A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer’s disease

PubMed Central

Deardorff, William James; Grossberg, George T

2016-01-01

Currently available therapies for the treatment of Alzheimer’s disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified. PMID:27757016

Bioequivalence of fixed-dose combination RIN®-150 to each reference drug in loose combination.

PubMed

Wang, H F; Wang, R; O'Gorman, M; Crownover, P; Damle, B

2015-03-01

RIN(®)-150 is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg) and isoniazid (INH, 75 mg) developed for the treatment of tuberculosis. This study was conducted at a single center: the Pfizer Clinical Research Unit in Singapore. To demonstrate bioequivalence of each drug component between RIN-150 and individual products in a loose combination. This was a randomized, open-label, single-dose, two-way crossover study. Subjects received single doses of RIN-150 or two individual reference products under fasting conditions in a crossover fashion, with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC). Of 28 subjects enrolled, 26 completed the study. The adjusted geometric mean ratios of Cmax and AUClast between the FDC and single-drug references and 90% confidence intervals were respectively 91.63% (90%CI 83.13-101.01) and 95.45% (90%CI 92.07-98.94) for RMP, and 107.58% (90%CI 96.07-120.47) and 103.45% (90%CI 99.33-107.75) for INH. Both formulations were generally well tolerated in this study. The RIN-150 FDC tablet formulation is bioequivalent to the two single-drug references for RMP and INH at equivalent doses.

Bioequivalence of fixed-dose combination Myrin®-P Forte and reference drugs in loose combination.

PubMed

Wang, H F; Wang, R; O'Gorman, M; Crownover, P; Naqvi, A; Jafri, I

2013-12-01

Myrin®-P Forte is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg), isoniazid (INH, 75 mg), ethambutol (EMB) hydrochloride (275 mg) and pyrazinamide (PZA, 400 mg) developed for the treatment of tuberculosis (TB). This study was conducted at a single centre--the Pfizer Clinical Research Unit in Singapore. To demonstrate the bioequivalence of each drug component of the Myrin-P Forte FDC and the individual product in loose combination. In a randomized, open-label, single-dose, two-way, crossover study, subjects received single doses of Myrin-P Forte or four individual products under fasting conditions in a crossover fashion with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (C(max)) and the area under plasma concentration-time curve (AUC). Of 36 subjects enrolled, 35 completed the study. The adjusted geometric mean ratios and 90% confidence intervals for C(max) and AUC values were completely contained within bioequivalence limits (80%, 125%) for all four drugs in both formulations. Both treatments were generally well tolerated in the study. The Myrin-P Forte FDC tablet formulation is bioequivalent to the four single-drug references for RMP, INH, EMB hydrochloride and PZA at equivalent doses.

Repaglinide/metformin fixed-dose combination to improve glycemic control in patients with type 2 diabetes: an update

PubMed Central

Moses, Robert G

2010-01-01

Type 2 diabetes is a progressive disease associated with high levels of morbidity and mortality and for which there is both a large and growing prevalence worldwide. Lifestyle advice plus metformin is commonly recommended initially to manage hyperglycemia and to minimize the risk of vascular complications. However, additional agents are required when glycemic targets cannot be achieved or maintained due to the progressive nature of the disease. Repaglinide/metformin fixed-dose combination (FDC) therapy (PrandiMet®; Novo Nordisk, Bagsværd, Denmark) has been approved for use in the USA. This FDC is a rational second-line therapy given the complementary mechanisms of action of the components. Repaglinide is a rapidly absorbed, short-acting insulin secretagogue targeting postprandial glucose excursions; metformin is an insulin sensitizer with a longer duration of action that principally regulates basal glucose levels. A pivotal, 26-week, randomized study with repaglinide/metformin FDC therapy has been conducted in patients experiencing suboptimal control with previous oral antidiabetes therapy. Repaglinide/metformin FDC improved glycemic control and weight neutrality without adverse effects on lipid profiles. There were no major hypoglycemic episodes and patients expressed greater satisfaction with repaglinide/metformin FDC than previous treatments. Repaglinide/metformin FDC is expected to be more convenient than individual tablets for patients taking repaglinide and metformin in loose combination, and it is expected to improve glycemic control in patients for whom meglitinide or metformin monotherapies provide inadequate control. PMID:21437084

Repaglinide/metformin fixed-dose combination to improve glycemic control in patients with type 2 diabetes: an update.

PubMed

Moses, Robert G

2010-05-10

Type 2 diabetes is a progressive disease associated with high levels of morbidity and mortality and for which there is both a large and growing prevalence worldwide. Lifestyle advice plus metformin is commonly recommended initially to manage hyperglycemia and to minimize the risk of vascular complications. However, additional agents are required when glycemic targets cannot be achieved or maintained due to the progressive nature of the disease. Repaglinide/metformin fixed-dose combination (FDC) therapy (PrandiMet(®); Novo Nordisk, Bagsværd, Denmark) has been approved for use in the USA. This FDC is a rational second-line therapy given the complementary mechanisms of action of the components. Repaglinide is a rapidly absorbed, short-acting insulin secretagogue targeting postprandial glucose excursions; metformin is an insulin sensitizer with a longer duration of action that principally regulates basal glucose levels. A pivotal, 26-week, randomized study with repaglinide/metformin FDC therapy has been conducted in patients experiencing suboptimal control with previous oral antidiabetes therapy. Repaglinide/metformin FDC improved glycemic control and weight neutrality without adverse effects on lipid profiles. There were no major hypoglycemic episodes and patients expressed greater satisfaction with repaglinide/metformin FDC than previous treatments. Repaglinide/metformin FDC is expected to be more convenient than individual tablets for patients taking repaglinide and metformin in loose combination, and it is expected to improve glycemic control in patients for whom meglitinide or metformin monotherapies provide inadequate control.

Pharmacokinetics of fixed-dose combinations of empagliflozin/metformin compared with individual tablets in healthy subjects.

PubMed

Rojas, Christina; Link, Jasmin; Meinicke, Thomas; Macha, Sreeraj

2016-04-01

To compare the pharmacokinetics of fixed-dose combination (FDC) tablets of empagliflozin/metformin with individual tablets taken together. In 3 randomized, open-label studies, healthy subjects received a single FDC tablet of empagliflozin/metformin in 1 of 6 dose combinations (empagliflozin 12.5 mg or 5 mg; metformin 500 mg, 850 mg, or 1,000 mg) in 1 period and the individual tablets taken together under fed conditions in another period. Empagliflozin 12.5 mg/metformin 1,000 mg FDC and individual tablets were also given under fasted conditions. Adjusted geometric mean ratios (GMRs) of empagliflozin area under the plasma concentration-time curve (AUC(0-∞)) for the FDCs vs. individual tablets ranged from 97.92 to 106.00%, and 90% CIs ranged from 93.53 to 109.39%. Adjusted GMRs of empagliflozin maximum plasma concentrations (C(max)) for the FDCs vs. individual tablets ranged from 100.97 to 106.52%, and 90% CIs ranged from 95.86 to 118.35%. Adjusted GMRs of metformin AUC(0-∞) for the FDCs vs. individual tablets ranged from 96.25 to 101.61%, and 90% CIs ranged from 88.54 to 106.62%. Adjusted GMRs of metformin C(max) for the FDCs vs. individual tablets ranged from 93.83 to 102.95%, and 90% CIs ranged from 88.01 to 109.08%. Bioequivalence was also established under fasted conditions for empagliflozin 12.5 mg/metformin 1,000 mg FDC vs. individual tablets taken together. All treatments were well tolerated. Empagliflozin/metformin FDC tablets were found to be bioequivalent to individual tablets taken together at all tested dose strengths.

New Fixed-Dose Combinations of Fenofibrate/Simvastatin Therapy Significantly Improve the Lipid Profile of High-Risk Patients with Mixed Dyslipidemia Versus Monotherapies.

PubMed

Foucher, Christelle; Aubonnet, Patrick; Reichert, Petr; Berli, Mario; Schaeffer, Axel; Calvo Vargas, Cesar Gonzalo; Lochocka, Anna; Belenky, Dmitry; Koch, Hans-Friedrich

2015-12-01

Guidelines propose additional therapy to statin to treat elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDLC) in dyslipidemic patients. We evaluated the effects of new fixed-dose combinations (FDC) of fenofibrate/simvastatin on plasma lipids versus simvastatin or fenofibrate monotherapies. Subjects with mixed dyslipidemia at high or very high cardiovascular risk on stable statin therapy for at least 3 months were included in a randomized, double-blind, active-control, parallel-group study. Patients were treated with FDC fenofibrate/simvastatin 145/20 mg or 145/40 mg, simvastatin 20 mg or 40 mg, or fenofibrate 145 mg for 12 weeks. Plasma lipids, C-reactive protein, and cystatin C were measured before and after treatments. Differences in % changes were compared between FDC fenofibrate/simvastatin and monotherapies. Significant differences between FDC fenofibrate/simvastatin and simvastatin monotherapies were observed for the % change of TG (LS mean difference [two-sided 95% CI]: -32.2% [-38.6%, -25.8%], P < 0.001) and HDL-C (7.5% [4.7%, 10.2%], P < 0.001). A significant difference between the FDC fenofibrate/simvastatin and fenofibrate was observed for LDLC % changes (-34.7% [-40.8%, -28.5%], P < 0.001). Significant differences between FDC fenofibrate/simvastatin and their respective monotherapies were also observed for Apo B and non-HDLC % changes. The FDC were well tolerated with a similar safety profile compared with monotherapies. FDC fenofibrate/simvastatin are effective and well-tolerated therapies to improve the TG and HDLC profile in high-risk patients with mixed dyslipidemia. © 2015 John Wiley & Sons Ltd.

Acarbose plus metformin fixed-dose combination outperforms acarbose monotherapy for type 2 diabetes.

