Talan, David A; Klimberg, Ira W; Nicolle, Lindsay E; Song, James; Kowalsky, Steven F; Church, Deborah A
2004-02-01
We assessed the efficacy and safety of 1,000 mg extended release ciprofloxacin orally once daily vs conventional 500 mg ciprofloxacin orally twice daily, each for 7 to 14 days, in patients with a complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP). In this prospective, randomized, double-blind, North American multicenter clinical trial adults were stratified based on clinical presentation of cUTI or AUP and randomized to extended release ciprofloxacin or ciprofloxacin twice daily. Efficacy valid patients had positive pretherapy urine cultures (105 or greater cFU/ml) and pyuria within 48 hours of study entry. Bacteriological and clinical outcomes were assessed at the test of cure visit (5 to 11 days after therapy) and the late followup visit (28 to 42 days after therapy). The intent to treat population comprised 1,035 patients (extended release ciprofloxacin in 517 and twice daily in 518), of whom 435 were efficacy valid (cUTI in 343 and AUP in 92). For efficacy valid patients (cUTI and AUP combined) bacteriological eradication rates at test of cure were 89% (183 of 206) vs 85% (195 of 229) (95% CI -2.4%, 10.3%) and clinical cure rates were 97% (198 of 205) vs 94% (211 of 225) (95% CI -1.2%, 6.9%) for extended release vs twice daily ciprofloxacin. Late followup outcomes were consistent with test of cure findings. Eradication rates for Escherichia coli, which accounted for 58% of pathogens, were 97% or greater per group. Drug related adverse event rates were similar for extended release and twice daily ciprofloxacin (13% and 14%, respectively). Extended release ciprofloxacin at a dose of 1,000 mg once daily was as safe and effective as conventional treatment with 500 mg ciprofloxacin twice daily, each given orally for 7 to 14 days in adults with cUTI or AUP. It provides a convenient, once daily, empirical treatment option.
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S Yu Vorotnikova
2012-09-01
Full Text Available Реферат по статье: Assessment of efficacy and tolerability of once-daily extended release metformin in patients with type 2 diabetes mellitus Juliana Levy, Roberta A Cobas, Marilia B Gomes. Diabetol Metab Syndr. 2010 Mar 18; 2:16.
Cambell, L M; Ross, J R; Goves, J R; Lees, C T; McCullagh, A; Barnes, P; Timerick, S J; Richardson, P D
1989-12-01
Hypertensive patients received a beta-blocker plus placebo once daily for 4 weeks. If their diastolic blood pressure (DBP) was then 95-115 mm Hg, they were randomized to receive, in addition to the beta-blocker, placebo (n = 36), felodipine-extended release (ER) 10 mg (n = 36), or felodipine-ER 20 mg (n = 37) in a 4-week double-blind parallel-group trial. All medication was administered once daily and, when BP was measured 24 h after the last dose, felodipine-ER 10 mg reduced DBP by 14 +/- 9 mm Hg (mean +/- SD) from a mean of 103 mm Hg and felodipine-ER 20 mg reduced DBP by 18 +/- 9 mm Gg from 101 mm Hg. The reductions in DBP with both doses of felodipine were greater than reductions with placebo (5 +/- 8 mm Hg, from 102 mm Hg--both p less than 0.001). At the end of the study, 21% of patients receiving placebo had a DBP less than or equal to 90 mm Hg. In contrast, 69% of patients receiving felodipine-ER 10 mg and 82% receiving 20 mg attained this level. More than 90% of patients receiving 10 mg felodipine-ER once daily had a reduction in DBP greater than 5 mm Hg 24 h postdose. Felodipine-ER was well tolerated. Felodipine-ER once daily is an effective antihypertensive drug for patients who require therapy in addition to a beta-blocker; the tolerability in this study was good, and a starting dose greater than 10 mg once daily is not indicated.
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
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Lars Pape
2011-01-01
Full Text Available It is speculated that a once-daily dosage of immunosuppression can increase adherence and thereby graft survival. Until now, there have been no studies on once-daily use of Tacrolimus extended-release formulation (TAC-ER in children following pediatric kidney transplantation. In 11 stable pediatric kidney recipients >10 years, efficacy, safety, and tolerability of a switch to TAC-ER were observed over one year. Adherence was determined by use of the BAASIS-Scale Interview and comparison of individual variability of Tacrolimus trough levels. Over the observation period, two acute rejections were observed in one girl with nonadherence and repeated Tacrolimus trough levels of 0 ng/m. Beside this, there were no acute rejections in this trial. TAC dose was increased in 3/11 patients and decreased in 2/11 patients within the course of the study. Six patients did not require a dose adjustment. All but one patient had a maximum of 1 dose change during therapy. Mean Tacrolimus dose, trough levels, and Glomerular filtration rates were also stable. Adherence, as measured by BAASIS-Scale Interview and coefficient of variation of Tacrolimus trough levels, was good at all times. It is concluded that conversion to Tac-ER is safe in low-risk children following pediatric kidney transplantation.
Philosophe, Benjamin; Leca, Nicolae; West-Thielke, Patricia M; Horwedel, Timothy; Culkin-Gemmell, Christine; Kistler, Kristin; Stevens, Daniel R
2018-02-20
The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice-daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers. Novel once-daily tacrolimus formulations such as LCPT (an extended-release tablet by Veloxis Pharmaceuticals, Inc., Cary, North Carolina) have allowed for blood draws on a once-daily basis; however, even that schedule can be restrictive. Results from tests taken either before or after that 24-hour target time may be discarded, or worse, may lead to inappropriate dose changes. Data from ASTCOFF, a phase 3B pharmacokinetic clinical trial (NCT02339246), demonstrated that the unique pharmacokinetic curve of LCPT may allow for a therapeutic monitoring window that extends for 3 hours before or after the 24-hour monitoring target. Furthermore, important tools to help clinicians interpret these levels, such as formulas to estimate the 24-hour trough level if an alternative monitoring time is used, were constructed from these data. These study results give treating clinicians access to data that allow them to safely use and monitor LCPT in their patients and expand the body of evidence surrounding differentiation and practical application of the novel LCPT tacrolimus formulation. © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.
Lamba, Manisha; Wang, Rong; Fletcher, Tracey; Alvey, Christine; Kushner, Joseph; Stock, Thomas C
2016-11-01
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended-release (XR) formulation has been designed to provide a once-daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice-daily immediate-release (IR) formulation. We conducted 2 randomized, open-label, phase 1 studies in healthy volunteers. Study A characterized single-dose and steady-state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single-dose and steady-state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high-fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half-life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) after single- and multiple-dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. C max increased by 27% under the fed state. On repeat administration, negligible accumulation (Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies. © 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.
Jenner, Peter; Könen-Bergmann, Michael; Schepers, Cornelia; Haertter, Sebastian
2009-11-01
Pramipexole is a dopamine agonist used in the treatment of Parkinson's disease. The currently available immediate-release (IR) formulation is taken orally 3 times daily. These studies were conducted to evaluate the pharmacokinetic properties of a variety of prototypes for a once-daily extended-release (ER) formulation of pramipexole and to further characterize the prototype whose pharmacokinetics best matched those of the IR formulation. Three Phase I studies were conducted, all in healthy adult men aged food effect. In the third study, steady-state pharmacokinetics of the optimal ER formulation were assessed across a range of pramipexole doses (0.375-4.5 mg/d), including investigation of the food effect at steady state for the highest dose. Tolerability was assessed throughout all studies based on physical examinations, laboratory measurements, and adverse events (AEs). The 3 studies included 18, 15, and 39 subjects, respectively. Among the ER prototypes tested at 0.75 mg once daily in study 1, a matrix tablet had the optimal pharmacokinetic resemblance to IR pramipexole 0.25 mg TID, with a geometric mean AUC(0-24h,ss) of 17.4 ng.h/mL (vs 16.0 ng.h/mL for the IR formulation), C(max,ss) of 0.967 ng/mL (vs 1.09 ng/mL), and C(min,ss) of 0.455 ng/mL (vs 0.383 ng/mL). For single-dose ER 0.375 mg administered in the fasted state in study 2, in vivo bioavailability was predictable from in vitro dissolution data, with internal mean absolute percent prediction errors of 3.18% for AUC(0-30h) and 4.87% for C(max), and external mean absolute prediction errors of 6.61% and 3.34%, respectively, satisfying current guidelines for a level A IVIVC. For single-dose ER 0.375 mg administered in the fed state, the upper bound of the 90% CI for fed:fasted values was 119.8 for AUC(0-30h) (within the bioequivalence limits of 80%-125%) and 134.1 for C(max). At steady state in study 3 (subjects' 5th treatment day), dosing at 0.375 to 4.5 mg in the fasted state was associated with a linear
The antianginal efficacy and tolerability of controlled-release metoprolol once daily
DEFF Research Database (Denmark)
Egstrup, K; Gundersen, T; Härkönen, R
1988-01-01
In a randomized, double-blind, cross-over study treatment with a new controlled-release (CR) preparation of metoprolol, given once daily, was compared with treatment with conventional metoprolol tablets, given twice daily, in 115 patients with stable effort angina pectoris. The patients were...... questionnaire. When all patients were analysed together there were no differences in antianginal efficacy between the two treatment regimens. However, when the group taking 200 mg daily was analysed separately better exercise tolerance was found during metoprolol CR therapy, as measured by onset of chest pain...... and ST-segment change, compared with conventional metoprolol therapy. The two formulations were well tolerated. When given once daily in a total daily dose of 100 mg, the CR preparation induced less adverse effects than the conventional tablets, 50 mg twice daily. It was concluded that the new metoprolol...
Fass, Ronnie; Inadomi, John; Han, Cong; Mody, Reema; O'Neil, Janet; Perez, M Claudia
2012-03-01
Many patients with gastroesophageal reflux disease (GERD) take a proton pump inhibitor (PPI) twice daily to control symptoms. Once-daily dexlansoprazole modified release (MR) has a dual-delayed release formulation, making it attractive for step-down management of patients whose symptoms are well controlled on twice-daily PPIs. We investigated whether step-down to once-daily dexlansoprazole controls heartburn in patients with GERD who were receiving twice-daily PPI therapy. Patients 18 years and older taking a twice-daily PPI for symptom control were enrolled (n = 178) in a single-blind, multicenter study; 163 patients completed the study and 142 patients met criteria for the efficacy analysis. During the 6-week screening and treatment periods, patients recorded the presence of heartburn symptoms twice daily in electronic diaries. Patients' heartburn was considered well controlled if they had an average of 1 symptom or fewer per week during the last 4 weeks of screening and treatment. After screening, qualified patients were switched to masked dexlansoprazole MR 30 mg and placebo for 6 weeks. The primary efficacy end point was the proportion of patients whose heartburn remained well controlled after step-down. GERD-related symptoms and quality of life (QOL) also were evaluated using the Patient Assessment of Upper Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM) and the PAGI-QOL questionnaires, respectively. After step-down to once-daily dexlansoprazole MR 30 mg, heartburn remained well controlled in 88% of patients (125 of 142). These patients were able to maintain their GERD-related symptom severity and QOL, indicated by marginal changes in the PAGI-SYM and PAGI-QOL total and subscale scores, respectively. Most patients with GERD who take twice-daily PPI to control heartburn are able to successfully step down to once-daily dexlansoprazole 30 mg. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
Pramipexole Extended Release: A Novel Treatment Option in Parkinson's Disease
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Wolfram Eisenreich
2010-01-01
Full Text Available Pramipexole, the most commonly prescribed dopamine agonist worldwide, meanwhile serves as a reference substance for evaluation of new drugs. Based on numerous clinical data and vast experiences, efficacy and safety profiles of this non-ergoline dopamine agonist are well characterized. Since October 2009, an extended-release formulation of pramipexole has been available for symptomatic treatment of Parkinson's disease. Pramipexole administration can be cut down from three times to once a day due to the newly developed extended-release formulation. This is considerable progress in regard to minimizing pill burden and enhancing compliance. Moreover, the 24 h continuous drug release of the once-daily extended-release formulation results in fewer fluctuations in plasma concentrations over time compared to immediate-release pramipexole, given three times daily. The present study summarizes pharmacokinetics and all essential pharmacological and clinical characteristics of the extended-release formulation. In addition, it provides all study data, available so far, with regard to transition and de-novo administration of extended-release formulation for patients with Parkinson's disease. It further compares efficacy and safety data of immediate-release pramipexole with the extended-release formulation of pramipexole.
Gabapentin for once-daily treatment of post-herpetic neuralgia: a review
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Beal B
2012-07-01
Full Text Available Benjamin Beal,1 Tobias Moeller-Bertram,1,2 Jan M Schilling,1 Mark S Wallace11Division of Pain Medicine, Department of Anesthesiology, University of California, 2VA San Diego Healthcare System, San Diego, CA, USAAbstract: Post-herpetic neuralgia is a neuropathic pain syndrome resulting from an insult to the peripheral and central nervous systems caused by the varicella zoster virus. Spontaneous pain may result in the persistent sensation of burning, tingling, or aching and may be associated with thermally or mechanically provoked pain, resulting in hyperalgesia or allodynia. The majority of cases occur in patients over the age of 50 years. Gabapentin is a structural analog of gamma aminobutyric acid that binds to the α2-δ site of voltage-dependent calcium channels and modulates the influx of calcium, with a resulting reduction in excitatory neurotransmitter release. Gabapentin is effective in reducing neuropathic pain due to post-herpetic neuralgia when given at least three times per day, due to its short half-life, resulting in demonstrable fluctuations in plasma levels. Gabapentin has dose-limiting side effects that prevent some patients from achieving therapeutic plasma levels, such as somnolence (27.4%, dizziness (23.9%, and ataxia (7.1%. Gralise™ is a once-daily extended-release formulation of gabapentin that has been developed using AcuForm™ technology. AcuForm is a polymer-based drug delivery system that retains the tablet in the stomach and upper gastrointestinal tract for a sustained period of time. Once-daily dosing has been shown to provide comparable drug exposure with an identical daily dose of the immediate-release formulation when administered three times daily. Participants given Gralise 1800 mg daily had a statistically significant reduction in average daily pain intensity scores compared with placebo, reduced sleep interference due to pain, and a greater percent of participants reporting being much or very much improved on
Extended Efficacy of Once-Daily Atomoxetine in ADHD
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J Gordon Millichap
2004-07-01
Full Text Available The efficacy of atomoxetine administered once daily (final dose 1.3 +/- 0.3 mg/kg; mean 44.5 mg per day; range 10-80 mg per day in the morning was assessed throughout the day, including evening and early morning, in a total of 197 children, 6 to 12 years of age (71% male, diagnosed with attention-deficit/hyperactivity disorder (ADHD (69% had combined subtype ADHD, and 35% had comorbid oppositional defiant disorder.
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Hale ME
2013-05-01
Full Text Available Martin E Hale,1 Srinivas R Nalamachu,2 Arif Khan,3 Michael Kutch4,* 1Gold Coast Research, LLC, Weston, FL, USA; 2International Clinical Research Institute, Overland Park, KS, USA; 3MedNorthwest Clinical Research Center, Bellevue, WA, USA; Duke University Medical Center, Durham, NC, USA; 4Applied Clinical Intelligence, LLC, Bala Cynwyd, PA, USA *Affiliation at the time this work was completed. Michael Kutch is currently affiliated with Cytel Inc, Chesterbrook, PA, USA Purpose: To describe the efficacy and safety of hydromorphone extended-release tablets (OROS hydromorphone ER during dose conversion and titration. Patients and methods: A total of 459 opioid-tolerant adults with chronic moderate to severe low back pain participated in an open-label, 2- to 4-week conversion/titration phase of a double-blind, placebo-controlled, randomized withdrawal trial, conducted at 70 centers in the United States. Patients were converted to once-daily OROS hydromorphone ER at 75% of the equianalgesic dose of their prior total daily opioid dose (5:1 conversion ratio, and titrated as frequently as every 3 days to a maximum dose of 64 mg/day. The primary outcome measure was change in pain intensity numeric rating scale; additional assessments included the Patient Global Assessment and the Roland–Morris Disability Questionnaire scores. Safety assessments were performed at each visit and consisted of recording and monitoring all adverse events (AEs and serious AEs. Results: Mean (standard deviation final daily dose of OROS hydromorphone ER was 37.5 (17.8 mg. Mean (standard error of the mean [SEM] numeric rating scale scores decreased from 6.6 (0.1 at screening to 4.3 (0.1 at the final titration visit (mean [SEM] change, -2.3 [0.1], representing a 34.8% reduction. Mean (SEM change in Patient Global Assessment was -0.6 (0.1, and mean change (SEM in the Roland–Morris Disability Questionnaire was -2.8 (0.3. Patients achieving a stable dose showed greater improvement
Pharmacological and clinical evidence of nevirapine immediate- and extended-release formulations
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Ena J
2012-11-01
Full Text Available Javier Ena, Concepción Amador, Conxa Benito, Francisco PasquauHIV Unit, Hospital Marina Baixa, Villajoyosa, SpainAbstract: We reviewed the current information available on nevirapine immediate- and extended-release formulations and its role in single-dose and combination antiretroviral therapy. Nevirapine was approved in 1996 and was the first non-nucleoside reverse-transcriptase inhibitor available for the treatment of HIV-1 infection. Nevirapine has demonstrated good efficacy and a well-characterized safety profile. A major drawback is the low genetic barrier, allowing the emergence of resistance in the presence of single mutations in the reverse-transcriptase gene. This shortcoming is particularly relevant when nevirapine is administered in a single dose to prevent mother-to-child transmission of HIV-1 infection, compromising the efficacy of future non-nucleoside reverse transcriptase–inhibitor regimens. Studies published recently have probed the noninferiority of nevirapine compared to ritonavir-boosted atazanavir with both tenofovir disoproxil fumarate and emtricitabine in antiretroviral treatment–naïve patients. In 2011, a new formulation of nevirapine (nevirapine extended release that allowed once-daily dosing was approved by the Food and Drug Administration and by the European Medicines Agency. VERxVe, a study comparing nevirapine extended release with nevirapine immediate release in antiretroviral treatment–naïve patients, and TRANxITION, a study carried out in antiretroviral treatment–experienced patients who switched therapy from nevirapine immediate release to nevirapine extended release, provided data on the noninferiority of the new formulation of nevirapine compared with nevirapine immediate release in terms of efficacy and safety. Nevirapine extended release will further increase the durability and persistence of nevirapine-containing antiretroviral therapy, allowing once-daily dosing regimens.Keywords: nevirapine
Hale, Martin E; Nalamachu, Srinivas R; Khan, Arif; Kutch, Michael
2013-01-01
Purpose To describe the efficacy and safety of hydromorphone extended-release tablets (OROS hydromorphone ER) during dose conversion and titration. Patients and methods A total of 459 opioid-tolerant adults with chronic moderate to severe low back pain participated in an open-label, 2- to 4-week conversion/titration phase of a double-blind, placebo-controlled, randomized withdrawal trial, conducted at 70 centers in the United States. Patients were converted to once-daily OROS hydromorphone ER at 75% of the equianalgesic dose of their prior total daily opioid dose (5:1 conversion ratio), and titrated as frequently as every 3 days to a maximum dose of 64 mg/day. The primary outcome measure was change in pain intensity numeric rating scale; additional assessments included the Patient Global Assessment and the Roland–Morris Disability Questionnaire scores. Safety assessments were performed at each visit and consisted of recording and monitoring all adverse events (AEs) and serious AEs. Results Mean (standard deviation) final daily dose of OROS hydromorphone ER was 37.5 (17.8) mg. Mean (standard error of the mean [SEM]) numeric rating scale scores decreased from 6.6 (0.1) at screening to 4.3 (0.1) at the final titration visit (mean [SEM] change, −2.3 [0.1], representing a 34.8% reduction). Mean (SEM) change in Patient Global Assessment was −0.6 (0.1), and mean change (SEM) in the Roland–Morris Disability Questionnaire was −2.8 (0.3). Patients achieving a stable dose showed greater improvement than patients who discontinued during titration for each of these measures (P < 0.001). Almost 80% of patients achieving a stable dose (213/268) had a ≥30% reduction in pain. Commonly reported AEs were constipation (15.4%), nausea (11.9%), somnolence (8.7%), headache (7.8%), and vomiting (6.5%); 13.0% discontinued from the study due to AEs. Conclusion The majority of opioid-tolerant patients with chronic low back pain were successfully converted to effective doses of
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Levy Juliana
2010-03-01
Full Text Available Abstract Aims To determine prospectively the efficacy, tolerability and patient satisfaction of an extended release formulation of metformin (metformin XR in hospital based outpatients with type 2 diabetes mellitus currently treated with standard metformin. Methods Patients on immediate release standard metformin either alone or combined with other oral agents were switched to extended release metformin XR 500 mg tablets and titrated to a maximum dose of 2000 mg/day Measurements to include glucose and lipid control, blood pressure, body weight, waist circumference, C-reactive protein, adverse events and patient satisfaction were recorded at baseline, three and six months. Results Complete data were obtained for 35 of the 61 patients enrolled to the study. At three and six months no changes were reported for any of the cardiovascular risk factors except for lipids where there was a modest rise in plasma triglycerides. These effects were achieved with a reduced dose of metformin XR compared to pre-study dosing with standard metformin (1500 mg +/- 402 vs 1861 +/- 711 p = 0.004. A total of 77% of patients were free of gastrointestinal side effects and 83% of patients stated a preference for metformin XR at the end of the study. Ghost tablets were reported in the faeces by the majority of the patients (54.1%. Conclusions Patients switched to extended release metformin XR derived the same clinical and metabolic benefits as for standard metformin but with reduced dosage, fewer gastrointestinal side effects and a greater sense of well being and satisfaction on medication.
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N. V. Fedorova
2014-11-01
Full Text Available The paper considers a clinical case of early-stage mixed Parkinson’s disease (PD with significant affective disorders and restless legs syndrome. Once-daily extended-release pramipexole 3 mg significantly improved a patient’s status and led to regression of movement and affective disorders. The paper gives data on the efficacy of dopamine receptor agonists in treating PD and the benefits of their extended-release formulations.
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 (Cmax), and plasma concentrations at the end of the dosing interval (Cτ,ss,24h) of OOD could be classified as comparable to OTD considering 90% confidence intervals (CIs) and acceptance limits of 80
Clegg, Herbert W; Ryan, Amy G; Dallas, Steven D; Kaplan, Edward L; Johnson, Dwight R; Norton, H James; Roddey, Oliver F; Martin, Edward S; Swetenburg, Raymond L; Koonce, Elizabeth W; Felkner, Mary M; Giftos, P Michael
2006-09-01
Two relatively small previous studies comparing once-daily amoxicillin with conventional therapy for group A streptococcal (GAS) pharyngitis reported similar rates of bacteriologic success for each treatment group. The purpose of this study was to further evaluate once-daily amoxicillin for GAS pharyngitis in a larger study. In a single pediatric practice, from October through May for 2 consecutive years (2001-2003), we recruited children 3 to 18 years of age who had symptoms and signs suggestive of GAS pharyngitis. Patients with a positive rapid test for GAS were stratified by weight (or=40 kg) and then randomly assigned to receive once-daily (750 mg or 1000 mg) or twice-daily (2 doses of 375 mg or 500 mg) amoxicillin for 10 days. We determined bacteriologic failure rates for GAS in the pharynx from subsequent swabs taken at 14 to 21 (visit 2) and 28 to 35 (visit 3) days after treatment initiation. We conducted a randomized, controlled, investigator-blinded, noninferiority trial to evaluate whether amoxicillin given once daily would have a bacteriologic failure rate no worse than that of amoxicillin given twice daily within a prespecified margin of 10%. GAS isolates were characterized to distinguish bacteriologic failures from new acquisitions. Adverse events were described and adherence was evaluated by review of returned daily logs and dosage bottles. Of 2139 potential study patients during the 2-year period, we enrolled 652 patients, 326 into each treatment group. Children in the 2 groups were comparable with respect to all demographic and clinical characteristics except that children <40 kg more often presented with rash in each treatment group. At visit 2, failure rates were 20.1% (59 of 294) for the once-daily group and 15.5% (46 of 296) for the twice-daily group (difference, 4.53%; 90% confidence interval [CI], -0.6 to 9.7). At visit 3, failure rates were 2.8% (6 of 216) for the once-daily group and 7.1% (16 of 225) for the twice-daily group (difference, -4
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Inoue S
2017-08-01
Full Text Available Satoshi Inoue,1 Yoji Saito,2 Satoru Tsuneto,3 Etsuko Aruga,4 Azusa Ide,1 Yasuyuki Kakurai5 1Clinical Development Department, R&D Division, Daiichi Sankyo, Tokyo,2Department of Anesthesiology, Faculty of Medicine, Shimane University, Shimane, 3Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, 4Department of Palliative Medicine, School of Medicine, Teikyo University, Tokyo, 5Biostatistics and Data Management Department, R&D Division, Daiichi Sankyo, Tokyo, Japan Background: In Japan, there are limited options for switching opioid analgesics. Hydromorphone is an opioid analgesic that is routinely used instead of morphine for cancer pain; however, it is not yet available in Japan. The aim of this study was to assess the efficacy and safety of hydromorphone (DS-7113b extended-release tablets in opioid-naïve patients with cancer pain not relieved by non-opioid analgesics.Subjects and methods: This was a multicenter, randomized, double-blind, parallel-group trial. A double-dummy method was used for blinding. Each randomized subject received either hydromorphone extended-release tablets plus placebo oxycodone hydrochloride extended-release tablets 4 mg/day (n=88 or placebo hydromorphone extended-release tablets plus oxycodone hydrochloride extended-release tablets 10 mg/day (n=93 orally for 7 days (once-daily dosing for hydromorphone and twice-daily dosing for oxycodone. The doses were adjusted as necessary. Efficacy was evaluated by change in visual analog scale (VAS score from baseline to completion of treatment.Results: The between-group difference in least squares mean changes in VAS score from baseline to completion or discontinuation of treatment was −0.4 mm (95% CI −5.9 to 5 mm by analysis of covariance where the baseline VAS score was used as a covariate. The upper limit of the 95% CI was below 10 mm, which was predefined as the noninferiority limit. This verified the noninferiority of hydromorphone tablets
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Yoon S
2014-01-01
Full Text Available Seonghae Yoon,1,* Howard Lee,2,* Tae-Eun Kim,1 SeungHwan Lee,1 Dong-Hyun Chee,3 Joo-Youn Cho,1 Kyung-Sang Yu,1 In-Jin Jang1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 2Clinical Trials Center, Seoul National University Hospital, 3AbbVie Ltd., Seoul, Republic of Korea *These authors contributed equally to this work Background: This study was conducted to compare the oral bioavailability of an itopride extended-release (ER formulation with that of the reference immediate-release (IR formulation in the fasting state. The effect of food on the bioavailability of itopride ER was also assessed. Methods: A single-center, open-label, randomized, multiple-dose, three-treatment, three-sequence, crossover study was performed in 24 healthy male subjects, aged 22–48 years, who randomly received one of the following treatments for 4 days in each period: itopride 150 mg ER once daily under fasting or fed conditions, or itopride 50 mg IR three times daily in the fasting state. Steady-state pharmacokinetic parameters of itopride, including peak plasma concentration (Cmax and area under the plasma concentration versus time curve over 24 hours after dosing (AUC0–24h, were determined by noncompartmental analysis. The geometric mean ratio of the pharmacokinetic parameters was derived using an analysis of variance model. Results: A total of 24 healthy Korean subjects participated, 23 of whom completed the study. The geometric mean ratio and its 90% confidence interval of once-daily ER itopride versus IR itopride three times a day for AUC0–24h were contained within the conventional bioequivalence range of 0.80–1.25 (0.94 [0.88–1.01], although Cmax was reached more slowly and was lower for itopride ER than for the IR formulation. Food delayed the time taken to reach Cmax for itopride ER, but AUC0–24h was not affected. There were no serious adverse events and both formulations were
Auiler, J F; Liu, K; Lynch, J M; Gelotte, C K
2002-01-01
Stimulant therapy is the mainstay of treatment for children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). Once-daily, extended-release oral formulations offer long acting control of symptoms by modifying drug delivery and absorption. In particular, consistency in early drug exposure is important for symptom control during school or work hours. Because these once-daily formulations are usually taken in the morning, the timing of the doses with breakfast is important. This study compared the effect of a high-fat breakfast on early drug exposure from a morning dose of two extended-release stimulant formulations: the osmotic-controlled OROS tablet of methylphenidate HCI (CONCERTA) and the capsule containing extended-release beads of mixed amphetamine salts (ADDERALL XR). The study had a single-dose, open-label, randomised, four-treatment, crossover design in which healthy subjects received either 36 mg CONCERTA or 20 mg ADDERALL XR in the morning after an overnight fast or a high-fat breakfast. Serial blood samples were collected over 28h to determine plasma concentrations of methylphenidate and amphetamine. The food effect on early drug exposure and the pharmacokinetic profiles up to 8 h after dosing of the two extended-release stimulants were directly compared using partial area (AUC(p4h), AUC(p6h) and AUC(p8h)) fed/fasted ratios. Amphetamine concentrations were markedly lower when the subjects had eaten breakfast, resulting in lower early drug exposures (p food, for patients with ADHD.
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
Detemir as a once-daily basal insulin in type 2 diabetes
Directory of Open Access Journals (Sweden)
Nelson SE
2011-08-01
Full Text Available Scott E NelsonCleveland Family Medicine, Cleveland, Mississippi, USABackground: Insulin detemir, a long-acting basal insulin analog, is labeled for once-daily or twice-daily dosing in patients with type 1 (T1DM or type 2 (T2DM diabetes mellitus. Protocols for some earlier clinical studies of detemir evaluated twice-daily dosing, which may have generated the misperception that detemir should be prescribed twice daily for most patients. This review examines pharmacokinetic and pharmacodynamic (PK/PD, observational, and controlled studies that have evaluated once-daily and twice-daily detemir in patients with T2DM to determine the efficacy and safety of once-daily dosing.Methods: PubMed was searched using the keywords “detemir,” “once daily,” “twice daily,” and “type 2 diabetes” with the limits of clinical trial, human, and English.Results: Detemir has a relatively flat time–action profile and duration of action of up to 24 hours for patients with T2DM. Once-daily dosing is the most commonly used detemir regimen reported in observational studies, and controlled clinical studies indicate that once-daily dosing controls glycosylated hemoglobin when detemir is administered alone or in combination with a prandial insulin or oral antidiabetes drugs. In comparative clinical trials, detemir had a similar time–action profile and duration of action to another long-acting insulin analog, glargine, with less within-subject variability. Once-daily detemir was associated with no weight gain or less weight gain than comparator regimens. For patients who had not achieved glycemic control with a basal dose of once-daily detemir, adding a prandial insulin provided better glycemic control, less postprandial hypoglycemia, and a lower total daily dose of detemir than twice-daily detemir. Involvement of a multidisciplinary team and the use of a holistic approach for the treatment of T2DM patients are recommended to achieve and maintain the best
Bäckman, Lars; Persson, Carl-Axel
2014-03-17
Immunosuppression regimens in transplantation medicine are complex. Drugs with extended release action have simplified medication dosing without affecting efficacy. This prospective, observational, multicenter study, conducted in a routine medical practice setting, evaluated changes in tacrolimus daily dose and trough levels and patient-reported medication adherence at day 90 after 1:1 (mg: mg) conversion to once-daily tacrolimus in adult liver and kidney transplant recipients. Data from 224 recipients of a liver (n=19) or kidney (n=205) transplant, average age 51±14.5 years, were evaluated. The mean change in tacrolimus daily dose was +0.04 mg/day. Dose remained stable after conversion in 62.5%, was lower in 15.6%, and higher in 22% of patients. Trough level after conversion was lower in 62.6% and higher in 36.5%; generally, levels were 12.8% lower than pre-conversion levels. No acute rejection, graft loss, or serious safety events were observed. Two deaths occurred due to myocardial infarction. Conversion helped 19% to less frequently forget medications and 55% reported no difference in remembering to take the once-daily dose after conversion. The change in dosing frequency was identified as "better" for 55%. Tacrolimus daily dose remained stable while trough levels were significantly lower after conversion to once-daily dosing. Safety and efficacy were maintained; reduced dosing frequency had no apparent influence on patient-reported medication adherence.
The management of schizophrenia: focus on extended-release quetiapine fumarate
Directory of Open Access Journals (Sweden)
Peuskens J
2011-09-01
Full Text Available Joseph Peuskens Universitair Psychiatrisch Centrum KU Leuven, Campus St Jozef Kortenberg, Kortenberg, Belgium Abstract: Effective management of schizophrenia remains a significant clinical challenge. While antipsychotic medications have proven efficacy in this disease, there remains an opportunity to further improve symptom control and long-term relapse prevention. Also, a number of factors, including tolerability and complex dosing regimens, can result in nonadherence to medication. Quetiapine is an atypical antipsychotic with proven efficacy and an established tolerability profile in schizophrenia. The once-daily extended-release formulation (quetiapine XR offers a simplified dosing regimen and titration schedule. Short-term clinical studies have shown that quetiapine XR (400–800 mg/d is efficacious in the acute treatment of schizophrenia, while a long-term study has shown that quetiapine XR was significantly more effective than placebo at preventing relapse. Furthermore, an investigation in which stable patients switched from the immediate-release formulation (quetiapine IR to quetiapine XR showed that quetiapine XR is generally well tolerated and has no loss of efficacy compared with quetiapine IR. In patients who experienced insufficient efficacy or poor tolerability on their previous antipsychotic, switching to quetiapine XR significantly improved efficacy compared with the previous treatment. In conclusion, quetiapine XR is an effective and generally well tolerated treatment for schizophrenia. Furthermore, once-daily dosing may improve patient adherence, which may impact positively on patient outcomes. Keywords: adherence, atypical antipsychotics, adverse events
Grossberg, George T; Manes, Facundo; Allegri, Ricardo F; Gutiérrez-Robledo, Luis Miguel; Gloger, Sergio; Xie, Lei; Jia, X Daniel; Pejović, Vojislav; Miller, Michael L; Perhach, James L; Graham, Stephen M
2013-06-01
Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors. In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations. A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9
Yoon, Seonghae; Lee, Howard; Kim, Tae-Eun; Lee, SeungHwan; Chee, Dong-Hyun; Cho, Joo-Youn; Yu, Kyung-Sang; Jang, In-Jin
2014-01-01
This study was conducted to compare the oral bioavailability of an itopride extended-release (ER) formulation with that of the reference immediate-release (IR) formulation in the fasting state. The effect of food on the bioavailability of itopride ER was also assessed. A single-center, open-label, randomized, multiple-dose, three-treatment, three-sequence, crossover study was performed in 24 healthy male subjects, aged 22-48 years, who randomly received one of the following treatments for 4 days in each period: itopride 150 mg ER once daily under fasting or fed conditions, or itopride 50 mg IR three times daily in the fasting state. Steady-state pharmacokinetic parameters of itopride, including peak plasma concentration (Cmax) and area under the plasma concentration versus time curve over 24 hours after dosing (AUC(0-24h)), were determined by noncompartmental analysis. The geometric mean ratio of the pharmacokinetic parameters was derived using an analysis of variance model. A total of 24 healthy Korean subjects participated, 23 of whom completed the study. The geometric mean ratio and its 90% confidence interval of once-daily ER itopride versus IR itopride three times a day for AUC(0-24h) were contained within the conventional bioequivalence range of 0.80-1.25 (0.94 [0.88-1.01]), although Cmax was reached more slowly and was lower for itopride ER than for the IR formulation. Food delayed the time taken to reach Cmax for itopride ER, but AUC(0-24h) was not affected. There were no serious adverse events and both formulations were generally well tolerated. At steady state, once-daily itopride ER at 150 mg has a bioavailability comparable with that of itopride IR at 50 mg given three times a day under fasting conditions. Food delayed the absorption of itopride ER, with no marked change in its oral bioavailability.
Jones, Terry M; Ellman, Herman; deVries, Tina
2017-10-01
To characterize minocycline pharmacokinetics and relative bioavailability following multiple-dose topical administration of minocycline hydrochloride (HCl) foam 4% (FMX101 4%) as compared with single-dose oral administration of minocycline HCl extended-release tablets (Solodyn®) in subjects with moderate-to-severe acne. A Phase 1, single-center, nonrandomized, open-label, active-controlled, 2-period, 2-treatment crossover clinical study. The study included 30 healthy adults (mean age, 22.6 years; 90% white, and 60% females) who had moderate-to-severe acne. Subjects were assigned to first receive a single oral dose of a minocycline HCl extended-release tablet (approximately 1 mg/kg). At 10 days after the oral minocycline dose, topical minocycline foam 4% was applied, once daily for 21 days. Serial blood samples were obtained before and after administration of oral minocycline and each topical application of minocycline foam 4% on days 1, 12, and 21. Following oral administration of minocycline (approximately 1 mg/kg), plasma minocycline concentration increased until 3 hours, followed by a log-linear decrease over the remainder of the 96-hour sampling period. Following topical application of a 4-g maximal-use dose of minocycline foam 4% for 21 days, plasma minocycline concentration was very low, with geometric mean Cmax values ranging from 1.1 ng/mL to 1.5 ng/mL. Steady state was achieved by day 6. Overall, minocycline exposure with topical minocycline foam 4% was 730 to 765 times lower than that with oral minocycline. There was no evidence of minocycline accumulation over the 21 days of topical application of minocycline foam 4%. Topical minocycline foam 4% appeared to be safe and well tolerated, with no serious treatment-emergent adverse events (TEAEs), treatment-related TEAEs, or TEAEs that led to treatment discontinuation. Once-daily topical application of minocycline foam 4% did not lead to significant systemic exposure to minocycline. It appears to be a well
Directory of Open Access Journals (Sweden)
Patel C
2011-06-01
Full Text Available Chirag G Patel, Li Li, Suzette Girgis, David M Kornhauser, Ernest U Frevert, David W BoultonBristol-Myers Squibb, Princeton, NJ, USABackground: Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin, antihypertensives (eg, diltiazem, nifedipine, verapamil, and antifungals (eg, ketoconazole are metabolized by and/or inhibit the cytochrome P450 (CYP 3A4 metabolic pathway. These types of medicines are commonly coprescribed to treat comorbidities in patients with type 2 diabetes mellitus (T2DM and the potential for drug-drug interactions of these medicines with new medicines for T2DM must be carefully evaluated.Objective: To investigate the effects of CYP3A4 substrates or inhibitors, simvastatin (substrate, diltiazem (moderate inhibitor, and ketoconazole (strong inhibitor on the pharmacokinetics and safety of saxagliptin, a CYP3A4/5 substrate; and the effects of saxagliptin on these agents in three separate studies.Methods: Healthy subjects were administered saxagliptin 10 mg or 100 mg. Simvastatin, diltiazem extended-release, and ketoconazole doses of 40 mg once daily, 360 mg once daily, and 200 mg twice daily, respectively, were used to determine two-way pharmacokinetic interactions.Results: Coadministration of simvastatin, diltiazem extended-release, or ketoconazole increased mean area under the concentration-time curve values (AUC of saxagliptin by 12%, 109%, and 145%, respectively, versus saxagliptin alone. Mean exposure (AUC of the CYP3A4-generated active metabolite of saxagliptin, 5-hydroxy saxagliptin, decreased with coadministration of simvastatin, diltiazem, and ketoconazole by 2%, 34%, and 88%, respectively. All adverse events were considered mild or moderate in all three studies; there were no serious adverse events or deaths.Conclusion: Saxagliptin, when coadministered with simvastatin, diltiazem extended-release, or ketoconazole, was safe and generally well tolerated in healthy subjects. Clinically
Once- versus twice-daily aspirin treatment in patients with essential thrombocytosis
DEFF Research Database (Denmark)
Larsen, Mads Lamm; Pedersen, Oliver Heidmann; Hvas, Anne-Mette
2018-01-01
Insufficient platelet inhibition has been reported in up to 40% of aspirin-treated patients, including patients with essential thrombocytosis. To maintain sufficient platelet inhibition, a shorter dosing interval with aspirin has been suggested. We aimed to investigate the antiplatelet effect...... of low-dose aspirin given twice-daily compared to standard once-daily dosing in patients with essential thrombocytosis. We included 22 patients, who were treated for 7 days with standard once-daily aspirin (75 mg once-daily) followed by 7 days treatment of twice-daily aspirin (37.5 mg twice......-daily). The two regimens were separated by 14 days aspirin washout. Blood samples were obtained 1h and 24h/12h after the last pill intake in each regimen. The effect of aspirin was evaluated by: (1) platelet aggregation measured by whole blood impedance aggregometry (Multiplate® Analyser) using arachidonic acid...
Calcagno, A; Pinnetti, C; De Nicolò, A; Scarvaglieri, E; Gisslen, M; Tempestilli, M; D'Avolio, A; Fedele, V; Di Perri, G; Antinori, A; Bonora, S
2018-06-01
Abacavir is a widely used nucleotide reverse transcriptase inhibitor, for which cerebrospinal fluid (CSF) exposure has been previously assessed in twice-daily recipients. We studied abacavir CSF concentrations in 61 and nine HIV-positive patients taking abacavir once daily and twice daily, respectively. Patients on once-daily abacavir had higher plasma and CSF concentrations (96 vs. 22 ng ml -1 , P = 0.038 and 123 vs. 49 ng ml -1 , P = 0.038) but similar CSF-to-plasma ratios (0.8 vs. 0.5, P = 0.500). CSF abacavir concentrations were adequate in patients receiving once-daily treatment. © 2018 The British Pharmacological Society.
Update on the clinical utility of once-daily tacrolimus in the management of transplantation
Directory of Open Access Journals (Sweden)
Revollo J
2015-05-01
Full Text Available Jane Revollo Department of Pharmacy, Jackson Memorial Hospital, University of Miami Leonard M Miller School of Medicine Miami, FL, USAThe review by Posadas Salas and Srinivas of the clinical utility of once-daily tacrolimus formulations in the management of transplant patients1 was timely and relevant. It is worth noting, however, the data were presented in a way that overlooked several key differences between two distinct once-daily tacrolimus formulations. These formulations differ in bioavailability, Cmax, Tmax, dose required to achieve target trough levels, and time to reach target trough. The specific formulation and dosing information of one product was detailed in this review (described as modified release 4 [MR-4]; Astagraf®, Astellas Pharma Inc., Tokyo, Japan, but no formulation or dosing details were provided for a very different once-daily tacrolimus formulation (LCP-Tacro™; Veloxis Pharmaceuticals A/S, Hørsholm, Denmark for which a thorough review was recently published.2 The latter product is currently approved in Europe and under review by the US Food and Drug Administration in the US. In presenting data in this review, the authors did not identify which product was investigated in each of the studies discussed. This could easily lead to misinterpretation of results or erroneous conclusions, ie, that both once-daily formulations are the same. In fact, a careful parsing of the data clearly demonstrates that they are not equivalent. Misunderstanding of this point could have a potentially serious impact on appropriate dosing, safety, and patient management in the post-transplant setting. Differentiation between the two products is needed to clarify what appear to be conflicting results of the studies presented in this review.View original paper by Posadas Salas and Srinivas
[Effectiveness of new, once-daily 5-aminosalicylic acid in the treatment of ulcerative colitis].
Lakatos, Péter László; Lakatos, László
2009-03-01
5-aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents is commercially available, including azo-bond pro-drugs such as sulfasalazine, olsalazine and balsalazide, and delayed- and controlled-release forms of mesalazine. In addition, the effectiveness of oral therapy relies on good compliance, which may be adversely affected by frequent daily dosing and a large number of tablets. Furthermore, poor adherence has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine including the unique multi-matrix delivery system and mesalazine granules were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of low pill burden and may contribute to increased long-term compliance and treatment success in clinical practice and might potentially further contribute to a decline in the risk for UC-associated colon cancers. In this systematic review, the authors summarize the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations.
Once-Daily Radiation Therapy for Inflammatory Breast Cancer
International Nuclear Information System (INIS)
Brown, Lindsay; Harmsen, William; Blanchard, Miran; Goetz, Matthew; Jakub, James; Mutter, Robert; Petersen, Ivy; Rooney, Jessica; Stauder, Michael; Yan, Elizabeth; Laack, Nadia
2014-01-01
Purpose: Inflammatory breast cancer (IBC) is a rare and aggressive breast cancer variant treated with multimodality therapy. A variety of approaches intended to escalate the intensity and efficacy of radiation therapy have been reported, including twice-daily radiation therapy, dose escalation, and aggressive use of bolus. Herein, we examine our outcomes for patients treated with once-daily radiation therapy with aggressive bolus utilization, focusing on treatment technique. Methods and Materials: A retrospective review of patients with nonmetastatic IBC treated from January 1, 2000, through December 31, 2010, was performed. Locoregional control (LRC), disease-free survival (DFS), overall survival (OS) and predictors thereof were assessed. Results: Fifty-two women with IBC were identified, 49 (94%) of whom were treated with neoadjuvant chemotherapy. All underwent mastectomy followed by adjuvant radiation therapy. Radiation was delivered in once-daily fractions of 1.8 to 2.25 Gy (median, 2 Gy). Patients were typically treated with daily 1-cm bolus throughout treatment, and 33 (63%) received a subsequent boost to the mastectomy scar. Five-year Kaplan Meier survival estimates for LRC, DFS, and OS were 81%, 56%, and 64%, respectively. Locoregional recurrence was associated with poorer OS (P<.001; hazard ratio [HR], 4.1). Extracapsular extension was associated with worse LRC (P=.02), DFS (P=.007), and OS (P=.002). Age greater than 50 years was associated with better DFS (P=.03). Pathologic complete response was associated with a trend toward improved LRC (P=.06). Conclusions: Once-daily radiation therapy with aggressive use of bolus for IBC results in outcomes consistent with previous reports using various intensified radiation therapy regimens. LRC remains a challenge despite modern systemic therapy. Extracapsular extension, age ≤50 years, and lack of complete response to chemotherapy appear to be associated with worse outcomes. Novel strategies are needed in IBC
Eron, Joseph J.; Rockstroh, Jürgen K.; Reynes, Jacques; Andrade-Villanueva, Jaime; Ramalho-Madruga, Jose Valdez; Bekker, Linda-Gail; Young, Benjamin; Katlama, Christine; Gatell-Artigas, Jose Maria; Arribas, Jose R.; Nelson, Mark; Campbell, Havilland; Zhao, Jing; Rodgers, Anthony J.; Rizk, Matthew L.; Wenning, Larissa; Miller, Michael D.; Hazuda, Daria; DiNubile, Mark J.; Leavitt, Randi; Isaacs, Robin; Robertson, Michael N.; Sklar, Peter; Nguyen, Bach-Yen; Bloch, M. T.; Hoy, J.; Workman, C.; Madruga, J. V.; Souza, T.; Telles, F. Q.; Zajdenverg, R.; Angel, J.; Montaner, J. S.; Smith, G. H. R.; Trottier, B.; Tamara, J. R.; Velez, J. D.; Gerstoft, J.; Laursen, A. L.; Mathiesen, L.; Katlama, C.; Molina, J. M.; Raffi, F.; Reynes, J.; Yazdanpanah, Y.; Bogner, J. R.; Fatkenheuer, G.; Hartl, H.; Jaeger, H.; Geerlings, S. E.
2011-01-01
Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to
Newcorn, Jeffrey H; Stein, Mark A; Childress, Ann C; Youcha, Sharon; White, Carla; Enright, Gail; Rubin, Jonathan
2013-09-01
To examine the efficacy and tolerability of guanfacine extended release (GXR) administered in the morning or evening in children with attention-deficit/hyperactivity disorder (ADHD). In this multicenter, double-blind, placebo-controlled, dose-optimization study, children 6 to 12 years of age with ADHD were randomized to receive GXR (1-4 mg/d) in the morning and placebo in the evening (GXR am), placebo in the morning and GXR in the evening (GXR pm), or twice-daily placebo. The primary efficacy measure was the ADHD Rating Scale-IV (ADHD-RS-IV). A total of 333 child participants received study drug in the following cohorts: GXR am (n = 107), GXR pm (n = 114), or placebo (n = 112). Mean (standard deviation) changes from baseline to week 8 (visit 10 or last observation carried forward) in ADHD-RS-IV total scores were significant for both GXR treatment groups combined (GXR all-active: -20.0 [12.97]) and separately (GXR am: -19.8 [12.95]; GXR pm: -20.1 [13.04]) compared with placebo (-11.0 [12.93]; p ADHD symptoms. The levels of response and tolerability observed with GXR were similar regardless of time of dosing (morning versus evening), indicating that once-daily GXR monotherapy is effective whether administered in the morning or evening. Clinical trial registration information-Tolerability and Efficacy of AM and PM Once Daily Dosing With Extended-release Guanfacine Hydrochloride in Children 6-12 With Attention-Deficit/Hyperactivity Disorder (ADHD) (The ADHD Tempo Study. Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
Directory of Open Access Journals (Sweden)
Balk JM
2015-08-01
Full Text Available Jiska M Balk,1 Guido RMM Haenen,1 Özgür M Koc,2 Ron Peters,3 Aalt Bast,1 Wim JF van der Vijgh,1 Ger H Koek,4 1Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, 2Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, 3DSM Resolve, Geleen, 4Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands Background: The combination of ribavirin (RBV and pegylated interferon (PEG-IFN is effective in the treatment of chronic hepatitis C infection. Reducing the frequency of RBV intake from twice to once a day will improve compliance and opens up the opportunity to combine RBV with new and more specific direct-acting agents in one pill. Therefore, the purpose of this study was to evaluate the pharmacokinetic profile of RBV in a once-daily to twice-daily regimen. The secondary aim was to determine tolerability as well as the severity and differences in side effects of both treatment regimens. Methods: In this randomized open-label crossover study, twelve patients with chronic type 1 hepatitis C infection and weighing more than 75 kg were treated with 180 µg of PEG-IFN weekly and 1,200 mg RBV daily for 24 weeks. The patients received RBV dosed as 1,200 mg once-daily for 12 weeks followed by RBV dosed as 600 mg twice-daily for 12 weeks, or vice versa. In addition to the pharmacokinetic profile, the hematological profile and side effects were recorded. The RBV concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Results: Eight of twelve patients completed the study. Neither the time taken for RBV to reach peak plasma concentration nor the AUC0-last (adjusted for difference in dose was significantly different between the two groups (P>0.05. Furthermore, the once-daily regimen did not give more side effects than the twice-daily regimen (P>0
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Mody R
2013-04-01
Full Text Available Reema Mody,1 Debra Eisenberg,2 Likun Hou,2 Siddhesh Kamat,2 Joseph Singer,2 Lauren B Gerson3 1Takeda Pharmaceuticals International Inc, Deerfield, IL, 2HealthCore Inc, Wilmington, DE, 3Stanford University School of Medicine, Stanford, CA, USA Background: The purpose of this study was to assess differences in health care resource utilization and costs associated with once-daily and twice-daily proton pump inhibitor (PPI therapy. Most patients with gastroesophageal reflux disease (GERD achieve symptom control on once-daily PPI therapy, but approximately 20%–30% require twice-daily dosing. Methods: Patients were ≥18 years of age with at least one medical claim for GERD and at least two PPI claims from HealthCore's Integrated Research Database (HIRDSM during 2004–2009. Patients were continuously eligible for 12 months before and after the index date (date of first PPI claim. Based on PPI dosing throughout the post-index period (quantity of medication dispensed/number of days supply, patients were classified as once-daily (dose ≤ 1.5 pills per day or twice-daily (≥1.5 PPI users. Results: The study cohort included 248,386 patients with GERD (mean age 52.8 ± 13.93 years, 56% females of whom 90% were once-daily and 10% were twice-daily PPI users. The Deyo-Charlson Comorbidity Index for once-daily and twice-daily PPI users was 0.70 ± 1.37 and 0.89 ± 1.54, respectively (P < 0.05. More once-daily patients had claims for Barrett's esophagus (5% versus 2%, P < 0.0001 than twice-daily patients. Post-index, higher proportions of twice-daily patients had at least one GERD-related inpatient visit (7% versus 5%, outpatient visit (60% versus 49%, and office visit (48% versus 38% versus once-daily patients (P < 0.0001. Mean total GERD-related health care costs were $2065 ± $6636 versus $3749 ± $11,081 for once-daily and twice-daily PPI users, respectively (P < 0.0001. Conclusion: Patients receiving twice-daily PPI therapy were likely to have more
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Müge Kuzu
2016-09-01
Full Text Available Objective: To evaluate the safety and efficacy of switching from immediate-release pramipexole (pex to extended-release pramipexole (pex-ER. Materials and Methods: Pex-ER became available in Turkey about a year ago, since then we documented satisfactory information on patients (26 women; 38% who were switched from pex to pex-ER. We recorded pre- and post-switch pex and levodopa, equivalent doses of other anti-parkinsonian medication, and analyzed the frequency and nature of reported adverse effects. Results: The mean age of the patients was 63.3 years (range, 44-88 years, and the mean disease duration was 7.1 years (range, 1-27 years. The other drugs were levodopa (57 patients, 82.6%, entacapone (24 patients, 34.58%, rasagiline (20 patients, 29%, amantadine (18 patients, 26.1%, and apomorphine (six patients, 8.7%. Switch from pex to pex-ER was uneventful in 62 (91.2% patients. Adverse events were reported in six (8.8% patients: ankle swelling (two patients, nausea (one patient, dyskinesia (one patient, hypersexuality (one patient, and psychosis (one patient. Problems resolved with further medication change in two patients. Four patients preferred to return to pex. Conclusion: The great majority of patients (91.2% switched from three times daily pex to once daily pex-ER uneventfully. A slight increase in pex daily dose, which was tailored according to patients’ symptomatic needs, resulted in an increase in post-switch levodopa equivalent doses. Our experience is compatible with previously reported studies.
Potential benefit of dolutegravir once daily: efficacy and safety
Directory of Open Access Journals (Sweden)
Fantauzzi A
2013-02-01
Full Text Available Alessandra Fantauzzi,1 Ombretta Turriziani,2 Ivano Mezzaroma11Department of Clinical Medicine, 2Department of Molecular Medicine, Sapienza, University of Rome, Rome, ItalyAbstract: The viral integrase enzyme has recently emerged as a primary alternative target to block HIV-1 replication, and integrase inhibitors are considered a pivotal new class of antiretroviral drugs. Dolutegravir is an investigational next-generation integrase inhibitor showing some novel and intriguing characteristics, ie, it has a favorable pharmacokinetic profile with a prolonged intracellular half-life, rendering feasible once-daily dosing without the need for ritonavir boosting and without regard to meals. Moreover, dolutegravir is primarily metabolized via uridine diphosphate glucuronosyltranferase 1A1, with a minor component of the cytochrome P450 3A4 isoform, thereby limiting drug–drug interactions. Furthermore, its metabolic profile enables coadministration with most of the other available antiretroviral agents without dose adjustment. Recent findings also demonstrate that dolutegravir has significant activity against HIV-1 isolates with resistance mutations associated with raltegravir and/or elvitegravir. The attributes of once-daily administration and the potential to treat integrase inhibitor-resistant viruses make dolutegravir an interesting and promising investigational drug. In this review, the main concerns about the efficacy and safety of dolutegravir as well as its resistance profile are explored by analysis of currently available data from preclinical and clinical studies.Keywords: antiretroviral drugs, HIV-1 integrase, integrase inhibitors, dolutegravir, once daily
Once versus twice daily gentamicin dosing for infective endocarditis
DEFF Research Database (Denmark)
Buchholtz, Kristine; Larsen, Carsten Toftager; Schaadt, Bente
2011-01-01
Objectives: The aim of this randomized study was to investigate the effects of once versus twice daily gentamicin dosing on renal function and measures of infectious disease in a population with infective endocarditis (IE). Methods: Seventy-one IE patients needing gentamicin treatment according...
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.
Arnold, Lesley M; Arsenault, Pierre; Huffman, Cynthia; Patrick, Jeffrey L; Messig, Michael; Chew, Marci L; Sanin, Luis; Scavone, Joseph M; Pauer, Lynne; Clair, Andrew G
2014-10-01
Safety and efficacy of a once daily controlled-released (CR) formulation of pregabalin was evaluated in patients with fibromyalgia using a placebo-controlled, randomized withdrawal design. This multicenter study included 6 week single-blind pregabalin CR treatment followed by 13 week double-blind treatment with placebo or pregabalin CR. The starting dose of 165 mg/day was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Patients with ≥50% reduction in average daily pain score at the end of the single-blind phase were randomized to continue pregabalin CR at the optimized dose (330-495 mg/day) or to placebo. The primary endpoint was time to loss of therapeutic response (LTR), defined as treatment' (Benefit, Satisfaction, and Willingness to Continue Scale) in the pregabalin CR group; no other secondary endpoints were statistically significant. Most AEs were mild to moderate in severity (most frequent: dizziness, somnolence). The percentage of pregabalin CR patients discontinuing because of AEs was 12.2% and 4.8% in the single-blind and double-blind phases, respectively (placebo, 0%). Time to LTR was significantly longer with pregabalin CR versus placebo in fibromyalgia patients who initially showed improvement with pregabalin CR, indicating maintenance of response. Pregabalin CR was well tolerated in most patients. Generalizability may be limited by study duration and selective population.
Alai, Milind; Lin, Wen Jen
2013-01-01
The objective of this study was to formulate and evaluate the lansoprazole (LPZ)-loaded microparticles to prevent nocturnal acid breakthrough in the case of gastro-esophageal reflux disease (GERD). The microparticulate delivery system was prepared by solvent evaporation method using Eudragit RS100 as a matrix polymer followed by enteric coated with Eudragit S100 and hydroxypropyl methylcellulose phthalate HP55 using spray drying method. The enteric coated microparticles were stable in gastric pH condition. In vivo pharmacokinetic and pharmacodynamic studies in male Wistar rats demonstrated that enteric coated microparticles sustained release of LPZ and promoted ulcer healing activity. In other words, the microparticulate dosage form provided effective drug concentration for a longer period as compared to conventional extended release dosage form, and showed sufficient anti-acid secretion activity to treat acid related disorders including the enrichment of nocturnal acid breakthrough event based on a once daily administration.
van Heeswijk, R. P.; Veldkamp, A. I.; Mulder, J. W.; Meenhorst, P. L.; Wit, F. W.; Lange, J. M.; Danner, S. A.; Foudraine, N. A.; Kwakkelstein, M. O.; Reiss, P.; Beijnen, J. H.; Hoetelmans, R. M.
2000-01-01
OBJECTIVE: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. DESIGN: Open-label, randomized, cross-over study. METHODS: Twenty HIV-1-infected individuals who already
Lepik, Katherine J; Yip, Benita; McGovern, Rachel A; Ding, Erin; Nohpal, Adriana; Watson, Birgit E; Toy, Junine; Akagi, Linda; Harrigan, P Richard; Moore, David M; Hogg, Robert S; Montaner, Julio S G; Barrios, Rolando
2015-01-01
Nevirapine 400 mg extended release tablets (nevirapine-XR) are a once-daily alternative to nevirapine 200 mg immediate release tablets (nevirapine-IR). Study objectives were to describe the effectiveness and tolerability of nevirapine-XR in clinical practice and, for patients who switched from once daily 2×200 mg nevirapine-IR to nevirapine-XR, compare virological suppression and plasma nevirapine concentrations during each treatment period. HIV-1-infected adults entered the study cohort if they initiated nevirapine-XR in British Columbia (BC) Canada between 1 April 2012 and 30 September 2012 and were followed until 30 September 2013. Demographic and clinical variables were abstracted from the BC Centre for Excellence in HIV/AIDS databases. Patients who switched from once daily nevirapine-IR to nevirapine-XR were monitored for 6 months pre- and post-switch with comparison of virological suppression (McNeamer's test) and median random plasma nevirapine concentrations (Wilcoxon-Mann-Whitney test) in each period. The 536 nevirapine-XR-treated patients were 96% male, median (IQR) age 49.9 (44.0-56.9) years. Median follow-up was 15.6 (14.7-16.5) months, with 474/536 (88%) maintaining virological suppression. Emergent drug resistance developed in 5/536 (1%), adverse drug reactions in 17/536 (3%) and, although 31/536 (6%) reported 'whole' tablets in their stools, this was not associated with adverse outcomes. Among the 305 patients who switched from nevirapine-IR to nevirapine-XR, median (IQR) random plasma nevirapine concentration was higher during nevirapine-IR 5,000 (3,690-6,090) ng/ml than nevirapine-XR 3,930 (3,050-5,150) ng/ml (Pmarketing study affirms the effectiveness and tolerability of nevirapine-XR as an alternative to nevirapine-IR in adults.
Lakatos, Peter Laszlo
2009-04-21
5-aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents are commercially available, including azobond pro-drugs, as well as delayed- and controlled-release forms of mesalazine. However, poor adherence due to frequent daily dosing and a large number of tablets has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine, including the unique multi-matrix delivery system and mesalazine granules, were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of a low pill burden and might contribute to increased long-term compliance and treatment success in clinical practice. This editorial summarizes the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations.
LENUS (Irish Health Repository)
Ní Ainle, Fionnuala
2008-10-01
Low molecular weight heparin (LMWH) is widely regarded as the anticoagulant treatment of choice for the prevention and treatment of venous thromboembolism during pregnancy. However, previous studies have demonstrated that the pharmacokinetic profiles of LMWH vary significantly with increasing gestation. Consequently, it remains unclear whether LMWH regimens recommended for use in nonpregnant individuals can be safely extrapolated to pregnant women. The aims of this study were to assess the safety and the efficacy of tinzaparin sodium (Innohep) administered only once daily during pregnancy. A systematic retrospective review identified a cohort of 37 high-risk pregnancies which had been managed using tinzaparin 175 IU\\/kg once daily. In 26 cases, the index pregnancy had been complicated by development of an acute venous thromboembolism (17 deep vein thrombosis and nine pulmonary embolism). For each individual, case notes were examined and data extracted using a predetermined questionnaire. No episodes of recurrent venous thromboembolism were identified amongst this cohort of pregnancies managed using once daily LMWH administration. However, two unusual thrombotic complications were observed, including a parietal infarct in one patient, and a postpartum cerebral venous thrombosis in another. Once daily tinzaparin was well tolerated, with no cases of heparin-induced thrombocytopaenia, symptomatic osteoporosis, or foetal malformations. Tinzaparin dose modification based upon peak anti-Xa levels occurred in 45% of the cases examined. The present study is the largest study to have examined the clinical efficacy of once daily LMWH for use in pregnant women at high risk of venous thromboembolism. Our data support the safety and efficacy of antenatal tinzaparin at a dose of 175 IU\\/kg. In order to determine whether this once daily regimen provides equivalent (or indeed greater) thromboprophylaxis to twice daily LMWH regimens during pregnancy will require highly powered
Tramadol extended-release in the management of chronic pain
McCarberg, Bill
2007-01-01
Chronic, noncancer pain such as that associated with osteoarthritis of the hip and knee is typically managed according to American College of Rheumatology guidelines. Patients unresponsive to first-line treatment with acetaminophen receive nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors. However, many patients may have chronic pain that is refractory to these agents, or they may be at risk for the gastrointestinal, renal, and cardiovascular complications associated with their use. Tramadol, a mild opioid agonist and norepinephrine and serotonin reuptake inhibitor, is recommended by current guidelines for the treatment of moderate to moderately severe pain in patients who have not responded to previous oral therapy, or in patients who have contraindications to COX-2 inhibitors and nonselective NSAIDs. An extended-release (ER) formulation of tramadol was approved by the US Food and Drug Administration in September 2005. In contrast with immediate-release (IR) tramadol, this ER formulation allows once-daily dosing, providing around-the-clock analgesia. In clinical studies, tramadol ER has demonstrated a lower incidence of adverse events than that reported for IR tramadol. Unlike nonselective NSAIDs and COX-2 inhibitors, tramadol ER is not associated with gastrointestinal, renal, or cardiovascular complications. Although tramadol is an opioid agonist, significant abuse has not been demonstrated after long-term therapy. It is concluded that tramadol ER has an efficacy and safety profile that warrants its early use for the management of chronic pain, either alone or in conjunction with nonselective NSAIDs and COX-2 inhibitors. PMID:18488071
A once-daily dose of tadalafil for erectile dysfunction: compliance and efficacy
Directory of Open Access Journals (Sweden)
Samuel L Washington III
2010-08-01
Full Text Available Samuel L Washington III1, Alan W Shindel21School of Medicine, University of California at San Francisco, San Francisco, California, USA; 2Department of Urology, University of California at San Francisco, San Francisco, California, USAAbstract: Selective phosphodiesterase type 5 inhibitors (PDE5Is have revolutionized the treatment of erectile dysfunction (ED in men. As an on-demand treatment, PDE5Is have excellent efficacy and safety in the treatment of ED due to a broad spectrum of etiologies. Nevertheless, these drugs do have side-effect profiles that are troublesome to some patients, eg, headache, dyspepsia, myalgia, etc. Furthermore, many patients and their partners dislike the necessity of on-demand treatment for ED, citing a desire for greater spontaneity with sexual interactions. In 2008, approximately 10 years after the release of the first commercially available PDE5I, a paradigm shift in the management of ED occurred with the approval of once-daily dose of tadalafil by the US Food and Drug Administration for the management of ED. The prolonged half-life of tadalafil lends itself well to this dosing regimen and conveys the advantage of separating medication from sexual interactions; lower dose therapy also carries the theoretical benefit of lower incidence of side effects. In this study, we review the current state of the art with respect to this new management strategy for ED, highlighting published reports of the efficacy and tolerability of the daily dose tadalafil regimen.Keywords: PDE5 inhibitor, on-demand therapy, side effects, daily dosing
Prevention of organ rejection in renal and liver transplantation with extended release tacrolimus
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Reschen ME
2014-09-01
Full Text Available Michael E Reschen, Christopher A O’Callaghan Henry Wellcome Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Abstract: Tacrolimus is the key immunosuppressant used to prevent allograft rejection in kidney and liver transplant recipients. Despite the efficacy of tacrolimus and adjunctive immunosuppressants, a substantial number of patients experience episodes of acute rejection and late graft loss. Nonadherence is an etiological factor in both acute rejection and graft loss. In 2007, a prolonged release version of tacrolimus became available that allows once daily administration, thus halving the pill burden compared to the standard twice-daily tacrolimus. An increasing number of studies in de novo transplantation and in treatment conversion have evaluated the pharmacokinetic profile, efficacy, and safety of prolonged-release tacrolimus. We have reviewed the literature on the use of prolonged-release tacrolimus and hope that this will be of value in the design of protocols for transplant immunosuppression.Keywords: immunosuppression, kidney, hepatic, allograft, adherence
Wongwiwatthananukit, Supakit; Sansanayudh, Nakarin; Dhummauppakorn, Rawadee; Kitiyadisai, Chutiporn
2006-11-01
Although most patients with hypercholesterolemia require life-long therapy with statins, these drugs are underused due to high costs. Every-other-day therapy could be one strategy to resolve this problem. To compare the efficacy and safety of rosuvastatin 10 mg administered every other day versus once daily. An 8 week, randomized, open-label, parallel trial was conducted at the outpatient department of Phramongkutklao Hospital in Bangkok, Thailand. Eighty patients with primary hypercholesterolemia were equally randomized to receive rosuvastatin 10 mg once daily or every other day; 76 patients completed the study. Laboratory data were assessed at baseline and at the end of the study. Low-density lipoprotein cholesterol (LDL-C) levels were reduced by 48% and 39% in the once-daily and every-other-day groups, respectively (p = 0.011). The percentage of patients who achieved LDL-C goals according to National Cholesterol Education Program-Adult Treatment Panel III guidelines was not significantly different between the once-daily (85%) and every-other-day (70%) groups (p = 0.180). In addition, both regimens were well tolerated, with no patient developing an elevation of more than 3 times baseline levels of aspartate aminotransferase or alanine aminotransferase or 10 times that of creatine kinase. As expected, the monthly cost per percent LDL-C reduction of the once-daily (0.72 dollars) regimen was about 38% higher than that of the every-other-day (0.44 dollars) regimen. Every-other-day dosing of rosuvastatin may be an alternative regimen for cost savings, without a major decrease in therapeutic benefit or increase in adverse events, in patients with hypercholesterolemia. The number of patients achieving their LDL-C goal using the every-other-day regimen is comparable with the number using the once-daily regimen, especially in the low-risk patient category.
French, JA; Baroldi, P; Brittain, ST; Johnson, JK
2014-01-01
Objective To evaluate the efficacy, tolerability, and safety of once-daily 1200 mg and 2400 mg SPN-804 (Oxtellar XR™, Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization. Methods The Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double-blind, parallel-group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week double-blind treatment period in the intent-to-treat (ITT) population with analyzable seizure data. Other efficacy analyses included proportion of patients with ≥ 50% seizure reduction, proportion of patients seizure free, and the relationship between clinical response and plasma concentration. Results Median percent reduction was -28.7% for placebo, −38.2% (P = 0.08 vs placebo) for once-daily SPN-804 1200 mg, and −42.9% (P = 0.003) for SPN-804 2400 mg. Responder rates were 28.1%, 36.1% (P = 0.08), and 40.7% (P = 0.02); 16-week seizure-free rates in a pragmatic ITT analysis were 3.3%, 4.9% (P = 0.59), and 11.4% (P = 0.008), respectively. When data were analyzed separately for study site clusters, a post hoc analysis demonstrated that both SPN-804 dosages were significantly superior to placebo in median percent seizure reduction (placebo: −13.3%; 1200 mg: −34.5%, P = 0.02; 2400 mg: −52.7%, P = 0.006) in the North American study site cluster. A concentration–response analysis also supported a clinically meaningful effect for 1200 mg. Adverse event types reflected the drug's established profile. Adverse event frequency was consistent with a pharmacokinetic profile in which SPN-804 produces lower peak plasma concentrations vs immediate-release OXC. Once-daily dosing was not
Update on extended release quetiapine fumarate in schizophrenia and bipolar disorders
Directory of Open Access Journals (Sweden)
El-Khalili N
2012-11-01
Full Text Available Nizar El-KhaliliAlpine Clinic, Lafayette, IN, USAAbstract: The atypical antipsychotic quetiapine fumarate is available both as an immediate release (IR and as an extended release (XR formulation allowing flexibility of dosing for individual patients. Approved uses of quetiapine XR include the treatment of schizophrenia (including maintenance therapy for prevention of relapse, the treatment of bipolar disorder (manic and depressive episodes, and the prevention of recurrence in patients with bipolar disorder who respond to quetiapine XR. This narrative review provides an update on quetiapine XR in these indications. The pharmacological profile of quetiapine, including a moderate affinity for dopamine D2 receptors and higher affinity for serotonin 5-hydroxytryptophan (5-HT2A receptors, may explain its broad efficacy and low propensity for extrapyramidal symptoms (EPS. The XR formulation has similar bioavailability but prolonged plasma levels compared with the IR formulation, allowing for less frequent (once-daily dosing. Clinical studies have confirmed the efficacy of quetiapine XR in relieving the acute symptoms of schizophrenia during short-term trials, and reducing the risk for relapse in long-term studies. Direct switching from the IR formulation to the same dose of the XR formulation did not reveal any loss of efficacy or tolerability issues, and switching patients to quetiapine XR from conventional or other atypical antipsychotics (for reasons of insufficient efficacy or tolerability also proved to be beneficial and generally well tolerated. In bipolar disorder, quetiapine XR has also proven effective in relieving acute depressive and manic symptoms. Adverse events with quetiapine XR in patients with either schizophrenia or bipolar disorder are similar to those associated with the IR formulation, the most common being sedation, dry mouth, somnolence, dizziness, and headache. The low propensity for EPS is maintained with the XR formulation
Rehbein, S; Baggott, D G; Johnson, E G; Kunkle, B N; Yazwinski, T A; Yoon, S; Cramer, L G; Soll, M D
2013-03-01
The efficacy of eprinomectin in an extended-release injection (ERI) formulation was evaluated against infections with third-stage larvae or eggs of gastrointestinal and pulmonary nematodes in cattle under 120-day natural challenge conditions in a series of five studies conducted in the USA (three studies) and in Europe (two studies). For each study, 30 nematode-free (four studies) or 30 cattle harboring naturally acquired nematode infections (one study) were included. The cattle were of various breeds or crosses, weighed 107.5-273 kg prior to treatment and aged approximately 4-11 months. For each study, animals were blocked based on pre-treatment bodyweight and then randomly allocated to treatment: ERI vehicle (control) at 1 mL/50 kg bodyweight or Eprinomectin 5% (w/v) ERI at 1 mL/50 kg bodyweight (1.0 mg eprinomectin/kg) for a total of 15 and 15 animals in each group. Treatments were administered once on Day 0 by subcutaneous injection in front of the shoulder. In each study, all animals grazed one naturally contaminated pasture for 120 days. At regular intervals during the studies, fecal samples from all cattle were examined for nematode egg and larval counts. In four studies pairs of tracer cattle were used to monitor pasture infectivity at 28-day intervals before and/or during the grazing period. All calves were weighed before turnout onto pasture and at regular intervals until housing on Day 120. For parasite recovery, all study animals were humanely euthanized 27-30 days after removal from pasture. Cattle treated with Eprinomectin ERI had significantly (p92%: Dictyocaulus viviparus (adults and fourth-stage larvae (L4), Bunostomum phlebotomum, Cooperia curticei, Cooperia oncophora, Cooperia punctata, Cooperia surnabada, Cooperia spp. inhibited L4, Haemonchus contortus, Haemonchus placei, Haemonchus spp. inhibited L4, Nematodirus helvetianus, Nematodirus spp. inhibited L4, Oesophagostomum radiatum, Oesophagostomum spp. inhibited L4, Ostertagia leptospicularis
Childress, Ann; Newcorn, Jeffrey; Stark, Jeffrey G; McMahen, Russ; Tengler, Mark; Sikes, Carolyn
2016-08-01
To determine the pharmacokinetic (PK) profile of a proprietary formulation of methylphenidate (MPH) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in a phase 1 study. Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) combine two technologies in a single-tablet formulation-an extended-release profile that was designed for once-daily dosing in an ODT that does not require water or chewing for ingestion. This was a single-dose, open-label, single-period, single-treatment study, in which 32 children with ADHD who were receiving MPH in doses of 40 or 60 mg before beginning the study each received a 60-mg dose (2 × 30 mg) of MPH XR-ODT. The following plasma PK parameters of MPH were determined for participants grouped by age (6-7, 8-9, 10-12, and 13-17 years old): maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), area under the curve from 0 hours to infinity (AUCinf), oral clearance (CL/F), and volume of distribution in the terminal phase (Vz/F). Safety and tolerability were also assessed. A total of 32 participants received the study drug. For all participants, plasma concentration-time profiles of MPH exhibited a broad peak after administration of MPH XR-ODT through ∼8 hours, indicating extended release from the formulation, followed by an apparent first-order elimination phase. As age increased, MPH exposure decreased and mean estimates of CL/F increased; however, weight-normalized CL/F values were comparable across age groups. Similarly, mean estimates of Vz/F increased with age, but weight-normalization decreased differences across age groups, with the exception of the youngest age group, which had higher values. All adverse events (AEs) were mild. This XR-ODT formulation of MPH demonstrated weight-normalized clearance rates that were consistent across all age groups, a PK profile consistent with once-daily dosing, and an AE profile consistent with
Blume-Peytavi, Ulrike; Shapiro, Jerry; Messenger, Andrew G; Hordinsky, Maria K; Zhang, Paul; Quiza, Carlos; Doshi, Uday; Olsen, Elise A
2016-07-01
A once-daily minoxidil topical foam (MTF) has been developed to treat female pattern hair loss. Determine noninferiority of once-daily 5% MTF versus twice-daily 2% minoxidil topical solution (MTS) based on the change from baseline in target area hair count (TAHC) at 24 weeks. In a randomized, phase III trial, women with female pattern hair loss received once-daily 5% MTF (n=161) or twice-daily 2% MTS (n=161) for 52 weeks. Primary endpoint was change from baseline in TAHC at 24 weeks. Secondary endpoint was change from baseline in TAHC at 12 weeks. Exploratory endpoints included change in total unit area density and change in overall scalp coverage. Once-daily 5% MTF increased TAHC from baseline (adjusted mean ± standard error) by 23.9 ± 2.1 hairs/cm2 at week 24. Twice-daily 2% MTS increased TAHC 24.2 ± 2.1 hairs/cm2 at week 24. The treatment difference was -0.3 hairs/cm2 (95% CI = -6.0, 5.4). Since the lower bound of the 95% CI was less than -5.0, the prespecified noninferiority goal was not met. Both treatments were well tolerated. Once-daily 5% MTF and twice-daily 2% MTS induced hair regrowth in female pattern hair loss, but prespecified noninferiority criteria were not met. ClinicalTrials.gov identifier: NCT01145625 J Drugs Dermatol. 2016;15(7):883-889.
