supported by CPRIT Individual Investigator Research Award RP150386.« less

Contribution of time-activity pattern and microenvironment to black carbon (BC) inhalation exposure and potential internal dose among elementary school children

NASA Astrophysics Data System (ADS)

Jeong, Hyeran; Park, Donguk

2017-09-01

The aims of this study were to quantify the contributions of activities or microenvironments (MEs) to daily total exposure to and potential dose of black carbon (BC). Daily BC exposures (24-h) were monitored using a micro-aethalometer micoAeth AE51 with forty school-aged children living in an urban area in Korea from August 2015 to January 2016. The children's time-activity patterns and the MEs they visited were investigated by means of a time-activity diary (TAD) and follow-up interviews with the children and their parents. Potential inhaled dose was estimated by multiplying the airborne BC concentrations (μg/m3) we monitored for the time the children spent in a particular ME by the inhalation rate (IR, m3/h) for the time-activity performed. The contribution of activities and MEs to overall daily exposure to and potential dose of BC was quantified. Overall mean daily potential dose was equal to 24.1 ± 10.6 μg/day (range: 6.6-46.3 μg/day). The largest contribution to BC exposure and potential dose (51.9% and 41.7% respectively) occurred in the home thanks to the large amount of time spent there. Transportation was where children received the most intense exposure to (14.8%) and potential dose (20.2%) of BC, while it accounted for 7.6% of daily time. School on weekdays during the semester was responsible for 20.3% of exposure and 22.5% of potential dose. Contribution to BC exposure and potential dose was altered by several time-activity parameters, such as type of day (weekdays vs. weekends; school days vs. holidays), season, and gender. Traveling by motor vehicle and subway showed more elevated exposure or potential dose intensity on weekdays or school days, probably influenced by the increased surrounding traffic volumes on these days compared to on weekends or holidays. This study may be used to prioritize targets for minimizing children's exposure to BC and to indicate outcomes of BC control strategies.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia.

PubMed

Rafii, Michael S; Skotko, Brian G; McDonough, Mary Ellen; Pulsifer, Margaret; Evans, Casey; Doran, Eric; Muranevici, Gabriela; Kesslak, Patrick; Abushakra, Susan; Lott, Ira T

2017-01-01

ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer's disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia

PubMed Central

Rafii, Michael S.; Skotko, Brian G.; McDonough, Mary Ellen; Pulsifer, Margaret; Evans, Casey; Doran, Eric; Muranevici, Gabriela; Kesslak, Patrick; Abushakra, Susan; Lott, Ira T.

2018-01-01

Background ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer’s disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. Objective To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. Methods This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase 2 study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2:1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. Results There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram (ECG) results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Conclusion Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy. PMID:28453471

Initiatives to improve prescribing efficiency for drugs to treat Parkinson's disease in Croatia: influence and future directions.

PubMed

Brkicic, Ljiljana Sovic; Godman, Brian; Voncina, Luka; Sovic, Slavica; Relja, Maja

2012-06-01

Parkinson's disease (PD) is the second most common neurological disease affecting older adults. Consequently, this disease should be a focus among payers, with increasing utilization of newer premium-priced patent-protected add-on therapies to stabilize or even improve motor function over time. However, expenditure can be moderated by reforms. Consequently, there is a need to assess the influence of these reforms on the prescribing efficiency for drugs to treat PD in Croatia before proposing additional measures. Prescribing efficiency is defined as increasing the use of add-on therapies for similar expenditure. An observational retrospective study of the Croatian Institute for Health Insurance database of drugs to treat patients with PD in Croatia from 2000 to 2010 was carried out, with utilization measured in defined daily doses (defined as the average maintenance dose of a drug when used in its major indication in adults). The study years were chosen to reflect recent reforms. Only reimbursed expenditure is measured from a health insurance perspective. Utilization of drugs to treat PD increased by 218% between 2000 and 2010. Reimbursed expenditure increased by 360%, principally driven by increasing utilization of premium-priced patent-protected add-on therapies, including ropinirole and pramipexole. However, following recent reforms, reducing expenditure/defined daily dose for the different drugs, as well as overall expenditure, stabilized reimbursed expenditure between 2005 and 2010. Treatment of PD is complex, and add-on therapies are needed to improve care. Reimbursed expenditure should now fall following stabilization, despite increasing volumes, as successive add-on therapies lose their patents, further increasing prescribing efficiency.

Evaluation of an every-other-day palonosetron schedule to control emesis in multiple-day high-dose chemotherapy.

PubMed

Mirabile, Aurora; Celio, Luigi; Magni, Michele; Bonizzoni, Erminio; Gianni, Alessandro Massimo; Di Nicola, Massimo

2014-12-01

Efficacy of intermittent palonosetron dosing in patients undergoing multiple-day, high-dose chemotherapy (HDC) was investigated. Fifty-eight patients received palonosetron (0.25 mg intravenous [iv.]) every other day plus daily dexamethasone (8 mg iv. twice daily) dosing. The primary end point was complete control (CC; no emesis, no rescue anti-emetics, and no more than mild nausea) in the overall acute-period (until 24 h after chemotherapy completion). Acute-period CC occurred in 81% and 50% of patients receiving palonosetron and ondansetron (historical control cohort), respectively. Palonosetron (odds ratio [OR]: 4.37; p = 0.001) and a longer duration of HDC regimen (OR: 3.47; p = 0.011) independently predicted a better anti-emetic outcome. Palonosetron every other day plus daily dexamethasone is an effective anti-emetic coverage in patients undergoing HDC.

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.

PubMed

Feagan, Brian G; Macdonald, John K

2012-10-17

Oral 5-aminosalicylic acid (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5-ASA drugs in doses of at least 2 g/day, were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis. This updated review includes more recent studies and evaluates the efficacy and safety of 5-ASA preparations used for the treatment of mild to moderately active ulcerative colitis. The primary objectives were to assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for induction of remission in active ulcerative colitis. A secondary objective of this systematic review was to compare the efficacy and safety of once daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens. A computer-assisted literature search for relevant studies (inception to January 20, 2012) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies. Studies were accepted for analysis if they were randomized controlled clinical trials of parallel design, with a minimum treatment duration of four weeks. Studies of oral 5-ASA therapy for treatment of patients with active ulcerative colitis compared with placebo, SASP or other formulations of 5-ASA were considered for inclusion. Studies that compared once daily 5-ASA treatment with conventional dosing of 5-ASA (two or three times daily) and 5-ASA dose ranging studies were also considered for inclusion. The outcomes of interest were the failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5-ASA versus comparator 5-ASA, and 5-ASA dose-ranging. Placebo-controlled trials were subgrouped by dosage. SASP-controlled trials were subgrouped by 5-ASA/SASP mass ratios. Once daily versus conventional dosing studies were subgrouped by formulation. 5-ASA-controlled trials were subgrouped by common 5-ASA comparators (e.g. Asacol, Claversal, Salofalk and Pentasa). Dose-ranging studies were subgrouped by 5-ASA formulation. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention to treat basis. Forty-eight studies (7776 patients) were included. The majority of included studies were rated as low risk of bias. 5-ASA was significantly superior to placebo with regard to all measured outcome variables. Seventy-two per cent of 5-ASA patients failed to enter clinical remission compared to 85% of placebo patients (RR 0.86, 95% CI 0.81 to 0.91). A dose-response trend for 5-ASA was also observed. No statistically significant differences in efficacy were found between 5-ASA and SASP. Fifty-four per cent of 5-ASA patients failed to enter remission compared to 58% of SASP patients (RR 0.90, 95% CI 0.77 to 1.04). No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Forty-two per cent of once daily patients failed to enter clinical remission compared to 44% of conventionally dosed patients (RR 0.95, 95% CI 0.82 to 1.10). Eight per cent of patients dosed once daily failed to adhere to their medication regimen compared to 6% of conventionally dosed patients (RR 1.36, 95% CI 0.64 to 2.86). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Forty-eight per cent of patients in the 5-ASA group failed to enter remission compared to 50% of patients in the 5-ASA comparator group (RR 0.94, 95% CI 0.86 to 1.03). A pooled analysis of the ASCEND (I, II and III, n = 1459 patients) studies found no statistically significant difference in clinical improvement between Asacol 4.8 g/day and 2.4 g/day used for the treatment of moderately active ulcerative colitis. Thirty-seven per cent of patients in the 4.8 g/day group failed to improve clinically compared to 41% of patients in the 2.4 g/day group (RR 0.89; 95% CI 0.78 to 1.01). Subgroup analysis indicated that patients with moderate disease may benefit from the higher dose of 4.8 g/day. One study compared (n = 123 patients) Pentasa 4 g/day to 2.25 g/day in patients with moderate disease. Twenty-five per cent of patients in the 4 g/day group failed to improve clinically compared to 57% of patients in the 2.25 g/day group (RR 0.44; 95% CI 0.27 to 0.71). A pooled analysis of two studies comparing MMX mesalamine 4.8 g/day to 2.4 g/day found no statistically significant difference in efficacy (RR 1.03, 95% CI 0.82 to 1.29). 5-ASA was generally safe and common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening ulcerative colitis. There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulation and 5-ASA dose ranging (high dose versus low dose) studies. SASP was not as well tolerated as 5-ASA. Twenty-nine percent of SASP patients experienced an adverse event compared to 15% of 5-ASA patients (RR 0.48, 95% CI 0.37 to 0.63). 5-ASA was superior to placebo and no more effective than SASP. Considering their relative costs, a clinical advantage to using oral 5-ASA in place of SASP appears unlikely. 5-ASA dosed once daily appears to be as efficacious and safe as conventionally dosed 5-ASA. Adherence does not appear to be enhanced by once daily dosing in the clinical trial setting. It is unknown if once daily dosing of 5-ASA improves adherence in a community-based setting. There do not appear to be any differences in efficacy or safety among the various 5-ASA formulations. A daily dosage of 2.4 g appears to be a safe and effective induction therapy for patients with mild to moderately active ulcerative colitis. Patients with moderate disease may benefit from an initial dose of 4.8 g/day.

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.

PubMed

Wang, Yongjun; Parker, Claire E; Bhanji, Tania; Feagan, Brian G; MacDonald, John K

2016-04-21

Oral 5-aminosalicylic acid (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5-ASA drugs in doses of at least 2 g/day, were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis. This updated review includes more recent studies and evaluates the efficacy and safety of 5-ASA preparations used for the treatment of mild to moderately active ulcerative colitis. The primary objectives were to assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for induction of remission in active ulcerative colitis. A secondary objective of this systematic review was to compare the efficacy and safety of once daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens. A computer-assisted literature search for relevant studies (inception to July 9, 2015) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies. Studies were accepted for analysis if they were randomized controlled clinical trials of parallel design, with a minimum treatment duration of four weeks. Studies of oral 5-ASA therapy for treatment of patients with active ulcerative colitis compared with placebo, SASP or other formulations of 5-ASA were considered for inclusion. Studies that compared once daily 5-ASA treatment with conventional dosing of 5-ASA (two or three times daily) and 5-ASA dose ranging studies were also considered for inclusion. The outcomes of interest were the failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5-ASA versus comparator 5-ASA, and 5-ASA dose-ranging. Placebo-controlled trials were subgrouped by dosage. SASP-controlled trials were subgrouped by 5-ASA/SASP mass ratios. Once daily versus conventional dosing studies were subgrouped by formulation. 5-ASA-controlled trials were subgrouped by common 5-ASA comparators (e.g. Asacol, Claversal, Salofalk and Pentasa). Dose-ranging studies were subgrouped by 5-ASA formulation. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis. Fifty-three studies (8548 patients) were included. The majority of included studies were rated as low risk of bias. 5-ASA was significantly superior to placebo with regard to all measured outcome variables. Seventy-one per cent of 5-ASA patients failed to enter clinical remission compared to 83% of placebo patients (RR 0.86, 95% CI 0.82 to 0.89). A dose-response trend for 5-ASA was also observed. No statistically significant differences in efficacy were found between 5-ASA and SASP. Fifty-four per cent of 5-ASA patients failed to enter remission compared to 58% of SASP patients (RR 0.90, 95% CI 0.77 to 1.04). No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Forty-five per cent of once daily patients failed to enter clinical remission compared to 48% of conventionally dosed patients (RR 0.94, 95% CI 0.83 to 1.07). Eight per cent of patients dosed once daily failed to adhere to their medication regimen compared to 6% of conventionally dosed patients (RR 1.36, 95% CI 0.64 to 2.86). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Fifty per cent of patients in the 5-ASA group failed to enter remission compared to 52% of patients in the 5-ASA comparator group (RR 0.94, 95% CI 0.86 to 1.02). A pooled analysis of 3 studies (n = 1459 patients) studies found no statistically significant difference in clinical improvement between Asacol 4.8 g/day and 2.4 g/day used for the treatment of moderately active ulcerative colitis. Thirty-seven per cent of patients in the 4.8 g/day group failed to improve clinically compared to 41% of patients in the 2.4 g/day group (RR 0.89; 95% CI 0.78 to 1.01). Subgroup analysis indicated that patients with moderate disease may benefit from the higher dose of 4.8 g/day. One study compared (n = 123 patients) Pentasa 4 g/day to 2.25 g/day in patients with moderate disease. Twenty-five per cent of patients in the 4 g/day group failed to improve clinically compared to 57% of patients in the 2.25 g/day group (RR 0.44; 95% CI 0.27 to 0.71). A pooled analysis of two studies comparing MMX mesalamine 4.8 g/day to 2.4 g/day found no statistically significant difference in efficacy (RR 1.03, 95% CI 0.82 to 1.29). There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulation and 5-ASA dose ranging (high dose versus low dose) studies. Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening ulcerative colitis. SASP was not as well tolerated as 5-ASA. Twenty-nine percent of SASP patients experienced an adverse event compared to 15% of 5-ASA patients (RR 0.48, 95% CI 0.37 to 0.63). 5-ASA was superior to placebo and no more effective than SASP. Considering their relative costs, a clinical advantage to using oral 5-ASA in place of SASP appears unlikely. 5-ASA dosed once daily appears to be as efficacious and safe as conventionally dosed 5-ASA. Adherence does not appear to be enhanced by once daily dosing in the clinical trial setting. It is unknown if once daily dosing of 5-ASA improves adherence in a community-based setting. There do not appear to be any differences in efficacy or safety among the various 5-ASA formulations. A daily dosage of 2.4 g appears to be a safe and effective induction therapy for patients with mild to moderately active ulcerative colitis. Patients with moderate disease may benefit from an initial dose of 4.8 g/day.

Cost-effectiveness of allopurinol and febuxostat for the management of gout.