PubMed

Wang, Jun-Sing; Huang, Chien-Ning; Hung, Yi-Jen; Kwok, Ching-Fai; Sun, Jui-Hung; Pei, Dee; Yang, Chwen-Yi; Chen, Ching-Chu; Lin, Ching-Ling; Sheu, Wayne Huey-Herng

2013-10-01

To compare the efficacy and safety of acarbose plus metformin fixed-dose combination (FDC) versus acarbose monotherapy for type 2 diabetes (T2D). Eligible T2D patients undergoing treatment with diet control only or oral antidiabetic medications were run-in on acarbose 50mg thrice-daily for 4 weeks, then randomised either to continue this monotherapy, or to acarbose 50mg plus metformin hydrochloride 500mg FDC (acarbose/metformin FDC), each thrice-daily for 16 weeks. Acarbose/metformin FDC therapy significantly reduced HbA1c, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) from baseline (all p<0.0001) with superior efficacy compared with acarbose monotherapy (between-group differences; HbA1c -1.35%; FPG -29.5mg/dl; PPG -41.6mg/dl; all p<0.0001). Proportionally more patients treated with acarbose/metformin FDC achieved HbA1c <7.0% (47.8% vs. 10.7%, p<0.0001). Both treatments reduced bodyweight (p<0.0001), with a significant between-group difference (-0.6kg, p<0.01) favouring acarbose/metformin FDC. Hypoglycaemia was not reported with either treatment, and the incidence of other adverse events did not differ significantly between the groups. Compared with acarbose monotherapy, acarbose/metformin FDC has superior antihyperglycaemic efficacy, brings proportionally more T2D patients to HbA1c goal, and further reduces bodyweight. Acarbose/metformin FDC is well-tolerated without significant risk of hypoglycaemia and is a potentially advantageous therapy for T2D. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability.

PubMed

Dennison, Thomas J; Smith, Julian C; Badhan, Raj K; Mohammed, Afzal R

2017-01-01

Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (P app ) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability ≤1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f 1 ) and similarity (f 2 ) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating P app and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in C max and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated bioequivalence of an FDC ODT for amlodipine and atorvastatin, while highlighting several limitations of f 1 and f 2 bioequivalence testing and strengths of mechanistic pharmacokinetic modeling for oral drug absorption.

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability

PubMed Central

Dennison, Thomas J; Smith, Julian C; Badhan, Raj K; Mohammed, Afzal R

2017-01-01

Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability ≤1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f1) and similarity (f2) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating Papp and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in Cmax and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated bioequivalence of an FDC ODT for amlodipine and atorvastatin, while highlighting several limitations of f1 and f2 bioequivalence testing and strengths of mechanistic pharmacokinetic modeling for oral drug absorption. PMID:28352156

Improved Stability of Tuberculosis Drug Fixed-Dose Combination Using Isoniazid-Caffeic Acid and Vanillic Acid Cocrystal.

PubMed

Battini, Swapna; Mannava, M K Chaitanya; Nangia, Ashwini

2018-06-01

The classic fixed-dose combination (FDC) of 4 tuberculosis drugs, namely rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol dihydrochloride (EDH) has the twin issues of physical stability and RIF cross-reaction in the 4-FDC. The major reason for these quality issues is the interaction between RIF and INH to yield isonicotinyl hydrazone in drug tablets. Pharmaceutical cocrystals of INH with caffeic acid (CFA) (PZA + EDH + RIF + INH-CFA cocrystal) and vanillic acid (VLA) (PZA + EDH + RIF + INH-VLA cocrystal) are able to stabilize the FDC formulation compared with the reference batch (PZA + EDH + RIF + INH). Stability studies under accelerated humidity and temperature stress conditions of 40°C and 75% relative humidity showed that the physical stability of the cocrystal formulation was superior by powder X-ray diffraction and scanning electron microscopy analysis, and chemical purity was analyzed by high-performance liquid chromatography. Changes in the composition and structure were monitored on samples drawn at 7, 15, 22, and 30 days of storage. FDC-INH-CFA cocrystal batch exhibited greater stability compared with FDC-INH-VLA cocrystal and FDC reference drug batches. The superior stability of INH-CFA cocrystal is attributed to the presence of stronger hydrogen bonds and cyclic O-H⋯O synthon in the crystal structure. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Nebivolol/valsartan: Fixed-dose combination for treatment of hypertension.

PubMed

Paton, D M

2017-01-01

Clinical trials demonstrated that a fixed-dose combination (FDC) of the beta-blocker nebivolol (5 mg) and the angiotensin II antagonist valsartan (80 mg) produced a significant reduction of both diastolic and systolic blood pressure in patients with hypertension. Both nebivolol and valsartan contributed to this effect, partial additivity of 86.6% and 82.2% being observed for diastolic and systolic blood pressure, respectively. These values are very similar to the additivity ratios of other recently approved FDCs for hypertension. Use of the FDC nebivolol 5 mg/valsartan 80 mg formulation was associated with a low incidence of treatment-related adverse effects and of serious adverse effects. There was no evidence of adverse effects due to beta2-adrenoceptor blockade. The FDC (Byvalson) was approved and launched in 2016 in the U.S. for the treatment of hypertension. Copyright 2017 Clarivate Analytics.

Treatment outcomes of fixed-dose combination versus separate tablet regimens in pulmonary tuberculosis patients with or without diabetes in Qatar.

PubMed

Al-Shaer, Mohammad H; Mansour, Hanine; Elewa, Hazem; Salameh, Pascale; Iqbal, Fatima

2017-02-02

Tuberculosis is considered the second most common cause of death due to infectious agent. The currently preferred regimen for treatment of pulmonary tuberculosis (PTB) is isoniazid, rifampin, pyrazinamide, and ethambutol, which has been used either as separate tablets (ST) or as fixed-dose combination (FDC). To date, no studies have compared both regimens in Qatar. We aim to evaluate the safety and effectiveness of FDC and ST regimen for treating PTB, in addition to comparing safety and efficacy of FDC and ST regimens in patients with diabetes treated for TB. A retrospective observational study was conducted in two general hospitals in Qatar. Patients diagnosed with PTB received anti-tuberculosis medications (either as FDC or ST) administered by the nurse. Sputum smears were tested weekly. We assessed the time to negative sputum smear and incidence of adverse events among FDC and ST groups. The study included 148 patients. FDC was used in 90 patients (61%). Effectiveness was not different between FDC and ST regimens as shown by mean time to sputum conversion (29.9 ± 18.3 vs. 35.6 ± 23 days, p = 0.12). Similarly, there was no difference in the incidence of adverse events, except for visual one that was higher in ST group. Among the 33 diabetic patients, 19 received the FDC and had faster sputum conversion compared to those who received ST (31 ± 12 vs. 49.4 ± 30.9 days, p = 0.05). Overall, diabetic patients needed longer time for sputum conversion and had more hepatotoxic and gastric adverse events compared to non-diabetics. ST group had higher visual side effects compared to FDC. FDC may be more effective in diabetic patients; however, further studies are required to confirm such finding.

The effect of fixed-dose combination of valsartan and amlodipine on nighttime blood pressure in patients with non-dipper hypertension.

PubMed

Erdoğan, Doğan; İçli, Atilla; Aksoy, Fatih; Akçay, Salaheddin; Yücel, Habil; Ersoy, İbrahim; Özaydın, Mehmet

2016-07-01

Failure to decrease blood pressure (BP) during the night is associated with higher cardiovascular (CV) morbidity and mortality. There is strong evidence that fixed-dose combinations (FDCs) of antihypertensive agents are associated with significant improvement and non-significant adverse effects. The aim of the present study was to evaluate whether FDC affected nocturnal BP favorably in patients with uncontrolled, non-dipper hypertension (HT). All non-dipper hypertensives were either newly diagnosed with stage 2-3 HT or had HT uncontrolled with monotherapy. Patients (n=195) were consecutively assigned to 4 treatment groups: FDC of valsartan/amlodipine (160/5 mg), free-drug combination of valsartan 160 mg and amlodipine 5 mg, amlodipine 10 mg, and valsartan 320 mg. Ambulatory blood pressure monitoring (ABPM) was repeated at 4th and 8th week. Average 24-h (24-hour) and nocturnal BP were similar among the groups at baseline evaluation, and had significantly decreased by the fourth week of treatment. However, BP continued to decrease only slightly between the 4th and 8th weeks in the valsartan and amlodipine monotherapy groups, but continued to decrease significantly in both combination groups. After 4 weeks, day-night BP difference and day-night BP % change were significantly elevated in the combination and valsartan groups. Between the 4th and 8th weeks, however, day-night BP difference and day-night BP % change continued to rise only in the FDC group, nearly reducing to baseline levels in the free-drug combination and valsartan groups. An additional 2.2 mmHg decrease was observed in the FDC group, compared to the free-drug combination group. In non-dipper HT, FDC of valsartan and amlodipine improved diurnal-nocturnal ratio of BP and provided 24-h coverage.

Fixed-dose combination ezetimibe+atorvastatin lowers LDL-C equivalent to co-administered components in randomized trials: use of a dose-response model.

PubMed

Bays, Harold E; Chen, Erluo; Tomassini, Joanne E; McPeters, Gail; Polis, Adam B; Triscari, Joseph

2015-04-01

Co-administration of ezetimibe with atorvastatin is a generally well-tolerated treatment option that reduces LDL-C levels and improves other lipids with greater efficacy than doubling the atorvastatin dose. The objective of the study was to demonstrate the equivalent lipid-modifying efficacy of fixed-dose combination (FDC) ezetimibe/atorvastatin compared with the component agents co-administered individually in support of regulatory filing. Two randomized, 6-week, double-blind cross-over trials compared the lipid-modifying efficacy of ezetimibe/atorvastatin 10/20 mg (n = 353) or 10/40 mg (n = 280) vs. separate co-administration of ezetimibe 10 mg plus atorvastatin 20 mg (n = 346) or 40 mg (n = 280), respectively, in hypercholesterolemic patients. Percent changes from baseline in LDL-C (primary endpoint) and other lipids (secondary endpoints) were assessed by analysis of covariance; triglycerides were evaluated by longitudinal-data analysis. Expected differences between FDC and the corresponding co-administered doses were predicted from a dose-response relationship model; sample size was estimated given the expected difference and equivalence margins (±4%). LDL-C-lowering equivalence was based on 97.5% expanded confidence intervals (CI) for the difference contained within the margins; equivalence margins for other lipids were not prespecified. Ezetimibe/atorvastatin FDC 10/20 mg was equivalent to co-administered ezetimibe+atorvastatin 20 mg in reducing LDL-C levels (54.0% vs. 53.8%) as was FDC 10/40 mg and ezetimibe+atorvastatin 40 mg (58.9% vs. 58.7%), as predicted by the model. Changes in other lipids were consistent with equivalence (97.5% expanded CIs <±3%, included 0); triglyceride changes varied more. All treatments were generally well tolerated. Hypercholesterolemic patients administered ezetimibe/atorvastatin 10/20 and 10/40 mg FDC had equivalent LDL-C lowering. This FDC formulation proved to be an efficacious and generally well-tolerated lipid-lowering therapy. © 2014 Société Française de Pharmacologie et de Thérapeutique.

Pharmacokinetics and relative bioavailability of fixed-dose combination of clopidogrel and aspirin versus coadministration of individual formulations in healthy Korean men.