Effect of sprint training: training once daily versus twice every second day.
Ijichi, Toshiaki; Hasegawa, Yuta; Morishima, Takuma; Kurihara, Toshiyuki; Hamaoka, Takafumi; Goto, Kazushige
2015-01-01
This study compared training adaptations between once daily (SINGLE) and twice every second day (REPEATED) sprint training, with same number of training sessions. Twenty physically active males (20.9 ± 1.3 yr) were assigned randomly to the SINGLE (n = 10) or REPEATED (n = 10) group. The SINGLE group trained once per day (5 days per week) for 4 weeks (20 sessions in total). The REPEATED group conducted two consecutive training sessions on the same day, separated by a rest period of 1 h (2-3 days per week) for 4 weeks (20 sessions in total). Each training session consisted of three consecutive 30-s maximal pedalling sets with a 10-min rest between sets. Before and after the training period, the power output during two bouts of 30-s maximal pedalling, exercise duration during submaximal pedalling and resting muscle phosphocreatine (PCr) levels were evaluated. Both groups showed significant increases in peak and mean power output during the two 30-s bouts of maximal pedalling after the training period (P every second day improved OBLA during endurance exercise more than the same training once daily.
Kizilbash, Arshi; Ngô-Minh, Cường
2014-01-01
Patients with chronic non-malignant pain report impairments of physical, social, and psychological well-being. The goal of pain management should include reducing pain and improving quality of life. Patients with chronic pain require medications that are able to provide adequate pain relief, have minimum dosing intervals to maintain efficacy, and avoid breakthrough pain. Tramadol has proven efficacy and a favourable safety profile. The positive efficacy and safety profile has been demonstrated historically in numerous published clinical studies as well as from post-marketing experience. It is a World Health Organization “Step 2” opioid analgesic that has been shown to be effective, well-tolerated, and valuable, where treatment with strong opioids is not required. A number of extended release formulations of Tramadol are available in Canada and the United States. An optimal extended release Tramadol formulation would be expected to provide consistent pain control with once daily dosing, few sleep interruptions, flexible dosing schedules, and no limitation on taking with meals. Appropriate treatment options should be based on the above proposed attributes. A comparative review of available extended release Tramadol formulations shows that these medications are not equivalent in their pharmacokinetic profile and this may have implications for selecting the optimal therapy for patients with pain syndromes where Tramadol is an appropriate analgesic agent. Differences in pharmacokinetics amongst the formulations may also translate into varied clinical responses in patients. Selection of the appropriate formulation by the health care provider should therefore be based on the patient’s chronic pain condition, needs, and lifestyle. PMID:24711710
Design and evaluation of nicorandil extended-release tablet
Directory of Open Access Journals (Sweden)
Ju-Young Kim
2015-04-01
Full Text Available The aim of this study was to design and evaluate extended-release formulations of a model drug, nicorandil, in order to achieve the desired steady-state plasma concentration of drug in vivo. Simulation was employed to estimate optimum dissolution and absorption rate of nicorandil. The dissolution test was employed using pH 1.2, 4.0, 6.8 buffer solution, or water, to measure the in vitro release behaviors of nicorandil formulations. A single dose (15 mg of each formulation was orally administered to four beagle dogs under fasted conditions, and the pharmacokinetic parameters were calculated. The in vitro/in vivo relationship of the extended-release formulation was confirmed using in vitro dissolution profiles and plasma concentrations of drug in beagle dogs. Nicorandil was released completely within 30 min from the immediate-release tablets and released for 24 h from the extended-release tablets. The nicorandil plasma concentration could be modified by adjusting the drug release rate from the extended-release formulation. The release rate of nicorandil was the rate-limiting step in the overall absorption of drug from the extended-release formulations. These results highlight the potential of a nicorandil extended-release formulation in the treatment of angina pectoris.
Directory of Open Access Journals (Sweden)
Przemyslaw Kardas
2007-05-01
Full Text Available Przemyslaw KardasThe First Department of Family Medicine, Medical University of LodzBackground: 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.Keywords: patient compliance, quality of life, stable angina pectoris, randomized controlled trial
Accelerated in-vitro release testing methods for extended-release parenteral dosage forms.
Shen, Jie; Burgess, Diane J
2012-07-01
This review highlights current methods and strategies for accelerated in-vitro drug release testing of extended-release parenteral dosage forms such as polymeric microparticulate systems, lipid microparticulate systems, in-situ depot-forming systems and implants. Extended-release parenteral dosage forms are typically designed to maintain the effective drug concentration over periods of weeks, months or even years. Consequently, 'real-time' in-vitro release tests for these dosage forms are often run over a long time period. Accelerated in-vitro release methods can provide rapid evaluation and therefore are desirable for quality control purposes. To this end, different accelerated in-vitro release methods using United States Pharmacopeia (USP) apparatus have been developed. Different mechanisms of accelerating drug release from extended-release parenteral dosage forms, along with the accelerated in-vitro release testing methods currently employed are discussed. Accelerated in-vitro release testing methods with good discriminatory ability are critical for quality control of extended-release parenteral products. Methods that can be used in the development of in-vitro-in-vivo correlation (IVIVC) are desirable; however, for complex parenteral products this may not always be achievable. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.
Accelerated in vitro release testing methods for extended release parenteral dosage forms
Shen, Jie; Burgess, Diane J.
2012-01-01
Objectives This review highlights current methods and strategies for accelerated in vitro drug release testing of extended release parenteral dosage forms such as polymeric microparticulate systems, lipid microparticulate systems, in situ depot-forming systems, and implants. Key findings Extended release parenteral dosage forms are typically designed to maintain the effective drug concentration over periods of weeks, months or even years. Consequently, “real-time” in vitro release tests for these dosage forms are often run over a long time period. Accelerated in vitro release methods can provide rapid evaluation and therefore are desirable for quality control purposes. To this end, different accelerated in vitro release methods using United States Pharmacopoeia (USP) apparatus have been developed. Different mechanisms of accelerating drug release from extended release parenteral dosage forms, along with the accelerated in vitro release testing methods currently employed are discussed. Conclusions Accelerated in vitro release testing methods with good discriminatory ability are critical for quality control of extended release parenteral products. Methods that can be used in the development of in vitro-in vivo correlation (IVIVC) are desirable, however for complex parenteral products this may not always be achievable. PMID:22686344
Blume-Peytavi, Ulrike; Hillmann, Kathrin; Dietz, Ekkehart; Canfield, Douglas; Garcia Bartels, Natalie
2011-12-01
Although twice-daily application of propylene glycol-containing 2% minoxidil topical solution (MTS) stimulates new hair growth, higher concentrations of minoxidil in a once-daily, propylene glycol-free formulation may improve efficacy and reduce unpleasant side effects. We sought to compare the efficacy, safety, and acceptability and to show noninferiority of once-daily 5% minoxidil topical foam (MTF) with twice-daily 2% MTS in women with androgenetic alopecia. A total of 113 women with androgenetic alopecia were randomized to 24 weeks of treatment with 5% MTF or 2% MTS. The primary efficacy parameter was change from baseline in nonvellus target area hair count at week 24. Secondary end points included change in nonvellus target area hair width, overall efficacy by global photographic review as assessed by treatment-blinded evaluators and the subject herself, adverse events, and participants' assessment of product aesthetics. After 24 weeks, women randomized to 5% MTF once daily showed noninferior target area hair count and target area hair width and experienced greater, but nonsignificant, improvements in target area hair count, target area hair width, and overall efficacy by global photographic review than those randomized to 2% MTS used twice daily. 5% MTF was significantly superior to 2% MTS in participants' agreement with "the treatment does not interfere with styling my hair" (P = .002). Women randomized to 5% MTF experienced significantly lower rates of local intolerance (P = .046) especially in pruritus and dandruff compared with 2% MTS. Because of differences in the formulations tested, study participants were not blinded to treatment. Once-daily 5% MTF is noninferior and as effective for stimulating hair growth as twice-daily 2% MTS in women with androgenetic alopecia and is associated with several aesthetic and practical advantages. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
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
Effects of Tadalafil 5 mg Dosed Once Daily in Men with Premature Ejaculation.
Ozcan, Levent; Polat, Emre Can; Onen, Efe; Kocaaslan, Ramazan; Otunctemur, Alper; Cekmen, Mustafa; Eraldemir, Ceyla; Ozbek, Emin
2017-01-01
In this study, we evaluated the effect of 5 mg tadalafil once daily in men with premature ejaculation (PE). Thirty married men with lifelong PE and 30 healthy men as control group were included in this study. All the patients received 5 mg tadalafil once a day for a month. The international index of erectile function questionnaire and intravaginal ejaculatory latency times (IELTs) and PE profile were recorded before and after treatment. Plasma samples were collected before and after treatment. The mean baseline IELTs was 40.8 ± 8.1 s in the PE group and 196.5 ± 26.2 s in the control group. After treatment in the PE group, the mean IELTs values showed a statistically significant improvement from the baseline values. At the end of 4 weeks, in the PE group, the mean IELT values showed a statistically significant improvement from the baseline values. Baseline serum nitric oxide (NO) levels were 27.3 ± 1.7 in the PE group and in the 31.1 ± 1.4 healthy control groups. After treatment, NO levels were increased from baseline. We consider that 5 mg tadalafil once daily is safety and effective for the treatment of PE. © 2016 S. Karger AG, Basel.
Randomized Trial of Once-Daily Fluticasone Furoate in Children with Inadequately Controlled Asthma
DEFF Research Database (Denmark)
Oliver, Amanda J.; Covar, Ronina A.; Goldfrad, Caroline H.
2016-01-01
Objective To evaluate the dose-response, efficacy, and safety of fluticasone furoate (FF; 25 µg, 50 µg, and 100 µg), administered once daily in the evening during a 12-week treatment period to children with inadequately controlled asthma. Study design This was a Phase IIb, multicenter, stratified...
Directory of Open Access Journals (Sweden)
Shen J
2017-09-01
Full Text Available Jie Shen,1 Margot L Goodkin,2 Warren Tong,2 Mayssa Attar3 1Clinical Pharmacology, 2Clinical Development, 3Clinical Pharmacology, Metabolism and Immunology, Allergan plc, Irvine, CA, USA 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
Topiramate Extended-Release Options: A Focus on Efficacy and Safety in Epilepsy and Comorbidities
Directory of Open Access Journals (Sweden)
Yuchen Wang
2017-02-01
Full Text Available Topiramate (TPM is effective for multiple seizure types and epilepsy syndromes in children and adults. Topiramate has adverse effects (including cognitive, depression, renal stones, but many of these are low incidence when started at a low dose and slowly titrated to 100 to 200 mg/day. Also, TPM has proven benefit for migraine, obesity, eating disorders, and alcohol use disorders, which can be comorbid in patients with epilepsy and may also be effective in subpopulations within specific psychiatric diagnoses. Recently approved extended-release formulations of TPM (Trokendi and Qudexy in the United States have reliable data supporting their safety and efficacy for patients with epilepsy. They have potential for more rapid titration within 1 month to 200 mg/day and have better patient retention than TPM immediate-release, but there are no robust double-blind randomized controlled trials comparing the different formulations. We expect the once per day extended-release formulations to improve medication adherence compared with the twice per day formulations. This has significant potential to improve outcomes in epilepsy and the other TPM-responsive disorders.
Once-daily use of inhaled corticosteroids: A new regimen in the treatment of persistent asthma
Directory of Open Access Journals (Sweden)
Jeffrey Leflein
2000-01-01
Strict patient adherence with prescribed anti-inflammatory medication is crucial for obtaining optimal therapeutic benefit for patients with asthma. Despite the proven effectiveness of inhaled corticosteroids, patient adherence to prescribed therapy is often low, resulting in increased patient morbidity. Complex dosing regimens contribute greatly to patient non-adherence. Thus, new once-daily regimens of inhaled corticosteroid treatment have been introduced as means to improve patient adherence and provide optimal therapeutic benefit. In the present review, the complex inflammatory and remodeling processes in asthma and their contributions to the clinical manifestations of the disease will be discussed. Currently available, once-daily inhaled corticosteroid treatment options and the advantages of these therapeutic options in the treatment of persistent asthma also will be discussed.
Design and in vivo evaluation of oxycodone once-a-day controlled-release tablets
Directory of Open Access Journals (Sweden)
Kim JY
2015-01-01
Full Text Available Ju-Young Kim,1,* Sung-Hoon Lee,2,3,* Chun-Woong Park,4 Yun-Seok Rhee,5 Dong-Wook Kim,6 Junsang Park,3 Moonseok Lee,3 Jeong-Woong Seo,2 Eun-Seok Park2 1College of Pharmacy, Woosuk University, Wanju-gun, Republic of Korea; 2School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; 3GL Pharmtech, Seongnam, Republic of Korea; 4College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea; 5College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea; 6Department of Pharmaceutical Engineering, Cheongju University, Cheongju, Republic of Korea *These authors contributed equally to this work Abstract: The aim of present study was to design oxycodone once-a-day controlled-release (CR tablets and to perform in vitro/in vivo characterizations. Release profiles to achieve desired plasma concentration versus time curves were established by using simulation software and reported pharmacokinetic parameters of the drug. Hydroxypropyl methylcellulose (HPMC 100,000 mPa·s was used as a release modifier because the polymer was found to be resistant to changes in conditions of the release study, including rotation speed of paddle and ion strength. The burst release of the drug from the CR tablets could be suppressed by applying an additional HPMC layer as a physical barrier. Finally, the oxycodone once-a-day tablet was comprised of two layers, an inert HPMC layer and a CR layer containing drug and HPMC. Commercial products, either 10 mg bis in die (bid [twice a day] or once-a-day CR tablets (20 mg were administered to healthy volunteers, and calculated pharmacokinetic parameters indicated bioequivalence of the two different treatments. The findings of the present study emphasize the potential of oxycodone once-a-day CR tablets for improved patient compliance, safety, and efficacy, which could help researchers to develop new CR dosage forms of oxycodone. Keywords
Wilens, Timothy E; Robertson, Brigitte; Sikirica, Vanja; Harper, Linda; Young, Joel L; Bloomfield, Ralph; Lyne, Andrew; Rynkowski, Gail; Cutler, Andrew J
2015-11-01
Despite the continuity of attention-deficit/hyperactivity disorder (ADHD) into adolescence, little is known regarding use of nonstimulants to treat ADHD in adolescents. This phase 3 trial evaluated the safety and efficacy of guanfacine extended release (GXR) in adolescents with ADHD. This 13-week, multicenter, randomized, double-blind, placebo-controlled trial evaluated once-daily GXR (1-7 mg per day) in adolescents with ADHD aged 13 to 17 years. The primary endpoint was the change from baseline in the ADHD Rating Scale-IV (ADHD-RS-IV) total score; key secondary endpoints included scores from the Clinical Global Impressions-Severity of Illness (CGI-S), and Learning and School domain and Family domain scores from the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at week 13. A total of 314 participants were randomized (GXR, n = 157; placebo, n = 157). The majority of participants received optimal doses of 3, 4, 5, or 6 mg (30 [22.9%], 26 [19.8%], 27 [20.6%], or 24 [18.3%] participants, respectively), with 46.5% of participants receiving an optimal dose above the currently approved maximum dose limit of 4 mg. Participants receiving GXR showed improvement in ADHD-RS-IV total score compared with placebo (least-squares mean score change, -24.55 [GXR] versus -18.53 [placebo]; effect size, 0.52; p ADHD symptoms in adolescents. GXR was well tolerated, with no new safety signals reported. Dose-Optimization in Adolescents Aged 13-17 Diagnosed With Attention-Deficit/Hyperactivity Disorder (ADHD) Using Extended-Release Guanfacine HCl; http://ClinicalTrials.gov/; NCT01081132. Copyright © 2015. Published by Elsevier Inc.
Development and in-vitro Evaluation of Once Daily Tablet Dosage ...
African Journals Online (AJOL)
Kuksal A, Tiwary AK, Jain NK, Jain S. Formulation and in vitro, in vivo evaluation of extended-release matrix tablet of zidovudine: influence of combination of hydrophilic and hydrophobic matrix formers. AAPS,. Pharm Sci Tech 2006; 7: 1-9. 6. Kumar R, Patil S, Patil MB, Patil SR, Paschapur MS. Design and In vitro Evaluation ...
DEFF Research Database (Denmark)
Beeh, Kai-Michael; Kirsten, Anne-Marie; Dusser, Daniel
2016-01-01
BACKGROUND: This study was conducted to confirm the 24-hour bronchodilator efficacy and pharmacokinetic profile of once-daily tiotropium Respimat(®) 5 μg add-on to inhaled corticosteroids (ICS) in adults with symptomatic asthma. It used a trial protocol designed to minimize the risk of pharmacoki...
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.
Pratley, Richard E.; Nauck, Michael A.; Barnett, Anthony H.; Feinglos, Mark N.; Ovalle, Fernando; Harman-Boehm, Illana; Ye, June; Scott, Rhona; Johnson, Susan; Stewart, Murray; Rosenstock, Julio; Adamson, K.; Ahmann, A.; Ahn, C. W.; Ajani, D.; Akright, L.; Alwine, L.; Alzohaili, O.; Andrawis, N.; Arbañil Huaman, H.; Arora, S.; Bailey, T.; Barnett, A.; Baron, M.; Barreda Caceres, L.; Barrera, J.; Berg, J.; Bertenshaw, R.; Bode, B.; Bolton, D.; Brito, M.; Brock, S.; Brockmyre, A.; Broker, R.; Brusco, O.; Buynak, R.; Canadas-Zizzias, R.; Canas, G.; Capo, J.; Castillo Gamarra, M.; Cathcart, H.; Catindig, E. A.; Chilka, S.; Cho, Y. W.; Choi, D. S.; Chuck, L.; Cooper, M.; Corder, C.; Hoekstra, J.; Kemp, S.
2014-01-01
Background As new members of a drug class are developed, head-to-head trials are an important strategy to guide personalised treatment decisions. We assessed two glucagon-like peptide-1 receptor agonists, once-weekly albiglutide and once-daily liraglutide, in patients with type 2 diabetes
Sallee, Floyd R.; McGough, James; Wigal, Tim; Donahue, Jessica; Lyne, Andrew; Biederman, Joseph
2009-01-01
A double-blind, 9-week, randomized trial was done to compare the efficacy of guanfacine extended release (GXR) with a placebo in treating children and adolescents with attention-deficit/hyperactivity disorders (ADHD). Results find a significant reduction in ADHD from baseline to endpoint for all daily doses of GXR which were measured at 1-, 2-,…
Cassuto, Elisabeth; Pageaux, Georges P; Cantarovich, Diego; Rostaing, Lionel; Loupy, Alexandre; Roche, Bruno; Duvoux, Christophe; Moreau, Karine; Thervet, Eric; Mazouz, Hakim; Bourhis, Yann; Dharancy, Sébastien; Kessler, Michèle
2016-10-01
Adherence to immunosuppressive treatments is a major concern in transplanted patients. This 6-month French observational, longitudinal, prospective study aimed to assess patient adherence to and acceptance of once-daily tacrolimus (Advagraf) initiation in kidney and liver transplant recipients. Data from 1106 patients initiating once-daily tacrolimus during posttransplant follow-up were analyzed. Adherence and acceptance were assessed using self-administered questionnaires at inclusion and at 3 and 6 months. Mean age was 52.4 ± 13.2 years, 61.5% were men. For 94.9% of patients, once-daily tacrolimus was prescribed after switching from twice-daily tacrolimus. At inclusion, 20.9% of patients reported good treatment adherence, 72.0% minor nonadherence, and 7.1% were nonadherent. Mean general acceptance score (range, 0-100) was 77.7 (±24.7). At 3 months, adherence was improved in 21.1%, unchanged in 69.2%, and worsened in 9.7% of patients. Mean general acceptance score was 75.4 (±26.5). General acceptance score was improved in 28.0%, unchanged in 39.4%, and worsened in 32.7% of patients. At 6 months, similar changes in adherence and acceptance were observed. Higher general acceptance score at month 3 was significantly associated with better adherence at month 6. Conversion to once-daily tacrolimus led to an improved rate of adherence at month 3 in more than 20% of patients and a worsened rate of adherence in less than 10% of patients.
DEFF Research Database (Denmark)
Bretzel, R.G.; Nuber, U.; Landgraf, W.
2008-01-01
BACKGROUND: As type 2 diabetes mellitus progresses, oral hypoglycaemic agents often fail to maintain blood glucose control and insulin is needed. We investigated whether the addition of once-daily insulin glargine is non-inferior to three-times daily prandial insulin lispro in overall glycaemic c...
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
Directory of Open Access Journals (Sweden)
Dhull K
2009-03-01
Full Text Available Aims and Objective: To determine the fluoride release from Giomer and Compomer, using different topical fluoride regimes, and to compare the amount of fluoride release from giomer with that of compomer. Materials and Method: Forty-eight specimens of each giomer and compomer were divided into four treatment groups, namely, control group, fluoridated dentifrice (500 ppm once daily group, fluoridated dentifrice (500 ppm twice daily group, fluoridated dentifrice (500 ppm once daily + fluoridated mouthwash (225 ppm group. Each specimen was suspended in demineralizing solution for six hours and remineralizing solution for 18 hours. Fluoride release was measured in both the demineralizing solution and remineralizing solution daily for seven days. Total daily fluoride release for each specimen was calculated by adding the amount released in the demineralizing solution to that released in remineralizing solution. Results and Conclusion: The fluoride release (ppm was found to be more in Giomer when compared to Compomer. The fluoride released from Giomer and Compomer was significantly greater in the acidic demineralizing solution than in the neutral remineralizing solution. It was found that increasing fluoride exposure significantly increased fluoride release from the giomer and compomer. It was found that the fluoride release from the subgroups of giomer and compomer was in the following order: fluoridated dentifrice twice daily > fluoridated dentifrice once daily + fluoridated mouthwash > fluoridated dentifrice once daily > control group. It was found that the giomer showed a greater fluoride uptake than the compomer.
DEFF Research Database (Denmark)
Jensen, Margit Bak; Pedersen, Lene Juul; Theil, Peter Kappel
2012-01-01
in an operant conditioning test, and samples of peripheral blood were taken in a balanced design, at 0900, 1200, 1900, and 0700 h, corresponding to 1, 4, 11, and 23 h after feeding for restricted sows fed once daily. No differences in the feeding motivation were found between the 4 restricted diets at any......, indicating that feeding twice daily reduced feeding motivation during the night compared with feeding once daily. Among restricted-fed sows, plasma concentrations of short-chain fatty acids (SCFA) were greater in sows fed high-fiber diets compared with the control (P = 0.02). Nonesterified fatty acid...... level of fiber in the diet of restrictedly fed sows did not reduce their feeding motivation irrespective of fiber source....
Model‐Informed Development and Registration of a Once‐Daily Regimen of Extended‐Release Tofacitinib
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
Pharmacokinetic drug evaluation of extended release lorcaserin for the treatment of obesity.
Hurren, Kathryn M; Dunham, Marissa W
2017-08-01
Lorcaserin is a serotonin 2C receptor antagonist that was FDA approved in 2012. Lorcaserin is recently available as an extended-release (ER) formulation for the treatment of obesity as an adjunct to lifestyle modification. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of lorcaserin ER will be reviewed. Expert opinion: Lorcaserin ER 20mg daily provides drug exposure bioequivalent to lorcaserin immediate release (IR) 10mg twice daily. Lorcaserin IR is associated with 3.3 and 3.0% placebo-subtracted weight loss in patients without and with diabetes, respectively. A1C was reduced by 0.9% in patients with diabetes. Common side effects include headache, dry mouth, constipation, dizziness, fatigue, and nausea. Lorcaserin provides potential advantages over other antiobesity medications in regards to tolerability and simplicity of medication initiation, but may not be as effective as other options. Lorcaserin ER offers improved ease of administration and anticipated adherence compared to the IR formulation. The place in therapy for lorcaserin ER and other antiobesity medications will be further clarified by results of pending clinical trials addressing cardiovascular outcomes as well as the role pharmacogenomics and comorbid disease states may play in choosing patient-specific therapy.
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 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.
DEFF Research Database (Denmark)
Nijman, Rien J M; Borgstein, Niels G; Ellsworth, Pamela
2007-01-01
OBJECTIVE: To evaluate the long-term tolerability of tolterodine extended release (ER) in children (aged 5-11 yr) with urgency urinary incontinence (UUI). METHODS: This was a multicenter, open-label extension of a 12-wk, double-blind, placebo-controlled study of tolterodine ER. Patients had UUI...... suggestive of detrusor overactivity (>/=1 diurnal incontinence episode per 24h for >/=5 of 7 d) and >/=6 voids per 24h at baseline and had completed the 12-wk double-blind study. Patients received tolterodine ER (2mg once daily) for 12 mo. The primary end points were the incidence and severity of adverse......-blind tolterodine ER, n=221; placebo, n=97). The majority of patients were white (90%), mean+/-SD age was 7.6+/-1.5 yr, and 54% were boys. Forty-nine percent of patients reported >/=1 AE during the study, similar to that observed in the preceding 12-wk study (42%). The most frequent AEs were urinary tract infection...
Directory of Open Access Journals (Sweden)
A. V. Susekov
2010-01-01
Full Text Available Aim. To evaluate quality of life changes and compliance to therapy in patients following successful transluminal angioplasty, who have indications for fluvastatin extended release in addition to standard treatment.Material and methods. This is a national observational multicenter study. An inclusion of 60 investigator centers is planned (out-patient medical centers, the total number of patients to be included is 600. Patients (men and women with coronary heart disease following successful transluminal coronary angioplasty, who were prescribed fluvastatinextended release (Lescol Forte, Novartis 80 mg once daily will be included in the observation. The following efficacy and safety parameters will be evaluated: quality of life assessed with SF-36 scale before and during treatment; compliance to therapy; adverse events and serious adverse events. Observation period is planned for 6 months. During this period patient is expected to make 4 visits to treating physician. According to the physician’s decision, observation period can be extended to 12 months.Present study status. The study is completed. 524 patients completed the observation, including 116 patients who were followed up for 12 months. There are 414 men (79% and 110 women (21% among patients enrolled into the study.
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Edoardo Spina
2011-01-01
Full Text Available Paliperidone, the major active metabolite of risperidone, is a second-generation antipsychotic that has been developed as an extended-release (ER tablet formulation that minimizes peak-trough fluctuations in plasma concentrations, allowing once-daily administration and constant drug delivery. Paliperidone ER has demonstrated efficacy in the reduction of acute schizophrenia symptoms in 6-week, placebo-controlled, double-blind trials and clinical benefits were maintained in the longer-term according to extension studies of up to 52 weeks in duration. Compared with quetiapine, paliperidone ER was associated with a more rapid symptom improvement. In addition, it was more effective than placebo in the prevention of symptom recurrence. Paliperidone ER is generally well tolerated with a predictable adverse event profile. Like risperidone, it is associated with a dose-dependent risk of extrapyramidal symptoms and prolactin elevation. Short-and longer-term studies have indicated a low liability for paliperidone ER to cause metabolic (ie, weight gain, hyperglycaemia and lipid dysregulation or cardiovascular adverse effects. Available safety data from elderly patients appear to be promising. Due to negligible hepatic biotransformation, paliperidone ER is unlikely to be involved in clinically significant metabolic drug-drug interactions. Additional active comparator trials evaluating efficacy, tolerability and cost-effectiveness are required to better define the role of paliperidone ER in the treatment of schizophrenia in relation to other currently available second-generation antipsychotics, particularly risperidone.
Ispaghula Husk-Based Extended Release Tablets of Diclofenac ...
African Journals Online (AJOL)
1Vels College of Pharmacy, Pallavaram, Chennai, India, 2Jeffrey Cheah School of Medicine and Health Sciences, Monash University, ... Keywords: Ispaghula husk, Extended release tablet, Diclofenac sodium, Release kinetics. .... release, i.e., Qt vs t, log (Q0-Qt) vs t and Qt vs .... Wallis TE, Textbook of Pharmacognosy, CBS.
International Nuclear Information System (INIS)
Hameed, M.; Khan, K.; Salman, S.; Mehmood, N.
2017-01-01
Diabetes Mellitus type 2 is very common worldwide, with majority of cases in Asia Pacific region. Metformin is the first line therapy, along with lifestyle modification for all type 2 diabetics as recommended by ADA. Metformin is available as conventional Metformin Immediate Release (MIR) and Metformin Extended Release (MXR). Metformin XR has better gastrointestinal tolerability and fewer side effects as compared to Metformin IR, with similar efficacy regarding anti-hyperglycaemic effects. The objective of this study was to determine whether metformin XR is as effective as Metformin IR in maintaining glycaemic control at equivalent doses or even at reduced doses; and to compare the side effect profile of the two preparations. Methods: This randomized control trial was conducted at Medical and Endocrinology OPD of Jinnah Hospital Lahore A total of 90 type 2 diabetics of both genders were recruited using nonprobability purposive sampling. Patients were randomized into 3 groups; 30 in each group. Group 1 received Metformin IR 1000 mg twice daily; group 2 received metformin XR 1000mg twice daily; and group 3 received metformin XR 500 mg twice daily, for a period of three months. HbA1c was done at baseline and after three months of therapy along with fasting blood sugars and random blood sugars weekly. Results: The mean age of patients was 46+-9 years, with 54% being males and 46% being females. There was a 1% reduction in HbA1c in group 1, 0.7% reduction in group 2 and only 0.4% reduction in group 3. Similarly, all three therapies were equally effective in reducing blood sugar fasting and blood sugar random at three months. Side effects namely diarrhoea, dyspepsia and flatulence were greatest with Metformin IR (40%) but less than half with Metformin XR at equivalent dose and negligible at half the dose. Conclusions: All three Metformin groups were effective in reduction of HbA1C and glycaemic control clinically and there is no statistical difference in HbA1c reduction
Development of Modified-Release Tablets of Zolpidem Tartrate by Biphasic Quick/Slow Delivery System
Mahapatra, Anjan Kumar; Sameeraja, N. H.; Murthy, P. N.
2014-01-01
Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration of action is considered too short in certain circumstances. Thus, it is desirable to lengthen the duration of action. The formulation design was implemented by preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology, where sodium s...
DEFF Research Database (Denmark)
Vilsbøll, Tina; Brock, Birgitte; Perrild, Hans
2008-01-01
To assess the effect of liraglutide, a once-daily human glucagon-like peptide-1 analogue on pancreatic B-cell function. methods: Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin...... release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin...
Efficacy and Safety of Terbinafine 500 mg Once Daily in Patients with Dermatophytosis.
Babu, P Ravindra; Pravin, A J S; Deshmukh, Gaurav; Dhoot, Dhiraj; Samant, Aniket; Kotak, Bhavesh
2017-01-01
Dermatophytosis are the most common fungal infections globally. Terbinafine is considered to have good potency against dermatophytes, but resistance to terbinafine is on the rise. The objective of this study was to evaluate the efficacy and safety of terbinafine 500 mg given once daily in treatment of patients with superficial dermatophytosis. It was a retrospective questionnaire-based survey. Each doctor was given survey questionnaire booklet containing survey forms. Clinical response was graded according to the improvement in the affected lesion. Mycological cure was defined as negative microscopy under potassium hydroxide examination and a negative culture in Sabouraud's dextrose agar. Patients were divided into three groups depending on the duration of therapy, Group A - terbinafine 500 mg for 2 weeks, Group B - terbinafine 500 mg for 4 weeks, and Group C - terbinafine 500 mg for 6 weeks. Total 50 doctors completed the survey involving 440 patients. In Group A, out of 194 patients, 87% ( n = 169) patients showed very good response. In Group B, out of 211 patients, 92% ( n = 194) of the patients showed very good response with >75% improvement in their lesion. In Group C, out of 35 patients, 80% ( n = 30) patients showed very good response. Adverse drug reactions of mild to moderate intensity related to terbinafine were seen in 57 patients. Our survey indicates that terbinafine in a dose of 500 mg given once daily was efficacious and safe in the treatment of patients with dermatophytosis.
Tsuchiya, Yoshifumi; Ijichi, Toshiaki; Goto, Kazushige
2016-04-01
Exercise twice every other day has been shown to lead to increasing peroxisome proliferator receptor γ coactivator-1α (PGC-1α) expression (up-stream factor of irisin) via lowered muscle glycogen level during second of exercise compared with exercise once daily. This study determined the influence of 4weeks of sprint training (training once daily vs. twice every other day) on the serum irisin concentration. Twenty healthy males (20.9±1.3years) were assigned randomly to either the SINGLE or REPEATED group (n=10 per group). The subjects in the SINGLE group participated in a sprint training session once daily (5days per week), whereas those in the REPEATED group performed two consecutive training sessions on the same day with a 1-h rest between sessions (2-3days per week). Both groups completed 20 training sessions over 4weeks. Each training session consisted of three consecutive 30-s maximal pedaling exercises with a 10-min rest between sets. Blood samples were collected before and after training period (48h after completing the last training session). The serum irisin concentration decreased significantly after training in each group (SINGLE, 338.5±77.8 to 207.6±64.6ng/mL; REPEATED, 329.5±83.9 to 234.2±72.8ng/mL, pevery other day). Copyright © 2016 Elsevier Inc. All rights reserved.
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William A Prescott
2014-01-01
Full Text Available Once-daily dosing intravenous tobramycin is commonly used to treat cystic fibrosis pulmonary exacerbations. Clinicians often utilize historical therapeutic drug monitoring data to individualize the dose among patients who have been treated with tobramycin previously. This case series involves three patients with cystic fibrosis who had supra-therapeutic tobramycin levels despite use of a once-daily dosing that produced therapeutic drug levels during a previous hospital admission, raising questions about the validity of these levels. Investigation into several potential sources of error led to the discovery of an analyzer error in the laboratory. Once the laboratory’s tobramycin analyzer was recalibrated, the reported levels were comparable to historical levels. This case series emphasizes the clinical importance of critically analyzing reported levels, and specifically, the importance of utilizing past therapeutic drug monitoring data, if available, for all patients treated with intravenous tobramycin. If a patient was therapeutic on a similar dose of tobramycin during a previous admission, a dose adjustment may not be necessary, and clinicians should consider repeating levels while pursuing alternative explanations for the discrepant serum levels.
Role of extended release quetiapine in the management of bipolar disorders
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Rayan K Al Jurdi
2010-02-01
Full Text Available Rayan K Al Jurdi1,2, Lena A Dixit1, Martha Sajatovic3 1Baylor College of Medicine, Department of Psychiatry, Houston, Texas, USA; 2South Central Mental Illness Research and Clinical Core, Department of Veterans Affairs, Houston, Texas; 3Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USAAbstract: Atypical antipsychotics have become a widely utilized component of the bipolar disorder treatment armamentarium, with approximately 45% of bipolar patients prescribed atypicals. Over the last decade all atypical drugs except for clozapine have received a Food and Drug Administration (FDA bipolar indication. In October 2008, the FDA approved quetiapine XR monotherapy for the treatment of acute depressive episodes of bipolar disorder and acute manic or mixed episodes in bipolar I disorder based on two placebo-control trials. Quetiapine was also approved as adjunct therapy with lithium and divalproex for the treatment of acute manic or mixed episodes as well as maintenance of bipolar I disorder. In contrast to immediate release quetiapine which may require a twice-daily regimen, the XR formulation is intended for once-daily administration. This drug profile of quetiapine XR will address chemistry, pharmacodynamics, pharmacokinetics, metabolism, safety and tolerability and clinical trials in bipolar disorder.Keywords: quetiapine XR, bipolar disorder
Efficacy and safety of terbinafine 500 mg once daily in patients with dermatophytosis
Directory of Open Access Journals (Sweden)
P Ravindra Babu
2017-01-01
Full Text Available Introduction: Dermatophytosis are the most common fungal infections globally. Terbinafine is considered to have good potency against dermatophytes, but resistance to terbinafine is on the rise. Objective: The objective of this study was to evaluate the efficacy and safety of terbinafine 500 mg given once daily in treatment of patients with superficial dermatophytosis. Materials and Methods: It was a retrospective questionnaire-based survey. Each doctor was given survey questionnaire booklet containing survey forms. Clinical response was graded according to the improvement in the affected lesion. Mycological cure was defined as negative microscopy under potassium hydroxide examination and a negative culture in Sabouraud's dextrose agar. Patients were divided into three groups depending on the duration of therapy, Group A – terbinafine 500 mg for 2 weeks, Group B – terbinafine 500 mg for 4 weeks, and Group C – terbinafine 500 mg for 6 weeks. Results: Total 50 doctors completed the survey involving 440 patients. In Group A, out of 194 patients, 87% (n = 169 patients showed very good response. In Group B, out of 211 patients, 92% (n = 194 of the patients showed very good response with >75% improvement in their lesion. In Group C, out of 35 patients, 80% (n = 30 patients showed very good response. Adverse drug reactions of mild to moderate intensity related to terbinafine were seen in 57 patients. Conclusion: Our survey indicates that terbinafine in a dose of 500 mg given once daily was efficacious and safe in the treatment of patients with dermatophytosis.
Nickols-Richardson, Sharon M.; Piehowski, Kathryn E.; Metzgar, Catherine J.; Miller, Debra L.; Preston, Amy G.
2014-01-01
BACKGROUND/OBJECTIVES The type of sweet snack incorporated into an energy-restricted diet (ERD) may produce differential effects on metabolic improvements associated with body weight (BW) loss. This study compared effects of incorporating either twice daily energy-controlled dark chocolate snacks plus once daily sugar-free cocoa beverage (DC) to non-chocolate snacks plus sugar-free non-cocoa beverage (NC) into an ERD on BW loss and metabolic outcomes. MATERIALS/METHODS In an 18-week randomize...
Treatment-Continuity of ADHD Compared Using Immediate-Release and Extended-Release MPH
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J Gordon Millichap
2005-07-01
Full Text Available The continuity of methylphenidate (MPH therapy for ADHD in young Medicaid beneficiaries (ages 6 to 17 years treated with immediate-release (IR or extended-release (ER MPH formulations was compared in an analysis of statewide California Medicaid claims (2000-2003 conducted at Columbia University, New York; University of Pennsylvania, Philadelphia; and McNeil Pharmaceuticals, Fort Washington, PA.
Mizuno, Yoshikuni; Yamamoto, Mitsutoshi; Kuno, Sadako; Hasegawa, Kazuko; Hattori, Nobutaka; Kagimura, Tatsuro; Sarashina, Akiko; Rascol, Olivier; Schapira, Anthony H V; Barone, Paolo; Hauser, Robert A; Poewe, Werner
2012-01-01
To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.
Fluticasone furoate: once-daily evening treatment versus twice-daily treatment in moderate asthma
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Woodcock Ashley
2011-12-01
Full Text Available Abstract Background Inhaled corticosteroids are the recommended first-line treatment for asthma but adherence to therapy is suboptimal. The objectives of this study were to compare the efficacy and safety of once-daily (OD evening and twice-daily (BD regimens of the novel inhaled corticosteroid fluticasone furoate (FF in asthma patients. Methods Patients with moderate asthma (age ≥ 12 years; pre-bronchodilator forced expiratory volume in 1 second (FEV1 40-85% predicted; FEV1 reversibility of ≥ 12% and ≥ 200 ml were randomized to FF or fluticasone propionate (FP regimens in a double-blind, crossover study. Patients were not permitted to have used any ICS for ≥ 8 weeks prior to enrolment and subsequently received doses of FF or FP 200 μg OD, FF or FP 100 μg BD and matching placebo by inhalation for 28 days each. Primary endpoint was Day 28 evening pre-dose (trough FEV1; non-inferiority of FF 200 μg OD and FF 100 μg BD was assessed, as was superiority of all active treatment relative to placebo. Adverse events (AEs and 24-hour urinary cortisol excretion were assessed. Results The intent-to-treat population comprised 147 (FF and 43 (FP patients. On Day 28, pre-dose FEV1 showed FF 200 μg OD to be non-inferior (pre-defined limit -110 ml to FF 100 μg BD (mean treatment difference 11 ml; 95% CI: -35 to +56 ml; all FF and FP regimens were significantly superior to placebo (p ≤ 0.02. AEs were similar to placebo; no serious AEs were reported. Urinary cortisol excretion at Day 28 for FF was lower than placebo (ratios: 200 μg OD, 0.75; 100 μg BD, 0.84; p ≤ 0.02. Conclusions FF 200 μg OD in the evening is an efficacious and well tolerated treatment for asthma patients and is not inferior to the same total BD dose. Trial registration Clinicaltrials.gov; NCT00766090.
Features of the extended-release metformin
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T O Yalochkina
2013-03-01
Full Text Available Реферат по материалам статьи Ali S, Fonseca V. Overview of metformin: special focus on metformin extended release. Expert Opin Pharmacother. 2012 Aug;13(12:1797-805.
Development of modified-release tablets of zolpidem tartrate by biphasic quick/slow delivery system.
Mahapatra, Anjan Kumar; Sameeraja, N H; Murthy, P N
2015-06-01
Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration of action is considered too short in certain circumstances. Thus, it is desirable to lengthen the duration of action. The formulation design was implemented by preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology, where sodium starch glycolate acts as a superdisintegrant in immediate-release part and hydroxypropyl methyl cellulose as a release retarding agent in extended-release core. Tablets were prepared by direct compression. Both the core and the coat contained the drug. The pre-compression blends were evaluated for angle of repose, bulk density, and compressibility index. The tablets were evaluated for thickness, hardness, weight variation test, friability, and in vitro release studies. No interaction was observed between zolpidem tartrate and excipients from the Fourier transform infrared spectroscopy and differential scanning calorimetry analysis. The results of all the formulations prepared were compared with reference product Stilnoct®. Optimized formulations showed release patterns that match the United States Pharmacopeia (USP) guidelines for zolpidem tartrate extended-release tablets. The mechanism of drug release was studied using different mathematical models, and the optimized formulation has shown Fickian diffusion. Accelerated stability studies were performed on the optimized formulation.
Berger, Darren J; Lewis, Thomas P; Schick, Anthea E; Stone, Richard T
2012-10-01
Terbinafine, an allylamine antifungal, is used in pulsatile dose regimens for superficial mycoses in human medicine. To compare the clinical efficacy of twice-weekly versus once-daily terbinafine administration to determine whether preliminary proof-of-concept evidence exists for pulsatile administration of terbinafine in the treatment of canine Malassezia dermatitis and to determine whether twice-weekly treatment results in fewer clinical and owner-perceived adverse events. Twenty client-owned dogs with Malassezia dermatitis. In this randomized, single-blinded clinical trial, dogs were randomly assigned to receive terbinafine (30 mg/kg) either once daily for 21 days (n = 10) or once daily on two consecutive days per week for six doses (n = 10). On day 0 and day 21, a mean yeast count was calculated from eight anatomical locations via adhesive tape-strip cytology, clinical lesion scores were assigned to the same locations, and owners assessed pruritus using a visual analog scale. There was no significant difference between treatment groups with respect to the reduction in mean yeast count (P = 0.343) and clinical lesion scores (P = 0.887). Pruritus measured by visual analog scale was significantly decreased in the twice-weekly treatment group compared with the daily treatment group (P = 0.047). Seven of 20 dogs had a clinically measurable or owner-reported adverse event during treatment that included gastrointestinal disturbances, excessive panting and elevated hepatic enzymes, with no significant difference noted between treatment groups. This pilot study indicates that twice-weekly terbinafine administration may be an effective alternative treatment for canine Malassezia dermatitis and merits further investigation. © 2012 The Authors. Veterinary Dermatology © 2012 ESVD and ACVD.
van Heeswijk, R. P.; Veldkamp, A. I.; Mulder, J. W.; Meenhorst, P. L.; Lange, J. M.; Beijnen, J. H.; Hoetelmans, R. M.
2000-01-01
To investigate the steady-state pharmacokinetics of a once-daily dosing regimen of saquinavir soft gelatin capsules in combination with a low dose of ritonavir in HIV-1-infected individuals. Open-label, multi-dose, pharmacokinetic pilot study. Seven HIV-1-infected individuals who were treated with
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Roberto Mantovani
2010-01-01
Full Text Available The objective of this experiment is to evaluate the changes of particle size distribution and chemical composition of the total mixed ration (TMR based on hay as the main forage component (“dry” TMR and distributed once (7.00 am or twice (7.00 am and 1.00 pm daily to 32 lactating cows. The trial was divided in two periods of 14 days each. Diet (DM=53.7% was formulated in order to assure the nutritional requirements of cows producing 24 kg/d of milk (crude protein=14.4% DM; NDF=40.9% DM; milk FU=0.88/kg DM and additional amounts of concentrates were distributed using automatic feeders. Four TMR samples were collected daily (7.00 am, 10.00 am, 1.00 pm, 4.00 pm for six days during each experiment period for a total number of 48 feed samples. Each feed sample was subjected to the estimation of the particle size distribution using the separator of Pennsylvania State University composed of two sieves (diameters of 19 and 8 mm and a collector on the bottom, and to the determination of the chemical composition. Changes of all three particle size fractions for TMRs were observed during the day with distributions of the TMR both once and twice daily. With the once daily distribution, the large particles fraction increased linearly (P<0.001 from 19.7 to 23.4, 32.2, and 35.1%, while the finest particle fraction decreased (from 60.1 to 58.3, 50.0, 47.8%. According to particle size changes, the chemical composition varied significantly at the different times of sampling when TMR was distributed once daily. Significant variations of DM were detected for TMR with a linear (P<0.001 increase (from 54.4 to 57.9, 60.7, 61.5%. Considering once TMR distribution, the values of NDF and starch showed an opposite trend with an increase of 6.5 and a decrease of 8.3 points from 7.00 am to 4.00 pm (i.e., 9 hrs after distribution. Correlations were estimated between chemical and physical characteristics of TMRs. NDF content was positively and significantly correlated to
Höfner, K.; Claes, H.; de Reijke, T. M.; Folkestad, B.; Speakman, M. J.
1999-01-01
To evaluate the effect of tamsulosin, 0.4 mg once daily, on sexual function in comparison with placebo and alfuzosin, 2.5 mg three times daily, in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO). Data from 830 patients randomized into three European
Extended release formulations for local anaesthetic agents.
Weiniger, C F; Golovanevski, L; Domb, A J; Ickowicz, D
2012-08-01
Systemic toxicity through overdose of local anaesthetic agents is a real concern. By encapsulating local anaesthetics in biodegradable carriers to produce a system for prolonged release, their duration of action can be extended. This encapsulation should also improve the safety profile of the local anaesthetic as it is released at a slower rate. Work with naturally occurring local anaestheticss has also shown promise in the area of reducing systemic and neurotoxicity. Extended duration local anaesthetic formulations in current development or clinical use include liposomes, hydrophobic based polymer particles such as Poly(lactic-co-glycolic acid) microspheres, pasty injectable and solid polymers like Poly(sebacic-co-ricinoleic acid) P(SA:RA) and their combination with synthetic and natural local anaesthetic. Their duration of action, rationale and limitations are reviewed. Direct comparison of the different agents is limited by their chemical properties, the drug doses encapsulated and the details of in vivo models described. Anaesthesia © 2012 The Association of Anaesthetists of Great Britain and Ireland.
Wilson, Darrell M; Abrams, Stephanie H; Aye, Tandy; Lee, Phillip D K; Lenders, Carine; Lustig, Robert H; Osganian, Stavroula V; Feldman, Henry A
2010-02-01
Metformin has been proffered as a therapy for adolescent obesity, although long-term controlled studies have not been reported. To test the hypothesis that 48 weeks of daily metformin hydrochloride extended release (XR) therapy will reduce body mass index (BMI) in obese adolescents, as compared with placebo. Multicenter, randomized, double-blind, placebo-controlled clinical trial. The 6 centers of the Glaser Pediatric Research Network from October 2003 to August 2007. Obese (BMI > or = 95th percentile) adolescents (aged 13-18 years) were randomly assigned to the intervention (n = 39) or placebo groups. Intervention Following a 1-month run-in period, subjects following a lifestyle intervention program were randomized 1:1 to 48 weeks' treatment with metformin hydrochloride XR, 2000 mg once daily, or an identical placebo. Subjects were monitored for an additional 48 weeks. Main Outcome Measure Change in BMI, adjusted for site, sex, race, ethnicity, and age and metformin vs placebo. After 48 weeks, mean (SE) adjusted BMI increased 0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in the metformin XR group (P = .03). This difference persisted for 12 to 24 weeks after cessation of treatment. No significant effects of metformin on body composition, abdominal fat, or insulin indices were observed. Metformin XR caused a small but statistically significant decrease in BMI when added to a lifestyle intervention program. clinicaltrials.gov Identifiers: NCT00209482 and NCT00120146.
Metoprolol succinate extended release/hydrochlorothiazide combination tablets
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James W Hainer
2007-07-01
Full Text Available James W Hainer, Jennifer SuggAstraZeneca LP, Wilmington, DE, USAAbstract: Lowering elevated blood pressure (BP with drug therapy reduces the risk for catastrophic fatal and nonfatal cardiovascular events such as stroke and myocardial infarction. Given the heterogeneity of hypertension as a disease, the marked variability in an individual patient’s BP response, and low response rates with monotherapy, expert groups such as the Joint National Committee (JNC emphasize the value of combination antihypertensive regimens, noting that combinations, usually of different classes, have additive antihypertensive effects. Metoprolol succinate extended-release tablet is a beta-1 (cardio-selective adrenoceptor-blocking agent formulated to provide controlled and predictable release of metoprolol. Hydrochlorothiazide (HCT is a well-established diuretic and antihypertensive agent, which promotes natruresis by acting on the distal renal tubule. The pharmacokinetics, efficacy, and safety/tolerability of the antihypertensive combination tablet, metoprolol extended release hydrochlorothiazide, essentially reflect the well-described independent characteristics of each of the component agents. Not only is the combination product more effective than monotherapy with the individual components but the combination product allows a low-dose multidrug regimen as an alternative to high-dose monotherapy, thereby, minimizing the likelihood of dose-related side-effects.Keywords: antihypertensive, blood pressure, cardiovascular disease, combination product
Orbelo, Diana M; Enders, Felicity T; Romero, Yvonne; Francis, Dawn L; Achem, Sami R; Dabade, Tushar S; Crowell, Michael D; Geno, Debra M; DeJesus, Ramona S; Namasivayam, Vikneswaran; Adamson, Steven C; Arora, Amindra S; Majka, Andrew J; Alexander, Jeffrey A; Murray, Joseph A; Lohse, Matthew; Diehl, Nancy N; Fredericksen, Mary; Jung, Kee Wook; Houston, Margaret S; O'Neil, Angela E; Katzka, David A
2015-01-01
Morning dose or twice-daily proton pump inhibitor (PPI) use is often prescribed to heal severe reflux esophagitis. Compare the effect of single dose morning (control arm) versus nighttime (experimental arm) omeprazole/sodium bicarbonate (Zegerid(®)) (IR-OME) on esophagitis and gastroesophageal reflux symptoms. Adult outpatients with Los Angeles grade C or D esophagitis were allocated to open-label 40 mg IR-OME once a day for 8 weeks in a prospective, randomized, parallel design, single center study. Esophagogastroduodenoscopy (EGD) and validated self-report symptom questionnaires were completed at baseline and follow-up. Intention-to-treat and per-protocol analyses were performed. Ninety-two of 128 (72 %) eligible subjects participated [64 (70 %) male, mean age 58 (range 19-86), median BMI 29 (range 21-51), 58 C:34 D]. Overall, 81 (88 %) subjects healed [n = 70 (76 %)] or improved [n = 11 (12 %)] erosions. There was no significant difference (morning vs. night) in mucosal healing [81 vs. 71 %, (p = 0.44)] or symptom resolution [heartburn (77 vs. 65 %, p = 0.12), acid regurgitation (82 vs. 73 %, p = 0.28)]. Prevalence of newly identified Barrett's esophagus was 14 % with half diagnosed only after treatment. Once-daily IR-OME (taken morning or night) effectively heals severe reflux esophagitis and improves GERD symptoms. Results support the clinical practice recommendation to repeat EGD after 8 weeks PPI therapy in severe esophagitis patients to assure healing and exclude Barrett's esophagus.
Jensen, M B; Pedersen, L J; Theil, P K; Yde, C C; Bach Knudsen, K E
2012-06-01
The present study investigated the effects of source and level of dietary fiber (DF) and feeding frequency (once vs. twice daily) on feeding motivation and plasma metabolites at 4 different time points post feeding. Sixty pregnant sows (Sus scrofa, 4 blocks of 15 sows) were allocated to 1 of 5 diets within blocks. Four diets were restricted (approximately 35 MJ ME/d): a barley and wheat control diet (171 g DF/kg DM; 12 g DF/MJ ME), and 3 fiber diets formulated to contain 35% DF by including pectin residue (323 g DF/kg DM; 25 g DF/MJ ME), potato pulp (404 g DF/kg DM; 29 g DF/MJ ME), or sugar beet pulp (367 g DF/kg DM; 25 g DF/MJ ME). The fifth diet was a mixture including an equal amount of the 3 fiber diets offered semi ad libitum (ad libitum access to feed during 6 periods of 1 h starting at 0300, 0600, 1100, 1500, 1800, and 2300; 354 g DF/kg DM; 25 g DF/MJ ME). The experimental period included 2 periods of 4 wk each. Restricted-fed sows were fed once daily (0800 h) during the first period and twice daily (0800 and 1500 h) during the second period, or vice versa. Semi ad libitum fed sows had access to feed 6 times a day in both periods. In each period, the feeding motivation was assessed in an operant conditioning test, and samples of peripheral blood were taken in a balanced design, at 0900, 1200, 1900, and 0700 h, corresponding to 1, 4, 11, and 23 h after feeding for restricted sows fed once daily. No differences in the feeding motivation were found between the 4 restricted diets at any of the time points post feeding, but semi ad libitum fed sows had a decreased feeding motivation (P motivation at 1900 h (P motivation during the night compared with feeding once daily. Among restricted-fed sows, plasma concentrations of short-chain fatty acids (SCFA) were greater in sows fed high-fiber diets compared with the control (P = 0.02). Nonesterified fatty acid was least in sows on the control diet and greatest in sows on the potato diet, whereas sows on the pectin and
Food interactions with sustained-release theophylline preparations. A review.
Jonkman, J H
1989-03-01
Currently, theophylline is being used predominantly as sustained-release capsules or tablets. In the mid-seventies the first preparations for use with a dosage interval of 12 hours (twice-daily preparations) were introduced. Since 1983, theophylline preparations that can be given with an interval of 24 hours (once-daily preparations) have become available. The release of theophylline from some of these products can be influenced (either increased or decreased) by concomitant intake of food. With some preparations the composition of the meal (especially the fat content) has an influence on the degree of effect. The consequence may be an effect on the rate of absorption or on the amount absorbed, or both simultaneously. This could result in an unexpected shift of the plasma theophylline concentration. Such a shift is therapeutically undesirable, because theophylline has a fairly narrow therapeutic range. A review is given of those food interactions with the sustained-release theophylline preparations, both twice-daily and once-daily products, that are currently on the world market. Special attention is paid to the specific (bio)pharmaceutical characteristics of the different products, and to the influence of the composition and timing of the meals. For each preparation the effect of food on the following pharmacokinetic parameters is discussed: area under the plasma concentration-time curve, peak plasma drug concentration and time to reach this peak. Where possible, the results for both adults and children are discussed. There are indications that children are more susceptible to food-effects than adults. The regulatory aspects are mentioned briefly. Clinically important effects of food have been observed with the following twice-daily products: 'Theo-Dur Sprinkle', 'Theolair SR' (= 'Nuelin SR') and 'Theograd'. Pronounced effects could have an even greater impact with once-daily preparations, as the total daily dose will be given at a single time. A particularly
2013-11-04
...] Determination That INVEGA (Paliperidone) Extended-Release Tablet, 12 Milligrams, Was Not Withdrawn From Sale for... Food and Drug Administration (FDA) has determined that INVEGA (paliperidone) extended-release tablet...-release tablet, 12 mg, if all other legal and regulatory requirements are met. FOR FURTHER INFORMATION...
Profile of extended-release oxycodone/acetaminophen for acute pain
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Bekhit MH
2015-10-01
Full Text Available Mary Hanna Bekhit1–51David Geffen School of Medicine, 2Ronald Reagan UCLA Medical Center, 3UCLA Ambulatory Surgery Center, 4UCLA Wasserman Eye Institute, 5UCLA Martin Luther King Community Hospital, University of California Los Angeles, Los Angeles, CA, USA Abstract: This article provides a historical and pharmacological overview of a new opioid analgesic that boasts an extended-release (ER formulation designed to provide both immediate and prolonged analgesia for up to 12 hours in patients who are experiencing acute pain. This novel medication, ER oxycodone/acetaminophen, competes with current US Food and Drug Administration (FDA-approved opioid formulations available on the market in that it offers two benefits concurrently: a prolonged duration of action, and multimodal analgesia through a combination of an opioid (oxycodone with a nonopioid component. Current FDA-approved combination analgesics, such as Percocet (oxycodone/acetaminophen, are available solely in immediate-release (IR formulations. Keywords: opioid, analgesic, xartemis, acute postsurgical pain, substance abuse, acetaminophen, extended release
Fatemeh Pourhashem; Mohammad Reza Avadi
2016-01-01
The goal of this study was to design and evaluate extended - release system of the hypnotic agent, Zolpidem tartrate usefulness for the treatment of insomnia. The half-life of this drug is about 1.9 - 3 hours that indicating it a candidate for the extended release formulation. Our investigation relates to development of extended drug delivery system based on Hydroxy propyl methyl cellulose (HPMCK4M) as release retardant, polyvinyl pyrrolidone (PVP k30) as binder and Magnesium S...
International Nuclear Information System (INIS)
Goyal, Sharad; Daroui, Parima; Khan, Atif J; Kearney, Thomas; Kirstein, Laurie; Haffty, Bruce G
2013-01-01
The aim of this study was to report 3-year outcomes of toxicity, cosmesis, and local control using a once daily fractionation scheme (49.95 Gy in 3.33 Gy once daily fractions) for accelerated partial breast irradiation (APBI) using three-dimensional conformal radiotherapy (3D-CRT). Between July 2008 and August 2010, women aged ≥40 years with ductal carcinoma in situ or node-negative invasive breast cancer ≤3 cm in diameter, treated with breast-conserving surgery achieving negative margins, were accrued to a prospective study. Women were treated with APBI using 3–5 photon beams, delivering 49.95 Gy over 15 once daily fractions over 3 weeks. Patients were assessed for toxicities, cosmesis, and local control rates before APBI and at specified time points. Thirty-four patients (mean age 60 years) with Tis 0 (n = 9) and T1N0 (n = 25) breast cancer were treated and followed up for an average of 39 months. Only 3% (1/34) patients experienced a grade 3 subcutaneous fibrosis and breast edema and 97% of the patients had good/excellent cosmetic outcome at 3 years. The 3-year rate of ipsilateral breast tumor recurrence (IBTR) was 0% while the rate of contralateral breast events was 6%. The 3-year disease-free survival (DFS), overall survival (OS), and breast cancer-specific survival (BCSS) was 94%, 100%, and 100%, respectively. Our novel accelerated partial breast fractionation scheme of 15 once daily fractions of 3.33 Gy (49.95 Gy total) is a remarkably well-tolerated regimen of 3D-CRT-based APBI. A larger cohort of patients is needed to further ascertain the toxicity of this accelerated partial breast regimen
Extended Daily Eye Patching Effective at Treating Stubborn Amblyopia in Children
... Spanish Spanish Stargardt Disease Stem Cells Usher Syndrome Uveitis/Inflammatory Eye Disease Vision Screening World Sight Day Extended daily eye patching effective at treating stubborn amblyopia in children News Brief 09/20/13 The standard treatment for amblyopia, a condition of poor vision in ...
Ispaghula Husk-Based Extended Release Tablets of Diclofenac ...
African Journals Online (AJOL)
Purpose: To formulate extended-release tablets of diclofenac sodium based on ispaghula husk. Methods: Tablets with varying proportions of diclofenac sodium and ispaghula husk were formulated by wet granulation technique at a fixed compression force of 10 kN. The formulated tablets were evaluated for ...
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Fatemeh Pourhashem
2016-06-01
Full Text Available The goal of this study was to design and evaluate extended - release system of the hypnotic agent, Zolpidem tartrate usefulness for the treatment of insomnia. The half-life of this drug is about 1.9 - 3 hours that indicating it a candidate for the extended release formulation. Our investigation relates to development of extended drug delivery system based on Hydroxy propyl methyl cellulose (HPMCK4M as release retardant, polyvinyl pyrrolidone (PVP k30 as binder and Magnesium Stearate using Factorial design. In vitro release study of matrix tablets was carried out in 0.01N HCl for 2 hours. All prepared matrix tablets were evaluated for physicochemical evaluation and drug content. The formulation that had release profile according to United State Pharmacopoeia selected for stability study according to ICH guidelines.
Pratley, Richard E; Nauck, Michael A; Barnett, Anthony H; Feinglos, Mark N; Ovalle, Fernando; Harman-Boehm, Illana; Ye, June; Scott, Rhona; Johnson, Susan; Stewart, Murray; Rosenstock, Julio
2014-04-01
As new members of a drug class are developed, head-to-head trials are an important strategy to guide personalised treatment decisions. We assessed two glucagon-like peptide-1 receptor agonists, once-weekly albiglutide and once-daily liraglutide, in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs. We undertook this 32-week, open-label, phase 3 non-inferiority study at 162 sites in eight countries: USA (121 sites), Australia (9 sites), Peru (7 sites), Philippines (7 sites), South Korea (5 sites), UK (5 sites), Israel (4 sites), and Spain (4 sites). 841 adult participants (aged ≥18 years) with inadequately controlled type 2 diabetes and a BMI between 20 and 45 kg/m(2) were enrolled and randomised in a 1:1 ratio to receive albiglutide 30 mg once weekly titrated to 50 mg at week 6, or liraglutide 0·6 mg once daily titrated to 1·2 mg at week 1 and 1·8 mg at week 2. The randomisation schedule was generated by an independent randomisation team by the permuted block method with a fixed block size of 16. Participants and investigators were unmasked to treatment. The primary endpoint was change from baseline in HbA1c for albiglutide versus liraglutide, with a 95% CI non-inferiority upper margin of 0·3%. The primary analysis was by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT01128894. 422 patients were randomly allocated to the albigultide group and 419 to the liraglutide group; 404 patients in the abliglutide group and 408 in the liraglutide group received the study drugs. The primary endpoint analysis was done on the modified intention-to-treat population, which included 402 participants in the albiglutide group and 403 in the liraglutide group. Model-adjusted change in HbA1c from baseline to week 32 was -0·78% (95% CI -0·87 to -0·69) in the albigludite group and -0·99% (-1·08 to -0·90) in the liraglutide group; treatment difference was 0·21% (0·08-0·34; non-inferiority p value=0
Rhabdomyolysis following Acute Extended-Release Quetiapine Poisoning: A Case Report
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Antonios Liolios
2012-01-01
Full Text Available Background. During the past few years, there have been a number of case reports concerning rhabdomyolysis following quetiapine poisoning; however, there has been none concerning the medication in its extended-release form. Methods. We present the case report of a 48-year-old man presenting a major depressive disorder and borderline personality disorder, who after voluntary intoxication with 12000 mg of quetiapine extended-release developed signs of acute rhabdomyolysis. Results. The rhabdomyolysis was confirmed by the laboratory and the clinical findings, with elevated levels of creatinine, creatine phosphokinase, and CRP. Discussion. We would like to pinpoint the importance of this complication and our concern of prescribing it for psychiatric patients with chronic somatic comorbidities.
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Jayanthi Mungara
2013-01-01
Full Text Available Aim: This in vitro study was designed to investigate the effects of daily fluoride exposures on fluoride release and recharge by prereacted glass ionomer (PRG composite and nano-ionomeric glass ionomer. Materials and Methods: Seventy-two specimens (36 of each material were prepared and by placing the restorative materials into Teflon mold. Each specimen was subjected to one of three daily treatments (n = 12: (1 No fluoride treatment (control; (2 application of a fluoride dentifrice (1,000 ppm once daily; and (3 the same regimen as (2, plus immersion in a 0.05% sodium fluoride (NaF mouth rinse (225 ppm immediately following the dentifrice application. Specimens were suspended in a storage vial containing 10 ml demineralizing solution for 6 h and transferred to a new test tube containing 10 ml remineralizing solution for 18 h. Fluoride treatments of the specimens were completed every day prior to their immersion in the demineralizing solution. Media solutions were buffered with equal volumes of total ionic strength adjustment buffer (TISAB II; fluoride levels were measured using a digital ion analyzer and fluoride electrode throughout the 21 day duration of the experiment. Results: Nano-ionomeric glass ionomer showed a better amount of fluoride release than PRG composite irrespective of the fluoride treatment supplementation (P < 0.01. Additional fluoride supplementation improved fluoride release and recharge ability for both the materials when compared to their respective control groups. The fluoride recharge for both materials did not show any sustained pattern of release. Conclusion: Nano-ionomeric glass ionomer demonstrated a greater ability to release and recharge compared with that of PRG composite.
Update on prescription extended-release opioids and appropriate patient selection
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Brennan MJ
2013-07-01
Full Text Available Michael J Brennan The Pain Center of Fairfield, Fairfield, CT, USA Abstract: Chronic pain is largely underdiagnosed, often undertreated, and expected to increase as the American population ages. Many patients with chronic pain require long-term treatment with analgesic medications, and pain management may involve use of prescription opioids for patients whose pain is inadequately controlled through other therapies. Yet because of the potential for abuse and addiction, many clinicians hesitate to treat their patients with pain with potentially beneficial agents. Finding the right opioid for the right patient is the first – often complicated – step. Ensuring that patients continue to properly use the medication while achieving therapeutic analgesic effects is the long-term goal. Combined with careful patient selection and ongoing monitoring, new formulations using extended-release technologies incorporating tamper-resistant features may help combat the growing risk of abuse or misuse, which will hopefully reduce individual suffering and the societal burden of chronic pain. The objective of this manuscript is to provide an update on extended-release opioids and to provide clinicians with a greater understanding of which patients might benefit from these new opioid formulations and how to integrate the recommended monitoring for abuse potential into clinical practice. Keywords: chronic pain, opioid analgesics, extended release, abuse prevention
Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease
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Bateman Eric D
2011-04-01
Full Text Available Abstract Background The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD. Methods In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843 and II (n = 804, patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1/forced vital capacity ratio of ≤70% and FEV1 1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ and time to first moderate or severe COPD exacerbation. Results At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p Conclusion Aclidinium is effective and well tolerated in patients with moderate to severe COPD. Trial registration ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I and NCT00358436 (ACCLAIM/COPD II.
Liraglutide: a once-daily GLP-1 analogue for the treatment of type 2 diabetes mellitus
DEFF Research Database (Denmark)
Vilsbøll, Tina
2007-01-01
properties that are suitable for once-daily dosing. Liraglutide has demonstrated lasting improvement of HbA(1c )levels, weight reduction and improved beta-cell function in patients with Type 2 diabetes mellitus. Liraglutide is well tolerated; the adverse events that are most frequently reported being...... transient nausea and diarrhoea. This article reviews the mechanisms of action and efficacy of liraglutide for the treatment of Type 2 diabetes mellitus. This agent is presently in Phase III clinical development.......The incretin hormones are intestinal peptides that enhance insulin secretion following ingestion of nutrients. Liraglutide is a glucagon-like peptide-1 receptor analogue, which is obtained by derivatising glucagon-like peptide-1 with a fatty acid, providing a compound with pharmacokinetic...
Critical appraisal of extended-release hydrocodone for chronic pain: patient considerations
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Gould HJ III
2015-10-01
Full Text Available Harry J Gould III,1,3–7 Dennis Paul1–8 1Department of Neurology, 2Department of Pharmacology and Experimental Therapeutics, 3Department of Internal Medicine, Section of Physical Medicine and Rehabilitation, 4Department of Anesthesiology, 5Neuroscience Center of Excellence, 6Center of Excellence for Oral and Craniofacial Biology, 7Pain Mastery Center of Louisiana, 8Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA Abstract: Opioid analgesics are currently the most effective pharmacologic option for the management of both acute and chronic forms of moderate-to-severe pain. Although the “as-needed” use of immediate-release formulations is considered optimum for treating acute, painful episodes of limited duration, the scheduled dosing of extended-release formulations with immediate-release supplementation for breakthrough pain is regarded to be most effective for managing chronic conditions requiring around-the-clock treatment. The recent introduction of extended-release formulations of the opioid analgesic hydrocodone potentially broadened the possibility of providing pain relief for individuals for whom current formulations are either ineffective or not tolerated. However, reaction to the approval of the new formulations has fueled controversy over the general safety and need for opioid medications, in light of their potential for misuse, abuse, diversion, and addiction. Here, we discuss how the approval of extended-release formulations of hydrocodone and the emotionally charged controversy over their release may affect physician prescribing and the care available to patients in need of chronic opioid therapy for the management of pain. Keywords: opioid analgesics, patient risks, patient benefits, misuse, addiction
Takahashi, Satoshi; Ichihara, Kohji; Hashimoto, Jiro; Kurimura, Yuichiro; Iwasawa, Akihiko; Hayashi, Kenji; Sunaoshi, Kenichi; Takeda, Koichi; Suzuki, Nobukazu; Satoh, Takashi; Tsukamoto, Taiji
2011-06-01
To confirm the efficacy of the treatment regimen with oral levofloxacin (LVFX) 500 mg once daily for 7 days for patients with non-gonococcal urethritis (NGU), we evaluated the microbiological and clinical outcomes of the regimen in those patients. We finally evaluated 53 patients with symptomatic NGU and 5 patients with asymptomatic NGU. As a result of microbiological examinations, 19 of the symptomatic patients were diagnosed as having non-gonococcal chlamydial urethritis (NGCU); 13 had non-gonococcal non-chlamydial urethritis (NGNCU), and 21 had urethritis without any microbial detection. Five of the asymptomatic patients were diagnosed as having NGCU. Microbiological cure was achieved in 91% of the 32 patients with symptomatic NGU and in 80% of the 5 patients with asymptomatic NGCU. Clinical cure was obtained in 92% of the 53 patients with symptomatic NGU. The microbiological eradication rate for Chlamydia trachomatis was 92% in 24 patients. As for other organisms, the microbiological eradication rate for Mycoplasma genitalium was 60% in 5 patients and that for Ureaplasma urealyticum was 100% in 10. The microbiological and clinical efficacy of oral LVFX 500 mg once daily for 7 days for the patients with NGU was the same for the azithromycin (AZM) 1,000 mg single dose that we previously reported. The eradication rates of C. trachomatis and U. urealyticum in the treatment regimen with LVFX 500 mg were high enough in the clinical setting; however, for M. genitalium, the rate was relatively inferior to that with AZM.