PubMed

Jutkowitz, Eric; Choi, Hyon K; Pizzi, Laura T; Kuntz, Karen M

2014-11-04

Gout is the most common inflammatory arthritis in the United States. To evaluate the cost-effectiveness of urate-lowering treatment strategies for the management of gout. Markov model. Published literature and expert opinion. Patients for whom allopurinol or febuxostat is a suitable initial urate-lowering treatment. Lifetime. Health care payer. 5 urate-lowering treatment strategies were evaluated: no treatment; allopurinol- or febuxostat-only therapy; allopurinol-febuxostat sequential therapy; and febuxostat-allopurinol sequential therapy. Two dosing scenarios were investigated: fixed dose (80 mg of febuxostat daily, 0.80 success rate; 300 mg of allopurinol daily, 0.39 success rate) and dose escalation (≤120 mg of febuxostat daily, 0.82 success rate; ≤800 mg of allopurinol daily, 0.78 success rate). Discounted costs, discounted quality-adjusted life-years, and incremental cost-effectiveness ratios. In both dosing scenarios, allopurinol-only therapy was cost-saving. Dose-escalation allopurinol-febuxostat sequential therapy was more costly but more effective than dose-escalation allopurinol therapy, with an incremental cost-effectiveness ratio of $39 400 per quality-adjusted life-year. The relative rankings of treatments did not change. Our results were relatively sensitive to several potential variations of model assumptions; however, the cost-effectiveness ratios of dose escalation with allopurinol-febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109 000 per quality-adjusted life-year. Long-term outcome data for patients with gout, including medication adherence, are limited. Allopurinol single therapy is cost-saving compared with no treatment. Dose-escalation allopurinol-febuxostat sequential therapy is cost-effective compared with accepted willingness-to-pay thresholds. Agency for Healthcare Research and Quality.

Long-Acting C-Terminal Peptide-Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children.

PubMed

Zelinska, Nataliya; Iotova, Violeta; Skorodok, Julia; Malievsky, Oleg; Peterkova, Valentina; Samsonova, Lubov; Rosenfeld, Ron G; Zadik, Zvi; Jaron-Mendelson, Michal; Koren, Ronit; Amitzi, Leanne; Raduk, Dmitri; Hershkovitz, Oren; Hart, Gili

2017-05-01

Daily injections are required for growth hormone (GH) replacement therapy, which may cause low compliance as a result of inconvenience and distress in patients. C-terminal peptide-modified human GH (MOD-4023) is developed for once-a-week dosing regimen in GH-deficient (GHD) adults and children. The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children. A multicenter, open-label, randomized, controlled phase 2 study in children with GHD, evaluating the safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy of three different weekly MOD-4023 doses, compared with daily recombinant human GH (r-hGH). The trial was conducted in 14 endocrinology centers in Europe. Fifty-three prepubertal children with GHD completed 12 months of treatment with either MOD-4023 (N = 42) or r-hGH (N = 11). C-terminal peptide-modified hGH (MOD-4023) was administered weekly at a dose of either 0.25, 0.48, or 0.66 mg/kg/wk and compared with daily hGH at a dose of 0.24 mg/kg/wk. MOD-4023 showed an estimated half-life approximately fivefold to 10-fold longer when compared with daily r-hGH. Insulin-like growth factor (IGF)-I and IGF-binding peptide 3 showed a dose-dependent increase during MOD-4023 treatment. IGF-I standard deviation score for MOD-4023 did not exceed +2. All MOD-4023 cohorts demonstrated adequate catch-up growth. The 0.66 mg/kg/wk dose demonstrated efficacy closest to daily r-hGH. No serious adverse events were observed during MOD-4023 treatment, and its tolerability was consistent with known properties of r-hGH. This study confirms the long-acting properties of MOD-4023 and shows a promising safety and tolerability profile. This provides support for initiation of a phase 3 study in GHD children using a single weekly injection of MOD-4023. Copyright © 2017 by the Endocrine Society

Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

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

Corn, Paul G., E-mail: pcorn@mdanderson.org; Song, Danny Y.; Heath, Elisabeth

Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles).more » A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.« less

The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the PRINC (Plavix Response in Coronary Intervention) trial.

PubMed

Gladding, Patrick; Webster, Mark; Zeng, Irene; Farrell, Helen; Stewart, Jim; Ruygrok, Peter; Ormiston, John; El-Jack, Seif; Armstrong, Guy; Kay, Patrick; Scott, Douglas; Gunes, Arzu; Dahl, Marja-Liisa

2008-12-01

This study evaluated the antiplatelet effect of a higher loading and maintenance dose regimen of clopidogrel and a possible drug interaction with verapamil. Clopidogrel loading doses above 600 mg have not resulted in more rapid or complete platelet inhibition. Higher maintenance dosages may be more effective than 75 mg/day. A double-blind, randomized, placebo-controlled trial was undertaken in 60 patients undergoing percutaneous coronary intervention. All patients received clopidogrel 600 mg at the start of the procedure. Using a 2 x 2 design, patients were allocated to clopidogrel 600 mg given 2 h later or matching placebo, and to verapamil 5 mg intra-arterial or placebo. Platelet function was measured using the VerifyNow P2Y12 analyzer (Accumetrics Ltd., San Diego, California) at 2, 4, and 7 h. Patients were further randomized to receive a clopidogrel 75 or 150 mg once daily, with platelet function assessed after 1 week. Two hours after the second dose of clopidogrel or placebo, platelet inhibition was 42 +/- 27% with clopidogrel, compared with 24 +/- 22% with placebo (p = 0.0006). By 5 h after the second dose, platelet inhibition was 49 +/- 30% with clopidogrel, compared with 29 +/- 22% with placebo (p = 0.01). No drug interaction was seen with verapamil. A clopidogrel maintenance dosage of 150 mg daily for 1 week resulted in greater platelet inhibition than 75 mg daily (50 +/- 28% vs. 29 +/- 19%, p = 0.01). In an unselected population undergoing percutaneous coronary intervention a clopidogrel 1,200-mg loading dose, given as two 600-mg doses 2 h apart, results in more rapid and complete platelet inhibition than a single 600-mg dose. A maintenance dosage of 150 mg daily produces greater platelet inhibition than 75 mg daily. (The PRINC trial; ACTRN12606000129583).

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

Trofimov, A; Carpenter, K; Shih, HA

Purpose: To quantify daily set-up variations in fractionated proton therapy of ocular melanomas, and to assess the effect on the fidelity of delivered distribution to the plan. Methods: In a typical five-fraction course, daily set-up is achieved by matching the position of fiducial markers in orthogonal radiographs to the images generated by treatment planning program. A patient maintains the required gaze direction voluntarily, without the aid of fixation devices. Confirmation radiographs are acquired to assess intrafractional changes. For this study, daily radiographs were analyzed to determine the daily iso-center position and apparent gaze direction, which were then transferred to themore » planning system to calculate the dose delivered in individual fractions, and accumulated dose for the entire course. Dose-volume metrics were compared between the planned and accumulated distributions for the tumor and organs at risk, for representative cases that varied by location within the ocular globe. Results: The analysis of the first set of cases (3 posterior, 3 transequatorial and 4 anterior tumors) revealed varying dose deviation patterns, depending on the tumor location. For anterior and posterior tumors, the largest dose increases were observed in the lens and ciliary body, while for the equatorial tumors, macula, optic nerve and disk, were most often affected. The iso-center position error was below 1.3 mm (95%-confidence interval), and the standard deviation of daily polar and azimuthal gaze set-up were 1.5 and 3 degrees, respectively. Conclusion: We quantified interfractional and intrafractional set-up variation, and estimated their effect on the delivered dose for representative cases. Current safety margins are sufficient to maintain the target coverage, however, the dose delivered to critical structures often deviates from the plan. The ongoing analysis will further explore the patterns of dose deviation, and may help to identify particular treatment scenarios which are at a higher risk for such deviations.« less

Safety and efficacy of fixed-dose 10 mg daily isotretinoin treatment for acne vulgaris in Malaysia.

PubMed

Yap, Felix Boon-Bin

2017-09-01

Low-dose isotretinoin is used to reduce side effects albeit higher relapse. This study aimed to determine the efficacy and safety of fixed-dose 10 mg daily isotretinoin for the treatment of acne. This prospective study was performed between 2011 and 2015. All 150 patients were given 10 mg daily isotretinoin until a cumulative dose of 90-110 mg/kg. The mean age was 26.6 years with 64.7% moderate acne, 29.3% severe, and 6% very severe. The mean cumulative dose was 98.8 ± 6.05 mg/kg. All 150 patients had total clearance with a mean time to clearance of 24.0 weeks. Patients with severe/very severe acne had higher cumulative dosage (102.1 vs. 97.0, P < 0.001) and longer duration to clearance (32.9 weeks vs. 19.1 weeks, P < 0.001). Mild relapse was seen in 4%. The mean time to relapse was 32.3 weeks. Lip dryness was the commonest side effects (100%). Mild transient elevation of liver enzymes was detected in 3.3% and a slight increase of serum lipid in 2.7% with no treatment discontinuation. Fixed-dose 10 mg daily treatment with isotretinoin until a cumulative dose of 90-110 mg/kg is safe with low relapse rate. © 2016 Wiley Periodicals, Inc.

Daily mean temperature estimate at the US SUFRAD stations as an average of the maximum and minimum temperatures

DOE PAGES

Chylek, Petr; Augustine, John A.; Klett, James D.; ...

2017-09-30

At thousands of stations worldwide, the mean daily surface air temperature is estimated as a mean of the daily maximum (T max) and minimum (T min) temperatures. In this paper, we use the NOAA Surface Radiation Budget Network (SURFRAD) of seven US stations with surface air temperature recorded each minute to assess the accuracy of the mean daily temperature estimate as an average of the daily maximum and minimum temperatures and to investigate how the accuracy of the estimate increases with an increasing number of daily temperature observations. We find the average difference between the estimate based on an averagemore » of the maximum and minimum temperatures and the average of 1440 1-min daily observations to be - 0.05 ± 1.56 °C, based on analyses of a sample of 238 days of temperature observations. Considering determination of the daily mean temperature based on 3, 4, 6, 12, or 24 daily temperature observations, we find that 2, 4, or 6 daily observations do not reduce significantly the uncertainty of the daily mean temperature. The bias reduction in a statistically significant manner (95% confidence level) occurs only with 12 or 24 daily observations. The daily mean temperature determination based on 24 hourly observations reduces the sample daily temperature uncertainty to - 0.01 ± 0.20 °C. Finally, estimating the parameters of population of all SURFRAD observations, the 95% confidence intervals based on 24 hourly measurements is from - 0.025 to 0.004 °C, compared to a confidence interval from - 0.15 to 0.05 °C based on the mean of T max and T min.« less

Daily mean temperature estimate at the US SUFRAD stations as an average of the maximum and minimum temperatures

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

Chylek, Petr; Augustine, John A.; Klett, James D.

At thousands of stations worldwide, the mean daily surface air temperature is estimated as a mean of the daily maximum (T max) and minimum (T min) temperatures. In this paper, we use the NOAA Surface Radiation Budget Network (SURFRAD) of seven US stations with surface air temperature recorded each minute to assess the accuracy of the mean daily temperature estimate as an average of the daily maximum and minimum temperatures and to investigate how the accuracy of the estimate increases with an increasing number of daily temperature observations. We find the average difference between the estimate based on an averagemore » of the maximum and minimum temperatures and the average of 1440 1-min daily observations to be - 0.05 ± 1.56 °C, based on analyses of a sample of 238 days of temperature observations. Considering determination of the daily mean temperature based on 3, 4, 6, 12, or 24 daily temperature observations, we find that 2, 4, or 6 daily observations do not reduce significantly the uncertainty of the daily mean temperature. The bias reduction in a statistically significant manner (95% confidence level) occurs only with 12 or 24 daily observations. The daily mean temperature determination based on 24 hourly observations reduces the sample daily temperature uncertainty to - 0.01 ± 0.20 °C. Finally, estimating the parameters of population of all SURFRAD observations, the 95% confidence intervals based on 24 hourly measurements is from - 0.025 to 0.004 °C, compared to a confidence interval from - 0.15 to 0.05 °C based on the mean of T max and T min.« less

Twice-daily versus once-daily applications of pimecrolimus cream 1% for the prevention of disease relapse in pediatric patients with atopic dermatitis.

PubMed

Ruer-Mulard, Mireille; Aberer, Werner; Gunstone, Anthony; Kekki, Outi-Maria; López Estebaranz, Jose Luis; Vertruyen, André; Guettner, Achim; Hultsch, Thomas

2009-01-01

The aim of this study is to compare twice-daily and once-daily applications of pimecrolimus cream 1% for prevention of atopic dermatitis relapses in pediatric patients. This multicenter trial enrolled 300 outpatients aged 2 to 17 years, with mild-to-severe atopic dermatitis. The patients were initially treated with twice-daily topical pimecrolimus until complete clearance or for up to 6 weeks (open-label period). Those who achieved a decrease of at least 1 point in the Investigator's Global Assessment score were then randomized to double-blind treatment with pimecrolimus cream 1% either twice daily or once daily for up to 16 weeks. Study medication was discontinued during periods of disease remission (Investigator's Global Assessment = 0). The primary efficacy end point of the double-blind phase was disease relapse (worsening requiring topical corticosteroids or additional/alternative therapy and confirmed by Investigator's Global Assessment score > or = 3 and pruritus score > or = 2). Of the 300 patients enrolled in the study, 268 were randomized to treatment with pimecrolimus cream 1% either twice daily or once daily (n = 134 in each group). The relapse rate was lower in the twice-daily dose group (9.9%) than that in the once-daily dose group (14.7%), but analysis of the time to disease relapse, using a Cox proportional model to adjust for confounding variables, did not show a statistically significant difference between treatment arms (hazard ratio: 0.64; 95% CI: 0.31-1.30). Treatment of active atopic dermatitis lesions with pimecrolimus cream 1% twice daily, followed by the once-daily dosing regimen, was sufficient to prevent subsequent atopic dermatitis relapses over 16 weeks in pediatric patients.