PubMed

Choi, Hyang-Ki; Ghim, Jong-Lyul; Shon, Jihong; Choi, Young-Kyung; Jung, Jin Ah

2016-01-01

Simultaneous prescription of clopidogrel and low-dose aspirin is recommended for the treatment of acute coronary syndrome because of improvements in efficacy and patient compliance. In this study, the pharmacokinetics of a fixed-dose combination (FDC) of clopidogrel and aspirin was compared with coadministration of individual formulations to clarify the equivalence of the FDC. This was a randomized, open-label, two-period, two-treatment, crossover study in healthy Korean men aged 20-55 years. Subjects received two FDC capsules of clopidogrel/aspirin 75/100 mg (test) or two tablets of clopidogrel 75 mg and two capsules of aspirin 100 mg (reference) with a 14-day washout period. Plasma concentrations of clopidogrel, aspirin, and salicylic acid were measured using validated ultraperformance liquid chromatography-tandem mass spectrometry. Bioequivalence was assessed by analysis of variance and calculation of the 90% confidence intervals (CIs) of the ratios of the geometric means (GMRs) for AUC last and C max for clopidogrel and aspirin. Sixty healthy subjects were enrolled, and 53 completed the study. Clopidogrel, aspirin, and salicylic acid showed similar absorption profiles and no significant differences in C max , AUC last , and T max between FDC administration and coadministration of individual formulations. The GMRs (90% CI) for the C max and AUC last of clopidogrel were 1.08 (0.95, 1.23) and 0.93 (0.84, 1.03), respectively. The GMRs (90% CI) for the C max and AUC last of aspirin were 0.98 (0.84, 1.13) and 0.98 (0.93, 1.04), respectively. Both treatments were well tolerated in the study subjects. The FDC of clopidogrel and aspirin was bioequivalent to coadministration of each individual formulation. The FDC capsule exhibited similar safety and tolerability profiles to the individual formulations. Therefore, clopidogrel/aspirin 75 mg/100 mg FDC capsules can be prescribed to improve patient compliance.

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

PubMed

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

2009-06-01

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

Effects of food on the pharmacokinetics of gemigliptin/metformin sustained-release 50/1,000 mg (25/500 mg x 2 tablets) fixeddose combination tablet in healthy male volunteers.

PubMed

Choi, Hee Youn; Noh, Yook-Hwan; Kim, Yo Han; Kim, Mi Jo; Lee, Shi Hyang; Kim, Jeong-Ae; Kim, Bogyeong; Lim, Hyeong-Seok; Bae, Kyun-Seop

2014-05-01

For patient convenience, a gemigliptin/metformin sustainedrelease fixed-dose combination (FDC) tablet was developed. This study was conducted to investigate the effects of food on the pharmacokinetic (PK) profile of the FDC tablets. This was an open-label, randomized, single dose, 2-period, 2-sequence crossover study in 24 healthy male volunteers. The FDC tablets (25/500 mg × 2 tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. PK blood samplings were conducted from predose to 48 hours after dosing. Tolerability assessments were performed throughout the study. Nine adverse events (AEs) of mild intensity were reported from 8 subjects after study drug administration, and the AE frequency was similar between treatments. No serious AEs were reported. The PK parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (GMRs) (fed : fasted state) of the Cmax and AUClast were 0.886 (90% confidence interval (CI) 0.781 - 1.006) and 1.021 (90% CI 0.949 - 1.099), respectively. For metformin, the GMRs of the Cmax and AUClast were 0.811 (90% CI 0.712 - 0.923) and 1.144 (90% CI 1.013 - 1.291), respectively. A prolonged tmax for metformin was observed. These results are similar to the effects of food on each component. The FDC tablet may have a similar PK profile as that of individual drugs and is generally tolerable when administered with food. These results indicate that the FDC tablet can be administered in the same dosing regimen as each component, especially that of metformin sustained-release.

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

PubMed

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

2018-01-01

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

Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation.

PubMed

Tedesco-Silva, Helio; Pescovitz, Mark D; Cibrik, Diane; Rees, Michael A; Mulgaonkar, Shamkant; Kahan, Barry D; Gugliuzza, Kristene K; Rajagopalan, P R; Esmeraldo, Ronaldo de M; Lord, Hélène; Salvadori, Maurizio; Slade, Jennifer M

2006-12-27

Phase II trials of FTY720, a novel immunomodulator, have shown promise in preventing rejection with both standard and reduced cyclosporine exposure. This study was designed to confirm those findings. This one-year, multicenter, randomized, phase III study in 696 de novo renal transplant patients compared FTY720 5 mg plus reduced-dose cyclosporine (RDC) or FTY720 2.5 mg plus full-dose cyclosporine (FDC) with mycophenolate mofetil (MMF) plus FDC. All patients received concomitant corticosteroid therapy without antibody induction. The primary efficacy composite endpoint was the incidence of first treated biopsy-proven acute rejection (treated BPAR), graft loss, death or premature study discontinuation at month 12. FTY720 2.5 mg plus FDC was demonstrated to be non-inferior to MMF plus FDC as the primary efficacy endpoint (30.8% and 30.6%) was comparable. The FTY720 5 mg plus RDC treatment regimen was discontinued due to an increased incidence of acute rejection episodes (primary endpoint 43.3%). FTY720 was associated with significantly lower creatinine clearance with a mean difference at 12 months between FTY720 2.5 mg plus FDC and MMF plus FDC of 8 ml/min. While FTY720 2.5 mg plus FDC yielded similar efficacy to MMF plus FDC, the FTY720 5 mg plus RDC did not allow a 50% reduction in cyclosporine exposure. The associated lower creatinine clearance indicated that FTY720 combined with cyclosporine provided no benefit over standard care.

Comparisons of the pharmacokinetics and tolerability of fixed-dose combinations of amlodipine besylate/losartan and amlodipine camsylate/losartan in healthy subjects: a randomized, open-label, single-dose, two-period, two-sequence crossover study.

PubMed

Choi, YoonJung; Lee, SeungHwan; Cho, Sang-Min; Kang, Won-Ho; Nam, Kyu-Yeol; Jang, In-Jin; Yu, Kyung-Sang

2016-01-01

A fixed-dose combination (FDC) of amlodipine and losartan has been used to reduce blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The aim of this study was to evaluate the pharmacokinetic (PK) characteristics and tolerability of an FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium compared to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium in healthy subjects. A randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted on 46 healthy male subjects. Blood concentrations were measured by liquid chromatography-tandem mass spectrometry. Blood samples were collected up to 144 hours post dose for each period. PK parameters were calculated in each treatment group using a noncompartmental method. The 90% confidence intervals (CIs) of the geometric mean ratios of the two treatments for the maximum plasma concentration ( C max ) and the area under the concentration curve from time zero to the last quantifiable time point (AUC 0-t ) were estimated. Tolerability assessments were performed for all subjects who received the drug at least once. The PK profiles of the two treatments were similar. For amlodipine, the geometric mean ratios (90% CIs) of amlodipine besylate to amlodipine camsylate for the C max and AUC 0-t were 0.98 (0.94-1.01) and 0.97 (0.93-1.01), respectively. The corresponding values for losartan were 0.91 (0.81-1.02) and 1.05 (0.98-1.12), respectively. The incidence of adverse events was not significantly different between the two treatments, and both were well tolerated. An FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium produced similar results to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium treatment with respect to the PK parameters of amlodipine and losartan based on C max and AUC 0-t values. The amlodipine besylate/losartan potassium combination was well tolerated by healthy male subjects.

Efficacy and safety of fixed-dose combination therapy, alogliptin plus metformin, in Asian patients with type 2 diabetes: A phase 3 trial.

PubMed

Ji, Linong; Li, Ling; Kuang, Jian; Yang, Tao; Kim, Dong-Jun; Kadir, Azidah A; Huang, Chien-Ning; Lee, Douglas

2017-05-01

This study evaluated the efficacy and safety of 26 weeks of twice-daily (BID) alogliptin + metformin fixed-dose combination (FDC) therapy in Asian patients with type 2 diabetes. Patients aged 18 to 75 years with hemoglobin A1c (HbA1c) of 7.5% to 10.0% after ≥2 months of diet and exercise and a 4-week placebo run-in were enrolled. Eligible patients were randomized (1:1:1:1) to placebo, alogliptin 12.5 mg BID, metformin 500 mg BID or alogliptin 12.5 mg plus metformin 500 mg FDC BID. The primary endpoint was change in HbA1c from baseline to end of treatment (Week 26). In total, 647 patients were randomized. The least-squares mean change in HbA1c from baseline to Week 26 was -0.19% with placebo, -0.86% with alogliptin, -1.04% with metformin and -1.53% with alogliptin + metformin FDC. Alogliptin + metformin FDC was significantly more effective ( P  < .0001) in lowering HbA1c than either alogliptin or metformin alone. The safety profile of alogliptin + metformin FDC was similar to that of the individual components alogliptin and metformin. The study demonstrated that treatment with alogliptin + metformin FDC BID resulted in better glycaemic control than either monotherapy and was well tolerated in Asian patients with type 2 diabetes. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Fixed dose darunavir boosted with cobicistat combined with emtricitabine and tenofovir alafenamide fumarate.

PubMed

Cevik, Muge; Orkin, Chloe

2018-07-01

In an era when virological efficacy approaches 100%, novel antiretroviral (ARV) therapies must deliver better tolerability, safety, and convenient coformulated regimens. We review the phase II and III clinical data on the fixed dose combination (FDC) darunavir (DRV) 800mg / cobicistat (COBI/C) 150 mg / emtricitabine (F/FTC) 200 mg / tenofovir alafenamide fumarate (TAF) 10mg (D/C/F/TAF) for the treatment of HIV-1 infection. In an exploratory phase II study, D/C/F/TAF FDC demonstrated similar virological efficacy to darunavir/cobicistat FDC + F /tenofovir disoproxil fumarate (TDF) FDC in treatment-naive HIV-1-infected individuals with favorable bone and renal outcomes. These findings led to two subsequent international phase III double-blind randomized controlled trials; AMBER and EMERALD. In the (treatment naïve) AMBER study, D/C/F/TAF FDC was noninferior to component regimen F/TDF + darunavir/cobicistat with favorable bone and renal outcomes at week 48. In the EMERALD study (switch study for virologically suppressed patients), D/C/F/TAF showed noninferior efficacy to F/TDF and boosted protease inhibitor (bPI) regimen at week 48 also with favorable renal and bone outcomes. No virological failure was observed, and no resistance to TDF or darunavir emerged in either study. In clinical trials, D/C/F/TAF FDC demonstrated excellent, noninferior virological efficacy, maintained a high genetic barrier and conferred the additional safety benefits of TAF. As the first one pill, once daily, protease inhibitor-based regimen, D/C/F/TAF FDC offers a new option for the treatment of HIV infection.