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Yang Shao
2015-02-01
Full Text Available The objective of this study is to develop chitosan–anionic polymers based extended-release tablets and test the feasibility of using this system for the sustained release of highly water-soluble drugs with high drug loading. Here, the combination of sodium valproate (VPS and valproic acid (VPA were chosen as the model drugs. Anionic polymers studied include xanthan gum (XG, carrageenan (CG, sodium carboxymethyl cellulose (CMC-Na and sodium alginate (SA. The tablets were prepared by wet granulation method. In vitro drug release was carried out under simulated gastrointestinal condition. Drug release mechanism was studied. Compared with single polymers, chitosan–anionic polymers based system caused a further slowdown of drug release rate. Among them, CS–xanthan gum matrix system exhibited the best extended-release behavior and could extend drug release for up to 24 h. Differential scanning calorimetry (DSC and Fourier transform infrared spectroscopy (FTIR studies demonstrated that polyelectrolyte complexes (PECs were formed on the tablet surface, which played an important role on retarding erosion and swelling of the matrix in the later stage. In conclusion, this study demonstrated that it is possible to develop highly water-soluble drugs loaded extended-release tablets using chitosan–anionic polymers based system.
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Albertson TE
2016-12-01
Full Text Available Timothy E Albertson,1–3 Samuel W Bullick,1,3 Michael Schivo,1 Mark E Sutter2,3 1Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, 2Department of Emergency Medicine, School of Medicine, UC Davis, Sacramento, 3Department of Medicine, Veterans Administration Northern California Health Care System, Mather, CA, USA Abstract: The use of inhaled corticosteroids (ICSs plays a key role in the treatment of asthmatic patients, and international guidelines have designated ICSs as an early maintenance therapy in controlling asthma symptoms. When asthmatic patients remain symptomatic on ICSs, one common option is to add a long-acting beta2 agonist (LABA to the maintenance treatment. Fixed combination inhalers that contain both an ICS and a LABA have been popular for both chronic obstructive pulmonary disease (COPD and asthma. Historically, these inhalers have been dosed twice daily. However, currently, there is a once-daily combination therapy with the ICS fluticasone furoate (FF and the LABA vilanterol trifenatate (VI with indications for use in both COPD and asthma. This dry powder inhaler (DPI comes in two doses of FF (100 or 200 µg both combined with VI (25 µg. This article reviews the clinical trial data for FF, VI and FF/VI combination inhalers and documents the efficacy and safety of once-daily inhaled maintenance therapy by DPI in asthmatic patients. Keywords: fluticasone furoate/vilanterol trifenatate, asthma, long-acting beta2 agonist, inhaled corticosteroid, combined inhaler, persistent asthma, dry powder inhaler
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Carol M Ulloa
2009-09-01
Full Text Available Carol M Ulloa, Allen Towfigh, Joseph SafdiehDepartment of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USAAbstract: Levetiracetam is a second-generation antiepileptic drug (AED with a unique chemical structure and mechanism of action. The extended release formulation of levetiracetam (Keppra XR™; UCB Pharma was recently approved by the Food and Drug Administration for adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. This approval is based on a double-blind, randomized, placebo-controlled, multicenter, multinational trial. Levetiracetam XR allows for once-daily dosing, which may increase compliance and, given the relatively constant plasma concentrations, may minimize concentration-related adverse effects. Levetiracetam’s mode of action is not fully elucidated, but it has been found to target high-voltage, N-type calcium channels as well as the synaptic vesicle protein 2A (SV2A. Levetiracetam has nearly ideal pharmacokinetics. It is rapidly and almost completely absorbed after oral ingestion, is ‹10% protein-bound, demonstrates linear kinetics, is minimally metabolized through a pathway independent of the cytochrome P450 system, has no significant drug–drug interactions, and has a wide therapeutic index. The most common reported adverse events with levetiracetam XR were somnolence, irritability, dizziness, nausea, influenza, and nasopharyngitis. Levetiracetam XR provides an efficacious and well-tolerated treatment option for adjunctive therapy in the treatment of partial-onset seizures.Keywords: levetiracetam, partial-onset seizures, antiepileptic drugs
Effect of Daily Contact Lens Cleaning on Ocular Adverse Events during Extended Wear.
Ozkan, Jerome; Rathi, Varsha M; de la Jara, Percy Lazon; Naduvilath, Thomas; Holden, Brien A; Willcox, Mark D P
2015-02-01
The purpose of the study was to assess what effect daily cleaning of contact lenses with a multipurpose disinfection solution (MPDS), during 30 nights extended wear, would have on contact lens-related adverse events. This was a prospective, open-label, randomized, controlled, parallel-group, 3-month clinical study in which 193 participants were dispensed with lotrafilcon A silicone hydrogel lenses for a 30-day extended-wear schedule and with lenses replaced monthly. Participants were randomized to a control or test group. Test subjects were required to remove lenses daily after waking, clean them with the MPDS, and reinsert the lenses. Control subjects wore lenses without removal for 30 days extended wear. Handling-related lens contamination was assessed at the baseline visit. There was no significant difference between the test and control groups for the incidence of significant corneal infiltrative events (1.3 vs. 4.9%, p = 0.368), total corneal infiltrative events (2.6 vs. 4.9%, p = 0.682), or mechanical events (1.3 vs. 2.5%, p = 1.00). The test group had greater corneal staining (p lenses) resulted in isolation of Gram-positive bacteria from 92.5% of test lenses compared with 87.5% of control lenses (p = 0.712). Gram-negative bacteria were isolated from 5% of test subjects compared with 2.5% of control subjects (p = 1.00). Fungus was isolated from 2.5% of subjects in both the test and control groups (p = 1.00). The intervention of daily morning cleaning of the lens surface with an MPDS during extended wear did not significantly influence the incidence of adverse events.
Liraglutide: a once-daily GLP-1 analogue for the treatment of type 2 diabetes mellitus
DEFF Research Database (Denmark)
Vilsbøll, Tina
2007-01-01
The incretin hormones are intestinal peptides that enhance insulin secretion following ingestion of nutrients. Liraglutide is a glucagon-like peptide-1 receptor analogue, which is obtained by derivatising glucagon-like peptide-1 with a fatty acid, providing a compound with pharmacokinetic propert...... transient nausea and diarrhoea. This article reviews the mechanisms of action and efficacy of liraglutide for the treatment of Type 2 diabetes mellitus. This agent is presently in Phase III clinical development....... properties that are suitable for once-daily dosing. Liraglutide has demonstrated lasting improvement of HbA(1c )levels, weight reduction and improved beta-cell function in patients with Type 2 diabetes mellitus. Liraglutide is well tolerated; the adverse events that are most frequently reported being...
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Eric Laille
Full Text Available CC-486 (oral azacitidine is an epigenetic modifier in development for patients with myelodysplastic syndromes and acute myeloid leukemia. In part 1 of this two-part study, a 7-day CC-486 dosing schedule showed clinical activity, was generally well tolerated, and reduced DNA methylation. Extending dosing of CC-486 beyond 7 days would increase duration of azacitidine exposure. We hypothesized that extended dosing would therefore provide more sustained epigenetic activity. Reported here are the pharmacokinetic (PK and pharmacodynamic (PD profiles of CC-486 extended dosing schedules in patients with myelodysplastic syndromes (MDS, chronic myelomonocytic leukemia (CMML or acute myeloid leukemia (AML from part 2 of this study. PK and/or PD data were available for 59 patients who were sequentially assigned to 1 of 4 extended CC-486 dosing schedules: 300mg once-daily or 200mg twice-daily for 14 or 21 days per 28-day cycle. Both 300mg once-daily schedules and the 200mg twice-daily 21-day schedule significantly (all P < .05 reduced global DNA methylation in whole blood at all measured time points (days 15, 22, and 28 of the treatment cycle, with sustained hypomethylation at cycle end compared with baseline. CC-486 exposures and reduced DNA methylation were significantly correlated. Patients who had a hematologic response had significantly greater methylation reductions than non-responding patients. These data demonstrate that extended dosing of CC-486 sustains epigenetic effects through the treatment cycle.ClinicalTrials.gov NCT00528983.
Fanous, Helen; Zheng, Rebecca; Campbell, Carolyn; Huang, Michael; Nash, Michelle M; Rapi, Lindita; Zaltzman, Jeffrey S; Prasad, G V Ramesh
2013-02-01
BACKGROUND: Limited comparative data are available on the outcomes between extended-release and standard-release tacrolimus when used de novo in kidney transplant recipients (KTRs). METHODS: We identified KTRs transplanted at our institution during 2009-10 routinely prescribed extended-release tacrolimus and compared them with those transplanted during 2008-09 prescribed standard-release tacrolimus. Graft function (eGFR by MDRD-7 equation) at 12 months post-transplant (primary outcome); new-onset diabetes and other cardiovascular risk factors, BK viremia incidence, acute rejection, and graft survival to 12 months (secondary outcomes) were compared by intent-to-treat analysis. Time-to-steady-state concentration and number of dose adjustments required to attain steady state were recorded. RESULTS: There were no important demographic differences between the extended-release (N = 106) and standard-release (N = 95) cohorts. The estimated glomerular filtration rate (eGFR) at 12 months was similar (58.8 ± 17 versus 59.2 ± 18 mL/min/1.73 m(2), P = 0.307). There was no difference in new-onset diabetes (17 versus 20%, P = 0.581), BK viremia (10 versus 7%, P = 0.450), acute rejection (7 versus 16%, P = 0.067) or graft survival (97 versus 95%, P = 0.301). Time-to-steady state was similar (9.2 ± 1.1 versus 8.1 ± 4.7 days, P = 0.490) although extended-release patients required fewer adjustments to attain steady state (1.2 ± 1.7 [0-8] versus 1.7 ± 1.5 [0-7], P = 0.030) but a similar dose (7.2 ± 2.4 [2-17] versus 7 ± 2.7 [2-16] mg/day, P = 0.697). CONCLUSION: De novo KTRs prescribed extended-release or standard-release tacrolimus demonstrate similar 12-month outcomes.
Spergel, J M; Boguniewicz, M; Paller, A S; Hebert, A A; Gallagher, P R; McCormick, C; Parneix-Spake, A; Hultsch, T
2007-08-01
Combination therapy with pimecrolimus cream 1%, a topical calcineurin inhibitor (TCI), and fluticasone propionate cream 0.05% (FP), a mid-potency topical corticosteroid, may have a synergistic effect for treatment of atopic dermatitis (AD) because their mechanism of action differs. To assess the efficacy of concomitant pimecrolimus twice daily/FP once daily vs. vehicle twice daily/FP once daily in patients with severe AD. An exploratory, 2-week, double-blind, randomized, within-patient study was conducted (n = 45). Two target areas of similar severity, size and location were assessed. Assessments included the modified Eczema Area and Severity Index (0-12 scale) (primary variable), localized investigator global assessment (0-4 scale) and Patients' Self-Assessment of Disease Severity (0-4 scale). Data for all variables were similar for the TCI/FP and vehicle/FP treatments. The efficacy observed for treatment of severe AD flares with this TCI/FP combination regimen was equivalent to that of vehicle/FP.
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Inder S Anand
2010-06-01
Full Text Available Inder S Anand1, Anita Deswal2, Dean J Kereiakes3, Das Purkayastha4, Dion H Zappe41Veterans Administration Medical Center, Minneapolis, MN, USA; 2Michael E DeBakey VA Medical Center, Houston, TX, USA; 3The Christ Hospital Heart and Vascular Center, Cincinnati, OH, USA; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Clinical trial registration information: www.clinicaltrials.gov/ct2/show/NC T00294086 Unique identification number: NC T00294086Background: The safety of once-daily (qd dosing of valsartan in heart failure (HF patients is not known. Hypothesis: This 10-week, double-blind trial examined the relative safety and efficacy of valsartan administered qd versus twice-daily (bid.Methods: HF patients (NYHA class II–III receiving diuretics (87%, angiotensin-converting enzyme inhibitors (98%, beta-blockers (92%, aldosterone antagonists (25%, or digoxin (32% were randomized to valsartan 40 mg bid (n = 60 or 80 mg qd (n = 55 and titrated to a maximum dose of 320 mg/day; doubling the dose every 2 weeks. Clinical and biochemical parameters were measured at Weeks 2, 4, 6, and 10.Results: The average dose of valsartan at the end of study was 245 mg in the bid group vs 256 mg in the qd group (P = NS. Similar proportions of patients tolerated qd vs bid dosing (bid 67% vs qd 68%. Outcome measures including reduction in blood pressure, incidence of hypotension, renal impairment, orthostatic dizziness or fatigue, changes in serum K+, creatinine, cystatin-C, and estimated glomerular filtration rate were similar between the 2 groups at all time-points. Brain natriuretic peptide levels decreased and plasma renin activity increased from baseline by the same amount in both groups at all time-points.Conclusion: Valsartan administered qd has a similar safety and tolerability profile with comparable 24-hour RAAS blockade, as assessed by increases in PRA, as bid dosing in patients with moderate to severe (NYHA class II–III heart failure
Brock, Gerald; Broderick, Gregory; Roehrborn, Claus G; Xu, Lei; Wong, David; Viktrup, Lars
2013-11-01
To assess the safety and efficacy of tadalafil once daily on lower urinary tract symptoms suggestive of clinical benign prostatic hyperplasia (BPH-LUTS) in men without erectile dysfunction (ED). To compare these with effects in men with ED. After a 4-week washout period and 4-week placebo run-in period, 1089 men without ED (n = 338) and with ED (n = 751) were randomly assigned to placebo or tadalafil 5 mg once daily for 12 weeks in three global clinical studies with similar designs. In the pooled dataset, post hoc analyses of covariance assessed the impact and severity of BPH-LUTS using the International Prostate Symptom Score (IPSS) and the BPH Impact Index (BII) and IPSS quality-of-life (IPSS-QoL) subscores. Safety was assessed using treatment-emergent adverse events. The treatment-by-ED-status interaction was used to assess efficacy differences between the with/without ED subgroups. Men without ED were similar in BPH-LUTS severity/previous therapy to men with ED. Tadalafil significantly reduced BPH-LUTS from baseline when compared with placebo in men without ED (IPSS -5.4 vs -3.3, P 0.68). Tadalafil was safe and well tolerated. Tadalafil 5 mg once daily improved BPH-LUTS in men without ED by a magnitude similar to that observed in men with ED. The adverse event profile in men without ED was consistent with that observed in men with ED. © 2013 The Authors. BJU International © 2013 BJU International.
Sprague, Stuart M; Crawford, Paul W; Melnick, Joel Z; Strugnell, Stephen A; Ali, Shaukat; Mangoo-Karim, Roberto; Lee, Sungchun; Petkovich, P Martin; Bishop, Charles W
2016-01-01
Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23. Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks. ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events. Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD. © 2016 S. Karger AG, Basel.
Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke
DEFF Research Database (Denmark)
Sacco, Ralph L; Diener, Hans-Christoph; Yusuf, Salim
2008-01-01
BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. METHODS: In this double-blind, 2-by-2 factorial trial, we randomly...
Hill, K E; Gieseg, M A; Kingsbury, D; Lopez-Villalobos, N; Bridges, J; Chambers, P
2011-01-01
Previous studies on transdermal methimazole have used pluronic lecithin organogel as the vehicle. This might not be the most suitable vehicle for a lipophilic drug, such as methimazole. Once daily transdermal administration of a novel lipophilic formulation of methimazole is as safe and effective as oral carbimazole in treating hyperthyroidism in cats. Forty-five client-owned cats diagnosed with hyperthyroidism. Prospective study. Cats with newly diagnosed, untreated hyperthyroidism were treated with carbimazole (5 mg p.o., q12h) or methimazole (10 mg) applied to the inner pinnae q24h. Cats were examined after 0, 1, 4, 8, and 12 weeks of treatment. Clinical signs, body weight, systolic blood pressure, hematologic, serum biochemical and urine parameters, total serum thyroxine concentrations (TT4), and serum methimazole concentrations were recorded. No significant differences between groups were detected at day 0. Both formulations were effective in treating hyperthyroidism. No significant differences were detected in thyroxine concentrations, body weight, blood pressure, heart rate, alkaline phosphatase, alanine aminotransferase, creatinine, urea, and urine specific gravity (USG) between groups. The serum methimazole concentrations correlated poorly with TT4-concentrations in both groups. In this 12-week trial, once daily application of a novel formulation of transdermal methimazole applied to the pinnae was as effective and safe as twice daily oral carbimazole in the treatment of cats with hyperthyroidism. This novel formulation and transdermal application could have practical advantages to some pet owners. Copyright © 2011 by the American College of Veterinary Internal Medicine.
Onychomycosis of Toenails and Post-hoc Analyses with Efinaconazole 10% Solution Once-daily Treatment
2016-01-01
Topical treatment for toenail onychomycosis has been fraught with a long-standing reputation of poor efficaey, primarily due to physical properties of the nail unit that impede drug penetration. Newer topical agents have been formulated as Solution, which appear to provide better therapeutic response in properly selected patients. It is important to recognize the impact the effects that mitigating and concomitant factors can have on efficaey. These factors include disease severity, gender, presence of tinea pedis, and diabetes. This article reviews results achieved in Phase 3 pivotal studies with topical efinaconazole 10% Solution applied once daily for 48 weeks with a focus on how the aforementioned factors influenced therapeutic outcomes. It is important for clinicians treating patients for onychomycosis to evaluate severity, treat concomitant tinea pedis, address control of diabetes if present by encouraging involvement of the patient’s primary care physician, and consider longer treatment courses when clinically relevant. PMID:27047631
DEFF Research Database (Denmark)
Mortensen, Ole Hartvig; Plomgaard, Peter; Fischer, Christian P
2007-01-01
We hypothesized that the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) family of transcriptional coactivators (PGC-1alpha, PGC-1beta, and PRC) is differentially regulated by training once daily vs. training twice daily every second day and that this difference might...... be observed in the acute response to endurance exercise. Furthermore, we hypothesized that expression levels of the PGC-1 family differ with muscular fiber-type composition. Thus, before and after 10 wk of knee extensor endurance training, training one leg once daily and the other leg twice daily every second...... day, keeping the total amount of training for the legs equal, skeletal muscle mRNA expression levels of PGC-1alpha, PGC-1beta, and PRC were determined in young healthy men (n = 7) in response to 3 h of acute exercise. No significant difference was found between the two legs, suggesting that regulation...
Ostovaneh, M R; Saeidi, B; Hajifathalian, K; Farrokhi-Khajeh-Pasha, Y; Fotouhi, A; Mirbagheri, S S; Emami, H; Barzin, G; Mirbagheri, S A
2014-05-01
Patients with heartburn but without esophageal erosion respond less well to proton pump inhibitors (PPIs). There is a growing body of evidence implicating the role of psychological comorbidities in producing reflux symptoms. Pain modulators improve symptoms in patients with other functional gastrointestinal disorders. We aimed to compare the efficacy of fluoxetine with omeprazole and placebo to achieve symptomatic relief in patients with heartburn and normal endoscopy who failed once daily PPIs. Endoscopy-negative patients with heartburn who failed once daily PPIs were randomly allocated to receive 6 weeks treatment of fluoxetine, omeprazole, or placebo. Random allocation was stratified according to ambulatory pH monitoring study. Percentage of heartburn-free days and symptom severity was assessed. Sixty patients with abnormal and 84 patients with normal pH test were randomized. Subjects receiving fluoxetine experienced more improvement in percentage of heartburn-free days (median 35.7, IQR 21.4-57.1) than those on omeprazole (median 7.14, IQR 0-50, p heartburn-free days (median improvement, 57.1, IQR 35.7-57.1 vs 13.9, IQR, 0-45.6 and 7.14, 0-23.8, respectively, p heartburn and normal endoscopy who failed once daily PPIs. The superiority of fluoxetine was mostly attributed to those with normal esophageal pH rather than those with abnormal pH (ClinicalTrials.gov, number NCT01269788). © 2014 John Wiley & Sons Ltd.
Kent, Seamus; Haynes, Richard; Hopewell, Jemma C; Parish, Sarah; Gray, Alastair; Landray, Martin J; Collins, Rory; Armitage, Jane; Mihaylova, Borislava
2016-07-01
Extended-release niacin with laropiprant did not significantly reduce the risk of major vascular events and increased the risk of serious adverse events in Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), but its net effects on health and healthcare costs are unknown. 25 673 participants aged 50 to 80 years with previous cardiovascular disease were randomized to 2 g of extended-release niacin with 40 mg of laropiprant daily versus matching placebo, in addition to effective statin-based low-density lipoprotein cholesterol-lowering treatment. The net effects of niacin-laropiprant on quality-adjusted life years and hospital care costs (2012 UK £; converted into US $ using purchasing power parity index) during 4 years in HPS2-THRIVE were evaluated using estimates of the impact of serious adverse events on health-related quality of life and hospital care costs. During the study, participants assigned niacin-laropiprant experienced marginally but not statistically significantly lower survival (0.012 fewer years [standard error (SE) 0.007]), fewer quality-adjusted life years (0.023 [SE 0.007] fewer using UK EQ-5D scores; 0.020 [SE 0.006] fewer using US EQ-5D scores) and accrued greater hospital costs (UK £101 [SE £37]; US $145 [SE $53]). Stroke, heart failure, musculoskeletal events, gastrointestinal events, and infections were associated with significant decreases in health-related quality of life in both the year of the event and in subsequent years. All serious vascular and nonvascular events were associated with substantial increases in hospital care costs. In HPS2-THRIVE, the addition of extended-release niacin-laropiprant to statin-based therapy reduced quality of life-adjusted survival and increased hospital costs. URL: http://clinicaltrials.gov. Unique identifier: NCT00461630. © 2016 American Heart Association, Inc.
Leedle, J A; Greening, R C
1988-01-01
Four ruminally fistulated Hereford steers (400 kg) were fed two isocaloric diets at 1.5 x maintenance once daily in a repeated measurement crossover experiment. Postprandial changes in hydrogen-oxidizing, carbon dioxide-reducing bacterial groups were monitored. The methanogenic bacterial populations were present at densities of 4 x 10(8) to 8 x 10(8)/g of ruminal contents on either the high- or low-forage diet. Numbers remained constant postprandially on the high-forage diet but showed a dist...
DEFF Research Database (Denmark)
Ulrik, Charlotte Suppli
2014-01-01
BACKGROUND AND AIM: Long-acting bronchodilators are the preferred option for maintenance therapy of patients with chronic obstructive pulmonary disease (COPD). The aim of this review is to provide an overview of the clinical studies evaluating the clinical efficacy of the once-daily fixed-dose du...... for chronic Obstructive Lung Disease [GOLD] spirometric criteria). Furthermore, a very recent study has shown that fixed-dose indacaterol/glycopyrronium improves exercise endurance time compared with placebo, although no significant difference was observed between fixed-dose indacaterol...
Tapentadol extended-release for treatment of chronic pain: a review
Directory of Open Access Journals (Sweden)
Vadivelu N
2011-08-01
Full Text Available Nalini Vadivelu1, Alexander Timchenko1, Yili Huang2, Raymond Sinatra11Department of Anesthesiology, Yale University School of Medicine, New Haven, CT; 2Internal Medicine, North Shore-LIJ Plainview Hospital, Plainview, NY, USAAbstract: Tapentadol is a centrally acting analgesic with a dual mechanism of action of mu receptor agonism and norepinephrine reuptake inhibition. Tapentadol immediate-release is approved by the US Food and Drug Administration for the management of moderate-to-severe acute pain. It was developed to decrease the intolerability issue associated with opioids. Tapentadol extended-release has a 12-hour duration of effect, and has recently been evaluated for pain in patients with chronic osteoarthritis, low back pain, and pain associated with diabetic peripheral neuropathy. Tapentadol extended-release was found to provide safe and highly effective analgesia for the treatment of chronic pain conditions, including moderate-to-severe chronic osteoarthritis pain and low back pain. Initial trials demonstrating efficacy in neuropathic pain suggest that tapentadol has comparable analgesic effectiveness and better gastrointestinal tolerability than opioid comparators, and demonstrates effectiveness in settings of inflammatory, somatic, and neuropathic pain. Gastrointestinal intolerance and central nervous system effects were the major adverse events noted. Tapentadol will need to be rigorously tested in chronic neuropathic pain, cancer-related pain, and cancer-related neuropathic pain.Keywords: osteoarthritis, neuropathic pain, analgesic, opioids, norepinephrine
Directory of Open Access Journals (Sweden)
Athanasios Zachariou
Full Text Available ABSTRACT Introduction Overactive bladder (OAB is a common condition, especially in middle aged women, requiring long term therapy with anticholinergics to maintain symptoms relief. The aim of the study was to determine the effect of tolterodine extended release (ER used for OAB treatment on the sexual function of women. Materials and Methods Between August 2010 and August 2014, 220 women with confirmed OAB, attended Urogynecology Outpatient Clinic and were prospectively enrolled in this study. 158 women were evaluated, with a comprehensive history, physical examination, urodynamic studies and Female Sexual Function Index (FSFI questionnaire. 73 patients of group A (control group received no treatment and 85 patients of group B received an anticholinergic regimen – tolterodine ER 4mg once daily. Data were evaluated again in accordance with FSFI after three months, using SPSS software. Results A statistically significant increase was noted in group B in domains of desire (pre-treatment 2.5±0.2 to 4.5±0.2 post-treatment, arousal (3.1±0.2 to 3.1±0.2 respectively, lubrication (3.4±0.3 to 4.3±0.3 respectively, orgasm (3.5±0.3 to 4.5±0.3 respectively, satisfaction (2.6±0.2 to 4.2±0.3 respectively and pain (2.4±0.2 to 4.6±0.4 respectively after three months treatment with tolterodine ER. In group A there were no statistically significant changes in pre and post treatment values (p>0.05. Total FSFI score for group B was significantly higher after tolterodine treatment (26.5±1.5 compared to pre-treatment values (17.4±1.4, p0,05 respectively. Conclusions This preliminary study demonstrates that treatment of OAB with tolterodine ER was found to have positive effect on sexual function of patients with OAB.
Directory of Open Access Journals (Sweden)
Liu Y
2012-12-01
Full Text Available Yang Liu, Weiming MaoDepartment of Cell Biology and Anatomy, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TXAbstract: Glaucoma is a leading cause of visual loss worldwide. Current antiglaucoma therapy focuses on lowering intraocular pressure to a safe level. In recent years, prostaglandin analogs have become the first-line agents for treating open angle glaucoma. Tafluprost, which was first reported in 2003, is a novel prostaglandin analog, and has been shown to be a potent ocular hypotensive agent in a number of preclinical and clinical studies. Also, its unique preservative-free formulation helps to decrease preservative-associated ocular disorders and improve patient compliance. In this review, studies from 2003 to 2012 focusing on the structure, metabolism, efficacy, and safety of tafluprost are summarized. These studies suggested that application of tafluprost once daily is a safe and effective treatment for patients with open angle glaucoma.Keywords: tafluprost, prostaglandin analog, glaucoma, intraocular pressure, preservative-free formulation
Directory of Open Access Journals (Sweden)
Shaikh Arif Y
2012-02-01
Full Text Available Abstract Background There are limited data on accelerated partial breast irradiation (APBI using external beam techniques. Moreover, there are recent reports of increased fibrosis and unacceptable cosmesis with APBI using external beam with BID fractionation. We adopted a once daily regimen of APBI with fractionation similar to that shown to be effective in a Canadian randomized trial of whole breast irradiation. It is unclear whether patients with DCIS or invasive lobular carcinoma (ILC are suitable for APBI. Methods The retrospective cohort included 310 patients with 312 tumors of T1-T2N0-N1micM0 invasive ductal carcinoma (IDC, ILC, or Tis (DCIS treated with APBI via external beam. Most patients were treated using IMRT with 16 daily fractions of 270 cGy to a dose of 4320 cGy. The target volume included the lumpectomy cavity plus 1.0 cm to account for microscopic disease and an additional 0.5 to 1.0 cm for setup uncertainty and breathing motion. Ipsilateral breast failure (IBF was pathologically confirmed as a local failure (LF or an elsewhere failure (EF. Results Median follow-up was 49 months. Among the 312 cases, 213 were IDC, 31 ILC, and 68 DCIS. Median tumor size was 1.0 cm. There were 9 IBFs (2.9% including 5 LFs and 4 EFs. The IBF rates among patients with IDC, ILC, and DCIS were 2.4%, 3.2%, and 4.4%, respectively, with no significant difference between histologies. When patients were analyzed by the ASTRO APBI consensus statement risk groups, 32% of treated cases were considered suitable, 50% cautionary, and 18% unsuitable. The IBF rates among suitable, cautionary, and unsuitable patients were 4.0%, 2.6%, and 1.8%, respectively, with no significant difference between risk groups. Acute skin reactions were rare and long-term cosmetic outcome was very good to excellent. Conclusions External beam APBI with once daily fractionation has a low rate of IBF consistent with other published APBI studies. The ASTRO risk stratification did not
Gordon, Michael S.; Vocci, Frank J.; Fitzgerald, Terrence T.; O'Grady, Kevin E.; O'Brien, Charles P.
2017-01-01
Background Extended-release naltrexone (XR-NTX), is an effective treatment for opioid use disorder but is rarely initiated in US prisons or with criminal justice populations. Mobile treatment for chronic diseases have been implemented in a variety of settings. Mobile treatment may provide an opportunity to expand outreach to parolees to surmount barriers to traditional clinic treatment. Methods Male and female prisoners (240) with pre-incarceration histories of opioid use disorder who are within one month of release from prison will be enrolled in this randomized clinical trial. Participants are randomized to one of two study arms: 1) [XR-NTX-OTx] One injection of long-acting naltrexone in prison, followed by 6 monthly injections post-release at a community opioid treatment program; or 2) [XR-NTX+ MMTx] One injection of long-acting naltrexone in prison followed by 6 monthly injections post-release at the patient's place of residence utilizing mobile medical treatment. The primary outcomes are: treatment adherence; opioid use; criminal activity; re-arrest; reincarceration; and HIV risk-behaviors. Results We describe the background and rationale for the study, its aims, hypotheses, and study design. Conclusions The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release prisoners. Finally, as many individuals in the criminal justice system drop out of treatment, this study will assess whether treatment at their place of residence will improve adherence and positively affect treatment outcomes. PMID:28011389
Gordon, Michael S; Vocci, Frank J; Fitzgerald, Terrence T; O'Grady, Kevin E; O'Brien, Charles P
2017-02-01
Extended-release naltrexone (XR-NTX), is an effective treatment for opioid use disorder but is rarely initiated in US prisons or with criminal justice populations. Mobile treatment for chronic diseases has been implemented in a variety of settings. Mobile treatment may provide an opportunity to expand outreach to parolees to surmount barriers to traditional clinic treatment. Male and female prisoners (240) with pre-incarceration histories of opioid use disorder who are within one month of release from prison will be enrolled in this randomized clinical trial. Participants are randomized to one of two study arms: 1) [XR-NTX-OTx] One injection of long-acting naltrexone in prison, followed by 6 monthly injections post-release at a community opioid treatment program; or 2) [XR-NTX+ MMTx] One injection of long-acting naltrexone in prison followed by 6 monthly injections post-release at the patient's place of residence utilizing mobile medical treatment. The primary outcomes are: treatment adherence; opioid use; criminal activity; re-arrest; reincarceration; and HIV risk-behaviors. We describe the background and rationale for the study, its aims, hypotheses, and study design. The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release prisoners. Finally, as many individuals in the criminal justice system drop out of treatment, this study will assess whether treatment at their place of residence will improve adherence and positively affect treatment outcomes. ClinicalTrials.gov: NCT02867124. Copyright © 2016 Elsevier Inc. All rights reserved.
Directory of Open Access Journals (Sweden)
Saunders WB
2016-07-01
Full Text Available William B Saunders,1 Hiep Nguyen,2 Iftekhar Kalsekar2 1Department of Public Health Sciences, College of Health and Human Services, The University of North Carolina at Charlotte, Charlotte, NC, 2AstraZeneca, Fort Washington, PA, USA Aim: The glucagon-like peptide-1 receptor agonists exenatide once weekly (QW and liraglutide once daily (QD have demonstrated improvements in glycemic outcomes in patients with type 2 diabetes mellitus in randomized clinical trials. However, little is known about their real-world comparative effectiveness. This retrospective cohort study used the Quintiles Electronic Medical Record database to evaluate the 6-month change in glycated hemoglobin (A1C for patients initiating exenatide QW or liraglutide QD.Methods: Patients with type 2 diabetes mellitus prescribed exenatide QW (n=664 or liraglutide QD (n=3,283 between February 1, 2012 and May 31, 2013 were identified. Baseline A1C measures were from 75 days before to 15 days after initiating exenatide QW or liraglutide QD, with follow-up measures documented at 6 months (±45 days. Adjusted linear regression models compared the difference in mean A1C change. A priori defined sensitivity analysis was performed in the subgroup of patients with baseline A1C ≥7.0% and no prescription for insulin during the 12-month pre-index period.Results: For exenatide QW and liraglutide QD, respectively, mean (SD age of the main study cohort was 58.01 (10.97 and 58.12 (11.05 years, mean (SD baseline A1C was 8.4% (1.6 and 8.4% (1.6, and 48.2% and 54.2% of patients were women. In adjusted models, change in A1C did not differ between exenatide QW and liraglutide QD during 6 months of follow-up. Results were consistent in the subgroup analyses.Conclusion: In a real-world setting, A1C similarly improves in patients initiating exenatide QW or liraglutide QD. Keywords: diabetes, exenatide, outcomes
International Nuclear Information System (INIS)
Rashid, S.; Khan, B.A.; Khan, G.M.
2017-01-01
Ketoprofen is propionic acid derivative and belongs to the Non-Steroidal anti-inflammatory group of drugs. Due to the short half-life, dosage frequency, patient non-compliance and side effects such as gastrointestinal disturbance, peptic ulceration and gastro intest inal bleeding, it is considered to be good candidate for formulation into controlled release dosage forms. Directly compressed controlled released ( CR) tablets using Acrylic acid derivatives were prepared and evaluated. In-Vitro Physicochemical assessment of the formulated tablets were performed using different physicochemical, dimensional and quality control tests such as weight variation, thickness and diameter, hardness test, friability test, content uniformity, disintegration and dissolution testing. Results of all these tests were formed within acceptable range. The effect of carbomer polymers on the tablet characteristics, drug release rates, release patterns and release kinetics were investigated. The F2-metric technique was applied to compare dissolution profiles of ketoprofen and carbopol tablets with ketoprofen SR - tablets taken as standard preparation. Acrylic acid derivatives when used as polymers resulted in an extended release profile of about 12 h. Using Higuchi's model and the Korsmeyer equation, the drug release mechanism from the tablets was found to be an anomalous type involving diffusion and erosion. Controlled- release Ketoprofen tablets appear to be a good choice for the symptomatic treatment of rheumatoid arthritis and osteoarthritis. Convenient once-daily administration may help improve patient's compliance. (author)
... Duchenne / Managing Daily Life Print Email Managing Daily Life Environmental accessibility As the person with Duchenne starts ... such as wider doorways and ramps, can make life easier once the person with Duchenne cannot climb ...
International Nuclear Information System (INIS)
Ikusawa, Yoshihisa; Ozawa, Takayuki
2008-03-01
IFA-554/555 load-follow tests were performed in HALDEN reactor (HBWR) to study the MOX fuel behavior under the daily-load-follow operation condition in the framework of ATR-MOX fuel development in JAEA. IFA-554/555 rig had the instruments of rod inner pressure, fuel center temperature, fuel stack elongation, and cladding elongation. Although the daily-load-follow operation in nuclear power plant is one of the available options for economical improvement, the power change in a short period in this operation causes the change of thermal and mechanical irradiation conditions. In this report, FP gas release behavior of MOX fuel rod was evaluated under the daily-load-follow operation condition with the examination data from IFA-554/555 by using the computation code 'FASTGRASS'. From the computation results of FASTGRASS code which could compute the FP gas release behavior under the transient condition, it could be concluded that FP gas was released due to the relaxation of fuel pellet inner stress and pellet temperature increase, which were caused by the cyclic power change during the daily-load-follow operation. In addition, since the amount of released FP gas decreased during the steady operation after the daily-load-follow, it could be mentioned that the total of FP gas release at the end of life with the daily-load-follow is not so much different from that without the daily-load-follow. (author)
Preparation and scale up of extended-release tablets of bromopride
Directory of Open Access Journals (Sweden)
Guilherme Neves Ferreira
2014-04-01
Full Text Available Reproducibility of the tablet manufacturing process and control of its pharmaceutics properties depends on the optimization of formulation aspects and process parameters. Computer simulation such as Design of Experiments (DOE can be used to scale up the production of this formulation, in particular for obtaining sustained-release tablets. Bromopride formulations are marketed in the form of extended-release pellets, which makes the product more expensive and difficult to manufacture. The aim of this study was to formulate new bromopride sustained release formulations as tablets, and to develop mathematical models to standardize the scale up of this formulation, controlling weight and hardness of the tablets during manufacture according to the USP 34th edition. DOE studies were conducted using Minitab(tm software. Different excipient combinations were evaluated in order to produce bromopride sustained-release matrix tablets. In the scale-up study, data were collected and variations in tableting machine parameters were measured. Data were processed by Minitab(tm software, generating mathematical equations used for prediction of powder compaction behavior, according to the settings of the tableting machine suitable for scale-up purposes. Bromopride matrix tablets with appropriate characteristics for sustained release were developed. The scale-up of the formulation with the most suitable sustained release profile was established by using mathematical models, indicating that the formulation can be a substitute for the pellets currently marketed.
Wang, Rong; Fletcher, Tracey; Alvey, Christine; Kushner, Joseph; Stock, Thomas C.
2016-01-01
Abstract Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended‐release (XR) formulation has been designed to provide a once‐daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice‐daily immediate‐release (IR) formulation. We conducted 2 randomized, open‐label, phase 1 studies in healthy volunteers. Study A characterized single‐dose and steady‐state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single‐dose and steady‐state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high‐fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half‐life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration‐time curve (AUC) and maximum plasma concentration (Cmax) after single‐ and multiple‐dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. Cmax increased by 27% under the fed state. On repeat administration, negligible accumulation (Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies. PMID:26970526
The emergence of oral tadalafil as a once-daily treatment for pulmonary arterial hypertension
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Jeremy A Falk
2010-04-01
Full Text Available Jeremy A Falk, Kiran J Philip, Ernst R SchwarzCedars Sinai Women’s Guild Lung Institute, Cedars Sinai Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA, USAAbstract: Pulmonary hypertension (PH is found in a vast array of diseases, with a minority representing pulmonary arterial hypertension (PAH. Idiopathic PAH or PAH in association with other disorders has been associated with poor survival, poor exercise tolerance, progressive symptoms of dyspnea, and decreased quality of life. Left untreated, patients with PAH typically have a progressive decline in function with high morbidity ultimately leading to death. Advances in medical therapy for PAH over the past decade have made significant inroads into improved function, quality of life, and even survival in this patient population. Three classes of pulmonary artery-specific vasodilators are currently available in the United States. They include prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 (PDE5 inhibitors. In May 2009, the FDA approved tadalafil, the first once-daily PDE5 inhibitor for PAH. This review will outline the currently available data on tadalafil and its effects in patients with PAH.Keywords: PDE-5 inhibition, pulmonary hypertension, tadalafil
Pichichero, M E; Casey, J R; Block, S L; Guttendorf, R; Flanner, H; Markowitz, D; Clausen, S
2008-07-01
An a priori pharmacokinetic/pharmacodynamic (PK/PD) target of 40% daily time above the MIC (T >MIC; based on the MIC(90) of 0.06 microg/ml for Streptococcus pyogenes reported in the literature) was shown to be achievable in a phase 1 study of 23 children with a once-daily (QD) modified-release, multiparticulate formulation of amoxicillin (amoxicillin sprinkle). The daily T >MIC achieved with the QD amoxicillin sprinkle formulation was comparable to that achieved with a four-times-daily (QID) penicillin VK suspension. An investigator-blinded, randomized, parallel-group, multicenter study involving 579 children 6 months to 12 years old with acute streptococcal tonsillopharyngitis was then undertaken. Children were randomly assigned 1:1 to receive either the amoxicillin sprinkle (475 mg for ages 6 months to 4 years, 775 mg for ages 5 to 12 years) QD for 7 days or 10 mg/kg of body weight of penicillin VK QID for 10 days (up to the maximum dose of 250 mg QID). Unexpectedly, the rates of bacteriological eradication at the test of cure were 65.3% (132/202) for the amoxicillin sprinkle and 68.0% (132/194) for penicillin VK (95% confidence interval, -12.0% to 6.6%). Thus, neither antibiotic regimen met the minimum criterion of > or =85% eradication ordinarily required by the U.S. FDA for first-line treatment of tonsillopharyngitis due to S. pyogenes. The results of subgroup analyses across demographic characteristics and current infection characteristics and by age/weight categories were consistent with the primary-efficacy result. The clinical cure rates for amoxicillin sprinkle and penicillin VK were 86.1% (216/251) and 91.9% (204/222), respectively (95% confidence interval, -11.6% to -0.4%). The results of a post hoc PD analysis suggested that a requirement for 60% daily T >MIC(90) more accurately predicted the observed high failure rates for bacteriologic eradication with the amoxicillin sprinkle and penicillin VK suspension studied. Based on the association between
Directory of Open Access Journals (Sweden)
Jurjen van der Schans
Full Text Available Attention-Deficit/Hyperactivity Disorder (ADHD is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at school often leads to reduced compliance, sub-optimal treatment, and therefore economic loss. Replacement of IR-MPH with a single-dose extended release (ER-MPH formulation may improve drug response and economic efficiency.To evaluate the cost-effectiveness from a societal perspective of a switch from IR-MPH to ER-MPH in patients who are sub-optimally treated.A daily Markov-cycle model covering a time-span of 10 years was developed including four different health states: (1 optimal response, (2 sub-optimal response, (3 discontinued treatment, and (4 natural remission. ER-MPH options included methylphenidate osmotic release oral system (MPH-OROS and Equasym XL/Medikinet CR. Both direct costs and indirect costs were included in the analysis, and effects were expressed as quality-adjusted life years (QALYs. Univariate, multivariate as well as probabilistic sensitivity analysis were conducted and the main outcomes were incremental cost-effectiveness ratios.Switching sub-optimally treated patients from IR-MPH to MPH-OROS or Equasym XL/Medikinet CR led to per-patient cost-savings of €4200 and €5400, respectively, over a 10-year treatment span. Sensitivity analysis with plausible variations of input parameters resulted in cost-savings in the vast majority of estimations.This study lends economic support to switching patients with ADHD with suboptimal response to short-acting IR-MPH to long-acting ER-MPH regimens.
The Influence of Polyethylene Glycol Solution on the Dissolution Rate of Sustained Release Morphine.
Hodgman, Michael; Holland, Michael G; Englich, Ulrich; Wojcik, Susan M; Grant, William D; Leitner, Erich
2016-12-01
Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations. An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations. In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG. The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.
Chin, M.Y.; Sandham, A.; Rumachik, E.N.; Ruben, J.L.; Huysmans, M.C.D.N.J.M.
2009-01-01
INTRODUCTION: In this study, we aimed to evaluate the fluoride-release profiles and caries lesion development in an enamel model with brackets cemented with 4 orthodontic adhesives with and without daily fluoride exposure. METHODS: Four orthodontic adhesives (Ketac Cem mu, 3M ESPE, Seefeld, Germany;
Chin, Yeen; Sandham, John; Rumachik, Elena N.; Ruben, Jan L.; Huysmans, Marie-Charlotte D. N. J. M.
2009-01-01
Introduction: In this study, we aimed to evaluate the fluoride-release profiles and caries lesion development in an enamel model with brackets cemented with 4 orthodontic adhesives with and without daily fluoride exposure. Methods: Four orthodontic adhesives (Ketac Cem mu, 3M ESPE, Seefeld, Germany;
Tanzi, Maria G; Undre, Nasrullah; Keirns, James; Fitzsimmons, William E; Brown, Malcolm; First, M Roy
2016-08-01
Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Risk based In Vitro Performance Assessment of Extended Release Abuse Deterrent Formulations
Xu, Xiaoming; Gupta, Abhay; Al-Ghabeish, Manar; Calderon, Silvia N.; Khan, Mansoor A.
2016-01-01
High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products. PMID:26784976
Kako, Shinichi; Fujiwara, Shinichiro; Sato, Miki; Kimura, Shun-Ichi; Nakasone, Hideki; Ohashi, Kazuteru; Kawakita, Toshiro; Maeda, Tetsuo; Morishita, Takanobu; Suzuki, Ritsuro; Fukuda, Takahiro; Ichinohe, Tatsuo; Kurata, Mio; Atsuta, Yoshiko; Kanda, Yoshinobu
2018-04-19
Compared with 4-times-daily infusion of intravenous busulfan (ivBU4), the safety and efficacy of once-daily infusion of ivBU (ivBU1) has not been fully clarified. We have been routinely using ivBU1 in a conditioning regimen in adult patients with myeloid malignancy who undergo allogeneic hematopoietic stem cell transplantation. In this study, a total of 91 patients who received ivBU1 for 2 days (n = 18) or 4 days (n = 73) in our institutions were compared with 273 control patients who received ivBU4, who were matched for age, sex, performance status, disease risk, conditioning regimen, and donor type, selected from the database of the Japanese Society for Hematopoietic Cell Transplantation using optimal matching algorithms. One-year overall survival (56.8% versus 57.1%, P = .94), disease-free survival (51.6% versus 50.8%, P = .73), relapse rate (28.5% versus 26.2%, P = .94), nonrelapse mortality (19.9% versus 23.0%, P = .71), and the incidence of graft-versus-host disease were not significantly different between the ivBU1 and ivBU4 groups. In patients who received ivBU1, neutrophil recovery was slower (median days: 22 versus 17, P = .001), and the incidence of veno-occlusive disease was lower (2.6% versus 17.4%, P = .04). In conclusion, ivBU1 can be safely administered with clinical outcomes similar to those with ivBU4. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial
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D'Urzo Anthony
2011-12-01
Full Text Available Abstract Background NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease (COPD. The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1 evaluated the efficacy, safety and tolerability of NVA237 in patients with moderate-to-severe COPD. Methods Patients with COPD with a smoking history of ≥ 10 pack-years, post-bronchodilator forced expiratory volume in 1 second (FEV1 1/forced vital capacity 1 antagonists permitted in patients stabilized on them prior to study entry. The primary outcome measure was trough FEV1 at Week 12. Results A total of 822 patients were randomized to NVA237 (n = 552 or placebo (n = 270. Least squares mean (± standard error trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 (1.408 ± 0.0105 L, versus placebo (1.301 ± 0.0137 L; treatment difference 108 ± 14.8 mL, p 1 were apparent at the end of Day 1 and sustained through Week 26. FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26, and at all other visits and timepoints. Transition dyspnoea index focal scores and St. George's Respiratory Questionnaire scores were significantly improved with NVA237 versus placebo at Week 26, with treatment differences of 1.04 (p Conclusions Once-daily NVA237 was safe and well tolerated and provided rapid, sustained improvements in lung function, improvements in dyspnoea, and health-related quality of life, and reduced the risk of exacerbations and the use of rescue medication. Trial registration ClinicalTrials.gov: NCT01005901
Fröhlich, F; Burrello, T N; Mellin, J M; Cordle, A L; Lustenberger, C M; Gilmore, J H; Jarskog, L F
2016-03-01
Auditory hallucinations are resistant to pharmacotherapy in about 25% of adults with schizophrenia. Treatment with noninvasive brain stimulation would provide a welcomed additional tool for the clinical management of auditory hallucinations. A recent study found a significant reduction in auditory hallucinations in people with schizophrenia after five days of twice-daily transcranial direct current stimulation (tDCS) that simultaneously targeted left dorsolateral prefrontal cortex and left temporo-parietal cortex. We hypothesized that once-daily tDCS with stimulation electrodes over left frontal and temporo-parietal areas reduces auditory hallucinations in patients with schizophrenia. We performed a randomized, double-blind, sham-controlled study that evaluated five days of daily tDCS of the same cortical targets in 26 outpatients with schizophrenia and schizoaffective disorder with auditory hallucinations. We found a significant reduction in auditory hallucinations measured by the Auditory Hallucination Rating Scale (F2,50=12.22, PtDCS for treatment of auditory hallucinations and the pronounced response in the sham-treated group in this study contrasts with the previous finding and demonstrates the need for further optimization and evaluation of noninvasive brain stimulation strategies. In particular, higher cumulative doses and higher treatment frequencies of tDCS together with strategies to reduce placebo responses should be investigated. Additionally, consideration of more targeted stimulation to engage specific deficits in temporal organization of brain activity in patients with auditory hallucinations may be warranted. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
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Koch A
2014-07-01
Full Text Available Andrea Koch,1 Emilio Pizzichini,2 Alan Hamilton,3 Lorna Hart,3 Lawrence Korducki,4 Maria Cristina De Salvo,5 Pierluigi Paggiaro6 1Medical Clinic III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bochum-Bergmannsheil, Bochum, Germany; 2NUPAIVA (Asthma Research Center, Universidade Federal de Santa Catarina, Santa Catarina, Brazil; 3Boehringer Ingelheim, Burlington, Ontario, Canada; 4Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA; 5Centro Médico Dra. De Salvo, Fundación Respirar, Buenos Aires, Argentina; 6Cardio-Thoracic and Vascular Department, University of Pisa, Pisa, Italy Abstract: Two replicate, multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase III studies investigated the long-term efficacy and safety of once-daily olodaterol via Respimat® versus placebo and formoterol over 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease receiving usual-care background therapy. Patients received once-daily olodaterol 5 or 10 µg, twice-daily formoterol 12 µg, or placebo. Co-primary end points were forced expiratory volume in 1 second (FEV1 area under the curve from 0–3 hours response, FEV1 trough response, and Mahler transition dyspnea index total score after 24 weeks; secondary end points included St George's Respiratory Questionnaire. Overall, 904 (Study 1222.13 and 934 (Study 1222.14 patients received treatment. Olodaterol significantly improved FEV1 area under the curve from 0–3 hours versus placebo in both studies (with olodaterol 5 µg, 0.151 L and 0.129 L; with olodaterol 10 µg, 0.165 L and 0.154 L; for all comparisons P<0.0001 and FEV1 trough responses versus placebo (0.053–0.085 L; P<0.01, as did formoterol. Primary analysis revealed no significant difference in transition dyspnea index focal score for any active treatment versus placebo. Post hoc analysis using pattern mixture modeling (accounting for
Pichichero, M. E.; Casey, J. R.; Block, S. L.; Guttendorf, R.; Flanner, H.; Markowitz, D.; Clausen, S.
2008-01-01
An a priori pharmacokinetic/pharmacodynamic (PK/PD) target of 40% daily time above the MIC (T >MIC; based on the MIC90 of 0.06 μg/ml for Streptococcus pyogenes reported in the literature) was shown to be achievable in a phase 1 study of 23 children with a once-daily (QD) modified-release, multiparticulate formulation of amoxicillin (amoxicillin sprinkle). The daily T >MIC achieved with the QD amoxicillin sprinkle formulation was comparable to that achieved with a four-times-daily (QID) penicillin VK suspension. An investigator-blinded, randomized, parallel-group, multicenter study involving 579 children 6 months to 12 years old with acute streptococcal tonsillopharyngitis was then undertaken. Children were randomly assigned 1:1 to receive either the amoxicillin sprinkle (475 mg for ages 6 months to 4 years, 775 mg for ages 5 to 12 years) QD for 7 days or 10 mg/kg of body weight of penicillin VK QID for 10 days (up to the maximum dose of 250 mg QID). Unexpectedly, the rates of bacteriological eradication at the test of cure were 65.3% (132/202) for the amoxicillin sprinkle and 68.0% (132/194) for penicillin VK (95% confidence interval, −12.0% to 6.6%). Thus, neither antibiotic regimen met the minimum criterion of ≥85% eradication ordinarily required by the U.S. FDA for first-line treatment of tonsillopharyngitis due to S. pyogenes. The results of subgroup analyses across demographic characteristics and current infection characteristics and by age/weight categories were consistent with the primary-efficacy result. The clinical cure rates for amoxicillin sprinkle and penicillin VK were 86.1% (216/251) and 91.9% (204/222), respectively (95% confidence interval, −11.6% to −0.4%). The results of a post hoc PD analysis suggested that a requirement for 60% daily T >MIC90 more accurately predicted the observed high failure rates for bacteriologic eradication with the amoxicillin sprinkle and penicillin VK suspension studied. Based on the association between longer
Jain, Rakesh; Segal, Scott; Kollins, Scott H.; Khayrallah, Moise
2011-01-01
Objective: This study examined the efficacy and safety of clonidine hydrochloride extended-release tablets (CLON-XR) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Method: This 8-week, placebo-controlled, fixed-dose trial, including 3 weeks of dose escalation, of patients 6 to 17 years old with ADHD evaluated the…
Lofwall, Michelle R.; Babalonis, Shanna; Nuzzo, Paul A.; Siegel, Anthony; Campbell, Charles; Walsh, Sharon L.
2013-01-01
Background Tramadol is an atypical analgesic with monoamine and modest mu opioid agonist activity. The purpose of this study was to evaluate: 1) the efficacy of extended-release (ER) tramadol in treating prescription opioid withdrawal and 2) whether cessation of ER tramadol produces opioid withdrawal. Methods Prescription opioid users with current opioid dependence and observed withdrawal participated in this inpatient, two-phase double blind, randomized placebo-controlled trial. In Phase 1 (days 1-7), participants were randomly assigned to matched oral placebo or ER tramadol (200 or 600 mg daily). In Phase 2 (days 8-13), all participants underwent double blind crossover to placebo. Breakthrough withdrawal medications were available for all subjects. Enrollment continued until 12 completers/group was achieved. Results Use of breakthrough withdrawal medication differed significantly (popioid withdrawal. Mild opioid withdrawal occurred after cessation of treatment with 600 mg tramadol. These data support the continued investigation of tramadol as a treatment for opioid withdrawal. PMID:23755929
Lofwall, Michelle R; Babalonis, Shanna; Nuzzo, Paul A; Siegel, Anthony; Campbell, Charles; Walsh, Sharon L
2013-11-01
Tramadol is an atypical analgesic with monoamine and modest mu opioid agonist activity. The purpose of this study was to evaluate: (1) the efficacy of extended-release (ER) tramadol in treating prescription opioid withdrawal and (2) whether cessation of ER tramadol produces opioid withdrawal. Prescription opioid users with current opioid dependence and observed withdrawal participated in this inpatient, two-phase double blind, randomized placebo-controlled trial. In Phase 1 (days 1-7), participants were randomly assigned to matched oral placebo or ER tramadol (200 or 600 mg daily). In Phase 2 (days 8-13), all participants underwent double blind crossover to placebo. Breakthrough withdrawal medications were available for all subjects. Enrollment continued until 12 completers/group was achieved. Use of breakthrough withdrawal medication differed significantly (popioid withdrawal. Mild opioid withdrawal occurred after cessation of treatment with 600 mg tramadol. These data support the continued investigation of tramadol as a treatment for opioid withdrawal. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Prantera, Cosimo; Lochs, Herbert; Grimaldi, Maria; Danese, Silvio; Scribano, Maria Lia; Gionchetti, Paolo
2012-03-01
Bacteria might be involved in the development and persistence of inflammation in patients with Crohn's disease (CD), and antibiotics could be used in therapy. We performed a clinical phase 2 trial to determine whether a gastroresistant formulation of rifaximin (extended intestinal release [EIR]) induced remission in patients with moderately active CD. We performed a multicenter, randomized, double-blind trial of the efficacy and safety of 400, 800, and 1200 mg rifaximin-EIR, given twice daily to 402 patients with moderately active CD for 12 weeks. Data from patients given rifaximin-EIR were compared with those from individuals given placebo, and collected during a 12-week follow-up period. The primary end point was remission (Crohn's Disease Activity Index <150) at the end of the treatment period. At the end of the 12-week treatment period, 62% of patients who received the 800-mg dosage of rifaximin-EIR (61 of 98) were in remission, compared with 43% of patients who received placebo (43 of 101) (P = .005). A difference was maintained throughout the 12-week follow-up period (45% [40 of 89] vs 29% [28 of 98]; P = .02). Remission was achieved by 54% (56 of 104) and 47% (47 of 99) of the patients given the 400-mg and 1200-mg dosages of rifaximin-EIR, respectively; these rates did not differ from those of placebo. Patients given the 400-mg and 800-mg dosages of rifaximin-EIR had low rates of withdrawal from the study because of adverse events; rates were significantly higher among patients given the 1200-mg dosage (16% [16 of 99]). Administration of 800 mg rifaximin-EIR twice daily for 12 weeks induced remission with few adverse events in patients with moderately active CD. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
Directory of Open Access Journals (Sweden)
A. Kowsari
2005-09-01
Full Text Available Statement of Problem: Since the fluoride releases from materials with the property of releasing fluoride are decreasing gradually, it seems that probably the material rechargeability is more important than their long-term fluoride release.Purpose: the objective of this study was to asses the fluoride release and rechargeability of 2 types of fluoride releasing restorative materials, a resin modified glass ionomer(Vitremer and a compomer (Compoglass F, after exposure to daily NaF solutionscontaining 1000 ppm F, for 1 minute.Materials and Methods: Twelve discs ( 8 mm ×2 mm of each of the materials were fabricated, and divided into 2 groups (test and control. All discs were stored in 4 mL artificial saliva at 37°C. In group 1 (N=6, the specimens were immersed in artificialsaliva which was changed daily for 25 days. In group 2 (N=6, in addition to receiving the same treatment as group 1, the specimens were immersed in NaF solution (1000ppm F, ph=6.9 for 1 minute before daily saliva change. A potentiometer was used to determine the amount of fluoride released on days 1, 2, 3, 5, 10, 15, 20 and 25, after the daily saliva change, in all study groups. Data were analyzed by the t-student test after confirmation of the equality of variances by Leven’s test.Results: Both materials continued releasing fluoride throughout the whole study period. For each material, the release was highest on day one. During the first 3 days,glass ionomer released significantly higher amounts of fluoride as compared to compomer (p0.05. After exposure to NaF solution, none of the materials showed statistically significant rechargeability (p>0.05 and the amount of fluoride-releasecontinued to drop during the study period in similar patterns for both the test and the control groups.Conclusion: It may be concluded that rechargeability of glass ionomer and compomer,using daily neutral fluoride mouth rinses and toothpastes does not occur in reliable amounts.
Lundkvist, Per; Sjöström, C David; Amini, Sam; Pereira, Maria J; Johnsson, Eva; Eriksson, Jan W
2017-01-01
To explore the effects of dual therapy with dapagliflozin and exenatide on body weight, body composition, glycaemic variables and systolic blood pressure (SBP) in obese adults without diabetes. In this single-centre, double-blind trial, we randomized 50 obese adults without diabetes (aged 18-70 years; body mass index 30-45 kg/m 2 ) to oral dapagliflozin 10 mg once daily plus subcutaneous long-acting exenatide 2 mg once weekly or placebo. MRI was used to assess change in body composition. Participants were instructed to follow a balanced diet and exercise moderately. Of 25 dapagliflozin/exenatide- and 25 placebo-treated participants, 23 (92.0%) and 20 (80.0%) completed 24 weeks of treatment, respectively. At baseline, the mean participant age was 52 years, 61% were female, the mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). After 24 weeks, for dapagliflozin/exenatide versus placebo: the difference in body weight change was -4.13 kg (95% confidence interval -6.44, -1.81; P prediabetes was less frequent with active treatment (34.8% vs 85.0%, respectively; P prediabetes and SBP over 24 weeks and was well tolerated in obese adults without diabetes. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
Kushner, Pamela R; Snoddy, Andrew M; Gilderman, Larry; Peura, David A
2009-07-01
To investigate the efficacy and safety of a 14-day treatment period with lansoprazole 15 mg for frequent heartburn in patients who are likely to select a nonprescription medication before consulting a prescriber. Adults with untreated frequent heartburn > or = 2 days a week over the past month were recruited for 2 identical multicenter, double-blind studies conducted with a 1-week screening and heartburn medication washout, a 1-week placebo run-in, a 2-week placebo-controlled treatment, and a 1-week placebo follow-up. After the washout and placebo run-in, subjects were randomly assigned to receive lansoprazole 15 mg or placebo once daily for 14 days in a double-blind fashion. Antacid tablets were permitted as rescue medication. Endpoints included percentage of 24-hour days without heartburn (primary), percentage of night-times without heartburn, and percentage of subjects without heartburn during day 1 of treatment (secondary endpoints). Data were collected daily via an interactive voice response system. In studies 1 and 2, 282 and 288 subjects, respectively, were randomly assigned to lansoprazole, and 282 in each study received placebo. The mean percentage of days without heartburn was greater among lansoprazole recipients compared with placebo recipients (P heartburn and no heartburn during day 1 of the 14-day treatment. Adverse events were infrequent and were similar for lansoprazole and placebo groups. During the 14-day treatment period in a population with frequent heartburn who were likely to select a medication without consulting a prescriber, lansoprazole 15 mg once daily showed rapid and sustained effectiveness throughout a 24-hour period and was well tolerated.
Montelius, Caroline; Erlandsson, Daniel; Vitija, Egzona; Stenblom, Eva-Lena; Egecioglu, Emil; Erlanson-Albertsson, Charlotte
2014-10-01
The frequency of obesity has risen dramatically in recent years but only few effective and safe drugs are available. We investigated if green-plant membranes, previously shown to reduce subjective hunger and promote satiety signals, could affect body weight when given long-term. 38 women (40-65 years of age, body mass index 25-33 kg/m(2)) were randomized to dietary supplementation with either green-plant membranes (5 g) or placebo, consumed once daily before breakfast for 12 weeks. All individuals were instructed to follow a three-meal paradigm without any snacking between the meals and to increase their physical activity. Body weight change was analysed every third week as was blood glucose and various lipid parameters. On days 1 and 90, following intake of a standardized breakfast, glucose, insulin and glucagon-like peptide 1 (GLP-1) in plasma were measured, as well as subjective ratings of hunger, satiety and urge for different palatable foods, using visual analogue scales. Subjects receiving green-plant membranes lost significantly more body weight than did those on placebo (p weight loss with green-plant extract was 5.0 ± 2.3 kg compared to 3.5 ± 2.3 kg in the control group. Consumption of green-plant membranes also reduced total and LDL-cholesterol (p meal tests performed on day 1 and day 90 demonstrated an increased postprandial release of GLP-1 and decreased urge for sweet and chocolate on both occasions in individuals supplemented with green-plant membranes compared to control. Waist circumference, body fat and leptin decreased in both groups over the course of the study, however there were no differences between the groups. In conclusion, addition of green-plant membranes as a dietary supplement once daily induces weight loss, improves obesity-related risk-factors, and reduces the urge for palatable food. The mechanism may reside in the observed increased release of GLP-1. Copyright © 2014 The Authors. Published by Elsevier Ltd
Martarelli, D; Casettari, L; Shalaby, K S; Soliman, M E; Cespi, M; Bonacucina, G; Fagioli, L; Perinelli, D R; Lam, J K W; Palmieri, G F
2016-01-01
Efficacy of melatonin in treating sleep disorders has been demonstrated in numerous studies. Being with short half-life, melatonin needs to be formulated in extended-release tablets to prevent the fast drop of its plasma concentration. However, an attempt to mimic melatonin natural plasma levels during night time is challenging. In this work, Artificial Neural Networks (ANNs) were used to optimize melatonin release from hydrophilic polymer matrices. Twenty-seven different tablet formulations with different amounts of hydroxypropyl methylcellulose, xanthan gum and Carbopol®974P NF were prepared and subjected to drug release studies. Using dissolution test data as inputs for ANN designed by Visual Basic programming language, the ideal number of neurons in the hidden layer was determined trial and error methodology to guarantee the best performance of constructed ANN. Results showed that the ANN with nine neurons in the hidden layer had the best results. ANN was examined to check its predictability and then used to determine the best formula that can mimic the release of melatonin from a marketed brand using similarity fit factor. This work shows the possibility of using ANN to optimize the composition of prolonged-release melatonin tablets having dissolution profile desired.
Daily Fluoride Intake from Iranian Green Tea: Evaluation of Various Flavorings on Fluoride Release
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Afshin Maleki
2016-01-01
Full Text Available With increased awareness of the health benefits of the compounds in green tea, especially polyphenols, its consumption is rising. The main purpose of this study is to determine the effect of different additives on the released fluoride into tea liquor and also daily fluoride intake. The concentrations of fluoride, nitrate, sulfate, and chloride were measured in 15 different flavored green teas (Refah-Lahijan. The fluoride and other anion concentrations were measured by ion chromatography method. The data were analyzed with Statistical Package for the Social Sciences version 16.0. The results showed that the minimum and maximum concentrations of fluoride in the green tea infusions were 0.162 mg/L (cinnamon-flavored green tea and 3.29 mg/L (bagged peach-flavored green tea, respectively. The mean concentration of fluoride in the green tea leaves was 52 mg/kg, and approximately 89% of the fluoride was released from the green tea leaves into the infusions after brewing. The fluoride concentrations varied significantly among the examined green teas ( P 0.05. Finally, drinking of the studied green teas cannot make a significant contribution to the daily dietary intake of F for consumers.
Extending Agent Based Telehealth Platform with Activities of Daily Living Reasoning Capabilities
DEFF Research Database (Denmark)
Jørgensen, Daniel Bjerring; Hallenborg, Kasper; Demazeau, Yves
2016-01-01
it will influence his or her everyday live. Therefore we believe that a telehealth system shall adapt its behavior so that it will not be a burden for the patient/resident to use. To this aim we have extended an existing telehealth platform to reason about activities of daily living in a smart home scenario......In the future patients will have a more active role in strengthening and maintaining their own health. Telehealth can empower and motivate patients by giving them the chance to stay in their own homes instead of going to the hospital. A telehealth system is deployed in a patient’s home hence...
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Vincken W
2014-02-01
Full Text Available Walter Vincken,1 Joseph Aumann,2 Hungta Chen,3 Michelle Henley,3 Danny McBryan,4 Pankaj Goyal4 1Respiratory Division, University Hospital, UZ Brussel, Free University of Brussels, Brussels, Belgium; 2Longartsenpraktijk, Prins Bisschopssingel, Hasselt, Belgium; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 4Novartis Pharma AG, Basel, Switzerland Background: Addition of a second bronchodilator from a different pharmacological class may benefit patients with moderate-to-severe chronic obstructive pulmonary disease (COPD whose symptoms are insufficiently controlled by bronchodilator monotherapy. GLOW6 evaluated the efficacy and safety of once-daily coadministration of the long-acting β2-agonist indacaterol (IND and the long-acting muscarinic antagonist glycopyrronium (GLY versus IND alone in patients with moderate-to-severe COPD. Materials and methods: In this randomized, double-blind, parallel group, placebo-controlled, 12-week study, patients were randomized 1:1 to IND 150 µg and GLY 50 µg daily (IND + GLY or IND 150 µg daily and placebo (IND + PBO (all delivered via separate Breezhaler® devices. The primary objective was to demonstrate the superiority of IND + GLY versus IND + PBO for trough forced expiratory volume in 1 second (FEV1 at week 12. Other end points included trough FEV1 at day 1, FEV1 area under the curve from 30 minutes to 4 hours (AUC30min–4h, peak FEV1, inspiratory capacity and trough forced vital capacity (FVC at day 1 and week 12, and transition dyspnea index (TDI focal score, COPD symptoms, and rescue medication use over 12 weeks. Results: A total of 449 patients were randomized (IND + GLY, 226; IND + PBO, 223; 94% completed the study. On day 1 and at week 12, IND + GLY significantly improved trough FEV1 versus IND + PBO, with treatment differences of 74 mL (95% CI 46–101 mL and 64 mL (95% CI 28–99 mL, respectively (both P<0.001. IND + GLY significantly improved postdose peak FEV1, FEV1 AUC30min–4h
Qazi, Faaiza; Shoaib, Muhammad Harris; Yousuf, Rabia Ismail; Nasiri, Muhammad Iqbal; Ahmed, Kamran; Ahmad, Mansoor
2017-04-12
Antiemetic agent Meclizine HCl, widely prescribed in vertigo, is available only in immediate release dosage forms. The approved therapeutic dose and shorter elimination half-life make Meclizine HCl a potential candidate to be formulated in extended release dosage form. This study was aimed to develop extended release Meclizine HCl pellets by extrusion spheronization using natural and synthetic lipids. Influence of lipid type, drug/lipid ratio and combinations of different lipids on drug release and sphericity of pellets were evaluated. Thirty two formulations were prepared with four different lipids, Glyceryl monostearate (Geleol ® ), Glyceryl palmitostearate (Precirol ® ), Glyceryl behenate (Compritol ® ) and Carnauba wax, utilized either alone or in combinations of drug/lipid ratio of 1:0.5-1:3. Dissolution studies were performed at variable pH and release kinetics were analyzed. Fourier transform infrared spectroscopy was conducted and no drug lipid interaction was found. Sphericity indicated by shape factor (e R ) varied with type and concentration of lipids: Geleol ® (e R = 0.891-0.997), Precirol ® (e R = 0.611-0.743), Compritol ® (e R = 0.665-0.729) and Carnauba wax (e R = 0.499-0.551). Highly spherical pellets were obtained with Geleol ® (Aspect ratio = 1.005-1.052) whereas irregularly shaped pellets were formed using Carnauba wax (Aspect ratio = 1.153-1.309). Drug release was effectively controlled by three different combinations of lipids: (i) Geleol ® and Compritol ® , (ii) Geleol ® and Carnauba wax and (iii) Geleol ® , Compritol ® and Carnauba wax. Scanning electron microscopy of Compritol ® pellets showed smooth surface with pores, whereas, irregular rough surface with hollow depressions was observed in Carnauba wax pellets. Energy dispersive spectroscopy indicated elemental composition of lipid matrix pellets. Kinetics of (i) Geleol ® and Compritol ® pellets, explained by Korsmeyer-Peppas (R 2 = 0.978-0.993) indicated
Nuttall, Jeremy P; Thake, Daryl C; Lewis, Mark G; Ferkany, John W; Romano, Joseph W; Mitchnick, Mark A
2008-03-01
Dapivirine is a nonnucleoside reverse transcriptase inhibitor being developed as a topical microbicide for the prevention of human immunodeficiency virus infection. The distribution of radioactivity and drug in plasma and in vaginal, cervical, and draining lymph node tissues was investigated after daily application of a vaginal gel formulation of [14C]dapivirine to rhesus macaques. This was preceded by a preliminary study with rabbits. Following the intravaginal administration of [14C]dapivirine ( approximately 0.1 mg/ml [15 microCi/ml]) to rabbits (0.5 ml/day) and macaques (1 ml/day) for 7 days, the dapivirine levels associated with vaginal and cervical tissue samples 1 h after the final dose were high (quantities of microg/g of tissue) and remained detectable at 24 h (mean, >or=2.5 ng/g in rabbits) and 48 h (mean, >80 ng/g in macaques). Radioactivity levels were low in the plasma and very low or unquantifiable in the draining lymph nodes of the macaques. Microautoradiography identified drug-related material (DRM) on the surfaces of the vaginal and cervical tissues of the rabbits and macaques. Although DRM was primarily associated with the outermost layer of shedding cells in rabbits, two animals showed some evidence of small quantities in the mucosal epithelium of the cervix. In macaques, DRM was seen within the keratinized layer of the vaginal epithelium and and was found to extend into the superficial cellular layers, and in at least one animal it appeared to be present in the deepest (germinal) layer of the epithelium and in submucosal tissues. The persistence of biologically significant concentrations of dapivirine in vaginal and cervical tissues for >24 h supports the development of dapivirine as a microbicide for once daily application.
Nuttall, Jeremy P.; Thake, Daryl C.; Lewis, Mark G.; Ferkany, John W.; Romano, Joseph W.; Mitchnick, Mark A.