A method to estimate the effect of deformable image registration uncertainties on daily dose mapping

PubMed Central

Murphy, Martin J.; Salguero, Francisco J.; Siebers, Jeffrey V.; Staub, David; Vaman, Constantin

2012-01-01

Purpose: To develop a statistical sampling procedure for spatially-correlated uncertainties in deformable image registration and then use it to demonstrate their effect on daily dose mapping. Methods: Sequential daily CT studies are acquired to map anatomical variations prior to fractionated external beam radiotherapy. The CTs are deformably registered to the planning CT to obtain displacement vector fields (DVFs). The DVFs are used to accumulate the dose delivered each day onto the planning CT. Each DVF has spatially-correlated uncertainties associated with it. Principal components analysis (PCA) is applied to measured DVF error maps to produce decorrelated principal component modes of the errors. The modes are sampled independently and reconstructed to produce synthetic registration error maps. The synthetic error maps are convolved with dose mapped via deformable registration to model the resulting uncertainty in the dose mapping. The results are compared to the dose mapping uncertainty that would result from uncorrelated DVF errors that vary randomly from voxel to voxel. Results: The error sampling method is shown to produce synthetic DVF error maps that are statistically indistinguishable from the observed error maps. Spatially-correlated DVF uncertainties modeled by our procedure produce patterns of dose mapping error that are different from that due to randomly distributed uncertainties. Conclusions: Deformable image registration uncertainties have complex spatial distributions. The authors have developed and tested a method to decorrelate the spatial uncertainties and make statistical samples of highly correlated error maps. The sample error maps can be used to investigate the effect of DVF uncertainties on daily dose mapping via deformable image registration. An initial demonstration of this methodology shows that dose mapping uncertainties can be sensitive to spatial patterns in the DVF uncertainties. PMID:22320766

Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine

PubMed Central

Peng, Shiwen; Lyford-Pike, Sofia; Akpeng, Belinda; Wu, Annie; Hung, Chien-Fu; Hannaman, Drew; Saunders, John R.; Wu, T.-C.

2012-01-01

Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8+ T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8+ T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8+ T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic anti-tumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8+ T cells, which led to higher ratios of CD8+/Treg and CD8+/CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8+ T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. PMID:23011589

Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.

PubMed

Kazierad, D J; Bergman, A; Tan, B; Erion, D M; Somayaji, V; Lee, D S; Rolph, T

2016-08-01

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia. © 2016 John Wiley & Sons Ltd.

De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels.

PubMed

Crespo, M; Mir, M; Marin, M; Hurtado, S; Estadella, C; Gurí, X; Rap, O; Moral, R; Puig, J M; Lloveras, J

2009-01-01

Advagraf is a new modified-release once-daily formulation of tacrolimus with a similar efficacy and safety profile to twice-daily tacrolimus (Prograf) according to clinical trials. Few data are published about its use in clinical practice, outside of sponsored clinical trials. We compared efficacy and basic pharmacokinetics of once-daily and twice-daily tacrolimus in de novo renal transplantation. The Advagraf group included 26 de novo renal cases who had received initial immunosuppression with once-daily tacrolimus (0.2 mg/kg from day 1 posttransplantation) combined with mycophenolic acid, steroids, and anti-CD25 monoclonal antibodies (2 doses). We compared them with a Prograf group of 26 transplants performed immediately before, who received equivalent immunosuppression with twice-daily tacrolimus (0.2 mg/kg from day 1). We did not observe significant differences between groups in demographics, efficacy, and basic pharmacokinetics, namely, tacrolimus trough levels at 7, 15, 30, 60, or 90 days. We found that recipients on Advagraf needed significantly higher tacrolimus doses per kg up to 6 months post-transplantation than those on Prograf: 0.16 vs 0.11; 0.14 vs 0.08; and 0.12 vs 0.08 mg/kg at 1, 3, and 6 months. No patient suffered severe liver dysfunction. There were no differences between groups in the administration of drugs interacting with CYP3A4 or prokinetics, which could alter tacrolimus pharmacokinetics. Among de novo renal cases, the new once-daily formulation of tacrolimus offered a similar short-term efficacy profile as the twice-daily tacrolimus. But it was necessary to use up to a 50% higher dose of Advagraf than Prograf to achieve similar trough levels during the first 6 months.

Defined daily doses (DDD) do not accurately reflect opioid doses used in contemporary chronic pain treatment.

PubMed

Nielsen, Suzanne; Gisev, Natasa; Bruno, Raimondo; Hall, Wayne; Cohen, Milton; Larance, Briony; Campbell, Gabrielle; Shanahan, Marian; Blyth, Fiona; Lintzeris, Nicholas; Pearson, Sallie; Mattick, Richard; Degenhardt, Louisa

2017-05-01

To assess how well the defined daily dose (DDD) metric reflects opioid utilisation among chronic non-cancer pain patients. Descriptive, cross-sectional study, utilising a 7-day medication diary. Community-based treatment settings, Australia. A sample of 1101 people prescribed opioids for chronic non-cancer pain. Opioid dose data was collected via a self-completed 7-day medication diary capturing names, strengths and doses of each medication taken in the past week. Median daily dose was calculated for each opioid. Comparisons were made to the World Health Organization's (WHO) DDD metric. WHO DDDs ranged from 0.6 to 7.1 times the median opioid doses used by the sample. For transdermal fentanyl and oral hydromorphone, the median dose was comparable with the DDD. The DDD for methadone was 0.6 times lower than the median doses used by this sample of chronic pain patients. In contrast, the DDD for oxycodone and transdermal buprenorphine, the most commonly used strong opioids for chronic pain in Australia, was two to seven times higher than actual doses used. For many opioids, there are key differences between the actual doses used in clinical practice and the WHO's DDDs. The interpretation of opioid utilisation studies using population-level DDDs may be limited, and a recalibration of the DDD for many opioids or the reporting of opioid utilisation in oral morphine equivalent doses is recommended. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Metronidazole stewardship initiative at Christchurch hospitals-achievable with immediate benefits.

PubMed

Gardiner, Sharon J; Metcalf, Sarah Cl; Chin, Paul Kl; Doogue, Matthew P; Dalton, Simon C; Chambers, Stephen T

2018-04-13

To evaluate an antimicrobial stewardship (AMS) initiative to change hospital prescribing practice for metronidazole. In October 2015, the Canterbury District Health Board (CDHB) AMS committee changed advice for metronidazole to promote two times daily dosing for most indications, prioritisation of the oral route and avoidance of double anaerobic cover. Adoption of the initiative was facilitated via change in prescribing guidelines, education and ongoing pharmacy support. Usage and expenditure on metronidazole for adult inpatients were compared for the five years pre- and two years post-change. Other district health boards (DHBs) were surveyed to determine their dosing recommendation for metronidazole IV. Mean annual metronidazole IV use, as defined daily doses per 1,000 occupied bed days, decreased by 43% post-initiative. Use of non-IV (oral or rectal) formulations increased by 104%. Total savings associated with the initiative were approximately $33,400 in drug costs plus $78,200 per annum in IV giving sets and post-dose flushes. Twelve of 20 (60%) DHBs (including CDHB) endorse twice daily IV dosing. In addition to financial savings, reduction in IV doses has potential benefits, including avoidance of IV catheter-associated complications such as bloodstream infections. Approaches to metronidazole dosing vary across DHBs and could benefit from national coordination.

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

PubMed Central

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

2016-01-01

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

Radon as a tracer of daily, seasonal and spatial air movements in the Underground Tourist Route "Coal Mine" (SW Poland).

PubMed

Tchorz-Trzeciakiewicz, Dagmara Eulalia; Parkitny, Tomasz

2015-11-01

The surveys of radon concentrations in the Underground Tourist Route "Coal Mine" were carried out using passive and active measurement techniques. Passive methods with application of Solid State Nuclear Track Detectors LR115 were used at 4 points in years 2004-2007 and at 21 points in year 2011. These detectors were exchanged at the beginning of every season in order to get information about seasonal and spatial changes of radon concentrations. The average radon concentration noted in this facility was 799 Bq m(-3) and is consistent with radon concentrations noted in Polish coal mines. Seasonal variations, observed in this underground tourist route, were as follows: the highest radon concentrations were noted during summers, the lowest during winters, during springs and autumns intermediate but higher in spring than in autumn. The main external factor that affected seasonal changes of radon concentrations was the seasonal variation of outside temperature. No correlation between seasonal variations of radon concentrations and seasonal average atmospheric pressures was found. Spatial variations of radon concentrations corresponded with air movements inside the Underground Tourist Route "Coal Mine". The most vivid air movements were noted along the main tunnel in adit and at the place located near no blinded (in the upper part) shaft. Daily variations of radon concentrations were recorded in May 2012 using RadStar RS-230 as the active measurement technique. Typical daily variations of radon concentrations followed the pattern that the highest radon concentrations were recorded from 8-9 a.m. to 7-8 p.m. and the lowest during nights. The main factor responsible for hourly variations of radon concentrations was the daily variation of outside temperatures. No correlations were found between radon concentration and other meteorological parameters such as atmospheric pressure, wind velocity or precipitation. Additionally, the influence of human factor on radon concentrations was noticed. As human factor, we consider open entrance door during restorations works carried out inside the underground facility. Comprehensive surveys of radon concentrations in the Underground Tourist Route "Coal Mine", which included hourly, seasonal and spatial measurements, have revealed that radon can be the excellent tracer of air movements inside the underground facilities that are not equipped with mechanical ventilation system. The main external factor that affects hourly, seasonal and even spatial changes of radon concentrations inside Underground Tourist Route "Coal Mine" is the variation of outside temperature. The maximum effective dose received by employees during 2000 working hours in a year was 5.8 mSv y(-1) and the minimum was 3.5 mSv y(-1). Tourist guides, who usually spend underground about 1000 h y(-1), received effective dose from 1.7 mSv y(-1) to 2.3 mSv y(-1). According to Polish Law, employees, receiving effective dose for occupational exposure higher than 1 mSv y(-1) but below 6 mSv y(-1), are allocated to category B of workers and the level of radiation in their place of work should be controlled and continuously monitored. The radiation monitoring system in the Underground Tourist Route "Coal Mine" does not exist. None of Polish tourist routes or caves has installed radiation monitoring system although effective doses received by employees, in some of them, exceed values defined by law. Effective dose received by tourist during one trip was lower than 0.001 mSv y(-1) and risk of cancer induction was lower than 0.00001%. The probability, that tourists inside the Underground Tourist Route "Coal Mine" receive effective dose exceeding allowable annual limit for members of the public of 1 mSv y(-1) does not exist. The Underground Tourist Route Coal Mine is a safe place for tourists from radiological point of view. Copyright © 2015 Elsevier Ltd. All rights reserved.

SU-E-J-43: Deformed Planning CT as An Electron Density Substitute for Cone-Beam CT

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

Mishra, K; Godley, A

2014-06-01

Purpose: To confirm that deforming the planning CT to the daily Cone-Beam CTs (CBCT) can provide suitable electron density for adaptive planning. We quantify the dosimetric difference between plans calculated on deformed planning CTs (DPCT) and daily CT-on-rails images (CTOR). CTOR is used as a test of the method as CTOR already contains accurate electron density to compare against. Methods: Five prostate only IMRT patients, each with five CTOR images, were selected and re-planned on Panther (Prowess Inc.) with a uniform 5 mm PTV expansion, prescribed 78 Gy. The planning CT was deformed to match each CTOR using ABAS (Elektamore » Inc.). Contours were drawn on the CTOR, and copied to the DPCT. The original treatment plan was copied to both the CTOR and DPCT, keeping the center of the prostate as the isocenter. The plans were then calculated using the collapsed cone heterogeneous dose engine of Prowess and typical DVH planning parameters used to compare them. Results: Each DPCT was visually compared to its CTOR with no differences observed. The agreement of the copied CTOR contours with the DPCT anatomy further demonstrated the deformation accuracy. The plans calculated using CTOR and DPCT were compared. Over the 25 plan pairs, the average difference between them for prostate D100, D98 and D95 were 0.5%, 0.2%, and 0.2%; PTV D98, D95 and mean dose: 0.3%, 0.2% and 0.3%; bladder V70, V60 and mean dose: 1.1%, 0.7%, and 0.2%; and rectum mean dose: 0.3%. (D100 is the dose covering 100% of the target; V70 is the volume of the organ receiving 70 Gy). Conclusion: We observe negligible difference between the dose calculated on the DPCT and the CTOR, implying that deformed planning CTs are a suitable substitute for electron density. The method can now be applied to CBCTs. Research version of Panther provided by Prowess Inc. Research version of ABAS provided by Elekta Inc.« less

Non-daily pre-exposure prophylaxis for HIV prevention

PubMed Central

Anderson, Peter L.; García-Lerma, J. Gerardo; Heneine, Walid

2015-01-01

Purpose of review To discuss non-daily pre-exposure prophylaxis (PrEP) modalities that may provide advantages compared with daily PrEP in cost and cumulative toxicity, but may have lower adherence forgiveness. Recent Findings Animal models have informed our understanding of early viral transmission events, which help guide event-driven PrEP dosing strategies. These models indicate early establishment of viral replication in rectal or cervicovaginal tissues, so event-driven PrEP should rapidly deliver high mucosal drug concentrations within hours of the potential exposure event. Macaque models have demonstrated the high biological efficacy for event-driven dosing of oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) against both vaginal and rectal virus transmission. In humans, the IPERGAY study demonstrated 86% efficacy for event-driven oral TDF/FTC dosing among men who have sex with men (MSM), while no similar efficacy data are available on women or heterosexual men. The HPTN 067 study showed that certain MSM populations adhere well to non-daily PrEP while other populations of women adhere more poorly to non-daily versus daily regimens. Pharmacokinetic studies following oral TDF/FTC dosing in humans, indicate that TFV-diphosphate (the active form of TFV) accumulates to higher concentrations in rectal versus cervicovaginal tissue but non-adherence in trials complicates the interpretation of differential mucosal drug concentrations. Summary Event-driven dosing for TFV-based PrEP has promise for HIV prevention in MSM. Future research of event-driven PrEP in women and heterosexual men should be guided by a better understanding of the importance of mucosal drug concentrations for PrEP efficacy and its sensitivity to adherence. PMID:26633641

Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats

PubMed Central

Walter, Patrick B.; Knutson, Mitchell D.; Paler-Martinez, Andres; Lee, Sonia; Xu, Yu; Viteri, Fernando E.; Ames, Bruce N.

2002-01-01

Approximately two billion people, mainly women and children, are iron deficient. Two studies examined the effects of iron deficiency and supplementation on rats. In study 1, mitochondrial functional parameters and mitochondrial DNA (mtDNA) damage were assayed in iron-deficient (≤5 μg/day) and iron-normal (800 μg/day) rats and in both groups after daily high-iron supplementation (8,000 μg/day) for 34 days. This dose is equivalent to the daily dose commonly given to iron-deficient humans. Iron-deficient rats had lower liver mitochondrial respiratory control ratios and increased levels of oxidants in polymorphonuclear-leukocytes, as assayed by dichlorofluorescein (P < 0.05). Rhodamine 123 fluorescence of polymorphonuclear-leukocytes also increased (P < 0.05). Lowered respiratory control ratios were found in daily high-iron-supplemented rats regardless of the previous iron status (P < 0.05). mtDNA damage was observed in both iron-deficient rats and rats receiving daily high-iron supplementation, compared with iron-normal rats (P < 0.05). Study 2 compared iron-deficient rats given high doses of iron (8,000 μg) either daily or every third day and found that rats given iron supplements every third day had less mtDNA damage on the second and third day after the last dose compared to daily high iron doses. Both inadequate and excessive iron (10 × nutritional need) cause significant mitochondrial malfunction. Although excess iron has been known to cause oxidative damage, the observation of oxidant-induced damage to mitochondria from iron deficiency has been unrecognized previously. Untreated iron deficiency, as well as excessive-iron supplementation, are deleterious and emphasize the importance of maintaining optimal iron intake. PMID:11854522

Does altered fractionation influence the risk of radiation-induced optic neuropathy?