Effects of Food Intake on the Pharmacokinetics of Azilsartan Medoxomil and Chlorthalidone Alone and in Fixed‐Dose Combination in Healthy Adults

PubMed Central

Karim, Aziz; Munsaka, Melvin

2016-01-01

Abstract Azilsartan medoxomil is a long‐acting angiotensin II receptor blocker used to treat hypertension as monotherapy or in fixed‐dose combination (FDC) with chlorthalidone. This study assessed the effects of food intake on the plasma pharmacokinetics of the active moiety, azilsartan, and of chlorthalidone when administered as separate tablets or in FDC. Cohort 1 (n = 24) received azilsartan medoxomil (80 mg) and chlorthalidone (25 mg) once in a fasted condition and once 30 minutes after the initiation of a high‐fat meal (fed). Cohort 2 (n = 24) received the same drugs as an FDC tablet in the fasted and fed conditions. In cohort 1, the fed‐fasted ratios for AUC0–inf and Cmax were 108.3 (101.6–115.5) and 103.7 (94.3–114.1), respectively, for azilsartan and 112.3 (106.5–118.4) and 100.3 (90.6–111.1), respectively, for chlorthalidone. In cohort 2, the corresponding ratios were 78.6 (67.6–91.4) and 78.6 (64.4–96.0) for azilsartan and 101.0 (96.5–86.7) and 75.9 (66.5–86.7) for chlorthalidone. The combination therapies were well tolerated, and food intake had no consistent effect on adverse events. Food intake had a somewhat greater effect on plasma pharmacokinetics after administration of the FDC tablet than after administration of separate tablets, but the effects of food on the plasma pharmacokinetics of the FDC were not expected to be clinically meaningful. PMID:27514506

The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

PubMed

Adjuik, Martin A; Allan, Richard; Anvikar, Anupkumar R; Ashley, Elizabeth A; Ba, Mamadou S; Barennes, Hubert; Barnes, Karen I; Bassat, Quique; Baudin, Elisabeth; Björkman, Anders; Bompart, François; Bonnet, Maryline; Borrmann, Steffen; Brasseur, Philippe; Bukirwa, Hasifa; Checchi, Francesco; Cot, Michel; Dahal, Prabin; D'Alessandro, Umberto; Deloron, Philippe; Desai, Meghna; Diap, Graciela; Djimde, Abdoulaye A; Dorsey, Grant; Doumbo, Ogobara K; Espié, Emmanuelle; Etard, Jean-Francois; Fanello, Caterina I; Faucher, Jean-François; Faye, Babacar; Flegg, Jennifer A; Gaye, Oumar; Gething, Peter W; González, Raquel; Grandesso, Francesco; Guerin, Philippe J; Guthmann, Jean-Paul; Hamour, Sally; Hasugian, Armedy Ronny; Hay, Simon I; Humphreys, Georgina S; Jullien, Vincent; Juma, Elizabeth; Kamya, Moses R; Karema, Corine; Kiechel, Jean R; Kremsner, Peter G; Krishna, Sanjeev; Lameyre, Valérie; Ibrahim, Laminou M; Lee, Sue J; Lell, Bertrand; Mårtensson, Andreas; Massougbodji, Achille; Menan, Hervé; Ménard, Didier; Menéndez, Clara; Meremikwu, Martin; Moreira, Clarissa; Nabasumba, Carolyn; Nambozi, Michael; Ndiaye, Jean-Louis; Nikiema, Frederic; Nsanzabana, Christian; Ntoumi, Francine; Ogutu, Bernhards R; Olliaro, Piero; Osorio, Lyda; Ouédraogo, Jean-Bosco; Penali, Louis K; Pene, Mbaye; Pinoges, Loretxu; Piola, Patrice; Price, Ric N; Roper, Cally; Rosenthal, Philip J; Rwagacondo, Claude Emile; Same-Ekobo, Albert; Schramm, Birgit; Seck, Amadou; Sharma, Bhawna; Sibley, Carol Hopkins; Sinou, Véronique; Sirima, Sodiomon B; Smith, Jeffery J; Smithuis, Frank; Somé, Fabrice A; Sow, Doudou; Staedke, Sarah G; Stepniewska, Kasia; Swarthout, Todd D; Sylla, Khadime; Talisuna, Ambrose O; Tarning, Joel; Taylor, Walter R J; Temu, Emmanuel A; Thwing, Julie I; Tjitra, Emiliana; Tine, Roger C K; Tinto, Halidou; Vaillant, Michel T; Valecha, Neena; Van den Broek, Ingrid; White, Nicholas J; Yeka, Adoke; Zongo, Issaka

2015-03-31

Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

Bioequivalence and food effect assessment for vildagliptin/metformin fixed-dose combination tablets relative to free combination of vildagliptin and metformin in Japanese healthy subjects.

PubMed

Mita, Sachiko; Chitnis, Shripad D; Kulmatycki, Kenneth; Salunke, Atish; He, Yan-Ling; Zhou, Wei; Suzuki, Hikoe

2016-04-01

To assess the bioequivalence of vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of vildagliptin and metformin following administration of 50/500 mg FDC tablets. Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 - 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, C(max), t(max), t(1/2)) were calculated for vildagliptin and metformin. In both studies, vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged t(max) (3 hours in fasted state vs. 4 hours in fed state) and decrease in C(max) by 26%, however, the extent of absorption (AUC(last)) was similar to that in the fasted state. Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C(max) of metformin by 26%, while AUC(last) was unchanged, consistent with previous reports. No food effect was observed on the C(max) or AUC(last) of vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or vildagliptin.

Add-on LABA in a separate inhaler as asthma step-up therapy versus increased dose of ICS or ICS/LABA combination inhaler.

PubMed

Price, David B; Colice, Gene; Israel, Elliot; Roche, Nicolas; Postma, Dirkje S; Guilbert, Theresa W; van Aalderen, Willem M C; Grigg, Jonathan; Hillyer, Elizabeth V; Thomas, Victoria; Martin, Richard J

2016-04-01

Asthma management guidelines recommend adding a long-acting β 2 -agonist (LABA) or increasing the dose of inhaled corticosteroid (ICS) as step-up therapy for patients with uncontrolled asthma on ICS monotherapy. However, it is uncertain which option works best, which ICS particle size is most effective, and whether LABA should be administered by separate or combination inhalers. This historical, matched cohort study compared asthma-related outcomes for patients (aged 12-80 years) prescribed step-up therapy as a ≥50% extrafine ICS dose increase or add-on LABA, via either a separate inhaler or a fine-particle ICS/LABA fixed-dose combination (FDC) inhaler. Risk-domain asthma control was the primary end-point in comparisons of cohorts matched for asthma severity and control during the baseline year. After 1:2 cohort matching, the increased extrafine ICS versus separate ICS+LABA cohorts included 3232 and 6464 patients, respectively, and the fine-particle ICS/LABA FDC versus separate ICS+LABA cohorts included 7529 and 15 058 patients, respectively (overall mean age 42 years; 61-62% females). Over one outcome year, adjusted OR (95% CI) for achieving asthma control were 1.25 (1.13-1.38) for increased ICS versus separate ICS+LABA and 1.06 (1.05-1.09) for ICS/LABA FDC versus separate ICS+LABA. For patients with asthma, increased dose of extrafine-particle ICS, or add-on LABA via ICS/LABA combination inhaler, is associated with significantly better outcomes than ICS+LABA via separate inhalers.

Pharmacokinetic and bioequivalence study of a telmisartan/S-amlodipine fixed-dose combination (CKD-828) formulation and coadministered telmisartan and S-amlodipine in healthy subjects.

PubMed

Kang, Woo Youl; Seong, Sook Jin; Ohk, Boram; Gwon, Mi-Ri; Kim, Bo Kyung; La, Sookie; Kim, Hyun-Ju; Cho, Seungil; Yoon, Young-Ran; Yang, Dong Heon; Lee, Hae Won

2018-01-01

A new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance. The pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography-tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period. Forty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (C max ) and the area under the plasma concentration-time curve from time 0 to the last measurement (AUC 0-t ) values of telmisartan were 522.29 ng/mL and 2,475.16 ng·h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng·h/mL for the individual agents concomitantly administered, respectively. The mean C max and AUC 0-t values of S-amlodipine were 2.71 ng/mL and 130.69 ng·h/mL for the FDC, and 2.74 ng/mL and 129.81 ng·h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan C max and AUC 0-t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353-0.9846) and 0.9431 (0.8698-1.0226), respectively. The GMR and 90% CI for the S-amlodipine C max and AUC 0-t (FDC/concomitant administration) were 0.9829 (0.9143-1.0567) and 0.9632 (0.8798-1.0546), respectively. As the intrasubject variability of the C max for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study. CKD-828 FDC tablets were shown to be bioequivalent to coadministration of the individual agents with the respective strength, in healthy subjects under fasting conditions. There was no significant difference in safety profile between the two treatments.

Valsartan plus hydrochlorothiazide: a review of its use since its introduction.

PubMed

Bains, Jujhar; Smith, William B

2011-08-01

This review focuses on the role of the fixed-dose combination (FDC) drug valsartan/hydrochlorothiazide (HCTZ) in the treatment of hypertension. Effective blood pressure control often is not achieved with monotherapy and, instead, requires combinations of drugs with different mechanisms of action to produce additive or synergistic effects. FDC valsartan/HCTZ enhances not only efficacy for blood pressure control but also provides beneficial effects on target organs beyond that expected from arterial pressure reduction alone. Data describe key clinical trial experiences with the FDC, with particular attention to efficacy and tolerability. Literature searches of these various topics were conducted in January 2011. There is evidence of potential benefits with this combination associated with left ventricular hypertrophy, left ventricular dysfunction and renal disease. The FDC is an effective treatment for patients with hypertension and is superior to monotherapy than either drug alone. In addition to the benefits of each drug, valsartan/HCTZ's metabolic interactions reduce some of the negative effects of both compounds. With its increased simplicity, minimal side-effect profile and efficacy without a significant cost penalty, valsartan/HCTZ represents an excellent choice for antihypertensive therapy.

The Effect on Treatment Adherence of Administering Drugs as Fixed-Dose Combinations versus as Separate Pills: Systematic Review and Meta-Analysis.