2008-01-01
Dapivirine is a nonnucleoside reverse transcriptase inhibitor being developed as a topical microbicide for the prevention of human immunodeficiency virus infection. The distribution of radioactivity and drug in plasma and in vaginal, cervical, and draining lymph node tissues was investigated after daily application of a vaginal gel formulation of [14C]dapivirine to rhesus macaques. This was preceded by a preliminary study with rabbits. Following the intravaginal administration of [14C]dapivirine (∼0.1 mg/ml [15 μCi/ml]) to rabbits (0.5 ml/day) and macaques (1 ml/day) for 7 days, the dapivirine levels associated with vaginal and cervical tissue samples 1 h after the final dose were high (quantities of μg/g of tissue) and remained detectable at 24 h (mean, ≥2.5 ng/g in rabbits) and 48 h (mean, >80 ng/g in macaques). Radioactivity levels were low in the plasma and very low or unquantifiable in the draining lymph nodes of the macaques. Microautoradiography identified drug-related material (DRM) on the surfaces of the vaginal and cervical tissues of the rabbits and macaques. Although DRM was primarily associated with the outermost layer of shedding cells in rabbits, two animals showed some evidence of small quantities in the mucosal epithelium of the cervix. In macaques, DRM was seen within the keratinized layer of the vaginal epithelium and and was found to extend into the superficial cellular layers, and in at least one animal it appeared to be present in the deepest (germinal) layer of the epithelium and in submucosal tissues. The persistence of biologically significant concentrations of dapivirine in vaginal and cervical tissues for >24 h supports the development of dapivirine as a microbicide for once daily application. PMID:18086845
Ilany, Jacob; Bhandari, Hamad; Nabriski, Dan; Toledano, Yoel; Konvalina, Noa; Cohen, Ohad
2018-05-01
To evaluate the glycaemic control achieved by prandial once-daily insulin glulisine injection timing adjustment, based on a continuous glucose monitoring sensor, in comparison to once-daily insulin glulisine injection before breakfast in patients with type 2 diabetes who are uncontrolled with once-daily basal insulin glargine. This was a 24-week open-label, randomized, controlled, multicentre trial. At the end of an 8-week period of basal insulin optimization, patients with HbA1c ≥ 7.5% and FPG sensor) or arm B (sensor) to receive 16-week intensified prandial glulisine treatment. Patients in arm A received pre-breakfast glulisine, and patients in arm B received glulisine before the meal with the highest glucose elevation based on sensor data. The primary outcome was mean HbA1c at week 24 and secondary outcomes included rates of hypoglycaemic events and insulin dosage. A total of 121 patients were randomized to arm A (n = 61) or arm B (n = 60). There was no difference in mean HbA1c at week 24 between arms A and B (8.5% ± 1.2% vs 8.4% ± 1.0%; P = .66). The prandial insulin glulisine dosage for arm A and arm B was 9.3 and 10.1 units, respectively (P = .39). The frequency of hypoglycaemic events did not differ between study arms (36.1% vs 51.7%; P = .08). Using a CGM sensor to identify the meal with the highest glucose excursion and adjusting the timing of prandial insulin treatment did not show any advantage in terms of glycaemic control or safety in our patients. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
Ramiro, Miguel A; Llibre, Josep M
2014-11-01
The availability of generic lamivudine in the context of the current economic crisis has raised a new issue in some European countries: breaking up the once-daily fixed-dose antiretroviral combinations (FDAC) of efavirenz/tenofovir/emtricitabine, tenofovir/emtricitabine, or abacavir/lamivudine, in order to administer their components separately, thereby allowing the use of generic lamivudine instead of branded emtricitabine or lamivudine. The legal, ethical, and economic implications of this potential strategy are reviewed, particularly in those patients receiving a once-daily single-tablet regimen. An unfamiliar change in antiretroviral treatment from a successful patient-friendly FDAC into a more complex regimen including separately the components to allow the substitution of one (or some) of them for generic surrogates (in the absence of a generic bioequivalent FDAC) could be discriminatory because it does not guarantee access to equal excellence in healthcare to all citizens. Furthermore, it could violate the principle of non-maleficence by potentially causing harm both at the individual level (hindering adherence and favouring treatment failure and resistance), and at the community level (hampering control of disease transmission and transmission of HIV-1 resistance). Replacing a FDAC with the individual components of that combination should only be permitted when the substituting medication has the same qualitative and quantitative composition of active ingredients, pharmaceutical form, method of administration, dosage and presentation as the medication being replaced, and a randomized study has demonstrated its non-inferiority. Finally, a strict pharma-economic study supporting this change, comparing the effectiveness and the cost of a specific intervention with the best available alternative, should be undertaken before its potential implementation. Copyright © 2013 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiolog
Pecknold, J; Luthe, L; Munjack, D; Alexander, P
1994-10-01
This is a double-blind, placebo-controlled, flexible-dose, multicenter, 6-week study comparing regular alprazolam (compressed tablet, CT), given four times per day, and extended release alprazolam (XR), given once in the morning. The aim of the XR preparation is to offer less frequent dosing and to reduce interdose anxiety. Of the intent-to-treat group of 209 patients, 184 completed 3 weeks of medication and were evaluated according to protocol. There was a completer rate for the 6 weeks of 94% (CT), 97% (XR), and 87% (placebo). On global measures, Hamilton Rating Scale for Anxiety, phobia rating, and work disability measures, both active treatment groups were equally effective and significantly more efficacious than the placebo cell on endpoint MANOVA analysis. On analysis of the panic factor with endpoint data, both active treatment groups were equally effective throughout the 6-week trial and significantly more efficacious than the placebo group. Drowsiness occurred more frequently with CT alprazolam (86% of patients) than with the XR preparation (79%) or placebo (49%).
Seymour, Travis L; Adams, Sean C; Felt, Stephen A; Jampachaisri, Katechan; Yeomans, David C; Pacharinsak, Cholawat
2016-01-01
Postoperative analgesia in laboratory rats is complicated by the frequent handling associated with common analgesic dosing requirements. Here, we evaluated sustained-release buprenorphine (Bup-SR), sustained-release meloxicam (Melox-SR), and carprofen gel (CG) as refinements for postoperative analgesia. The aim of this study was to investigate whether postoperative administration of Bup-SR, Melox-SR, or CG effectively controls behavioral mechanical and thermal hypersensitivity in a rat model of incisional pain. Rats were randomly assigned to 1 of 5 treatment groups: saline, 1 mL/kg SC BID; buprenorphine HCl (Bup HCl), 0.05 mg/kg SC BID; Bup-SR, 1.2 mg/kg SC once; Melox-SR, 4 mg/kg SC once; and CG, 2 oz PO daily. Mechanical and thermal hypersensitivity were tested daily from day-1 through 4. Bup HCl and Bup-SR attenuated mechanical and thermal hypersensitivity on days 1 through 4. Melox-SR and CG attenuated mechanical hypersensitivity-but not thermal hypersensitivity-on days 1 through 4. Plasma concentrations, measured by using UPLC with mass spectrometry, were consistent between both buprenorphine formulations. Gross pathologic examination revealed no signs of toxicity in any group. These findings suggest that postoperative administration of Bup HCl and Bup-SR-but not Melox-SR or CG-effectively attenuates mechanical and thermal hypersensitivity in a rat model of incisional pain.
Long-Term Effectiveness and Safety of Dexmethylphenidate Extended-Release Capsules in Adult ADHD
Adler, Lenard A.; Spencer, Thomas; McGough, James J.; Jiang, Hai; Muniz, Rafael
2009-01-01
Objective: This study evaluates dexmethylphenidate extended release (d-MPH-ER) in adults with ADHD. Method: Following a 5-week, randomized, controlled, fixed-dose study of d-MPH-ER 20 to 40 mg/d, 170 adults entered a 6-month open-label extension (OLE) to assess long-term safety, with flexible dosing of 20 to 40 mg/d. Exploratory effectiveness…
Directory of Open Access Journals (Sweden)
Donald E Low
1994-01-01
in the study. Clinical cure and clinical improvement were achieved in 64.6 and 28.3% of the evaluable patients. respectively. Relapse of infection occurred in two patients (1.8%. and treatment failure was recorded in six cases (5.3%. Twelve patients (8.8% died clue to reasons unrelated to the sludy treatment. Three adverse event (hives, diarrhea and phlebitis at the injection site were possibly related to the study drug. A cross-Canada in vitro susceptibility surveillance study of bacterial pathogens. frequently the cause of pneumonia. found ceftriaxone to have minimal inhibitory concentrations in 90% of isolates that would support such a dosing regimen. with the exception of Enterobacter species. These rcsults support the use of 1 g, once daily ceftriaxone for the empirical treatment of pneumonia in those patients requiring hospitalization.
Directory of Open Access Journals (Sweden)
Bruce Wang
Full Text Available Type 2 diabetes mellitus (T2DM is a chronic metabolic disease with substantial morbidity, mortality, and economic impacts. Glucagon-like peptide-1 (GLP-1 receptor agonists, such as once-daily (QD liraglutide and once-weekly (QW exenatide, are FDA-approved treatment for T2DM. Head-to-head trials and meta-analyses comparing these agents have reported clinically meaningful improvements but small differences in glycemic control between both agents. In this study, we calculate and compare the cost-effectiveness implications of these alternative effectiveness outcomes.We developed a decision model to evaluate the short-term cost-effectiveness of exenatide QW 2 mg versus liraglutide QD 1.8 mg in T2DM patients, with effectiveness measured as reduction in glycated hemoglobin (HbA1c. In the base case, the model tracks change in HbA1c and direct medical expenditure over a 6-month time horizon. We calculated and compared the cost per 1% reduction in HbA1c of models populated with clinical data from a head-to-head randomized, controlled trial (DURATION-6 and a network meta-analysis. Expenditure inputs were derived from wholesale acquisition costs and published sources.In the base case, 6-month expenditure for the liraglutide and exenatide strategies were $3,509 and $2,618, respectively. Using clinical data from DURATION-6 and the network meta-analysis, the liraglutide strategy had an incremental cost per 1% reduction in HbA1c of $4,773 and $27,179, respectively. The most influential model parameters were drug costs, magnitude of HbA1c reduction in patients on treatment for >1 month, and liraglutide gastrointestinal adverse event rate. In probabilistic sensitivity analyses (PSA using DURATION-6 data, the exenatide strategy was optimal at willingness-to-pay levels below $4,800 per 1% reduction in HbA1c. In a PSA using meta-analysis data, the exenatide strategy was dominant.Our modeled results demonstrate that the effectiveness and cost-effectiveness of
Nandi, Gouranga; Nandi, Amit Kumar; Khan, Najim Sarif; Pal, Souvik; Dey, Sibasish
2018-07-15
Development of tamarind seed gum (TSG)-hydrolyzed polymethacrylamide-g-gellan (h-Pmaa-g-GG) composite beads for extended release of diclofenac sodium using 3 2 full factorial design is the main purpose of this study. The ratio of h-Pmaa-g-GG and TSG and concentration of cross-linker CaCl 2 were taken as independent factors with three different levels of each. Effects of polymer ratio and CaCl 2 on drug entrapment efficiency (DEE), drug release, bead size and swelling were investigated. Responses such as DEE and different drug release parameters were statistically analyzed by 3 2 full factorial design using Design-Expert software and finally the formulation factors were optimized to obtain USP-reference release profile. Drug release rate was found to decrease with decrease in the ratio of h-Pmaa-g-GG:TSG and increase in the concentration of Ca 2+ ions in cross-linking medium. The optimized formulation showed DEE of 93.25% and an extended drug release profile over a period of 10h with f 2 =80.13. Kinetic modeling unveiled case-I-Fickian diffusion based drug release mechanism. Copyright © 2018 Elsevier B.V. All rights reserved.
Wilens, Timothy E.; Bukstein, Oscar; Brams, Matthew; Cutler, Andrew J.; Childress, Ann; Rugino, Thomas; Lyne, Andrew; Grannis, Kara; Youcha, Sharon
2012-01-01
Objective: To examine efficacy, tolerability, and safety of guanfacine extended release (GXR; less than or equal to 4 mg/d) adjunctive to a long-acting psychostimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years of age with suboptimal, but partial, response to psychostimulant…
Fission gas release and fuel rod chemistry related to extended burnup
International Nuclear Information System (INIS)
1993-04-01
The purpose of the meeting was to review the state of the art in fission gas release and fuel rod chemistry related to extended burnup. The meeting was held in a time when national and international programmes on water reactor fuel irradiated in experimental reactors were still ongoing or had reached their conclusion, and when lead test assemblies had reached high burnup in power reactors and been examined. At the same time, several out-of-pile experiments on high burnup fuel or with simulated fuel were being carried out. As a result, significant progress has been registered since the last meeting, particularly in the evaluation of fuel temperature, the degradation of the global thermal conductivity with burnup and in the understanding of the impact on fission gas release. Fifty five participants from 16 countries and one international organization attended the meeting. 28 papers were presented. A separate abstract was prepared for each of the papers. Refs, figs, tabs and photos
Extended latanoprost release from commercial contact lenses: in vitro studies using corneal models.
Directory of Open Access Journals (Sweden)
Saman Mohammadi
Full Text Available In this study, we compared, for the first time, the release of a 432 kDa prostaglandin F2a analogue drug, Latanoprost, from commercially available contact lenses using in vitro models with corneal epithelial cells. Conventional polyHEMA-based and silicone hydrogel soft contact lenses were soaked in drug solution (131 μg = ml solution in phosphate buffered saline. The drug release from the contact lens material and its diffusion through three in vitro models was studied. The three in vitro models consisted of a polyethylene terephthalate (PET membrane without corneal epithelial cells, a PET membrane with a monolayer of human corneal epithelial cells (HCEC, and a PET membrane with stratified HCEC. In the cell-based in vitro corneal epithelium models, a zero order release was obtained with the silicone hydrogel materials (linear for the duration of the experiment whereby, after 48 hours, between 4 to 6 μg of latanoprost (an amount well within the range of the prescribed daily dose for glaucoma patients was released. In the absence of cells, a significantly lower amount of drug, between 0.3 to 0.5 μg, was released, (p <0:001. The difference observed in release from the hydrogel lens materials in the presence and absence of cells emphasizes the importance of using an in vitro corneal model that is more representative of the physiological conditions in the eye to more adequately characterize ophthalmic drug delivery materials. Our results demonstrate how in vitro models with corneal epithelial cells may allow better prediction of in vivo release. It also highlights the potential of drug-soaked silicone hydrogel contact lens materials for drug delivery purposes.
Connolly, M.; Kuyvenhoven, J.; Postma, M.; Nielsen, S.
2013-01-01
Background: Dosing frequency is an important treatment consideration that has been shown to influence adherence and outcomes when treating ulcerative colitis (UC). In this analysis we evaluate the economic consequences of outcome differences observed in the study comparing mesalazine 4g per day once
DEFF Research Database (Denmark)
Mulhall, John P; Brock, Gerald; Oelke, Matthias
2016-01-01
INTRODUCTION AND AIM: The multicenter, randomized, double-blind, double-dummy, placebo-controlled REACTT trial suggested that treatment with tadalafil once daily (OaD) started early after bilateral nerve-sparing radical prostatectomy (nsRP) for prostate cancer may contribute to erectile function......: REACTT included 422 men blind treatment (DBT) with tadalafil 5 mg OaD (n = 139), tadalafil 20 mg on...
Johannsson, Gudmundur; Feldt-Rasmussen, Ulla; Håkonsson, Ida Holme; Biering, Henrik; Rodien, Patrice; Tahara, Shigeyuki; Toogood, Andrew; Rasmussen, Michael Højby
2018-05-01
Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin ® . Local tolerability and treatment satisfaction were also assessed. 26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan ( n = 61) or once-daily Norditropin ( n = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin ( P = 0.0171). In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin. © 2018 The authors.
Barilla, Denise; Prasad, Pratapa; Hubert, Martine; Gumbhir-Shah, Kavita
2004-03-01
This was an open-label, randomized, three-period, three-treatment, multiple dose, crossover study in 12 healthy male and female subjects. This study evaluated single dose and steady-state pharmacokinetics of fluvastatin following single and multiple dose administrations of a new extended release fluvastatin 8 h matrix tablet, Lescol XL 80 mg and 160 mg doses once a day. The study also included a twice a day administration of an immediate release (IR) form of fluvastatin capsule, Lescol, for comparative purposes. All doses were administered for 7 days. The safety and tolerability were also assessed. The pharmacokinetics of fluvastatin were evaluated on days 1 and 7 following each treatment. Fluvastatin systemic exposure was 50% less when administered as Lescol XL 80 mg qd compared with Lescol IR 40 mg bid. Conversely, fluvastatin systemic exposure was 22% higher when administered as Lescol XL 160 mg qd compared with Lescol IR 40 mg bid. Single doses of Lescol XL 80 mg and 160 mg were dose proportional but, deviation (30%) from dose proportionality was observed for the Lescol XL 160 mg at steady-state. There appeared to be moderate (20%-40%) accumulation of serum fluvastatin maximal concentrations and exposure after multiple doses of Lescol XL tablets. Both Lescol XL 80 mg and 160 mg showed delayed absorption and longer apparent elimination half-life compared with fluvastatin IR capsule. Single and multiple doses of fluvastatin were generally well tolerated in this healthy volunteer population. Adverse event profiles were consistent with the published safety profile of the marketed formulations. Aside from one incidence of creatine phosphokinase (CPK) elevation (following Lescol XL 160 mg qd treatment), there were no safety concerns with any of the treatments when administered acutely (7 days). Copyright 2004 John Wiley & Sons, Ltd.
Zaaijer, Eline; Goudriaan, Anna E.; Koeter, Maarten W. J.; Booij, Jan; van den Brink, Wim
2016-01-01
Background: Extended-release naltrexone (XRNT) was developed to overcome poor treatment compliance with oral naltrexone in alcohol and opioid-dependent patients. XRNT injections are registered in the United States and Russia, but not in The Netherlands. However, XRNT can be obtained for individual
Farwig, Phillip A; Zielinski, Angela J; Accursi, Mallory L; Burant, Christopher J
2017-12-01
To evaluate the efficacy and safety of adjuvant exenatide extended release (ER) therapy in patients treated with regular U-500 insulin. In this retrospective chart review at an ambulatory care center in the Midwest, 18 patients with type 2 diabetes being treated with regular U-500 insulin and adjuvant exenatide ER were identified. These patients were evaluated for outcomes following the addition of exenatide ER. The primary outcome was change in HbA 1C from baseline to 3, 6, and 12months. Secondary outcomes included change in weight, total daily dose (TDD) of insulin, and hypoglycemia. Repeated measures ANOVA was performed to assess the differences in mean scores over four time periods. A total of 18 of 50 patients met inclusion criteria with sufficient data to be included in analysis. HbA 1C showed non-significant findings from baseline to 12months (8.08% vs. 8.23%; p=0.75). A non-significant, modest weight loss occurred (146.4kgvs. 144.2kg; -2.2kg; p=0.31). A significant decrease in TDD of insulin was observed (378 units vs. 326 units; p1). There was a trend towards hypoglycemia from baseline to month 3 post addition of exenatide ER (0.33 events vs. 1.33 events; p=0.055). In patients treated with regular U-500 insulin, adjuvant exenatide ER therapy showed no significant improvement in HbA 1C , but did show modest weight loss as well as decreased insulin requirements to achieve a HbA 1C that was comparable to baseline. Published by Elsevier B.V.
International Nuclear Information System (INIS)
Bolek, Timothy W.; Marcus, Robert B.; Mendenhall, Nancy Price; Scarborough, Mark T.; Graham-Pole, John
1996-01-01
Purpose: Radiotherapy (RT) has been the predominant local treatment for Ewing's sarcoma of bone at the University of Florida. Twice-daily hyperfractionated RT was initiated in 1982 to improve local control and functional outcome. This retrospective review compares the results of once-daily vs. twice-daily RT in patients with primary Ewing's sarcoma of an extremity, with emphasis on functional outcome. Methods and Materials: Between June 1971 and January 1990, 37 patients were treated at the University of Florida for nonmetastatic Ewing's sarcoma of bone with a primary lesion in an extremity. Three patients underwent amputation. Of 34 patients treated with RT, 31 had RT alone and 3 had a combination of RT and local excision. Before 1982, 14 patients received once-daily RT; since 1982, 17 patients have received twice-daily RT. Doses of once-daily RT varied from 47 to 61 Gy at 1.8-2 Gy per fraction. Doses of twice-daily RT varied, depending on the response of the soft-tissue component of the tumor to chemotherapy, and ranged from 50.4 to 60 Gy at 1.2 Gy per fraction. Some patients in the twice-daily RT group also received total body irradiation 1-3 months after local RT as part of a conditioning regimen before marrow-ablative therapy with stem cell rescue. They received either 8 Gy in two once-daily fractions or 12 Gy in six twice-daily fractions. The six patients who received surgery were excluded from local control analysis. Local control rates were calculated using the Kaplan-Meier (actuarial) method. Fifteen patients had a formal functional evaluation. Results: In the 31 patients treated with RT alone, the actuarial local control rate at 5 years was 81% for patients treated twice daily and 77% for those treated once daily (p = NS). No posttreatment pathologic fractures occurred in patients treated twice daily, whereas five fractures occurred in those treated once daily (p = 0.01). On functional evaluation, less loss in range of motion (15 deg. vs. 28 deg. of loss
Ginsberg, F; Famaey, J P
1985-01-01
Two double-blind studies were carried out to compare the effectiveness and tolerance of a slow-release tablet formulation of 300 mg fentiazac, given once daily, with the standard tablet formulations of 100 mg, given 4-times daily, or 200 mg, given twice daily. A total of 60 patients suffering from acute bicipital tendinitis and/or subdeltoid bursitis was studied, 15 patients on the slow-release and 15 on one of the two standard tablets in each of the two trials. Patients were assessed on entry and at Days 7 and 14 of treatment. The results in both studies showed that there was significant improvement in tenderness, pain on movement, overall pain and in the range of movement after treatment, there being no significant difference between those receiving the slow-release form or the standard tablets. Tolerance was good in all groups and only a few minor or moderate side-effects, mainly of a gastro-intestinal type, were reported.
International Nuclear Information System (INIS)
Floyd, M.R.; Novak, J.; Truant, P.T.
1992-06-01
The average discharge burnup of CANDU fuel is about 200 MWh/kgU. A significant number of 37-element bundles have achieved burnups in excess of 400 MWh/kgU. Some of these bundles have experienced failures related to their extended operation. To date, hot-cell examinations have been performed on fuel elements from nine 37-element bundles irradiated in Bruce NGS-A that have burnups in the range of 300-800 MWh/kgU. 1 Most of these have declining power histories from peak powers of up to 59 kW/m. Fission-gas releases of up to 26% have been observed and exhibit a strong dependence on fuel power. This obscures any dependence on burnup. The extent of fission-gas release at extended burnups was not predicted by low-burnup code extrapolations. This is attributed primarily to a reduction in fuel thermal conductivity which results in elevated operating temperatures. Reduced conductivity is due, at least in part, to the buildup of fission products in the fuel matrix. Some evidence of hyperstoichiometry exists, although this needs to be further investigated along with any possible relation to CANLUB graphite coating behaviour and sheath oxidation. Residual tensile sheath strains of up to 2% have been observed and can be correlated with fuel power/fission-gas release. SCC 2 -related defects have been observed in the sheath and endcaps of elements from bundles experiencing declining power histories to burnups in excess of 500 MWh/kgU. This indicates that the current recommended burnup limit of 450 MWh/kgU is justified. SCC-related defects have also been observed in ramped bundles having burnups < 450 MWh/kgU. Hence, additional guidelines are in place for power ramping extended-burnup fuel
2011-08-30
... proceedings that could result in the withdrawal of approval of the ANDAs that refer to the listed drug. OPANA... relief of moderate to severe pain in patients requiring continuous, around-the-clock opioid treatment for... withdrawal of OPANA ER (oxymorphone HCl) extended-release tablets, 7.5 mg and 15 mg, from sale. We have also...
Achilla, Evanthia; McCrone, Paul
2013-04-01
Antipsychotic medication is the mainstay of treatment in schizophrenia. Long-acting medication has potential advantages over daily medication in improving compliance and thus reducing hospitalization and relapse rates. The high acquisition and administration costs of such formulations raise the need for pharmacoeconomic evaluation. The aim of this article is to provide a comprehensive review of the available evidence on the cost effectiveness of long-acting/extended-release antipsychotic medication and critically appraise the strength of evidence reported in the studies from a methodological viewpoint. Relevant studies were identified by searching five electronic databases: PsycINFO, MEDLINE, EMBASE, the NHS Economic Evaluation Database and the Health Technology Assessment database (HTA). Search terms included, but were not limited to, 'long-acting injection', 'economic evaluation', 'cost-effectiveness' and 'cost-utility'. No limits were applied for publication dates and language. Full economic evaluations on long-acting/extended-release antipsychotics were eligible for inclusion. Observational studies and clinical trials were also checked for cost-effectiveness information. Conference abstracts and poster presentations on the cost effectiveness of long-acting antipsychotics were excluded. Thirty-two percent of identified studies met the selection criteria. Pertinent abstracts were reviewed independently by two reviewers. Relevant studies underwent data extraction by one reviewer and were checked by a second, with any discrepancies being clarified during consensus meetings. Eligible studies were assessed for methodological quality using the quality checklist for economic studies recommended by the NICE guideline on interventions in the treatment and management of schizophrenia. After applying the selection criteria, the final sample consisted of 28 studies. The majority of studies demonstrated that risperidone long-acting injection, relative to oral or other long
Wagner, Jessica; Kline, Christina Leah; Ralff, Marie D; Lev, Avital; Lulla, Amriti; Zhou, Lanlan; Olson, Gary L; Nallaganchu, Bhaskara Rao; Benes, Cyril H; Allen, Joshua E; Prabhu, Varun V; Stogniew, Martin; Oster, Wolfgang; El-Deiry, Wafik S
2017-10-02
Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.
Kay, Gary G.; Michaels, M. Alex; Pakull, Barton
2009-01-01
Background: Psychostimulant treatment may improve simulated driving performance in young adults with attention-deficit/hyperactivity disorder (ADHD). Method: This was a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with mixed amphetamine salts--extended release (MAS XR) 50 mg/day (Cohort 1) and…
Management of obesity and cardiometabolic risk – role of phentermine/extended release topiramate
Directory of Open Access Journals (Sweden)
Sweeting AN
2014-02-01
Full Text Available Arianne N Sweeting,1 Eddy Tabet,1 Ian D Caterson,1,2 Tania P Markovic1,2 1Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; 2Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, University of Sydney, NSW, Australia Abstract: The US Food and Drug Administration (FDA recently approved lorcaserin and the combination of phentermine and extended release topiramate (phentermine/topiramate ER for the treatment of obesity in conjunction with a lifestyle intervention, expanding the therapeutic options for long-term obesity pharmacotherapy, which was previously limited to orlistat. Combination phentermine/topiramate ER is associated with greater weight loss compared to its constituent monotherapy, with a more favorable adverse effect profile. Phentermine/topiramate ER also appears to have beneficial effects on cardiometabolic risk, although longer-term cardiovascular safety data are required. While there are no head-to-head studies among the currently available obesity pharmacotherapy agents, phentermine/topiramate ER appears to have a superior weight loss profile. This review will discuss the epidemiology, natural history, and cardiometabolic risk associated with obesity, provide an overview on current obesity pharmacotherapy, and summarize the recent clinical efficacy and safety data underpinning the FDA's approval of both phentermine/topiramate ER and lorcaserin as pharmacotherapy for a long-term obesity intervention. Keywords: obesity, phentermine/topiramate extended release, safety and efficacy, review
Leyden, James J; Sniukiene, Vilma; Berk, David R; Kaoukhov, Alexandre
2018-03-01
There is a need for new oral antibiotics for acne with improved safety profiles and targeted antibacterial spectra. Sarecycline is a novel, tetracycline-class antibiotic specifically designed for acne, offering a narrow spectrum of activity compared with currently available tetracyclines, including less activity against enteric Gram-negative bacteria. This phase 2 study evaluated the efficacy and safety of three doses of sarecycline for moderate to severe facial acne vulgaris. In this multicenter, double-blind, placebo-controlled study, patients aged 12 to 45 years were randomized to once-daily sarecycline 0.75 mg/kg, 1.5 mg/kg, 3.0 mg/kg, or placebo. Efficacy analyses included change from baseline in inflammatory and noninflammatory lesion counts at week 12, with between-group comparisons using analysis of covariance. Safety assessments included adverse events (AEs), clinical laboratories, vital signs, electrocardiograms, and physical examinations. Overall, 285 randomized patients received at least one dose of study drug. At week 12, sarecycline 1.5 mg/kg and 3.0 mg/kg groups demonstrated significantly reduced inflammatory lesions from baseline (52.7% and 51.8%, respectively) versus placebo (38.3%; P=0.02 and P=0.03, respectively). Sarecycline was safe and well tolerated, with similar gastrointestinal AE rates in sarecycline and placebo groups. Vertigo and photosensitivity AEs occurred in less than 1% of patients when pooling sarecycline groups; no vulvovaginal candidiasis AEs occurred. Discontinuation rates due to AEs were low. No serious AEs occurred. Once-daily sarecycline 1.5 mg/kg significantly reduced inflammatory lesions versus placebo and was safe and well tolerated with low rates of AEs, including gastrointestinal AEs. Sarecycline 3.0 mg/kg did not result in additional efficacy versus 1.5 mg/kg. Sarecycline may represent a novel, once-daily treatment for patients with moderate to severe acne. It offers a narrow antibacterial spectrum relative to other
The metamorphosis of hydromorphone.
Reisfield, Gary M; Wilson, George R
2005-01-01
Hydromorphone, one of the oldest and most potent of opioids, is an effective alternative to morphine. With a variety of routes of administration, it has an efficacy similar to that of morphine. The FDA has recently approved the first commercially available extended-release formulation, a once-daily hydromorphone for the management of moderate to severe pain in opioid tolerant individuals with an anticipated extended period of use. The formulation exhibits less peak-to-trough fluctuation in plasma concentration, while providing analgesia statistically indistinguishable from its immediate-release counterpart. The manufacturer and the FDA have articulated a plan to minimize unskillful prescribing and abuse/diversion through education, supply-chain integrity, and surveillance. It is anticipated that Palladone will be a valuable addition to the limited armamentarium of extended-release opioids.
Major, Ian; Boyd, Peter; Kilbourne-Brook, Maggie; Saxon, Gene; Cohen, Jessica; Malcolm, R Karl
2013-07-01
There is considerable interest in developing new multipurpose prevention technologies to address women's reproductive health needs. This study describes an innovative barrier contraceptive device--based on the SILCS diaphragm--that also provides long-term controlled release of the lead candidate anti-HIV microbicide dapivirine. Diaphragm devices comprising various dapivirine-loaded polymer spring cores overmolded with a nonmedicated silicone elastomer sheath were fabricated by injection molding processes. In vitro release testing, thermal analysis and mechanical characterization were performed on the devices. A diaphragm device containing a polyoxymethylene spring core loaded with 10% w/w dapivirine provided continuous and controlled release of dapivirine over a 6-month period, with a mean in vitro daily release rate of 174 mcg/day. The mechanical properties of the new diaphragm were closely matched to the SILCS diaphragm. The study demonstrates proof of concept for a dapivirine-releasing diaphragm with daily release quantities potentially capable of preventing HIV transmission. In discontinuous clinical use, release of dapivirine may be readily extended over 1 or more years. Copyright © 2013 Elsevier Inc. All rights reserved.
Deng, Jing; Gu, Shuyan; Shao, Hui; Dong, Hengjin; Zou, Dajin; Shi, Lizheng
2015-01-01
To estimate cost-effectiveness of exenatide twice daily (BID) vs insulin glargine once daily (QD) as add-on therapy in Chinese type 2 diabetes patients not well controlled by oral anti-diabetic (OAD) agents. The Cardiff model was populated with data synthesized from three head-to-head randomized clinical trials of up to 30 weeks in China comparing exenatide BID vs insulin glargine as add-on therapies to oral therapies in the Chinese population. The Cardiff model generated outputs including macrovascular and microvascular complications, diabetes-specific mortality, costs, and quality-adjusted life years (QALYs). Cost and QALYs were estimated with a time horizon of 40 years at a discount rate of 3% from a societal perspective. Compared with insulin glargine plus OAD treatments, patients on exenatide BID plus OAD gained 1.88 QALYs, at an incremental cost saving of Chinese Renminbi (RMB) 114,593 (i.e., cost saving of RMB 61078/QALY). The cost-effectiveness results were robust to various sensitivity analyses including probabilistic sensitivity analysis. The variables with the most impact on incremental cost-effectiveness ratio included HbA1c level at baseline, health utilities decrement, and BMI at baseline. Compared with insulin glargine QD, exenatide BID as add-on therapy to OAD is a cost-effective treatment in Chinese patients inadequately controlled by OAD treatments.
Bossie, Cynthia
2008-01-01
Ibrahim Turkoz, Cynthia A Bossie, Bryan Dirks, Carla M CanusoOrtho-McNeil Janssen Scientific Affairs, LLC, Titusville, NJ, USAAbstract: Direct and indirect effects of the new psychotropic paliperidone extended-release (paliperidone ER) tablets on negative symptom improvement in schizophrenia were investigated using path analysis. A post hoc analysis of pooled data from three 6-week, double-blind, placebo-controlled studies of paliperidone ER in patients experiencing acute exacerbation was con...
Rybczynska, Helena; Melander, Eva; Johansson, Hugo; Lundberg, Fredrik
2014-06-01
Extended-spectrum beta-lactamase (ESBL)-producing bacteria are an escalating problem threatening health. Devastating consequences can result in neonatal intensive care units (NICU) due to these bacteria. The aim of this study was to investigate the efficacy of once-a-week screening (July 2010 to September 2012) versus screening on demand (April 2008 to June 2010). The investigation was an open retrospective descriptive study comparing 2 unpaired groups, the first exposed to screening on demand and the second to screening once a week. All other infection control measures were unchanged. Both groups were cared for in the NICU of Skåne University Hospital. Parameters compared were the proportion of cultured neonates, prevalence, time before detection, number of secondary cases, and clinical infections due to ESBL-producing bacteria. The proportion of cultured neonates increased from 28% to 49% (p control the epidemiology of unwanted pathogens among newborn infants. It provides the opportunity for early intervention, thereby avoiding secondary cases and infections. Premature neonates in particular benefit from this approach. The prevalence of ESBL of 1.77% is low from an international perspective. ESBL appear to be introduced onto the ward by mothers colonized with ESBL.
Darwish, Mona; Bond, Mary; Tracewell, William; Robertson, Philmore; Yang, Ronghua
2015-01-01
A hydrocodone extended-release (ER) formulation employing the CIMA(®) Abuse-Deterrence Technology platform was developed to provide resistance against rapid release of hydrocodone when tablets are comminuted or taken with alcohol. This study evaluated the pharmacokinetics of three hydrocodone ER tablet prototypes with varying levels of polymer coating to identify the prototype expected to have the greatest abuse deterrence potential based on pharmacokinetic characteristics that maintain systemic exposure to hydrocodone comparable to that of a commercially available hydrocodone immediate-release (IR) product. In this four-period crossover study, healthy subjects aged 18-45 years were randomized to receive a single intact, oral 45-mg tablet of one of three hydrocodone ER prototypes (low-, intermediate-, or high-level coating) or an intact, oral tablet of hydrocodone IR/acetaminophen (APAP) 10/325 mg every 6 h until four tablets were administered, with each of the four treatments administered once over the four study periods. Dosing periods were separated by a minimum 5-day washout. Naltrexone 50 mg was administered to block opioid receptors. Blood samples for pharmacokinetic assessments were collected predose and through 72 h postdose. Parameters assessed included maximum observed plasma hydrocodone concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve from time 0 to infinity (AUC(0-∞)). Mean C(max) values were 49.2, 32.6, and 28.4 ng/mL for the low-, intermediate-, and high-level coating hydrocodone ER tablet prototypes, respectively, and 37.3 ng/mL for the hydrocodone IR/APAP tablet; respective median t(max) values were 5.9, 8.0, 8.0, and 1.0 h. Total systemic exposure to hydrocodone (AUC(0-∞)) was comparable between hydrocodone ER tablet prototypes (640, 600, and 578 ng·h/mL, respectively) and hydrocodone IR/APAP (581 ng·h/mL). No serious adverse events or deaths were reported. The most common adverse events included
Xhaard, A; Rzepecki, P; Valcarcel, D; Santarone, S; Fürst, S; Serrano, D; De Angelis, G; Krüger, W; Scheid, C
2014-04-01
Previous studies have shown an equivalent pharmacokinetic profile between four-times-daily (4QD) and once-daily (QD) administration of intra-venous (IV) BU, without increased toxicity. We assess the impact of a switch in IV BU from a 4QD to a QD schedule, in terms of health-care organization, staff working conditions, quality of care dispensed and perceived patient comfort. Clinicians, nurses and pharmacists from nine allogeneic transplantation units in five European countries were interviewed face to face. Overall perception of QD versus 4QD BU was very positive. Both administration schemes were evaluated to be equally efficaciousZ. QD BU was perceived to be safer and more convenient. Clinicians and nurses perceived that patient comfort was improved, due to fewer complications associated with repeated infusions, and avoiding night infusions associated with stress, anxiety and decreased quality of sleep. Switching from 4QD to QD BU had a significant impact on health-care organization, with a better integration in the overall management and usual timelines in the pharmacies and transplantation units. Time spent to prepare and administer BU was significantly reduced, leading to potential financial savings that merit further assessment and would be of particular interest in the current economic climate.
Review of once-monthly oral ibandronate and the use thereof
African Journals Online (AJOL)
The MOBILE study was a prospective, randomised, phase lll, non- inferiority study that compared the efficacy and safety of three once-monthly oral ibandronate doses (50+50 mg monthly, given on 2 consecutive days; 100 mg monthly; 150 mg monthly) with. 2.5 mg daily ibandronate, which has previously been shown.
Control of hypertension with single daily doses of sotalol hydrochloride.
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.
2011-11-07
... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0771] Draft Blueprint for Prescriber Education for Long-Acting/ Extended-Release Opioid Class-Wide Risk... announcing the availability of a draft document entitled ``Blueprint for Prescriber Education for the Long...
Murphy, Tanya K; Fernandez, Thomas V; Coffey, Barbara J; Rahman, Omar; Gavaletz, Allison; Hanks, Camille E; Tillberg, Caitlin S; Gomez, Laura Ibanez; Sukhodolsky, Denis G; Katsovich, Lily; Scahill, Lawrence
2017-11-01
To evaluate the tolerability, safety, and preliminary efficacy of extended-release guanfacine in children with chronic tic disorders, including Tourette's disorder (collectively referred to as CTD). This was a multisite, 8-week, randomized, double-blind, placebo-controlled trial. The primary outcome measure was the Yale Global Tic Severity Scale (YGTSS) total score. Key secondary outcomes included the Improvement item of Clinical Global Impressions-Improvement (CGI-I) scale and the Tic Symptom Self-report (TSSR). Adverse events were monitored at each visit. Thirty-four subjects (23 boys and 11 girls) of ages 6 to 17 years (mean = 11.1 ± 3.1) with CTD were randomly assigned to extended-release guanfacine (n = 16) or placebo (n = 18). At baseline, the mean YGTSS total score was 26.3 ± 6.6 for the guanfacine group versus 27.7 ± 8.7 for the placebo group. Within the guanfacine group (mean final daily dose of 2.6 ± 1.1 mg, n = 14), the mean YGTSS total score declined to 23.6 ± 6.42 [t(15) = 1.84, p = 0.08; effect size = 0.35]. The results were similar in the placebo group with a score of 24.7 ± 10.54 at week 8 [t(17) = 1.83, p = 0.08; effect size = 0.38]. There was no significant difference in the rate of positive response on the CGI-I between the guanfacine group and placebo (19% [3/16] vs. 22% [4/18], p = 1.0). The most common adverse events were fatigue, drowsiness, dry mouth, headache, and irritability. Two subjects in the guanfacine group discontinued early-one because of an adverse event (depressed mood) and one because of lack of efficacy; two subjects in the placebo group discontinued because of lack of efficacy. This pilot study did not confirm a clinically meaningful effect size within the guanfacine group. These results do not support the launch of a larger efficacy trial for tics in children and adolescents with CTD.
DEFF Research Database (Denmark)
Pagsberg, Anne Katrine; Jeppesen, Pia; Klauber, Dea Gowers
2017-01-01
of quetiapine-extended release (quetiapine-ER) versus aripiprazole in children and adolescents with first-episode psychosis, to determine whether differences between the two treatments were sufficient to guide clinicians in their choice of one drug over the other. METHODS: In this multicentre, double-blind...... (47 [92%] vs 39 [71%]), orthostatic dizziness (42 [78%] vs 46 [81%]), depression (43 [80%] vs 44 [77%]), tension/inner unrest (37 [69%] vs 50 [88%]), failing memory (41 [76%] vs 44 [77%]), and weight gain (46 [87%] vs 38 [68%]). INTERPRETATION: This first head-to-head comparison of quetiapine...
Miller, Aaron E
2015-10-01
The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy. Copyright © 2015 The Authors
Formulation of Extended-Release Metformin Hydrochloride Matrix ...
African Journals Online (AJOL)
Methods: Various metformin hydrochloride formulations containing a hydrophobic carrier (stearic acid) and a hydrophilic polymer (polyethylene oxide) were prepared using a 32 factorial design. ... The release data were subjected to various release kinetic models and also compared with those of a commercial brand.
Rugoho, I; Edwards, G R
2018-01-01
The objective of this study was to examine the effect of wintering pregnant, nonlactating dairy cows outdoors on either kale or grass, fed in 1 [11 kg dry matter (DM) of kale or grass + 3 kg DM of baled barley straw offered in the morning] or 2 allocations (5.5 kg DM of kale or grass grazed + 1.5 kg DM of barley straw offered morning and afternoon) per day. The body condition score (BCS) gain over the 47-d winter feeding period was higher for grass-fed (0.5 BCS units) than kale-fed cows (0.3 BCS units), but was unaffected by feeding frequency. Forage DM utilization was higher for kale-fed (97%) than grass-fed cows (76%), leading to higher estimated dry matter intake (DMI) in kale-fed (10.7 kg of DM/cow per day) than grass-fed cows (7.7 kg of DM/cow per day). Forage DM utilization and estimated DMI were not affected by feeding frequency. Prehension bite rate was greater for grass-fed (37.3 bites/min) than kale-fed cows (7.6 bites/min), but more mastication bites were required for kale-fed cows. Cumulative DMI after 2, 3, and 6 h was greater in cows allocated forage once than twice a day and for kale than grass after 3 and 6 h. Mean eating time was greater for cows offered forage once (477 min) than twice (414 min) per day. In conclusion, increasing feeding frequency from once to twice per day decreased the intake rate within the first 6 h after allocation, but did not affect total daily DMI, DM utilization or BCS gain. Thus, moving cows more frequently would not have any significant advantage. It may increase labor requirements, thereby creating a more challenging wintering management than feeding once per day. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
Reimer, C; Lødrup, A B; Smith, G; Wilkinson, J; Bytzer, P
2016-04-01
Many reflux patients remain symptomatic on a standard dose of proton pump inhibitor (PPI). Alginates decrease the number of reflux events by forming a raft on top of the stomach content and thus offer a supplemental mechanism of action to acid suppression. To assess the efficacy of an alginate (Gaviscon Advance, Reckitt Benckiser, Slough, UK) on reflux symptoms in patients with persistent symptoms despite once daily PPI. This was a multicentre, randomised, placebo-controlled, 7-day double-blind trial preceded by a 7-day run-in period. Reflux symptoms were assessed using the Heartburn Reflux Dyspepsia Questionnaire (HRDQ). Based on symptom score during run-in, eligible patients were randomised to Gaviscon Advance 10 mL four times a day or placebo in addition to a once daily PPI. The primary endpoint was change in HRDQ score post-treatment compared to baseline. One hundred and thirty-six patients were randomised. Change in HRDQ reflux score was significantly greater for Gaviscon Advance (mean: -5.0, s.d.: 4.7) than for placebo (mean: -3.5, s.d.: 5.5) with an LS mean difference of 1.6 [95% CI -3.1 to -0.1], P = 0.03. A decrease in the mean (s.d.) number of nights with symptoms was observed from 3.6 (2.8) to 3.0 (3.0) in the placebo group and from 3.9 (2.8) to 2.2 (2.7) for the Gaviscon Advance group. This reduction was significantly greater in the Gaviscon Advance group than in the placebo group [LS mean difference = -0.9, 95% CI (-1.6 to -0.2), P < 0.01]. In patients with residual reflux symptoms despite PPI treatment, adding an alginate offers additional decrease in the burden of reflux symptoms (EudraCT/IND Number: 2011-005486-21). © 2016 John Wiley & Sons Ltd.
Once upon an algorithm how stories explain computing
Erwig, Martin
2017-01-01
How Hansel and Gretel, Sherlock Holmes, the movie Groundhog Day, Harry Potter, and other familiar stories illustrate the concepts of computing. Picture a computer scientist, staring at a screen and clicking away frantically on a keyboard, hacking into a system, or perhaps developing an app. Now delete that picture. In Once Upon an Algorithm, Martin Erwig explains computation as something that takes place beyond electronic computers, and computer science as the study of systematic problem solving. Erwig points out that many daily activities involve problem solving. Getting up in the morning, for example: You get up, take a shower, get dressed, eat breakfast. This simple daily routine solves a recurring problem through a series of well-defined steps. In computer science, such a routine is called an algorithm. Erwig illustrates a series of concepts in computing with examples from daily life and familiar stories. Hansel and Gretel, for example, execute an algorithm to get home from the forest. The movie Groundho...
Calabro, J J; Londino, A V; Eyvazzadeh, C
1985-10-25
Of all the forms of nonarticular rheumatism, by far the most common are bursitis and tendinitis. Yet, the bursae and neighboring tendon sheaths are the most neglected anatomic structures of the body. Moreover, like the joints, they are lined by synovial membrane, secrete synovial fluid, and are common sites of rheumatic problems. The vast majority of painful shoulder problems are caused by acute subacromial (subdeltoid) bursitis and bicipital tendinitis. In the management of these periarticular disorders, the ultimate goal is to preserve shoulder motion. Although this is accomplished by daily range-of-motion exercises, it is clearly facilitated by suppression of periarticular inflammation and discomfort through the use of nonsteroidal anti-inflammatory drugs. Of these, sustained-release indomethacin provides the anti-inflammatory efficacy of indomethacin and by virtue of its sustained-release formulation, may promote patient compliance since it need be given only once or twice daily.
Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations.
Lionberger, Robert A; Raw, Andre S; Kim, Stephanie H; Zhang, Xinyuan; Yu, Lawrence X
2012-04-01
FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times. Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem. Models were validated using in-house data submitted to the FDA. Using dissolution profiles expressed by the Weibull model as input for the CAT model, dissolution spaces were derived for simulated test formulations. The AUC(0-1.5) parameter was indicative of IR characteristics of early exposure and effectively distinguished among formulations that produced different pharmacodynamic effects. The AUC(1.5-t) parameter ensured equivalence with respect to the sustained release phase of Ambien CR. The variability of AUC(0-1.5) is higher than other PK parameters, but is reasonable for use in an equivalence test. In addition to the traditional PK parameters of AUCinf and Cmax, AUC(0-1.5) and AUC(1.5-t) are recommended to provide bioequivalence measures with respect to label indications for Ambien CR: onset of sleep and sleep maintenance.
Yoon, Seonghae; Lee, Howard; Kim, Tae-Eun; Lee, SeungHwan; Chee, Dong-Hyun; Cho, Joo-Youn; Yu, Kyung-Sang; Jang, In-Jin
2014-01-01
Seonghae Yoon,1,* Howard Lee,2,* Tae-Eun Kim,1 SeungHwan Lee,1 Dong-Hyun Chee,3 Joo-Youn Cho,1 Kyung-Sang Yu,1 In-Jin Jang1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 2Clinical Trials Center, Seoul National University Hospital, 3AbbVie Ltd., Seoul, Republic of Korea *These authors contributed equally to this work Background: This study was conducted to compare the oral bioavailability of an itopride extended-release (ER...
Paliperidone extended-release: does it have a place in antipsychotic therapy?
Directory of Open Access Journals (Sweden)
Carlos Schönfeldt-Lecuona
2011-03-01
Full Text Available Maximilian Gahr1,*, Markus A Kölle1,*, Carlos Schönfeldt-Lecuona1, Peter Lepping2, Roland W Freudenmann11Department of Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany; 2Department of Psychiatry, Glyndwr University, Wales, UK *Both authors contributed equally and their order was determined by coin toss.Abstract: Paliperidone (9-hydroxy-risperidone, the active metabolite of risperidone, was approved for treating schizophrenia worldwide in 2006 as paliperidone extended-release (PER, and became the first second-generation antipsychotic specifically licensed for treating schizoaffective disorder in 2009. However, at the same time, its comparatively high cost gave rise to concerns about the cost-effectiveness of PER as compared with its precursor, risperidone. This paper reviews the existing knowledge of the pharmacology, kinetics, efficacy, tolerability, and fields of application of PER, and compares PER with risperidone in order to determine whether it has a place in antipsychotic therapy. An independent assessment of all relevant publications on PER published until July 2010 was undertaken. PER has a unique pharmacological profile, including single dosing, predominantly renal excretion, low drug–drug interaction risk, and differs from risperidone in terms of mode of action and pharmacokinetics. High-level evidence suggests that PER is efficacious and safe in schizophrenia, schizoaffective disorder, and acute manic episodes. There is a striking lack of published head-to-head comparisons between PER and risperidone, irrespective of indication. Low-level evidence shows a lower risk for hyperprolactinemia and higher patient satisfaction with PER than with risperidone. PER adds to the still limited arsenal of second-generation antipsychotics. In the absence of direct comparisons with risperidone, it remains difficult to come to a final verdict on the potential additional therapeutic benefits of PER which would justify its substantially
Opioid rotation with extended-release opioids: where should we begin?
Directory of Open Access Journals (Sweden)
Nalamachu S
2011-12-01
Full Text Available Srinivas NalamachuInternational Clinical Research Institute and Pain Management Institute, Overland Park, KS, USAAbstract: Opioid rotation is a common and necessary clinical practice in the management of chronic non-cancer pain to improve therapeutic efficacy with the lowest opioid dose. When dose escalations fail to achieve adequate analgesia or are associated with intolerable side effects, a trial of a new opioid should be considered. Much of the scientific rationale of opioid rotation is based on the wide interindividual variability in sensitivity to opioid analgesics and the novel patient response observed when introducing an opioid-tolerant patient to a new opioid. This article discusses patient indicators for opioid rotation, the conversion process between opioid medications, and additional practical considerations for increasing the effectiveness of opioid therapy during a trial of a new opioid. A Patient vignette that demonstrates a step-wise approach to opioid rotation is also presented.Keywords: extended-release opioids, chronic pain, opioid rotation
Armstrong, J Scott; Greenberg, Shoil M
2008-04-01
Boll weevil traps baited with a ComboLure (25 of mg grandlure + 30 mg of eugenol + 90 of mg dichlorvos [DDVP]), an extended-release lure (25 mg of grandlure + 30 mg of eugenol + 60 of mg DDVP kill-strip), and extended-release lure with no DDVP were evaluated for boll weevil, Anthonomus grandis grandis Boheman (Coleoptera: Curculionidae), captures in South Texas cotton, Gossypium hirsutum L., fields during February-March 2005 and March-April 2006. The traps were serviced once a week for five consecutive weeks by using the same methodology as active boll weevil eradication programs. Mean captured boll weevils from extended-release lures with no DDVP were significantly higher in five of 10 trapping weeks compared with captures of the ComboLure and extended lure. Weekly mortality of boll weevils captured was similar for the ComboLure (72.6 +/- 4.7%) and extended lure + DDVP (73.5 +/- 4.0%), and both were significantly higher than the extended lure (32.8 +/- 5.0%) with no DDVP. The presence or absence of DDVP did not significantly affect the sex ratio of field-captured boll weevils. We found no functional reasoning for using DDVP in large scale trapping of boll weevils regardless of the formulation or presentation in the trap. We conducted two additional trapping evaluations after the 2005 and 2006 studies, but the numbers of boll weevils captured were too low for statistical comparisons, indicating that boll weevil eradication is reducing populations in the Rio Grande Valley of Texas.
Tapentadol extended release for the management of chronic neck pain
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Billeci D
2017-03-01
Full Text Available Domenico Billeci,1 Flaminia Coluzzi2 1Division of Neurosurgery, Ca’Foncello Hospital, University of Padova, Treviso, 2Department of Medical and Surgical Sciences and Biotechnologies, Unit of Anaesthesiology, Intensive Care Medicine, and Pain Therapy, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Latina, Italy Background: The role of opioids in the management of chronic neck pain is still poorly investigated. No data are available on tapentadol extended release (ER. In this article, we present 54 patients with moderate-to-severe chronic neck pain treated with tapentadol ER. Patients and methods: Patients received tapentadol ER 100 mg/day; dosage was then adjusted according to clinical needs. The following parameters were recorded: pain; Douleur Neuropathique 4 score; Neck Disability Index score; range of motion; pain-associated sleep interference; quality of life (Short Form [36] Health Survey; Patient Global Impression of Change (PGIC; Clinician GIC; opioid-related adverse effects; and need for other analgesics. Results: A total of 44 of 54 patients completed the 12-week observation. Tapentadol ER daily doses increased from 100 mg/day to a mean (standard deviation dosage of 204.5 (102.8 mg/day at the final evaluation. Mean pain intensity at movement significantly decreased from baseline (8.1 [1.1] to all time points (P<0.01. At baseline, 70% of patients presented a positive neuropathic component. This percentage dropped to 23% after 12 weeks. Tapentadol improved Neck Disability Index scores from 55.6 (18.6 at baseline to 19.7 (20.9 at the final evaluation (P<0.01. Tapentadol significantly improved neck range of motion in all three planes of motion, particularly in lateral flexion. Quality of life significantly improved in all Short Form (36 Health Survey subscales (P<0.01 and in both physical and mental status (P<0.01. Based on PGIC results, approximately 90% of patients rated their overall condition as much/very much
Jonklaas, Jacqueline; Burman, Kenneth D
2016-06-01
TSH to the values seen during levothyroxine therapy. There were significant excursions in serum total and free T3 concentrations with once-daily therapy. Trials of combination therapy are likely to be associated with similar excursions, albeit of a lesser magnitude. Only the physical component score of the SF36 questionnaire and hyperthyroid symptoms changed significantly with conversion to liothyronine monotherapy. Sustained release preparations with stable serum T3 profiles may have entirely different outcomes.
Johnson, James G; Langan, Jennifer N; Gilor, Chen
2016-09-01
An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.
Boyd, Peter; Fetherston, Susan M; McCoy, Clare F; Major, Ian; Murphy, Diarmaid J; Kumar, Sandeep; Holt, Jonathon; Brimer, Andrew; Blanda, Wendy; Devlin, Brid; Malcolm, R Karl
2016-09-10
A matrix-type silicone elastomer vaginal ring providing 28-day continuous release of dapivirine (DPV) - a lead candidate human immunodeficiency virus type 1 (HIV-1) microbicide compound - has recently demonstrated moderate levels of protection in two Phase III clinical studies. Here, next-generation matrix and reservoir-type silicone elastomer vaginal rings are reported for the first time offering simultaneous and continuous in vitro release of DPV and the contraceptive progestin levonorgestrel (LNG) over a period of between 60 and 180days. For matrix-type vaginal rings comprising initial drug loadings of 100, 150 or 200mg DPV and 0, 16 or 32mg LNG, Day 1 daily DPV release values were between 4132 and 6113μg while Day 60 values ranged from 284 to 454μg. Daily LNG release ranged from 129 to 684μg on Day 1 and 2-91μg on Day 60. Core-type rings comprising one or two drug-loaded cores provided extended duration of in vitro release out to 180days, and maintained daily drug release rates within much narrower windows (either 75-131μg/day or 37-66μg/day for DPV, and either 96-150μg/day or 37-57μg/day for LNG, depending on core ring configuration and ignoring initial lag release effect for LNG) compared with matrix-type rings. The data support the continued development of these devices as multi-purpose prevention technologies (MPTs) for HIV prevention and long-acting contraception. Copyright © 2016 Elsevier B.V. All rights reserved.
Bernardo-Escudero, Roberto; Alonso-Campero, Rosalba; Francisco-Doce, María Teresa de Jesús; Cortés-Fuentes, Myriam; Villa-Vargas, Miriam; Angeles-Uribe, Juan
2012-12-01
The study aimed to assess the pharmacokinetics of a new, modified-release metoclopramide tablet, and compare it to an immediate-release tablet. A single and multiple-dose, randomized, open-label, parallel, pharmacokinetic study was conducted. Investigational products were administered to 26 healthy Hispanic Mexican male volunteers for two consecutive days: either one 30 mg modified-release tablet every 24 h, or one 10 mg immediate-release tablet every 8 h. Blood samples were collected after the first and last doses of metoclopramide. Plasma metoclopramide concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed through vital signs measurements, clinical evaluations, and spontaneous reports from study subjects. All 26 subjects were included in the analyses [mean (SD) age: 27 (8) years, range 18-50; BMI: 23.65 (2.22) kg/m², range 18.01-27.47)]. Peak plasmatic concentrations were not statistically different with both formulations, but occurred significantly later (p 0.05)]. One adverse event was reported in the test group (diarrhea), and one in the reference group (headache). This study suggests that the 30 mg modified-release metoclopramide tablets show features compatible with slow-release formulations when compared to immediate-release tablets, and is suitable for once-a-day administration.
One-by-one or all-at-once? Self-reporting policies and dishonesty
Rilke, R.M.; Schurr, A.; Barkan, R.; Shalvi, S.
2016-01-01
Organizational monitoring relies frequently on self-reports (e.g., work hours, progress reports, travel expenses). A "one-by-one" policy requires employees to submit a series of reports (e.g., daily or itemized reports). An "all-at-once" policy requires an overall report (e.g., an annual or an
Rascol, O.; Brooks, D.J.; Melamed, E.; Oertel, W.; Poewe, W.; Stocchi, F.; Tolosa, E.; LARGO study group
2005-01-01
Lancet. 2005 Mar 12-18;365(9463):947-54. Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Rascol O, Brooks DJ, Melamed E, Oertel W, Poewe W, Stocchi F, Tolosa E; LARGO study group. Clinical Investigation Centre, Department of Clinical Pharmacology, University Hospital, Toulouse, France. ...
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Devarakonda K
2015-09-01
Full Text Available Krishna Devarakonda,1 Kenneth Kostenbader,2 Michael J Giuliani,3 Jim L Young41Department of Clinical Pharmacology, Mallinckrodt Pharmaceuticals, 2Mallinckrodt Pharmaceuticals, 3Research and Development, Mallinckrodt Pharmaceuticals, 4Department of Clinical Affairs and Program Management, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USAObjective: To characterize the single-dose and steady-state pharmacokinetics (PK of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (IR/ER HB/APAP, IR HB/ibuprofen, and IR tramadol HCl/APAP.Methods: In this single-center, open-label, randomized, four-period crossover study, healthy participants received four treatments under fasted conditions: 1 a single dose of two IR/ER HB/APAP 7.5/325 mg tablets (15/650 mg total dose on day 1, followed by two tablets every 12 hours (q12h beginning on day 3; 2 a single dose of IR HB/ibuprofen 15/400 mg (divided as one 7.5/200 mg tablet at hour 0 and 6, followed by one tablet every 6 hours (q6h beginning on day 3; 3 a single dose of IR tramadol HCl/APAP 75/650 mg (divided as one 37.5/325 mg tablet at hour 0 and 6, followed by one tablet q6h beginning on day 3; and 4 a single dose of three IR/ER HB/APAP 7.5/325 mg tablets (22.5/975 mg total dose on day 1, a three-tablet initial dose at 48 hours followed by two-tablet doses q12h beginning on day 3. Hydrocodone and APAP single-dose and steady-state PK were assessed. Adverse events were monitored.Results: The PK analysis was carried out on 29 of 48 enrolled participants who completed all treatment periods. Single-dose hydrocodone exposure was similar for IR/ER HB/APAP 22.5/975 mg and IR HB/ibuprofen 15/400 mg; time to maximum observed plasma concentration was shorter and half-life was longer for IR/ER HB/APAP (22.5/975 mg and 15/650 mg vs IR HB/ibuprofen. Single-dose APAP exposure was similar for IR/ER HB/APAP 15/650 mg and IR tramadol HCl/APAP 75/650 mg. Steady-state hydrocodone and APAP exposures
International Nuclear Information System (INIS)
Buchholz, Thomas A.; Strom, Eric A.; Oswald, Mary Jane; Perkins, George H.; Oh, Julia; Domain, Delora; Yu, Tse-Kuan; Woodward, Wendy A.; Tereffe, Welela; Singletary, S. Eva; Thomas, Eva; Buzdar, Aman U.; Hortobagyi, Gabriel N.; McNeese, Marsha D.
2006-01-01
Purpose: To analyze the results of a Phase III clinical trial that investigated whether a hyperfractionated radiotherapy (RT) schedule could reduce the risk of locoregional recurrence in patients with locally advanced breast cancer treated with chemotherapy and mastectomy. Methods and Materials: Between 1985 and 1989, 200 patients with clinical Stage III noninflammatory breast cancer were enrolled in a prospective study investigating neoadjuvant and adjuvant chemotherapy. Of the 179 patients treated with mastectomy after neoadjuvant chemotherapy, 108 participated in a randomized component of the trial that compared a dose-escalated, hyperfractionated (twice-daily, b.i.d.) chest wall RT schedule (72 Gy in 1.2-Gy b.i.d. fractions) with a once-daily (q.d.) schedule (60 Gy in 2-Gy q.d. fractions). In both arms of the study, the supraclavicular fossa and axillary apex were treated once daily to 50 Gy. The median follow-up period was 15 years. Results: The 15-year actuarial locoregional recurrence rate was 7% for the q.d. arm and 12% for the b.i.d. arm (p = 0.36). The rates of severe acute toxicity were similar (4% for q.d. vs. 5% for b.i.d.), but moist desquamation developed in 42% of patients in the b.i.d. arm compared with 28% of the patients in the q.d. arm (p = 0.16). The 15-year actuarial rate of severe late RT complications did not differ between the two arms (6% for q.d. vs. 11% for b.i.d., p = 0.54). Conclusion: Although the sample size of this study was small, we found no evidence that this hyperfractionation schedule of postmastectomy RT offered a clinical advantage. Therefore, we have concluded that it should not be further studied in this cohort of patients
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Schacht Alexander
2009-02-01
Full Text Available Abstract Background The impact of once daily atomoxetine treatment on symptoms in children and adolescents with ADHD may vary over the day. In order to capture such variations, two studies were undertaken in children and adolescents with ADHD using two instruments that capture morning and evening behavior and ADHD-related difficulties over the day. This secondary measure analysis builds on two primary analyses that were conducted separately for children and adolescents and also published separately. Methods In two open-label studies, ADHD patients aged 6–17 years (n = 421, received atomoxetine in the morning (target-dose 0.5–1.2 mg/kg/day for up to 24 weeks. Morning and evening behavior was assessed using the investigator-rated Weekly Rating of Evening and Morning Behavior (WREMB-R scale. ADHD-related difficulties at various times of the day (morning, during school, during homework, evening were assessed using the Global Impression of Perceived Difficulties (GIPD scale, rated by patients, parents and physicians. Data from both studies were combined for this secondary measure analysis. Results Both WREMB-R subscores decreased significantly over time, the evening subscore from 13.7 (95% CI 13.2;14.2 at baseline to 8.0 (7.4;8.5 at week 2, the morning subscore from 4.3 (4.0;4.5 to 2.4 (2.2;2.6. Scores then remained stable until week 24. All GIPD items improved correspondingly. At all times of the day, patients rated ADHD-related difficulties as less severe than parents and physicians. Conclusion These findings from two open-label studies suggest that morning and evening behavior and ADHD-related difficulties in the mornings and evenings improve over time with once daily atomoxetine treatment.
United States Historical Climatology Network Daily Temperature and Precipitation Data (1871-1997)
Energy Technology Data Exchange (ETDEWEB)
Easterling, D.R.
2002-10-28
This document describes a database containing daily observations of maximum and minimum temperature, precipitation amount, snowfall amount, and snow depth from 1062 observing stations across the contiguous US. This database is an expansion and update of the original 138-station database previously released by the Carbon Dioxide Information Analysis Center (CDIAC) as CDIAC numeric data package NDP-042. These 1062 stations are a subset of the 1221-station US Historical Climatology Network (HCN), a monthly database compiled by the National Climatic Data Center (Asheville, North Carolina) that has been widely used in analyzing US climate. Data from 1050 of these daily records extend into the 1990s, while 990 of these extend through 1997. Most station records are essentially complete for at least 40 years; the latest beginning year of record is 1948. Records from 158 stations begin prior to 1900, with that of Charleston, South Carolina beginning the earliest (1871). The daily resolution of these data makes them extremely valuable for studies attempting to detect and monitor long-term climatic changes on a regional scale. Studies using daily data may be able to detect changes in regional climate that would not be apparent from analysis of monthly temperature and precipitation data. Such studies may include analyses of trends in maximum and minimum temperatures, temperature extremes, daily temperature range, precipitation ''event size'' frequency, and the magnitude and duration of wet and dry periods. The data are also valuable in areas such as regional climate model validation and climate change impact assessment. This database is available free of charge from CDIAC as a numeric data package (NDP).
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Jara M
2015-12-01
Full Text Available Michele Jara, Thomas Aquilina, Peter Aupperle, Adrian L Rabinowicz Acorda Therapeutics, Inc., Ardsley, NY, USA Background: Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine outside the US, 10 mg twice daily, was approved by the US Food and Drug Administration (FDA in January 2010 to improve walking in people with multiple sclerosis, as determined by an increase in walking speed. Objective: To provide a descriptive analysis of reported adverse events (AEs for commercially available dalfampridine-ER from March 2010 through March 31, 2015. Methods: Five-year postmarketing data for dalfampridine-ER were available from the exposure of approximately 107,000 patients in the US (103,700 patient-years. Commonly reported AEs (≥2% of all reported AEs and serious AEs were determined. The incidence of reported seizures was determined and the events were further investigated. Results: Among the 107,000 patients exposed to dalfampridine-ER (70% female; mean age 52.1, the most common AEs were dizziness (3.7%, insomnia (3.2%, balance disorder (3%, fall (2.4%, headache (2.4%, nausea (2.1%, and urinary tract infection (2%. Other common AEs were drug ineffectiveness (5.8%, gait disturbance (4.6%, and inappropriate dosing (3.1%. Serious AEs included rare anaphylactic reactions (five cases and drug hypersensitivity reactions (eight cases. A total of 657 seizure cases were reported (6.3/1,000 patient-years; of these, 324 were medically confirmed (3.1/1,000 patient-years. Incidence of reported seizures was stable over time. Duration of treatment prior to a seizure ranged from a single dose to >4 years; 12% of the seizures occurred within a week of starting treatment. Conclusion: The 5-year US postmarketing safety data of dalfampridine-ER is consistent with the safety profile observed in clinical trials. Incidence of reported seizures remained stable over time. Since commercial availability in March 2010, a
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Xiaoxia Yang
Full Text Available A previously presented physiologically-based pharmacokinetic model for immediate release (IR methylphenidate (MPH was extended to characterize the pharmacokinetic behaviors of oral extended release (ER MPH formulations in adults for the first time. Information on the anatomy and physiology of the gastrointestinal (GI tract, together with the biopharmaceutical properties of MPH, was integrated into the original model, with model parameters representing hepatic metabolism and intestinal non-specific loss recalibrated against in vitro and in vivo kinetic data sets with IR MPH. A Weibull function was implemented to describe the dissolution of different ER formulations. A variety of mathematical functions can be utilized to account for the engineered release/dissolution technologies to achieve better model performance. The physiological absorption model tracked well the plasma concentration profiles in adults receiving a multilayer-release MPH formulation or Metadate CD, while some degree of discrepancy was observed between predicted and observed plasma concentration profiles for Ritalin LA and Medikinet Retard. A local sensitivity analysis demonstrated that model parameters associated with the GI tract significantly influenced model predicted plasma MPH concentrations, albeit to varying degrees, suggesting the importance of better understanding the GI tract physiology, along with the intestinal non-specific loss of MPH. The model provides a quantitative tool to predict the biphasic plasma time course data for ER MPH, helping elucidate factors responsible for the diverse plasma MPH concentration profiles following oral dosing of different ER formulations.
Turkoz, Ibrahim; Fu, Dong-Jing; Bossie, Cynthia A; Alphs, Larry
2015-01-01
This analysis evaluates improvement in symptoms of depression in patients with schizoaffective disorder administered oral paliperidone extended-release by accounting for the magnitude of direct and indirect (changes in negative and positive symptoms and worsening of extrapyramidal symptoms) treatment effects on depressive symptoms. Data for this post hoc analysis were drawn from two six-week, randomized, placebo-controlled studies of paliperidone extended-release versus placebo in adult subjects with schizoaffective disorder (N=614; NCT00412373, NCT00397033). Subjects with baseline 17-item Hamilton Rating Scale for Depression scores of 16 or greater were included. Structural equation models (path analyses) were used to separate total effects into direct and indirect effects on depressive symptoms. Change from baseline in 17-item Hamilton Rating Scale for Depression score at the Week 6 end point was the dependent variable; changes in Positive and Negative Syndrome Scale positive and negative factors and Simpson-Angus Scale (to evaluate extrapyramidal symptoms) scores were independent variables. At baseline, 332 of 614 (54.1%) subjects had a 17-item Hamilton Rating Scale for Depression score of 16 or greater. Path analysis determined that up to 26.4 percent of the paliperidone extended-release versus placebo effect on depressive symptoms may be attributed to a direct treatment effect, and 45.8 percent and 28.4 percent were mediated indirectly through improvements on positive and negative symptoms, respectively. No effects were identified as mediated through extrapyramidal symptoms changes (-0.7%). RESULTS of this analysis suggest that paliperidone's effect on depressive symptoms in subjects with schizoaffective disorder participating in two six-week, randomized, placebo-controlled studies is mediated through indirect effects (e.g., positive and negative symptom changes) and a direct treatment effect.
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Wang G
2014-01-01
Full Text Available Gang Wang,1 Alexander McIntyre,2 Willie R Earley,3 Shane R Raines,3 Hans Eriksson4 1Beijing Anding Hospital, Capital Medical University, Beijing, People's Republic of China; 2Department of Psychiatry, Penticton Regional Hospital, Penticton, BC, Canada; 3AstraZeneca Pharmaceuticals, Wilmington, DE, USA; 4AstraZeneca R&D, Södertälje, Sweden Objectives: To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR monotherapy in patients with major depressive disorder (MDD. Patients and methods: This was a 10-week (8-week active treatment/2-week post-treatment randomized, double-blind, placebo- and active-controlled study (D1448C00004. Patients received quetiapine XR 150 mg/day, escitalopram 10 mg/day, or placebo; patients with an inadequate response (<20% improvement in Montgomery–Åsberg Depression Rating Scale [MADRS] total score at week two received double-dose treatment. The primary end point was week eight change from randomization in MADRS total score. Secondary end points included MADRS response (≥50% improvement and remission (score ≤8; Hamilton Rating Scale for Depression total and item 1; Hamilton Rating Scale for Anxiety total, psychic, and somatic; Clinical Global Impressions – Severity of Illness total; Pittsburgh Sleep Quality Index (PSQI global; and Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form percentage maximum total scores. Tolerability was assessed throughout. Results: A total of 471 patients was randomized. No significant improvements in MADRS total score were observed at week eight (last observation carried forward with either active treatment (quetiapine XR, -17.21 [P=0.174]; escitalopram, -16.73 [P=0.346] versus placebo (-15.61. There were no significant differences in secondary end points versus placebo, with the exception of week-eight change in PSQI global score (quetiapine XR, -4.96 [P<0.01] versus placebo, -3.37. Mixed-model repeated
Whole-abdomen radiotherapy for non-Hodgkin's lymphoma using twice-daily fractionation
International Nuclear Information System (INIS)
Liauw, Stanley L.; Yeh, Alexander M.; Morris, Christopher G.; Olivier, Kenneth R.; Mendenhall, Nancy Price
2006-01-01
Purpose: To report the tolerability and efficacy of twice-daily whole-abdomen irradiation (WAI) for non-Hodgkin's lymphoma (NHL). Methods and Materials: Of 123 patients treated for NHL with WAI, 37% received previous chemotherapy, 28% received WAI as part of comprehensive lymphatic irradiation (CLI), and 32% received WAI for palliation. The median dose to the whole abdomen was 25.0 Gy, followed by a median tumor boost of 9.8 Gy in 58 patients. Fractionation was 1.0 Gy once daily (54%) or 0.8 Gy twice daily (46%). Blood counts were measured weekly. Results: At a median follow-up of 4.3 years, local control was 72% and overall survival was 55% at 5 years. Median time of WAI was 42 days for once-daily treatment and 32 days for twice-daily treatment. Patients receiving twice-daily WAI did not have a significantly higher rate of acute side effects (e.g., nausea, diarrhea, platelet or red blood cell toxicity). Overall, acute thrombocytopenia was the most frequent side effect of treatment; 24 of 96 patients (25%) with available hematologic data had Grade 3+ toxicity. There was no acute Grade 3 gastrointestinal toxicity and no late small bowel obstruction. Multiple regression indicated that patients with four or less involved sites and disease size ≤6 cm had improved local control and overall survival. Conclusions: Twice-daily WAI using 0.8 Gy/fraction does not appear to have any greater toxicity compared with once-daily treatment using 1 Gy/fraction. Small doses per fraction (0.8-1 Gy/fx) are effective, tolerated well in the acute setting, and associated with a low rate of late toxicity
Effects of compost age on the release of nutrients
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Bilal B. Al-Bataina
2016-09-01
Full Text Available Composted organic materials are applied to help restore disturbed soils, speed revegetation, and control erosion; these changes are generally beneficial for stormwater quality. Ensuring that nutrient release from compost is adequate for plant needs without degrading stormwater quality is important since composts release nitrogen at variable rates (1–3% of total N/yr and the leaching process can extend for many years. The aim of this work was to understand the effect of compost age on the extent and rates of nitrogen release by conducting detailed rainfall simulation studies of one compost type at three different ages. Models describing temporal changes in nitrogen release to runoff during a single storm and across multiple storms were developed and applied to the runoff data. Nitrogen content (% and bulk density of compost increased with the increase in compost age and total nitrogen release decreased with increasing compost age. The three rain simulations (storms performed on each of the three compost ages show that nitrogen release declined each day of the repeated daily storms. A first-order kinetic model was used to estimate the amount of nitrogen remaining on compost after several storms.
Once-daily transdermal rivastigmine in the treatment of Alzheimer’s disease
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Andreas Wentrup
2008-11-01
Full Text Available Andreas Wentrup, Wolfgang H Oertel, Richard DodelDepartment of Neurology, Philipps-University Marburg, GermanyAbstract: During the past decade, transdermal delivery systems (TDS have become increasingly important for treating neurologic and psychiatric disorders. The rivastigmine patch was the first patch to be approved to treat Alzheimer’s disease (AD. The 9.5 mg/24 h patch has equal efficacy to the capsules and reduces gastrointestinal adverse events, such as nausea and vomiting, by two-thirds. This treatment is well tolerated by patients because drug delivery is even and continuous, reducing fluctuation in drug plasma level, and attenuating the development of centrally mediated cholinergic side effects. Furthermore, once-a-day application of the patch enables an easy treatment schedule, ease of handling, infrequent skin irritations, and a patient- and caregiver-friendly mode of administration. Improved compliance with a subsequent drug administration may contribute to better clinical efficacy, reduce caregiver burden, result in a slower rate of institutionalization, and lead to a decrease in healthcare and medical costs. Because of these advantages, the rivastigmine patch has enabled great progress in the treatment of AD, and represents an excellent alternative to the orally administered cholinesterase inhibitors.Keywords: Alzheimer’s disease, rivastigmine, patch, dementia
Granisetron Extended-Release Injection: A Review in Chemotherapy-Induced Nausea and Vomiting.