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

Bhandare, Niranjan; Monroe, Alan T.; Morris, Christopher G.

2005-07-15

Purpose: To analyze the parameters that influence the risk of radiation-induced optic neuropathy (RION) after radiotherapy for head-and-neck tumors. Methods and Materials: Between 1964 and 2000, 273 patients with tumors of the nasopharynx, paranasal sinuses, nasal cavity, and hard palate adenoid cystic carcinomas were treated with curative intent and had radiation fields that included the optic nerves and/or chiasm. Patients were followed for at least 1 year after radiotherapy. Results: Radiation-induced optic neuropathy developed in 32 eyes of 24 patients (9%). The 5-year rates of freedom from RION according to the total dose and once- vs. twice-daily fractionation were asmore » follows: {<=}63 Gy once daily, 95%; {<=}63 Gy twice daily, 98%; >63 Gy once daily, 78%; and >63 Gy twice daily, 91%. Multivariate analysis revealed that the total dose affected the risk of RION (p = 0.0047), with patient age (p = 0.0909), once-daily vs. twice-daily fractionation (p = 0.0684), and overall treatment time (p = 0.0972) were marginally significant. The use of adjuvant chemotherapy did not significantly influence the likelihood of developing RION. Conclusion: The likelihood of developing RION is primarily influenced by the total dose. Hyperfractionation may reduce the risk of experiencing this complication.« less

Validation of a deformable image registration technique for cone beam CT-based dose verification

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

Moteabbed, M., E-mail: mmoteabbed@partners.org; Sharp, G. C.; Wang, Y.

2015-01-15

Purpose: As radiation therapy evolves toward more adaptive techniques, image guidance plays an increasingly important role, not only in patient setup but also in monitoring the delivered dose and adapting the treatment to patient changes. This study aimed to validate a method for evaluation of delivered intensity modulated radiotherapy (IMRT) dose based on multimodal deformable image registration (DIR) for prostate treatments. Methods: A pelvic phantom was scanned with CT and cone-beam computed tomography (CBCT). Both images were digitally deformed using two realistic patient-based deformation fields. The original CT was then registered to the deformed CBCT resulting in a secondary deformedmore » CT. The registration quality was assessed as the ability of the DIR method to recover the artificially induced deformations. The primary and secondary deformed CT images as well as vector fields were compared to evaluate the efficacy of the registration method and it’s suitability to be used for dose calculation. PLASTIMATCH, a free and open source software was used for deformable image registration. A B-spline algorithm with optimized parameters was used to achieve the best registration quality. Geometric image evaluation was performed through voxel-based Hounsfield unit (HU) and vector field comparison. For dosimetric evaluation, IMRT treatment plans were created and optimized on the original CT image and recomputed on the two warped images to be compared. The dose volume histograms were compared for the warped structures that were identical in both warped images. This procedure was repeated for the phantom with full, half full, and empty bladder. Results: The results indicated mean HU differences of up to 120 between registered and ground-truth deformed CT images. However, when the CBCT intensities were calibrated using a region of interest (ROI)-based calibration curve, these differences were reduced by up to 60%. Similarly, the mean differences in average vector field lengths decreased from 10.1 to 2.5 mm when CBCT was calibrated prior to registration. The results showed no dependence on the level of bladder filling. In comparison with the dose calculated on the primary deformed CT, differences in mean dose averaged over all organs were 0.2% and 3.9% for dose calculated on the secondary deformed CT with and without CBCT calibration, respectively, and 0.5% for dose calculated directly on the calibrated CBCT, for the full-bladder scenario. Gamma analysis for the distance to agreement of 2 mm and 2% of prescribed dose indicated a pass rate of 100% for both cases involving calibrated CBCT and on average 86% without CBCT calibration. Conclusions: Using deformable registration on the planning CT images to evaluate the IMRT dose based on daily CBCTs was found feasible. The proposed method will provide an accurate dose distribution using planning CT and pretreatment CBCT data, avoiding the additional uncertainties introduced by CBCT inhomogeneity and artifacts. This is a necessary initial step toward future image-guided adaptive radiotherapy of the prostate.« less

Fluconazole penetration in cerebral parenchyma in humans at steady state.

PubMed Central

Thaler, F; Bernard, B; Tod, M; Jedynak, C P; Petitjean, O; Derome, P; Loirat, P

1995-01-01

We studied fluconazole penetration in the brain in five patients who had a deep cerebral tumor whose removal required the excision of healthy brain tissue. Plasma and brain samples were simultaneously obtained after oral ingestion of 400 mg of fluconazole daily for 4 days (90% of steady state). Fluconazole penetration in healthy cerebral parenchyma was determined. Plasma and brain samples were assayed by high-pressure liquid chromatography. Concentrations in plasma and brain tissue were 13.5 +/- 5.5 micrograms/ml and 17.6 +/- 6.6 micrograms/g, respectively. The average ratio of concentrations in the brain and plasma (four patients) was 1.33 (range, 0.70 to 2.39). Despite the lack of data concerning the penetration of fluconazole in brain abscesses, these results should permit the use of a daily dose of 400 mg of fluconazole in prospective clinical studies that evaluate the effectiveness of this drug in the treatment of brain abscesses due to susceptible species of fungi. PMID:7625804

Average ovarian hormone levels, rather than daily values and their fluctuations, are related to facial preferences among women.

PubMed

Marcinkowska, Urszula M; Kaminski, Gwenael; Little, Anthony C; Jasienska, Grazyna

2018-05-24

Hormones are of crucial importance for human behavior. Cyclical changes of ovarian hormones throughout women's menstrual cycle are suggested to underlie fluctuation in masculinity preference for both faces and bodies. In this study we tested this hypothesis based on daily measurements of estradiol and progesterone throughout menstrual cycle, and multiple measurements of women's preference towards masculinity of faces and bodies of men. We expected that due to a large variation among daily hormonal levels we would not observe a direct effect of daily hormone levels, but rather that average levels of ovarian hormones throughout the cycle (a reliable marker of a probability of conception) would better predict women's preferences. We found a negative relationship between average progesterone levels and facial masculinity preference, but only among women who were in long-term relationships. There was no relationship between facial masculinity preference and either of the estradiol or progesterone daily levels. Similarly, only average levels of hormones were significantly related to facial symmetry preference. For women who were in relationships estradiol was positively related to symmetry preference, while for single women this relationship was opposite. For body masculinity preference there were no significant relationships with neither averaged nor daily hormonal levels. Taken together, our results further suggest that overall cycle levels of ovarian hormones (averaged for a cycle) are better predictors of facial masculinity and symmetry preference than daily levels assessed during preferences' tests. Importantly, including information about relationship status in the investigations of hormonal bases of preferences is crucial. Copyright © 2018 Elsevier Inc. All rights reserved.

Assessment of occupational cosmic radiation exposure of flight attendants using questionnaire data.

PubMed

Anderson, Jeri L; Waters, Martha A; Hein, Misty J; Schubauer-Berigan, Mary K; Pinkerton, Lynne E

2011-11-01

Female flight attendants may have a higher risk of breast and other cancers than the general population because of routine exposure to cosmic radiation. As part of a forthcoming study of breast and other cancer incidence, occupational cosmic radiation exposure of a cohort of female flight attendants was estimated. Questionnaire data were collected from living female cohort members who were formerly employed as flight attendants with Pan American World Airways. These data included airline at which the flight attendant was employed, assigned domicile, start and end dates for employment at domicile, and number of block hours and commuter segments flown per month. Questionnaire respondents were assigned daily absorbed and effective doses using a time-weighted dose rate specific to the domicile and/or work history era combined with self-reported work history information. Completed work history questionnaires were received from 5898 living cohort members. Mean employment time as a flight attendant was 7.4 yr at Pan Am and 12 yr in total. Estimated mean annual effective dose from all sources of occupational cosmic radiation exposure was 2.5 +/- 1.0 mSv, with a mean career dose of 30 mSv. Annual effective doses were similar to doses assessed for other flight attendant cohorts; however, questionnaire-based cumulative doses assessed in this study were on average higher than those assessed for other flight attendant cohorts using company-based records. The difference is attributed to the inclusion of dose from work at other airlines and commuter flights, which was made possible by using questionnaire data.

Mechanisms and biological importance of photon-induced bystander responses: do they have an impact on low-dose radiation responses

PubMed Central

Tomita, Masanori; Maeda, Munetoshi

2015-01-01

Abstract Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced bystander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect. PMID:25361549

Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study.

PubMed

Hurwitz, Herbert I; Smith, David C; Pitot, Henry C; Brill, Jeffrey M; Chugh, Rashmi; Rouits, Elisabeth; Rubin, Joseph; Strickler, John; Vuagniaux, Gregoire; Sorensen, J Mel; Zanna, Claudio

2015-04-01

To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response. DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.

Central Nervous System Medication Burden and Serious Falls in Older Nursing Home Residents

PubMed Central

Hanlon, Joseph T.; Zhao, Xinhua; Naples, Jennifer G.; Aspinall, Sherrie L.; Perera, Subashan; Nace, David A.; Castle, Nicholas G.; Greenspan, Susan L.; Thorpe, Carolyn T.

2016-01-01

Objectives To examine the association between CNS medication burden and serious falls in those with a recent fall history. Design Nested-case control study; cases matched to four controls by age, gender, and date. Setting US nursing homes Participants 5,556 residents age ≥ 65 with a recent fall history admitted to a nursing home between 1/1–9/30/2010 and followed until discharge, death, or 12/31/2010. Measurements Outcome was serious falls as per Medicare Part A and B ICD/CPT codes. CNS burden, from Medicare Part D data, was calculated by dividing the daily dose of each CNS agent (i.e., specific antidepressants, antiepileptic, antipsychotic, benzodiazepine and opioid receptor agonists) received during the six days prior to the index (outcome) date by the minimum effective geriatric daily dose and summing the results across medications. Results There were 367 cases and 1468 matched controls. Those taking 3+ CNS standardized daily doses were more likely to have a serious fall than those not taking any CNS medications (Adjusted Odds Ratio 1.83; 95% confidence interval 1.35–2.48). There was no significant difference in fall risk for residents taking >0 to <3 CNS standardized daily doses compared to residents taking no CNS medications (Adjusted Odds Ratio 0.85; 95% CI 0.63–1.15). Conclusion CNS medication burden, approximately 3+ standardized daily doses, was associated with an increased risk of serious falls in nursing home residents with recent fall. Clinicians should be vigilant for opportunities to discontinue or decrease the doses of individual CNS medications and/or consider non-pharmacological alternatives. Such interventions that reduce use of CNS medications in nursing homes could reduce fall rates but further research is needed to confirm this. PMID:28152179

Investigation of pretreatment prediction of proton pump inhibitor (PPI)-resistant patients with gastroesophageal reflux disease and the dose escalation challenge of PPIs-TORNADO study: a multicenter prospective study by the Acid-Related Symptom Research Group in Japan.

PubMed

Furuta, Takahisa; Shimatani, Tomohiko; Sugimoto, Mitsushige; Ishihara, Shunji; Fujiwara, Yasuhiro; Kusano, Motoyasu; Koike, Tomoyuki; Hongo, Michio; Chiba, Tsutomu; Kinoshita, Yoshikazu

2011-11-01

Some non-erosive reflux disease (NERD) and reflux esophagitis (RE) patients are unresponsive to a proton pump inhibitor (PPI) at standard dose. We investigated the predictive marker of the efficacy of PPI for GERD patients including NERD and RE treated with standard and increased doses of a PPI. Patients with symptomatic gastroesophageal reflux disease (GERD) (NERD and RE) were treated with rabeprazole (RPZ) 10 mg once daily for 4 weeks. The RPZ dosage was increased to 10 mg twice daily for an additional 2 weeks and again to 20 mg twice daily for another 2 weeks if heartburn was not relieved. Baseline characteristics and efficacy of RPZ were assessed on the basis of a heartburn diary and frequency scale for symptoms of GERD (FSSG). Complete heartburn relief rates after 4 weeks were 42.5% (31/73) and 67.9% (19/28) in NERD and RE groups, respectively, which rose to 68.9 and 91.7% after dose escalation. Multivariate analysis revealed that parameters associated with resistance to RPZ 10 mg once daily were female, non-smoking, frequent heartburn, low score for question 4 (Q4) of the FSSG (subconsciously rubbing the chest), and high scores for Q3 (heavy stomach after meal) and Q7 (unusual sensation in the throat). Frequent heartburn and a high score for Q7 were associated with resistance to RPZ 20 mg twice daily. FSSG scores of patients resistant to RPZ were significantly higher in comparison with responders before and during treatment. FSSG could predict response to a PPI for symptomatic GERD. Increase of RPZ dose is useful for treatment of GERD refractory to the standard dose of RPZ.

Considerations for applying VARSKIN mod 2 to skin dose calculations averaged over 10 cm2.

PubMed

Durham, James S

2004-02-01

VARSKIN Mod 2 is a DOS-based computer program that calculates the dose to skin from beta and gamma contamination either directly on skin or on material in contact with skin. The default area for calculating the dose is 1 cm2. Recently, the U.S. Nuclear Regulatory Commission issued new guidelines for calculating shallow dose equivalent from skin contamination that requires the dose be averaged over 10 cm2. VARSKIN Mod 2 was not filly designed to calculate beta or gamma dose estimates averaged over 10 cm2, even though the program allows the user to calculate doses averaged over 10 cm2. This article explains why VARSKIN Mod 2 overestimates the beta dose when applied to 10 cm2 areas, describes a manual method for correcting the overestimate, and explains how to perform reasonable gamma dose calculations averaged over 10 cm2. The article also describes upgrades underway in Varskin 3.

Organization of vertical shear of wind and daily variability of monsoon rainfall

NASA Astrophysics Data System (ADS)

Gouda, K. C.; Goswami, P.