PubMed

van Galen, Katy A; Nellen, Jeannine F; Nieuwkerk, Pythia T

2014-01-01

Administering drugs as fixed-dose combinations (FDCs) versus the same active drugs administered as separate pills is assumed to enhance treatment adherence. We synthesized evidence from randomized controlled trials (RCTs) about the effect of FDCs versus separate pills on adherence. We searched PubMed for RCTs comparing a FDC with the same active drugs administered as separate pills, including a quantitative estimate of treatment adherence, without restriction to medical condition. The odds ratio (OR) of optimal adherence with FDCs versus separate pills was used as common effect size and aggregated into a pooled effect estimate using a random effect model with inverse variance weights. Out of 1258 articles screened, only six studies fulfilled inclusion criteria. Across medical conditions, administering drugs as FDC significantly increased the likelihood of optimal adherence (OR 1.33 (95% CI, 1.03-1.71)). Within subgroups of specific medical conditions, the favourable effect of FDCs on adherence was of borderline statistical significance for HIV infection only (OR 1.46 (95% CI, 1.00-2.13)). We observed a remarkable paucity of RCTs comparing the effect on adherence of administering drugs as FDC versus as separate pills. Administering drugs as FDC improved medication adherence. However, this conclusion is based on a limited number of RCTs only.

Efficacy and safety of fixed-dose combination therapy with olmesartan medoxomil and rosuvastatin in Korean patients with mild to moderate hypertension and dyslipidemia: an 8-week, multicenter, randomized, double-blind, factorial-design study (OLSTA-D RCT: OLmesartan rosuvaSTAtin from Daewoong)

PubMed Central

Park, Jin-Sun; Shin, Joon-Han; Hong, Taek-Jong; Seo, Hong-Seog; Shim, Wan-Joo; Baek, Sang-Hong; Jeong, Jin-Ok; Ahn, Youngkeun; Kang, Woong-Chol; Kim, Young-Hak; Kim, Sang-Hyun; Hyon, Min-Su; Choi, Dong-Hoon; Nam, Chang-Wook; Park, Tae-Ho; Lee, Sang-Chol; Kim, Hyo-Soo

2016-01-01

The pill burden of patients with hypertension and dyslipidemia can result in poor medication compliance. This study aimed to evaluate the efficacy and safety of fixed-dose combination (FDC) therapy with olmesartan medoxomil (40 mg) and rosuvastatin (20 mg) in Korean patients with mild to moderate hypertension and dyslipidemia. This multicenter, randomized, double-blind, factorial-design study included patients aged ≥20 years with mild to moderate essential hypertension and dyslipidemia. Patients were randomly assigned to receive FDC therapy (40 mg olmesartan medoxomil, 20 mg rosuvastatin), 40 mg olmesartan medoxomil, 20 mg rosuvastatin, or a placebo. The percentage change from baseline in low-density lipoprotein cholesterol levels was compared between FDC therapy and olmesartan medoxomil, and the change from baseline in diastolic blood pressure was compared between FDC therapy and rosuvastatin 8 weeks after treatment. A total of 162 patients were included. The least square mean percentage change (standard error) from baseline in low-density lipoprotein cholesterol levels 8 weeks after treatment was significantly greater in the FDC than in the olmesartan medoxomil group (−52.3% [2.8%] vs −0.6% [3.5%], P<0.0001), and the difference was −51.7% (4.1%) (95% confidence interval: −59.8% to −43.6%). The least square mean change (standard error) from baseline in diastolic blood pressure 8 weeks after treatment was significantly greater in the FDC group than in the rosuvastatin group (−10.4 [1.2] mmHg vs 0.1 [1.6] mmHg, P<0.0001), and the difference was −10.5 (1.8) mmHg (95% confidence interval: −14.1 to −6.9 mmHg). There were 50 adverse events in 41 patients (22.7%) and eight adverse drug reactions in five patients (2.8%). The study found that FDC therapy with olmesartan medoxomil and rosuvastatin is an effective, safe treatment for patients with hypertension and dyslipidemia. This combination may improve medication compliance in patients with a large pill burden. PMID:27574399

Effects of Food Intake on the Pharmacokinetics of Azilsartan Medoxomil and Chlorthalidone Alone and in Fixed-Dose Combination in Healthy Adults.

PubMed

Dudkowski, Caroline; Karim, Aziz; Munsaka, Melvin

2016-09-01

Azilsartan medoxomil is a long-acting angiotensin II receptor blocker used to treat hypertension as monotherapy or in fixed-dose combination (FDC) with chlorthalidone. This study assessed the effects of food intake on the plasma pharmacokinetics of the active moiety, azilsartan, and of chlorthalidone when administered as separate tablets or in FDC. Cohort 1 (n = 24) received azilsartan medoxomil (80 mg) and chlorthalidone (25 mg) once in a fasted condition and once 30 minutes after the initiation of a high-fat meal (fed). Cohort 2 (n = 24) received the same drugs as an FDC tablet in the fasted and fed conditions. In cohort 1, the fed-fasted ratios for AUC0-inf and Cmax were 108.3 (101.6-115.5) and 103.7 (94.3-114.1), respectively, for azilsartan and 112.3 (106.5-118.4) and 100.3 (90.6-111.1), respectively, for chlorthalidone. In cohort 2, the corresponding ratios were 78.6 (67.6-91.4) and 78.6 (64.4-96.0) for azilsartan and 101.0 (96.5-86.7) and 75.9 (66.5-86.7) for chlorthalidone. The combination therapies were well tolerated, and food intake had no consistent effect on adverse events. Food intake had a somewhat greater effect on plasma pharmacokinetics after administration of the FDC tablet than after administration of separate tablets, but the effects of food on the plasma pharmacokinetics of the FDC were not expected to be clinically meaningful. © 2016, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Bioavailability of rifampicin in a separate formulation and fixed dose combination with isoniazid NIH: a case for a fixed dose combination (FDC) for the treatment of tuberculosis.

PubMed

Nyazema, N Z; Rabvukwa, P; Gumbo, J; Ndudzo, P; Chitemerere, C

1999-06-01

To study and compare the bioavailability of rifampicin (RIF), in two locally manufactured formulations; an FDC and a separate formulation and an imported FDC formulation. Open within subjects, single blind cross over study. Each volunteer subject, acting as their own control, received the two fixed dose combinations and the separate formulation with the same amount of 450 mg RIF. Cmax (peak drug concentration achieved), Tmax (time at which peak drug concentration is achieved), T1/2el (biological half-life of elimination) and area under the curve (AUC) for zero to 10 hours and zero to infinity. These are obtained from plotting plasma concentration against time. There was a significant difference in the Cmax between free and RIF combined with INH (6.1 and 7.6 mg/l respectively) and no significant difference in the other parameters measured, of the local products. Comparison of the local products and imported product showed no significant difference in AUC but significant differences in T1/2el, C max and Tmax (p = 0.003, 0.041 and 0.025 respectively). The Zimbabwe manufactured and the German products had "demonstrable bioavailability" as defined by the International Union Against Tuberculosis and Lung Diseases (IUATLD). The local manufacturer appeared to have the technological capability to produce a registrable combined RIF/INH table to be used in the treatment of tuberculosis and to prevent the irrational use of RIF.

Comparisons of the pharmacokinetics and tolerability of fixed-dose combinations of amlodipine besylate/losartan and amlodipine camsylate/losartan in healthy subjects: a randomized, open-label, single-dose, two-period, two-sequence crossover study

PubMed Central

Choi, YoonJung; Lee, SeungHwan; Cho, Sang-Min; Kang, Won-Ho; Nam, Kyu-Yeol; Jang, In-Jin; Yu, Kyung-Sang

2016-01-01

Background A fixed-dose combination (FDC) of amlodipine and losartan has been used to reduce blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The aim of this study was to evaluate the pharmacokinetic (PK) characteristics and tolerability of an FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium compared to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium in healthy subjects. Subjects and methods A randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted on 46 healthy male subjects. Blood concentrations were measured by liquid chromatography–tandem mass spectrometry. Blood samples were collected up to 144 hours post dose for each period. PK parameters were calculated in each treatment group using a noncompartmental method. The 90% confidence intervals (CIs) of the geometric mean ratios of the two treatments for the maximum plasma concentration (Cmax) and the area under the concentration curve from time zero to the last quantifiable time point (AUC0–t) were estimated. Tolerability assessments were performed for all subjects who received the drug at least once. Results The PK profiles of the two treatments were similar. For amlodipine, the geometric mean ratios (90% CIs) of amlodipine besylate to amlodipine camsylate for the Cmax and AUC0–t were 0.98 (0.94−1.01) and 0.97 (0.93−1.01), respectively. The corresponding values for losartan were 0.91 (0.81−1.02) and 1.05 (0.98−1.12), respectively. The incidence of adverse events was not significantly different between the two treatments, and both were well tolerated. Conclusion An FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium produced similar results to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium treatment with respect to the PK parameters of amlodipine and losartan based on Cmax and AUC0–t values. The amlodipine besylate/losartan potassium combination was well tolerated by healthy male subjects. PMID:27703330

Fed and Fasted Single-dose Assessment of Bioequivalence of Dapagliflozin and Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects.

PubMed

Boulton, David W; Chang, Ming; Griffen, Steven C; Kitaura, Catia; Lubin, Susan; Pollack, Allyson; LaCreta, Frank

2016-01-01

In patients with type 2 diabetes mellitus, fixed-dose combinations (FDCs) of antihyperglycemic medications may provide complementary efficacy while reducing tablet burden and improving compliance. The aim of this study was to assess the bioequivalence and tolerability of 2 FDCs of dapagliflozin and metformin extended-release (XR) versus their individual component (IC) tablets. An open-label, balanced, randomized, 2-way crossover, 4-arm study was conducted in 129 healthy Brazilian subjects (aged 18-55 years). Two oral doses of the FDCs (5 mg dapagliflozin and 500 mg metformin XR, and 10 mg dapagliflozin and 1000 mg metformin XR) were evaluated in fed and fasted states. Under fed and fasted conditions the 5 mg dapagliflozin and 500 mg metformin XR FDC showed bioequivalence to its ICs. The 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent to its ICs in fed subjects. Although AUC for the 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent in fasted subjects, the Cmax for metformin was not bioequivalent to its ICs in fasted subjects (upper 90% CI was 127.5%, and thus outside the 80%-125% bioequivalence interval). The small increase in the fasted state is not considered clinically meaningful due to the small magnitude of the difference (9.2%), the lack of metformin Cmax being associated with efficacy or tolerability concerns, and the fasted state not being the recommended state for dosing of metformin XR. The safety profile and tolerability of the FDCs were similar to those of their ICs and no deaths or serious adverse events were reported. Both FDCs of dapagliflozin and metformin XR were bioequivalent to their ICs in fed and fasted subjects, except for the metformin Cmax from the 10 mg dapagliflozin and 1000 mg metformin XR FDC in fasted subjects. These data support the use of a dapagliflozin and metformin XR FDC in patients with type 2 diabetes mellitus. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Patient Adherence to Olmesartan/Amlodipine Combinations: Fixed Versus Extemporaneous Combinations.