Deeks, Emma D
2016-12-01
An extended-release (ER) subcutaneously injectable formulation of the first-generation 5-HT 3 receptor antagonist granisetron is now available in the USA (Sustol ® ), where it is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) following moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide combination chemotherapy regimens in adults. Granisetron ER is administered as a single subcutaneous injection and uses an erosion-controlled drug-delivery system to allow prolonged granisetron release. Primary endpoint data from phase III studies after an initial cycle of chemotherapy indicate that, when used as part of an antiemetic regimen, granisetron ER injection is more effective than intravenous ondansetron in preventing delayed CINV following highly emetogenic chemotherapy (HEC); is noninferior to intravenous palonosetron in preventing both acute CINV following MEC or HEC and delayed CINV following MEC; and is similar, but not superior, to palonosetron in preventing delayed CINV following HEC. The benefits of granisetron ER were seen in various patient subgroups, including those receiving anthracycline plus cyclophosphamide-based HEC, and (in an extension of one of the studies) over multiple MEC or HEC cycles. Granisetron ER injection is generally well tolerated, with an adverse event profile similar to that of ondansetron or palonosetron. Thus, granisetron ER injection expands the options for preventing both acute and delayed CINV in adults with cancer receiving MEC or anthracycline plus cyclophosphamide-based HEC.
Role of paliperidone extended-release in treatment of schizoaffective disorder.
Canuso, Carla M; Turkoz, Ibrahim; Fu, Dong Jing; Bossie, Cynthia A
2010-10-05
Schizoaffective disorder is characterized by the presence of symptoms of both schizophrenia and a major mood disorder. The coexistence of these symptoms can be difficult to manage, and these patients are generally treated with antipsychotics as well as mood stabilizers and/or antidepressants. Additionally, no established treatment guidelines exist for this disorder. This review describes the combined results of two international, double-blind, placebo-controlled clinical studies of paliperidone extended-release (ER), an atypical antipsychotic recently approved in the US for the treatment of schizoaffective disorder. Subjects in these six-week trials were aged 18-65 years, had a diagnosis of schizoaffective disorder based on the Structural Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) Disorders, and were experiencing an acute exacerbation. The subjects from these studies had significant symptomatology as evidenced by a mean (standard deviation) baseline Positive and Negative Syndrome Scale total score of 92.8 (13.0). Based on Young Mania Rating Scale and/or a 21-item Hamilton Rating Scale for Depression score of ≥16 at baseline, 79.5% and 66.9% of subjects presented with prominent manic and depressive symptoms, respectively, and 46.4% presented with mixed symptoms. Approximately half (45%) of subjects were taking adjunctive mood stabilizers and/or antidepressants. Paliperidone ER was found to be effective in improving psychotic and mood symptoms in these subjects. Paliperidone ER was also effective as monotherapy or adjunctive to mood stabilizers and/or antidepressants for subjects with prominent manic, depressive, or mixed symptoms at baseline. No new tolerability signals were observed in this population. To the best of our awareness, these pooled data provide the largest data set of patients with schizoaffective disorder, and extend our knowledge of disease characteristics and treatment response.
Nabais, Teresa; Leclair, Grégoire
2014-01-01
Substituted amylose (SA) polymers were produced from high-amylose corn starch by etherification of its hydroxyl groups with chloroacetate. Amorphous high-amylose sodium carboxymethyl starch (HASCA), the resulting SA polymer, was spray-dried to obtain an excipient (SD HASCA) with optimal binding and sustained-release (SR) properties. Tablets containing different percentages of SD HASCA and tramadol hydrochloride were produced by direct compression and evaluated for dissolution. Once-daily and twice-daily SD HASCA tablets containing two common dosages of tramadol hydrochloride (100 mg and 200 mg), a freely water-soluble drug, were successfully developed. These SR formulations presented high crushing forces, which facilitate further tablet processing and handling. When exposed to both a pH gradient simulating the pH variations through the gastrointestinal tract and a 40% ethanol medium, a very rigid gel formed progressively at the surface of the tablets providing controlled drug-release properties. These properties indicated that SD HASCA was a promising and robust excipient for oral, sustained drug-release, which may possibly minimize the likelihood of dose dumping and consequent adverse effects, even in the case of coadministration with alcohol.
Ruane, Peter; Lang, Joseph; DeJesus, Edwin; Berger, Daniel S; Dretler, Robin; Rodriguez, Allan; Ward, Douglas J; Lim, Michael L; Liao, Qiming; Reddy, Sunila; Clair, Marty St; Vila, Tania; Shaefer, Mark S
2006-01-01
The purpose of this pilot study was to explore the efficacy and safety of the abacavir/lamivudine/zidovudine fixed-dose combination tablet administered as two tablets once daily (qd) versus one tablet twice daily (bid) in combination with efavirenz (EFV). This was a prospective, randomized, open-label, multicenter study with a 24-week treatment period in 7 outpatient HIV clinics in the United States. Patients currently receiving an initial regimen of abacavir/lamivudine/zidovudine bid plus EFV qd for at least 6 months with HIV-1 RNA or = 200 cells/mm3 were eligible. Thirty-six patients enrolled, and 35 (97%) completed the study. Participants were randomized to switch to 2 tablets of abacavir/lamivudine/zidovudine qd plus EFV qd (QD arm) or continue current treatment (BID arm) for 24 weeks. Efficacy, safety, and adherence were evaluated. Median baseline CD4+ cell count was 521 cells/mm3. At week 24, HIV-1 RNA or = 0.29 to +0.18, p = 1.000). At week 24, median CD4+ cell count change from baseline was +26 cells/mm3 for the QD arm and -39 cells/mm3 for BID arm. One patient randomized to the QD arm met virologic failure criteria (confirmed HIV-1 RNA >120 copies/mL) at week 20 and viral genotype showed M184V. After failure, this patient revealed he never took EFV throughout the entire study after randomization, effectively receiving only abacavir/lamivudine/zidovudine qd alone. Median adherence was slightly higher in the QD arm, although both arms had broad variability and overlapping interquartile ranges. Adverse events were infrequent and occurred with similar frequency between arms; treatment-related adverse events were abdominal pain, flatulence, nausea, headache, and abnormal dreams (1 patient [3%] for each adverse event). No patients withdrew due to adverse events, and no abacavir hypersensitivity reactions were reported. In this pilot study of patients suppressed on abacavir/lamivudine/zidovudine bid plus EFV, 94% of participants switching to abacavir
Directory of Open Access Journals (Sweden)
Satoshi Takahashi
2014-04-01
Full Text Available To clarify the clinical efficacy of a single oral 2 g dose of azithromycin extended-release for heterosexual male patients with urethritis, and the current antimicrobial sensitivity of Neisseria gonorrhoeae to azithromycin, a prospective clinical trial was conducted from 2011–2013. In patients with gonococcal urethritis, the eradication rate was 90.9% (30 of 33. The susceptibility rates of isolated Neisseria gonorrhoeae strains to ceftriaxone, spectinomycin, cefixime and azithromycin were 100%, 100%, 95.3% (41/43 and 37.2% (16/43, respectively. In the patients with nongonococcal urethritis, the eradication rate was 90.0% (45 of 50. The microbiological eradication rates for the pathogens were 90.9% (30/33 for Neisseria gonorrhoeae, 91.5% (43/47 for Chlamydia trachomatis, 71.4% (5/7 for Mycoplasma genitalium, and 100% (13/13 for Ureaplasma urealyticum. The main adverse event was diarrhea and its manifestation rate was 35.2% (32 of 120. The symptom of diarrhea was mostly temporary and resolved spontaneously. The conclusion was that the treatment regimen with a single oral 2 g dose of azithromycin extended-release would be effective for patients with urethritis. However, the antimicrobial susceptibilities of Neisseria gonorrhoeae and Mycoplasma genitalium should be carefully monitored because of possible treatment failure.
Takahashi, Satoshi; Kiyota, Hiroshi; Ito, Shin; Iwasawa, Akihiko; Hiyama, Yoshiki; Uehara, Teruhisa; Ichihara, Koji; Hashimoto, Jiro; Masumori, Naoya; Sunaoshi, Kenichi; Takeda, Koichi; Suzuki, Nobukazu; Hosobe, Takahide; Goto, Hirokazu; Suzuki, Hidenori; Onodera, Shoichi
2014-04-02
To clarify the clinical efficacy of a single oral 2 g dose of azithromycin extended-release for heterosexual male patients with urethritis, and the current antimicrobial sensitivity of Neisseria gonorrhoeae to azithromycin, a prospective clinical trial was conducted from 2011-2013. In patients with gonococcal urethritis, the eradication rate was 90.9% (30 of 33). The susceptibility rates of isolated Neisseria gonorrhoeae strains to ceftriaxone, spectinomycin, cefixime and azithromycin were 100%, 100%, 95.3% (41/43) and 37.2% (16/43), respectively. In the patients with nongonococcal urethritis, the eradication rate was 90.0% (45 of 50). The microbiological eradication rates for the pathogens were 90.9% (30/33) for Neisseria gonorrhoeae, 91.5% (43/47) for Chlamydia trachomatis, 71.4% (5/7) for Mycoplasma genitalium, and 100% (13/13) for Ureaplasma urealyticum. The main adverse event was diarrhea and its manifestation rate was 35.2% (32 of 120). The symptom of diarrhea was mostly temporary and resolved spontaneously. The conclusion was that the treatment regimen with a single oral 2 g dose of azithromycin extended-release would be effective for patients with urethritis. However, the antimicrobial susceptibilities of Neisseria gonorrhoeae and Mycoplasma genitalium should be carefully monitored because of possible treatment failure.
Jaishankar, Dinesh; Buhrman, Jason S.; Valyi-Nagy, Tibor; Gemeinhart, Richard A.; Shukla, Deepak
2016-01-01
Purpose To prolong the release of a heparan sulfate binding peptide, G2-C, using a commercially available contact lens as a delivery vehicle and to demonstrate the ability of the released peptide to block herpes simplex virus-1 (HSV-1) infection using in vitro, ex vivo, and in vivo models of corneal HSV-1 infection. Methods Commercially available contact lenses were immersed in peptide solution for 5 days prior to determining the release of the peptide at various time points. Cytotoxicity of the released samples was determined by MTT and cell cycle analysis, and the functional activity of the released samples were assessed by viral entry, and viral spread assay using human corneal epithelial cells (HCE). The ability to suppress infection in human and pig cornea ex vivo and mouse in vivo models were also assessed. Results Peptide G2-C was released through the contact lens. Following release for 3 days, the peptide showed significant activity by inhibiting HSV-1 viral entry and spread in HCE cells. Significant suppression of infection was also observed in the ex vivo and in vivo experiments involving corneas. Conclusions Extended release of an anti–HS peptide through a commercially available contact lens can generate significant anti–HSV-1 activity and provides a new and effective way to control corneal herpes. PMID:26780322
Viability of bull semen extended with commercial semen extender ...
African Journals Online (AJOL)
Andrea Raseona
stored at 24 °C. Sperm motility parameters, morphology, and viability were analysed ... body size, slow average daily weight gain, decreased fertility, extended .... were determined by counting a total of 200 spermatozoa per each stained slide.
Safety Precautions for Total Release Foggers
Total release foggers, also known as bug bombs, are pesticide products containing aerosol propellants that release their contents at once to fumigate an area. They can pose a hazard if used incorrectly. Find safety information and videos on this page.
Rascol, O; Brooks, D J; Melamed, E; Oertel, W; Poewe, W; Stocchi, F; Tolosa, E
Rasagiline mesylate is a novel drug for Parkinson's disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinson's disease and motor fluctuations. In an 18-week, double-blind, multicentre (74 hospitals and academic centres in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline (231 individuals; 1 mg once daily), entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary outcome was change in total daily off-time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinson's disease rating scale (UPDRS) scores. Analysis was by intention to treat. 88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n=34) and adverse events (n=34). Both rasagiline and entacapone reduced mean daily off-time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4 h; p=0.0001, prasagiline and -0.72 entacapone vs -0.37 placebo; prasagiline reduces mean daily off-time and improves symptoms of Parkinson's disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.
Directory of Open Access Journals (Sweden)
Arasteh K
2009-05-01
Full Text Available Abstract Objectives To assess the efficacy and safety of a treatment switch from a twice-daily (BID regimen containing zidovudine (ZDV and lamivudine (3TC plus a third agent to a once daily (QD regimen containing the fixed-dose combination of tenofovir DF/emtricitabine (TDF/FTC, Truvada® plus a divergent third QD agent in HIV-1 infected patients. Methods Prospective, 48-week, non-randomised, single-group, open-label, study. Fifty-one patients on stable ZDV/3TC-containing HAART, with HIV-1 RNA 50 cells/μl, were switched to TDF/FTC plus a third agent. Plasma HIV-1 RNA, CD4+ and CD8+ T-cell counts were assessed at baseline and weeks 4, 12, 24, 36 and 48 post-switch. Results During the 48-week study, 10 patients discontinued prematurely, including three due to adverse events (AEs. At week 48, plasma HIV-1 RNA was p Conclusions Results from this study support switching from a ZDV/3TC-containing HAART regimen to a completely QD regimen of TDF/FTC plus a third agent. Virologic and immunologic control are maintained, with apparent benefits in haemoglobin.
Tramadol Extended-Release for the Management of Pain due to Osteoarthritis
Guetti, Cristiana; Paladini, Antonella; Varrassi, Giustino
2013-01-01
Current knowledge on pathogenesis of osteoarticular pain, as well as the consequent several, especially on the gastrointestinal, renal, and cardiovascular systems, side effects of NSAIDs, makes it difficult to perform an optimal management of this mixed typology of pain. This is especially observable in elderly patients, the most frequently affected by osteoarthritis (OA). Tramadol is an analgesic drug, the action of which has a twofold action. It has a weak affinity to mu opioid receptors and, at the same time, can result in inhibition of the reuptake of noradrenaline and serotonin in nociceptorial descending inhibitory control system. These two mechanisms, “opioidergic” and “nonopioidergic,” are the grounds for contrasting certain types of pain that are generally less responsive to opioids, such as neuropathic pain or mixed OA pain. The extended-release formulation of tramadol has good efficacy and tolerability and acts through a dosing schedule that allows a high level of patients compliance to therapies with a good recovery outcome for the patients' functional status. PMID:27335872
Single-use autoinjector for once-weekly intramuscular injection of IFNβ-1a.
Limmroth, Volker; Gerbershagen, Kathrin
2014-12-01
IFNβ products and glatiramer acetate are established treatment first-line options in long-term disease-modifying therapy of multiple sclerosis (MS). These self-injectable medications are used once weekly to once daily. Injection-related issues are common patient-cited reasons for nonadherence. Autoinjectors have been shown to support long-term adherence to injectable medications. The ability to self-inject in MS patients has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patient independence. The recently introduced easy-to-use prefilled once-weekly pen is a safe and effective device for intramuscular (IM) IFNβ-1a application and provides a convenient method for self-injection. We reviewed the available published evidence on the characteristics of this device. The once-weekly pen facilitates self-injection and was preferred over prefilled syringes by patients in a prospective open-label, multicenter Phase IIIb trial in MS patients who had been using IM IFNβ-1a in prefilled syringes. The simple and safe handling, shielded short needle, single-use disposable design and virtually painless injection by the device may contribute to adherence, quality of life and independence in patients using IM IFNβ-1a.
North, James M; Hong, Kyung-Soo J; Rauck, Richard L
2016-07-01
We assessed the efficacy and safety of extended-release gabapentin in a 15-week, open-label, single-arm, single-center study in patients with fibromyalgia (FM). Subjects with documented diagnosis of FM were allowed to participate in the study. We opened enrollment to those who have tried and failed gabapentinoids such as gabapentin or pregabalin due to side effects. Subjects with autoimmune conditions, and or taking opioids for management of their FM pain, were excluded from the study. Subjects were given an extended-release gabapentin starter pack and treated for total of 12 weeks. The primary study endpoint of pain relief was measured using Numeric Pain Rating System (NPRS) scores, and secondary study endpoints were measured with Fibromyalgia Impact Questionnaire (FIQ), Patient's Global Impression of Change (PGIC), and Medical Outcome Sleep questionnaires (MOS). A total of 34 subjects were enrolled and 29 subjects completed the starter pack (85%). Patients reported significant pain relief on NPRS by end of 4 weeks (P life by end of 4 weeks on FIQ (P quality. Improvements in primary and secondary measurements were reflected in PGIC, with significant improvement in patient's impression of FM by week 8. Small sample size, geographical bias, relatively short duration of treatment, and single-arm study without control group. Extended-release gabapentin relieved FM pain symptoms and improved quality-of-life for the FM subjects studied. Subjects reported improvements in both quantity and quality of sleep. © 2015 World Institute of Pain.
A flexible-dose dispenser for immediate and extended release 3D printed tablets.
Pietrzak, Katarzyna; Isreb, Abdullah; Alhnan, Mohamed A
2015-10-01
The advances in personalised medicine increased the demand for a fast, accurate and reliable production method of tablets that can be digitally controlled by healthcare staff. A flexible dose tablet system is presented in this study that proved to be suitable for immediate and extended release tablets with a realistic drug loading and an easy-to-swallow tablet design. The method bridges the affordable and digitally controlled Fused Deposition Modelling (FDM) 3D printing with a standard pharmaceutical manufacturing process, Hot Melt Extrusion (HME). The reported method was compatible with three methacrylic polymers (Eudragit RL, RS and E) as well as a cellulose-based one (hydroxypropyl cellulose, HPC SSL). The use of a HME based pharmaceutical filament preserved the linear relationship between the mass and printed volume and was utilized to digitally control the dose via an input from computer software with dose accuracy in the range of 91-95%. Higher resolution printing quality doubled the printing time, but showed a little effect on in vitro release pattern of theophylline and weight accuracy. Physical characterization studies indicated that the majority of the model drug (theophylline) in the 3D printed tablet exists in a crystal form. Owing to the small size, ease of use and the highly adjustable nature of FDM 3D printers, the method holds promise for future individualised treatment. Copyright © 2015. Published by Elsevier B.V.
Sakurai, Miyuki; Naruto, Ikue; Matsuyama, Kenji
2008-05-01
Many generic drugs have been released to decrease medical expenses, but some problems have been reported with regard to bioavailability and safety. In this study, we compared three once-a-day controlled-release preparations of nifedipine by the dissolution test (one branded and two generic preparations). Although the two generic drugs were equivalent to the branded drug according to the criteria listed in the Japanese "Guideline for Bioequivalence Studies of Generic Products", there was still a possibility of problems arising. For example, side effects could be caused by a rapid increase in the blood level of nifedipine with one generic drug, while bioavailability might be inadequate with the other due to its small area under the concentration vs. time curve. When each drug was prescribed at a dosage of 20 mg once daily for two weeks, the difference in the copayment for the patient was only 10 yen. Accordingly, it is important for doctors and pharmacists to carefully consider whether such a slight difference in price is really a benefit for the patient.
Film Coating of Nifedipine Extended Release Pellets in a Fluid Bed Coater with a Wurster Insert
Directory of Open Access Journals (Sweden)
Luciane Franquelin Gomes de Souza
2014-01-01
Full Text Available The objective of this work was to study the coating process of nifedipine extended release pellets using Opadry and Opadry II, in a fluid bed coater with a Wurster insert. The coating process was studied using a complete experimental design of two factors at two levels for each polymer. The variables studied were the inlet air temperature and the coating suspension flow rate. The agglomerate fraction and coating efficiency were the analyzed response variables. The air temperature was the variable that most influenced the coating efficiency for both polymers. In addition, a study of the dissolution profiles of coated and uncoated pellets using 0.5% sodium lauryl sulfate in simulated gastric fluid without enzymes (pH 1.2 was conducted. The results showed a prolonged release profile for the coated and uncoated pellets that was very similar to the standards established by the U.S. Pharmacopoeia. The drug content and the release profiles were not significantly affected by storage at 40°C and 75% relative humidity. However, when exposed to direct sunlight and fluorescent light (light from fluorescent bulbs, the coated pellets lost only 5% of the drug content, while the uncoated ones lost more than 35%; furthermore, the dissolution profile of the uncoated pellets was faster.
Film Coating of Nifedipine Extended Release Pellets in a Fluid Bed Coater with a Wurster Insert
de Souza, Luciane Franquelin Gomes; Nitz, Marcello; Taranto, Osvaldir Pereira
2014-01-01
The objective of this work was to study the coating process of nifedipine extended release pellets using Opadry and Opadry II, in a fluid bed coater with a Wurster insert. The coating process was studied using a complete experimental design of two factors at two levels for each polymer. The variables studied were the inlet air temperature and the coating suspension flow rate. The agglomerate fraction and coating efficiency were the analyzed response variables. The air temperature was the variable that most influenced the coating efficiency for both polymers. In addition, a study of the dissolution profiles of coated and uncoated pellets using 0.5% sodium lauryl sulfate in simulated gastric fluid without enzymes (pH 1.2) was conducted. The results showed a prolonged release profile for the coated and uncoated pellets that was very similar to the standards established by the U.S. Pharmacopoeia. The drug content and the release profiles were not significantly affected by storage at 40°C and 75% relative humidity. However, when exposed to direct sunlight and fluorescent light (light from fluorescent bulbs), the coated pellets lost only 5% of the drug content, while the uncoated ones lost more than 35%; furthermore, the dissolution profile of the uncoated pellets was faster. PMID:24772426
Gu, Shuyan; Wang, Xiaoyong; Qiao, Qing; Gao, Weiguo; Wang, Jian; Dong, Hengjin
2017-12-01
To estimate the long-term cost-effectiveness of exenatide twice daily vs insulin glargine once daily as add-on therapy to oral antidiabetic agents (OADs) for Chinese patients with type 2 diabetes (T2DM). The Cardiff Diabetes Model was used to simulate disease progression and estimate the long-term effects of exenatide twice daily vs insulin glargine once daily. Patient profiles and treatment effects required for the model were obtained from literature reviews (English and Chinese databases) and from a meta-analysis of 8 randomized controlled trials comparing exenatide twice daily with insulin glargine once daily add-on to OADs for T2DM in China. Medical expenditure data were collected from 639 patients with T2DM (aged ≥18 years) with and without complications incurred between January 1, 2014 and December 31, 2015 from claims databases in Shandong, China. Costs (2014 Chinese Yuan [¥]) and benefits were estimated, from the payers' perspective, over 40 years at a discount rate of 3%. A series of sensitivity analyses were performed. Patients on exenatide twice daily + OAD had a lower predicted incidence of most cardiovascular and hypoglycaemic events and lower total costs compared with those on insulin glargine once daily + OAD. A greater number of quality-adjusted life years (QALYs; 1.94) at a cost saving of ¥117 706 gained was associated with exenatide twice daily vs insulin glargine once daily. (i.e. cost saving of ¥60 764/QALY) per patient. In Chinese patients with T2DM inadequately controlled by OADs, exenatide twice daily is a cost-effective add-on therapy alternative to insulin glargine once daily, and may address the problem of an excess of medical needs resulting from weight gain and hypoglycaemia in T2DM treatment. © 2017 John Wiley & Sons Ltd.
Directory of Open Access Journals (Sweden)
Vladimir Skljarevski
2012-01-01
Full Text Available We summarize efficacy and safety findings from 4 double-blind, placebo-controlled, 12-week studies and 1 open-label, uncontrolled, 34-week maintenance-of-effect (MOE study that examine duloxetine 40 and 60 mg once daily (QD in patients with diabetic peripheral neuropathic pain (DPNP. In all placebo-controlled studies, duloxetine showed significantly (P≤.01 greater reduction in pain severity (weekly mean of 24-hour average pain severity ratings, primary outcome measure compared with placebo. In all placebo-controlled studies, duloxetine showed significantly (P≤.05 greater improvement on brief pain inventory-Interference ratings. Patient global impression of improvement ratings were superior to placebo (P≤.01 for duloxetine patients in all placebo-controlled studies. Response rates (based on 30% pain reduction ranged from 57% to 68% for duloxetine and from 35% to 47% for placebo and were statistically significantly different (P≤.01 between treatment groups in 3 out of 4 studies. The open-label study showed maintenance of analgesic effect of duloxetine in DPNP. In the duloxetine groups, 4.3% to 14.9% of patients discontinued because of adverse events (placebo groups: 2.6% to 7.4%. Most commonly reported treatment-emergent adverse events were nausea, somnolence, and headache. Duloxetine 40 and 60 mg QD was efficacious and well tolerated in the management of DPNP.
Whitaker, Martin; Debono, Miguel; Huatan, Hiep; Merke, Deborah; Arlt, Wiebke; Ross, Richard J
2014-04-01
It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology. Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population. Field laboratories and clinical research facility. Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily 'toothbrush' regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg. A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a 'toothbrush' regimen provides physiological cortisol exposure. © 2013 John Wiley & Sons Ltd.
Riederer, A; Zini, E; Salesov, E; Fracassi, F; Padrutt, I; Macha, K; Stöckle, T M; Lutz, T A; Reusch, C E
2016-01-01
Exenatide extended release (ER) is a glucagon-like peptide-1 analogue that increases insulin secretion, inhibits glucagon secretion and induces satiation in humans with type 2 diabetes mellitus. The use of exenatide ER is safe and stimulates insulin secretion in healthy cats. The objective of this study is to assess the safety of exenatide ER and its effect on body weight, remission and metabolic control in newly diagnosed diabetic cats receiving insulin and a low-carbohydrate diet. Thirty client-owned cats. Prospective placebo-controlled clinical trial. Cats were treated with exenatide ER or 0.9% saline, administered SC, once weekly. Both groups received insulin glargine and a low-carbohydrate diet. Exenatide ER was administered for 16 weeks, or in cats that achieved remission it was given for 4 weeks after discontinuing insulin treatment. Nonparametric tests were used for statistical analysis. Cats in the exenatide ER and placebo groups had transient adverse signs including decreased appetite (60% vs. 20%, respectively, P = .06) and vomiting (53% vs. 40%, respectively, P = .715). Body weight increased significantly in the placebo group (P = .002), but not in cats receiving exenatide ER. Cats on exenatide ER achieved remission or good metabolic control in 40% or 89%, respectively, whereas in control cats percentages were 20% or 58% (P = .427 and P = .178, respectively). Exenatide ER is safe in diabetic cats and does not result in weight gain. Our pilot study suggests that, should there be an additional clinically relevant beneficial effect of exenatide ER in insulin-treated cats on rate of remission and good metabolic control, it would likely approximate 20% and 30%, respectively. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
DEFF Research Database (Denmark)
Nilsson, Lena; Andersen, A.N.; Lindenberg, Svend
2010-01-01
To enhance oocyte yield and pregnancy outcome in poor responder women undergoing IVF treatment, daily low dose GnRH antagonist administration was given during the late luteal phase to induce luteolysis and possibly secure a more synchronous cohort of recruitable follicles. An open extended pilot...... study in four Scandinavian fertility centers was done including 60 patients. Poor response was defined as when 2000 IU FSH. GnRH antagonist (ganirelix) was given, 0.25 mg s.c. daily, from days 3 to 5...... oocyte retrievals resulting in 5 pregnancies (4 delivered). Despite GnRH antagonist administration in the late luteal phase and menstrual bleeding, FSH was not sufficiently reduced to secure a more synchronic cohort of recruitable follicles. Novel GnRH antagonists more specifically targeting FSH release...
International Nuclear Information System (INIS)
Barboza, Fernanda M.; Vecchia, Debora D.; Tagliari, Monika P.; Ferreira, Andrea Granada; Silva, Marcos A.S.; Stulzer, Hellen K.
2009-01-01
Acyclovir (ACV) has been investigated during the past years, mainly due to its antiviral activity. Assessment of possible incompatibility between an active component and different excipients along with the evaluation of thermal stability are crucial parts of a normal study prior to the final formulation setting of a medicine. Thermal analysis studies were used as important and complementary tools during pre-formulation to determine the compatibility of drug excipients with the purpose of developing an acyclovir extended release formulation. Fourier transform infrared spectroscopy and X-ray powder diffraction analyses were also realized. The results showed that ACV only exhibited interaction which could influence the stability of the product in the binary mixtures of ACV/magnesium stearate. (author)
Hawi, Amale; Alcorn, Harry; Berg, Jolene; Hines, Carey; Hait, Howard; Sciascia, Thomas
2015-04-08
Uremic pruritus is a common and deleterious condition among hemodialysis (HD) patients. Central gating of μ/κ opiate circuitry plays an important role in mediating and countering pruritogenic sensation. The objective of this study was to assess the safety and pharmacokinetics (PK) of the mixed μ-antagonist/κ-agonist nalbuphine, administered orally as nalbuphine HCl extended release (ER) tablets in HD patients, and explore its effect on pruritus. In this open-label multiple escalating dose study, 15 HD patients with pruritus and 9 matched healthy subjects were enrolled. Nalbuphine HCl ER dose was escalated from 30 mg QD to 240 mg BID over 15 days. A full PK profile was obtained under dialysis and non-dialysis conditions as a function of dose. Clearance during dialysis was determined by sampling dialysate and arterial/venous blood during dialysis. Pruritus severity was assessed twice daily using a Visual Analog Scale (VAS). Safety monitoring included extensive monitoring of EKG, blood pressure, and pulse oximetry. In HD patients, nalbuphine concentration peaked within 4-9 hours and attained steady state within 2-3 days, with no significant accumulation. Mean half-life was 14.2 hours, mean Cmax and AUCtau ranged between 13 and 83 ng/mL and 118 and 761 ng∙h/mL, respectively, with exposure increasing in a nearly dose-proportional fashion. Exposure in HD patients was about 2-fold higher than in healthy subjects. There was no meaningful difference between exposure on dialysis and non-dialysis days with 1% or less of the dose removed by dialysis. Nalbuphine suppressed itch in a dose-dependent manner, reducing mean VAS score from 4.0 to 1.2 at 180 mg and 0.4 at 240 mg. Nalbuphine HCl ER tablets can be safely administered to HD patients without dose adjustment up to 240 mg BID and may hold promise in treating uremic pruritus.
Christensen, Steven; Paluch, Ed; Jayawardena, Shyamalie; Daniels, Stephen; Meeves, Suzanne
2017-05-01
Analgesic effects of ibuprofen immediate-release/extended-release (IR/ER) 600-mg tablets were evaluated in 2 randomized, double-blind, placebo-controlled dental pain studies. Patients 16-40 years old with moderate-severe pain following third-molar extraction received single-dose ibuprofen 600 mg IR/ER (formulation A or B), naproxen sodium 220 mg, or placebo (2:2:2:1; study 1) or 4 doses of ibuprofen 600 mg IR/ER (formulation A) or placebo (1:1; study 2). In study 1 (n = 196), mean (standard deviation [SD]) time-weighted sum of pain intensity difference scores for placebo, ibuprofen IR/ER A, ibuprofen IR/ER B, and naproxen, respectively, were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) over 0-12 hours and -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) over 8-12 hours (all P ibuprofen IR/ER, respectively (P ibuprofen. Gastrointestinal adverse events predominated with placebo both after study medication administration and after rescue medication use, if applicable. Ibuprofen 600 mg IR/ER provided safe and effective analgesia after single and multiple doses. © 2016, The American College of Clinical Pharmacology.
Delea, Thomas E; Sofrygin, Oleg; Thomas, Simu K; Baladi, Jean-Francois; Phatak, Pradyumna D; Coates, Thomas D
2007-01-01
Deferasirox is a recently approved once-daily oral iron chelator that has been shown to reduce liver iron concentrations and serum ferritin levels to a similar extent as infusional deferoxamine. To determine the cost effectiveness of deferasirox versus deferoxamine in patients with beta-thalassaemia major from a US healthcare system perspective. A Markov model was used to estimate the total additional lifetime costs and QALYs gained with deferasirox versus deferoxamine in patients with beta-thalassaemia major and chronic iron overload from blood transfusions. Patients were assumed to be 3 years of age at initiation of chelation therapy and to receive prescribed dosages of deferasirox and deferoxamine that have been shown to be similarly effective in such patients. Compliance with chelation therapy and probabilities of iron overload-related cardiac disease and death by degree of compliance were estimated using data from published studies. Costs ($US, year 2006 values) of deferoxamine administration and iron overload-related cardiac disease were based on analyses of health insurance claims of transfusion-dependent thalassaemia patients. Utilities were based on a study of patient preferences for oral versus infusional chelation therapy, as well as published literature. Probabilistic and deterministic sensitivity analyses were employed to examine the robustness of the results to key assumptions. Deferasirox resulted in a gain of 4.5 QALYs per patient at an additional expected lifetime cost of $US126,018 per patient; the cost per QALY gained was $US28,255. The cost effectiveness of deferasirox versus deferoxamine was sensitive to the estimated costs of deferoxamine administration and the quality-of-life benefit associated with oral versus infusional therapy. Cost effectiveness was also relatively sensitive to the equivalent daily dose of deferasirox, and the unit costs of deferasirox and deferoxamine, and was more favourable in younger patients. Results of this analysis
Akhlaq, Muhammad; Khan, Gul Majid; Jan, Syed Umer; Wahab, Abdul; Hussain, Abid; Nawaz, Asif; Abdelkader, Hamdy
2014-11-01
Diclofenac sodium (DCL-Na) conventional oral tablets exhibit serious side effects when given for a longer period leading to noncompliance. Controlled release matrix tablets of diclofenac sodium were formulated using simple blending (F-1), solvent evaporation (F-2) and co-precipitation techniques (F-3). Ethocel® Standard 7 FP Premium Polymer (15%) was used as a release controlling agent. Drug release study was conducted in 7.4 pH phosphate buffer solutions as dissolution medium in vitro. Pharmacokinetic parameters were evaluated using albino rabbits. Solvent evaporation technique was found to be the best release controlling technique thereby prolonging the release rate up to 24 hours. Accelerated stability studies of the optimized test formulation (F-2) did not show any significant change (prelease rate when stored for six months. A simple and rapid method was developed for DCL-Na active moiety using HPLC-UV at 276nm. The optimized test tablets (F-2) significantly (prelease. The study showed that once-daily controlled release matrix tablets of DCL-Na were successfully developed using Ethocel® Standard 7 FP Premium.
Schnadig, Ian D; Agajanian, Richy; Dakhil, Christopher; Gabrail, Nashat Y; Smith, Robert E; Taylor, Charles; Wilks, Sharon T; Schwartzberg, Lee S; Cooper, William; Mosier, Michael C; Payne, J Yvette; Klepper, Michael J; Vacirca, Jeffrey L
2016-06-01
APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen. HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication). A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions. APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.
76 FR 6794 - 30-Day Submission Period for Requests for ONC-Approved Accreditor (ONC-AA) Status
2011-02-08
... Accreditor (ONC-AA) Status AGENCY: Office of the National Coordinator for Health Information Technology... submission of requests for ONC-Approved Accreditor (ONC-AA) status. Authority: 42 U.S.C. 300jj-11. DATES: The... for ONC-AA status may be submitted. The 30-day period for submission of requests for ONC-AA status...
Huatan, Hiep; Merke, Deborah; Arlt, Wiebke; Ross, Richard J.
2013-01-01
Objective It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multi-particulate technology. Design and Measurements Screening by in-vitro dissolution profiles, pharmacokinetic testing in dexamethasone suppressed dogs and humans, and comparison to a reference population. Setting Field laboratories and clinical research facility. Results Formulations were generated using an enteric (delayed-release) design configuration with an extended (sustained-release) dissolution profile. In-vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained release functionality. Pharmacokinetic characterisation of DIURF-006 showed that, despite absence of a sustained release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n=16) receiving a twice daily ‘toothbrush’ regimen (20mg at 23:00h and 10mg at 07:00h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 hr*nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8.5h vs clock time 08:12 hours for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89% and cortisol levels increased linearly with doses between 5 and 30mg. Conclusion A multi-particulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a ‘toothbrush’ regimen provides physiological cortisol exposure. PMID:23980724
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism
DEFF Research Database (Denmark)
Weitz, Jeffrey I; Lensing, Anthonie W A; Prins, Martin H
2017-01-01
BACKGROUND: Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin. METHODS: In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous...... thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months...... in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio...
Kim, Edward; Seftel, Allen; Goldfischer, Evan; Baygani, Simin; Burns, Patrick
2015-02-01
Phosphodiesterase type-5 inhibitors (PDE5Is) are first-line therapies for erectile dysfunction (ED). Sildenafil (SIL) and vardenafil (VAR) are approved for as-needed (PRN) dosing; tadalafil (TAD) is approved for both PRN and once-a-day (OaD) dosing for ED. Recent evidence suggests that TAD-OaD may be effective as therapy in men with an incomplete response to PRN-PDE5I therapy. This study evaluated whether TAD-OaD provides similar efficacy in men with ED who had previously demonstrated a partial response to PRN-PDE5I therapy. In this randomized, double-blind, placebo-controlled trial, men with a ≥3 month ED history received SIL 100 mg, TAD 20 mg, or VAR 20 mg during a 4 week open-label lead-in period. Those with International Index of Erectile Function - Erectile Function (IIEF-EF) domain scores TAD 2.5 mg up-titrated to 5 mg, TAD 5 mg, or placebo (PBO) OaD for 12 weeks. MAIN OUTCOME MEASURES obtained from patients treated with TAD-OaD were compared to PBO-treated patients. Additionally, results of treatment with TAD-OaD were compared to results obtained from 4 week PRN-PDE5I therapy to determine whether OaD and PRN regimens provided comparable efficacy. NCT01130532. International Index of Erectile Function (IIEF) domain scores; Sexual Encounter Profile (SEP) questions 2-5. Endpoint data was obtained from 590 men (391 TAD; 199 PBO). RESULTS for all IIEF and SEP measures were significantly better for TAD-OaD (p TAD 2.5 mg and TAD 5 mg OaD therapy were safe and generally well tolerated. Tadalafil once daily is a viable alternative to as-needed PDE5I therapy in men with ED. Key limitations include the lack of a PRN PDE5I study group during the double-blind period, and that many more patients took tadalafil than sildenafil or vardenafil during the PRN period.
Chime, Salome Amarachi; Attama, Anthony Amaechi; Builders, Philip F; Onunkwo, Godswill C
2013-01-01
To formulate sustained-release diclofenac potassium-loaded solid lipid microparticles (SLMs) based on solidified reverse micellar solution (SRMS) and to evaluate the in vitro and in vivo properties. SRMS consisting of mixtures of Phospholipon® 90H and Softisan® 154 were used to formulate diclofenac potassium-loaded SLMs. Characterization based on the particle size and morphology, stability and encapsulation efficiency (EE%) were carried out on the SLMs. In vitro release was carried out in simulated intestinal fluid (pH 7.5). Anti-inflammatory and ulcerogenic properties were studied using rats. Maximum EE% of 95%, 94% and 93% were obtained for SLMs formulated with SRMS 1:1, 2:1 and 1:2, respectively. In vitro release showed about 85-90% drug release at 13 h. Diclofenac potassium-loaded SLMs showed good anti-inflammatory and gastro-protective properties. Diclofenac potassium-loaded SLMs based on SRMS could be used orally or parenterally under controlled conditions, for once daily administration.
Kay, J K; Phyn, C V C; Rius, A G; Morgan, S R; Grala, T M; Roche, J R
2013-10-01
The objective of this study was to investigate the effect of milking frequency (MF) at 2 feeding levels (FL) on milk production, body condition score, and metabolic indicators of energy status in grazing dairy cows during early lactation. Multiparous Holstein-Friesian and Holstein-Friesian × Jersey cows (n=120) grazed pasture and were milked twice daily (2×) from calving until 34 ± 6 d in milk (mean ± standard deviation). Cows were then allocated to 1 of 4 treatments in a 2 × 2 factorial arrangement. Treatments consisted of 2 FL: adequately fed [AF; 14.3 kg dry matter intake (DMI)/cow per d] or underfed (UF; 8.3 kg of DMI/cow per d) and 2 MF: 2× or once daily (1×). Treatments were imposed for 3 wk. After the treatment period, all cows were offered a generous pasture allowance (grazing residuals >1,600 kg of dry matter/ha) and milked 2×. During the 3-wk treatment period, we observed an interaction between FL and MF for energy-corrected milk (ECM), such that the decrease due to 1× milking was greater in AF than in UF cows (20 and 14% decrease, respectively). No interactions were found posttreatment. Cows previously UF produced 7% less ECM than AF cows during wk 4 to 12; however, no subsequent effect was observed of the previous underfeeding. Cows previously milked 1× produced 5% less ECM during wk 4 to 12, and differences remained during wk 13 to 23. During the 3-wk treatment period, UF cows lost 0.2 body condition score units (1-10 scale) and this was not affected by 1× milking. During the treatment period, UF cows had lower plasma glucose, insulin, and insulin-like growth factor I, and greater nonesterified fatty acids and β-hydroxybutyrate concentrations than AF cows. Cows milked 1× had greater plasma glucose, insulin, and insulin-like growth factor I, and lower nonesterified fatty acids and β-hydroxybutyrate concentrations compared with cows milked 2×. In conclusion, energy status was improved by 1× milking; however, when UF cows were milked 1
Johannsson, G; Nilsson, A G; Bergthorsdottir, R; Burman, P; Dahlqvist, P; Ekman, B; Engström, B E; Olsson, T; Ragnarsson, O; Ryberg, M; Wahlberg, J; Biller, B M K; Monson, J P; Stewart, P M; Lennernäs, H; Skrtic, S
2012-02-01
Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile. The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets. We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers. The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM). The same daily dose of hydrocortisone was administered as OD dual-release or TID. We evaluated cortisol pharmacokinetics. Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004). The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.
Efficacy of Tramadol Extended-Release for Opioid Withdrawal: A Randomized Clinical Trial.
Dunn, Kelly E; Tompkins, D Andrew; Bigelow, George E; Strain, Eric C
2017-09-01
Opioid use disorder (OUD) is a significant public health problem. Supervised withdrawal (ie, detoxification) from opioids using clonidine or buprenorphine hydrochloride is a widely used treatment. To evaluate whether tramadol hydrochloride extended-release (ER), an approved analgesic with opioid and nonopioid mechanisms of action and low abuse potential, is effective for use in supervised withdrawal settings. A randomized clinical trial was conducted in a residential research setting with 103 participants with OUD. Participants' treatment was stabilized with morphine, 30 mg, administered subcutaneously 4 times daily. A 7-day taper using clonidine (n = 36), tramadol ER (n = 36), or buprenorphine (n = 31) was then instituted, and patients were crossed-over to double-blind placebo during a post-taper period. The study was conducted from October 25, 2010, to June 23, 2015. Retention, withdrawal symptom management, concomitant medication utilization, and naltrexone induction. Results were analyzed over time and using area under the curve for the intention-to-treat and completer groups. Of the 103 participants, 88 (85.4%) were men and 43 (41.7%) were white; mean (SD) age was 28.9 (10.4) years. Buprenorphine participants (28 [90.3%]) were significantly more likely to be retained at the end of the taper compared with clonidine participants (22 [61.1%]); tramadol ER retention was intermediate and did not differ significantly from that of the other groups (26 [72.2%]; χ2 = 8.5, P = .01). Time-course analyses of withdrawal revealed significant effects of phase (taper, post taper) for the Clinical Opiate Withdrawal Scale (COWS) score (taper mean, 5.19 [SE, .26]; post-taper mean, 3.97 [SE, .23]; F2,170 = 3.6, P = .03) and Subjective Opiate Withdrawal Scale (SOWS) score (taper mean,8.81 [SE, .40]; post-taper mean, 4.14 [SE, .30]; F2,170 = 15.7, P withdrawal severity between the taper and post-taper periods for clonidine (taper mean, 13.1; post
Lê, Minh P; Mandelbrot, Laurent; Descamps, Diane; Soulié, Cathia; Ichou, Houria; Bourgeois-Moine, Agnès; Damond, Florence; Lariven, Sylvie; Valantin, Marc-Antoine; Landman, Roland; Faucher, Philippe; Tubiana, Roland; Duro, Dominique; Meier, Françoise; Legac, Sylvie; Bourse, Patricia; Mortier, Emmanuel; Dommergues, Marc; Calvez, Vincent; Matheron, Sophie; Peytavin, Gilles
2015-01-01
Atazanavir/ritonavir (ATV/r) is a boosted protease inhibitor recommended to minimize the risk of mother-to-child HIV-1 transmission (MTCT). We aimed to assess the pharmacokinetics, safety and efficacy of ATV/r in HIV-1-infected pregnant women and their neonates. A multicentre, cross-sectional, non-interventional cohort of HIV-1-infected pregnant women receiving ATV/r (300/100 mg once daily) who delivered in three Paris hospitals from 2006 to 2013 was designed. We determined antiretroviral trough plasma concentrations using liquid chromatography-mass spectrometry at each of the three trimesters, delivery and post-partum. ATV concentrations at 24 h (C24h) were interpreted by the 150-850 ng/ml efficacy-tolerance thresholds. Safety data and newborn HIV status were recorded. A mother's virological failure was defined as two successive measurements of plasma HIV-1 RNA>50 copies/ml within the 2 months before delivery. 103 pregnant women were included, mostly from sub-Saharan Africa (88%). ATV C24h at each of the three trimesters and delivery remained similar to post-partum values. No dose adjustment was needed during pregnancy. The median plasma ratio of fetal/maternal ATV level was 0.19 (n=28). Only three patients showed two successive detectable viral loads but <400 copies/ml. Among 82 available newborn data, 16 were born preterm. Three in utero deaths occurred. Tolerance was good with one case of maternal grade 3 hyperbilirubinaemia, no cases in neonates at delivery and no clinically relevant adverse event. No case of MTCT was reported. In this population, an ATV/r-containing antiretroviral regimen demonstrated good pharmacokinetics, virological efficacy and safety. No significant impact of pregnancy on ATV C24h was found. No dose adjustment was required.
Scheduling reinforcement about once a day.
Eckerman, D A
1999-04-01
A pigeon earned its daily food by pecking a key according to reinforcement schedules that produced food about once per day. Fixed-interval (FI), Fixed-time (FT), and various complex schedules were arranged to demonstrate the degree to which a scalloped pattern of responding remained. Pausing continued until about an hour before the reinforcer could be earned for FIs of 12, 24, and 48 h. Pausing was not as long for FIs of 18, 19, and 23 h. Pausing of about 24 h was seen for FI 36 h. FT 24 h produced continued responding but at a diminished frequency. The pattern of responding was strongly controlled by the schedule of reinforcement and seemed relatively independent of the cycle of human activity in the surrounding laboratory. Effects of added ratio contingencies and of signaling the availability of reinforcement in FT were also examined. Signaled FTs of 5 min-3 h produced more responding during the signal (autoshaping) than did FTs of 19 or 24 h.
Directory of Open Access Journals (Sweden)
Chinhwa Cheng
2014-06-01
Full Text Available The objective of this study was to develop an in vitro–in vivo correlation (IVIVC model for hydrophilic matrix extended-release (ER propranolol dosage formulations. The in vitro release characteristics of the drug were determined using USP apparatus I at 100 rpm, in a medium of varying pH (from pH 1.2 to pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in male beagle dogs were obtained after administering oral, ER formulations and immediate-release (IR commercial products. The similarity factor f2 was used to compare the dissolution data. The IVIVC model was developed using pooled fraction dissolved and fraction absorbed of propranolol ER formulations, ER-F and ER-S, with different release rates. An additional formulation ER-V, with a different release rate of propranolol, was prepared for evaluating the external predictability. The results showed that the percentage prediction error (%PE values of Cmax and AUC0–∞ were 0.86% and 5.95%, respectively, for the external validation study. The observed low prediction errors for Cmax and AUC0–∞ demonstrated that the propranolol IVIVC model was valid.
Directory of Open Access Journals (Sweden)
Muduma G
2014-03-01
Full Text Available Gorden Muduma,1 Isaac Odeyemi,1 Jayne Smith-Palmer,2 Richard F Pollock21Astellas Pharma Europe, Chertsey, UK; 2Ossian Health Economics and Communications, Basel, SwitzerlandBackground and aims: Advagraf is a once-daily prolonged-release formulation of tacrolimus with proven noninferiority to Prograf, a twice-daily immediate-release formulation of tacrolimus, in biopsy-proven acute rejection, graft survival and patient survival in renal transplant recipients. Advagraf is associated with improved adherence compared with Prograf, which may ultimately improve long-term outcomes. The present study assessed the budget impact of switching patients from Prograf to Advagraf in the UK.Materials and methods: A budget-impact model was constructed based on published data on acute rejection, graft failure, and mortality in the UK setting. Patients were assumed to convert from Prograf to Advagraf on a 1:1 milligram:milligram basis. In a study comparing the adherence rates between once-daily versus twice-daily formulations of tacrolimus, the proportion of patients taking the prescribed number of daily doses was 88.2% in Advagraf patients and 78.8% in Prograf patients. The model applied a relative risk of graft failure of 3.47 to nonadherent patients based on data from a 2004 meta-analysis (based on graft-failure rates of 1.3%–40.0% in adherent patients, compared with 6.1%–100% in nonadherent patients. Cost data were taken from the March 2013 British National Formulary and 2012–2013 National Health Service tariff information. The analysis was performed over a 5-year time horizon and future costs were not discounted, in line with International Society for Pharmacoeconomics and Outcomes Research guidelines.Results: Over a 5-year time horizon, the mean cost per patient (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection was £29,328 (standard deviation [SD] £2,844 for Advagraf
Extended release of hyaluronic acid from hydrogel contact lenses for dry eye syndrome.
Maulvi, Furqan A; Soni, Tejal G; Shah, Dinesh O
2015-01-01
Current dry eye treatment includes delivering comfort enhancing agents to the eye via eye drops, but low residence time of eye drops leads to low bioavailability. Frequent administration leads to incompliance in patients, so there is a great need for medical device such as contact lenses to treat dry eye. Studies in the past have demonstrated the efficacy of hyaluronic acid (HA) in the treatment of dry eyes using eye drops. In this paper, we present two methods to load HA in hydrogel contact lenses, soaking method and direct entrapment. The contact lenses were characterized by studying their optical and physical properties to determine their suitability as extended wear contact lenses. HA-laden hydrogel contact lenses prepared by soaking method showed release up to 48 h with acceptable physical and optical properties. Hydrogel contact lenses prepared by direct entrapment method showed significant sustained release in comparison to soaking method. HA entrapped in hydrogels resulted in reduction in % transmittance, sodium ion permeability and surface contact angle, while increase in % swelling. The impact on each of these properties was proportional to HA loading. The batch with 200-μg HA loading showed all acceptable values (parameters) for contact lens use. Results of cytotoxicity study indicated the safety of hydrogel contact lenses. In vivo pharmacokinetics studies in rabbit tear fluid showed dramatic increase in HA mean residence time and area under the curve with lenses in comparison to eye drop treatment. The study demonstrates the promising potential of delivering HA through contact lenses for the treatment of dry eye syndrome.
Directory of Open Access Journals (Sweden)
Nalamachu S
2014-11-01
Full Text Available Srinivas Nalamachu,1,2 Richard L Rauck,3 Martin E Hale,4 Orlando G Florete Jr,5 Cynthia Y Robinson,6 Stephen J Farr,6 1International Clinical Research Institute, Overland Park, KS, USA; 2Kansas University Medical Center, Kansas City, KS, USA; 3Carolinas Pain Institute, Center for Clinical Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA; 4Gold Coast Research, LLC, Weston, FL, USA; 5Institute of Pain Management, Jacksonville, FL, USA; 6Zogenix, Inc., Emeryville, CA, USA Objective: To evaluate the long-term safety, tolerability, and effectiveness of single-entity extended-release hydrocodone in opioid-experienced subjects with moderate to severe chronic pain not receiving adequate pain relief or experiencing intolerable side effects from their current opioid. Methods: This multicenter, open-label study started with a conversion/titration phase (≤6 weeks where subjects (n=638 were converted to individualized doses (range 20–300 mg of extended-release hydrocodone dosed every 12 hours, followed by a 48-week maintenance phase (n=424. The primary objective (safety and tolerability and the secondary objective (long-term efficacy as measured by change in average pain score; 0= no pain, 10= worst imaginable pain were monitored throughout the study. Results: Subjects were treated for a range of chronic pain etiologies, including osteoarthritis, low back pain, and neuropathic and musculoskeletal conditions. The mean hydrocodone equivalent dose at screening was 68.9±62.2 mg/day and increased to 139.5±81.7 mg/day at the start of the maintenance phase. Unlimited dose adjustments were permitted at the investigator's discretion during the maintenance phase, reflecting typical clinical practice. No unexpected safety issues were reported. Common adverse events during the conversion/titration and maintenance phases, respectively, were constipation (11.3% and 12.5%, nausea (10.7% and 9.9%, vomiting (4.1% and 9.7%, and somnolence (7
Jeong, In-Kyung; Chung, Choon Hee; Zhou, Zhiguang; Han, Jeong Hee; Duan, Ran; Edralin, Diana M; Rodriguez, Angel
2017-04-01
This analysis evaluated efficacy and safety of insulin lispro low mixture (LM25) twice daily (breakfast and dinner) versus basal insulin glargine (bedtime) plus prandial insulin lispro (IGL) once daily before the largest meal in East Asian (EA) and Caucasian patients with type 2 diabetes mellitus who failed to reach glycemic targets on basal insulin glargine with metformin and/or pioglitazone. Included patients had an HbA1c ≥7.5% and ≤10.5% and fasting plasma glucose ≤6.7 mmol/L. Primary outcome was HbA1c change at 24 weeks. Baseline mean HbA1c was numerically similar between groups in EA (n = 79) and Caucasian (n = 278) patients. Mean (± SD) HbA1c decreased significantly from baseline to 24 weeks for LM25 and IGL in both subpopulations (EA: -1.32 ± 0.96% and -0.89 ± 0.96%; Caucasian: -1.24 ± 0.98% and -1.04 ± 0.97; all P 1). The respective proportions reaching HbA1c ≤7.0% at Week 24 in the LM25 and IGL groups were 33.3% and 22.9% (EA) and 37.2% and 34.1% (Caucasian). Mean (± SD) rates of hypoglycemia per 30 days in the LM25 and IGL groups were 0.74 ± 1.16 and 1.22 ± 1.36 (EA) and 1.38 ± 2.04 and 1.65 ± 2.43 (Caucasian). Mean (± SD) weight gain changes in the LM25 and IGL groups were 0.62 ± 2.78 and 0.51 ± 2.63 kg (EA) and 1.77 ± 2.91 and 0.67 ± 3.09 kg (Caucasian). Both strategies improved glycemic control in a small group of EA and Caucasian patients not adequately controlled on insulin glargine plus metformin and/or pioglitazone. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
Wagner, Karen Dineen; Redden, Laura; Kowatch, Robert A.; Wilens, Timothy E.; Segal, Scott; Chang, Kiki; Wozniak, Patricia; Vigna, Namita V.; Abi-Saab, Walid; Saltarelli, Mario
2009-01-01
A double-blind study that involves 150 patients aged 10-17 on the effect of divalproex extended-release in the treatment of bipolar disorder shows that the drug was similar to placebo based on adverse events and that no treatment effect was observed in the drug. The drug is not suitable for treatment of youths with bipolar I disorder, mixed or…
Shahiwala, Aliasgar; Zarar, Aisha
2018-01-01
In order to prove the validity of a new formulation, a considerable amount of effort is required to study bioequivalence, which not only increases the burden of carrying out a number of bioequivalence studies but also eventually increases the cost of the optimization process. The aim of the present study was to develop sustained release matrix tablets containing diclofenac sodium using natural polymers and to demonstrate step by step process of product development till the prediction of in vivo marketed product equivalence of the developed product. Different batches of tablets were prepared by direct compression. In vitro drug release studies were performed as per USP. The drug release data were assessed using model-dependent, modelindependent and convolution approaches. Drug release profiles showed that extended release action were in the following order: Gum Tragacanth > Sodium Alginate > Gum Acacia. Amongst the different batches prepared, only F1 and F8 passed the USP criteria of drug release. Developed formulas were found to fit Higuchi kinetics model with Fickian (case I) diffusion-mediated release mechanism. Model- independent kinetics confirmed that total of four batches were passed depending on the similarity factors based on the comparison with the marketed Diclofenac. The results of in vivo predictive convolution model indicated that predicted AUC, Cmax and Tmax values for batch F8 were similar to that of marketed product. This study provides simple yet effective outline of pharmaceutical product development process that will minimize the formulation development trials and maximize the product success in bioequivalence studies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Effect of MK-801 on the development of nicotine sensitization of nucleus accumbens dopamine release
Energy Technology Data Exchange (ETDEWEB)
Hong, Soo Kyung; Choung, In Soon; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)
2005-07-01
We have previously found that MK-801, a noncompetitive NMDA receptor antagonist, prevents behavioral sensitization to nicotine. This study aimed to investigate the effect of MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drug on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague-Dawley rats were pretreated with MK-801 (0.3 mg/kg, i.p.) or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for 7 consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens and DA release was monitored using in vivo microdialysis. In rats pretreated with chronic nicotine, local nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response 969 {+-} 235% (mean {+-} SEM) of basal level vs. 520 {+-} 93%, P < 0.05). Co-administration of MK-801 with nicotine attenuated an increase of DA release elicited by local nicotine challenge, compared with nicotine alone (maximal DA response 427 {+-} 83% of basal level vs. 969 {+-} 235%, P < 0.01). These results suggest that MK-801 blocks the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of NMDA receptors in the development of behavioral sensitization to nicotine.
Effect of MK-801 on the development of nicotine sensitization of nucleus accumbens dopamine release
International Nuclear Information System (INIS)
Hong, Soo Kyung; Choung, In Soon; Kim, Sang Eun
2005-01-01
We have previously found that MK-801, a noncompetitive NMDA receptor antagonist, prevents behavioral sensitization to nicotine. This study aimed to investigate the effect of MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drug on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague-Dawley rats were pretreated with MK-801 (0.3 mg/kg, i.p.) or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for 7 consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens and DA release was monitored using in vivo microdialysis. In rats pretreated with chronic nicotine, local nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response 969 ± 235% (mean ± SEM) of basal level vs. 520 ± 93%, P < 0.05). Co-administration of MK-801 with nicotine attenuated an increase of DA release elicited by local nicotine challenge, compared with nicotine alone (maximal DA response 427 ± 83% of basal level vs. 969 ± 235%, P < 0.01). These results suggest that MK-801 blocks the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of NMDA receptors in the development of behavioral sensitization to nicotine
Bilayer tablets of Paliperidone for Extended release osmotic drug delivery
Chowdary, K. Sunil; Napoleon, A. A.
2017-11-01
The purpose of this study is to develop and optimize the formulation of paliperidone bilayer tablet core and coating which should meet in vitro performance of trilayered Innovator sample Invega. Optimization of core formulations prepared by different ratio of polyox grades and optimization of coating of (i) sub-coating build-up with hydroxy ethyl cellulose (HEC) and (ii).enteric coating build-up with cellulose acetate (CA). Some important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated. The optimization of formulation and process was conducted by comparing different in vitro release behaviours of Paliperidone. In vitro dissolution studies of Innovator sample (Invega) with formulations of different release rate which ever close release pattern during the whole 24 h test is finalized.
Glossop, Paul A; Lane, Charlotte A L; Price, David A; Bunnage, Mark E; Lewthwaite, Russell A; James, Kim; Brown, Alan D; Yeadon, Michael; Perros-Huguet, Christelle; Trevethick, Michael A; Clarke, Nicholas P; Webster, Robert; Jones, Rhys M; Burrows, Jane L; Feeder, Neil; Taylor, Stefan C J; Spence, Fiona J
2010-09-23
A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
Directory of Open Access Journals (Sweden)
Gudin JA
2012-05-01
Full Text Available Jeffrey A GudinEnglewood Hospital and Medical Center, Englewood, NJ, USAAbstract: Prescriptions for opioid analgesics to manage moderate-to-severe chronic noncancer pain have increased markedly over the last decade, as have postmarketing reports of adverse events associated with opioids. As an unintentional consequence of greater prescription opioid utilization, there has been the parallel increase in misuse, abuse, and overdose, which are serious risks associated with all opioid analgesics. In response to these concerns, the Food and Drug Administration announced the requirement for a class-wide Risk Evaluation and Mitigation Strategy (REMS for long-acting and extended-release (ER opioid analgesics in April 2011. An understanding of the details of this REMS will be of particular importance to primary care providers. The class-wide REMS is focused on educating health care providers and patients on appropriate prescribing and safe use of ER opioids. Support from primary care will be necessary for the success of this REMS, as these clinicians are the predominant providers of care and the main prescribers of opioid analgesics for patients with chronic pain. Although currently voluntary, future policy will likely dictate that providers undergo mandatory training to continue prescribing medications within this class. This article outlines the elements of the class-wide REMS for ER opioids and clarifies the impact on primary care providers with regard to training, patient education, and clinical practice.Keywords: long-acting opioid, extended-release opioid, risk, REMS, FDA, primary care
Levin, Frances R.; Mariani, John; Brooks, Daniel J.; Pavlicova, Martina; Nunes, Edward V.; Agosti, Vito; Bisaga, Adam; Sullivan, Maria A.; Carpenter, Kenneth M.
2013-01-01
Aim To evaluate whether venlafaxine-extended release (VEN-XR) is an effective treatment for cannabis dependence with concurrent depressive disorders. Design This was a randomized, 12 week, double-blind, placebo-controlled trial of outpatients (n = 103) with DSM-IV cannabis dependence and major depressive disorder or dysthymia. Participants received up to 375 mg VEN-XR on a fixed-flexible schedule or placebo. All patients received weekly individual cognitive-behavioral psychotherapy that primarily targeted marijuana use. Settings The trial was conducted at two university research centers in the United States. Participants One hundred and three cannabis dependent adults participated in the trial. Measurements The primary outcome measures were 1) abstinence from marijuana defined as at least two consecutive urine-confirmed abstinent weeks and 2) improvement in depressive symptoms based on the Hamilton Depression Rating Scale. Findings The proportion of patients achieving a clinically significant mood improvement [50% decrease in Hamilton Depression score from baseline] was high and did not differ between groups receiving VEN-XR (63%) and placebo (69%) (X12=0.48, p-value= 0.49). The proportion of patients achieving abstinence was low overall, but was significantly worse on VEN-XR (11.8%) compared to placebo (36.5%) (X12=7.46, p-valuemarijuana use in the placebo group (F1,179=30.49, p-valuedepressed, cannabis-dependent patients, venlafaxine-extended release does not appear to be effective at reducing depression and may lead to an increase in cannabis use. PMID:23297841
Bacterial contamination of stethoscope chest pieces and the effect of daily cleaning.
Fujita, H; Hansen, B; Hanel, R
2013-01-01
Stethoscopes are a potential source of nosocomial infection for hospitalized humans, a phenomenon not previously studied in companion animals. To determine if daily cleaning of stethoscope chest pieces reduces bacterial contamination between cleanings. Client-owned dogs and cats. Prospective observational study. In phase 1, bacterial cultures were obtained from the chest pieces of 10 participant stethoscopes once weekly for 3 weeks. In phase 2, stethoscopes were cleaned daily and 2 culture samples were obtained once weekly, immediately before and after cleaning with 70% isopropyl alcohol, for 3 weeks. Daily cleaning eliminated bacteria immediately after each cleaning (P = .004), but did not reduce the rate of positive cultures obtained before cleaning in phase 2. Cultures were positive for 20/30 (67%) samples during phase 1 and 18/30 (60%) obtained before daily cleaning during phase 2. Recovered organisms included normal skin flora, agents of opportunistic infections, and potential pathogens. The only genus that was repeatedly recovered from the same stethoscope for 2 or more consecutive weeks was Bacillus sp. Daily cleaning was highly effective at removing bacteria, but provided no reduction in precleaning contamination. Cleaning stethoscopes after use on dogs or cats infected with pathogenic bacteria and before use on immunocompromised animals should be considered. Copyright © 2013 by the American College of Veterinary Internal Medicine.
Evaluation of Extended-Wear Hearing Technology for Children with Hearing Loss.
Wolfe, Jace; Schafer, Erin; Martella, Natalie; Morais, Mila; Mann, Misty
2015-01-01
Research shows that many older children and teenagers who have mild to moderately severe sensorineural hearing loss do not use their hearing instruments during all waking hours. A variety of reasons may contribute toward this problem, including concerns about cosmetics associated with hearing aid use and the inconvenience of daily maintenance associated with hearing instruments. Extended-wear hearing instruments are inserted into the wearer's ear canal by an audiologist and are essentially invisible to outside observers. The goal of this study was to evaluate the potential benefits and limitations associated with use of extended-wear hearing instruments in a group of children with hearing loss. A two-way repeated measures design was used to examine performance differences obtained with the participants' daily-wear hearing instruments versus that obtained with extended-wear hearing instruments. Sixteen children, ages 10-17 yr old, with sensorineural hearing loss ranging from mild to moderately severe. Probe microphone measures were completed to evaluate the aided output of device. Behavioral test measures included word recognition in quiet, sentence recognition in noise, aided warble-tone thresholds, and psychophysical loudness scaling. Questionnaires were also administered to evaluate subjective performance with each hearing technology. Data logging suggested that many participants were not using their daily-wear hearing instruments during all waking hours (mean use was less than 6 h/day). Real ear probe microphone measurements indicated that a closer fit to the Desired Sensation Level Version 5 prescriptive targets was achieved with the children's daily-wear instruments when compared to the extended-wear instruments. There was no statistically significant difference in monosyllabic word recognition at 50 or 60 dBA obtained with the two hearing technologies. Sentence recognition in noise obtained with use of the extended-wear devices was, however, significantly
Stawski, Robert S; Cichy, Kelly E; Piazza, Jennifer R; Almeida, David M
2013-11-01
While much research has focused on linking stressful experiences to emotional and biological reactions in laboratory settings, there is an emerging interest in extending these examinations to field studies of daily life. The current study examined day-to-day associations among naturally occurring daily stressors and salivary cortisol in a national sample of adults from the second wave of the National Study of Daily Experiences (NSDE). A sample of 1694 adults (age=57, range=33-84; 44% male) completed telephone interviews detailing their stressors and emotions on eight consecutive evenings. Participants also provided saliva samples upon waking, 30min post-waking, before lunch and before bed, on four consecutive interview days resulting in 5995 days of interview/cortisol data. Analyses revealed three main findings. First, cortisol AUC was significantly higher on stressor days compared to stressor-free days, particularly for arguments and overloads at home, suggesting that daily stressors are associated with increased cortisol output, but that not all daily stressors have such an influence. Second, individuals reporting a greater frequency of stressor days also exhibited a steeper diurnal cortisol slope. Finally, daily stressor-cortisol associations were unaltered after adjustment for daily negative affect and physical symptoms. Our discussion focuses on the influence of naturally occurring daily stressors on daily cortisol and the role of daily diary approaches for studying healthy cortisol responses to psychosocial stressors outside of traditional laboratory settings. Copyright © 2013 Elsevier Ltd. All rights reserved.
Stawski, Robert S.; Cichy, Kelly E.; Piazza, Jennifer R.; Almeida, David M.
2013-01-01
While much research has focused on linking stressful experiences to emotional and biological reactions in laboratory settings, there is an emerging interest in extending these examinations to field studies of daily life. The current study examined day-to-day associations among naturally-occurring daily stressors and salivary cortisol in a national sample of adults from the second wave of the National Study of Daily Experiences (NSDE). A sample of 1,694 adults (Age=57, Range=33–84; 44% male) completed telephone interviews detailing their stressors and emotions on eight consecutive evenings. Participants also provided saliva samples upon waking, 30 minutes post-waking, before lunch and before bed, on four consecutive interview days resulting in 5,995 days of interview/cortisol data. Analyses revealed three main findings. First, cortisol AUC was significantly higher on stressor days compared to stressor-free days, particularly for arguments and overloads at home, suggesting that daily stressors are associated with increased cortisol output, but that not all daily stressors have such an influence. Second, individuals reporting a greater frequency of stressor days also exhibited a steeper diurnal cortisol slope. Finally, daily stressor-cortisol associations were unaltered after adjustment for daily negative affect and physical symptoms. Our discussion focuses on the influence of naturally-occurring daily stressors on daily cortisol and the role of daily diary approaches for studying healthy cortisol responses to psychosocial stressors outside of traditional laboratory settings. PMID:23856186
Once vs. twice daily thoracic irradiation in limited stage small cell lung cancer
International Nuclear Information System (INIS)
Kim, Jun Sang; Kim, Jae Sung; Kim, Ju Ock; Kim, Sun Young; Cho, Moon June
1998-01-01
A retrospective study was conducted comparing single dally fraction (SDF) thoracic radiotherapy (TRT) with twice daily (BID) TRT to determine the potential benefit of BID TRT in limited-stage small cell lung cancer (SCLC). Endpoints of the study were response, survival, pattern of failure, and acute toxicity. Between November 1989 to December 1996, 78 patients with histologically proven limited-stage SCLC were treated at the Department of Therapeutic Radiology, Chungnam National University Hospital. Of these, 9 were irradiated for palliative intent, and 1 had recurrent disease. Remaining 68 patients were enrolled in this study. There were 26 patients with a median age of 58 years, and 22 (85%) ECOG performance score of less than 1 in SDF TRT. There were 42 patients with a median age of 57 years, and 36 (86%) ECOG performance score of less than 1 in BID TRT. By radiation fractionation regimen, there were 26 in SDF TRT and 42 in BID TRT. SDF TRT consisted of 180 cGy, 5 days a week. BID TRT consisted of 150 cGY BID, 5 days a week in 13 of 42 and 120 cGy BID, in 29 of 42. And the twice daily fractions were separated by at least 4 hours. Total radiotherapy doses were between 5040 and 6940 cGy (median, 5040 cGy) in SDF TRT and was between 4320 and 5100 cGy (median, 4560 cGy) in BID TRT. Prophylactic cranial irradiation (PCI) was recommended for patients who achieved a CR. The recommended PCI dose was 2500 cGy/10 fractions. Chemotherapy consisted of CAV (cytoxan 1000 mg/m 2 , adriamycin 40 mg/m 2 , vincristine 1 mg/m 2 ) alternating with VPP (cisplatin 60 mg/m 2 , etoposide 100 mg/m 2 ) every 3 weeks in 25 (96%) of SDF TRT and in 40 (95%) of BID TRT. Median cycle of chemotherapy was six in both group. Timing for chemotherapy was sequential in 23 of SDF TRT and in 3 BID TRT, and concurrent in 3 of SDF TRT and in 39 of BID TRT. Follow-up ranged from 2 of 99 months (median, 14 months) in both groups. Of the 26 SDF TRT, 9 (35%) achieved a complete response (CR) and 14 (54
Extended release local anesthetic agents in a postoperative arthritic pain model.
Ickowicz, Diana E; Golovanevski, Ludmila; Haze, Amir; Domb, Abraham J; Weiniger, Carolyn F
2014-01-01
Local anesthetics play an important role in postoperative pain management in orthopedic joint procedures. The aim of this study was to determine the effect of an intraoperative extra-articular injection of poly(DL-lactic acid co castor oil 3:7), p(DLLA:CO) 3:7 loaded with 15% bupivacaine, for postoperative analgesia following knee arthroplasty. Prolonged release local anesthetic formulation was synthesized by mixing p(DLLA:CO) 3:7 with bupivacaine base. Under anesthesia, the knee joint of Sprague-Dawley rats was exposed, a hole drilled in the femoral trochlea. 0.2 mL of either 15% polymer-bupivacaine formulation or plain bupivacaine (control) was injected locally and compared with a nonsurgery control group. Mechanical hyperalgesia was determined by counting the vocalizations and leg withdrawal after joint squeezing. Behavioral assessments over a day postoperative period revealed a reduction in rearing and ambulation in an open-field apparatus in animals of both experimental groups compared with the nonsurgery control. The vocalizations during the hyperalgesia test increased compared with the control at 24 h. At 48 h, 3.667 ± 0.5138, p = 0.0076 vocalizations were recorded for the plain bupivacaine group versus 1.417 ± 0.5138, p < 0.0001 in the 15% polymer-bupivacaine formulation. Bupivacaine encapsulated in p(DLLA:CO) 3:7 extended the duration of the analgesia compared with plain drug in rats and could represent effective postoperative analgesic in orthopedic joint procedures. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.
Ananworanich, J.; Gorowara, M.; Avihingsanon, A.; Kerr, S.J.; Heesch, N. van; Khongpetch, C.; Uanithirat, A.; Hill, A.; Ruxrungtham, K.; Burger, D.M.
2012-01-01
Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were
Iodine-131 releases from the Hanford Site, 1944--1947
International Nuclear Information System (INIS)
Heeb, C.M.