2016-10-01

Very little is known about the mechanisms that govern the day to day variability of the Indian summer monsoon (ISM) rainfall; in the current dominant view, the daily rainfall is essentially a result of chaotic dynamics. Most studies in the past have thus considered monsoon in terms of its seasonal (June-September) or monthly rainfall. We show here that the daily rainfall in June is associated with vertical shear of horizontal winds at specific scales. While vertical shear had been used in the past to investigate interannual variability of seasonal rainfall, rarely any effort has been made to examine daily rainfall. Our work shows that, at least during June, the daily rainfall variability of ISM rainfall is associated with a large scale dynamical coherence in the sense that the vertical shear averaged over large spatial extents are significantly correlated with area-averaged daily rainfall. An important finding from our work is the existence of a clearly delineated monsoon shear domain (MSD) with strong coherence between area-averaged shear and area-averaged daily rainfall in June; this association of daily rainfall is not significant with shear over only MSD. Another important feature is that the association between daily rainfall and vertical shear is present only during the month of June. Thus while ISM (June-September) is a single seasonal system, it is important to consider the dynamics and variation of June independently of the seasonal ISM rainfall. The association between large-scale organization of circulation and daily rainfall is suggested as a basis for attempting prediction of daily rainfall by ensuring accurate simulation of wind shear.

Scaling analysis on Indian foreign exchange market

NASA Astrophysics Data System (ADS)

Sarkar, A.; Barat, P.

2006-05-01

In this paper, we investigate the scaling behavior of the average daily exchange rate returns of the Indian Rupee against four foreign currencies: namely, US Dollar, Euro, Great Britain Pound and Japanese Yen. The average daily exchange rate return of the Indian Rupee against US Dollar is found to exhibit a persistent scaling behavior and follow Levy stable distribution. On the contrary, the average daily exchange rate returns of the other three foreign currencies do not show persistency or antipersistency and follow Gaussian distribution.

Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies.

PubMed

Planchard, David; Brown, Kathryn H; Kim, Dong-Wan; Kim, Sang-We; Ohe, Yuichiro; Felip, Enriqueta; Leese, Philip; Cantarini, Mireille; Vishwanathan, Karthick; Jänne, Pasi A; Ranson, Malcolm; Dickinson, Paul A

2016-04-01

Osimertinib (AZD9291) 80 mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure. AURA (NCT01802632): single- and multiple-dose PK of osimertinib (20-240 mg daily) was determined in patients with advanced NSCLC. Bioavailability study (NCT01951599): single-dose PK of osimertinib (20 mg) was determined in healthy volunteers with administration of capsule, solution, or tablet formulations fasted, and as a tablet in the fed and fasted state. Osimertinib was slowly absorbed and displayed dose-proportional increases in exposure from 20 to 240 mg. Distribution was extensive and clearance low to moderate, resulting in a mean half-life of 48.3 h. Steady state was achieved by 15 days of dosing, consistent with single-dose PK, with a peak-to-trough ratio of 1.6. Two active metabolites circulated at ~10 % of osimertinib exposure. Ethnicity did not appear to affect exposure. Osimertinib PK profiles in healthy volunteers were similar to those in patients and were unaffected by formulation. Food caused a clinically insignificant increase in exposure. Osimertinib PK supports once-daily dosing; the same dose for Asian and non-Asian populations; a fixed-dosing approach; a minimal effect of food on exposure; and a switch to tablet formulation without alteration to dose or schedule. Osimertinib plasma concentrations are sustained throughout the dosing period, which is considered optimal for efficacy.

Pharmacokinetics and Safety of Tenofovir in HIV-infected Women during Labor and their Infants During the First Week of Life

PubMed Central

Mirochnick, Mark; Taha, Taha; Kreitchmann, Regis; Nielsen-Saines, Karin; Kumwenda, Newton; Joao, Esau; Pinto, Jorge; Santos, Breno; Parsons, Teresa; Kearney, Brian; Emel, Lynda; Herron, Casey; Richardson, Paul; Hudelson, Sarah E.; Eshleman, Susan H.; George, Kathleen; Fowler, Mary Glenn; Sato, Paul; Mofenson, Lynne

2013-01-01

Background Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking. Methods HPTN 057 was a phase 1, open label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/infant 4 mg/kg doses day 0, 3 and 5; maternal 900 mg doses/infant 6 mg/kg doses day 0, 3 and 5; maternal 600 mg doses/infant 6 mg/kg doses daily ×7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid and breast milk tenofovir concentrations were determined by liquid chromatographic – tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing. Results 122 mother-infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 mg and 900 mg exceeded that in non-pregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74–97% of infants receiving daily dosing. Conclusion A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in studies of TDF efficacy for HIV PMTCT and early infant treatment. PMID:23979002

Arsenic in Drinking Water and Mortality for Cancer and Chronic Diseases in Central Italy, 1990-2010

PubMed Central

D’Ippoliti, Daniela; Santelli, Enrica; De Sario, Manuela; Scortichini, Matteo; Davoli, Marina; Michelozzi, Paola

2015-01-01

Background In several volcanic areas of Italy, arsenic levels exceed European regulatory limits (10 μg/L in drinking water). There is still uncertainty about health risks from arsenic at low-medium doses (<100 μg/L). Objectives A large population-based study using an administrative cohort of residents in the Viterbo province (Central Italy), chronically exposed to low-medium arsenic levels via drinking water, was investigated to evaluate the effects of a lifetime exposure to arsenic on mortality from cancers and chronic diseases. Methods The study population consisted of 165,609 residents of 17 municipalities, followed from 1990 until 2010. Average individual arsenic exposure at the first residence (AsI) was estimated through a space-time modeling approach using residential history and arsenic concentrations from water supply. A time-dependent Cumulative Arsenic dose Indicator (CAI) was calculated, accounting for daily water intake and exposure duration. Mortality Hazard Ratios (HR) were estimated by gender for different diseases using Cox proportional models, adjusting for individual and area-level confounders. A flexible non-parametric approach was used to investigate dose-response relationships. Results Mean AsI exposure was 19.3 μg/L, and average exposure duration was 39.5 years. Associations of AsI and CAI indicators with several diseases were found, with greatest risks found for lung cancer in both sexes (HR = 2.61 males; HR = 2.09 females), myocardial infarction, peripheral arterial disease and COPD in males (HR = 2.94; HR = 2.44; HR = 2.54 respectively) and diabetes in females (HR = 2.56). For lung cancer and cardiovascular diseases dose-response relationship is modelled by piecewise linear functions revealing effects even for doses lower than 10 μg/L, and no threshold dose value was identified as safe for health. Conclusions Results provide new evidence for risk assessment of low-medium concentrations of arsenic and contribute to the ongoing debate about the threshold-dose of effect, suggesting that even concentrations below 10 μg/L carry a mortality risk. Policy actions are urgently needed in areas exposed to arsenic like in the Viterbo province, to comply with current EU regulations. PMID:26383851

21 CFR 320.31 - Applicability of requirements regarding an “Investigational New Drug Application.”

Code of Federal Regulations, 2010 CFR

2010-04-01

... patients where either the maximum single or total daily dose exceeds that specified in the labeling of the... application. (2) A multiple-dose study in normal subjects or patients where either the single or total daily... conducting the study, including any contract research organization, shall retain reserve samples of any test...

Once-daily MMX(®) mesalamine for endoscopic maintenance of remission of ulcerative colitis.

PubMed

D'Haens, Geert; Sandborn, William J; Barrett, Karen; Hodgson, Ian; Streck, Paul

2012-07-01

Treatment with mesalamine to maintain endoscopic remission (mucosal healing) of ulcerative colitis (UC) has been shown to reduce the risk of relapse and is the recommended first-line maintenance therapy. To improve treatment adherence, a mesalamine formulation that can be administered once-daily, MMX(®) mesalamine (Lialda; Shire Pharmaceuticals LLC, Wayne, PA), was developed. This study was conducted to determine the efficacy and safety of once-daily MMX mesalamine compared with twice-daily delayed-release mesalamine (Asacol; Warner Chilcott, Dublin, Ireland) for maintaining endoscopic remission in patients with UC. A multicenter, randomized, double-blind, 6-month, active-control trial was conducted to assess the non-inferiority of once-daily MMX mesalamine 2.4 g/day compared with twice-daily delayed-release mesalamine at a total daily dose of 1.6 g/day in patients with UC in endoscopic remission. The primary end point was maintenance of endoscopic remission at month 6 in the per-protocol (PP) population. Overall, 826 patients were randomized and dosed. The primary objective (non-inferiority) was met. At month 6, 83.7 and 77.8% of patients receiving MMX mesalamine in the PP and intent-to-treat (ITT) populations, respectively, had maintained endoscopic remission compared with 81.5% (PP) and 76.9% (ITT) of patients receiving delayed-release mesalamine (95% confidence interval for difference: -3.9%, 8.1% (PP); -5.0%, 6.9% (ITT)). Time to relapse was not significantly different between the two treatment groups (log-rank test, P=0.5116 (PP); P=0.5455 (ITT)). The proportion of patients with adverse events was 37.1 and 36.0% in patients receiving MMX mesalamine and delayed-release mesalamine, respectively. Once-daily dosing of MMX mesalamine 2.4 g/day was shown to be well tolerated and non-inferior to twice-daily dosing with delayed-release mesalamine 1.6 g/day for maintenance of endoscopic remission in patients with UC.

Health and productivity of dairy cows fed polychlorinated biphenyls

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

Willett, L.B.; Liu, T.T.; Durst, H.I.

1987-07-01

Holstein cows were studied through a complete lactation, a nonlactating period, and 42 days of a subsequent lactation for overt and subtle responses to a commercial mixture of polychlorinated biphenyls. Dosed cows (n = 4) received consecutive 60-day periods of daily dosing with 10, 100, and 1000 mg of Aroclor 1254. Control cows (n = 6) received daily sham doses. The following were recorded: daily milk production, feed intake, and health observations; weekly body weight, temperature, heart and respiratory rates and rectal palpation; semi-monthly clinical chemistry determinations; and monthly milk fat, microbiological culture of quarter foremilk samples, and composite milkmore » somatic cell counts. Mean daily milk production (22.4 +/- 1.1 vs 24.8 +/- 1.0 kg) and net energy of a complete lactation (1.46 +/- 0.05 vs 1.45 +/- 0.03 Mcal/kg dry matter intake) were not different (p = 0.85) for control and PCB-dosed cows. Milk production during the first 42 days of the subsequent lactation was also similar for control and dosed cows. Occurrences of injuries, dysfunctions, and general infections were not related to polychlorinated biphenyl exposure. Intramammary infections were detected for both lactations with 51 and 32 infections detected in microbiological cultures, respectively, for the control and dosed groups. Environmental pathogens were most frequently isolated from cases of clinically apparent mastitis. The majority of quarter infections detected were due to Corynebacterium bovis. Only one animal (dosed, necropsy revealed left oviduct obstructed) failed to conceive with three to six services required before conception for the other control and dosed cows. Exposure to polychlorinated biphenyls resulting in maximal residues in milk fat, near 100 micrograms/g, had no apparent effect on health and productivity.« less

Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics.

PubMed

Freise, Kevin J; Hu, Beibei; Salem, Ahmed Hamed

2018-04-01

Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects. In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2. In cohort 3, subjects received 10-mg venetoclax doses on day 1 of period 1 and days 1 and 11 of period 2, and 50 mg ritonavir daily on days 1 to 14 of period 2. Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration (C max ) 2.3- to 2.4-fold compared to venetoclax alone and the area under the curve (AUC) 6.1- and 8.1-fold, respectively. Daily 50 mg ritonavir resulted in a 2.4- and 7.9-fold increase in venetoclax C max and AUC, respectively. Administration of 50 mg ritonavir daily saturated CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50 mg ritonavir was offset by ritonavir CYP3A induction, resulting in a limited net increase in CYP3A inhibition with multiple doses. After completion of the dose ramp-up, venetoclax dose reductions of at least 75% are recommended when administered concomitantly with strong CYP3A inhibitors to maintain venetoclax exposures within the established therapeutic window for CLL treatment.

Pergolide: multiple-dose pharmacokinetics in patients with mild to moderate Parkinson disease.

PubMed

Thalamas, Claire; Rajman, Iris; Kulisevsky, Jaime; Lledó, Alberto; Mackie, Alison E; Blin, Olivier; Gillespie, Todd A; Seger, Mary; Rascol, Olivier

2005-01-01

The primary objective of this study was to describe the pharmacokinetics of oral pergolide in patients with mild to moderate Parkinson disease using a new high-performance liquid chromatography-tandem mass spectrometry assay. A secondary objective was to investigate the relationship between plasma concentrations and efficacy. Fourteen patients with a diagnosis of Parkinson disease completed this multicenter, open-label, dose-escalating study. Pergolide was administered for 58 days, using increasing daily doses from 0.05 mg daily up to 1 mg three times daily and then tapering the dose. The steady-state pharmacokinetic profile and motor score were determined at dose levels of 0.25, 0.5, and 1 mg three times a day and during elimination after the last dose. Pergolide was absorbed with a median time to maximum concentration of 2 to 3 hours across the dose range. Systemic exposure appeared to increase proportionally with dose over the range of 0.25 to 1 mg three times daily within a patient, but there was a large variability in exposures between patients (interpatient coefficients of variation were 56.4% for the area under the curve). Pergolide was widely distributed (volume of distribution, approximately 14,000 L) and was eliminated with a mean half-life of 21 hours. Motor scores improved as both peak plasma pergolide concentrations and exposure increased. No unexpected safety concerns were identified. Pergolide is absorbed relatively quickly into the systemic circulation, has a large apparent volume of distribution, and has a relatively long half-life (mean, 21 hours). This prolonged half-life is of particular interest, given the current hypothesis that more continuous dopaminergic receptor stimulation may reduce motor complications in patients with Parkinson disease.

Radiological study on newly developed composite corn advance lines in Malaysia

NASA Astrophysics Data System (ADS)

Adekunle Olatunji, Michael; Bemigho Uwatse, Onosohwo; Uddin Khandaker, Mayeen; Amin, Y. M.; Faruq, G.

2014-12-01

Owing to population growth, there has been high demand for food across the world, and hence, different agricultural activities such as use of phosphate fertilizers, recycling of organic matters, etc, have been deployed to increase crop yields. In Malaysia, a total of nine composite corn advance lines have been developed at the Institute of Biological Sciences, University of Malaya and are being grown under different conditions with a bid to meet the average daily human need for energy and fiber intake. To this end, the knowledge of radioactivity levels in these corn advance lines are of paramount importance for the estimation of possible radiological hazards due to its consumption. Hence, the radioactivity concentrations of 226Ra, 228Ra and 40K in the corn have been determined using HPGe γ-ray spectrometry. The activity concentrations in the corn ranged from 0.05 to 19.18 Bq kg-1 for 226Ra, from 0.10 to 3.22 Bq kg-1 for 228Ra and from 26.4 to 129 Bq kg-1 for 40K. In order to ascertain the radiological safety of the population regarding maize consumption, the daily intakes of these radionuclides as well as the annual effective dose were estimated. The total effective dose obtained due to the ingestion of radionuclides via maize consumption is 15.39 μSv y-1, which is less than the international recommendations.