PubMed

Levi, Miriam; Pasqua, Alessandro; Cricelli, Iacopo; Cricelli, Claudio; Piccinni, Carlo; Parretti, Damiano; Lapi, Francesco

2016-03-01

Lack of adherence to prescribed therapies is often a cause of suboptimal blood pressure control in patients with hypertension. To enhance patients' adherence to treatment, fixed-dose combinations of active substances with complementary mechanisms of action have been developed. An angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (ARB) is often combined with a calcium channel blocker. Olmesartan is the most used ARB in combination therapy. In Italy, in September 2011, a fixed-dose combination of olmesartan/amlodipine (olmesartan/amlodipine 20/5 mg, 40/5 mg, or 40/10 mg) was introduced to treat patients with hypertension for whom control of blood pressure is not reached with either olmesartan or amlodipine alone. Prior research on adherence to olmesartan/amlodipine combinations was carried out in local contexts (e.g., claims databases of Italian regions or local health authorities), and/or it was limited by the fact that adherence was assessed against monotherapies already known for their low compliance profile, such as diuretics. To compare adherence with olmesartan/amlodipine fixed-dose combination (FDC) and extemporaneous combination in primary care in Italy. A nationwide, population-based study was conducted by using the Health Search IMS Health Longitudinal Patient Database. Patients aged > 17 years, affected by hypertension and treated with the FDC or extemporaneous combination of olmesartan/amlodipine, were identified. Adherence to these 2 therapeutic regimens was estimated by calculating the proportion of days covered (PDC). Patients were classified into 3 levels of adherence: high (PDC ≥ 80%), intermediate (PDC = 40%-79%), or low (PDC < 40%). In the 6-month follow-up, FDC showed higher adherence compared with an extemporaneous combination (55.1% vs. 15.9%, P < 0.001). This difference was confirmed in a multivariable logistic regression model clustered on patient identifier (odds ratio = 6.65; 95% CI = 3.10-14.26; P < 0.001). The proportion of patients adherent to FDC varied from 60.4% for the 40/5 mg formulation to 47.5% for the 40/10 mg formulation. These findings suggest that higher adherence may be achieved with FDCs than with extemporaneous combinations. To improve the degree of adherence, general practitioners may consider prescribing fixed combinations of antihypertensive agents as soon as monotherapies fail to achieve the expected therapeutic objective.

Investigation of bioequivalence of a new fixed-dose combination of acarbose and metformin with the corresponding loose combination as well as the drug-drug interaction potential between both drugs in healthy adult male subjects.

PubMed

Kim, S; Jang, I-J; Shin, D; Shin, D S; Yoon, S; Lim, K S; Yu, K-S; Li, J; Zhang, H; Liu, Y; Brendel, E; Blode, H; Wang, Y

2014-08-01

Both metformin and acarbose are recommended monotherapy and add-on therapy in type 2 diabetes mellitus (T2DM). A fixed-dose combination (FDC) of acarbose and metformin has been developed to reduce pill burden and potentially improve compliance. The current study investigated the bioequivalence of the acarbose/metformin FDC compared with the individual agents administered simultaneously (loose combination). Secondary endpoints were the safety and tolerability of the FDC and the potential for drug-drug interactions between acarbose and metformin. A single-centre, randomized, open-label, four-period crossover study was conducted in healthy male Korean subjects aged 18-45 years. Following one-period balanced Williams design, participants were randomized to receive four single oral treatments on different study days separated by ≥7 days' washout. Treatments were as follows: (i) acarbose/metformin 50/500 mg FDC (test); (ii) acarbose 50 mg and metformin 500 mg as loose combination (reference); (iii) acarbose 50 mg; and (iv) metformin 500 mg. Serial blood samples were taken for glucose and insulin levels for 4 h after a sucrose load on the day before and day of study drug administration. Additionally, serial blood samples were taken for analysis of metformin levels for 24 h after each drug containing metformin. The area under the curve for 4 h post-test (AUC0-4 h ) and the maximal serum concentration (Cmax ) of plasma glucose and serum insulin were primary pharmacodynamic (PD) parameters, and Cmax , AUC0-last and AUC for metformin levels were primary pharmacokinetic (PK) parameters. The bioequivalence of the FDC to the loose combination was considered established if the 90% confidence intervals (CIs) of the baseline-adjusted PD parameter ratios (test vs. reference) for plasma glucose and the PK parameter ratios for metformin fell completely within current acceptance limits (0·8-1·25). Thirty-three of 40 randomized subjects completed the study; five withdrew consent and two discontinued because of adverse events (AEs). The 24-h plasma concentration-time curves of metformin and the 4-h plasma glucose-time curves after acarbose/metformin FDC (test) and acarbose + metformin loose combination (reference) were almost superimposable. The geometric least squares (LS) mean of the RatioAUC and RatioCmax for plasma glucose after the FDC vs. loose combination, and the LS mean of the ratios in metformin AUC, AUC0-last and Cmax were close to unity, and the 90% CI of all these parameters fell within the predefined equivalence range of 0·8-1·25, confirming bioequivalence. The metformin AUC was reduced by 26% and Cmax by 34% after acarbose + metformin compared with metformin alone. Eight subjects (20·0%) reported AEs, but all were mild, and most were gastrointestinal, as expected for these agents. The incidence of AEs was not higher with the combinations vs. monotherapy. These data demonstrate that the acarbose/metformin FDC is bioequivalent to the loose combination of these agents. Although acarbose slightly reduced the bioavailability of metformin, the accumulated evidence of the efficacy of this combination implies that this is clinically irrelevant. The observed AE profile was consistent with the established knowledge on the safety of the two drugs. © 2014 John Wiley & Sons Ltd.

Optimization of the strength of the efavirenz/lamivudine/abacavir fixed-dose combination for paediatric patients.

PubMed

Bouazza, Naïm; Cressey, Tim R; Foissac, Frantz; Bienczak, Andrzej; Denti, Paolo; McIlleron, Helen; Burger, David; Penazzato, Martina; Lallemant, Marc; Capparelli, Edmund V; Treluyer, Jean-Marc; Urien, Saïk

2017-02-01

Child-friendly, low-cost, solid, oral fixed-dose combinations (FDCs) of efavirenz with lamivudine and abacavir are urgently needed to improve clinical management and drug adherence for children. Data were pooled from several clinical trials and therapeutic drug monitoring datasets from different countries. The number of children/observations was 505/3667 for efavirenz. Population pharmacokinetic analyses were performed using a non-linear mixed-effects approach. For abacavir and lamivudine, data from 187 and 920 subjects were available (population pharmacokinetic models previously published). Efavirenz/lamivudine/abacavir FDC strength options assessed were (I) 150/75/150, (II) 120/60/120 and (III) 200/100/200 mg. Monte Carlo simulations of the different FDC strengths were performed to determine the optimal dose within each of the WHO weight bands based on drug efficacy/safety targets. The probability of being within the target efavirenz concentration range 12 h post-dose (1-4 mg/L) varied between 56% and 60%, regardless of FDC option. Option I provided a best possible balance between efavirenz treatment failure and toxicity risks. For abacavir and lamivudine, simulations showed that for option I >75% of subjects were above the efficacy target. According to simulations, a paediatric efavirenz/lamivudine/abacavir fixed-dose formulation of 150 mg efavirenz, 75 mg lamivudine and 150 mg abacavir provided the most effective and safe concentrations across WHO weight bands, with the flexibility of dosage required across the paediatric population. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Use of Fixed Dose Combination (FDC) Drugs in India: Central Regulatory Approval and Sales of FDCs Containing Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Metformin, or Psychotropic Drugs

PubMed Central

McGettigan, Patricia; Roderick, Peter; Mahajan, Rushikesh; Kadam, Abhay; Pollock, Allyson M.

2015-01-01

Background In 2012, an Indian parliamentary committee reported that manufacturing licenses for large numbers of fixed dose combination (FDC) drugs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organization (CDSCO) in violation of rules, and considered that some ambiguity until 1 May 2002 about states’ powers might have contributed. To our knowledge, no systematic enquiry has been undertaken to determine if evidence existed to support these findings. We investigated CDSCO approvals for and availability of oral FDC drugs in four therapeutic areas: analgesia (non-steroidal anti-inflammatory drugs [NSAIDs]), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics). Methods and Findings This was an ecologic study with a time-trend analysis of FDC sales volumes (2007–2012) and a cross-sectional examination of 2011–2012 data to establish the numbers of formulations on the market with and without a record of CDSCO approval (“approved” and “unapproved”), their branded products, and sales volumes. Data from the CDSCO on approved FDC formulations were compared with sales data from PharmaTrac, a database of national drug sales. We determined the proportions of FDC sales volumes (2011–2012) arising from centrally approved and unapproved formulations and from formulations including drugs banned/restricted internationally. We also determined the proportions of centrally approved and unapproved formulations marketed before and after 1 May 2002, when amendments were made to the drug rules. FDC approvals in India, the United Kingdom (UK), and United States of America (US) were compared. For NSAID FDCs, 124 formulations were marketed, of which 34 (27%) were centrally approved and 90 (73%) were unapproved; metformin: 25 formulations, 20 (80%) approved, five (20%) unapproved; anti-depressants/benzodiazepines: 16 formulations, three (19%) approved, 13 (81%) unapproved; anti-psychotics: ten formulations, three (30%) approved, seven (70%) unapproved. After 1 May 2002, the proportions of approved FDC formulations increased for NSAIDs (26%/28%) and anti-psychotics (0%/38%) and decreased for metformin (100%/75%) and anti-depressants/benzodiazepines (20%/18%), and the overall proportion approved remained similar before and after that date. FDC formulations gave rise to multiple branded products, ranging from 211 anti-psychotic FDC products from ten formulations to 2,739 NSAID FDC products from 124 formulations. The proportions of FDC sales volumes arising from unapproved formulations were as follows: anti-depressants/benzodiazepines, 69%; anti-psychotics, 43%; NSAIDs, 28%; and metformin, 0.4%. Formulations including drugs banned/restricted internationally comprised over 12% of NSAID FDC sales and 53% of anti-psychotic FDC sales. Across the four therapeutic areas, 14 FDC formulations were approved in the UK and 22 in the US. Conclusions There was evidence supporting concerns about FDCs. Metformin excepted, substantial numbers of centrally unapproved formulations for NSAID, anti-depressant/benzodiazepine, and anti-psychotic FDCs were marketed; sales volumes were high. The legal need for central approval of new drugs before manufacture has been in place continuously since 1961, including for FDCs meeting the applicable legal test. Proportions of centrally unapproved formulations after 1 May 2002 did not decrease overall, and no ambiguity was found about states’ licensing powers. Unapproved formulations should be banned immediately, prioritising those withdrawn/banned internationally and undertaking a review of benefits and risks for patients in ceasing or switching to other medicines. Drug laws need to be amended to ensure the safety and effectiveness of medicines marketed in India. PMID:25965416