1992-10-01
Detailed results of the Hanford Environmental Dose Reconstruction (HEDR) iodine-131 release reconstruction are presented in this volume. Included are daily data on B, D, and F Plant, reactor operations from the P-Department Daily Reports (General Electric Company 1947). Tables of B and T Plant material processed from the three principal sources on separations plant operations: The Jaech report (Jaech undated), the 200 Area Report (Acken and Bird 1945; Bird and Donihee 1945), and the Metal History Reports (General Electric Company 1946). A transcription of the Jaech report is also provided because it is computer-generated and is not readily readable in its original format. The iodine-131 release data are from the STRM model. Cut-by-cut release estimates are provided, along with daily, monthly, and yearly summations. These summations are based on the hourly release estimates. The hourly data are contained in a 28 megabyte electronic file. Interested individuals may request a copy
Del Rosso, James Q
2016-02-01
Topical treatment for toenail onychomycosis has been fraught with a long-standing reputation of poor efficaey, primarily due to physical properties of the nail unit that impede drug penetration. Newer topical agents have been formulated as Solution, which appear to provide better therapeutic response in properly selected patients. It is important to recognize the impact the effects that mitigating and concomitant factors can have on efficaey. These factors include disease severity, gender, presence of tinea pedis, and diabetes. This article reviews results achieved in Phase 3 pivotal studies with topical efinaconazole 10% Solution applied once daily for 48 weeks with a focus on how the aforementioned factors influenced therapeutic outcomes. It is important for clinicians treating patients for onychomycosis to evaluate severity, treat concomitant tinea pedis, address control of diabetes if present by encouraging involvement of the patient's primary care physician, and consider longer treatment courses when clinically relevant.
Levin, Frances R; Mariani, John; Brooks, Daniel J; Pavlicova, Martina; Nunes, Edward V; Agosti, Vito; Bisaga, Adam; Sullivan, Maria A; Carpenter, Kenneth M
2013-06-01
To evaluate whether venlafaxine-extended release (VEN-XR) is an effective treatment for cannabis dependence with concurrent depressive disorders. This was a randomized, 12-week, double-blind, placebo-controlled trial of out-patients (n = 103) with DSM-IV cannabis dependence and major depressive disorder or dysthymia. Participants received up to 375 mg VEN-XR on a fixed-flexible schedule or placebo. All patients received weekly individual cognitive-behavioral psychotherapy that primarily targeted marijuana use. The trial was conducted at two university research centers in the United States. One hundred and three cannabis-dependent adults participated in the trial. The primary outcome measures were (i) abstinence from marijuana defined as at least two consecutive urine-confirmed abstinent weeks and (ii) improvement in depressive symptoms based on the Hamilton Depression Rating Scale. The proportion of patients achieving a clinically significant mood improvement (50% decrease in Hamilton Depression score from baseline) was high and did not differ between groups receiving VEN-XR (63%) and placebo (69%) (χ1 (2) = 0.48, P = 0.49). The proportion of patients achieving abstinence was low overall, but was significantly worse on VEN-XR (11.8%) compared to placebo (36.5%) (χ1 (2) = 7.46, P marijuana use in the placebo group (F1,179 = 30.49, P depressed, cannabis-dependent patients, venlafaxine-extended release does not appear to be effective at reducing depression and may lead to an increase in cannabis use. © 2013 Society for the Study of Addiction.
TRENDS IN ESTIMATED MIXING DEPTH DAILY MAXIMUMS
Energy Technology Data Exchange (ETDEWEB)
Buckley, R; Amy DuPont, A; Robert Kurzeja, R; Matt Parker, M
2007-11-12
Mixing depth is an important quantity in the determination of air pollution concentrations. Fireweather forecasts depend strongly on estimates of the mixing depth as a means of determining the altitude and dilution (ventilation rates) of smoke plumes. The Savannah River United States Forest Service (USFS) routinely conducts prescribed fires at the Savannah River Site (SRS), a heavily wooded Department of Energy (DOE) facility located in southwest South Carolina. For many years, the Savannah River National Laboratory (SRNL) has provided forecasts of weather conditions in support of the fire program, including an estimated mixing depth using potential temperature and turbulence change with height at a given location. This paper examines trends in the average estimated mixing depth daily maximum at the SRS over an extended period of time (4.75 years) derived from numerical atmospheric simulations using two versions of the Regional Atmospheric Modeling System (RAMS). This allows for differences to be seen between the model versions, as well as trends on a multi-year time frame. In addition, comparisons of predicted mixing depth for individual days in which special balloon soundings were released are also discussed.
DEFF Research Database (Denmark)
Franek, F; Jarlfors, A; Larsen, F.
2015-01-01
Desvenlafaxine is a biopharmaceutics classification system (BCS) class 1 (high solubility, high permeability) and biopharmaceutical drug disposition classification system (BDDCS) class 3, (high solubility, poor metabolism; implying low permeability) compound. Thus the rate-limiting step...... not imply low intestinal permeability, as indicated by the BDDCS, merely low duodenal/jejunal permeability....... for desvenlafaxine absorption (i.e. intestinal dissolution or permeation) is not fully clarified. The aim of this study was to investigate whether dissolution and/or intestinal permeability rate-limit desvenlafaxine absorption from an immediate-release formulation (IRF) and Pristiq®, an extended release formulation...
Vora, J; Caputo, S; Damci, T; Orozco-Beltran, D; Pan, C; Svendsen, A L; Sølje, K S; Khunti, K
2014-04-01
There are acknowledged benefits to continuing metformin when initiating insulin, but there appears to be growing concern over the role of sulphonylureas and thiazolidinediones when used in combination with insulin. This analysis investigates the effects of continuing or discontinuing oral antidiabetic drugs (OADs) following the initiation of once-daily insulin detemir. SOLVE is a 24-week, multinational observational study of insulin detemir initiation in patients with type 2 diabetes mellitus treated with one or more OADs. In the total cohort (n = 17 374), there were significant improvements in HbA1c (-1·3%, 95% CI -1·34; -1·27%) and weight (-0·6 kg, 95% CI -0·65; -0·47 kg), with an increase in the incidence rate of minor hypoglycaemia (+0·256 events ppy, P use either prior to (n = 17 086) or during insulin initiation (n = 16 346). HbA1c reductions were significantly greater in patients continuing treatment with metformin (-1·3% vs. -1·1%, P < 0·01), thiazolidinediones (-1·3% vs. -1·0%, P < 0·01) and DPP-IV inhibitors (-1·3% vs. -0·9%, P < 0·001). Final insulin doses were significantly greater in patients discontinuing treatment with sulphonylureas (0·29 vs. 0·26 IU/kg, P < 0·001), glinides (0·28 vs. 0·26 IU/kg, P < 0·01), thiazolidinediones (0·31 vs. 0·26 IU/kg, P < 0·001) and DPP-IV inhibitors (0·35 vs. 0·29 IU/kg, P < 0·001) compared with patients continuing these respective agents. All patient subgroups had a mean weight loss irrespective of OAD continuation, apart from those continuing thiazolidinediones (+0·2 kg). The largest improvements in weight were seen following the withdrawal of sulphonylureas and thiazolidinediones (-1·1 and -1·1 kg, respectively). Discontinuation (or switching) of OADs at the time of insulin initiation appears to be governed principally by concerns about hypoglycaemia and weight. HbA1c improvements were smaller in patients discontinuing OADs at the time of insulin
Directory of Open Access Journals (Sweden)
Roskell NS
2014-07-01
Full Text Available Neil S Roskell,1 Antonio Anzueto,2 Alan Hamilton,3 Bernd Disse,4 Karin Becker5 1Statistics, Bresmed Health Solutions Ltd, Sheffield, UK; 2School of Medicine, University of Texas Health Science Center, San Antonio, TX, USA; 3Medical Department, Boehringer Ingelheim (Canada Ltd, Burlington, ON, Canada; 4Medical Department, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany; 5Global Health Economics and Outcomes Research, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany Purpose: In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD, an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted. Methods: A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1, Transition Dyspnea Index, St George’s Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations. Results: Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol. Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters, the following mean differences (95% confidence interval were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, –0.005 (–0.077 to 0.067, and indacaterol 150 mcg
Dual-release hydrocortisone treatment: glycometabolic profile and health-related quality of life
Directory of Open Access Journals (Sweden)
L M Mongioì
2018-01-01
Full Text Available Objective: Adrenal insufficiency (AI is a chronic condition associated with increased mortality and morbidity. The treatment of AI in the last years has been object of important changes due to the development of a dual-release preparation of hydrocortisone. It differs from previous therapeutic strategy as it contemplates a once-daily tablet that allows more closely mimicking the physiological circadian cortisol rhythm. The aim of the study was to evaluate the effects of dual-release hydrocortisone treatment on the glycometabolic profile and health-related quality of life of patients with AI. Design and Methods: In this clinical open trial, we enrolled ten patients with primary AI (41 ± 2.67 years and nine patients with AI secondary to hypopituitarism (53.2 ± 17.7 years. We evaluated the glycometabolic profile before and 3, 6, 9 and 12 months after dual-release hydrocortisone administration. We also evaluated health-related quality of life, estimated by the AddiQol questionnaire. The mean dose administered of dual-release hydrocortisone was 28.33 ± 6.68 mg/day. Results: One female hypopituitary patient dropped out from the study. After 12 months of treatment, the mean dosage administered of dual-release hydrocortisone was significantly lower (P < 0.05 and all patients reported improved quality of life and well-being. The glycometabolic profile improved and the glycosylated hemoglobin decreased significantly in patients with primary AI (6.25 ± 0.2 vs 5.35 ± 0.17, P < 0.05. In contrast, hypopituitary patients had worse glycometabolic profile and a trend toward hypertriglyceridemia. Conclusions: Dual-release hydrocortisone treatment improved the quality of life of patients with AI, and it allowed a decrease of cortisol dosage administered in the absence of side effects. The glycometabolic profile worsened in hypopituitary patients.
Once Daily Valacyclovir for Reducing Viral Shedding in Subjects Newly Diagnosed with Genital Herpes
Directory of Open Access Journals (Sweden)
Mark G. Martens
2009-01-01
Results. 52 subjects had at least one PCR measurement in both treatment periods and comprised the primary efficacy population. Valacyclovir significantly reduced HSV-2 shedding during all days compared to placebo (mean 2.9% versus 13.5% of all days (P<.01, a 78% reduction. Valacyclovir significantly reduced subclinical HSV-2 shedding during all days compared to placebo (mean 2.4% versus 11.0% of all days (P<.01, a 78% reduction. However, 79% of subjects had no GH recurrences while receiving valacyclovir compared to 52% of subjects receiving placebo (P<.01. Conclusion. In this study, the frequency of total and subclinical HSV-2 shedding was greater than reported in earlier studies involving subjects with a history of symptomatic genital recurrences. Our study is the first to demonstrate a significant reduction in viral shedding with valacyclovir 1 g daily compared to placebo in a population of subjects newly diagnosed with HSV-2 infection.
Directory of Open Access Journals (Sweden)
Juçara Ribeiro Franca
Full Text Available The purpose of the present study was to develop and assess a novel sustained-release drug delivery system of Bimatoprost (BIM. Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in vitro drug release. Biodistribution of 99mTc-BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intracameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 µg BIM were administered once into conjunctival sac, after ocular hypertension confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control. Intraocular pressure (IOP was monitored for four consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts sustainedly released BIM in vitro during 8 hours. Biodistribution studies showed that the amount of 99mTc-BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after one application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period. IOP results were reflected in RGC counting and optic nerve head cupping damage. BIM-loaded inserts provided sustained release of BIM and seem to be a
Directory of Open Access Journals (Sweden)
Martinez-Raga J
2015-05-01
Full Text Available Jose Martinez-Raga,1,2 Carlos Knecht,3 Raquel de Alvaro4 1Teaching Unit of Psychiatry and Psychological Medicine, University Hospital Doctor Peset, University of Valencia, 2CEU Cardenal Herrera University, 3Área de Salud Mental, Hospital Padre Jofré, Valencia, 4Hospital General, Consorcio Hospitalario Provincial, Castellon, Spain Abstract: The α2-adrenergic receptor agonist guanfacine, in its extended-release formulation (GXR, is the most recent nonstimulant medication approved in several countries for the treatment of attention-deficit hyperactivity disorder (ADHD as monotherapy and as adjunctive pharmacotherapy to stimulants in children and adolescents. The present paper aims to review comprehensively and critically the pharmacodynamic and pharmacokinetic characteristics and the published evidence on the efficacy and safety profile of GXR in the treatment of ADHD. A comprehensive search of relevant databases (PubMed, Embase, and PsycInfo was conducted to identify studies published in peer-reviewed journals until January 15, 2015. Though the precise mechanism of action of guanfacine in the treatment of ADHD is not fully understood, it is thought to act directly by enhancing noradrenaline functioning via α2A-adrenoceptors in the prefrontal cortex. Weight-adjusted doses should be used, with a dosing regime on a milligram per kilogram basis, starting at doses in the range 0.05–0.08 mg/kg/day, up to 0.12 mg/kg/day. As evidenced in short-term randomized controlled trials and in long-term open-label extension studies, GXR has been shown to be effective as monotherapy in the treatment of ADHD. Furthermore, GXR has also been found to be effective as adjunctive therapy to stimulant medications in patients with suboptimal responses to stimulants. Many of the adverse reactions associated with GXR, particularly sedation-related effects, were dose-related, transient, mild to moderate in severity, and did not interfere with attention or overall
Hinson, Vanessa K; Goetz, Christopher G; Leurgans, Sue; Fan, Wenqing; Nguyen, Tiffany; Hsu, Ann
2009-01-01
We compared IPX054, a bilayer tablet of immediate- and extended-release carbidopa/levodopa (CD/LD) given twice daily to standard CD/LD given 4 times daily in patients with stable Parkinson disease (PD). Twelve PD patients with no or mild fluctuations on CD/LD 25/100 mg 4 times daily were randomized to a double-blind crossover comparison with IPX054 (50/200 mg) twice daily. At the end of each 2-week treatment, patients were video recorded while performing a modified Unified Parkinson's Disease Rating Scale motor examination and Rush Dyskinesia Rating Scale at 30-minute intervals over 8.5 hours. The primary outcome measure was the number of videotape epochs rated as "ON" without troublesome dyskinesia by a blinded observer (Wilcoxon signed rank tests). The 9 men and 3 women had a mean age of 69 years and mean PD duration of 6 years. IPX054 and CD/LD showed no significant differences in the primary outcome measure (mean number of video epochs rated as ON without troublesome dyskinesia; P = 0.14). The mean time to ON was improved with IPX054 (P = 0.014), and the mean modified Unified Parkinson's Disease Rating Scale scores slightly favored IPX054 (14.4 vs 16.9; P = 0.052). Mean Rush Dyskinesia Rating Scale scores were not significantly different between IPX054 and CD/LD (0.45 vs 0.69; P = 0.25). No patient developed troublesome dyskinesias. In stable PD patients, no difference was detected between twice-daily treatment with IPX054 and CD/LD given 4 times daily. In this group, substitution with IPX054 reduced dosing frequency while maintaining CD/LD efficacy. In clinical practice, this ease of administration may offer improved treatment compliance.
Once-daily fosamprenavir with ritonavir in the treatment of HIV infection in therapy-naïve patients
Gisslen, Magnus; Flamholc,Leo; Gisslen,Magnus
2008-01-01
Leo Flamholc1, Magnus Gisslén21Department of Infectious Diseases, Malmö University Hospital, Malmö, Sweden; 2Sahlgrenska University Hospital/Östra, Gothenburg, SwedenAbstract: Treatment options for HIV patients have dramatically improved since the introduction of efficacious antiretroviral combination therapy more than a decade ago. Treatment regimens have been simplified with fewer pills and fewer daily dosages. Fosamprenavir is a protease inhibitor with...
Larochelle, Marc R; Zhang, Fang; Ross-Degnan, Dennis; Wharam, J Frank
2015-06-01
In the second half of 2010, abuse-deterrent extended-release oxycodone hydrochloride (OxyContin; Purdue Pharma) was introduced and propoxyphene was withdrawn from the US market. The effect of these pharmaceutical market changes on opioid dispensing and overdose rates is unknown. To evaluate the association between 2 temporally proximate changes in the opioid market and opioid dispensing and overdose rates. Claims from a large national US health insurer were analyzed, using an interrupted time series study design. Participants included an open cohort of 31.3 million commercially insured members aged 18 to 64 years between January 1, 2003, and December 31, 2012, with median follow-up of 20 months (last follow-up, December 31, 2012). Introduction of abuse-deterrent OxyContin (resistant to crushing or dissolving) on August 9, 2010, and market withdrawal of propoxyphene on November 19, 2010. Standardized opioid dispensing rates and prescription opioid and heroin overdose rates were the primary outcomes. We used segmented regression to analyze changes in outcomes from 30 quarters before to 8 quarters after the 2 interventions. Two years after the opioid market changes, total opioid dispensing decreased by 19% from the expected rate (absolute change, -32.2 mg morphine-equivalent dose per member per quarter [95% CI, -38.1 to -26.3]). By opioid subtype, the absolute change in dispensing by milligrams of morphine-equivalent dose per member per quarter at 2 years was -11.3 (95% CI, -12.4 to -10.1) for extended-release oxycodone, 3.26 (95% CI, 1.40 to 5.12) for other long-acting opioids, -8.19 (95% CI, -9.30 to -7.08) for propoxyphene, and -16.2 (95% CI, -18.8 to -13.5) for other immediate-release opioids. Two years after the market changes, the estimated overdose rate attributed to prescription opioids decreased by 20% (absolute change, -1.10 per 100,000 members per quarter [95% CI, -1.47 to -0.74]), but heroin overdose increased by 23% (absolute change, 0.26 per 100
Directory of Open Access Journals (Sweden)
Alice Monzani
2010-03-01
Full Text Available Alice Monzani, Giuseppina Oderda1Department of Pediatrics, Università del Piemonte Orientale, Novara, ItalyAbstract: Omeprazole is a proton-pump inhibitor indicated for gastroesophageal reflux disease and erosive esophagitis treatment in children. The aim of this review was to evaluate the efficacy of delayed-release oral suspension of omeprazole in childhood esophagitis, in terms of symptom relief, reduction in reflux index and/or intragastric acidity, and endoscopic and/or histological healing. We systematically searched PubMed, Cochrane and EMBASE (1990 to 2009 and identified 59 potentially relevant articles, but only 12 articles were suitable to be included in our analysis. All the studies evaluated symptom relief and reported a median relief rate of 80.4% (range 35%–100%. Five studies reported a significant reduction of the esophageal reflux index within normal limits (<7% in all children, and 4 studies a significant reduction of intra-gastric acidity. The endoscopic healing rate, reported by 9 studies, was 84% after 8-week treatment and 95% after 12-week treatment, the latter being significantly higher than the histological healing rate (49%. In conclusion, omeprazole given at a dose ranging from 0.3 to 3.5 mg/kg once daily (median 1 mg/kg once daily for at least 12 weeks is highly effective in childhood esophagitis.Keywords: proton pump inhibitors, children, ranitidine, H2-blockers
Clinical utility of guanfacine extended release in the treatment of ADHD in children and adolescents
Directory of Open Access Journals (Sweden)
Bello NT
2015-06-01
Full Text Available Nicholas T Bello Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA Abstract: Attention deficit hyperactivity disorder (ADHD is the most common psychiatric illness in children and adolescents. Several stimulant medications, such as methylphenidate and amphetamine derivatives, are available to treat ADHD in pediatric patients. Nonstimulant medications are more preferred by some parents, other caregivers, and patients because they lack the abuse potential of stimulant medications. In the US, one available nonstimulant option is guanfacine extended release (XR. As a selective α2A adrenergic receptor, guanfacine acts on the central noradrenergic pathways and cortical noradrenergic targets to improve working memory and attention. The XR formulation of guanfacine, compared with the immediate-release formulation, is more effective for the long-term management of ADHD and is associated with fewer adverse effects. Available data also indicate that guanfacine XR is superior to atomoxetine and is as effective as the nonselective α2 adrenergic receptor agonist, clonidine XR. The most common adverse effects associated with guanfacine XR are somnolence, fatigue, bradycardia, and hypotension. Somnolence is the most often cited reason for discontinuation. Guanfacine XR is also labeled for use as an adjuvant to stimulant treatment for ADHD. A similar profile of adverse effects as reported with monotherapy is reported when guanfacine XR is “added on” to stimulant therapy with somnolence as the most commonly reported adverse event. This review discusses the clinical efficacy and patient preference of guanfacine XR based on available published data on the safety, relative effectiveness, and tolerance of this medication to treat ADHD. Keywords: Intuniv, norepinephrine, prefrontal cortex, locus coeruleus, impulsivity, inattentive
Wang, Wen; Zhao, Xiping; Sun, Jinglei; Zhou, Guangquan
2016-12-01
Once electronic health records (EHRs) have been fully implemented and integrated into the daily work of a healthcare organisation/hospital, there is considerable pressure on management to demonstrate the benefits that these systems can deliver to the organisation. One practical way to maximise the value and highlight the benefits of EHRs is to encourage physicians to increase and extend their use of EHR functions. This study used a social influence theory context to examine the impact of mechanisms of social influence on the intentions of physicians to extend their use of EHRs. A survey of physicians (n = 205) in a first-class comprehensive hospital in southern China was conducted approximately 2 years after the hospital's introduction of EHRs. A 16-item questionnaire was developed to measure the impact of four social influence factors (reward, punishment, social image and group norm) on physicians' intentions to extend their use of EHRs. The research model included two additional control variables (perceived usefulness and perceived ease of use) to account for potential covariance among social influence measures. The study's research model showed significant relationships between physicians' responses on two of the social influence measures (rewards and group norm) and their intentions to extend their use of EHRs. Punishment and social image measures did not influence physicians' intentions to increase their use of EHRs. These findings have suggested that for healthcare organisations to maximise the benefits of EHRs, the efforts of hospital management should be directed towards rewarding those physicians who increase their use of EHRs; and to promoting and reinforcing the increased usage of EHRs among physicians as a group norm. © The Author(s) 2016.
Depth preference in released juvenile turbot Psetta maxima
DEFF Research Database (Denmark)
Albertsen, Christoffer Moesgaard; Støttrup, Josianne; Nielsen, Anders
2014-01-01
Hatchery-reared juvenile turbot Psetta maxima were tagged with Passive Integrated Transponder (PIT) tags and released at three different depths in a sandy bay in Denmark. About 2–7% of the released fish were registered daily to monitor their distribution using a tag antenna mounted on a modified...
Katzman, Martin A; Sternat, Tia
2014-11-01
Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioural disorder with onset during childhood. It affects a child's development, both at home and at school, and impacts on social, emotional and cognitive functioning, in both the home and the school environment. Untreated ADHD is very often associated with poor academic achievement, low occupational status, increased risk of substance abuse and delinquency. Current practice guidelines recommend a multimodal approach in the treatment of ADHD, which includes educational, behavioural and mental health interventions, and pharmacological management. Stimulant medications, including methylphenidate (MPH) and amphetamine products, are recommended as first-line pharmacotherapy in the treatment of ADHD. The choice of stimulant is influenced by several factors; the most influential factor is the duration of action. Long-acting medication provides benefits long after school and work. It also increases the likelihood of once-daily dosing, thereby eliminating the need for mid-day dosing, making the treatment more private, avoiding stigma and improving adherence to medication. MPH is the most widely used psychotropic medication in child psychiatry. It was first developed for use in children as an oral, immediate-release formulation and more recently as various extended-release formulations. These latter formulations include the 12 h preparation Concerta(®) (osmotic-release oral system [OROS] MPH), which utilizes an osmotic pump system, designed to overcome the difficulties of multiple daily dosing. Since it received approval from the US Food and Drug Administration in August 2000, OROS MPH has been quickly and widely accepted as one of the preferred treatments for ADHD because of its once-daily dosing. This paper reviews the data in support of long-acting OROS MPH in children, adolescents and adults, both in ADHD and in association with its comorbidities.
14 CFR 125.363 - Flight release over water.
2010-01-01
... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Flight release over water. 125.363 Section 125.363 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Flight release over water. (a) No person may release an airplane for a flight that involves extended...
Dalfampridine extended release tablets: 1 year of postmarketing safety experience in the US
Directory of Open Access Journals (Sweden)
Jara M
2013-03-01
Full Text Available Michele Jara,1 Graham Barker,2 Herbert R Henney 3rd1 1Acorda Therapeutics, Inc, Ardsley, NY, USA; 2Biogen Idec, Inc, Maidenhead, Berkshire, UK Background: Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine in some countries were approved in the US to improve walking in patients with multiple sclerosis, as demonstrated by improvement in walking speed. Postmarketing safety experience is available from exposure of approximately 46,000 patients in the US from product approval through March 2011. Objective: To provide a descriptive analysis of all spontaneously reported postmarketing adverse events (AEs for dalfampridine-ER since product launch. Methods: AE data were extracted from the safety database from product launch through March 31, 2011; AEs were classified using the Medical Dictionary for Regulatory Activities. Seizure cases were reviewed for patient demographics, time to event from treatment onset, and presence of additional risk factors. Results: The most frequently reported postmarketing AEs were similar to those reported during clinical development: dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia, and back pain (all included in US product labeling. New clinically significant findings are related to lack of efficacy and inappropriate dosing. Of the approximately 46,000 patients exposed, 85 seizures were reported (~5.4/1000 patient-years, of which 82 were reported or confirmed by a health care practitioner (~5.2/1000 patient-years. Beyond the intrinsic multiple sclerosis-related seizure risk, more than half of the 85 cases (62% had an additional potential risk factor for seizure including a previous history of convulsions, renal impairment, incorrect dosing, or use of concurrent medications with a labeled seizure risk. Duration of treatment prior to the seizure ranged from one dose to 365 days; 26/85 (31% patients suffered a seizure
Directory of Open Access Journals (Sweden)
Ruhul Kayesh
2017-01-01
Full Text Available A simple RP-HPLC method has been developed for simultaneous estimation of fexofenadine and pseudoephedrine in their extended release tablet. The method was developed based on statistical design of experiments (DoE and Response Surface Methodology. Separation was achieved on double end-capped C18 column (250 mm × 4 mm, 5 μm. In this experiment, two components of mobile phase, namely, acetonitrile (% v/v and methanol (% v/v, were the factors whereas retention and resolution of the chromatographic peaks were the responses. The effects of different composition of factors on the corresponding responses were investigated. The optimum chromatographic condition for the current case was found as an isocratic mobile phase consisting of 20 mM phosphate buffer (pH 6.8 and acetonitrile and methanol in a ratio of 50 : 36 : 14 (% v/v at a flow rate of 1 mL/min for 7 minutes. The retention of pseudoephedrine and fexofenadine was found to be 2.6 min and 4.7 min, respectively. The method was validated according to the ICH and FDA guidelines and various validation parameters were determined. Also, forced degradation studies in acid, base, oxidation, and reduction media and in thermal condition were performed to establish specificity and stability-indicating property of this method. Practical applicability of this method was checked in extended release tablets available in Bangladeshi market.
Chalmers, Robin L; Dillehay, Sally; Long, Bill; Barr, Joseph T; Bergenske, Peter; Donshik, Peter; Secor, Glenda; Yoakum, John
2005-06-01
This study measured the impact of previous contact lens wearing schedule on the resolution of signs and contact lens-related symptoms among wearers of lotrafilcon A lenses. One hundred forty adapted low Dk daily wear (DW) and 140 adapted low Dk extended wear (EW) subjects were enrolled and examined for 1 year (overall study length is 3 years). All subjects wore lotrafilcon A lenses on a wearing schedule of up to 30 nights continuous wear with monthly replacement of lenses. Examinations were conducted at 1 week, 1, 6, and 12 months. The former EW wearers presented at baseline with significantly higher conjunctival staining and epithelial microcysts (p Dk DW and EW wearers within 1 week as did severity of dryness during the day for the former DW wearers, in part as a result of their higher prevalence at baseline in the DW group. Subjects reported redness improved significantly by the 1-month visit. Continuous wear of high Dk silicone hydrogel lenses resulted in an improvement in ocular redness and neovascularization and dryness symptoms among subjects in this trial, regardless of their previous low Dk lens-wearing schedule. All improvements in signs and symptoms were sustained through 12 months.
Simulation of the thermomechanical interaction between pellet and cladding and fission gas release
International Nuclear Information System (INIS)
Denis, Alicia C.; Soba, Alejandro
2000-01-01
This paper summarizes the present status of a computer code that simulates some of the main phenomena occurring in a fuel element of a nuclear power reactor throughout its life. Temperature distribution, thermal expansion, elastic and plastic strains, creep, mechanical interaction between pellet and cladding, fission gas release, swelling and densification are modeled. Thermal expansion gives origin to elastic or plastic strains, which adequately describe the bamboo effect. The code assumes an axial symmetric rod and hence, cylindrical finite elements are employed for the discretization. The fission gas inventory is calculated by means of a diffusion model, which assumes spherical grains and uses also a finite element scheme. Once the temperature distribution in the pellet and the cladding is obtained and in order to reduce the calculation time, the rod is divided into five cylindrical rings where the temperature is averaged. In each ring the gas diffusion problem is solved in one representative grain and the results are then extended to the whole ring. The pressure, increased by the released gas, interacts with the stress field. Densification and swelling due to solid and gaseous fission products are also considered. Experiments, particularly those of the FUMEX series, are simulated with this code. A good agreement is obtained for the fuel center line temperature, the inside rod pressure and the fractional gas release. (author)
DEFF Research Database (Denmark)
Svendsen, Jesper Hastrup; Aldershvile, J; Abildgaard, U
1989-01-01
to a beta blocker. In bicycle ergometer exercise tests performed 4 h after study drug intake, total exercise time and time until 1-mm ST-depression increased significantly during both regimens as compared with placebo (p less than 0.05). However, only the 60-mg once-daily regimen was significantly better...... than placebo with regard to time until angina pectoris. The results indicate that ISMN-CR 60 mg once daily is effective as adjunctive to beta-blocker treatment, and nitrate tolerance appeared to develop during the twice-daily regimen. In 10 of the patients, the effect of additional sublingual...
Nakayama, Ayako; Yamaguchi, Naho; Ohno, Yukiko; Miyata, Chihiro; Kondo, Haruomi; Sunada, Hisakazu; Okamoto, Hirokazu
2013-01-01
Although progesterone vaginal suppositories (hospital-formulated) are used for the treatment of infertility, their half-life is so short that multiple doses are required. In this study, we aimed to develop sustained-release vaginal suppositories suitable for clinical use which maintain an effective blood concentration by once-a-day treatment, and prepared 7 types of suppository containing the sustained-release progesterone tablets to characterize their sustained-release performance. We selected one candidate suppository among them, taking recovery rate, reproducibility, and hardness, as well as the sustained-release performance into consideration. The shell of the selected suppository is composed of VOSCO S-55 and progesterone for rapid release. The molded progesterone tablets for sustained release were embedded inside. The distribution of the weight and content of the suppository was limited, and the release rate of progesterone was significantly slower than that of a conventional progesterone suppository prepared in our hospital. The single-dose administration of the selected suppository to five healthy volunteers led to significant extension of the blood concentration. We also confirmed the rise of the basic value by multiple administration. The simulation comparison suggested that the blood progesterone concentration is controlled by once-a-day administration of the selected suppository better than twice-a-day administration of the conventional suppository. In conclusion, the sustained-release vaginal suppository prepared in this study was considered to be useful for clinical treatment.
Developments in managing severe chronic pain: role of oxycodone–naloxone extended release
Directory of Open Access Journals (Sweden)
Fanelli G
2015-07-01
Full Text Available Guido Fanelli,1 Andrea Fanelli2 1Anesthesia and Intensive Care Unit, University of Parma, Parma, 2Anesthesia and Intensive Care Unit, Policlinico S Orsola-Malpighi, Bologna, Italy Abstract: Chronic pain is a highly disabling condition, which can significantly reduce patients’ quality of life. Prevalence of moderate and severe chronic pain is high in the general population, and it increases significantly in patients with advanced cancer and older than 65 years. Guidelines for the management of chronic pain recommend opioids for the treatment of moderate-to-severe pain in patients whose pain is not responsive to initial therapies with paracetamol and/or nonsteroidal anti-inflammatory drugs. Despite their analgesic efficacy being well recognized, adverse events can affect daily functioning and patient quality of life. Opioid-induced constipation (OIC occurs in 40% of opioid-treated patients. Laxatives are the most common drugs used to prevent and treat OIC. Laxatives do not address the underlying mechanisms of OIC; for this reason, they are not really effective in OIC treatment. Naloxone is an opioid receptor antagonist with low systemic bioavailability. When administered orally, naloxone antagonizes the opioid receptors in the gut wall, while its extensive first-pass hepatic metabolism ensures the lack of antagonist influence on the central-mediated analgesic effect of the opioids. A prolonged-release formulation consisting of oxycodone and naloxone in a 2:1 ratio was developed trying to reduce the incidence of OIC maintaining the analgesic effect compared with use of the sole oxycodone. This review includes evidence related to use of oxycodone and naloxone in the long-term management of chronic non-cancer pain and OIC. Keywords: chronic pain, opioid-induced constipation, opioids, oxycodone–naloxone
Dupoiron, D; Stachowiak, A; Loewenstein, O; Ellery, A; Kremers, W; Bosse, B; Hopp, M
2017-10-01
Oxycodone/naloxone (OXN PR) is a prolonged-release formulation containing oxycodone and naloxone in a 2:1 ratio. This study aimed to evaluate the tolerability and efficacy of doses up to OXN160/80 mg PR compared with oxycodone prolonged-release formulation (OxyPR) in a randomised controlled trial. Two hundred and forty-three patients were randomised to treatment with OXN PR (n = 123) or OxyPR (n = 120) during the 5-week double-blind study. Measured were: opioid-induced constipation [bowel function index score (BFI)]; analgesic efficacy (NRS 0-10); daily laxative rescue medication use; rescue medication use, and the number of complete spontaneous bowel movements (CSBMs) per week. A subanalysis was conducted in cancer patients. Greater reductions in mean BFI scores were reported for the OXN PR group compared with OxyPR from Week 1 onwards; at Week 5 the mean change from baseline was -32.5 versus -14.2. Average 24-h pain scores were low and remained stable in the range 3-4 in both treatment groups. Analgesic rescue medication use was similar between the groups. Patients receiving OXN PR used significantly lower mean daily doses of laxative rescue medication than those receiving OxyPR (P = 0.006). The number of CSBM in the OXN PR group approximately doubled compared with a 25% decrease in the OxyPR group. Comparable results to the total study population were reported in the cancer patient subgroup. OXN PR in daily doses of up to 160/80 mg significantly improves bowel function compared with equivalent doses of OxyPR while still providing comparable analgesic efficacy. Effective analgesia can be achieved using oxycodone/naloxone PR up to 160/80 mg daily without compromising bowel function. A similar outcome was reported in cancer and non-cancer patients. © 2017 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.
Formulation and Pharmacokinetic Evaluation of Controlled-Release ...
African Journals Online (AJOL)
The effect of several formulation variables on in ... The in vivo pharmacokinetics of the optimized formulation was compared ... Results: The core tablets exhibited extended release consisting of drug release from the embedded ... important factor in medical treatment with respect ... The solvents for high-performance liquid.
Adibkia, K; Ghanbarzadeh, S; Mohammadi, G; Khiavi, H Z; Sabzevari, A; Barzegar-Jalali, M
2014-03-01
This study was conducted to investigate the effects of HPMC (K4M and K100M) as well as tragacanth on the drug release rate of diltiazem (DLTZ) from matrix tablets prepared by direct compression method.Mechanism of drug transport through the matrices was studied by fitting the release data to the 10 kinetic models. 3 model independent parameters; i. e., mean dissolution time (MDT), mean release rate (MRR) and release rate efficacy (RE) as well as 5 time point approaches were established to compare the dissolution profiles. To find correlation between fraction of drug released and polymer's molecular weight, dissolution data were fitted into two proposed equations.All polymers could sustain drug release up to 10 h. The release data were fitted best to Peppas and Higuchi square root kinetic models considering squared correlation coefficient and mean percent error (MPE). RE and MRR were decreased when polymer to drug ratio was increased. Conversely, t60% was increased with raising polymer /drug ratio. The fractions of drug released from the formulations prepared with tragacanth were more than those formulated using the same amount of HPMC K4M and HPMC K100M.Preparation of DLTZ matrices applying HPMCK4M, HPMC K100M and tragacanth could effectively extend the drug release. © Georg Thieme Verlag KG Stuttgart · New York.
ONC201: Stressing tumors to death.
Endo Greer, Yoshimi; Lipkowitz, Stanley
2016-02-16
The small molecule ONC201 was identified in a screen for compounds that would induce expression of the gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in tumors and thus cause an autocrine- or paracrine-induced death in tumor cells. Two Research Articles in this issue of Science Signaling by Ishizawa et al. and Kline et al. describe how ONC201 can also trigger cytotoxicity by inducing a stress response. The mechanisms of the stress response induced differ between hematological malignancies and solid tumors, highlighting the complexity of ONC201-induced toxicity and raising intriguing issues of tissue-specific pathways activated by the drug. Copyright © 2016, American Association for the Advancement of Science.
Spectral shift controlled reactor, UO2 once-through cycle optimized
International Nuclear Information System (INIS)
1978-05-01
This paper presents technical and economic data on the SSCR which may be of use in the International Fuel Cycle Evaluation Program to intercompare alternative nuclear systems. Included in this data is information on the optimized UO 2 once-through fuel cycle. The ''optimized'' cycle refers to a UO 2 once-through cycle which has better fuel resource utilization than the conventional UO 2 cycle employed in current design PWRs. This fuel cycle uses more in-core batches and a higher discharge exposure than current PWR fuel management schemes. The proposed cycle is not optimal in a mathematical sense, however, since additional resource savings can be obtained if the discharge exposure is extended to even higher values and the number of in-core fuel batches is increased further. The present cycle was selected as ''optimal'' based on the assumption that it can be achieved with only an extension of fuel design technology and can therefore be deployed in a relatively short time frame. In the longer term, modification to reactor geometry as well as further extensions of discharge burnup might be considered to realize additional reduction in uranium resource requirements. The data contained in this paper has been developed by an ongoing program which at the present time is only 50% complete. The data presented here should therefore be considered preliminary and will be updated in the future as required
Wysham, Carol H; Rosenstock, Julio; Vetter, Marion L; Dong, Fang; Öhman, Peter; Iqbal, Nayyar
2018-01-01
To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID). This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m 2 ; diabetes duration, 8.5 years) received either exenatide QWS-AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by -1.4% and -1.0%, respectively (least-squares mean difference, -0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS-AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups (P = .37 for difference). Gastrointestinal adverse events (AEs) were reported in 22.7% (exenatide QWS-AI) and 35.6% (exenatide BID) of patients; fewer patients in the exenatide QWS-AI group withdrew because of AEs than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use. Exenatide QWS-AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
Algebraic Factoring algorithm to recognise read-once functions.
Naidu, S.R.
2003-01-01
A fast polynomial-time algorithm was recently proposed to determine whether a logic function expressed as a unate DNF (disjunctive normal form) can be expressed as a read-once formula where each variable appears no more than once. The paper uses a combinatorial characterisation of read-once formulas
Ruiz, Sara Melisa Arciniegas; Olvera, Lilia Gutiérrez; Chacón, Sara del Carmen Caballero; Estrada, Dinorah Vargas
2015-04-01
To determine the pharmacokinetics of doxycycline hyclate administered orally in the form of experimental formulations with different proportions of acrylic acid-polymethacrylate-based matrices. 30 healthy adult dogs. In a crossover study, dogs were randomly assigned (in groups of 10) to receive a single oral dose (20 mg/kg) of doxycycline hyclate without excipients (control) or extended-release formulations (ERFs) containing doxycycline, acrylic acid polymer, and polymethacrylate in the following proportions: 1:0.5:0.0075 (ERF1) or 1:1:0.015 (ERF2). Serum concentrations of doxycycline were determined for pharmacokinetic analysis before and at several intervals after each treatment. Following oral administration to the study dogs, each ERF resulted in therapeutic serum doxycycline concentrations for 48 hours, whereas the control treatment resulted in therapeutic serum doxycycline concentrations for only 24 hours. All pharmacokinetic parameters for ERF1 and ERF2 were significantly different; however, findings for ERF1 did not differ significantly from those for the control treatment. Results indicated that both ERFs containing doxycycline, acrylic acid polymer, and polymethacrylate had an adequate pharmacokinetic-pharmacodynamic relationship for a time-dependent drug and a longer release time than doxycycline alone following oral administration in dogs. Given the minimum effective serum doxycycline concentration of 0.26 μg/mL, a dose interval of 48 hours can be achieved for each tested ERF. This minimum inhibitory concentration has the potential to be effective against several susceptible bacteria involved in important infections in dogs. Treatment of dogs with either ERF may have several benefits over treatment with doxycycline alone.
Parejiya, Punit B; Barot, Bhavesh S; Patel, Hetal K; Shelat, Pragna K; Shukla, Arunkumar
2013-11-01
The study was aimed toward development of modified release oral drug delivery system for highly water soluble drug, Milnacipran HCl (MH). Novel Tablet in Tablet system (TITs) comprising immediate and extended release dose of MH in different parts was fabricated. The outer shell was composed of admixture of MH, lactose and novel herbal disintegrant obtained from seeds of Lepidium sativum. In the inner core, MH was matrixed with blend of hydrophilic (Benecel®) and hydrophobic (Compritol®) polymers. 3² full factorial design and an artificial neuron network (ANN) were employed for correlating effect of independent variables on dependent variables. The TITs were characterized for pharmacopoeial specifications, in vitro drug release, SEM, drug release kinetics and FTIR study. The release pattern of MH from batch A10 containing 25.17% w/w Benecel® and 8.21% w/w of Compritol® exhibited drug release pattern close proximal to the ideal theoretical profile (t(50%) = 5.92 h, t(75%) = 11.9 h, t(90%) = 18.11 h). The phenomenon of drug release was further explained by concept of percolation and the role of Benecel® and Compritol® in drug release retardation was studied. The normalized error obtained from ANN was less, compared with the multiple regression analysis, and exhibits the higher accuracy in prediction. The results of short-term stability study revealed stable chataracteristics of TITs. SEM study of TITs at different dissolution time points confirmed both diffusion and erosion mechanisms to be operative during drug release from the batch A10. Novel TITs can be a succesful once a day delivery system for highly water soluble drugs.
International Nuclear Information System (INIS)
Lee, J.H.; Atkins, J.E.; McNeish, J.A.; Vallikat, V.
1996-01-01
The first model assumed that dripping water directly contacts the waste form inside the ''failed'' waste package and radionuclides are released from the EBS by advection. The second model assumed that dripping water is diverted around the package (because of corrosion products plugging the perforations), thereby being prevented from directly contacting the waste form. In the second model, radionuclides were assumed to diffuse through the perforations, and, once outside the waste package, to be released from the EBS by advection. For the case with the second EBS release model, most radionuclides had lower peak EBS release rates than with the first model. Impacts of the alternative EBS release models were greater for the radionuclides with low solubility. The analysis indicated that the EBS release model representing advection through a ''failed'' waste package (the first model) may be too conservative; thus a ''failed'' waste package container with multiple perforations may still be an important barrier to radionuclide release
Directory of Open Access Journals (Sweden)
Yang FD
2017-04-01
Full Text Available Fu De Yang,1 Juan Li,1 Yun Long Tan,1 Wei Ye Liang,1 Rongzhen Zhang,1 Ning Wang,1 Wei Feng,1 Shangli Cai,2 Jian Min Zhuo,2 Li Li Zhang2 1Beijing Hui-Long-Guan Hospital, 2Department of Medical Affairs, Xian Janssen Pharmaceutical Ltd, Beijing, People’s Republic of China Objective: The aim of this study was to evaluate the changes in treatment satisfaction after switching to paliperidone extended-release (ER in Chinese schizophrenia patients dissatisfied with their previous antipsychotic treatment.Methods: In this 8-week, open-label, single-arm, multicenter, prospective study, 1,693 patients dissatisfied with previous antipsychotic medication were enrolled and switched to paliperidone ER tablets (3–12 mg/d based on clinical judgment. The primary efficacy end point was change in Medication Satisfaction Questionnaire (MSQ score from baseline to week 8. The secondary end points included percentage of patients with MSQ score ≥4, as well as changes in Clinical Global Improvement-Severity (CGI-S and Personal and Social Performance (PSP scores.Results: MSQ scores increased significantly from baseline (mean [standard deviation {SD}]: 2.48 [0.55] to week 8 (5.47 [0.89], P<0.0001; primary end point, full analysis set. The percentage of patients with MSQ score ≥4 was 95.9% at week 8, indicating that most of the patients were satisfied with their treatment. Significant (P<0.0001 improvements from baseline to week 8 were noted in CGI-S score (2.37 [1.20] and PSP score (25.5 [15.0]. A total of 174 (10.28% patients experienced adverse events (AEs. The most common (>10 patients events were extrapyramidal disorder (n=84, 4.96%, poor quality sleep (n=18, 1.06% and akathisia (n=13, 0.77%. The majority of AEs were mild to moderate in severity. No deaths occurred.Conclusion: Treatment satisfaction improved after switching to paliperidone ER from the previous antipsychotic in Chinese patients with schizophrenia. Keywords: atypical antipsychotics, open label
The new trends in theophylline therapy
Directory of Open Access Journals (Sweden)
Aida Mehmedagić
2002-02-01
Full Text Available Sustained-release theophylline pellets formulation for once-daily evening administration significantly improved patients compliance and adjusted serum levels profile of the drug. The patients conversion from i.v. to p.o. therapy is one of the most critical steps in the treatment of asthma according to its chronopathophysiological character. In our study we have examined safety and efficiency of this conversion in twelve hospitalised asthmatic patients who were given the new sustained-release theophylline pellets formulation for once-daily evening administration. The lung function parameters (FEV1, VC, RV, and Rt and serum theophylline concentrations were monitored. So, the values obtained for the last day of i.v. therapy and the fifth day of p.o. therapy were compared. We found that 75% of the patients had no change or improved lung function on the conversion. Our results indicate that this conversion from i.v. to p.o. theophylline therapy is safe and could be efficacious. Also, the maximum theophylline serum levels could safely be predicted by measuring only one serum concentration in p.o. therapy with sustained-release theophylline pellets formulation for once-daily evening administration.
Directory of Open Access Journals (Sweden)
William Insull Jr
2010-11-01
Full Text Available William Insull Jr1, Peter P Toth2, H Robert Superko3, Roopal B Thakkar4, Scott Krause4, Ping Jiang4, Rhea A Parreno4, Robert J Padley41Baylor College of Medicine and Methodist Hospital, Houston, Texas; 2University of Illinois College of Medicine, Peoria, Illinois; 3Celera, Alameda, California, Mercer University, Atlanta, Georgia; 4Abbott, Abbott Park, Illinois, USAObjective: To compare the effects of combination niacin extended-release + simvastatin (NER/S versus atorvastatin alone on apolipoproteins and lipid fractions in a post hoc analysis from SUPREME, a study which compared the lipid effects of niacin extended-release + simvastatin and atorvastatin in patients with hyperlipidemia or mixed dyslipidemia.Patients and methods: Patients (n = 137 with dyslipidemia (not previously receiving statin therapy or having discontinued any lipid-altering treatment 4–5 weeks prior to the study received NER/S (1000/40 mg/day for four weeks, then 2000/40 mg/day for eight weeks or atorvastatin 40 mg/day for 12 weeks. Median percent changes in apolipoprotein (apo A-1, apo B, and the apo B:A-I ratio, and nuclear magnetic resonance lipoprotein subclasses from baseline to week 12 were compared using the Wilcoxon rank-sum test and Fisher’s exact test.Results: NER/S treatment produced significantly greater percent changes in apo A-I and apo B:A-I, and, at the final visit, apo B <80 mg/dL was attained by 59% versus 33% of patients, compared with atorvastatin treatment (P = 0.003. NER/S treatment resulted in greater percent reductions in calculated particle numbers for low-density lipoprotein (LDL, 52% versus 43%; P = 0.022, small LDL (55% versus 45%; P = 0.011, very low-density lipoprotein (VLDL and total chylomicrons (63% versus 39%; P < 0.001, and greater increases in particle size for LDL (2.7% versus 1.0%; P = 0.007 and VLDL (9.3% versus 0.1%; P < 0.001, compared with atorvastatin.Conclusion: NER/S treatment significantly improved apo A-I levels and the apo
Directory of Open Access Journals (Sweden)
Patricia Echeverría
Full Text Available Etravirine (ETR was approved for patients with virological failure and antiretroviral resistance mutations. It has also shown antiviral efficacy in antiretroviral-naïve patients. However, data on the switching from protease inhibitors (PI to ETR are lacking.HIV-1-infected patients with suppressed viral load (VL during a PI-containing regimen (>12 months and no previous virological failure were randomized to switch from the PI to ETR (400 mg/day, dissolved in water (ETR group, n = 22 or to continue with the same regimen (control group, n = 21. Percentage of patients with VL ≤ 50 copies/mL were assessed at week 48, as well as changes in CD4 T-cell counts and metabolic profile.We included 43 patients [72.9% male, 46.3 (42.2; 50.6 years]. Two patients receiving ETR (grade-1 diarrhea and voluntary discontinuation and another in the control group (simplification discontinued therapy early. No patients presented virological failure (two consecutive VL>50 copies/mL; treatment was successful in 95.2% of the control group and 90.9% of the ETR group (intention-to-treat analysis, missing = failure (p = 0.58. CD4+ T-cell counts did not significantly vary [+49 cells/µL in the ETR group (p = 0.25 and -4 cells/µL in the control group (p = 0.71]. The ETR group showed significant reductions in cholesterol (p<0.001, triglycerides (p = <0.001, and glycemia (p = 0.03 and higher satisfaction (0-10 scale (p = 0.04. Trough plasma concentrations of ETR were similar to observed in studies using ETR twice daily.Switch from a PI-based regimen to a once-daily combination based on ETR maintained undetectable VL during 48 weeks in virologically suppressed HIV-infected patients while lipid profile and patient satisfaction improved significantly.ClinicalTrials.gov NCT01034917.
Directory of Open Access Journals (Sweden)
Ian LP Beales
2013-02-01
Full Text Available The role of the peptide hormone gastrin in stimulating gastric acid secretion is well established. Mature amidated gastrin is processed from larger peptide precursor forms. Increasingly these processing intermediates, such as glycine-extended gastrin (G-Gly and progastrin, have been shown to have biological activities of their own, often separate and complementary to gastrin. Although G-Gly is synthesized and secreted by gastric antral G-cells, the physiological functions of this putative mediator are unclear. Gastrin and cholecystokinin (CCK stimulate the secretion of somatostatin from gastric D-cells as part of the feedback control of gastric acid. In this study the effect of G-Gly and gastrin on the release of somatostatin from rabbit fundic D-cells was examined. D-cells were obtained by collagenase-EDTA digestion and elutriation and cultured for 48 hours. With a 2 hour exposure to the peptides, gastrin but not G-Gly stimulated somatostatin release. Treatment of D-cells for 24 hours with gastrin or G-Gly individually, significantly enhanced subsequent basal as well as CCK- and GLP-1-stimulated somatostatin release. Twenty four hours exposure to gastrin combined with G-Gly synergistically enhanced basal and agonist-stimulated somatostatin release and cellular somatostatin content. Gastrin and G-Gly may be important in the longer term regulation of D-cell function.
Directory of Open Access Journals (Sweden)
Khalifa N
2014-05-01
Full Text Available Nabil Khalifa,1 Timour El-Husseini,1 Ahmed Morrah,2 Elshenawy Mostafa,3 Hesham Hamoud41Department of Orthopedic Surgery, Ain Shams University, Cairo, Egypt; 2Department of Orthopedic Surgery, Cairo University, Cairo, Egypt; 3Department of Orthopedic Surgery, Mansoura University, Mansoura, Egypt; 4Department of Rheumatology, Azhar University, Cairo, EgyptPurpose: Ibuprofen sustained release (SR has been shown to provide effective symptomatic pain relief in chronic arthritic conditions such as osteoarthritis in European and US patient populations. Few studies have been conducted in other patient populations. A 4-week prospective multicenter open-label observational study was designed to explore and describe the combined effect of ibuprofen SR and standard medical care in patients suffering from osteoarthritis in 15 general medical practices in Egypt.Patients and methods: In total, 519 patients were prescribed ibuprofen SR 2 ×800 mg once daily for 4 weeks.Results: Ibuprofen SR combined with standard medical care significantly improved day and night pain, with 99.4% of the patients reporting improvement. The treatment reduced the symptom severity of joint tenderness/stiffness and the duration of morning stiffness, and allowed more patients to carry out normal activities. Overall compliance with the prescribed ibuprofen SR regimen was 98.6%. Ibuprofen SR was generally well tolerated with no serious adverse events reported during the study. There was no increase in blood pressure or heart rate.Conclusion: The combined treatment provided effective relief of pain in patients with osteoarthritis in a large real-life general medical practice setting in Egypt. Owing to its convenient once-daily dosing regimen, ibuprofen SR may enhance patient compliance.Keywords: chronic arthritis, compliance, pain score, real-life
An introduction to the Micrel Micropump MP Daily portable syringe driver.
Groves, Karen E
2003-11-01
In this article the author describes the Micrel Micropump MP Daily (MP Daily) portable syringe driver. This follows the author's experience of a 4-month pilot of the device by an inpatient palliative care unit. Portable syringe drivers are commonly used to deliver continuous subcutaneous infusions in palliative care situations. Those in current use are not without problems and serious adverse events have occasionally been reported, mainly resulting from confusion between models. The MP Daily syringe driver addresses some of these issues while remaining small, lightweight and inexpensive, with a long battery life and fitting into the pocket of a shirt of pyjama jacket. Improvements over current models include an on/off button, the absence of facilities to set a zero rate or change the rate once the syringe driver is running, and the absence of a boost button. In addition, there are improved alarms, a message display system and a configuration menu. Although confusion remains a problem, and the ideal has not yet been reached, the MP Daily goes some considerable way towards reducing risks and opportunities for human error.
Laguna Verde after the extended power increase
International Nuclear Information System (INIS)
Herrera C, M. N.; Castaneda G, M. A.; Cardenas J, J. B.; Garcia de la C, F. M.
2012-10-01
The project of extended power increase that was implemented in both units of the nuclear power plant of Laguna Verde beginning with the stage feasibility evaluation in nuclear side of the facilities, that is to say the affectation of the power increase in the equipment s, systems and components of the nuclear power plant; besides the feasibility evaluation a study cost-benefit for the rehabilitated and modernization of the equipment s, systems and components of Plant Balance was realized. Once considered technical and economically feasible the project began the engineering evaluations required to carry out the licensing of the new operation conditions, as well as beginning to the elaboration of the technical specifications purchase of the equipment s, systems and components of the Plant Balance. While on one hand was carried out the administration of the licensing of the extended power increase for other was carried out the necessary engineering to make the physical changes in the conventional side of the nuclear power plant. Once concluded the constructive stage beginning the final stage of the project, the starting-up tests, operation and performance of the Units under the new operation conditions. This work describes this last stage that contains the technical base, the realized tests and the obtained results. (Author)
Directory of Open Access Journals (Sweden)
Yadav M
2013-08-01
Full Text Available Manisha Yadav, Judith Volkar Center for Specialized Women’s Health, Cleveland Clinic Foundation, Cleveland, Ohio, USA Abstract: About 80% of postmenopausal women experience vasomotor symptoms, such as hot flashes and night sweats – symptoms that are associated with sleep disruption and can lead to fatigue and mood changes. Moreover, hot flashes can be embarrassing for women, causing difficulties at work and in their social lives. Many therapies have been advocated for relief of vasomotor symptoms, but only hormone therapy has been US Food and Drug Administration approved. However, after the Women's Health Initiative Study suggested that there was a correlation between hormone therapy and increased risk for breast cancer and cardiovascular events, many women stopped taking hormone therapy, and many do not want to initiate it. Hormone therapy is also contraindicated in certain women, such as those with a history of hormone-stimulated cancer like breast and uterine cancer. Gabapentin (Neurontin has shown efficacy in relieving vasomotor symptoms and is used as off-label for this indication. A new extended-release formulation of gabapentin has also shown efficacy in treating hot flashes and improving sleep quality with possibly fewer side effects than regular gabapentin. Keywords: Hot flushes, vasomotor symptoms, postmenopausal, hormone-sensitive cancer, non-hormonal therapy, gastric-retentive, Breeze
All-at-once Optimization for Coupled Matrix and Tensor Factorizations
DEFF Research Database (Denmark)
Evrim, Acar Ataman; Kolda, Tamara G.; Dunlavy, Daniel M.
2011-01-01
.g., the person by person social network matrix or the restaurant by category matrix, and higher-order tensors, e.g., the "ratings" tensor of the form restaurant by meal by person. In this paper, we are particularly interested in fusing data sets with the goal of capturing their underlying latent structures. We...... formulate this problem as a coupled matrix and tensor factorization (CMTF) problem where heterogeneous data sets are modeled by fitting outer-product models to higher-order tensors and matrices in a coupled manner. Unlike traditional approaches solving this problem using alternating algorithms, we propose...... an all-at-once optimization approach called CMTF-OPT (CMTF-OPTimization), which is a gradient-based optimization approach for joint analysis of matrices and higher-order tensors. We also extend the algorithm to handle coupled incomplete data sets. Using numerical experiments, we demonstrate...
Directory of Open Access Journals (Sweden)
Jeans Matthew
2011-07-01
Full Text Available Abstract Background Current guidance regarding the role of daily breakfast in human health is largely grounded in cross-sectional observations. However, the causal nature of these relationships has not been fully explored and what limited information is emerging from controlled laboratory-based experiments appears inconsistent with much existing data. Further progress in our understanding therefore requires a direct examination of how daily breakfast impacts human health under free-living conditions. Methods/Design The Bath Breakfast Project (BBP is a randomised controlled trial comparing the effects of daily breakfast consumption relative to extended fasting on energy balance and human health. Approximately 70 men and women will undergo extensive laboratory-based assessments of their acute metabolic responses under fasted and post-prandial conditions, to include: resting metabolic rate, substrate oxidation, dietary-induced thermogenesis and systemic concentrations of key metabolites/hormones. Physiological and psychological indices of appetite will also be monitored both over the first few hours of the day (i.e. whether fed or fasted and also following a standardised test lunch used to assess voluntary energy intake under controlled conditions. Baseline measurements of participants' anthropometric characteristics (e.g. DEXA will be recorded prior to intervention, along with an oral glucose tolerance test and acquisition of adipose tissue samples to determine expression of key genes and estimates of tissue-specific insulin action. Participants will then be randomly assigned either to a group prescribed an energy intake of ≥3000 kJ before 1100 each day or a group to extend their overnight fast by abstaining from ingestion of energy-providing nutrients until 1200 each day, with all laboratory-based measurements followed-up 6 weeks later. Free-living assessments of energy intake (via direct weighed food diaries and energy expenditure (via
DEFF Research Database (Denmark)
Søndergaard, Esben; Klose, Marianne; Hansen, Mette
2011-01-01
Background: Recombinant human GH (rhGH) replacement therapy in children and adults currently requires daily sc injections for several years or lifelong, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed for once-weekly administration. Objectives...
Directory of Open Access Journals (Sweden)
Ross Lisa L
2008-03-01
Full Text Available Abstract Background Once-daily (QD ritonavir 100 mg-boosted fosamprenavir 1400 mg (FPV/r100 or atazanavir 300 mg (ATV/r100, plus tenofovir/emtricitabine (TDF/FTC 300 mg/200 mg, have not been compared as initial antiretroviral treatment. To address this data gap, we conducted an open-label, multicenter 48-week study (ALERT in 106 antiretroviral-naïve, HIV-infected patients (median HIV-1 RNA 4.9 log10 copies/mL; CD4+ count 191 cells/mm3 randomly assigned to the FPV/r100 or ATV/r100 regimens. Results At baseline, the FPV/r100 or ATV/r100 arms were well-matched for HIV-1 RNA (median, 4.9 log10 copies/mL [both], CD4+ count (mean, 176 vs 205 cells/mm3. At week 48, intent-to-treat: missing/discontinuation = failure analysis showed similar responses to FPV/r100 and ATV/r100 (HIV-1 RNA 3, p = 0.398 [Wilcoxon rank sum test]. Fasting total/LDL/HDL-cholesterol changes-from-baseline were also similar, although week 48 median fasting triglycerides were higher with FPV/r100 (150 vs 131 mg/dL. FPV/r100-treated patients experienced fewer treatment-related grade 2–4 adverse events (15% vs 57%, with differences driven by ATV-related hyperbilirubinemia. Three patients discontinued TDF/FTC because their GFR decreased to Conclusion The all-QD regimens of FPV/r100 and ATV/r100, plus TDF/FTC, provided similar virologic, CD4+ response, and fasting total/LDL/HDL-cholesterol changes through 48 weeks. Fewer FPV/r100-treated patients experienced treatment-related grade 2–4 adverse events.
Hutsell, Blake A; Negus, S Stevens; Banks, Matthew L
2016-11-01
Clinical trial data suggest amphetamine treatment is most efficacious in moderate to high frequency cocaine users. However, preclinical studies have examined amphetamine treatment effects under relatively limited cocaine access conditions with low to moderate cocaine intakes. This study determined d-amphetamine treatment effects on cocaine self-administration in rhesus monkeys under cocaine access conditions allowing for high daily cocaine intake. For comparison and as a negative control, treatment effects with the antipsychotic risperidone were also examined. Continuous 21-day treatments with ramping doses of d-amphetamine (days 1-7: 0.032mg/kg/h; days 8-21: 0.1mg/kg/h, i.v.) or risperidone (days 1-7: 0.001mg/kg/h; days 8-14: 0.0032mg/kg/h; days 15-21: 0.0056mg/kg/h, i.v.) were administered to rhesus monkeys (n=4) with daily access to two types of cocaine self-administration sessions: (1) a 2-h 'choice' session with concurrent availability of 1-g food pellets and intravenous cocaine injections (0-0.1mg/kg per injection) and (2) a 20-h 'extended-access' session with 0.1mg/kg per injection cocaine availability. Total daily cocaine intake increased >6-fold during extended cocaine access. d-Amphetamine significantly decreased total cocaine intake, but not cocaine vs food choice. In contrast, risperidone did not significantly alter either total cocaine intake or cocaine vs. food choice. These results confirm and extend previous results supporting treatment effectiveness for monoamine releasers, but not dopamine antagonists, to reduce cocaine self-administration. Moreover, these results suggest amphetamine treatment efficacy to decrease preclinical cocaine vs. food choice may depend upon cocaine access conditions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Using Six Sigma to improve once daily gentamicin dosing and therapeutic drug monitoring performance.
LENUS (Irish Health Repository)
Egan, Sean
2012-08-07
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
A pharmacoeconomic evaluation of two new products for the treatment of overactive bladder.
Arikian, S R; Casciano, J; Doyle, J J; Tarride, J E; Casciano, R N
2000-02-01
The objective of this study is to evaluate the cost effectiveness of two new treatments for overactive bladder: once-daily controlled-release oxybutynin, and twice-daily tolterodine, with a comparison with oxybutynin immediate release. Also estimated are the potential cost savings to a health plan budget resulting from increased utilization of the most cost-effective treatment. The design is a decision-tree model based on clinical trial data and expert panel estimates with a six-month time horizon conducted from a payer perspective. The primary outcome measure used in the analysis was treatment success, with success defined as zero incontinence episodes per week. A secondary outcome measure was the expected number of continent days. As first-line therapy, controlled-release oxybutynin is the most cost-effective treatment as measured by expected cost per success and expected cost per continent days. Controlled-release, once-daily oxybutynin yielded the highest expected success rate and the highest number of expected continent days. The expected cost of treatment with controlled-release oxybutynin was lower than tolterodine and equivalent to immediate-release oxybutynin. Increased utilization of controlled-release oxybutynin results in an estimated saving of $0.007 to $0.026 per member per month for a hypothetical HMO. The model was robust, incorporating all assumptions based on univariate and multivariate sensitivity analysis. Initiating treatment with controlled-release oxybutynin is the most cost-effective approach to treatment for overactive bladder.
Investigation of delayed fission gas release
International Nuclear Information System (INIS)
Cayet, Nicolas
1996-05-01
The study of the fission gas release process in the high burnup rig IFA-562 has revealed a particular fuel behaviour: a delay in the fission gas release process. It appeared that an important release of gas was measured by the pressure transducers once the power had decreased, whereas, during steady-state operation, the pressure did not increase very much. After examinations, the gap size has been concluded to be the main parameter involving this delay. However the burnup could have been a potential factor, its role is mainly to close the gap by swelling. The observations of low burnup rods have shown the same delayed fission gas release, the gap being small by design and closed essentially by thermal expansion. The study of the kinetics has demonstrated the time-independency of the phenomenon. Thus the proposed mechanism driving this delayed fission gas release would involve three consecutives stages. During steady-state, the gas is released into the interlinkage network of grain boundary bubbles and cracks. Due to the closed gap, the gas is trapped in some void volumes, unable to escape the pellet. During power reduction, the gap and some old/new cracks open, immediately providing a path for the gas to the pressure transducers and explaining this delay in the fission gas release. (author)
Design and fuel management of PWR cores to optimize the once-through fuel cycle
International Nuclear Information System (INIS)
Fujita, E.K.; Driscoll, M.J.; Lanning, D.D.
1978-08-01
The once-through fuel cycle has been analyzed to see if there are substantial prospects for improved uranium ore utilization in current light water reactors, with a specific focus on pressurized water reactors. The types of changes which have been examined are: (1) re-optimization of fuel pin diameter and lattice pitch, (2) axial power shaping by enrichment gradation in fresh fuel, (3) use of 6-batch cores with semi-annual refueling, (4) use of 6-batch cores with annual refueling, hence greater extended (approximately doubled) burnup, (5) use of radial reflector assemblies, (6) use of internally heterogeneous cores (simple seed/blanket configurations), (7) use of power/temperature coastdown at the end of life to extend burnup, (8) use of metal or diluted oxide fuel, (9) use of thorium, and (10) use of isotopically separated low sigma/sub a/ cladding material. State-of-the-art LWR computational methods, LEOPARD/PDQ-7/FLARE-G, were used to investigate these modifications
Toward sensitive document release with privacy guarantees
David Sánchez; Montserrat Batet
2017-01-01
Toward sensitive document release with privacy guarantees DOI: 10.1016/j.engappai.2016.12.013 URL: http://www.sciencedirect.com/science/article/pii/S0952197616302408 Filiació URV: SI Inclòs a la memòria: SI Privacy has become a serious concern for modern Information Societies. The sensitive nature of much of the data that are daily exchanged or released to untrusted parties requires that responsible organizations undertake appropriate privacy protection measures. Nowadays, much...
A REVIEW ON CONTROLLED DRUG RELEASE FORMULATION: SPANSULES
Rinky Maurya; Dr. Pramod Kumar Sharma; Rishabha Malviya
2014-01-01
Spansules are a dosage form which was considered as one of the Advanced Drug Delivery System. Multidrug preparations can be delivered easily by spansules or granules in capsule technology. This type of delivery system designed to release a drug or a medicament at two or more different rates or in different span of time. A quick/slow release system provides an initial release of drug followed by a constant rate of drug release over a extended period or a defined period of time and in slow/quic...
Webster, Lynn R; Smith, Michael D; Lawler, John; Lindhardt, Karsten; Dayno, Jeffrey M
2017-09-01
To compare the relative human abuse potential after insufflation of manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine ER tablets. A randomized, double-blind, double-dummy, active- and placebo-controlled five-way crossover study was performed with adult volunteers who were experienced, nondependent, recreational opioid users. After intranasal (IN) administration of manipulated high-volume (HV) morphine-ADER-IMT (60 mg), participants were randomized (1:1:1:1) to receive IN manipulated low-volume (LV) morphine ER (60 mg), IN manipulated LV morphine-ADER-IMT, intact oral morphine-ADER-IMT (60 mg), and placebo in crossover fashion. Pharmacodynamic and pharmacokinetic assessments included peak effect of drug liking (E max ; primary endpoint) using drug liking visual analog scale (VAS) score, E max using overall drug liking, and take drug again (TDA) VASs scores, and mean abuse quotient (AQ), a pharmacokinetic parameter associated with drug liking. Forty-six participants completed the study. After insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT, drug liking E max was significantly lower ( P < 0.0001) compared with IN morphine ER. Overall drug liking and TDA E max values were significantly lower ( P < 0.0001) after insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT compared with IN morphine ER. Mean AQ was lower after insufflation of HV (9.2) and LV (2.3) morphine-ADER-IMT or ingestion of oral morphine-ADER-IMT (5.5) compared with insufflation of LV morphine ER (37.2). All drug liking, take drug again, and abuse quotient endpoints support a significantly lower abuse potential with insufflation of manipulated morphine-ADER-IMT compared with manipulated and insufflated non-AD ER morphine. © 2016 American Academy of Pain Medicine.
Current therapy for Parkinson's disease
Directory of Open Access Journals (Sweden)
A. V. Obukhova
2014-01-01
Full Text Available The main goal of therapy for Parkinson's disease (PD is to correct dopamine deficiency in the nigrostriatal system. Levodopa preparations and dopamine receptor agonists (DRAs that are prescribed with regards to patient age and disease severity are mainly used now. Notwithstanding the fact that levodopa preparations are the gold standard of therapy, their long-term use gives rise to complications as motor fluctuations and drug-induced dyskinesias. The currently available DRAs are the drugs of choice for the therapy of early-stage PD as they are as effective as levodopa preparations. In extensive-stage PD, DRAs are used to enhance the therapy and correction of developed motor fluctuations and dyskinesias. Pramipexole is one of the most commonly used representatives of non-ergoline DRAs. The paper analyzes the efficacy of the medication used as both monotherapy and part of combined therapy, its effect on tremor and depression in PD. A novel extended-release formulation of pramipexole is considered separately. Both immediate- and extended-release pramipexole formulations contain the same active ingredient and have the same dopamine-receptor interaction profile, but differ in the tablet release rate of the active ingredient. The advantages of the novel formulation are its more steady-state plasma concentration and 24-hour action, which ensures continuous dopaminergic stimulation ofpostsynaptic receptors to prevent and treat already developed motor complications. The once-daily extended-release formulation of the drug makes its treatment regimen easier and patient compliance higher.
Anghelescu, I-G; Dierkes, W; Volz, H-P; Loeschmann, P-A; Schmitt, A B
2009-11-01
The therapeutic effects of venlafaxine extended release have been investigated by two prospective observational studies including 8506 patients in the outpatient setting of office based general practitioners and specialists. The efficacy has been documented by the Clinical Global Impression (CGI) scale and by the Hamilton depression (HAMD-21) scale. The tolerability has been assessed by the documentation of adverse events. About (2/3) of the patients were treated because of depression and about (1/3) mainly because of anxiety disorder. The patients of specialists did receive higher dosages and were more severely affected. The response rate on the CGI scale was 87.4 for the patients of general practitioners and 74.2 % for the patients of specialists. The results of the HAMD-21 scale, which has been used by specialists, showed a response rate of 71.8 and a remission rate of 56.3 %. These positive effects could be demonstrated even for the more severely and chronically affected patients. The incidence of adverse events was low in both studies and comparable to the tolerability profile of randomized studies. Importantly, the good tolerability profile was similar even for patients with concomitant cardiovascular disease. In conclusion, these results confirm the efficacy and good tolerability of venlafaxine extended release in the outpatient setting in Germany. Georg Thieme Verlag KG Stuttgart, New York.
ONC201 kills breast cancer cells in vitro by targeting mitochondria.
Greer, Yoshimi Endo; Porat-Shliom, Natalie; Nagashima, Kunio; Stuelten, Christina; Crooks, Dan; Koparde, Vishal N; Gilbert, Samuel F; Islam, Celia; Ubaldini, Ashley; Ji, Yun; Gattinoni, Luca; Soheilian, Ferri; Wang, Xiantao; Hafner, Markus; Shetty, Jyoti; Tran, Bao; Jailwala, Parthav; Cam, Maggie; Lang, Martin; Voeller, Donna; Reinhold, William C; Rajapakse, Vinodh; Pommier, Yves; Weigert, Roberto; Linehan, W Marston; Lipkowitz, Stanley
2018-04-06
We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA-encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201.
Matsuura, Hiroki; Kimoto, Sohei; Harada, Izumi; Naemura, Satoshi; Yamamuro, Kazuhiko; Kishimoto, Toshifumi
2016-05-26
Antipsychotic drug treatment can potentially lead to adverse events such as leukopenia and neutropenia. Although these events are rare, they represent serious and life-threatening hematological side effects. We present a case study of a patient with schizoaffective disorder in a 50-year-old woman. We report a case of paliperidone extended-release (ER)-induced leukopenia and neutropenia in a female patient with schizoaffective disorder. Initiating lithium carbonate treatment and decreasing the dose of valproic acid improved the observed leukopenia and neutropenia. This treatment did not influence psychotic symptoms. The combination of paliperidone ER and valproic acid induces increased paliperidone ER plasma levels. Lithium carbonate was successfully used to treat paliperidone ER-induced leukopenia and neutropenia.
Why still philosophy?: Once again
Directory of Open Access Journals (Sweden)
Krstić Predrag
2007-01-01
Full Text Available The intention of this paper is to revisit, once again the question asked by Adorno and Habermas and other contemporary thinkers under different headings few decades ago. The author is suggesting that nowadays philosophy requires a final departure from the idea of having single and perennial face, and that this would not only allow, but also enable philosophy to test its various faces freely, that is, without norm or limit set in advance. At the same time, by creating such ′liberal′ climate philosophy would no longer be frightened by the possible answer, and hence would no longer dramatize the very question of ′why still?′. Even if philosophy turns out to be far less than the mission it once bestowed upon itself.