Variations in Daily Sleep Quality and Type 1 Diabetes Management in Late Adolescents

PubMed Central

Queen, Tara L.; Butner, Jonathan; Wiebe, Deborah; Berg, Cynthia A.

2016-01-01

Objective To determine how between- and within-person variability in perceived sleep quality were associated with adolescent diabetes management. Methods A total of 236 older adolescents with type 1 diabetes reported daily for 2 weeks on sleep quality, self-regulatory failures, frequency of blood glucose (BG) checks, and BG values. Average, inconsistent, and daily deviations in sleep quality were examined. Results Hierarchical linear models indicated that poorer average and worse daily perceived sleep quality (compared with one’s average) was each associated with more self-regulatory failures. Sleep quality was not associated with frequency of BG checking. Poorer average sleep quality was related to greater risk of high BG. Furthermore, inconsistent and daily deviations in sleep quality interacted to predict higher BG, with more consistent sleepers benefitting more from a night of high-quality sleep. Conclusions Good, consistent sleep quality during late adolescence may benefit diabetes management by reducing self-regulatory failures and risk of high BG. PMID:26994852

An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN-D0501 in healthy subjects

PubMed Central

Round, Patrick; Priestley, Anthony; Robinson, Jan

2011-01-01

AIMS XEN-D0501, a novel TRPV1 antagonist, is being developed to treat overactive bladder. This study investigated the safety and pharmacokinetics of repeat-dose XEN-D0501 in healthy subjects. METHODS The study was conducted in two parts. Part 1 was a double-blind, randomized, placebo-controlled, two-way crossover study in three cohorts of 12 young male subjects. Each subject received XEN-D0501 and placebo (in random order) twice daily for 13 days, with a final single dose on day 14. Doses of 1, 2.5 and 5 mg XEN-D0501 were investigated. Part 2 was an open-label, randomized, two-way crossover study in male and female subjects (45 to 65 years). Subjects received single doses of 5 mg XEN-D0501 under fasted and fed conditions in random order. Blood sampling and safety assessments were conducted throughout the study. RESULTS XEN-D0501 was rapidly absorbed (tmax generally 0.5–4 h post dose). XEN-D0501 exposure increased less than proportionally to dose over the range studied and exhibited minimal accumulation with twice daily dosing. Food had no clinically relevant effects on the pharmacokinetics of XEN-D0501. There were no severe or serious adverse events and all doses were well tolerated. A dose-related increase in body temperature was seen with XEN-D0501 which attenuated over time. Differences from placebo in mean maximum core body temperatures were 0.22°C, 0.5°C and 0.74°C following 1 mg, 2.5 mg and 5 mg twice daily XEN-D0501. The observed increase in body temperature was not considered to be of clinical concern. CONCLUSIONS XEN-D0501 appeared safe and well tolerated at doses up to 5 mg twice daily for 14 days in healthy subjects. PMID:21676011

Nutraceutic effect of free condensed tannins of Lysiloma acapulcensis (Kunth) benth on parasite infection and performance of Pelibuey sheep.

PubMed

García-Hernández, Cesar; Arece-García, Javier; Rojo-Rubio, Rolando; Mendoza-Martínez, German David; Albarrán-Portillo, Benito; Vázquez-Armijo, José Fernando; Avendaño-Reyes, Leonel; Olmedo-Juárez, Agustín; Marie-Magdeleine, Carine; López-Leyva, Yoel

2017-01-01

Forty-five Pelibuey sheep were experimentally infested with nematodes to evaluate the effect of three free condensed tannin (FCT) levels of Lysiloma acapulcensis on fecal egg counts (FECs), packed cell volumes (PCV), ocular mucosa colors (OMC), average daily gain (ADG), and adult nematode count. Five treatments were used: 12.5, 25.0, and 37.5 mg of FCT kg -1 of body weight (BW); sterile water (control); and ivermectine (0.22 mg kg -1 of BW) as chemical group. The data were processed through repeated measurement analysis. Even though the three FCT doses decreased (P < 0.05) the FEC, the highest reduction was obtained with 37.5 mg kg -1 of BW. No differences were observed in PCV and OMC. Higher ADG (P < 0.05) was observed with 37.5 mg kg -1 of BW of FCT. The count of adult nematodes (females and males) in the higher dose of FCT was similar to chemical treatment. Dose of 37.5 mg kg -1 of BW decreased the parasite infection and improved the lamb performance. Therefore, this dose could be used as a nutraceutic product in sheep production.

Using smartphone as a motion detector to collect time-microenvironment data for estimating the inhalation dose.

PubMed

Hoi, Tran Xuan; Phuong, Huynh Truc; Van Hung, Nguyen

2016-09-01

During the production of iodine-131 from neutron irradiated tellurium dioxide by the dry distillation, a considerable amount of (131)I vapor is dispersed to the indoor air. People who routinely work at the production area may result in a significant risk of exposure to chronic intake by inhaled (131)I. This study aims to estimate the inhalation dose for individuals manipulating the (131)I at a radioisotope production. By using an application installed on smartphones, we collected the time-microenvironment data spent by a radiation group during work days in 2015. Simultaneously, we used a portable air sampler combined with radioiodine cartridges for grabbing the indoor air samples and then the daily averaged (131)I concentration was calculated. Finally, the time-microenvironment data jointed with the concentration to estimate the inhalation dose for the workers. The result showed that most of the workers had the annual internal dose in 1÷6mSv. We concluded that using smartphone as a motion detector is a possible and reliable way instead of the questionnaires, diary or GPS-based method. It is, however, only suitable for monitoring on fixed indoor environments and limited the targeted people. Copyright © 2016 Elsevier Ltd. All rights reserved.

Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer.

PubMed

Moehler, Markus; Mahlberg, Rolf; Heinemann, Volker; Obermannová, Radka; Kubala, Eugen; Melichar, Bohuslav; Weinmann, Arndt; Scigalla, Paul; Tesařová, Marietta; Janda, Petr; Hédouin-Biville, Fabienne; Mansoor, Wasat

2017-03-01

This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS). Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m 2 followed by oxaliplatin 130 mg/m 2 (maximum 8 cycles) and then S-1 [20 mg/m 2 (cohort 1) or 25 mg/m 2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2-14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer. DLT was reported for two of the five patients in cohort 2, defining 20 mg/m 2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m 2 twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations. The promising activity of EOS (S-1 dose level, 25 mg/m 2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC*

PubMed Central

Karschner, Erin L.; Schwope, David M.; Schwilke, Eugene W.; Goodwin, Robert S.; Kelly, Deanna L.; Gorelick, David A.; Huestis, Marilyn A.

2012-01-01

Background Determining time since last cannabis/Δ9-tetrahydrocannabinol (THC) exposure is important in clinical, workplace, and forensic settings. Mathematical models calculating time of last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing. Methods Ten male chronic, daily cannabis smokers received escalating around-the-clock oral THC (40-120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by two-dimensional gas chromatography-mass spectrometry. Results Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5 h (4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n=196), 11-hydroxy-THC 0.60 (n=189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n=200). Predictive models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100% of specimens collected within 1-5 h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5 h after the last THC dose, respectively. Conclusions Predictive models estimating time since last cannabis intake from whole blood and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate during active THC dosing. THC redistribution from large cannabinoid body stores and high circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less than daily cannabis smokers that were used to derive the models. Thus, the models do not accurately predict time of last THC intake in individuals consuming THC daily. PMID:22464363

Double oral esomeprazole after a 3-day intravenous esomeprazole infusion reduces recurrent peptic ulcer bleeding in high-risk patients: a randomised controlled study.

PubMed

Cheng, Hsiu-Chi; Wu, Chung-Tai; Chang, Wei-Lun; Cheng, Wei-Chun; Chen, Wei-Ying; Sheu, Bor-Shyang

2014-12-01

Patients with high Rockall scores have increased risk of ulcer rebleeding after 3-day esomeprazole infusions. To investigate whether double oral esomeprazole given after a 3-day esomeprazole infusion decreases ulcer rebleeding for patients with high Rockall scores. We prospectively enrolled 293 patients with peptic ulcer bleeding who had achieved endoscopic haemostasis. After a 3-day esomeprazole infusion, patients with Rockall scores ≥6 were randomised into the oral double-dose group (n=93) or the oral standard-dose group (n=94) to receive 11 days of oral esomeprazole 40 mg twice daily or once daily, respectively. The patients with Rockall scores <6 served as controls (n=89); they received 11 days of oral esomeprazole 40 mg once daily. Thereafter, all patients received oral esomeprazole 40 mg once daily for two more weeks until the end of the 28-day study period. The primary end point was peptic ulcer rebleeding. Among patients with Rockall scores ≥6, the oral double-dose group had a higher cumulative rebleeding-free proportion than the oral standard-dose group (p=0.02, log-rank test). The proportion of patients free from recurrent bleeding during the 4th-28th day in the oral double-dose group remained lower than that of the group with Rockall scores <6 (p=0.03, log-rank test). Among patients with Rockall scores ≥6, the rebleeding rate was lower in the oral double-dose group than in the oral standard-dose group (4th-28th day: 10.8% vs 28.7%, p=0.002). Double oral esomeprazole at 40 mg twice daily after esomeprazole infusion reduced recurrent peptic ulcer bleeding in high-risk patients with Rockall scores ≥6. NCT01591083. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

The effect of functional insulin therapy on glycaemic parameters in children with diabetes mellitus type 1.

PubMed

Štimjanin-Koldžo, Diana; Alajbegović, Salem; Štimjanin, Ena; Mehinagić, Jasmina

2017-08-01

Aim The aim of the study is to evaluate the effect of a prospectively conducted interactive 5-day education programme based on Düsseldorf model on glycated haemoglobin (A1C), and total daily dose of insulin in type 1 diabetes patients. Methods A total of 67 type 1 diabetes patients was analysed; mean age of 11±0.68 years, 43 females and 24 males. The programme was led by a trained team of diabetes specialist doctors and nurses. All subjects and their parents completed a knowledge test about diabetes at beginning, and at the end of education, and after 12 months (30 questions). Subjects were evaluated for total daily insulin, and HbA1c at baseline, as well as 3, 6, 9 and 12 months after the end of the education programme. Results Results of the knowledge test after the education have shown higher knowledge at baseline. At the end of the education programme an average of total daily insulin dose was significantly lower. There was a 3.17% reduction in HbA1c values over 9 months, and 1.8% over 12 months in the comparison to the baseline values (p<0.001). Conclusions Structured education programme of functional insulin therapy was associated with improved glycaemic control in type 1 diabetes patients and their parents. It motivated patients and parents to improve glycaemic control. One year after the follow up, glycaemic control was worsening, due to lack of patients' motivation, therefore, there is a need for yearly re-education. Copyright© by the Medical Assotiation of Zenica-Doboj Canton.

Efficacy and safety of lesogaberan in gastro-oesophageal reflux disease: a randomised controlled trial.

PubMed

Shaheen, Nicholas J; Denison, Hans; Björck, Karin; Karlsson, Maria; Silberg, Debra G

2013-09-01

Lesogaberan (AZD3355) is a novel γ-aminobutyric acid B-type receptor agonist designed to treat gastro-oesophageal reflux disease (GERD) by inhibiting transient lower oesophageal sphincter relaxations. A randomised, double-blind, placebo-controlled, multi-centre phase IIb study was performed to assess the efficacy and safety of lesogaberan as an add-on to proton pump inhibitor (PPI) therapy in patients with GERD who are partially responsive to PPI therapy (ClinicalTrials.gov reference: NCT01005251). In total, 661 patients were randomised to receive 4 weeks of placebo or 60, 120, 180 or 240 mg of lesogaberan twice daily, in addition to ongoing PPI therapy. Symptoms were measured using the Reflux Symptom Questionnaire electronic Diary. Response to treatment was defined as having an average of ≥ 3 additional days per week of not more than mild GERD symptoms during treatment compared with baseline. In the primary analysis, 20.9%, 25.6%, 23.5% and 26.2% of patients responded to the 60, 120, 180 and 240 mg twice daily lesogaberan doses, respectively, and 17.9% responded to placebo. The response to the 240 mg twice daily dose was statistically significantly greater than the response to placebo using a one-sided test at the predefined significance level of p < 0.1. However, the absolute increases in the proportions of patients who responded to lesogaberan compared with placebo were low. Lesogaberan was generally well tolerated, although six patients receiving lesogaberan developed reversible elevated alanine transaminase levels. In patients with GERD symptoms partially responsive to PPI therapy, lesogaberan was only marginally superior to placebo in achieving an improvement in symptoms.

Comparing daily temperature averaging methods: the role of surface and atmosphere variables in determining spatial and seasonal variability

NASA Astrophysics Data System (ADS)

Bernhardt, Jase; Carleton, Andrew M.

2018-05-01

The two main methods for determining the average daily near-surface air temperature, twice-daily averaging (i.e., [Tmax+Tmin]/2) and hourly averaging (i.e., the average of 24 hourly temperature measurements), typically show differences associated with the asymmetry of the daily temperature curve. To quantify the relative influence of several land surface and atmosphere variables on the two temperature averaging methods, we correlate data for 215 weather stations across the Contiguous United States (CONUS) for the period 1981-2010 with the differences between the two temperature-averaging methods. The variables are land use-land cover (LULC) type, soil moisture, snow cover, cloud cover, atmospheric moisture (i.e., specific humidity, dew point temperature), and precipitation. Multiple linear regression models explain the spatial and monthly variations in the difference between the two temperature-averaging methods. We find statistically significant correlations between both the land surface and atmosphere variables studied with the difference between temperature-averaging methods, especially for the extreme (i.e., summer, winter) seasons (adjusted R2 > 0.50). Models considering stations with certain LULC types, particularly forest and developed land, have adjusted R2 values > 0.70, indicating that both surface and atmosphere variables control the daily temperature curve and its asymmetry. This study improves our understanding of the role of surface and near-surface conditions in modifying thermal climates of the CONUS for a wide range of environments, and their likely importance as anthropogenic forcings—notably LULC changes and greenhouse gas emissions—continues.

High-dose transdermal nicotine replacement for tobacco cessation.