Validation of a track repeating algorithm for intensity modulated proton therapy: clinical cases study

NASA Astrophysics Data System (ADS)

Yepes, Pablo P.; Eley, John G.; Liu, Amy; Mirkovic, Dragan; Randeniya, Sharmalee; Titt, Uwe; Mohan, Radhe

2016-04-01

Monte Carlo (MC) methods are acknowledged as the most accurate technique to calculate dose distributions. However, due its lengthy calculation times, they are difficult to utilize in the clinic or for large retrospective studies. Track-repeating algorithms, based on MC-generated particle track data in water, accelerate dose calculations substantially, while essentially preserving the accuracy of MC. In this study, we present the validation of an efficient dose calculation algorithm for intensity modulated proton therapy, the fast dose calculator (FDC), based on a track-repeating technique. We validated the FDC algorithm for 23 patients, which included 7 brain, 6 head-and-neck, 5 lung, 1 spine, 1 pelvis and 3 prostate cases. For validation, we compared FDC-generated dose distributions with those from a full-fledged Monte Carlo based on GEANT4 (G4). We compared dose-volume-histograms, 3D-gamma-indices and analyzed a series of dosimetric indices. More than 99% of the voxels in the voxelized phantoms describing the patients have a gamma-index smaller than unity for the 2%/2 mm criteria. In addition the difference relative to the prescribed dose between the dosimetric indices calculated with FDC and G4 is less than 1%. FDC reduces the calculation times from 5 ms per proton to around 5 μs.

Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum malaria: a phase II, multicentric, open-label study.

PubMed

Toure, Offianan Andre; Rulisa, Stephen; Anvikar, Anupkumar R; Rao, Ballamudi S; Mishra, Pitabas; Jalali, Rajinder K; Arora, Sudershan; Roy, Arjun; Saha, Nilanjan; Iyer, Sunil S; Sharma, Pradeep; Valecha, Neena

2015-11-25

The World Health Organization (WHO) recommends artemisinin combination therapy (ACT) for the treatment of uncomplicated Plasmodium falciparum malaria. The present study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate 37.5 mg and piperaquine phosphate (PQP) 187.5 mg dispersible tablets in paediatric patients aged 6 months to 12 years. Male and female patients aged 6 months to 12 years who were confirmed cases of P. falciparum mono-infection with fever or documented history of fever in the previous 24 h were included. The patients were administered FDC of arterolane maleate and PQP as single daily doses for three consecutive days based on their age. The primary efficacy outcome was proportion of patients with polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) on day 28. Safety was analysed based on adverse events (AE), laboratory abnormalities and abnormalities on electrocardiograph. A total of 141 eligible paediatric patients received FDC of arterolane maleate and PQP in a 42-day follow-up study. All the enrolled patients (141) were included in intention to treat (ITT) and safety analyses, and 126 patients were considered in per protocol (PP) population. The PCR-corrected ACPR on day 28 was achieved in all patients (100 %; 95 % CI 97.11-100) included in PP population. The median parasite clearance time (PCT) and fever clearance time (FCT) were 24 h (95 % CI 18.0-24.0) and 10 h (95 % CI 4.0-18.0), respectively. The most frequently reported clinical AE was vomiting. Majority of the AEs were mild to moderate in severity and resolved without sequelae. No patient was discontinued for any QTc (corrected QT interval) prolongation. No deaths or serious AEs were reported during the study. The findings from this study showed that FDC of arterolane maleate and PQP effectively cures P. falciparum malaria and attains acceptable level of cure by day 28 in paediatric patients. The efficacy and safety results observed in children warrants further studies on FDC of arterolane maleate and PQP dispersible tablets. Clinical Trial Registry India: CTRI/2009/091/000531.

Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult Chinese subjects.

PubMed

Gummesson, Anders; Li, Haiyan; Gillen, Michael; Xu, John; Niazi, Mohammad; Hirshberg, Boaz

2014-11-01

As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the potential for increased patient compliance with the convenience of once daily dosing. The aim of the present study was to show that the FDC of saxagliptin and metformin XR is bioequivalent to co-administration of the individual components when given to Chinese subjects residing in China. This was a randomized, open-label, single-dose, two-period, cross-over pharmacokinetic study in two cohorts of healthy adult Chinese male subjects (n = 32 in each cohort) under fed conditions. In cohort 1, the pharmacokinetic properties of a saxagliptin/metformin XR 5/500 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and a 500 mg metformin XR tablet. In cohort 2, the pharmacokinetic properties of a saxagliptin/metformin XR 5/1,000 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and 2 × 500 mg metformin XR tablets. The two cohorts were independent of each other with respect to treatment and results. The pharmacokinetic properties of the active metabolite of saxagliptin (5-hydroxy-saxagliptin), as well as the safety and tolerability of each treatment, were also evaluated. For both cohorts, saxagliptin and metformin in the FDCs were bioequivalent to the individual components, as the limits of the 90 % confidence intervals of the geometric least squares mean ratios were contained within the 80-125 % bioequivalence limits for the area under the plasma concentration-time curve parameters and within the 70-143 % bioequivalence limits for the maximum plasma concentration. Similar exposures of 5-hydroxy-saxagliptin were observed with the two treatment regimens within each cohort. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets. Saxagliptin/metformin XR 5/500 mg and saxagliptin/metformin XR 5/1,000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin XR of the same strengths and were generally well tolerated. These results in healthy Chinese subjects are consistent with those of previous assessments of saxagliptin/metformin XR FDC in the saxagliptin clinical development programme.

Bioequivalence assessment of rifampicin, isoniazid and pyrazinamide in a fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol vs. separate formulations.

PubMed

Agrawal, S; Singh, I; Kaur, K J; Bhade, S R; Kaul, C L; Panchagnula, R

2002-10-01

Depending on the patient category, tuberculosis requires treatment with 3 to 5 drugs which means that patient's compliance to therapy may not be optimal. To increase patient's adherence to treatment schedules, these drugs can be given as single drug preparations or fixed dose combinations (FDCs) of 2 or more drugs in a single formulation. However, an important issue associated with a rifampicin-containing FDC is its quality. Hence, to avoid spurious formulations entering the market, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have recommended FDCs only of proven bioavailability. In this study, the relative bioavailability of rifampicin, isoniazid and pyrazinamide was assessed in a group of 14 healthy male subjects using the FDC tablet containing 4 drugs versus separate formulations at the same dose levels. The study was designed as an open, crossover trial. A total of 9 blood samples were collected over a period of 24 h. The concentration of rifampicin, its main metabolite desacetyl rifampicin, isoniazid and pyrazinamide in plasma were assessed using HPLC analysis. The pharmacokinetic parameters AUC(0-24) and Cmax were subjected to parametric and non-parametric statistical tests at 90% confidence interval. In addition, time to reach peak concentration (tmax), elimination rate constant (Kel) and terminal elimination half-life (t1/2) for each drug were also calculated. It was concluded that the FDC tablet containing 4 drugs is bioequivalent to separate rifampicin, isoniazid and pyrazinamide formulations at the same dose levels.

Bioequivalence of a fixed-dose repaglinide/metformin combination tablet and equivalent doses of repaglinide and metformin tablets
.

PubMed

Cho, Hea-Young; Ngo, Lien; Kim, Sang-Ki; Choi, Yoonho; Lee, Yong-Bok

2018-06-01

This study was conducted to determine whether a fixed-dose combination (FDC) tablet of repaglinide/metformin (2/500 mg) is equivalent to coadministration of equivalent doses of individual (EDI) tablets of repaglinide (2 mg) and metformin (500 mg) in healthy Korean male subjects. This study was conducted as an open-label, randomized, single-dose, two-period, two-sequence crossover design in 50 healthy Korean male subjects who received an FDC tablet or EDI tablets. Plasma concentrations of repaglinide and metformin were determined for up to 24 hours using a validated UPLC-MS/MS method. Bioequivalence was assessed according to current guidelines issued by the U.S. Food and Drug Administration (FDA) and Korean legislation. Tolerability was also evaluated throughout the study via subject interview, vital signs, and blood sampling. Point estimates (90% CIs) for AUC_0-t, AUC_0-∞, and C_max based on EDI tablets were 110.07 (102.25 - 118.49), 109.90 (101.70 - 118.39), and 112.60 (101.49 - 124.85), respectively, for repaglinide. They were 95.18 (89.62 - 101.05), 95.00 (89.74 - 100.65), and 98.44 (92.72 - 104.50), respectively, for metformin. These results satisfied the bioequivalence criteria of 80.00 - 125.00% proposed by the FDA and Korean legislation. Results of pharmacokinetic analysis suggested that repaglinide and metformin in FDC tablets were bioequivalent to EDI tablets of repaglinide (2 mg) and metformin (500 mg) in healthy Korean male subjects. Both formulations appeared to be well tolerated.
.

Dutasteride plus tamsulosin fixed-dose combination first-line therapy versus tamsulosin monotherapy in the treatment of benign prostatic hyperplasia: a budget impact analysis in the Greek healthcare setting.