Reichmann, H; Jost, W H
2010-09-01
The MAO-B inhibitor rasagiline is indicated for the treatment of idiopathic Parkinson's disease (PD), and its use is supported by evidence from large-scale, controlled clinical studies. The post-marketing observational study presented here investigated the efficacy and tolerability of rasagiline treatment (monotherapy or combination therapy) in daily clinical practice. The study included patients with idiopathic PD who received rasagiline (recommended dose 1 mg, once daily) as monotherapy or combination therapy. The treatment and observation period was approximately 4 months. Outcome measures included the change from baseline in the Columbia University Rating Scale (CURS), the Unified PD Rating Scale fluctuation subscale, daily OFF time (patient home diaries) and the PD Questionnaire-39. Adverse drug reactions/adverse events (ADRs/AEs) and the physician's global judgement of tolerability and efficacy were also examined. Overall, 754 patients received rasagiline during the study. Patients treated with rasagiline (monotherapy or combination therapy) showed significant improvements from baseline in symptom severity (including classical motor and non-classical motor/non-motor symptoms) and quality of life (QoL). Patients receiving combination therapy also experienced significant reductions in daily OFF time. Tolerability was rated as good/very good in over 90% of patients. In daily clinical practice, monotherapy or combination therapy with rasagiline is able to improve PD symptoms, reduce OFF time, and improve QoL, whilst demonstrating favourable tolerability. In addition, rasagiline has a simple dosing schedule of one tablet, once daily, with no titration. These results are consistent with the pivotal rasagiline clinical studies (TEMPO, LARGO and PRESTO).
Oral sustained release tablets of zidovudine using binary blends of natural and synthetic polymers.
Emeje, Martins; Olaleye, Olajide; Isimi, Christiana; Fortunak, Joseph; Byrn, Stephen; Kunle, Olobayo; Ofoefule, Sabinus
2010-01-01
Oral sustained release matrix tablets of zidovudine (ZDV) were prepared using different types, proportions and blends of carbopol 71G (C71) and a plant gum obtained from Abelmoschus esculentus (AEG). The effect of various formulation factors like polymer proportion, polymer type and pH of the dissolution medium on the in vitro release of the drug was studied, using the half change technique, in 900 ml of dissolution medium, at 100 rpm. Release kinetics were analyzed using Zero-order, Higuchi's square-root and Ritger-Peppas' empirical equations. In vitro release performance as revealed by the time taken for 70% of the drug to be released (t70%), showed that the release rate decreased with increase in polymer proportion. Matrix tablets containing 10 and 20% AEG were found to exhibit immediate-release characteristics. Matrix tablets containing 30% AEG showed t70% value of 204 min and extended the release up to 5 h, while matrix tablets containing 30% carbopol showed t70% value of 234 min and extended the release up to 6 h. Three blends of AEG and C71 at the ratio of 1:2, 2:1 and 1:3 showed t70% values of 132, 312 and 102 min respectively and extended the release up to 8 h. Mathematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets followed Fickian and anomalous release. Drug release from matrix tablets of zidovudine containing blends of AEG and C71 demonstrates the advantage of blending a natural and synthetic polymer over single polymer use.
Multi-centre evaluation of two daily disposable contact lenses.
Walker, Jon; Young, Graeme; Hunt, Chris; Henderson, Terri
2007-05-01
To evaluate the clinical performance of two daily disposable contact lenses: 1-DAY ACUVUE (1DA) (etafilcon A, Johnson & Johnson Vision Care) and FOCUS DAILIES with AquaComfort (FD) (nelfilcon A, CIBA Vision, Inc.), which contains a quickly released moisture enhancing agent, polyvinyl alcohol (PVA). This was a 1-week, daily wear, subject-masked, bilateral, parallel group study with subjects randomly assigned to one of two daily disposable soft contact lenses. Subjects were existing soft contact lens wearers in the age range 18-39 years with a spherical refraction between -0.50 and -6.00 D. Subjects were assessed at baseline and after 1 week. Assessments included both subjective (symptoms, wearing time, vision) and objective (lens fit and ocular health) outcomes. Twenty clinical sites enrolled 282 subjects (74% female) of whom 276 (98%) successfully completed the study. Significantly more 1DA wearers reported higher mean comfort scores than with FD (3.95 versus 3.41, respectively, Pdisposable lenses highlight that, although both lenses may be considered as clinically acceptable, these lenses should not be regarded as interchangeable.
Modeling and field studies of fouling in once-through steam generators
International Nuclear Information System (INIS)
Thompson, R.; Gaudreau, T.
1995-01-01
Efforts of the past 10 years to minimize fouling of the Crystal River-3 once-through steam generators are reviewed. The major focus has been on improving at-temperature pH control in the secondary cycle. Various concentrations of different pH control agents were tested in the field for hundreds of days to determine their effect on steam generator fouling. High concentrations of morpholine (50--100 ppm) in the feedwater were found to apparently produce de-fouling of the steam generators without an associated decrease in feedwater iron concentration as compared to that at lower levels of morpholine. Computer modeling of the pH(t) within the OTSG for the various chemistries tested indicates that the pH can change significantly with elevation within the steam generator by varying the pH control agent or its concentration. It is postulated that these variations in pH may change the surface charge of the tubes, tube support plates, and/or corrosion product particles in solution, to favor either deposition or repulsion of the particles, and thereby producing conditions that either favor fouling or de-fouling of the OTSG. Crystal River-3 experience indicates that corrosion product deposition and release processes inside the steam generator can be chemically manipulated to favor release, and thereby maximize plant performance, and delay or avoid costly hydraulic or chemical cleanings
The impact of common metal allergens in daily devices.
Hamann, Dathan; Hamann, Carsten R; Thyssen, Jacob P
2013-10-01
We are widely exposed to metal allergens in our daily doings. As exposures constantly changes because of fashion trends and technological developments, there is a need for a continuous update of patch testers. An overview of consumer metal exposure studies that have been published in 2012 and 2013 is provided as well as lists of common metal exposures. Nickel release in concentrations that cause nickel allergy and contact dermatitis is seen from laptop computers. Cobalt is found in leather as a dye and may cause chronic dermatitis. Chromium is used as a dye and for tanning in leather items and is found in nearly all shoes and released from a high proportion. New consumer items should continuously be considered and investigated for metal release when patients with positive patch test results to metal allergens are evaluated.
Meteorological Reference Years of Daily Mean Temperature during the Slighting Time
International Nuclear Information System (INIS)
Marchante Jimenez, M.; Ramirez Santigosa, L.; Navarro Fernandez, A.; Mora Lopez, L.; Sidrach de Cardona Ortin, M.
2002-01-01
In this work the characterization of the daily mean temperature during the sunlight time has been analyzed. An algorithm for the hourly series generation from extreme daily values has been applied to evaluate the daily mean temperature during the sunlight time. A generic algorithm has been enhanced as a function of the sunrise time. This algorithm allows taking into account the fractions related to the sunrise and sunset hours. This methodology has been applied in data from 45 Spanish stations, uniformly distributed in the Iberian Peninsula. Data for a period of 14 years has been used in most of locations, and once the interest variable has been calculated, the meteorological reference year of the daily mean temperature during the sunlight time has been evaluated in each stations. The next step is the evaluation of the daily mean temperature during the sunlight time in any point into the zone of evaluation, not only in the measured stations. From the result data in each measured station, an geographic information system has been used in order to calculate the interpolation, obtaining maps with a data each 5 km. for each of the 365 days of the year. Then, this results can be superposed with the solar radiation evaluation obtaining the input data for the sizing of the photovoltaic grid connected system in any point of the Spanish geography. (Author) 64 refs
Mercadante, Sebastiano; Craig, David; Giarratano, Antonello
2012-12-24
Prescriptions for opioid analgesics to manage moderate-to-severe chronic non-cancer pain have increased markedly over the last decade. An unintentional consequence of greater prescription opioid utilization has been the parallel increase in misuse, abuse and overdose, which are serious risks associated with all opioid analgesics. In response to disturbing rises in prescription opioid abuse, the US Food and Drug Administration (FDA) has proposed the implementation of aggressive Risk Evaluation and Mitigation Strategies (REMS). While REMS could dramatically change the development, release, marketing and prescription of extended-release opioids, questions remain on how these programmes may influence prescribing practices, patient safety and ultimately patient access to these agents. The extent of the availability and misuse of prescription opioids in Europe is difficult to assess from the data currently available, due in large part to the considerable differences in prescribing patterns and regulations between countries. Balancing the availability of prescription opioids for those patients who have pain, while discouraging illicit use, is a complex challenge and requires effective efforts on many levels, particularly in Europe where policies are quite different between countries.
Koike, Kazuhiko; Terui, Takeshi; Nagasako, Tomokazu; Horiuchi, Iori; Machino, Takayuki; Kusakabe, Toshiro; Hirayama, Yasuo; Mihara, Hiroyoshi; Yamakage, Michiaki; Kato, Junji; Nishisato, Takuji; Ishitani, Kunihiko
2016-03-01
The recommended dosing interval for transdermal fentanyl is every 72 h. However, some patients will have "end-of-dose failure," which may be seen as an increase of episodes of severe pain flares at the third day after application of the patch. A new once-a-day fentanyl patch was developed in Japan since 2010. This study aimed to assess the efficacy of the once-a-day fentanyl citrate patch for patients with cancer-related pain receiving the 72-h transdermal fentanyl not lasting 72 h. We performed a cross-sectional retrospective analysis of 445 inpatients with the 72-h transdermal fentanyl at Higashi Sapporo Hospital. We could switch to the once-a-day fentanyl citrate patch if patients reported inadequate pain relief beyond 48 h after application of the 72-h transdermal fentanyl. Patients recorded baseline scores for background pain intensity (PI) and the frequency of use of daily rescue medication for breakthrough cancer pain (BTcP). Of all patients, 10.1% showed the increase in PI of 30% or more baseline PI on the third day after application of the 72-h transdermal fentanyl. Of patients, 84.4% were converted from equivalent dose of the 72-h transdermal fentanyl to the once-a-day fentanyl citrate patch. On the third day after switching, 60.5% of patients showed a reduction of more than 30% from baseline PI. Switching to the once-a-day fentanyl citrate patch significantly reduced the mean frequency of daily rescue dose for BTcP. A once-a-day fentanyl citrate patch provided stable pain control. Its use may be considered as the dominant strategy for patients receiving a 72-h transdermal fentanyl not lasting 72 h.
Fouda, Usama M; Sayed, Ahmed M
2011-12-01
To compare the efficacy and cost-effectiveness of extended high dose letrozole regimen/HPuFSH-gonadotropin releasing hormone antagonist (GnRHant) protocol with short low dose letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET. In this randomized controlled trial, 136 women who responded poorly to GnRH agonist long protocol in their first IVF cycle were randomized into two equal groups using computer generated list and were treated in the second IVF cycle by either extended letrozole regimen (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) combined with HPuFSH-GnRHant protocol or short letrozole regimen (2.5 mg/day from cycle day 3-7) combined with HPuFSH-GnRHant protocol. There were no significant differences between both groups with regard to number of oocytes retrieved and clinical pregnancy rate (5.39 ± 2.08 vs. 5.20 ± 1.88 and 22.06% vs. 16.18%, respectively).The total gonadotropins dose and medications cost per cycle were significantly lower in extended letrozole group (44.87 ± 9.16 vs. 59.97 ± 14.91 ampoules and 616.52 ± 94.97 vs. 746.84 ± 149.21 US Dollars ($), respectively).The cost-effectiveness ratio was 2794 $ in extended letrozole group and 4616 $ in short letrozole group. Extended letrozole regimen/HPuFSH-GnRHant protocol was more cost-effective than short letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.
Daily snow depth measurements from 195 stations in the United States
Energy Technology Data Exchange (ETDEWEB)
Allison, L.J. [ed.] [Oak Ridge National Lab., TN (United States). Carbon Dioxide Information Analysis Center; Easterling, D.R.; Jamason, P.; Bowman, D.P.; Hughes, P.Y.; Mason, E.H. [National Oceanic and Atmospheric Administration, Asheville, NC (United States). National Climatic Data Center
1997-02-01
This document describes a database containing daily measurements of snow depth at 195 National Weather Service (NWS) first-order climatological stations in the United States. The data have been assembled and made available by the National Climatic Data Center (NCDC) in Asheville, North Carolina. The 195 stations encompass 388 unique sampling locations in 48 of the 50 states; no observations from Delaware or Hawaii are included in the database. Station selection criteria emphasized the quality and length of station records while seeking to provide a network with good geographic coverage. Snow depth at the 388 locations was measured once per day on ground open to the sky. The daily snow depth is the total depth of the snow on the ground at measurement time. The time period covered by the database is 1893--1992; however, not all station records encompass the complete period. While a station record ideally should contain daily data for at least the seven winter months (January through April and October through December), not all stations have complete records. Each logical record in the snow depth database contains one station`s daily data values for a period of one month, including data source, measurement, and quality flags.
International Nuclear Information System (INIS)
Cummings, B.J.; Keane, T.J.; Pintilie, M.; O'Sullivan, B.; Payne, D.; Warde, P.; McLean, M.; Waldron, J.; Liu, F.-F.; Gullane, P.
1996-01-01
Purpose: To examine the effects of an increased dose of radiation therapy (RT) delivered by a hyperfractionated schedule compared to conventional once daily RT on toxicity, locoregional control and survival in the treatment of squamous cell carcinomas (SCC) of the larynx and pharynx. Materials/Methods: Between 1988 and 1995 336 patients were randomized to receive RT with curative intent. Eligible patients had biopsy proven SCC of the larynx or pharynx, with TN stages (AJC-UICC 1987) T3 or T4 N0, or any T with any N+. All patients were M0. Patients were stratified by site (larynx/oropharynx/hypopharynx), node status (clinically positive/negative), and performance status. Patients were treated with either 51 Gy TAD/20 fractions/4 wk (2.55 Gy 1x/d, conventional RT=CRT) or 58 Gy TAD/40 fractions/4 wk (1.45 Gy 2x/d, hyperfractionated RT=HFRT). Patients underwent EUA and selective biopsies 10 wk after RT; surgical salvage was performed for residual or recurrent cancer whenever possible. Results: The primary cancer arose in the oropharynx (138), larynx (133) or hypopharynx (65). T stages were distributed T1 22, T2 72, T3 133 and T4 109. N stage distribution was N0 127, N1 74, N2 117 and N3 18. The proportion of patients with acute mucosal toxicity (RTOG Grade 3 or 4) was increased by HFRT (60% versus 40%), but other acute and late toxicity was not significantly different. There was no difference in the incidence of morbidity in the two treatment groups in those who underwent surgery following RT. The locoregional control rates at 3 yrs for all cases were 45% (HFRT) vs 40% (CRT) log rank p=0.16; for primary tumors <4 cm 54% (HFRT) vs 42% (CRT) p=0.04; for primary tumors ≥ 4 cm 38% (HFRT) vs 41% (CRT) p=0.73. Local control was improved to some extent in SCC which arose in all sites, but most noticeably in hypopharyngeal cancers. The disease free survival rates at 3 yr for all cases were 37% (HFRT) vs 30% (CRT) p=0.15; for primary tumors < 4 cm 47% (HFRT) vs 34% (CRT) p=0
International Nuclear Information System (INIS)
Mims, M.G.; Mueller, M.D.; Ehlinger, J.C.
1992-01-01
This patent describes a hydraulic release tool. It comprises a setting assembly; a coupling member for coupling to drill string or petroleum production components, the coupling member being a plurality of sockets for receiving the dogs in the extended position and attaching the coupling member the setting assembly; whereby the setting assembly couples to the coupling member by engagement of the dogs in the sockets of releases from and disengages the coupling member in movement of the piston from its setting to its reposition in response to a pressure in the body in exceeding the predetermined pressure; and a relief port from outside the body into its bore and means to prevent communication between the relief port and the bore of the body axially of the piston when the piston is in the setting position and to establish such communication upon movement of the piston from the setting position to the release position and reduce the pressure in the body bore axially of the piston, whereby the reduction of the pressure signals that the tool has released the coupling member
Directory of Open Access Journals (Sweden)
Samaneh Ghasemifard
2015-07-01
Full Text Available The recommendations on the intake of long chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFA vary from eating oily fish (“once to twice per week” to consuming specified daily amounts of eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA (“250–500 mg per day”. It is not known if there is a difference in the uptake/bioavailability between regular daily consumption of supplementsvs. consuming fish once or twice per week. In this study, the bioavailability of a daily dose of n-3 LC-PUFA (Constant treatment, representing supplements, vs. a large weekly dose of n-3 LC-PUFA (Spike treatment, representing consuming once or twice per week, was assessed. Six-week old healthy male Sprague-Dawley rats were fed either a Constant treatment, a Spike treatment or Control treatment (no n-3 LC-PUFA, for six weeks. The whole body, tissues and faeces were analysed for fatty acid content. The results showed that the major metabolic fate of the n-3 LC-PUFA (EPA+docosapentaenoic acid (DPA + DHA was towards catabolism (β-oxidation accounting for over 70% of total dietary intake, whereas deposition accounted less than 25% of total dietary intake. It was found that significantly more n-3 LC-PUFA were β-oxidised when originating from the Constant treatment (84% of dose, compared with the Spike treatment (75% of dose. Conversely, it was found that significantly more n-3 LC-PUFA were deposited when originating from the Spike treatment (23% of dose, than from the Constant treatment (15% of dose. These unexpected findings show that a large dose of n-3 LC-PUFA once per week is more effective in increasing whole body n-3 LC-PUFA content in rats compared with a smaller dose delivered daily.
Castro López, María del Mar; Dopico García, Sonia; Ares Pernas, Ana; López Vilariño, José Manuel; González Rodríguez, María Victoria
2012-08-22
The feasibility of novel controlled release systems for the delivery of active substances from films intended for food packaging was investigated. Because polyolefins are used highly for food-packaging applications, the reported high retention degree of antioxidants has limited their use for active packaging. Thus, in this study, PP films modified with different chain extenders have been developed to favor and control the release rates of the low molecular weight antioxidant tocopherol. The use of different chain extenders as polymer modifiers (PE-PEG M(w), 575; and PPG-PEG-PPG M(w), 2000) has caused significant changes in tocopherol-specific release properties. High-performance liquid chromatography coupled to PDA-FL and PDA-MS was used to test tocopherol and chain extender migration, respectively. The release of tocopherol from the prepared films with two chain extenders into two food simulants was studied. Different temperatures and storage times were also tested. Varying the structural features of the films with the incorporation of different levels of PPG-PEG-PPG, the release of tocopherol (food-packaging additive) into different ethanolic simulants could be clearly controlled. The effect of the temperature and storage time on the release of the antioxidant has been outstanding as their values increased. The migration of the chain extender, also tested, was well below the limits set by European legislation.
Experimental and numerical analyses of different extended surfaces
International Nuclear Information System (INIS)
Diani, A; Mancin, S; Zilio, C; Rossetto, L
2012-01-01
Air is a cheap and safe fluid, widely used in electronic, aerospace and air conditioning applications. Because of its poor heat transfer properties, it always flows through extended surfaces, such as finned surfaces, to enhance the convective heat transfer. In this paper, experimental results are reviewed and numerical studies during air forced convection through extended surfaces are presented. The thermal and hydraulic behaviours of a reference trapezoidal finned surface, experimentally evaluated by present authors in an open-circuit wind tunnel, has been compared with numerical simulations carried out by using the commercial CFD software COMSOL Multiphysics. Once the model has been validated, numerical simulations have been extended to other rectangular finned configurations, in order to study the effects of the fin thickness, fin pitch and fin height on the thermo-hydraulic behaviour of the extended surfaces. Moreover, several pin fin surfaces have been simulated in the same range of operating conditions previously analyzed. Numerical results about heat transfer and pressure drop, for both plain finned and pin fin surfaces, have been compared with empirical correlations from the open literature, and more accurate equations have been developed, proposed, and validated.
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
Directory of Open Access Journals (Sweden)
Sakamoto Masaya
2012-08-01
Full Text Available Abstract Background No previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM and cardiovascular parameters. Methods Twenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1 mean (± standard deviation 24-hour blood glucose level, 2 mean amplitude of glycemic excursions (MAGE, 3 fasting blood glucose level, 4 highest postprandial blood glucose level and time, 5 increase in blood glucose level after each meal, 6 area under the curve (AUC for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7 area over the curve (AOC for daily blood glucose level Results The mean 24-hour blood glucose level was significantly lower in patients taking vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012. In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040, the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015, the AUC (≥180 mg/dL within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025, and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 μg/day; p = 0.008 than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin. Conclusions CGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There
2012-01-01
Background No previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM) and cardiovascular parameters. Methods Twenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1) mean (± standard deviation) 24-hour blood glucose level, 2) mean amplitude of glycemic excursions (MAGE), 3) fasting blood glucose level, 4) highest postprandial blood glucose level and time, 5) increase in blood glucose level after each meal, 6) area under the curve (AUC) for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7) area over the curve (AOC) for daily blood glucose level vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012). In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040), the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015), the AUC (≥180 mg/dL) within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025), and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 μg/day; p = 0.008) than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin. Conclusions CGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There were no significant differences in BNP and PAI-1 levels between patients taking vildagliptin and
Directory of Open Access Journals (Sweden)
Luciana Teofili
2012-01-01
Full Text Available
We retrospectively compared the incidence of neutropenia in two groups of HIV patients with lymphoma, who underwent chemotherapy supported by once-per-cycle administration of pegfilgrastim or by daily subcutaneous injection of filgrastim, respectively. Our findings indicate that pegfilgrastim and filgastrim produce similar results in preventing both neutropenia and febrile neutropenia.
Directory of Open Access Journals (Sweden)
Luciana Teofili
2012-10-01
Full Text Available We retrospectively compared the incidence of neutropenia in two groups of HIV patients with lymphoma, who underwent chemotherapy supported by once-per-cycle administration of pegfilgrastim or by daily subcutaneous injection of filgrastim, respectively. Our findings indicate that pegfilgrastim and filgastrim produce similar results in preventing both neutropenia and febrile neutropenia.
Mhalhal, Thaer R; Washington, Martha C; Newman, Kayla; Heath, John C; Sayegh, Ayman I
2017-02-01
We hypothesized that exogenous gastrin releasing peptide-29 (GRP-29), cholecystokinin-8 (CCK-8) and their combination reduce body weight (BW). To test this hypothesis, BW was measured in four groups of diet-induced obese (DIO) male rats infused in the aorta (close to the junctions of the celiac and cranial mesenteric arteries) with saline, CCK-8 (0.5 nmol/kg), GRP-29 (0.5 nmol/kg) and CCK-8+GRP-29 (0.5 nmol/kg each) once daily for a total of 23 days. We found that CCK-8, GRP-29 and CCK-8+GRP-29 reduce BW relative to saline control. In conclusion, CCK-8, GRP-29 and their combination reduce BW in the DIO rat model. If infused near their gastrointestinal sites of action CCK-8, GRP-29 and their combination may have a role in regulating BW. Published by Elsevier Ltd.
Directory of Open Access Journals (Sweden)
Teuscher NS
2015-05-01
Full Text Available Nathan S Teuscher,1 Akwete Adjei,2 Robert L Findling,3,4 Laurence L Greenhill,5 Robert J Kupper,2 Sharon Wigal6 1PK/PD Associates, Trophy Club, TX, 2Rhodes Pharmaceuticals L.P., Coventry, RI, 3Department of Psychiatric Services and Research, Kennedy Krieger Institute, Baltimore, MD, 4Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, 5Department of Psychiatry, Division of Child and Adolescent Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY, 6AVIDA Inc., Newport Beach, CA, USA Abstract: A new multilayer-bead formulation of extended-release methylphenidate hydrochloride (MPH-MLR has been evaluated in pharmacokinetic studies in healthy adults and in Phase III efficacy/safety studies in children and adolescents with attention deficit hyperactivity disorder (ADHD. Using available data in healthy adults, a two-input, one-compartment, first-order elimination population pharmacokinetic model was developed using nonlinear mixed-effect modeling. The model was then extended to pediatric subjects, and was found to adequately describe plasma concentration–time data for this population. A pharmacokinetic/pharmacodynamic model was also developed using change from baseline in the ADHD Rating Scale (ADHD-RS-IV total scores from a pediatric Phase III trial and simulated plasma concentration–time data. During simulations for each MPH-MLR dose level (10–80 mg, increased body weight resulted in decreased maximum concentration. Additionally, as maximum concentration increased, ADHD-RS-IV total score improved (decreased. Knowledge of the relationship between dose, body weight, and clinical response following the administration of MPH-MLR in children and adolescents may be useful for clinicians selecting initial dosing of MPH-MLR. Additional study is needed to confirm these results. Keywords: population pharmacokinetics, Aptensio XR™, MPH-MLR, methylphenidate
Kang, Won-Ho; Nguyen, Hien Van; Park, Chulhun; Choi, Youn-Woong; Lee, Beom-Jin
2017-05-01
This study was designed to develop a once-daily controlled-release matrix tablet of aceclofenac 200mg (AFC-CR) with dual release characteristics and to investigate the role of an alkalizer in enhancing drug solubility and reducing the occurrence of gastroduodenal mucosal lesions. Two formulation approaches were employed, namely a monolithic matrix tablet and a bilayered tablet. In vitro dissolution studies of AFC-CR tablets were carried out in simulated intestinal fluid (pH6.8 buffer). The in vivo pharmacokinetic studies and drug safety of the immediate-release reference tablet Airtal® 100mg (Daewoong Co., Korea) and the optimized AFC-CR tablet were compared in beagle dogs under fasted condition. The optimally selected AFC-CR formulation displayed the desired dual release characteristics in simulated intestinal fluid with satisfactory micromeritic properties. The swelling action of the optimal matrix tablet, which was visualized by near-infrared (NIR) chemical imaging, occurred rapidly following hydration. Incorporation of sodium carbonate (Na 2 CO 3 ) was found to enhance the release rate of the AFC-CR bilayered tablets at early stages and increase the microenvironmental pH (pH M ). A pharmacokinetic study in beagle dogs indicated a higher drug plasma concentration and a sustained-release pattern for the AFC-CR tablet compared to the Airtal® tablet. AFC-CR was also superior to Airtal® in terms of in vivo drug safety, since no beagle dog receiving AFC-CR experienced gastrointestinal bleeding. The significant enhancement of drug safety was attributed to the size reduction and the increase of pH M of drug particles by means of incorporation of the alkalizer. These findings provide a scientific rationale for developing a novel controlled-release matrix tablet with enhanced patient compliance and better pain control. Copyright © 2017 Elsevier B.V. All rights reserved.
Moen, Richelle; Freitag, Mary; Miller, Michael; Lee, Susanne; Romine, Ann; Song, Sue; Adityanjee, Adit; Schulz, S Charles
2012-11-01
Borderline personality disorder (BPD) is a significant psychiatric illness for which medication treatments are still being explored. The goal of this study was to assess divalproex extended release (ER) vs placebo for patients receiving dialectal behavior therapy (DBT). Patients with BPD received 4 weeks of "condensed DBT." Those with Symptom Checklist-90 (SCL-90) scores >150 after this treatment were then randomly and blindly assigned to placebo or divalproex ER for 12 weeks. Repeated measures analysis of variance utilizing last observation carried forward was used to assess the results. Seventeen participants completed the full assessment. Two patients had a significant decrease in SCL-90 in the first 4 weeks, leaving 15 patients for the medication phase of the trial. There were no significant differences between the participants assigned to divalproex ER compared with placebo. However, there was a significant improvement in both groups from baseline to endpoint (P = .001). The response of 2 of 17 participants in the first 4 weeks prior to medication may point to a practice strategy in approaching outpatients with BPD. Although the patients had a decrease in symptoms during the study, there was no advantage observed for divalproex ER and DBT over placebo and DBT.
Determination of source term for Krsko NPP extended fuel cycle
International Nuclear Information System (INIS)
Nemec, T.; Persic, A.; Zagar, T.; Zefran, B.
2004-01-01
The activity and composition of the potential radioactive releases (source term) is important in the decision making about off-site emergency measures in case of a release into environment. Power uprate of Krsko NPP during modernization in 2000 as well as changing of the fuel type and the core design have influenced the source term value. In 2003 a project of 'Jozef Stefan' Institute and Slovenian nuclear safety administration determined a plantspecific source term for new conditions of fuel type and burnup for extended fuel cycle. Calculations of activity and isotopic composition of the core have been performed with ORIGEN-ARP program. Results showed that the core activity for extended 15 months fuel cycle is slightly lower than for the 12 months cycles, mainly due to larger share of fresh fuel. (author)
Directory of Open Access Journals (Sweden)
Vaidya V
2012-02-01
Full Text Available Varun Vaidya, Pranav PatelCollege of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USABackground: Metoprolol, a selective beta-1 blocker, is available in two different salt forms in the market – metoprolol succinate (MS and metoprolol tartarate (MT. Both the formulations are Food and Drug Administration approved for the treatment of hypertension. Several studies have shown similar efficacies between the two salts; however, they differ in their pharmacokinetic properties and are therefore priced differently. The primary objective of this study was to compare the overall health care expenditures of hypertensive patients on MT and MS to see if the price difference in the two preparations is offset by savings in overall expenditure.Methods: Two cohorts of patients using MT and MS were selected from the 2008 Medical Expenditure Panel Survey. Propensity score matching technique was used to balance the cohorts on various parameters such as demographic information, insurance status, and comorbidity score. Patients using MT were matched to patients using MS on the logit of propensity score using calipers of width equal to 0.2 of the standard deviation of the logit of the propensity score. Multiple regression analysis was carried out to examine the association between health expenditure and type of metoprolol salt, adjusting for other covariates.Results: A total of 742 patients were found to use metoprolol (MT-388, MS-354. After propensity score matching, a total of 582 patients were left in the sample for final analysis (291 patients in each cohort. The average annual health care expenditure was slightly higher in the MT cohort; however, after adjusting for covariates in a multivariate analysis, the difference was found to be statistically insignificant (P = 0.23.Conclusion: Both the products of metoprolol were found to have similar average annual total health care expenditure; however, MS once a day has higher out
Predicting red wolf release success in the southeastern United States
van Manen, Frank T.; Crawford, Barron A.; Clark, Joseph D.
2000-01-01
Although the red wolf (Canis rufus) was once found throughout the southeastern United States, indiscriminate killing and habitat destruction reduced its range to a small section of coastal Texas and Louisiana. Wolves trapped from 1973 to 1980 were taken to establish a captive breeding program that was used to repatriate 2 mainland and 3 island red wolf populations. We collected data from 320 red wolf releases in these areas and classified each as a success or failure based on survival and reproductive criteria, and whether recaptures were necessary to resolve conflicts with humans. We evaluated the relations between release success and conditions at the release sites, characteristics of released wolves, and release procedures. Although <44% of the variation in release success was explained, model performance based on jackknife tests indicated a 72-80% correct prediction rate for the 4 operational models we developed. The models indicated that success was associated with human influences on the landscape and the level of wolf habituation to humans prior to release. We applied the models to 31 prospective areas for wolf repatriation and calculated an index of release success for each area. Decision-makers can use these models to objectively rank prospective release areas and compare strengths and weaknesses of each.
Light-Regulated Release of Entrapped Drugs from Photoresponsive Gold Nanoparticles
Directory of Open Access Journals (Sweden)
Kaniknun Sreejivungsa
2016-01-01
Full Text Available Release of a payload in a spatiotemporal fashion has a substantial impact on increasing therapeutic efficacy. In this work, a novel monolayer of gold nanoparticles (AuNPs featuring light-responsive ligands was investigated as a potential drug carrier whose drug release can be triggered by UV light. Hydrophobic molecules were noncovalently entrapped in the compartments of its monolayers. Once irradiated with UV light, the dinitrobenzyl linker was cleaved, leading to release of the entrapped agent. AuNPs were characterized using UV spectrophotometry, TEM, and a zetasizer. A naturally occurring compound extracted from Goniothalamus elegans Ast was chosen as a hydrophobic model drug. Entrapment and release of dye were monitored using fluorimetry. The percent encapsulation of dye was of 13.53%. Entrapped dye can be released upon UV irradiation and can be regulated by changing irradiation time. Up to 83.95±2.2% entrapped dye can be released after irradiation for 20 minutes. In the absence of UV light, dye release was only 19.75%. For comparison purposes, AuNPs having no dinitrobenzyl groups showed a minimal release of 12.23% and 11.69% with and without UV light, respectively. This demonstrated an alternative strategy to encapsulate drugs using a noncovalent approach followed by their controlled release upon UV irradiation.
Protostar Evolution in the Orion Nebula Cluster (ONC)
Sanchez, Michael Allan
2018-01-01
We present our preliminary analysis of the protostars within the Orion Nebula Cluster (ONC). We developed a pipeline to identify protostars in the ONC using the IRAC instrument aboard Spitzer. We verified our photometric measurements with the catalog provided by Megeath et al. (2012). We then classified the protostar evolution stages (0/I, Flatt, II, and III) based on their spectral slope.
International Nuclear Information System (INIS)
Lee, J.H.; Atkins, J.E.; McNeish, J.A.; Vallikat, V.
1996-01-01
Simulations were conducted to analyze the sensitivity of the engineered barrier system (EBS) release rate to alternative conceptual models of the advective release from waste packages under dripping fractures. The first conceptual model assumed that dripping water directly contacts the waste form inside the 'failed' waste package, and radionuclides are released from the EBS by advection. The second conceptual model assumed that dripping water is diverted around the 'failed' waste package (because of the presence of corrosion products plugging the perforations) and dripping water is prevented from directly contacting the waste form. In the second model, radionuclides were assumed to transport through the perforations by diffusion, and, once outside the waste package, to be released from the EBS by advection. The second model was to incorporate more realism into the EBS release calculations. For the case with the second EBS release model, most radionuclides had significantly lower peak EBS release rates (from at least one to several orders of magnitude) than with the first EBS release model. The impacts of the alternative EBS release models were greater for the radionuclides with a low solubility (or solubility-limited radionuclides) than for the radionuclides with a high solubility (or waste form dissolution-limited radionuclides). The analyses indicated that the EBS release model representing advection through a 'failed' waste package (the first EBS release model) may be too conservative in predicting the EBS performance. One major implication from this sensitivity study was that a 'failed' waste package container with multiple perforations may still be able to perform effectively as an important barrier to radionuclide release. (author)
USE OF ALTERNATIVE EXTENDERS AND TEMPERATURES IN LONG TERM STORAGE OF BOAR SEMEN
Lina Raquel Santos Araújo; Tatyane Bandeira Barros; Daianny Barboza Guimarães; Ludymila Furtado Cantanhêde; Aline Viana Dias; Ricardo Toniolli
2016-01-01
The use of appropriate extenders is important for the success of an artificial insemination program. The objective of this study was to evaluate the efficiency of alternative extenders for swine semen at different temperatures (17 to 10 °C). The following extenders were used: Beltsville Thawing Solution (BTS), powdered coconut water (ACP-103®), and skimmed milk powder (LPD). The 50 ejaculates were analyzed daily, in natura and after dilution, during the 5-day period of semen preservation (D0...
Directory of Open Access Journals (Sweden)
McDonell AL
2015-01-01
Full Text Available Amanda L McDonell,1 Urpo Kiiskinen,2 Danielle C Zammit,3 Robert W Kotchie,1 Per-Olof Thuresson,3 Claudia Nicolay,4 Thomas Haslam,1 Michiel Bruinsma,5 Anne-Jeanine Janszen-Van Oosterhout,6 Thorsten Otto41IMS Health, London, UK; 2Eli Lilly and Company, Helsinki, Finland; 3IMS Health, Basel, Switzerland; 4Eli Lilly and Company, Bad Homburg, Germany; 5IMS Health, Rotterdam, the Netherlands; 6Eli Lilly Nederland, Houten, the NetherlandsBackground: Glucagon-like peptide-1 (GLP-1 receptor agonists are indicated for improvement of glycemic control in adults with type 2 diabetes. Cost is one aspect of treatment to be considered, in addition to clinical benefits, when selecting optimal therapy for a patient. The objective of this study was to estimate the average dose usage and real world daily cost of the GLP-1 receptor agonists, exenatide twice daily and liraglutide once daily, in Germany, the Netherlands, and the UK.Methods: Administrative databases were used to source the data from longitudinal records of dispensed prescriptions. Data were extracted from the IMS Longitudinal Prescription database which captures details of prescriptions dispensed in pharmacies. Information on the dispensed quantity of each product was used to estimate average daily usage per patient. Daily dose usage was multiplied by the public price per unit to estimate daily cost.Results: The dispensed volume in Germany corresponded to a mean dispensed daily dose of 16.81 µg for exenatide twice daily and 1.37 mg for liraglutide (mean daily cost €4.02 and €4.54, respectively. In the Netherlands, average dispensed daily doses of 17.07 µg and 1.49 mg were observed for exenatide twice daily and liraglutide (mean daily cost €3.05 and €3.97, respectively. In the UK, the mean dispensed volume corresponded to a daily usage of 20.49 µg for exenatide twice daily and 1.50 mg for liraglutide (mean daily cost £2.53 and £3.28, respectively.Conclusion: Estimates of average daily
Murphy, Sean M; Polsky, Daniel; Lee, Joshua D; Friedmann, Peter D; Kinlock, Timothy W; Nunes, Edward V; Bonnie, Richard J; Gordon, Michael; Chen, Donna T; Boney, Tamara Y; O'Brien, Charles P
2017-08-01
Criminal justice-involved individuals are highly susceptible to opioid relapse and overdose-related deaths. In a recent randomized trial, we demonstrated the effectiveness of extended-release naltrexone (XR-NTX; Vivitrol ® ) in preventing opioid relapse among criminal justice-involved US adults with a history of opioid use disorder. The cost of XR-NTX may be a significant barrier to adoption. Thus, it is important to account for improved quality of life and downstream cost-offsets. Our aims were to (1) estimate the incremental cost per quality-adjusted life-year (QALY) gained for XR-NTX versus treatment as usual (TAU) and evaluate it relative to generally accepted value thresholds; and (2) estimate the incremental cost per additional year of opioid abstinence. Economic evaluation of the aforementioned trial from the taxpayer perspective. Participants were randomized to 25 weeks of XR-NTX injections or TAU; follow-up occurred at 52 and 78 weeks. Five study sites in the US Northeast corridor. A total of 308 participants were randomized to XR-NTX (n = 153) or TAU (n = 155). Incremental costs relative to incremental economic and clinical effectiveness measures, QALYs and abstinent years, respectively. The 25-week cost per QALY and abstinent-year figures were $162 150 and $46 329, respectively. The 78-week figures were $76 400/QALY and $16 371/abstinent year. At 25 weeks, we can be 10% certain that XR-NTX is cost-effective at a value threshold of $100 000/QALY and 62% certain at $200 000/QALY. At 78 weeks, the cost-effectiveness probabilities are 59% at $100 000/QALY and 76% at $200 000/QALY. We can be 95% confident that the intervention would be considered 'good value' at $90 000/abstinent year at 25 weeks and $500/abstinent year at 78 weeks. While extended-release naltrexone appears to be effective in increasing both quality-adjusted life-years (QALYs) and abstinence, it does not appear to be cost-effective using generally accepted value
Sexual objectification in women's daily lives: A smartphone ecological momentary assessment study.
Holland, Elise; Koval, Peter; Stratemeyer, Michelle; Thomson, Fiona; Haslam, Nick
2017-06-01
Sexual objectification, particularly of young women, is highly prevalent in modern industrialized societies. Although there is plenty of experimental and cross-sectional research on objectification, prospective studies investigating the prevalence and psychological impact of objectifying events in daily life are scarce. We used ecological momentary assessment to track the occurrence of objectifying events over 1 week in the daily lives of young women (N = 81). Participants reported being targeted by a sexually objectifying event - most often the objectifying gaze - approximately once every 2 days and reported witnessing sexual objectification of others approximately 1.35 times per day. Further, multilevel linear regression analyses showed that being targeted by sexual objectification was associated with a substantial increase in state self-objectification. Overall, individual differences had little impact in moderating these effects. © 2016 The British Psychological Society.
Effects of extended-release niacin with laropiprant in high-risk patients
DEFF Research Database (Denmark)
Landray, Martin J; Haynes, Richard; Hopewell, Jemma C
2014-01-01
BACKGROUND: Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) choleste......-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.)....
A robust estimate of the number and characteristics of persons released from prison in Australia.
Avery, Alex; Kinner, Stuart A
2015-08-01
To estimate the number and characteristics of adults released from prison in Australia. We calculated ratios, stratified by age, sex and Indigenous status, by comparing the number of persons released from prison in New South Wales (NSW), with the number in NSW prisons on 30 June of the corresponding year. These stratified ratios were applied to Australia-wide prison data to estimate the number and characteristics of persons released annually. We estimated that in 2013, 38,576 persons were released from prison in Australia - 25.3% more than the daily prison population. Young people, Indigenous people and women were over-represented among those released. We estimated that 3.69 Indigenous women aged 18-24 were released annually for each equivalent person in prison; and 2.75 non-Indigenous women aged 18-24 were released annually for each equivalent person in prison. The annual 'flow' through Australia's prisons is well in excess of the daily number, but information on those moving through prison systems is not yet publicly available. The characteristics of those released from prison differ meaningfully from those of people in prison. Routine, national reporting of prison separations is critical to informing upscaling and targeting of Throughcare services for this profoundly vulnerable population. © 2015 Public Health Association of Australia.
Cardozo, Linda; Thorpe, Andrew; Warner, Juliet; Sidhu, Manpreet
2010-08-01
To assess the cost-effectiveness of solifenacin vs other antimuscarinic strategies commonly used in UK clinical practice, based on the results of a recent published review. Overactive bladder (OAB) syndrome is characterized by symptoms of urgency, frequency, incontinence and nocturia. Pharmacological treatment comprises oral antimuscarinic agents, which are divided into older-generation treatments, including oxybutynin, and new-generation treatments, comprising solifenacin, tolterodine, darifenacin and fesoterodine. The latter have reduced central nervous system penetration and have better selectivity for the M3 subclass of acetylcholine receptors, resulting in improved tolerability. A recent systematic review and meta-analysis of the efficacy and safety of antimuscarinics provided an opportunity for an economic evaluation of these agents using a rigorous assessment of efficacy. A cost-utility analysis was undertaken using a 1-year decision-tree model. Treatment success was defined separately for urgency, frequency and incontinence, with efficacy data taken from the recent review. Treatment persistence rates were taken from the Information Management System database. Utility values for the calculation of quality-adjusted life-years (QALYs) were taken from published sources. The analysis included costs directly associated with treatment for OAB, i.e. antimuscarinic therapy, consultations with general practitioners, and outpatient contacts. Resource use was based on expert opinion. Costs were reported at 2007/2008 prices. Extensive deterministic and probabilistic analyses were conducted to test the robustness of the base-case results. Solifenacin was associated with the highest QALY gains (per 1000 patients) for all three outcomes of interest, i.e. urgency (712.3), frequency (723.1) and incontinence (695.0). Solifenacin was dominant relative to fesoterodine, tolterodine extended-release (ER) and tolterodine immediate-release (IR), and cost-effective relative to
Discovery and clinical introduction of first-in-class imipridone ONC201.
Allen, Joshua E; Kline, C Leah B; Prabhu, Varun V; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L; Pottorf, Richard S; Nallaganchu, B Rao; Olson, Gary L; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T; Talekar, Mala K; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S
2016-11-08
ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.
ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells.
Talekar, Mala K; Allen, Joshua E; Dicker, David T; El-Deiry, Wafik S
2015-08-03
ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin's lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin's lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL.
75 FR 35710 - Extended Carryback of Losses to or From a Consolidated Group
2010-06-23
... Extended Carryback of Losses to or From a Consolidated Group AGENCY: Internal Revenue Service (IRS... respondents: 4,000. Estimated frequency of responses: Once. An agency may not conduct or sponsor, and a person....1502-21 Net operating losses. [The text of proposed Sec. 1.1502-21 is the same as the text for Sec. 1...
Rasmussen, Michael Højby; Olsen, Minna W Brændholt; Alifrangis, Lene; Klim, Søren; Suntum, Mette
2014-10-01
Human growth hormone (hGH) replacement therapy currently requires daily sc injections for years/lifetime, which may be both inconvenient and distressing for patients. NNC0195-0092 is a novel hGH derivative intended for once-weekly treatment of GH deficiency. A noncovalent albumin binding moiety is attached to the hGH backbone. Clearance is reduced as a consequence of a reversible binding to circulating serum albumin, which prolongs the pharmacodynamic (PD) effect. To evaluate safety, local tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose (SD) and multiple doses (MD) of NNC0195-0092. Randomized, single-center, placebo-controlled, double-blind, SD/MD, dose-escalation trial of 105 healthy male subjects. NNC0195-0092 sc administration: Five cohorts of eight subjects received one dose of NNC0195-0092 (0.01-0.32 mg/kg) (n = 6) or placebo (n = 2). Sixteen subjects (equal numbers of Japanese and non-Asian) received once-weekly doses of NNC0195-0092 (0.02-0.24 mg/kg; n=12) or placebo (n=4) for 4 weeks. Blood samples were drawn for assessment of safety, PK, IGF-1, and IGF binding protein 3 profiles and anti-drug antibodies. SD and MD of NNC0195-0092 were well tolerated at all dose levels. No safety concerns or local tolerability issues were identified. A dose-dependent IGF-1 response was observed. IGF-1 profiles suggest that NNC0195-0092 may be suitable for once-weekly dosing, with a clinically relevant dose ≤0.08 mg/kg/week. No differences in PK and PD were observed between Japanese and non-Asian subjects. SD and MD of NNC0195-0092 administered to healthy Japanese and non-Asian male subjects were well tolerated at all doses. The present trial suggests that NNC0195-0092 has the potential for an efficacious, well-tolerated, once-weekly GH treatment.
mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.
Jin, Zhe-Zhu; Wang, Wei; Fang, Di-Long; Jin, Yong-Jun
2016-09-30
We here tested the anti-colorectal cancer (CRC) activity by a first-in-class small molecule TRAIL inducer ONC201. The potential effect of mTOR on ONC201's actions was also examined. ONC201 induced moderate cytotoxicity against CRC cell lines (HT-29, HCT-116 and DLD-1) and primary human CRC cells. Significantly, AZD-8055, a mTOR kinase inhibitor, sensitized ONC201-induced cytotoxicity in CRC cells. Meanwhile, ONC201-induced TRAIL/death receptor-5 (DR-5) expression, caspase-8 activation and CRC cell apoptosis were also potentiated with AZD-8055 co-treatment. Reversely, TRAIL sequestering antibody RIK-2 or the caspase-8 specific inhibitor z-IETD-fmk attenuated AZD-8055 plus ONC201-induced CRC cell death. Further, mTOR kinase-dead mutation (Asp-2338-Ala) or shRNA knockdown significantly sensitized ONC201's activity in CRC cells, leading to profound cell death and apoptosis. On the other hand, expression of a constitutively-active S6K1 (T389E) attenuated ONC201-induced CRC cell apoptosis. For the mechanism study, we showed that ONC201 blocked Akt, but only slightly inhibited mTOR in CRC cells. Co-treatment with AZD-8055 also concurrently blocked mTOR activation. These results suggest that mTOR could be a primary resistance factor of ONC201 in CRC cells. Copyright © 2016 Elsevier Inc. All rights reserved.
A single 2 g oral dose of extended-release azithromycin for treatment of gonococcal urethritis.
Yasuda, Mitsuru; Ito, Shin; Kido, Akira; Hamano, Kiminari; Uchijima, Yutaka; Uwatoko, Noriyasu; Kusuyama, Hiroyuki; Watanabe, Akiko; Miyamura, Ryuzou; Miyata, Kazutoyo; Deguchi, Takashi
2014-11-01
We treated gonococcal urethritis in men with a single 2 g dose of azithromycin extended-release formulation (azithromycin-SR) to determine its microbiological outcomes and tolerability. We enrolled 189 Japanese men with gonococcal urethritis between April 2009 and December 2013. The patients were given a single 2 g dose of azithromycin-SR. Microbiological efficacy was evaluated by the results of the post-treatment molecular testing of Neisseria gonorrhoeae. MIC testing was performed only for pretreatment isolates of N. gonorrhoeae collected from the patients. We evaluated 130 patients for microbiological outcomes. Of these patients, 122 (93.8%) were judged to be microbiologically cured on the basis of negative test results. All isolates for which the azithromycin MICs were ≤0.25 mg/L were eradicated, whereas 5 of 12 isolates for which the MICs were 1 mg/L persisted after the treatment. Forty-six adverse events occurred in 41 patients. However, all adverse events were classified as mild. The eradication rate of N. gonorrhoeae was 93.8% in men with gonococcal urethritis treated with a single 2 g dose of azithromycin-SR. The breakpoint MIC of a 2 g dose of azithromycin-SR for gonococcal urethritis associated with clinical treatment failures appeared to be 1 mg/L. With regard to side effects of higher doses of azithromycin, the 2 g dose of azithromycin-SR appeared to improve tolerability. However, the widespread use of a high-dose regimen of azithromycin might lead to the development of further resistance to azithromycin. © The Author 2014. 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.
Model-based computer-aided design for controlled release of pesticides
DEFF Research Database (Denmark)
Muro Sunè, Nuria; Gani, Rafiqul; Bell, G.
2005-01-01
In the field of controlled release technology for pesticides or active ingredients (AI), models that can predict its delivery during application are important for purposes of design and marketing of the pesticide product. Appropriate models for the controlled release of pesticides, if available, ...... extended models have been developed and implemented into a computer-aided system. The total model consisting of the property models embedded into the release models are then employed to study the release of different combinations of AIs and polymer-based microcapsules.......In the field of controlled release technology for pesticides or active ingredients (AI), models that can predict its delivery during application are important for purposes of design and marketing of the pesticide product. Appropriate models for the controlled release of pesticides, if available...
Operational control of material release and discharges from nuclear power plant
International Nuclear Information System (INIS)
Szabo, I. C.; Ranga, T.; Daroczi, L.; Deme, S.; Kerekes, A.
2003-01-01
The operational control of radioactive materials during atmospheric release and aquatic discharge from nuclear power plant is a licensing criterion for NPPs. Originally at the Paks NPP the release control was based on activity limits for four groups of elements. These groups were noble gases, long living radio-aerosols, radioiodine and radiostrontium for atmospheric release and specified activity limit for beta emitters, strontium and tritium for aquatic discharge into Danube. These groups were controlled with proper sampling and/or measuring instrumentation. The limit for atmospheric release was given as a 30-day moving average, for liquid discharges the annual limit was stipulated. The new release and discharge limitation system is based on the environmental dose limitation. The dose constraint for Paks NPP is 90 Sv/year of the critical group for all release pathways and the investigation dose limit is equal to 27 Sv/year. The regulation did not subdivide the dose limit for atmospheric and liquid components but for operational control subdivision of dose limits for atmospheric release and aquatic discharge and shorter time period (one day-one month) seems to be useful. The subdivision can be based on past release data and/or previous activity limits. To satisfy dose below the investigation dose limit there should be a proper operation control level for each separately measured component and pathway belonging to reasonable time interval significantly shorter than one year. The main task of the NPP staff is elaboration of reasonable control levels and reference time intervals for different radionuclide and element groups to be used in operational control. Operational control levels are based on measured daily or monthly release rates. In case of noble gases, aerosols and iodine the daily release rates have several sharp peaks per year. Operational control levels give opportunity to detect these peaks for internal investigation purposes. Investigation release limits
Role of Dopamine Receptors in the Anticancer Activity of ONC201.
Kline, Christina Leah B; Ralff, Marie D; Lulla, Amriti R; Wagner, Jessica M; Abbosh, Phillip H; Dicker, David T; Allen, Joshua E; El-Deiry, Wafik S
2018-01-01
ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed in Phase I/II trials in several advanced malignancies. Binding and reporter assays have shown that ONC201 is a selective antagonist of the dopamine D2-like receptors, specifically, DRD2 and DRD3. We hypothesized that ONC201's interaction with DRD2 plays a role in ONC201's anticancer effects. Using cBioportal and quantitative reverse-transcription polymerase chain reaction analyses, we confirmed that DRD2 is expressed in different cancer cell types in a cell type-specific manner. On the other hand, DRD3 was generally not detectable. Overexpressing DRD2 in cells with low DRD2 levels increased ONC201-induced PARP cleavage, which was preceded and correlated with an increase in ONC201-induced CHOP mRNA expression. On the other hand, knocking out DRD2 using CRISPR/Cas9 in three cancer cell lines was not sufficient to abrogate ONC201's anticancer effects. Although ONC201's anticancer activity was not dependent on DRD2 expression in the cancer cell types tested, we assessed the cytotoxic potential of DRD2 blockade. Transient DRD2 knockdown in HCT116 cells activated the integrated stress response and reduced cell number. Pharmacological antagonism of DRD2 significantly reduced cell viability. Thus, we demonstrate in this study that disrupting dopamine receptor expression and activity can have cytotoxic effects that may at least be in part due to the activation of the integrated stress response. On the other hand, ONC201's anticancer activity goes beyond its ability to antagonize DRD2, potentially due to ONC201's ability to activate other pathways that are independent of DRD2. Nevertheless, blocking the dopamine D1-like receptor DRD5 via siRNA or the use of a pharmacological antagonist promoted ONC201-induced anticancer activity. Copyright © 2018 The Authors
Role of Dopamine Receptors in the Anticancer Activity of ONC201
Directory of Open Access Journals (Sweden)
Christina Leah B. Kline
2018-01-01
Full Text Available ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed in Phase I/II trials in several advanced malignancies. Binding and reporter assays have shown that ONC201 is a selective antagonist of the dopamine D2-like receptors, specifically, DRD2 and DRD3. We hypothesized that ONC201’s interaction with DRD2 plays a role in ONC201’s anticancer effects. Using cBioportal and quantitative reverse-transcription polymerase chain reaction analyses, we confirmed that DRD2 is expressed in different cancer cell types in a cell type–specific manner. On the other hand, DRD3 was generally not detectable. Overexpressing DRD2 in cells with low DRD2 levels increased ONC201-induced PARP cleavage, which was preceded and correlated with an increase in ONC201-induced CHOP mRNA expression. On the other hand, knocking out DRD2 using CRISPR/Cas9 in three cancer cell lines was not sufficient to abrogate ONC201’s anticancer effects. Although ONC201’s anticancer activity was not dependent on DRD2 expression in the cancer cell types tested, we assessed the cytotoxic potential of DRD2 blockade. Transient DRD2 knockdown in HCT116 cells activated the integrated stress response and reduced cell number. Pharmacological antagonism of DRD2 significantly reduced cell viability. Thus, we demonstrate in this study that disrupting dopamine receptor expression and activity can have cytotoxic effects that may at least be in part due to the activation of the integrated stress response. On the other hand, ONC201’s anticancer activity goes beyond its ability to antagonize DRD2, potentially due to ONC201’s ability to activate other pathways that are independent of DRD2. Nevertheless, blocking the dopamine D1-like receptor DRD5 via siRNA or the use of a pharmacological antagonist promoted ONC201-induced anticancer activity.
45 CFR 170.423 - Principles of proper conduct for ONC-ATCBs.
2010-10-01
... 45 Public Welfare 1 2010-10-01 2010-10-01 false Principles of proper conduct for ONC-ATCBs. 170... § 170.423 Principles of proper conduct for ONC-ATCBs. An ONC-ATCB shall: (a) Operate its certification... EHR Module developer conspicuously include the following text on its Web site and in all marketing...
Smith-Bernardin, Shannon; Rowe, Chris; Behar, Emily; Geier, Michelle; Washington, Stuart; Santos, Glenn-Milo; Euren, Jason; Martin, Judith; Gleghorn, Alice; Coffin, Phillip O
2018-02-01
Extended-release naltrexone (XRNTX) is an effective treatment for alcohol use disorder (AUD). We sought to evaluate the feasibility, acceptability, and preliminary effectiveness and cost-effectiveness of XRNTX delivered as a stand-alone service to persons with severe AUD who are high utilizers of multiple urgent and emergency medical services (HUMS). Of 15 HUMS persons with severe AUD selected based on chart review, 11 agreed to participate. Participants received a mean of 4.5 injections (range 2-7). Modest benefits from XRNTX were observed in terms of patients' Urge-to-Drink Score and the costs of emergency medical services utilized. Though limited by a small sample size, costs including client utilization and study related expenses during the post-enrollment period were less than client utilization costs in the pre-enrollment period. We also observed non-significant improvements in the number of drinking days, but no change in quality of life as measured by the EQ-5D. Eighty-eight percent of participants perceived XRNTX as helping with their drinking. Findings need to be replicated in a larger study, however if replicated, the cost savings could be substantial. Copyright © 2017 Elsevier Inc. All rights reserved.
Global Historical Climatology Network - Daily (GHCN-Daily), Version 3
National Oceanic and Atmospheric Administration, Department of Commerce — The Global Historical Climatology Network - Daily (GHCN-Daily) dataset integrates daily climate observations from approximately 30 different data sources. Version 3...
Rauck, Richard L; Hale, Martin E; Bass, Almasa; Bramson, Candace; Pixton, Glenn; Wilson, Jacquelyn G; Setnik, Beatrice; Meisner, Paul; Sommerville, Kenneth W; Malhotra, Bimal K; Wolfram, Gernot
2015-09-01
The objective of this multicenter, double-blind, placebo-controlled, randomized withdrawal study was to evaluate the efficacy and safety of ALO-02, an abuse-deterrent formulation containing pellets of extended-release oxycodone hydrochloride (HCl) surrounding sequestered naltrexone HCl, compared with placebo in the treatment of moderate-to-severe chronic low back pain. An open-label titration period in which all patients received ALO-02 was followed by a double-blind treatment period where patients meeting treatment response criteria were randomized to either a fixed dose of ALO-02 or placebo. Daily average low back pain was assessed using an 11-point numeric rating scale (NRS)-Pain. Of the 663 patients screened, 410 received ALO-02 during the open-label conversion and titration period and 281 patients were randomized to the double-blind treatment period (n = 134, placebo; n = 147, ALO-02). Change in the mean NRS-Pain score from randomization baseline to the final 2 weeks of the treatment period was significantly different favoring ALO-02 compared with placebo (P = 0.0114). Forty-four percent of patients treated with placebo and 57.5% of patients treated with ALO-02 reported ≥30% improvement in weekly average NRS-Pain scores from screening to the final 2 weeks of the treatment period (P = 0.0248). In the double-blind treatment period, 56.8% of patients in the ALO-02 group and 56.0% of patients in the placebo group experienced a treatment-emergent adverse event (TEAE). The most common treatment-related TEAEs for ALO-02 during the treatment period were nausea, vomiting, and constipation, consistent with opioid therapy. ALO-02 has been demonstrated to provide significant reduction of pain in patients with chronic low back pain and has a safety profile similar to other opioids.
The extended arm of health professionals?
DEFF Research Database (Denmark)
Norlyk, Annelise; Martinsen, Bente
2013-01-01
responsibility for both the patient's well-being and for the patient's compliance with the daily regimen. Relatives were caught in a conflicting double role. They were the extended arm of the health professionals but also the caring, supporting partner. A tension arose between relatives' desire to help....... Due to the early discharge and the increasing demands on patients for self-care, patients' relatives seem to play a pivotal role in fast-track programmes. However, research is limited into how patients' close relatives are affected by and involved in the postoperative recovery process. Design...
Application of tumbling melt granulation (TMG) method to prepare controlled-release fine granules.
Maejima, T; Kubo, M; Osawa, T; Nakajima, K; Kobayashi, M
1998-03-01
The tumbling melt granulation (TMG) method was applied to prepare controlled-release fine granules of diltiazem hydrochloride (DH). The entire process, from the preparation of the cores by the adherence of DH to the sucrose crystal to the subsequent coating of the controlled-release layer, was performed without using any solvent. A mixture of meltable material, talc, and ethylcellulose was used for the controlled-release layer and controlled-release fine granules approximately 400 microns in diameter were obtained with excellent producibility. The dissolution rate of DH from these fine granules was similar to that of a once-a-day dosage form obtained in the market; further, the dependency of the dissolution profile on pH of the media was less. Thus, it was concluded that this TMG method was very useful for preparing not only controlled-release beads of granule size (usually 500 to 1400 microns) but also fine granules.
Directory of Open Access Journals (Sweden)
Eric Hoffmaster
2016-11-01
Full Text Available Once thought to be uniquely human, prosocial behavior has been observed in a number of species, including vampire bats that engage in costly food-sharing. Another social chiropteran, Jamaican fruit bats (Artibeus jamaicensis, have been observed to engage in cooperative mate guarding, and thus might be expected to display prosocial behavior as well. However, frugivory and hematophagy diets may impose different selection pressures on prosocial preferences, given that prosocial preferences may depend upon cognitive abilities selected by different ecological constraints. Thus, we assessed whether Jamaican fruit bats would assist a conspecific in an escape paradigm in which a donor could opt to release a recipient from an enclosure. The test apparatus contained two compartments—one of which was equipped with a sensor that, once triggered, released the trap door of the adjacent compartment. Sixty-six exhaustive pairs of 12 bats were tested, with each bat in each role, twice when the recipient was present and twice when absent. Bats decreased their behavior of releasing the trapdoor in both conditions over time, decreasing the behavior slightly more rapidly in the recipient absent condition. Bats did not release the door more often when recipients were present, regardless of the recipient; thus, there was no clear evidence of prosocial behavior.
Uranium resource utilization improvements in the once-through PWR fuel cycle
International Nuclear Information System (INIS)
Matzie, R.A.
1980-04-01
In support of the Nonproliferation Alternative Systems Assessment Program (NASAP), Combustion Engineering, Inc. performed a comprehensive analytical study of potential uranium utilization improvement options that can be backfit into existing PWRs operating on the once-through uranium fuel cycle. A large number of potential improvement options were examined as part of a preliminary survey of candidate options. The most attractive of these, from the standpoint of uranium utilization improvement, economic viability, and ease of implementation, were then selected for detailed analysis and were included in a single composite improvement case. This composite case represents an estimate of the total savings in U 3 O 8 consumption that can be achieved in current-design PWRs by implementing improvements which can be developed and demonstrated in the near term. The improvement options which were evaluated in detail and included in the composite case were a new five-batch, extended-burnup fuel management scheme, low-leakage fuel management, modified lattice designs, axial blankets, reinsertion of initial core batches, and end-of-cycle stretchout
Directory of Open Access Journals (Sweden)
Daniela Ponce
Full Text Available Intermittent hemodialysis (IHD and continuous renal replacement therapies (CRRT are used as Acute Kidney Injury (AKI therapy and have certain advantages and disadvantages. Extended daily dialysis (EDD has emerged as an alternative to CRRT in the management of hemodynamically unstable AKI patients, mainly in developed countries.We hypothesized that EDD is a safe option for AKI treatment and aimed to describe metabolic and fluid control of AKI patients undergoing EDD and identify complications and risk factors associated with death.This is an observational and retrospective study describing introduction of EDD at our institution. A total of 231 hemodynamically unstable AKI patients (noradrenalin dose between 0.3 and 1.0 ucg/kg/min were assigned to 1367 EDD session. EDD consisted of 6-8 h of HD 6 days a week, with blood flow of 200 ml/min, dialysate flows of 300 ml/min.Mean age was 60.6±15.8 years, 97.4% of patients were in the intensive care unit, and sepsis was the main etiology of AKI (76.2. BUN and creatinine levels stabilized after four sessions at around 38 and 2.4 mg/dl, respectively. Fluid balance decreased progressively and stabilized around zero after five sessions. Weekly delivered Kt/V was 5.94±0.7. Hypotension and filter clotting occurred in 47.5 and 12.4% of treatment session, respectively. Regarding AKI outcome, 22.5% of patients presented renal function recovery, 5.6% of patients remained on dialysis after 30 days, and 71.9% of patients died. Age and focus abdominal sepsis were identified as risk factors for death. Urine output and negative fluid balance were identified as protective factors.EDD is effective for AKI patients, allowing adequate metabolic and fluid control. Age, focus abdominal sepsis, and lower urine output as well as positive fluid balance after two EDD sessions were associated significantly with death.
Jayasena, C N; Nijher, G M K; Abbara, A; Murphy, K G; Lim, A; Patel, D; Mehta, A; Todd, C; Donaldson, M; Trew, G H; Ghatei, M A; Bloom, S R; Dhillo, W S
2010-12-01
Kisspeptin is a novel therapeutic target for infertility. A single kisspeptin-54 (KP-54) injection acutely stimulates the release of reproductive hormones in women with hypothalamic amenorrhea (HA), a commonly occurring condition characterized by absence of menstruation; however, twice-daily administration of KP-54 results in tachyphylaxis. We determined the time course of desensitization to twice-daily KP-54 injections, compared the effects of twice-daily and twice-weekly administration regimens of KP-54, and studied the effects of long-term twice-weekly administration of KP-54 on the release of reproductive hormones in women with HA. When KP-54 was administered twice daily, responsiveness to luteinizing hormone (LH) diminished gradually, whereas responsiveness to follicle-stimulating hormone (FSH) was nearly abolished by day 2. Twice-weekly KP-54 administration resulted in only partial desensitization, in contrast to the complete tolerance achieved with twice-daily administration. Women with HA who were treated with twice-weekly KP-54 injections had significantly elevated levels of reproductive hormones after 8 weeks as compared with treatment with saline. No adverse effects were observed. This study provides novel pharmacological data on the effects of KP-54 on the release of reproductive hormones in women with HA.
Kimani, Flora W; Jewett, John C
2015-03-23
Triazabutadienes are an understudied structural motif that have remarkable reactivity once rendered water-soluble. It is shown that these molecules readily release diazonium species in a pH-dependent manner in a series of buffer solutions with pH ranges similar to those found in cells. Upon further development, we expect that this process will be well suited to cargo-release strategies and organelle-specific bioconjugation reactions. These compounds offer one of the mildest ways of generating diazonium species in aqueous solutions. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
STUDIES ON NATURAL AND SYNTHETIC POLYMERS FOR CONTROLLED RELEASE MATRIX TABLET OF ACECLOFENAC
Abhishek S. Joshi *, Deepak A. Joshi , Avinash V. Dhobale , Sandhya S. Bundel , Vijay R. Chakote, Gunesh N. Dhembre
2018-01-01
The present study was aimed to design new oral controlled release matrix tablets of new NSAID Aceclofenac for once a day by using 10, 15, 20 and 25% of GG:HPMC and XG:HPMC mixture in the ratio 1:1 by wet granulation method. The prepared tablets subjected to in vitro drug release studies in pH 7.4 buffer solution. All the formulation meets the pre-compression and compression characteristics. All the tablets prepared with 10, 15, 20 and 25% of HPMC: XG mixture in the ratio 1:1 fails to meet the...
Kadry, Hossam; Al-Hilal, Taslim A; Keshavarz, Ali; Alam, Farzana; Xu, Changxue; Joy, Abraham; Ahsan, Fakhrul
2018-04-20
Three-dimensional printing (3DP), though developed for nonmedical applications and once regarded as futuristic only, has recently been deployed for the fabrication of pharmaceutical products. However, the existing feeding materials (inks and filaments) that are used for printing drug products have various shortcomings, including the lack of biocompatibility, inadequate extrudability and printability, poor drug loading, and instability. Here, we have sought to develop a filament using a single pharmaceutical polymer, with no additives, which can be multi-purposed and manipulated by computational design for the preparation of tablets with desired release and absorption patterns. As such, we have used hydroxypropyl-methylcellulose (HPMC) and diltiazem, a model drug, to prepare both drug-free and drug-impregnated filaments, and investigated their thermal and crystalline properties, studied the cytotoxicity of the filaments, designed and printed tablets with various infill densities and patterns. By alternating the drug-free and drug-impregnated filaments, we fabricated various types of tablets, studied the drug release profiles, and assessed oral absorption in rats. Both diltiazem and HPMC were stable at extrusion and printing temperatures, and the drug loading was 10% (w/w). The infill density, as well as infill patterns, influenced the drug release profile, and thus, when the infill density was increased to 100%, the percentage of drug released dramatically declined. Tablets with alternating drug-free and drug-loaded layers showed delayed and intermittent drug release, depending on when the drug-loaded layers encountered the dissolution media. Importantly, the oral absorption patterns accurately reproduced the drug release profiles and showed immediate, extended, delayed and episodic absorption of the drug from the rat gastrointestinal tract (GIT). Overall, we have demonstrated here that filaments for 3D printers can be prepared from a pharmaceutical polymer with no
Embedded spirituality: gardening in daily life and stressful life experiences.
Unruh, Anita; Hutchinson, Susan
2011-09-01
There is a limited body of research examining the relationship between spirituality and leisure, or the impact of leisure in the context of daily life, and life with stressful events. To examine the meaning of gardens and gardening across different life experiences using hermeneutic phenomenology to focus on the lived experience of leisure gardening. Most participants were interviewed once in each season over a 1 year period usually in their home. There were 42 participants (27 women and 15 men) in this study. Fifteen individuals had been diagnosed with cancer and were in varying stages of diagnosis and treatment. Three people had a chronic and progressive disease. Four women were grieving the death of their spouse. Participants ranged in age from 32 to 80 years. In this paper, we focus on the spirituality-related themes in this study: spirituality as connectedness; spirituality as an expression of inner being; the garden as a spiritual place and gardening as spiritual activity; gardening as a spiritual journey; and, stewardship. Participants with religious views saw their garden as an extension of their spirituality and a confirmation of their beliefs. Participants with secular or sacred views of spirituality that was not related to any religious beliefs were more likely to embed their spirituality in their relationship with nature as manifested in their garden. This study extends current theory regarding leisure and its contribution to meaning focused coping, and spirituality as a significant component of leisure in living with stressful health and life events. © 2011 The Authors. Scandinavian Journal of Caring Sciences © 2011 Nordic College of Caring Science.
Rajagopalan, Krithika; Meyer, Kellie; O'Day, Ken; Denno, Melissa; Loebel, Antony
2015-01-01
Bipolar disorder imposes a high economic burden on patients and society. Lurasidone and quetiapine extended-release (XR) are atypical antipsychotic agents indicated for monotherapy treatment of bipolar depression. Lurasidone is also indicated as adjunctive therapy with lithium or valproate for depressive episodes associated with bipolar disorder. The objective of this analysis was to estimate the cost-effectiveness of lurasidone and quetiapine XR in patients with bipolar depression. A cost-effectiveness model was developed to compare lurasidone to quetiapine XR. The model was based on a US third-party payer perspective over a 3-month time horizon. The effectiveness measure in the model was the percentage of patients achieving remission (Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≤12 by weeks 6-8). The comparison of remission rates was made through an adjusted indirect treatment comparison of lurasidone and quetiapine XR pivotal trials using placebo as the common comparator. Resource utilization for remission vs no remission was estimated from published expert panel data, and resource costs were obtained from a retrospective database study of bipolar I depression patients. Drug costs were estimated using the mean dose from clinical trials and wholesale acquisition costs. Over the 3-month model time period, lurasidone and quetiapine XR patients, respectively, had similar mean numbers of emergency department visits (0.48 vs 0.50), inpatient days (2.1 vs 2.2), and office visits (9.3 vs 9.6). More lurasidone than quetiapine XR patients achieved remission (52.0% vs 43.2%) with slightly higher total costs ($4982 vs $4676), resulting in an incremental cost-effectiveness ratio of $3474 per remission. The probabilistic sensitivity analysis showed lurasidone had an 86% probability of being cost-effective compared to quetiapine XR at a willingness-to-pay threshold of $10,000 per remission. Lurasidone may be a cost-effective option when compared to
Gommoll, Carl P.; Chen, Changzheng; Greenberg, William M.; Ruth, Adam
2015-01-01
Objective: In this post hoc analysis, improvement in functional impairment in patients with major depressive disorder (MDD) treated with levomilnacipran extended release (ER) was evaluated by assessing shifts from more severe to less severe functional impairment categories on individual Sheehan Disability Scale (SDS) subscales. Method: SDS data were pooled from 5 phase II/III studies conducted between December 2006 and March 2012 of levomilnacipran ER versus placebo in adult patients with MDD (DSM-IV-TR criteria). Proportions of patients shifting from moderate-extreme baseline impairment (score ≥ 4) to mild-no impairment (score ≤ 3) at end of treatment were assessed for each SDS subscale. Proportions of patients shifting from marked-extreme (score ≥ 7) baseline impairment to moderate-no (score ≤ 6) or mild-no impairment (score ≤ 3) at end of treatment, and shifts in which patients worsened from moderate-no to marked-extreme impairment, were also evaluated. Results: A significantly higher proportion of patients treated with levomilnacipran ER than placebo-treated patients improved from more severe categories of functional impairment at baseline to less severe impairment categories across all SDS subscales: work/school, social life, and family life/home responsibilities (P impairment at baseline improved to mild or no impairment, compared with no more than 40% of placebo patients on any subscale. Almost half (42%–47%) of levomilnacipran ER–treated patients versus only about one-third (29%–34%) of placebo patients improved from marked-extreme to mild or no impairment across functional domains. Conclusions: These results suggest that functional improvement was observed across the SDS functional domains. To our knowledge, this is the first such categorical analysis of functional improvement, as measured by the SDS, for an antidepressant. Trial Registration: ClinicalTrials.gov identifiers: NCT00969709, NCT01377194, NCT00969150, and NCT01034462 and Eudra
Daily Pill Can Prevent HIV PSA (:60)
Centers for Disease Control (CDC) Podcasts
2015-11-24
This 60 second public service announcement (PSA) is based on the November 24, 2015 CDC Vital Signs report. Preexposure prophylaxis, or PrEP, is a daily medicine that can be used to prevent getting HIV. PrEP is for people who donât have HIV but who are at very high risk for getting it from sex or injection drug use. Unfortunately, many people who can benefit from PrEP arenât taking it. Created: 11/24/2015 by National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP). Date Released: 11/24/2015.