PubMed

Brokowski, Laurie; Chen, Jiahui; Tanner, Sara

2014-04-15

The safety and efficacy of high-dose transdermal nicotine-replacement therapy (NRT) for the treatment of tobacco-use cessation were reviewed. Transdermal nicotine doses of 7, 14, and 21 mg daily are approved by the Food and Drug Administration for use in tobacco cessation. However, studies have suggested that these doses are more adequate for people who smoke fewer than 20 cigarettes per day. A literature search was conducted to identify English-language studies that evaluated the use of transdermal nicotine doses of ≥42 mg daily. A total of 11 articles were identified, representing 10 separate trials. In terms of safety, the majority of the trials had no reports of serious adverse events related to transdermal NRT at doses of ≥42 mg daily. A dose-response relationship with adverse events occurred in most trials. In terms of efficacy, a numerically higher abstinence rate was achieved with high-dose transdermal NRT in all trials but 1. However, none of the studies showed significant differences in final abstinence rates at follow-up. Some reasons why statistical significance was not achieved in these trials may be related to the limitations of these trials, such as their small samples and the lack of a power calculation. A more robust trial is needed to support higher nicotine transdermal doses in tobacco cessation and to help elucidate which patient population would be most suitable for their use. The safety and efficacy of high-dose transdermal NRT for tobacco cessation have not been established in the medical literature.

A stochastic approach to estimate the uncertainty of dose mapping caused by uncertainties in b-spline registration

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

Hub, Martina; Thieke, Christian; Kessler, Marc L.

2012-04-15

Purpose: In fractionated radiation therapy, image guidance with daily tomographic imaging becomes more and more clinical routine. In principle, this allows for daily computation of the delivered dose and for accumulation of these daily dose distributions to determine the actually delivered total dose to the patient. However, uncertainties in the mapping of the images can translate into errors of the accumulated total dose, depending on the dose gradient. In this work, an approach to estimate the uncertainty of mapping between medical images is proposed that identifies areas bearing a significant risk of inaccurate dose accumulation. Methods: This method accounts formore » the geometric uncertainty of image registration and the heterogeneity of the dose distribution, which is to be mapped. Its performance is demonstrated in context of dose mapping based on b-spline registration. It is based on evaluation of the sensitivity of dose mapping to variations of the b-spline coefficients combined with evaluation of the sensitivity of the registration metric with respect to the variations of the coefficients. It was evaluated based on patient data that was deformed based on a breathing model, where the ground truth of the deformation, and hence the actual true dose mapping error, is known. Results: The proposed approach has the potential to distinguish areas of the image where dose mapping is likely to be accurate from other areas of the same image, where a larger uncertainty must be expected. Conclusions: An approach to identify areas where dose mapping is likely to be inaccurate was developed and implemented. This method was tested for dose mapping, but it may be applied in context of other mapping tasks as well.« less

A stochastic approach to estimate the uncertainty of dose mapping caused by uncertainties in b-spline registration

PubMed Central

Hub, Martina; Thieke, Christian; Kessler, Marc L.; Karger, Christian P.

2012-01-01

Purpose: In fractionated radiation therapy, image guidance with daily tomographic imaging becomes more and more clinical routine. In principle, this allows for daily computation of the delivered dose and for accumulation of these daily dose distributions to determine the actually delivered total dose to the patient. However, uncertainties in the mapping of the images can translate into errors of the accumulated total dose, depending on the dose gradient. In this work, an approach to estimate the uncertainty of mapping between medical images is proposed that identifies areas bearing a significant risk of inaccurate dose accumulation. Methods: This method accounts for the geometric uncertainty of image registration and the heterogeneity of the dose distribution, which is to be mapped. Its performance is demonstrated in context of dose mapping based on b-spline registration. It is based on evaluation of the sensitivity of dose mapping to variations of the b-spline coefficients combined with evaluation of the sensitivity of the registration metric with respect to the variations of the coefficients. It was evaluated based on patient data that was deformed based on a breathing model, where the ground truth of the deformation, and hence the actual true dose mapping error, is known. Results: The proposed approach has the potential to distinguish areas of the image where dose mapping is likely to be accurate from other areas of the same image, where a larger uncertainty must be expected. Conclusions: An approach to identify areas where dose mapping is likely to be inaccurate was developed and implemented. This method was tested for dose mapping, but it may be applied in context of other mapping tasks as well. PMID:22482640

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

PubMed Central

Lu, Yanhui; Bliven-Sizemore, Erin; Weiner, Marc; Nuermberger, Eric; Burman, William; Dorman, Susan E.; Dooley, Kelly E.

2014-01-01

Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h−1, respectively, after a single dose to 2.2 and 5.0 liters · h−1, respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.) PMID:24614383

The Model Averaging for Dichotomous Response Benchmark Dose (MADr-BMD) Tool

EPA Pesticide Factsheets

Providing quantal response models, which are also used in the U.S. EPA benchmark dose software suite, and generates a model-averaged dose response model to generate benchmark dose and benchmark dose lower bound estimates.

Effects of oral doses of fluoride on nestling European starlings

USGS Publications Warehouse

Fleming, W.J.; Grue, C.E.; Schuler, C.A.; Bunck, C.M.

1987-01-01

Nestling European starlings (Sturnus vulgaris), raised and fed by free-living adults, were given daily oral doses of either distilled water, 193 mg sodium as Na2CO3 per kg of body weight (sodium control group), or 6, 10, 13, 17,23, 30, 40, 80, 160 mg of the fluoride ion as NaF in distilled water per kg of body weight (mg/kg). Dosing began when nestlings were 24-48 hr old and continued for 16 days. The 24-hr LD50 of fluoride for day-old starlings was 50 mg/kg. The 16-day LD50 was 17 mg/kg. The sodium control group did not differ from the water control group with respect to any of the measured variables. Growth rates were significantly reduced in the 13 and 17 mg of fluoride/kg groups; weights of birds given higher dose levels were omitted from growth comparisons because of high, fluoride-induced mortality. Although pre-fledging weights for the 10, 13, and 17 mg of fluoride/kg groups averaged 3.6 to 8.6% less than controls at 17 days, this difference was not significant. Feather and bone growth of the fluoride and control groups were not different, except for keel length measured at 17 days of age which averaged less in the fluoride groups. Liver and spleen weights were not affected by fluoride treatments. No histological damage related to fluoride treatments was found in liver, spleen, or kidney. The logarithm of bone fluoride and magnesium concentration increased with the logarithm of increasing fluoride treatment levels and were significantly correlated with each other. Fluoride treatments had no effect on percent calcium or phosphorus in bone or plasma alkaline phosphatase activity. Oral doses of fluoride appear to be more toxic than equivalent dietary levels. Most birds probably acquire fluoride through their diet. Therefore, the results of the study may overestimate the potential effects of fluorides on songbirds living in fluoride-contaminated environments.

A Feasibility Study of Bihormonal Closed-Loop Blood Glucose Control Using Dual Subcutaneous Infusion of Insulin and Glucagon in Ambulatory Diabetic Swine

PubMed Central

El-Khatib, Firas H.; Jiang, John; Damiano, Edward R.

2009-01-01

Background We sought to test the feasibility and efficacy of bihormonal closed-loop blood glucose (BG) control that utilizes subcutaneous (SC) infusion of insulin and glucagon, a model-predictive control algorithm for determining insulin dosing, and a proportional-derivative control algorithm for determining glucagon dosing. Methods Thirteen closed-loop experiments (∼7–27 h in length) were conducted in six ambulatory diabetic pigs weighing 26–50 kg. In all experiments, venous BG was sampled through a central line in the vena cava. Efficacy was evaluated in terms of the controller's ability to regulate BG in response to large meal disturbances (∼5 g of carbohydrate per kilogram of body mass per meal) based only on regular frequent venous BG sampling and requiring only the subject's weight for initialization. Results Closed-loop results demonstrated successful BG regulation to normoglycemic range, with average insulin-to-carbohydrate ratios between ∼1:20 and 1:40 U/g. The total insulin bolus doses averaged ∼6 U for a meal containing ∼6 g per kilogram body mass. Mean BG values in two 24 h experiments were ∼142 and ∼155 mg/dl, with the total daily dose (TDD) of insulin being ∼0.8–1.0 U per kilogram of body mass and the TDD of glucagon being ∼0.02–0.05 mg. Results also affirmed the efficacy of SC doses of glucagon in staving off episodic hypoglycemia. Conclusions We demonstrate the feasibility of bihormonal closed-loop BG regulation using a control system that employs SC infusion of insulin and glucagon as governed by an algorithm that reacts only to BG without any feed-forward information regarding carbohydrate consumption or physical activity. As such, this study can reasonably be regarded as the first practical implementation of an artificial endocrine pancreas that has a hormonally derived counterregulatory capability. PMID:20144330

Imatinib dose reduction in patients with chronic myeloid leukemia in sustained deep molecular response.

PubMed

Cervantes, Francisco; Correa, Juan-Gonzalo; Pérez, Isabel; García-Gutiérrez, Valentín; Redondo, Sara; Colomer, Dolors; Jiménez-Velasco, Antonio; Steegmann, Juan-Luis; Sánchez-Guijo, Fermín; Ferrer-Marín, Francisca; Pereira, Arturo; Osorio, Santiago

2017-01-01

To determine whether a lower imatinib dose could minimize toxicity while maintaining the molecular response (MR), imatinib dose was reduced to 300 mg daily in 43 patients with chronic myeloid leukemia (CML) in sustained deep molecular response to first-line imatinib 400 mg daily. At the time of dose reduction, median duration of the deep response was 4.1 (interquartile range (IQR) 2.2-5.9) years; molecular response was MR 4 , MR 4.5 , and MR 5 of the international scale in 6, 28, and 9 patients, respectively. Toxicity grade was 1, 2, and 3 in 28, 8, and 1 patients, respectively; 6 patients underwent dose reduction without having side effects. With a median of 1.6 (IQR 0.7-3.2) years on imatinib 300 mg daily, only one patient lost the deep molecular response to MR 3 . At the last follow-up, response was MR 3 , MR 4 , MR 4.5 , and MR 5 in 1, 3, 9, and 30 patients, respectively. Toxicity improvement was observed in 23 (62.2 %) of the 37 patients with side effects, decreasing to grade 0 in 20 of them. All but one anemic patients improved (p = 0.01), the median Hb increase in this subgroup of patients being 1 g/dL. In CML patients with sustained deep response to the standard imatinib dose, reducing to 300 mg daily significantly improves tolerability and preserves efficacy.

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

PubMed

Ettienne, Earl B; Chapman, Edwin; Maneno, Mary; Ofoegbu, Adaku; Wilson, Bradford; Settles-Reaves, Beverlyn; Clarke, Melissa; Dunston, Georgia; Rosenblatt, Kevin

2017-12-01

Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes. We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management. At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing. Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

Once daily vs multiple daily mesalamine therapy for mild to moderate ulcerative colitis: a meta-analysis.

PubMed

Li, W; Zhang, Z-M; Jiang, X-L

2016-07-01

5-Aminosalicylic acid is the first-line drug for mild to moderate ulcerative colitis (UC). The most commonly used 5-aminosalicylic acid is mesalamine. Several systematic reviews have demonstrated that mesalamine is effective in inducing and maintaining remission. Efficacy, safety and adherence to once daily (OD) and multiple daily (MD) dosing of mesalamine for the induction and maintenance of remission in mild to moderate UC were systematically reviewed and compared. PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched from inception to November 2014. Only randomized controlled trials were considered eligible. STATA software (version 12.0) was used to calculate the pooled risk ratios with 95% confidence interval. Seventeen randomized studies containing 5439 patients were identified. No significant differences were noted in comparisons between OD and MD dosing for maintenance and induction of remission. No significant differences were noted in rates of medication adherence or adverse events between OD and MD dosing. With regard to mesalamine suppository, no significant differences were noted for comparisons between dosing regimens and adverse events for induction of remission. OD dose of mesalamine is as effective and safe as MD doses for the induction and maintenance treatment of mild to moderate UC. OD mesalamine given as a suppository can attain the same effect and safety as MD mesalamine in inducing remission of mild to moderate ulcerative colitis. Colorectal Disease © 2016 The Association of Coloproctology of Great Britain and Ireland.

Memantine-induced chorea and dystonia.

PubMed

Borges, Letizia Goncalves; Bonakdarpour, Borna

2017-04-01

Memantine is an uncompetitive N -methyl-d-aspartate receptor antagonist and probably also has an indirect dopaminergic action at high concentrations. We describe a person with Alzheimer's disease who developed chorea and dystonia after inadvertently doubling of her daily dose by taking extended-release (XR) memantine twice daily, rather than once daily (planned dose memantine XR, 21 mg once daily), after the drug was switched from immediate release (IR, 10 mg twice daily). Memantine is rarely associated with movement disorders, but this case emphasises the need for awareness of potential problems when switching from memantine IR to XR. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Systematic review of the relationship of Helicobacter pylori infection with geographical latitude, average annual temperature and average daily sunshine.

PubMed

Lu, Chao; Yu, Ye; Li, Lan; Yu, Chaohui; Xu, Ping

2018-04-17

Helicobacter pylori (H. pylori) infection is a worldwide threat to human health with high prevalence. In this study, we analyzed the relationship between latitude, average annual temperature, average daily sunshine time and H. pylori infection. The PubMed, ClinicalTrials.gov , EBSCO and Web of Science databases were searched to identify studies reporting H. pylori infection. Latitude 30° was the cut-off level for low and mid-latitude areas. We obtained information for latitude, average annual temperature, average daily sunshine, and Human Development Index (HDI) from reports of studies of the relationships with H. pylori infection. Of the 51 studies included, there was significant difference in H. pylori infection between the low- and mid-latitude areas (P = 0.05). There was no significant difference in the prevalence of H. pylori infection in each 15°-latitude zone analyzed (P = 0.061). Subgroup analysis revealed the highest and lowest H. pylori infection rates in the developing regions at > 30° latitude subgroup and the developed regions at < 30° latitude subgroup, respectively (P < 0.001). Multivariate analysis showed that average annual temperature, average daily sunshine time and HDI were significantly correlated with H. pylori infection (P = 0.009, P < 0.001, P < 0.001), while there was no correlation between H. pylori infection and latitude. Our analysis showed that higher average annual temperature was associated with lower H. pylori infection rates, while average daily sunshine time correlated positively with H. pylori infection. HDI was also found to be a significant factor, with higher HDI associated with lower infection rates. These findings provide evidence that can be used to devise strategies for the prevention and control of H. pylori.

Monitoring of solar-UV exposure among schoolchildren in five Japanese cities using spore dosimeter and UV-coloring labels.