Directory of Open Access Journals (Sweden)
Edit Bosnyák
2014-01-01
Full Text Available The aim of this study was to compare the efficacy of the branded and a generic extended-release ropinirole formulation in the treatment of advanced Parkinson’s disease (PD. Of 22 enrolled patients 21 completed the study. A rater blinded to treatment evaluated Unified Parkinson’s Disease Rating Scale, Fahn-Tolosa-Marin Tremor Rating Scale, Nonmotor Symptoms Assessment Scale, and a structured questionnaire on ropinirole side effects. Besides, the patients self-administered EQ-5D, Parkinson’s Disease Sleep Scale (PDSS-2, and Beck Depression Inventories. Branded and generic ropinirole treatment achieved similar scores on all tests measuring severity of motor symptoms (primary endpoint, UPDRS-III: 27.0 versus 28.0 points, P=0.505. Based on patient diaries, the lengths of “good time periods” were comparable (10.5 and 10.0 hours for branded and generic ropinirole, resp., P=0.670. However, generic ropinirole therapy achieved almost 3.0 hours shorter on time without dyskinesia (6.5 versus. 9.5 hours, P<0.05 and 2.5 hours longer on time with slight dyskinesia (3.5 versus. 1.0 hours, P<0.05 than the branded ropinirole did. Except for gastrointestinal problems, nonmotor symptoms were similarly controlled. Patients did not prefer either formulation. Although this study has to be interpreted with limitations, it demonstrated that both generic and branded ropinirole administration can achieve similar control on most symptoms of PD.
International Nuclear Information System (INIS)
Chen, M.; Chen, J.; Sun, F.
2010-01-01
Agriculture related pollution has attracted the attention of policy makers as well as scientists in China as its contribution to water impairment has increased, and quantitative information at the national and regional levels is being sought to support decision making. However, traditional approaches are either time-consuming, expensive (e.g. national surveys) or oversimplified and crude (e.g. coefficient methods). Therefore, this study proposed an extended substance flow analysis (SFA) framework to estimate nutrient releases from agricultural and rural activities in China by depicting the nutrient flows in Chinese agro-ecosystems. The six-step process proposed herein includes: (a) system definition; (b) model development; (c) database development; (d) model validation; (e) results interpretation; and (f) uncertainty analysis. The developed Eubolism (Elementary Unit based nutrient Balance mOdeLIng in agro-ecoSysteM) model combined a nutrient balance module with an emission inventory module to quantify the nutrient flows in the agro-ecosystem. The model was validated and then applied to estimate the total agricultural nutrient loads, identify the contribution of different agricultural and rural activities and different land use types to the total loads, and analyze the spatial pattern of agricultural nutrient emissions in China. These results could provide an entire picture of agricultural pollution at the national level and be used to support policy making. Furthermore, uncertainties associated with the structure of the elementary units, spatial resolution, and inputs/parameters were also analyzed to evaluate the robustness of the model results.
Abolfathi, Bela; Aguado, D. S.; Aguilar, Gabriela; Allende Prieto, Carlos; Almeida, Andres; Tasnim Ananna, Tonima; Anders, Friedrich; Anderson, Scott F.; Andrews, Brett H.; Anguiano, Borja; Aragón-Salamanca, Alfonso; Argudo-Fernández, Maria; Armengaud, Eric; Ata, Metin; Aubourg, Eric; Avila-Reese, Vladimir; Badenes, Carles; Bailey, Stephen; Balland, Christophe; Barger, Kathleen A.; Barrera-Ballesteros, Jorge; Bartosz, Curtis; Bastien, Fabienne; Bates, Dominic; Baumgarten, Falk; Bautista, Julian; Beaton, Rachael; Beers, Timothy C.; Belfiore, Francesco; Bender, Chad F.; Bernardi, Mariangela; Bershady, Matthew A.; Beutler, Florian; Bird, Jonathan C.; Bizyaev, Dmitry; Blanc, Guillermo A.; Blanton, Michael R.; Blomqvist, Michael; Bolton, Adam S.; Boquien, Médéric; Borissova, Jura; Bovy, Jo; Andres Bradna Diaz, Christian; Nielsen Brandt, William; Brinkmann, Jonathan; Brownstein, Joel R.; Bundy, Kevin; Burgasser, Adam J.; Burtin, Etienne; Busca, Nicolás G.; Cañas, Caleb I.; Cano-Díaz, Mariana; Cappellari, Michele; Carrera, Ricardo; Casey, Andrew R.; Cervantes Sodi, Bernardo; Chen, Yanping; Cherinka, Brian; Chiappini, Cristina; Doohyun Choi, Peter; Chojnowski, Drew; Chuang, Chia-Hsun; Chung, Haeun; Clerc, Nicolas; Cohen, Roger E.; Comerford, Julia M.; Comparat, Johan; Correa do Nascimento, Janaina; da Costa, Luiz; Cousinou, Marie-Claude; Covey, Kevin; Crane, Jeffrey D.; Cruz-Gonzalez, Irene; Cunha, Katia; da Silva Ilha, Gabriele; Damke, Guillermo J.; Darling, Jeremy; Davidson, James W., Jr.; Dawson, Kyle; de Icaza Lizaola, Miguel Angel C.; de la Macorra, Axel; de la Torre, Sylvain; De Lee, Nathan; de Sainte Agathe, Victoria; Deconto Machado, Alice; Dell’Agli, Flavia; Delubac, Timothée; Diamond-Stanic, Aleksandar M.; Donor, John; José Downes, Juan; Drory, Niv; du Mas des Bourboux, Hélion; Duckworth, Christopher J.; Dwelly, Tom; Dyer, Jamie; Ebelke, Garrett; Davis Eigenbrot, Arthur; Eisenstein, Daniel J.; Elsworth, Yvonne P.; Emsellem, Eric; Eracleous, Michael; Erfanianfar, Ghazaleh; Escoffier, Stephanie; Fan, Xiaohui; Fernández Alvar, Emma; Fernandez-Trincado, J. G.; Cirolini, Rafael Fernando; Feuillet, Diane; Finoguenov, Alexis; Fleming, Scott W.; Font-Ribera, Andreu; Freischlad, Gordon; Frinchaboy, Peter; Fu, Hai; Gómez Maqueo Chew, Yilen; Galbany, Lluís; García Pérez, Ana E.; Garcia-Dias, R.; García-Hernández, D. A.; Garma Oehmichen, Luis Alberto; Gaulme, Patrick; Gelfand, Joseph; Gil-Marín, Héctor; Gillespie, Bruce A.; Goddard, Daniel; González Hernández, Jonay I.; Gonzalez-Perez, Violeta; Grabowski, Kathleen; Green, Paul J.; Grier, Catherine J.; Gueguen, Alain; Guo, Hong; Guy, Julien; Hagen, Alex; Hall, Patrick; Harding, Paul; Hasselquist, Sten; Hawley, Suzanne; Hayes, Christian R.; Hearty, Fred; Hekker, Saskia; Hernandez, Jesus; Hernandez Toledo, Hector; Hogg, David W.; Holley-Bockelmann, Kelly; Holtzman, Jon A.; Hou, Jiamin; Hsieh, Bau-Ching; Hunt, Jason A. S.; Hutchinson, Timothy A.; Hwang, Ho Seong; Jimenez Angel, Camilo Eduardo; Johnson, Jennifer A.; Jones, Amy; Jönsson, Henrik; Jullo, Eric; Sakil Khan, Fahim; Kinemuchi, Karen; Kirkby, David; Kirkpatrick, Charles C., IV; Kitaura, Francisco-Shu; Knapp, Gillian R.; Kneib, Jean-Paul; Kollmeier, Juna A.; Lacerna, Ivan; Lane, Richard R.; Lang, Dustin; Law, David R.; Le Goff, Jean-Marc; Lee, Young-Bae; Li, Hongyu; Li, Cheng; Lian, Jianhui; Liang, Yu; Lima, Marcos; Lin, Lihwai; Long, Dan; Lucatello, Sara; Lundgren, Britt; Mackereth, J. Ted; MacLeod, Chelsea L.; Mahadevan, Suvrath; Geimba Maia, Marcio Antonio; Majewski, Steven; Manchado, Arturo; Maraston, Claudia; Mariappan, Vivek; Marques-Chaves, Rui; Masseron, Thomas; Masters, Karen L.; McDermid, Richard M.; McGreer, Ian D.; Melendez, Matthew; Meneses-Goytia, Sofia; Merloni, Andrea; Merrifield, Michael R.; Meszaros, Szabolcs; Meza, Andres; Minchev, Ivan; Minniti, Dante; Mueller, Eva-Maria; Muller-Sanchez, Francisco; Muna, Demitri; Muñoz, Ricardo R.; Myers, Adam D.; Nair, Preethi; Nandra, Kirpal; Ness, Melissa; Newman, Jeffrey A.; Nichol, Robert C.; Nidever, David L.; Nitschelm, Christian; Noterdaeme, Pasquier; O’Connell, Julia; Oelkers, Ryan James; Oravetz, Audrey; Oravetz, Daniel; Aquino Ortíz, Erik; Osorio, Yeisson; Pace, Zach; Padilla, Nelson; Palanque-Delabrouille, Nathalie; Alonso Palicio, Pedro; Pan, Hsi-An; Pan, Kaike; Parikh, Taniya; Pâris, Isabelle; Park, Changbom; Peirani, Sebastien; Pellejero-Ibanez, Marcos; Penny, Samantha; Percival, Will J.; Perez-Fournon, Ismael; Petitjean, Patrick; Pieri, Matthew M.; Pinsonneault, Marc; Pisani, Alice; Prada, Francisco; Prakash, Abhishek; Queiroz, Anna Bárbara de Andrade; Raddick, M. Jordan; Raichoor, Anand; Barboza Rembold, Sandro; Richstein, Hannah; Riffel, Rogemar A.; Riffel, Rogério; Rix, Hans-Walter; Robin, Annie C.; Rodríguez Torres, Sergio; Román-Zúñiga, Carlos; Ross, Ashley J.; Rossi, Graziano; Ruan, John; Ruggeri, Rossana; Ruiz, Jose; Salvato, Mara; Sánchez, Ariel G.; Sánchez, Sebastián F.; Sanchez Almeida, Jorge; Sánchez-Gallego, José R.; Santana Rojas, Felipe Antonio; Santiago, Basílio Xavier; Schiavon, Ricardo P.; Schimoia, Jaderson S.; Schlafly, Edward; Schlegel, David; Schneider, Donald P.; Schuster, William J.; Schwope, Axel; Seo, Hee-Jong; Serenelli, Aldo; Shen, Shiyin; Shen, Yue; Shetrone, Matthew; Shull, Michael; Silva Aguirre, Víctor; Simon, Joshua D.; Skrutskie, Mike; Slosar, Anže; Smethurst, Rebecca; Smith, Verne; Sobeck, Jennifer; Somers, Garrett; Souter, Barbara J.; Souto, Diogo; Spindler, Ashley; Stark, David V.; Stassun, Keivan; Steinmetz, Matthias; Stello, Dennis; Storchi-Bergmann, Thaisa; Streblyanska, Alina; Stringfellow, Guy S.; Suárez, Genaro; Sun, Jing; Szigeti, Laszlo; Taghizadeh-Popp, Manuchehr; Talbot, Michael S.; Tang, Baitian; Tao, Charling; Tayar, Jamie; Tembe, Mita; Teske, Johanna; Thakar, Aniruddha R.; Thomas, Daniel; Tissera, Patricia; Tojeiro, Rita; Tremonti, Christy; Troup, Nicholas W.; Urry, Meg; Valenzuela, O.; van den Bosch, Remco; Vargas-González, Jaime; Vargas-Magaña, Mariana; Vazquez, Jose Alberto; Villanova, Sandro; Vogt, Nicole; Wake, David; Wang, Yuting; Weaver, Benjamin Alan; Weijmans, Anne-Marie; Weinberg, David H.; Westfall, Kyle B.; Whelan, David G.; Wilcots, Eric; Wild, Vivienne; Williams, Rob A.; Wilson, John; Wood-Vasey, W. M.; Wylezalek, Dominika; Xiao, Ting; Yan, Renbin; Yang, Meng; Ybarra, Jason E.; Yèche, Christophe; Zakamska, Nadia; Zamora, Olga; Zarrouk, Pauline; Zasowski, Gail; Zhang, Kai; Zhao, Cheng; Zhao, Gong-Bo; Zheng, Zheng; Zheng, Zheng; Zhou, Zhi-Min; Zhu, Guangtun; Zinn, Joel C.; Zou, Hu
2018-04-01
The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014–2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as “The Cannon” and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
Slide release mechanism. [for space shuttle orbiter/external tank connection device
Bunker, J. W.; Ritchie, R. S. (Inventor)
1985-01-01
A releasable support device is described which is comprised of a hollow body with a sleeve extending transversely there-through for receiving the end of a support shank. A slider-latch, optionally lubricated, extends through side recesses in the sleeve to straddle the shank, respectively, in latched and released positions. The slider-latch is slid from its latched to its unlatched position by a pressure squib whereupon a spring or other pressure means pushes the shank out of the sleeve. At the same time, a follower element is lodged in and closed the hole in the body wall from which the shank was discharged. The mechanism was designed for the shuttle orbiter/external tank connection device.
A Comparative Risk Assessment of Extended Integrated Leak Rate Testing Intervals
Energy Technology Data Exchange (ETDEWEB)
Oh, Ji Yong; Hwang, Seok Won; Lee, Byung Sik [Korea Hydro and Nuclear Power Co., Daejeon (Korea, Republic of)
2009-10-15
This paper presents the risk impacts of extending the Integrated Leak Rate Testing (ILRT) intervals (from five years to ten years) of Yonggwang (YGN) Unit 1 and 2. These risk impacts depended on the annual variances of meteorological data and resident population. Main comparisons were performed between the initial risk assessment (2005) for the purpose of extending ILRT interval and risk reassessment (2009) where the changed plant internal configurations (core inventory and radioisotope release fraction) and plant external alterations (wind directions, rainfall and population distributions) were monitored. The reassessment showed that there was imperceptible risk increase when the ILRT interval was extended compared to the initial risk assessment. In addition, the increased value of the Large Early Release Frequency (LERF) also satisfied the acceptance guideline proposed on Reg. Guide 1.174. The MACCS II code was used for evaluating the offsite consequence analysis. The primary risk index were used as the Probabilistic Population Dose (PPD) by considering the early effects within 80 km. The Probabilistic Safety Assessment (PSA) of YGN 1 and 2 was applied to evaluate the accident frequency of each source term category and the used PSA scope was limited to internal event.
Release strategies for rehabilitated sea otters
DeGange, Anthony R.; Ballachey, Brenda E.; Bayha, Keith; Williams, Terrie M.; Davis, Randall W.
1995-01-01
According to the U.S. Fish and Wildlife Services’ (USFWS) Response Plan for sea otters (USFWS, in preparation), in the event of an oil spill, the decision to release sea otters from rehabilitation centers following treatment will be linked to the decision on whether to capture sea otters for treatment. Assuming a scenario similar to the Exxon Valdez oil spill (EVOS), once the decision to capture sea otters is made, the ultimate goal is to return as many sea otters to the wild as possible, even though the rescue may not be expected to produce results significant at the population level. The decision by the USFWS to proceed with capture, rehabilitation, and release will be made on a case-by-case basis (USFWS, in preparation). Many factors will influence the decision. Perhaps the most important factors in deciding when and where to release sea otters are the location and availability of suitable release sites and verification that the otters are free of diseases that might be transmitted to the wild population.Alternative release strategies for sea otters will be contained in the sea otter response portion of the USFWS’s oil spill contingency plans for Alaska and California that are being developed as required by the Oil Pollution Act of 1990. Public review of these plans before they are implemented will help to reduce public concern about the survival of rehabilitated otters, their biological effect on the release area, and the potential introduction or spread of disease into the wild sea otter population.The objective of this chapter is to review alternative strategies for the disposition of rehabilitated sea otters. Our assumption is that returning as many animals to the wild as possible, whether it be for humanitarian or biological reasons, is the ultimate goal of this effort (Figure 10.1).
Reinemeyer, C R; Prado, J C; Andersen, U V; Nielsen, M K; Schricker, B; Kennedy, T
2014-08-29
Strongylid infections are ubiquitous in grazing horse populations. Infections with cyathostomin (small strongyle) and strongylin (large strongyle) nematodes have long been associated with clinical disease in horses, but little is known about their subclinical impact. A masked, randomized, controlled study was conducted to evaluate the effects of daily administration of pyrantel tartrate on body condition scores, weight gain, fecal egg counts, and total worm counts of young horses repeatedly inoculated with strongylid larvae. Twenty eight immature horses were treated with larvicidal anthelmintic regimens and randomly allocated to two groups. Group 1 horses were given a pelleted placebo product once daily, and those in Group 2 received pyrantel tartrate once daily at ∼ 2.64 mg/kg body weight. On five days during each week, ∼ 5000 infective cyathostomin larvae were administered to each horse. In addition, horses received ∼ 25 infective Strongylus vulgaris larvae once weekly. Horses were maintained on pasture for 154 days and had ad libitum access to grass hay throughout. At approximate, 14-day intervals, body weights were measured, body condition scores were assigned, fecal samples were collected for egg counts, and blood samples were collected for measurement of S. vulgaris antibodies and various physiologic parameters. After 22 weeks at pasture and 14-17 days in confinement, horses were euthanatized and necropsied. Nematodes were recovered and counted from aliquots of organ contents, representative samples of large intestinal mucosa, and the root of the cranial mesenteric artery. Daily treatment with pyrantel tartrate at the recommended dosage significantly reduced numbers of adult cyathostomins in the gut lumen and early third-stage larvae in the cecal mucosa, increased the proportions of fourth-stage larvae in the gut contents, and was accompanied by significant improvements in body condition scores. Fecal egg counts of horses receiving daily pyrantel
Daily text messages used as a method for assessing low back pain among workers.
Burström, Lage; Jonsson, Håkan; Björ, Bodil; Hjalmarsson, Ulla; Nilsson, Tohr; Reuterwall, Christina; Wahlström, Jens
2016-02-01
To evaluate a method for collecting data concerning low back pain (LBP) using daily text messages and to characterize the reported LBP in terms of intensity, variability, and episodes. We conducted a cohort study of LBP among workers used by a mining company. The participants were asked to answer the question "How much pain have you had in your lower back in the last 24 hours on a scale from 0 to 10, where 0 = no pain and 10 = the worst pain imaginable" once a day for 5 weeks, with this process being repeated 6 months later. A total of 121 workers participated in the first period of data collection, and 108 participated in the second period. The daily response rate was 93% for both periods, and cluster analysis was shown to be a feasible statistical method for clustering LBP into subgroups of low, medium, and high pain. The daily text messages method also worked well for assessing the episodic nature of LBP. We have demonstrated a method for repeatedly measuring of LBP using daily text messages. The data permitted clustering into subgroups and could be used to define episodes of LBP. Copyright © 2016 Elsevier Inc. All rights reserved.
De David, S C; Mário, T G; De Freitas, G C; Kantorski, K Z; Wikesjö, U M E; Moreira, Carlos Heitor Cunha
2018-02-15
To evaluate the correlation between dental plaque formation and gingival health in subjects performing high oral hygiene standards over short or extended intervals. Fifty-two non-dental students volunteered for this study. The subjects, trained to perform high oral hygiene standards, were randomized to perform oral hygiene at 12-, 24-, 48-, or 72-h interval over 30 days. The plaque index (PlI) and the gingival index (GI) were evaluated at baseline, 15, and 30 days. For the statistical analysis, oral hygiene intervals were collapsed into daily (12 and 24 h; G12/24) and extended (48 and 72 h; G48/72) intervals. Summary statistics (mean ± SD) and Spearman correlations between the PlI and the GI at baseline, 15, and 30 days were estimated. At baseline, correlation coefficients between PlI and GI were positive for both groups (r = 0.29 and r = 0.25). At day 15 and 30, correlation was maintained with similar baseline values for the G48/72 group. GI levels did not increase despite an increase in PlI for the G12/24 group, and the correlation was lower than that observed at baseline (r = 0.13 vs. r = 0.29). In subjects with high oral hygiene standards, the oral hygiene frequency governs the correlation between dental plaque formation and gingival health. Subjects performing high oral hygiene standards at daily intervals will maintain gingival health in difference to subjects using extended hygiene intervals. Subjects performing high oral hygiene standards at daily intervals will maintain gingival health in difference to subjects using extended hygiene intervals.
Intent to Quit among Daily and Non-Daily College Student Smokers
Pinsker, E. A.; Berg, C. J.; Nehl, E. J.; Prokhorov, A. V.; Buchanan, T. S.; Ahluwalia, J. S.
2013-01-01
Given the high prevalence of young adult smoking, we examined (i) psychosocial factors and substance use among college students representing five smoking patterns and histories [non-smokers, quitters, native non-daily smokers (i.e. never daily smokers), converted non-daily smokers (i.e. former daily smokers) and daily smokers] and (ii) smoking…
Directory of Open Access Journals (Sweden)
K. Yu. Mukhin
2015-01-01
Full Text Available Research on comparative efficаcy and tolerability of monotherapy with Depakine chronosphere, drugs of Carbamazepine group with extended release and oxcarbazepine in symptomatic and cryptogenic focal epilepsy has been conducted at Svt. Luka’s Institute of Child Neurology and Epilepsy (ICNE (Moscow. This retrospective study covers a random sample of patients treated in ICNE in the period from December 1, 2013 to September 1, 2014. The study included 131 patients aged 1 to 18 years with symptomatic and cryptogenic focal epilepsy receiving treatment with one of the study drugs in monotherapy: group 1 – monotherapy with Depakine chronosphere (n = 56; group 2 – monotherapy with drugs of carbamazepine group with extended release (n = 55; group 3 – monotherapy with oxcarbazepine (trileptal (n = 20. The obtained results allow us to conclude that the effectiveness of Depakin chronosphere, carbamazepine with extended release and oxcarbazepine in monotherapy of symptomatic and cryptogenic focal epilepsy was comparable (statistically significant differences in efficacy were not found. However, carbamazepine was awarded the highest frequency of seizures aggravation. Drugs showed approximately same tolerability (statistically significant differences in tolerability were not found. However, withdrawal of the drug due to side effects was the rarest in Depakine (3.5 %, and withdrawal due to intolerance was higher in carbamazepine and oxcarbazepine (5 and 10 % respectively. Depakinum and oxcarbazepine had the best results in the blocking of pathological activity on the electroencephalogram, whereas carbamazepine was clearly inferior to them. In this regard, complete clinical-electroencephalographic remission (lasting 12 months or more was achieved under treatment of Depakine chromosphere in 21.5 % of cases, oxcarbazepi on therapy for 12 months was similar in all study drugs. Considering that the objective of epilepsy treatment is to achieve complete
Participation of irradiated Anopheles arabiensis males in swarms following field release in Sudan
International Nuclear Information System (INIS)
Ageep, Tellal B; Alsharif, Bashir; Ahmed, Ayman; Salih, Elwaleed HO; Ahmed, Fayez TA; El Sayed, Badria B; Damiens, David; Gilles, Jeremie RL; Lees, Rosemary S; Diabaté, Abdoulaye
2015-01-01
BACKGROUND: The success of the SIT depends on the; release of large numbers of sterile males, which are able to; compete for mates with the wild male population within the; target area. The processes of colonisation, mass production; and irradiation may reduce the competitiveness of sterile; males through genetic selection, loss of natural traits and; somatic damage. In this context, the capacity of released; sterile Anopheles arabiensis males to survive, disperse and; participate in swarms occurring at varying distances from; the release site was studied using mark-release-recapture; techniques.; METHODS: In order to assess their participation in; swarms, irradiated and marked laboratory-reared male; mosquitoes were released 50, 100 or 200 m from the; known site of a large swarm on three consecutive nights.; Males were collected from this large swarm on subsequent; nights. Over the three days a total of 8,100 males were released.; Mean distance travelled (MDT), daily probability of; survival and estimated population size were calculated; from the recapture data. An effect of male age at the time; of release on these parameters was observed.; RESULTS: Five per cent of the males released over three; days were recaptured. In two-, three- and four-day-old; males, MDT was 118, 178 and 170 m, and the daily survival; probability 0.95, 0.90 and 0.75, respectively. From the; recapture data on the first day following each release, the; Lincoln index gives an estimation of 32,546 males in the; natural population.; DISCUSSION: Sterile An. arabiensis males released into; the field were able to find and participate in existing; swarms, and possibly even initiate swarms. The survival; probability decreased with the age of male on release but; the swarm participation and the distance travelled by older; males seemed higher than for younger males. The inclusion; of a pre-release period may thus be beneficial to male competitiveness; and increase the attractiveness of adult sexing
S Esser; H Heiken; L Gallo; S Schellberg; M Schlag; A Moll; R Pauli; A Stoehr; O Degen; H Jaeger; C Stephan; G Fätkenheuer
2012-01-01
The life-long antiretroviral treatment of HIV-1 infection requires effective and well tolerated medications complemented by high rates of adherence in order to achieve viral suppression, immunologic reconstitution and to prevent the development of resistance. Single-tablet regimens (STRs), combining a full antiretroviral regimen in one tablet taken once daily, have been designed to achieve high adherence and better long-term outcomes. “STRike” is the first cohort study, describi...
CDC Vital Signs-Daily Pill Can Prevent HIV
Centers for Disease Control (CDC) Podcasts
2015-11-24
This podcast is based on the November 24, 2015 CDC Vital Signs report. Preexposure prophylaxis, or PrEP, is a daily medicine that can be used to prevent getting HIV. PrEP is for people who donât have HIV but who are at very high risk for getting it from sex or injection drug use. Unfortunately, many people who can benefit from PrEP arenât taking it. Created: 11/24/2015 by National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP). Date Released: 11/24/2015.
Predicting hydrocarbon release from soil
International Nuclear Information System (INIS)
Poppendieck, D.; Loehr, R.C.
2002-01-01
'Full text:' The remediation of hazardous chemicals from soils can be a lengthy and costly process. As a result, recent regulatory initiatives have focused on risk-based corrective action (RBCA) approaches. Such approaches attempt to identify the amount of chemical that can be left at a site with contaminated soil and still be protective of human health and the environment. For hydrocarbons in soils to pose risk to human heath and the environment, the hydrocarbons must be released from the soil and accessible to microorganisms, earthworms, or other higher level organisms. The sorption of hydrocarbons to soil can reduce the availability of the hydrocarbon to receptors. Typically in soils and sediments, there is an initial fast release of a hydrocarbon from the soil to the aqueous phase followed by a slower release of the remaining hydrocarbon to the aqueous phase. The rate and extent of slow release can influence aqueous hydrocarbon concentrations and the fate and transport of hydrocarbons in the subsurface. Once the fast fraction of the chemical has been removed from the soil, the remaining fraction of a chemical may desorb at a rate that natural mechanisms can attenuate the released hydrocarbon. Hence, active remediation may be needed only until the fast fraction has been removed. However, the fast fraction is a soil and chemical specific parameter. This presentation will present a tier I type protocol that has been developed to quickly estimate the fraction of hydrocarbons that are readily released from the soil matrix to the aqueous phase. Previous research in our laboratory and elsewhere has used long-term desorption (four months) studies to determine the readily released fraction. This research shows that a single short-term (less than two weeks) batch extraction procedure provides a good estimate of the fast released fraction derived from long-term experiments. This procedure can be used as a tool to rapidly evaluate the release and bioavailability of
Carpentier, Patrick; van Bellen, Bonno; Karetova, Debora; Hanafiah, Harunarashid; Enriquez-Vega, Elizabeth; Kirienko, Alexander; Dzupina, Andrej; Sabovic, Miso; Reina Gutierrez, Lourdes; Subwongcharoen, Somboom; Tüzün, Hasan; Maggioli, Arnaud
2017-10-01
Chronic venous disorders (CVD) is estimated to affect 30% to 50% of women and 10% to 30% of men. The most widely prescribed treatment for CVD worldwide is micronized purified flavonoid fraction 500 mg (MPFF). The aim of this clinical trial was to develop a new once daily 1000-mg oral suspension of MPFF. In an international, randomized, double-blind, parallel-group study, symptomatic individuals classified CEAP C0s to C4s were randomized in either treatment arm and treated for 8 weeks. Lower limb symptoms (discomfort, pain and heaviness) were assessed using Visual Analog Scales (VAS), and quality of life (QoL) was measured with the CIVIQ-20 Questionnaire. A total of 1139 patients were included in the study. Both MPFF treatment regimens were well tolerated and associated with a significant reduction in lower limb symptoms. A non-inferiority of MPFF 1000-mg oral suspension once daily compared to MPFF 500-mg tablet twice daily (P1000 mg and -3.37 cm for MPFF 500 mg), leg pain (-3.27 cm for MPFF 1000 mg and -3.31 cm for MPFF 500 mg) and leg heaviness (-3.41 cm for MPFF 1000 mg and -3.46 cm for MPFF 500 mg). The patients' QoL was improved by about 20 points on the CIVIQ scale in both groups (19.33 points for MPFF 1000 mg and 20.28 points for MPFF 500 mg). MPFF 1000-mg oral suspension and MPFF 500-mg tablets treatments were associated with similar reductions in lower limb symptoms and QoL improvement. The new once daily MPFF1000-mg oral suspension has a similar safety profile to two tablets of MPFF 500 mg, with the advantage of one daily intake, potentially associated with improved patient adherence and easier CVD management.
International Nuclear Information System (INIS)
Lalle, M.; Antimi, M.; Pistillucci, G.; D'Aprile, M.
2005-01-01
The objective of this observational study was the early evaluation of the impact, a week after the first administration of epoetin alfa 40000 U once weekly and i.v. dose of 62.5 mg sodium ferric gluconate for seven days in improving hemoglobin levels in cancer patients affected by mild/moderate or severe anemia during chemotherapy. Twenty patients affected by solid tumors who received epoetin alfa 40000 U once weekly and daily i.v. sodium ferric gluconate for one week were evaluated: 90% of the patients showed hemoglobin increase, with a median level of hemoglobin increase of 0.73 g/L from baseline, and 50% of them showing a hemoglobin increase > 1 gr/L. The treatment was well tolerated and no adverse event was observed. The early increase of hemoglobin level from baseline is interesting and suggestive for the possibility of achieving an adequate hemoglobin level with a short-term treatment. It is still necessary to further explore the real need of iron supplementation to maintain adequate erythropoiesis prior and during epoetin therapy
Tritium release during inspection of reactor 'RA' at 'Vinca' institute
International Nuclear Information System (INIS)
Sipka, V.; Miljevic, N.; Grsic, Z.; Todorovic, D.; Radenkovic, M.
1997-01-01
Tritium content in daily precipitation, atmospheric water vapor inside of the reactor hall and around 'Vinca' Institute as well as in soil up to 800 m distance was monitoring during the regular inspection of the fuel channels. Tritium activity in the reactor hall air moisture was in the range from 0.022 to 6.7 MBq/m 3 . Tritium content in soil moisture between 12.7 and 530.9 Bq/l indicate a certain contamination due to tritium release in the environment, depending on the depth and distance from the place of release (author) [sr
History of the CERN Web Software Public Releases
Fluckiger, Francois; CERN. Geneva. IT Department
2016-01-01
This note is an extended version of the article “Licencing the Web” (http://home.web.cern.ch/topics/birthweb/licensing-web) published by CERN, Nov 2013, in the “Birth of the Web” series of articles (http://home.cern/topics/birth-web). It describes the successive steps of the public release of the CERN Web software, from public domain to open source, and explains their rationale. It provides in annexes historical documents including release announcement and texts of the licences used by CERN and MIT in public software distributions.
Release of Fluconazole from Contact Lenses Using a Novel In Vitro Eye Model.
Phan, Chau-Minh; Bajgrowicz, Magdalena; Gao, Huayi; Subbaraman, Lakshman N; Jones, Lyndon W
2016-04-01
Rapid drug release followed by a plateau phase is a common observation with drug delivery from contact lenses (CLs) when evaluated in a vial. The aim of this study was to compare the release of fluconazole from seven commercially available daily disposable CLs using a conventional vial-based method with a novel in vitro eye model. An eye model was created using two 3-dimensional printed molds, which were filled with polydimethylsiloxane to obtain an inexpensive model that would mimic the eyeball and eyelid. The model was integrated with a microfluidic syringe pump, and the flow-through was collected in a 12-well microliter plate. Four commercial daily disposable conventional hydrogels (nelfilcon A, omafilcon A, etafilcon A, ocufilcon B) and three silicone hydrogels (somofilcon A, narafilcon A, delefilcon A) were evaluated. These CLs were incubated with fluconazole for 24 h. The drug release was measured in a vial containing 4.8 mL of phosphate-buffered saline and in the polydimethylsiloxane eye model with a 4.8-mL tear flow across 24 h. Overall, conventional hydrogel CLs had a higher uptake and release of fluconazole than silicone hydrogel CLs (p eye model (p eye model under low tear volume was sustained and did not reach a plateau across 24 h (p eyes with fungal keratitis may have increased tearing, which would significantly accelerate drug release.
Wright, Leah; Rao, Shasha; Thomas, Nicky; Boulos, Ramiz A; Prestidge, Clive A
2018-04-11
Novel antibiotic Ramizol ® is advancing to clinical trials for the treatment of gastrointestinal Clostridium difficile associated disease. Despite this, previous studies have shown a rapid plasma clearance upon intravenous administration and low oral bioavailability indicating pure drug is unsuitable for systemic infection treatment following oral dosing. The current study aims to investigate the development of poly-lactic-(co-glycolic) acid (PLGA) particles to overcome this limitation and increase the systemic half-life following subcutaneous and intramuscular dosing. The development of new antibiotic treatments will help in combatting the rising incidence of antimicrobial resistance. Ramizol ® was encapsulated into PLGA nano and microparticles using nanoprecipitation and emulsification solvent evaporation techniques. Formulations were analyzed for particle size, loading level and encapsulation efficiency as well as in vitro drug release profiles. Final formulation was advanced to in vivo pharmacokinetic studies in Sprague-Dawley rats. Formulation technique showed major influence on particle size and loading levels with optimal loading of 9.4% and encapsulation efficiency of 92.06%, observed using emulsification solvent evaporation. Differences in formulation technique were also linked with subsequent differences in release profiles. Pharmacokinetic studies in Sprague-Dawley rats confirmed extended absorption and enhanced bioavailability following subcutaneous and intramuscular dosing with up to an 8-fold increase in T max and T 1/2 when compared to the oral and IV routes. Subcutaneous and intramuscular dosing of PLGA particles successfully increased systemic half-life and bioavailability of Ramizol ® . This formulation will allow further development of Ramizol ® for systemic infection eradication.
The diabetic frozen shoulder: arthroscopic release.
Ogilvie-Harris, D J; Myerthall, S
1997-02-01
Seventeen patients who were diabetics developed frozen shoulders which failed to respond to conservative management. They had persistent pain, stiffness, and limited function. An arthroscopic release was performed by progressively releasing the anterior structures from superior to inferior. Starting from the interval area we progressed to the anterior superior glenohumeral ligament, the intra-articular portion of the subscapularis, the anterior capsule, and the inferior capsule. Postoperatively physiotherapy was carried out daily to maintain the range of movement. At a follow up of 1 to 5 years the patients were assessed using the American Shoulder Society scheme. In addition the patients were assessed preoperatively and postoperatively on four criteria; pain, external rotation, abduction, and function. We found that the patients were statistically significantly improved in all four categories. Thirteen of the 17 patients had no pain, full range of motion compared with the opposite side, and full function. There was one poor result with no improvement. The remaining three patients had improved but still had residual abnormalities. We consider arthroscopic release to be an effective treatment for the resistant diabetic frozen shoulder.
The Second Data Release of the Sloan Digital Sky Survey
Abazajian, Kevork; ̈ueros, Marcel A. Ag; Allam, Sahar S.; Anderson, KurtS. J.; Anderson, Scott F.; Annis, James; Bahcall, Neta A.; Baldry, Ivan K.; StevenBastian; Berlind, Andreas; Bernardi, Mariangela; Blanton, Michael R.; BochanskiJr., John J.; Boroski, William N.; Briggs, John W.; Brinkmann, J.; Brunner, Robert J.; ́ari, Tam ́asBudav; Carey, Larry N.; Carliles, Samuel; Castander, Francisco J.; Connolly, A. J.; Csabai, Istvan; Doi, Mamoru; Dong, Feng; Eisenstein, Daniel J.; Evans, Michael L.; Fan, Xiaohui; Finkbeiner, Douglas P.; Friedman, Scott D.; Frieman, Joshua A.; Fukugita, Masataka; Gal, RoyR.; Gillespie, Bruce; Glazebrook, Karl; Gray, Jim; Grebel, Eva K.; Gunn, James E.; Gurbani, Vijay K.; Hall, Patrick B.; Hamabe, Masaru; Harris, Frederick H.; C.Harris, Hugh; Harvanek, Michael; Heckman, Timothy M.; Hendry, John S.; Hennessy, Gregory S.; Hindsley, Robert B.; Hogan, Craig J.; Hogg, David W.; Holmgren, Donald J.; Ichikawa, Shin-ichi; Ichikawa, Takashi; Ivezic, Zeljko; Jester, Sebastian; Johnston, David E.; Jorgensen, AndersM.; Kent, Stephen M.; Kleinman, S. J.; Knapp, G. R.; Kniazev, Alexei Yu.; Kron, Richard G.; Krzesinski, Jurek; Kunszt, Peter Z.; Kuropatkin, Nickolai; Q.Lamb, Donald; Lampeitl, Hubert; Lee, Brian C.; Leger, R. French; Li, Nolan; Lin, Huan; Loh, Yeong-Shang; Long, Daniel C.; Loveday, Jon; Lupton, Robert H.; Malik, Tanu; BruceMargon; Matsubara, Takahiko; McGehee, Peregrine M.; McKay, Timothy A.; AveryMeiksin; Munn, Jeffrey A.; Nakajima, Reiko; Nash, Thomas; Neilsen, Eric H. Jr.; JoNewberg, Heidi; Newman, Peter R.; Nichol, Robert C.; Nicinski, Tom; Nieto-Santisteban, Maria; Nitta, Atsuko; Okamura, Sadanori; O'Mullane, William; Ostriker, Jeremiah P.; Owen, Russell; Padmanabhan, Nikhil; Peoples, John; Pier, Jeffrey R.; Pope, Adrian C.; Quinn, Thomas R.; Richards, Gordon T.; Richmond, Michael W.; Rix, Hans-Walter; Rockosi, Constance M.; Schlegel, David J.; Schneider, Donald P.; Scranton, Ryan; Sekiguchi, Maki; Seljak, Uros; Sergey, Gary; Sesar, Branimir; Sheldon, Erin; Shimasaku, Kazu; Siegmund, Walter A.; Silvestri, Nicole M.; Smith, J. Allyn; ́c, Vernesa Smolči; Snedden, Stephanie A.; AlbertStebbins; Stoughton, Chris; Strauss, Michael A.; SubbaRao, Mark; Szalay, Alexander S.; Szapudi, Istv ́an; Szkody, Paula; Szokoly, Gyula P.; Tegmark, Max; Teodoro, Luis; Thakar, AniruddhaR.; Tremonti, Christy; Tucker, Douglas L.; Uomoto, Alan; Vanden Berk, Daniel E.; Vandenberg, Jan; Vogeley, Michael S.; Voges, Wolfgang; Vogt, Nicole P.; M.Walkowicz, Lucianne; Wang, Shu-i; Weinberg, David H.; West, Andrew A.; White, Simon D.M.; Wilhite, BrianC.; Xu, Yongzhong; Yanny, Brian; Yasuda, Naoki; Yip, Ching-Wa; Yocum, D. R.; York, Donald G.; Zehavi, Idit; Zibetti, Stefano; Zucker, Daniel B.
2004-01-01
The Sloan Digital Sky Survey has validated and made publicly available its Second Data Release. This data release consists of 3324 square degrees of five-band (u g r i z) imaging data with photometry for over 88 million unique objects, 367,360 spectra of galaxies, quasars, stars and calibrating blank sky patches selected over 2627 degrees of this area, and tables of measured parameters from these data. The imaging data reach a depth of r ~ 22.2 (95% completeness limit for point sources) and are photometrically and astrometrically calibrated to 2% rms and 100 milli-arcsec rms per coordinate, respectively. The imaging data have all been processed through a new version of the SDSS imaging pipeline, in which the most important improvement since the last data release is fixing an error in the model fits to each object. The result is that model magnitudes are now a good proxy for point spread function (PSF) magnitudes for point sources, and Petrosian magnitudes for extended sources. The spectroscopy extends from 38...
Directory of Open Access Journals (Sweden)
Mirbod Seyed
2002-01-01
Full Text Available Abstract Background This study was designed to evaluate the effects of a 24-month period of moderate exercise on serum lipids in menopausal women. Methods The subjects (40–60 y were randomly divided into an exercise group (n = 14 and a control group (n = 13. The women in the exercise group were asked to participate in a 90-minute physical education class once a week and to record their daily steps as measured by a pedometer for 24 months. Results Mean of daily steps was significantly higher in the exercise group from about 6,800 to over 8,500 steps (P P Conclusions These results suggest that daily exercise as well as increasing the number of daily steps can improve the profile of serum lipids.
Bucher Bartelson, Becki; Le Lait, M Claire; Green, Jody L; Cepeda, M Soledad; Coplan, Paul M; Maziere, Jean-Yves; Wedin, Gregory P; Dart, Richard C
2017-09-01
An unintended consequence of extended-release (ER) and long-acting (LA) prescription opioids is that these formulations can be more attractive to abusers than immediate-release (IR) formulations. The US Food and Drug Administration recognized these risks and approved the ER/LA Opioid Analgesic Risk Evaluation and Mitigation Strategy (ER/LA REMS), which has a goal of reducing opioid misuse and abuse and their associated consequences. The primary objective of this analysis is to determine whether ER/LA REMS implementation was associated with decreased reports of misuse and abuse. Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS(R)) System Poison Center Program were utilized. Poison center cases are assigned a reason for exposure, a medical outcome, and a level of health care received. Rates adjusted for population and drug utilization were analyzed over time. RADARS System Poison Center Program data indicate a notable decrease in ER/LA opioid rates of intentional abuse and misuse as well as major medical outcomes or hospitalizations following implementation of the ER/LA REMS. While similar decreases were observed for the IR prescription opioid group, the decreasing rate for the ER/LA opioids exceeded the decreasing rates for the IR prescription opioids and was distinctly different than that for the prescription stimulants, indicating that the ER/LA REMS program may have had an additional effect on decreases in opioid abuse and intentional misuse beyond secular trends. Copyright © 2017 John Wiley & Sons, Ltd.
Chronic and Daily Stressors Along With Negative Affect Interact to Predict Daily Tiredness.
Hartsell, Elizabeth N; Neupert, Shevaun D
2017-11-01
The present study examines the within-person relationship of daily stressors and tiredness and whether this depends on daily negative affect and individual differences in chronic stress. One hundred sixteen older adult participants were recruited via Amazon's Mechanical Turk for a 9-day daily diary study. Daily tiredness, daily stressors, and negative affect were measured each day, and chronic stress was measured at baseline. Daily stressors, daily negative affect, and chronic stress interacted to predict daily tiredness. People with high chronic stress who experienced an increase in daily negative affect were the most reactive to daily stressors in terms of experiencing an increase in daily tiredness. We also found that people with low levels of chronic stress were the most reactive to daily stressors when they experienced low levels of daily negative affect. Our results highlight the need for individualized and contextualized approaches to combating daily tiredness in older adults.
Shargil, A A
1987-03-01
Thirty husbands in childless couples, aged 24 to 35 years, were treated with luteinizing hormone-releasing hormone (LH-RH) for idiopathic hypogonadotropic hypogonadism (IHH) of peripubertal (incomplete) type. They were azoospermic or oligospermic, with less than 1.5 X 10(6)/ml nonmotile spermatozoa. The diagnosis of IHH was based on clinical and laboratory features and testicular biopsy specimen study and was further supported by results of stimulation tests and gonadotropin-releasing hormone (GnRH) test. Two treatment modalities were used: subcutaneous injections of 500 micrograms LH-RH twice daily; and perpetual subcutaneous injection, via portable infusion pump, of 25 ng/kg LH-RH, at 90-minute intervals. Two patients required a short second period of pulsatile treatment to cause a second pregnancy of their spouses. The pump proved to yield better results, compared with intermittent injections, in respect to endocrine responses, spermatogenesis, and fertility capacity. Normal levels of luteinizing hormone and follicle-stimulating hormone were reached in 2 to 3 weeks and normal testosterone levels in 8 to 10 weeks from the start of treatment. Sperm counts rose to greater than 60 X 10(6)/ml viable spermatozoa with less than 15% of abnormal forms in 3 to 5 months, and the wives conceived. Of a total of 18 deliveries of healthy infants, 12 offspring were identified genetically with their fathers. Four women were still pregnant at the conclusion of the study. The pump was well tolerated, without special operational problems to the patients. Pulsatile treatment is therefore recommended in the treatment of well-diagnosed and carefully selected cases of incomplete IHH.
Estimation of Release of Nickel and Chromium by Indian Made Orthodontic Appliance in Saliva.
Parashar, Sandeep; Maurya, Rajkumar; Gupta, Ankur; Hegde, Chatura; Anand, Neelima
2015-09-01
With increasing use of Indian made orthodontic materials, need was felt to know nickel and chromium release from these material. This study was conducted on simulated appliances consisting of brackets (022″Roth, Modern orthodontics, Ludhiana, India), from second premolar to central incisor, buccal tube and 0.019×0.025- inch SS arch wires secured with SS ligatures. Immersion was done in artificial saliva. Samples were analysed to using Atomic Absorption Photospectrometer (GVC ScientificEquipment Pvt. Ltd Australia) at AES Laboratories (P) Ltd., Noida India on 1(st), 7(th), 14(th) and 28(th) day. SPSS (ver 17, Inc., Chicago, Illinois, USA) was used toperform the statistical analysis. Descriptive statistics i.e. median and 25 and75 percentiles were used. Peak nickel release was on 7(th) day and subsequently declined over 14(th) and 28(th) day. The peak level of chromium concentration was on 14(th) day, which declined thereafter. Average daily release of nickel and chromium over a period of one month was 97.368 μg/day and 47.664 μg/day respectively. The estimated release rates were approximately 32% and 16% of the reported average daily dietary.
Atmospheric Release Advisory Capability
International Nuclear Information System (INIS)
Dickerson, M.H.; Gudiksen, P.H.; Sullivan, T.J.
1983-02-01
The Atmospheric Release Advisory Capability (ARAC) project is a Department of Energy (DOE) sponsored real-time emergency response service available for use by both federal and state agencies in case of a potential or actual atmospheric release of nuclear material. The project, initiated in 1972, is currently evolving from the research and development phase to full operation. Plans are underway to expand the existing capability to continuous operation by 1984 and to establish a National ARAC Center (NARAC) by 1988. This report describes the ARAC system, its utilization during the past two years, and plans for its expansion during the next five to six years. An integral part of this expansion is due to a very important and crucial effort sponsored by the Defense Nuclear Agency to extend the ARAC service to approximately 45 Department of Defense (DOD) sites throughout the continental US over the next three years
2012-01-27
... Factor Analog-Diphtheria Toxoid Conjugate AGENCY: Food and Drug Administration, HHS. ACTION: Final rule... extends the slaughter interval for intact male swine injected with gonadotropin releasing factor analog...-322 for IMPROVEST (gonadotropin releasing factor analog-diphtheria toxoid conjugate) Sterile Solution...
Prolonged maintenance of capsaicin-induced hyperalgesia by brief daily vibration stimuli.
Kim, Hee Kee; Schattschneider, Jörn; Lee, Inhyung; Chung, Kyungsoon; Baron, Ralf; Chung, Jin Mo
2007-05-01
This study tests the hypothesis that central sensitization initiated by nociceptive input can be maintained by repeated brief innocuous peripheral inputs. Capsaicin was injected intradermally into the hind paw of adult rats. Three different types of daily cutaneous mechanical stimulations (vibration, soft brush, or pressure) were applied to the capsaicin-injected paw for a period of 2 weeks. Daily stimulation consisted of a 10-s stimulation repeated every 30s for 30 min. Foot withdrawal thresholds to von Frey stimuli applied to the paw were measured once a day for 4 weeks. The capsaicin-only group (control rats without daily stimulation) showed hyperalgesia lasting for 3 days. In contrast, hyperalgesia persisted for 2 weeks in the group that received vibration stimulation. Neither the soft brush nor the pressure group showed a significant difference in mechanical threshold from the control group (capsaicin only). The vibration-induced prolonged hyperalgesia was significantly reduced by systemic injection of ifenprodil, an NMDA-receptor antagonist, but it was not influenced by either an AMPA-receptor blocker or a reactive oxygen species (ROS) scavenger. Furthermore, a dorsal column lesion did not interfere with the prolongation of hyperalgesia. Data suggest that vibration-induced prolongation of hyperalgesia is mediated by spinal NMDA-receptors, and a similar mechanism may underlie some forms of chronic pain with no obvious causes, such as complex regional pain syndrome type 1 (CRPS-1).
45 CFR 170.440 - ONC-ATCB status.
2010-10-01
... Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.440 ONC-ATCB status...
Kaunisto, Erik; Marucci, Mariagrazia; Borgquist, Per; Axelsson, Anders
2011-10-10
The time required for the design of a new delivery device can be sensibly reduced if the release mechanism is understood and an appropriate mathematical model is used to characterize the system. Once all the model parameters are obtained, in silico experiments can be performed, to provide estimates of the release from devices with different geometries and compositions. In this review coated and matrix systems are considered. For coated formulations, models describing the diffusional drug release, the osmotic pumping drug release, and the lag phase of pellets undergoing cracking in the coating due to the build-up of a hydrostatic pressure are reviewed. For matrix systems, models describing pure polymer dissolution, diffusion in the polymer and drug release from swelling and eroding polymer matrix formulations are reviewed. Importantly, the experiments used to characterize the processes occurring during the release and to validate the models are presented and discussed. Copyright © 2011 Elsevier B.V. All rights reserved.
Wu, Ching-yi; Chuang, Li-ling; Lin, Keh-chung; Lee, Shin-da; Hong, Wei-hsien
2011-08-01
To determine the responsiveness, minimal detectable change (MDC), and minimal clinically important differences (MCIDs) of the Nottingham Extended Activities of Daily Living (NEADL) scale and to assess percentages of patients' change scores exceeding the MDC and MCID after stroke rehabilitation. Secondary analyses of patients who received stroke rehabilitation therapy. Medical centers. Patients with stroke (N=78). Secondary analyses of patients who received 1 of 4 rehabilitation interventions. Responsiveness (standardized response mean [SRM]), 90% confidence that a change score at this threshold or higher is true and reliable rather than measurement error (MDC(90)), and MCID on the NEADL score and percentages of patients exceeding the MDC(90) and MCID. The SRM of the total NEADL scale was 1.3. The MDC(90) value for the total NEADL scale was 4.9, whereas minima and maxima of the MCID for total NEADL score were 2.4 and 6.1 points, respectively. Percentages of patients exceeding the MDC(90) and MCID of the total NEADL score were 50.0%, 73.1%, and 32.1%, respectively. The NEADL is a responsive instrument relevant for measuring change in instrumental activities of daily living after stroke rehabilitation. A patient's change score has to reach 4.9 points on the total to indicate a true change. The mean change score of a stroke group on the total NEADL scale should achieve 6.1 points to be regarded as clinically important. Our findings are based on patients with improved NEADL performance after they received specific interventions. Future research with larger sample sizes is warranted to validate these estimates. Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.
International Nuclear Information System (INIS)
Casares, F.J.; Lopez-Luque, R.; Posadillo, R.; Varo-Martinez, M.
2014-01-01
Sizing SAPV techniques try to assess the reliability of the system from the stochastic simulation of the energy balance. This stochastic simulation implies the generation, for an extended period of time, of the main state variables of the physical equations describing the energy balance of the system, that is, the energy delivered to the load and the energy stored in the batteries. Most of these methods consider the daily load as a constant over the year and control the variables indicating the reliability associated with the supply of power to the load. Furthermore, these methods rely on previous random models for generating solar radiation data and, since the approximations of the simulation methods are asymptotic, when more precise reliability indicators are required, the simulation period needs to be extended. This paper presents a mathematical methodology to address the daily energy balance without resorting to simulation methods. This method is directly based on daily solar radiation series modelled according to Markov stochastic processes and Aguiar matrices. The characterization presented is the base of a rational method in which reliability does not depend on the number of iterations but on the precision of the conditional probabilities included in Aguiar matrices. - Highlights: • A new SAPV sizing method is presented and validated. • This model relates the PV sizing methods to the autocorrelative Aguiar model. • This statistical approach is only limited by Markov matrixes. • It permits the study of PV systems with variable daily demands or solar tracking. • LLP for a SAPV can be estimated quickly and in an analytic and precise way
Banks, Matthew L; Blough, Bruce E; Fennell, Timothy R; Snyder, Rodney W; Negus, S Stevens
2013-12-01
There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).
Intent to quit among daily and non-daily college student smokers
Pinsker, E. A.; Berg, C. J.; Nehl, E. J.; Prokhorov, A. V.; Buchanan, T. S.; Ahluwalia, J. S.
2012-01-01
Given the high prevalence of young adult smoking, we examined (i) psychosocial factors and substance use among college students representing five smoking patterns and histories [non-smokers, quitters, native non-daily smokers (i.e. never daily smokers), converted non-daily smokers (i.e. former daily smokers) and daily smokers] and (ii) smoking category as it relates to readiness to quit among current smokers. Of the 4438 students at six Southeast colleges who completed an online survey, 69.7%...
Schneider, Jonathan D.
2016-01-01
In this age of data based decision making and accountability, parent involvement and data collection are paramount. This study represents a significant contribution to educational research by extending the understanding of home-school communication media with specific regard to daily progress reports. The purpose of this study was to compare…
The 'sniffer-patch' technique for detection of neurotransmitter release.
Allen, T G
1997-05-01
A wide variety of techniques have been employed for the detection and measurement of neurotransmitter release from biological preparations. Whilst many of these methods offer impressive levels of sensitivity, few are able to combine sensitivity with the necessary temporal and spatial resolution required to study quantal release from single cells. One detection method that is seeing a revival of interest and has the potential to fill this niche is the so-called 'sniffer-patch' technique. In this article, specific examples of the practical aspects of using this technique are discussed along with the procedures involved in calibrating these biosensors to extend their applications to provide quantitative, in addition to simple qualitative, measurements of quantal transmitter release.
van der Schans, Jurjen; Kotsopoulos, Niko; Hoekstra, Pieter J.; Hak, Eelko; Postma, Maarten J.
2015-01-01
BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH) is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at
Rizk, Ahmed Shawkat; Kandel, Wael A; Tabl, Eslam Abd Elshafi; Kandil, Mahmoud I
2017-11-01
Heel pain with or without calcaneal spur is a challenging problem. Once conservative measures have failed, surgery may be indicated; there has been debate about the best surgical procedure. Two standard operative procedures have been either releasing the plantar fascia or removing the spur with drilling of the calcaneus. In this study, we evaluated the results of percutaneous drilling of the calcaneus combined with mid-sole release of the plantar fascia for treatment of resistant heel pain. This study included 20 cases with resistant heel pain after failure of conservative measures for 6 months. Clinical, radiological evaluation and scoring patients' conditions according to the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot scale was done preoperatively and postoperatively. Percutaneous drilling of the calcaneus combined with mid-sole release of the plantar fascia was done in all cases, and the functional results were evaluated through the follow-up period that extended from 9 to 16 months with a mean duration of 12 ± 2.3 months. There was statistically significant improvement in the mean AOFAS Ankle-Hindfoot scale score from 50.8 ± 7.5 preoperatively to 91.6 ± 7 postoperatively at the last follow-up. There were no surgery-related complications, and the mean time for full recovery was 8 ± 3.7 weeks with no recurrence of pain by the last follow-up. The results were very satisfactory with using this minimally invasive and simple technique for treatment for resistant heel pain. Level IV, retrospective case series.
Bell, D; Duffin, A; Jacobs, A; Pediconi, C; Gruss, H J
2014-03-01
The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.
Mehta, Shahil; Gajjar, Shefali R; Padgett, Kyle R; Asher, David; Stoyanova, Radka; Ford, John C; Mellon, Eric A
2018-03-19
Radiation therapy (RT) plays a critical role in the treatment of glioblastoma. Studies of brain imaging during RT for glioblastoma have demonstrated changes in the brain during RT. However, frequent or daily utilization of standalone magnetic resonance imaging (MRI) scans during RT have limited feasibility. The recent release of the tri-cobalt-60 MRI-guided RT (MR-IGRT) device (ViewRay MRIdian, Cleveland, OH) allows for daily brain MRI for the RT setup. Daily MRI of three postoperative patients undergoing RT and temozolomide for glioblastoma over a six-week course allowed for the identification of changes to the cavity, edema, and visible tumor on a daily basis. The volumes and dimensions of the resection cavities, edema, and T2-hyperintense tumor were measured. A general trend of daily decreases in cavity measurements was observed in all patients. For the one patient with edema, a trend of daily increases followed by a trend of daily decreases were observed. These results suggest that daily MRI could be used for onboard resimulation and adaptive RT for future fluctuations in the sizes of brain tumors, cavities, or cystic components. This could improve tumor targeting and reduce RT of healthy brain tissue.
Marcus, Ruthanne; Makarenko, Iuliia; Mazhnaya, Alyona; Zelenev, Alexei; Polonsky, Maxim; Madden, Lynn; Filippovych, Sergii; Dvoriak, Sergii; Springer, Sandra A; Altice, Frederick L
2017-10-01
Scaling up HIV prevention for people who inject drugs (PWID) using opioid agonist therapies (OAT) in Ukraine has been restricted by individual and structural factors. Extended-release naltrexone (XR-NTX), however, provides new opportunities for treating opioid use disorders (OUDs) in this region, where both HIV incidence and mortality continue to increase. Survey results from 1613 randomly selected PWID from 5 regions in Ukraine who were currently, previously or never on OAT were analyzed for their preference of pharmacological therapies for treating OUDs. For those preferring XR-NTX, independent correlates of their willingness to initiate XR-NTX were examined. Among the 1613 PWID, 449 (27.8%) were interested in initiating XR-NTX. Independent correlates associated with interest in XR-NTX included: being from Mykolaiv (AOR=3.7, 95% CI=2.3-6.1) or Dnipro (AOR=1.8, 95% CI=1.1-2.9); never having been on OAT (AOR=3.4, 95% CI=2.1-5.4); shorter-term injectors (AOR=0.9, 95% CI 0.9-0.98); and inversely for both positive (AOR=0.8, CI=0.8-0.9), and negative attitudes toward OAT (AOR=1.3, CI=1.2-1.4), respectively. In the context of Eastern Europe and Central Asia where HIV is concentrated in PWID and where HIV prevention with OAT is under-scaled, new options for treating OUDs are urgently needed. here suggest that XR-NTX could become an option for addiction treatment and HIV prevention especially for PWID who have shorter duration of injection and who harbor negative attitudes to OAT. Decision aids that inform patient preferences with accurate information about the various treatment options are likely to guide patients toward better, patient-centered treatments and improve treatment entry and retention. Copyright © 2017 Elsevier B.V. All rights reserved.
Córdoba, Rodrigo; Cano, Juan Fernando; Arango-Dávila, César Augusto; Miranda, Carlos; Holguín, Jorge; Fernández, Darío; Márquez, Miguel; Lupo, Christian; Gargoloff, Pedro; Petracca, Gustavo; Lucchetti, César
2012-06-01
Extended-release (ER) paliperidone is an innovative atypical antipsychotic that allows minimal peak-to-through fluctuations with once-daily dosing. To evaluate effectiveness, safety and tolerability of flexible, once-daily doses of paliperidone ER (3-12 mg/day) in patients with schizophrenia from Argentina and Colombia who had previously failed treatment with other antipsychotic agents. The authors conducted a 6-month, open-label, prospective and multicentric study. Effectiveness was assessed with Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance scale (PSP). Other measures of effectiveness, safety and tolerability, were also conducted. Paliperidone ER 3-12 mg/day improved Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint) from baseline to study end (p < 0,001). In the PANSS total score, the mean change from baseline (83, 9 units) to end point (53,7 units) was significant (p < 0,001). Flexible doses of paliperidone ER demonstrated a ≥20% reduction in the PANSS total score (p<0.001) in almost two-thirds of patients. PSP mean change from baseline (52 units) to end point (85 units) was significant (p < 0,001). Secondary effectiveness assessments, as well as safety and tolerability measures, demonstrated favourable results throughout the study. Flexible doses of paliperidone ER over 6 months were effective, safe and well tolerated in patients with schizophrenia from Argentina and Colombia. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.
How controlled release technology can aid gene delivery.
Jo, Jun-Ichiro; Tabata, Yasuhiko
2015-01-01
Many types of gene delivery systems have been developed to enhance the level of gene expression. Controlled release technology is a feasible gene delivery system which enables genes to extend the expression duration by maintaining and releasing them at the injection site in a controlled manner. This technology can reduce the adverse effects by the bolus dose administration and avoid the repeated administration. Biodegradable biomaterials are useful as materials for the controlled release-based gene delivery technology and various biodegradable biomaterials have been developed. Controlled release-based gene delivery plays a critical role in a conventional gene therapy and genetic engineering. In the gene therapy, the therapeutic gene is released from biodegradable biomaterial matrices around the tissue to be treated. On the other hand, the intracellular controlled release of gene from the sub-micro-sized matrices is required for genetic engineering. Genetic engineering is feasible for cell transplantation as well as research of stem cells biology and medicine. DNA hydrogel containing a sequence of therapeutic gene and the exosome including the individual specific nucleic acids may become candidates for controlled release carriers. Technologies to deliver genes to cell aggregates will play an important role in the promotion of regenerative research and therapy.
Rai, Saroj; Jin, Shengyang; Meng, Chunqing; Chaudhary, Nabin; Tamang, Nira; Wang, Xiaohong; Liu, Xianzhe; Wang, Hong; Yang, Shuhua
2017-03-16
Gluteal muscle contracture (GMC), a debilitating disease, usually starts in early childhood after variable dose of injections around the buttock, if left untreated it worsens gradually and persists throughout the life. Because the disease mostly affects adolescents and adults, there is always an aesthetic concerns. Purposeof the study was to introduce the arthroscopic F and C method of GMC release, and to compare its clinical efficiency with conventional open surgery in terms of clinical outcome, rate of complications, patient's satisfactions, and recurrence. Between Jan 2013 and July 2015, 75 patients received an arthroscopic release with F and C release method and 71 patients received conventional open release of GMC. Primary surgeries in 16 years or older patients were included in the study. Two groups were compared clinically using Hip Outcome Scores - Activities of Daily Living Subscale (HOS-ADL), Hip Outcome Scores - Sports Subscale (HOS-Sports), Visual Analogue Scale (VAS), and Ye et al. evaluation criteria. No statistically significant differences were observed in Hip Outcome Scores - Activities of Daily Living Subscale (HOS-ADL) (P = 0.078), Hip Outcome Scores - Sports Subscale (HOS-Sports) (P = 0.340), and Visual Analogue Scale (VAS) (P = 0.524) between the two groups. 74 (98.7%) patients in the arthroscopic surgery group had good to excellent results, whereas 69 (97.1%) patients in the conventional open surgery group had good to excellent results (P = 0.727). No statistically significant difference was observed in recurrence rate (P = 0.612). Statistically significant differences were observed in incision length, use of post-operative analgesia, post-operative off-bed activity, and hospital stay. Complications were significantly higher in the conventional open surgery group (n = 21) than in the arthroscopic surgery group (n = 10) (P = 0.016). More importantly, cosmetic satisfaction was 100% in arthroscopic release group
Stochastic generation of multi-site daily precipitation focusing on extreme events
Directory of Open Access Journals (Sweden)
G. Evin
2018-01-01
Full Text Available Many multi-site stochastic models have been proposed for the generation of daily precipitation, but they generally focus on the reproduction of low to high precipitation amounts at the stations concerned. This paper proposes significant extensions to the multi-site daily precipitation model introduced by Wilks, with the aim of reproducing the statistical features of extremely rare events (in terms of frequency and magnitude at different temporal and spatial scales. In particular, the first extended version integrates heavy-tailed distributions, spatial tail dependence, and temporal dependence in order to obtain a robust and appropriate representation of the most extreme precipitation fields. A second version enhances the first version using a disaggregation method. The performance of these models is compared at different temporal and spatial scales on a large region covering approximately half of Switzerland. While daily extremes are adequately reproduced at the stations by all models, including the benchmark Wilks version, extreme precipitation amounts at larger temporal scales (e.g., 3-day amounts are clearly underestimated when temporal dependence is ignored.
Tiruneh, Gizachew Tadele; Karim, Ali Mehryar; Avan, Bilal Iqbal; Zemichael, Nebreed Fesseha; Wereta, Tewabech Gebrekiristos; Wickremasinghe, Deepthi; Keweti, Zinar Nebi; Kebede, Zewditu; Betemariam, Wuleta Aklilu
2018-05-02
Basic emergency obstetric and newborn care (BEmONC) is a primary health care level initiative promoted in low- and middle-income countries to reduce maternal and newborn mortality. Tailored support, including BEmONC training to providers, mentoring and monitoring through supportive supervision, provision of equipment and supplies, strengthening referral linkages, and improving infection-prevention practice, was provided in a package of interventions to 134 health centers, covering 91 rural districts of Ethiopia to ensure timely BEmONC care. In recent years, there has been a growing interest in measuring program implementation strength to evaluate public health gains. To assess the effectiveness of the BEmONC initiative, this study measures its implementation strength and examines the effect of its variability across intervention health centers on the rate of facility deliveries and the met need for BEmONC. Before and after data from 134 intervention health centers were collected in April 2013 and July 2015. A BEmONC implementation strength index was constructed from seven input and five process indicators measured through observation, record review, and provider interview; while facility delivery rate and the met need for expected obstetric complications were measured from service statistics and patient records. We estimated the dose-response relationships between outcome and explanatory variables of interest using regression methods. The BEmONC implementation strength index score, which ranged between zero and 10, increased statistically significantly from 4.3 at baseline to 6.7 at follow-up (p < .05). Correspondingly, the health center delivery rate significantly increased from 24% to 56% (p < .05). There was a dose-response relationship between the explanatory and outcome variables. For every unit increase in BEmONC implementation strength score there was a corresponding average of 4.5 percentage points (95% confidence interval: 2.1-6.9) increase in
Ferland, Mark B; Larente, Johanne; Rowland, Julia; Davidson, Patrick S R
2013-01-01
To use errorless learning to train a memory- and initiation-impaired woman on two activities of daily living routines and then to transfer these routines to a new home. Single case quasi-experimental. Over 9 months, a young woman with an anterior cerebral haemorrhagic stroke (secondary to a ruptured arteriovenous malformation) was trained on routines of morning self-care and diabetes management, involving extensive practice on a structured series of steps with intervention as needed to prevent errors. Once routines were established, family members were trained in the supervision and rating of the routines at home. Following discharge, caregivers continued to monitor the routines daily for 3 months. Errorless learning of self-care and diabetes routines was successful. The routines were transferred to a new home environment and maintained at a near perfect level over a 3-month follow-up period. The patient remained severely memory-impaired, indicating that her functional gains were not attributable to any recovery of her memory abilities over time. This case offers evidence that even people with severe memory and initiation impairments can be trained on new routines using errorless learning and that, once learned, these routines can be carried out in novel contexts.
Physical Behavior in Older Persons during Daily Life: Insights from Instrumented Shoes
Directory of Open Access Journals (Sweden)
Christopher Moufawad el Achkar
2016-08-01
Full Text Available Activity level and gait parameters during daily life are important indicators for clinicians because they can provide critical insights into modifications of mobility and function over time. Wearable activity monitoring has been gaining momentum in daily life health assessment. Consequently, this study seeks to validate an algorithm for the classification of daily life activities and to provide a detailed gait analysis in older adults. A system consisting of an inertial sensor combined with a pressure sensing insole has been developed. Using an algorithm that we previously validated during a semi structured protocol, activities in 10 healthy elderly participants were recorded and compared to a wearable reference system over a 4 h recording period at home. Detailed gait parameters were calculated from inertial sensors. Dynamics of physical behavior were characterized using barcodes that express the measure of behavioral complexity. Activity classification based on the algorithm led to a 93% accuracy in classifying basic activities of daily life, i.e., sitting, standing, and walking. Gait analysis emphasizes the importance of metrics such as foot clearance in daily life assessment. Results also underline that measures of physical behavior and gait performance are complementary, especially since gait parameters were not correlated to complexity. Participants gave positive feedback regarding the use of the instrumented shoes. These results extend previous observations in showing the concurrent validity of the instrumented shoes compared to a body-worn reference system for daily-life physical behavior monitoring in older adults.
Battistini, F D; Tártara, L I; Boiero, C; Guzmán, M L; Luciani-Giaccobbe, L C; Palma, S D; Allemandi, D A; Manzo, R H; Olivera, M E
2017-07-15
The aim of this work was to obtain information concerning the properties of ophthalmic formulations based on hyaluronic-drug ionic complexes, to identify the factors that determine the onset, intensity and duration of the pharmacotherapeutic effect. Dispersions of a complex of 0.5% w/v of sodium hyaluronate (HyNa) loaded with 0.5% w/v of timolol maleate (TM) were obtained and presented a counterionic condensation higher than 75%. For comparison a similar complex obtained with hyaluronic acid (HyH) was also prepared. Although the viscosity of HyNa-TM was significantly higher than that of HyH-TM, in vitro release of TM from both complexes showed a similar extended drug release profile (20-31% over 5h) controlled by diffusion and ionic exchange. Ocular pharmacokinetic study performed in normotensive rabbits showed that HyNa-TM complex exhibited attractive bioavailability properties in the aqueous humor (AUC and Cmax significantly higher and later Tmax) compared to commercial TM eye-drops. Moreover, a more prolonged period of lowered intra-ocular pressure (10h) and a more intense hypotensive activity was observed after instillation of a drop of HyNa-TM as compared to the eye-drops. Such behavior was related to the longer pre-corneal residence times (400%) observed with HyNa-TM complex. No significant changes in rabbit transcorneal permeation were detected upon complexation. These results demonstrate that the ability of HyNa to modulate TM release, together with its mucoadhesiveness related to the viscosity, affected both the pharmacokinetic and pharmacodynamic parameters. The HyNa-TM complex is a potentially useful carrier for ocular drug delivery, which could improve the TM efficacy and reduce the frequency of administration to improve patient compliance. Copyright © 2017 Elsevier B.V. All rights reserved.
On Computational Power of Quantum Read-Once Branching Programs
Directory of Open Access Journals (Sweden)
Farid Ablayev
2011-03-01
Full Text Available In this paper we review our current results concerning the computational power of quantum read-once branching programs. First of all, based on the circuit presentation of quantum branching programs and our variant of quantum fingerprinting technique, we show that any Boolean function with linear polynomial presentation can be computed by a quantum read-once branching program using a relatively small (usually logarithmic in the size of input number of qubits. Then we show that the described class of Boolean functions is closed under the polynomial projections.
Dynamic and control of a once through steam generator
International Nuclear Information System (INIS)
Gomes, Arivaldo Vicente
1979-01-01
This paper presents a non linear distributed parameter model for the dynamics and feedback control of a large countercurrent heat exchanger used as a once through steam generator for a breeder reactor power plant. A convergent, implicit method has been developed to solve simultaneously the equations of conservation of mass, momentum and energy. The model, applicable to heat exchanger systems in general, has been used specifically to study the performance of a once-through steam generator with respect to its load following ability and stability of throttle steam temperature and pressure. (author)
Once a physicist: David Florence
Florence, David
2009-03-01
I did mathematical physics because it was just what I was best at. I enjoyed it at school, so I applied to do it at Nottingham University. I fell into it, to be quite honest. Once at university, I struggled at first, partly because I found it quite difficult to combine studying with competing and training in sport, which is pretty much full time as well. But by the end of my university career, I had learned to be organized, and to manage my time pretty effectively, so I enjoyed it a lot more.
Formulation and In vitro/In vivo Evaluation of Sustained Release ...
African Journals Online (AJOL)
HP
2013-07-15
Jul 15, 2013 ... They are generally used to treat high blood pressure ... extending drug release for highly water-soluble drugs is limited ..... by the high water permeability of Kollidon SR while the ... due to the extremely low water solubility of.
Once-through cycle, supercritical-pressure light water cooled reactor concept
Energy Technology Data Exchange (ETDEWEB)
Oka, Y.; Koshizuka, S. [Tokyo Univ., Tokai, Ibaraki (Japan). Nuclear Engineering Research Lab
2001-07-01
Concept of once-through cycle, supercritical-pressure light water cooled reactors was developed. The research covered major aspects of conceptual design such as cores of thermal and fast reactors, plant system and heat balance, safety system and criteria, accident and transient analysis, LOCA, PSA, plant control and start-up. The advantages of the reactor lie in the compactness of the plant from high specific enthalpy of supercritical water, the simplicity of the once-through cycle and the experiences of major component technologies which are based on supercritical fossil-fired power plants and LWRs. The operating temperatures of the major components are within the experience in spite of high coolant outlet temperature. The once-through cycle is compatible with the tight fuel lattice fast reactor because of high head pumps and small coolant flow rate. (author)
Once-through cycle, supercritical-pressure light water cooled reactor concept
International Nuclear Information System (INIS)
Oka, Y.; Koshizuka, S.
2001-01-01
Concept of once-through cycle, supercritical-pressure light water cooled reactors was developed. The research covered major aspects of conceptual design such as cores of thermal and fast reactors, plant system and heat balance, safety system and criteria, accident and transient analysis, LOCA, PSA, plant control and start-up. The advantages of the reactor lie in the compactness of the plant from high specific enthalpy of supercritical water, the simplicity of the once-through cycle and the experiences of major component technologies which are based on supercritical fossil-fired power plants and LWRs. The operating temperatures of the major components are within the experience in spite of high coolant outlet temperature. The once-through cycle is compatible with the tight fuel lattice fast reactor because of high head pumps and small coolant flow rate. (author)