PubMed

Munakata, N; Ono, M; Watanabe, S

1998-03-01

To monitor personal exposure to biologically effective solar-UV radiation, Bacillus subtilis spores on a membrane filter and UV-coloring labels were incorporated into a monitoring badge. The samples were covered with one of three types of filter sheet, dependent on the season, to reduce the amounts of exposure to measurable levels. Five fifth- or sixth-grade classes of primary schools, each consisting of 30-40 children, were chosen in northern (Sapporo), central (Tsukuba and Tokyo), and southern (Miyazaki and Naha) cities in Japan. In all four season, each child wore a badge on an upper arm for the entire waking hours, changing it daily, for a week. Upon collection of the badges, the survival of spores and the extent of coloration of the label were determined. The results were used to estimate the amount of daily exposure to biologically effective UV radiation, expressed as the value of spore inactivation dose. Unexpectedly, the average amounts of exposure were not directly correlated with the outdoor UV irradiance: in the two southern cities, despite high outdoor irradiance from spring to autumn, the average amounts of exposure were less than 3.1% of the average irradiance. Highly concentrated exposures occurred in two central cities on three days when extensive outdoor exercise took place. These results contradict the simple notion that children's exposure is in proportion to the outdoor UV irradiance, and support the view that the extent of solar-UV exposure is primarily determined by life-style rather than living location.

Monitoring of Solar‐UV Exposure among Schoolchildren in Five Japanese Cities Using Spore Dosimeter and UV‐coloring Labels

PubMed Central

Ono, Masashi; Watanabe, Shaw

1998-01-01

To monitor personal exposure to biologically effective solar‐UV radiation, Bacillus subtilis spores on a membrane filter and UV‐coloring labels were incorporated into a monitoring badge. The samples were covered with one of three types of filter sheet, dependent on the season, to reduce the amounts of exposure to measurable levels. Five fifth‐ or sixth‐grade classes of primary schools, each consisting of 30–40 children, were chosen in northern (Sapporo), central (Tsukuba and Tokyo), and southern (Miyazaki and Naha) cities in Japan. In all four seasons, each child wore a badge on an upper arm for the entire waking hours, changing it daily, for a week. Upon collection of the badges, the survival of spores and the extent of coloration of the label were determined. The results were used to estimate the amount of daily exposure to biologically effective UV radiation, expressed as the value of spore inactivation dose. Unexpectedly, the average amounts of exposure were not directly correlated with the outdoor UV irradiance: in the two southern cities, despite high outdoor irradiance from spring to autumn, the average amounts of exposure were less than 3.1% of the average irradiance. Highly concentrated exposures occurred in two central cities on three days when extensive outdoor exercise took place. These results contradict the simple notion that childrens' exposure is in proportion to the outdoor UV irradiance, and support the view that the extent of solar‐UV exposure is primarily determined by life‐style rather than living location. PMID:9600116

Can oral 5-aminosalicylic acid be administered once daily in the treatment of mild-to-moderate ulcerative colitis? A meta-analysis of randomized-controlled trials.

PubMed

Zhu, Ying; Tang, Ren-Kuan; Zhao, Peng; Zhu, Shi-sheng; Li, Yong-guo; Li, Jian-bo

2012-05-01

Several trials have demonstrated that oral delayed-release mesalamine might be administered once daily. We aimed to conduct a meta-analysis to investigate this. A comprehensive and multiple-source literature search was carried out. Only randomized-controlled trials (RCTs) were investigated by comparing a once daily-dosing regime with a divided (twice or thrice daily)-dosing regime of oral delayed-release mesalamine formulations for induction or maintenance of remission in patients with mild-to-moderate ulcerative colitis. The quality of RCTs was assessed using the Jadad scores. Meta-analysis of pooled odds ratios was carried out using Review Manager 5.1. Nine RCTs were finally included. With regard to meta-analyses for induction trials, there were no significant differences for all comparisons between the once daily and the divided groups, including maintenance of just clinical remission (P=0.52) and just endoscopic remission (P=0.23), maintenance of combined clinical and endoscopic remission (P=0.78), and the overall incidence of adverse events (P=0.61). With regard to meta-analyses for maintenance trials, there were also no significant differences for all comparisons between once daily and divided groups, including maintenance of just clinical remission (P=0.73) and just endoscopic remission (P=0.43), maintenance of combined clinical and endoscopic remission (P=0.43), the overall incidence of adverse events (P=0.12) as well as compliance with the prescribed medication (P=0.34). The present work showed that oral delayed-release mesalazine administered as a single or a divided dose demonstrated a good safety profile, which was well tolerated and effective as either maintenance or induction treatment. High clinical and/or endoscopic remission rates can be achieved with once-daily dosing.

Phenformin in Insulin-Dependent Diabetics

PubMed Central

Bloom, Arnold; Kolbe, R. J.

1970-01-01

Forty-one diabetic patients on insulin were given 100mg. of phenformin daily for six weeks, either before or after a period of six weeks of inert capsules, in a double-blind cross-over trial. Eleven patients while on phenformin noticed hypoglycaemic effects and reduced their insulin on average by almost 20% without resultant rise in blood sugar levels. Twenty-eight patients felt no untoward effects and maintained their usual insulin dose. Phenformin led to improved control of the diabetes, with a significant decrease in blood sugar levels and a significant reduction in the variability of the weekly blood sugar readings. There was no increased ketosis, no change in cholesterol, and no significant loss of weight. PMID:4914612

Pupillometry as an indicator of L-DOPA dosages in Parkinson's disease patients.

PubMed

Bartošová, O; Bonnet, C; Ulmanová, O; Šíma, M; Perlík, F; Růžička, E; Slanař, O

2018-04-01

Dopamine was shown to induce mydriasis by excitation of alpha-adrenergic receptors at the dilator pupillae muscle. Pupilla diameter may thus serve as an indirect measure of peripheral pharmacokinetics of L-DOPA and dopamine. The aim of this study is to evaluate the effect of L-DOPA dosage on pupillometric parameters in Parkinson's disease (PD) patients. Sixteen PD patients and 14 healthy control subjects (CS) were studied. The statistical analysis revealed significant differences between CS and PD patients for the mean maximum and minimum pupil diameters (p = 0.017, p = 0.028, respectively), with higher values found in PD. Moreover, a significant dose-response relationship was found between the maximum pupil diameter and both the morning L-DOPA dose (R 2  = 0.78) and the total daily L-DOPA dose (R 2  = 0.93). A sigmoid-shaped curve best describes the dose-response relationship, with a ceiling effect at about 400 mg L-DOPA daily dose. In conclusion, measuring pupillometric parameters represents a sensitive tool for non-invasive evaluation of the peripheral effect of L-DOPA, especially with daily doses below 400 mg L-DOPA.

Survival, Intestinal Mucosa Adhesion, and Immunomodulatory Potential of Lactobacillus plantarum Strains.

PubMed

Santarmaki, Valentini; Kourkoutas, Yiannis; Zoumpopoulou, Georgia; Mavrogonatou, Eleni; Kiourtzidis, Mikis; Chorianopoulos, Nikos; Tassou, Chrysoula; Tsakalidou, Effie; Simopoulos, Constantinos; Ypsilantis, Petros

2017-09-01

Survival during transit through the gastrointestinal track, intestinal mucosa adhesion, and a potential immunomodulatory effect of Lactobacillus plantarum strains 2035 and ACA-DC 2640 were investigated in a rat model. According to microbiological and multiplex PCR analysis, both strains were detected in feces 24 h after either single-dose or daily administration for 7 days. Intestinal mucosa adhesion of L. plantarum 2035 was noted in the large intestine at 24 h after single-dose administration, while it was not detected at 48 h. Daily dosing, prolonged detection of the strain up to 48 h post-administration, and expanded adhesion to the small intestine. Adhesion of L. plantarum ACA-DC 2640 to the intestinal mucosa after single-dose administration was prolonged and more extended compared to L. plantarum 2035. Daily dosing increased both the levels and the rate of positive cultures of the strains compared to those of the single-dose scheme. In addition, both strains increased total IgG while decreased IgM and IgA serum levels. In conclusion, L. plantarum 2035 and L. plantarum ACA-DC 2640 survived transit through the gastrointestinal track, exhibited transient distinct adhesion to the intestinal mucosa and modulated the systemic immune response.

Single dose (400 mg) versus 7 day (200 mg) daily dose itraconazole in the treatment of tinea versicolor: a randomized clinical trial.

PubMed

Wahab, M A; Ali, M E; Rahman, M H; Chowdhury, S A; Monamie, N S; Sultana, N; Khondoker, L

2010-01-01

Tinea (pityriasis) versicolor is a superficial fungal infection and one of the most commonly found pigmentary disorders of skin caused by the yeast Malassezia. Multiple topical as well as systemic therapies are available for treatment. Systemic therapies are used for extensive disease, frequent relapse or where topical agents have failed. The aim that translates the rationale of the study was to compare the efficacy, safety, tolerability and cost effectiveness of single dose 400mg versus 7 day 200 mg daily dose of itraconazole in the treatment of tinea versicolor. A clinical study was done to compare the efficacy of single dose (400 mg) of itraconazole and 7 day 200 mg daily dose of itraconazole in the treatment of extensive tinea versicolor. Total 60 patients (aged 18-50 years) were selected for the study during the period of June 2007 to May 2008 in the department of Dermatology of three different hospitals in Bangladesh. Cases having with extensive involvement, diagnosed clinically and confirmed by wood's lamp and KOH microscopy were taken. Patients were randomly allocated into equal groups. Group A was given single dose 400 mg itraconazole and Group B was given 7 day 200 mg daily itraconazole. Fifty three (88%) male and 7(12%) female were included in the study. The mean age of group A was 32.37+/-9 years and in group B 33.23+/-8 years. The mean duration of the disease in group A was 2.63+/-2 months and 2.76+/-2 months in group B. In group A clinical responders was found cure 22(73.33%) and improvement 5(16.33%) and in group B it was found cure 24(79.99%) and improvement 4(13.33%). The measure at the End point (EP1) equals to 90% response and in-group B it was found cure 24 (79.99%) and improvement 4(13.33%). (Here the End point EP2) equals to 93.33%. The EP clinical analysis however shows 91.66% response. Both single dose and 7 day daily dose of itraconazole can be effective in the treatment of tinea versicolor with extensive involvement but single dose appears to be better for improving compliance and decreasing the cost of treatment.

Estimation of average daily traffic on local roads in Kentucky.

DOT National Transportation Integrated Search

2016-07-01

Kentucky Transportation Cabinet (KYTC) officials use annual average daily traffic (AADT) to estimate intersection : performance across the state maintained highway system. KYTC currently collects AADTs for state maintained : roads but frequently lack...

Serial sinus aspirate samples during high-dose, short-course levofloxacin treatment of acute maxillary sinusitis.

PubMed

Anon, Jack B; Paglia, Margaret; Xiang, Jim; Ambrose, Paul G; Jones, Ronald N; Kahn, James B

2007-01-01

This study assessed daily aspirate samples from an indwelling sinus catheter during high-dose, short-course levofloxacin (750 mg daily x 5 days) treatment of acute maxillary sinusitis. Pathogens were isolated from 4 of 18 recruited patients. Bacteriologic eradication occurred within 24 h for 3 patients and 72 h for the 4th.

Acute and Chronic Effects of Cocaine on the Spontaneous Behavior of Pigeons

ERIC Educational Resources Information Center

Pinkston, Jonathan W.; Branch, Marc N.

2010-01-01

The present experiment examined the effects of acute and daily cocaine on spontaneous behavior patterns of pigeons. After determining the acute effects of a range of doses, 9 pigeons were divided into three groups that received one of three doses of cocaine daily, either 1.0, 3.0, or 10.0 mg/kg cocaine. Measures were taken of spontaneous…

Acute migraine medication adherence, migraine disability and patient satisfaction: A naturalistic daily diary study.

PubMed

Seng, Elizabeth K; Robbins, Matthew S; Nicholson, Robert A

2017-09-01

Objective To examine the influence of acute migraine medication adherence on migraine disability and acute medication satisfaction. Methods Adults with migraine completed three months of daily electronic diaries assessing headache symptoms, acute medication taken, acute medication satisfaction, and daily migraine disability. Repeated measures mixed-effects models examined the effect of initial medication type [migraine-specific medication (MSM) vs. over-the-counter analgesic (OTC) vs. an opiate/barbiturate], the severity of pain at dosing, and their interaction with daily migraine disability and satisfaction with acute medication. Results Participants (N = 337; 92.5% female; 91.1% Caucasian, non-Hispanic; 84.0% with episodic migraine) recorded 29,722 diary days. Participants took acute medication on 96.5% of 8090 migraine days. MSM was most frequently taken first (58%), followed by OTC (29.9%) and an opiate/barbiturate (12.1%). Acute medication was most frequently taken when pain was mild (41.2%), followed by moderate (37.7%) and severe pain (11.4%). Initially dosing with MSM while pain was mild was associated with the lowest daily disability [medication × pain at dosing F (4, 6336.12) = 58.73, p < .001] and highest acute medication satisfaction [medication × pain at dosing F (4, 3867.36) = 24.00, p < .001]. Conclusion Using an MSM (triptan or ergot) first was associated with the lowest migraine disability and highest acute medication satisfaction.

High school start times after 8:30 am are associated with later wake times and longer time in bed among teens in a national urban cohort study.

PubMed

Nahmod, Nicole G; Lee, Soomi; Buxton, Orfeu M; Chang, Anne-Marie; Hale, Lauren

2017-12-01

High school start times are a key contributor to insufficient sleep. This study investigated associations of high school start times with bedtime, wake time, and time in bed among urban teenagers. Daily-diary study nested within the prospective Fragile Families and Child Wellbeing Study. Twenty US cities. Four hundred thirteen teenagers who completed ≥1 daily diary report on a school day. Participating teens were asked to complete daily diaries for 7 consecutive days. School-day daily diaries (3.8±1.6 entries per person) were used in analyses (N=1555 school days). High school start time, the main predictor, was categorized as 7:00-7:29 am (15%), 7:30-7:59 am (22%), 8:00-8:29 am (35%), and 8:30 am or later (28%). Multilevel modeling examined the associations of school start times with bedtime, wake time, and time in bed. Models adjusted for age, sex, race/ethnicity, household income, caregiver's education, and school type. Teens with the earliest high school start times (7:00-7:29 am) obtained 46 minutes less time in bed on average compared with teens with high school start times at 8:30 am or later (P<.001). Teens exhibited a dose-response relationship between earlier school start times and shorter time in bed, primarily due to earlier wake times (P<.05). Start times after 8:30 am were associated with increased time in bed, extending morning sleep by 27-57 minutes (P<.05) when compared with teens with earlier school start times. Later school start times are associated with later wake times in our large, diverse sample. Teens starting school at 8:30 am or later are the only group with an average time in bed permitting 8 hours of sleep, the minimum recommended by expert consensus for health and well-being. Copyright © 2017 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.