PubMed

Geitona, Maria; Karabela, Pinelopi; Katsoulis, Ioannis A; Kousoulakou, Hara; Lyberopoulou, Eleni; Bitros, Eleftherios; Xaplanteris, Loukas; Papanicolaou, Sotiria

2014-09-26

The purpose of this study was to explore the budget impact of dutasteride plus tamsulosin fixed-dose combination (DUT + TAM FDC) versus tamsulosin monotherapy, in the treatment of patients with benign prostatic hyperplasia (BPH) from the perspective of the Greek healthcare insurance system. A Microsoft Excel-based model was developed to estimate the financial consequences of adopting DUT + TAM FDC within the Greek healthcare setting. The model, compared six mutually exclusive health states in two alternative treatment options: current standard of care and the introduction of DUT + TAM FDC in the market. The model used clinical inputs from the CombAT study; data on resource use associated with the management of BPH in Greece were derived from expert panel, and unit cost data were derived from official reimbursement tariffs. A payer perspective was taken into account. As patient distribution data between public and private sectors are not available in Greece two scenarios were investigated, considering the whole eligible population in each scenario. A 4 year time horizon was taken into account and included treatment costs, number of transurethral resections of the prostate (TURPs) and acute urinary retention (AUR) episodes avoided. The clinical benefit from the market adoption of DUT + TAM FDC in Greece was 1,758 TURPs and 972 episodes of AUR avoided cumulatively in a four year period. The increase in total costs from the gradual introduction of DUT + TAM FDC to the Greek healthcare system ranges from €1.3 million in the first year to €5.8 million in the fourth year, for the public sector, and €1.2 million to €4.0 million, for the private sector. This represents an increase of 1.91% to 7.94% for the public sector and 1.10% 3.29% in the private sector, during the 4-year time horizon. Budget impact analysis (BIA) results indicated that the gradual introduction of DUT + TAM FDC, would increase the overall budget of the disease, however providing better clinical outcomes. DUT + TAM FDC drug acquisition cost is partly offset by the reduction in the costs associated with the treatment of the disease.

Development of an enhanced health-economic model and cost-effectiveness analysis of tiotropium + olodaterol Respimat® fixed-dose combination for chronic obstructive pulmonary disease patients in Italy.

PubMed

Selya-Hammer, Carl; Gonzalez-Rojas Guix, Nuria; Baldwin, Michael; Ternouth, Andrew; Miravitlles, Marc; Rutten-van Mölken, Maureen; Goosens, Lucas M A; Buyukkaramikli, Nasuh; Acciai, Valentina

2016-10-01

The objective of this study was to compare the cost-effectiveness of the fixed-dose combination (FDC) of tiotropium + olodaterol Respimat(®) FDC with tiotropium alone for patients with chronic obstructive pulmonary disease (COPD) in the Italian health care setting using a newly developed patient-level Markov model that reflects the current understanding of the disease. While previously published models have largely been based around a cohort approach using a Markov structure and GOLD stage stratification, an individual-level Markov approach was selected for the new model. Using patient-level data from the twin TOnado trials assessing Tiotropium + olodaterol Respimat(®) FDC versus tiotropium, outcomes were modelled based on the trough forced expiratory volume (tFEV1) of over 1000 patients in each treatment arm, tracked individually at trial visits through the 52-week trial period, and after the trial period it was assumed to decline at a constant rate based on disease stage. Exacerbation risk was estimated based on a random-effects logistic regression analysis of exacerbations in UPLIFT. Mortality by age and disease stage was estimated from an analysis of TIOSPIR trial data. Cost of bronchodilators and other medications, routine management, and costs of treatment for moderate and severe exacerbations for the Italian setting were included. A cost-effectiveness analysis was conducted over a 15-year time horizon from the perspective of the Italian National Health Service. Aggregating total costs and quality-adjusted life years (QALYs) for each treatment cohort over 15 years and comparing tiotropium + olodaterol Respimat(®) FDC with tiotropium alone, resulted in mean incremental costs per patient of €1167 and an incremental cost-effectiveness ratio (ICER) of €7518 per additional QALY with tiotropium + olodaterol Respimat(®) FDC. The lung function outcomes observed for tiotropium + olodaterol Respimat(®) FDC in TOnado drove the results in terms of slightly higher mean life-years (12.24 versus 12.07) exacerbation-free months (11.36 versus 11.32) per patient and slightly fewer moderate and severe exacerbations per patient-year (0.411 versus 0.415; 0.21 versus 0.24) versus tiotropium. Probabilistic sensitivity analyses showed tiotropium + olodaterol Respimat(®) FDC to be the more cost-effective treatment in 95.2% and 98.4% of 500 simulations at thresholds of €20,000 and €30,000 per QALY respectively. Tiotropium + olodaterol Respimat(®) FDC is a cost-effective bronchodilator in the maintenance treatment of COPD for the Italian health care system. © The Author(s), 2016.

Comparative effect on platelet function of a fixed-dose aspirin and clopidogrel combination versus separate formulations in patients with coronary artery disease: A phase IV, multicenter, prospective, 4-week non-inferiority trial.

PubMed

Oh, Pyung Chun; Ahn, Taehoon; Kim, Dong Woon; Hong, Bum-Kee; Kim, Dong-Soo; Kwan, Jun; Choi, Cheol Ung; Yang, Yong-Mo; Bae, Jang Ho; Jung, Kyung Tae; Choi, Woong Gil; Jeon, Dong Woon; Cho, Deok Kyu; Pyun, Wook Bum; Cha, Kwang Soo; Cha, Tae-Joon; Chun, Kook Jin; Kim, Young Dae; Kim, Byung Soo; Kim, Doo-Il; Kim, Tae Ik

2016-01-01

The effect of aspirin and clopidogrel in a fixed-dose combination (FDC) on platelet function was compared with separate formulations in patients that had undergone percutaneous coronary intervention (PCI) with drug-eluting stent (DES). This was a phase IV, prospective, multicenter, single-arm, non-inferiority study. Patients that had taken aspirin 100 mg and clopidogrel 75 mg once daily as separate formulations for >6 months after PCI with DES were enrolled, and then switched to an aspirin/clopidogrel FDC once-daily for 4 weeks. Platelet reactivity was determined using the VerifyNow® P2Y12 assay at baseline (immediately prior to switching) and 4 weeks later. A total of 648 patients (the full-analysis population; age, 63.6±9.0 years; male, 76.5%) finished the study, and 565 (the per-protocol population) completed without protocol violations. In the per-protocol population, the % inhibitions of P2Y12 and ARU were not significantly different between baseline and after 4 weeks of FDC treatment (29.2±20.0% to 29.0±19.9%, P=0.708; 445.1±69.2 to 446.2±63.0, P=0.799, respectively) and the difference in P2Y12 inhibition observed did not exceed the predetermined limit of non-inferiority (95% CI, -0.9 to 1.3). In the full-analysis population, the % inhibitions of P2Y12, PRU, and ARU were not significantly changed after 4 weeks of FDC treatment. This study demonstrates that the efficacy of platelet inhibition by an aspirin/clopidogrel FDC was not inferior to that of separate aspirin and clopidogrel formulations in patients that had undergone PCI with DES. Copyright © 2015. Published by Elsevier Ireland Ltd.

Efficacy and Safety of Fixed-dose Combination Therapy With Telmisartan and Rosuvastatin in Korean Patients With Hypertension and Dyslipidemia: TELSTA-YU (TELmisartan-rosuvaSTAtin from YUhan), a Multicenter, Randomized, 4-arm, Double-blind, Placebo-controlled, Phase III Study.

PubMed

Oh, Gyu Chul; Han, Jung-Kyu; Han, Ki Hoon; Hyon, Min-Su; Doh, Joon Hyung; Kim, Moo Hyun; Jeong, Jin-Ok; Bae, Jang-Ho; Kim, Sang Hyun; Yoo, Byung-Su; Baek, Sang Hong; Rhee, Moo-Yong; Ihm, Sang-Hyun; Sung, Jung Hoon; Choi, Young Jin; Kim, Soo-Joong; Hong, Kyung-Soon; Lee, Byoung Kwon; Cho, JangHyun; Shin, Eun Seok; Rhew, Jay Young; Kim, Hyunsu; Kim, Hyo-Soo

2018-05-01

Hypertension and dyslipidemia are 2 risk factors of cardiovascular disease that often present simultaneously. Traditionally, treatment of these multiple conditions required separate medications for each disease, which may result in poor compliance and thus lead to possible treatment failure. Fixed-dose combination (FDC) therapy with a single pill may be a solution in these situations. This multicenter, 8-week, randomized, double-blind, Phase III study evaluated the efficacy and safety of FDC treatment with telmisartan (80 mg) and rosuvastatin calcium (20 mg) in Korean patients with mild to moderate hypertension and dyslipidemia. Patients were randomly assigned to 4 groups: (1) FDC drug (80 mg of telmisartan and 20 mg of rosuvastatin); (2) 80 mg of telmisartan; (3) 20 mg of rosuvastatin; or (4) placebo. After 8 weeks of treatment, the change in mean sitting systolic blood pressure (MSSBP) and mean sitting diastolic blood pressure (MSDBP) between the FDC group and the rosuvastatin group, and the percent change in LDL-C between the FDC group and the telmisartan group, were compared. A total of 210 patients were enrolled in the study (84 in the FDC group, 42 in the rosuvastatin group, 43 in the telmisartan group, and 41 in the placebo group). The reduction in blood pressure was significantly greater in the FDC group than in the rosuvastatin group after 8 weeks of treatment (least squares mean change from baseline, -16.1 [1.6] mm Hg vs -1.7 [2.2] mm Hg [P < 0.001] for MSSBP; -8.8 [1.0] mm Hg vs -1.6 [1.4] mm Hg [P < 0.001] for MSDBP). Least squares mean percent change in LDL-C from baseline was also significantly greater in the FDC group compared with the telmisartan group (-49.3% [2.2%] vs 1.5% [3.0%]; P < 0.001). FDC therapy also had a higher rate of achieving the treatment goal in both blood pressure (60% vs 45%; P = 0.024) and LDL-C (88.8% vs 16.3%; P < 0.001) compared with rosuvastatin or telmisartan alone, respectively. In regression analysis, higher baseline MSSBP, female sex, and lower body mass index were associated with increased reductions in MSSBP, whereas higher baseline LDL-C level and lower body mass index were associated with greater reductions in LDL-C. There were 48 adverse events in 36 patients (17.3% [36 of 208]), and 17 adverse drug reactions in 12 patients (5.8% [12 of 208]), indicating no significant differences in short-term safety among study groups. Treatment with an FDC drug containing telmisartan and rosuvastatin showed similar efficacy in lowering blood pressure and LDL-C levels compared with that of each single drug. ClinicalTrials.gov identifier: NCT01914432. Copyright © 2018. Published by Elsevier Inc.

Cost-effectiveness and budget impact of the fixed-dose dual bronchodilator combination tiotropium–olodaterol for patients with COPD in the Netherlands

PubMed Central

van Boven, Job FM; Kocks, Janwillem WH; Postma, Maarten J

2016-01-01

Purpose The fixed-dose dual bronchodilator combination (FDC) of tiotropium and olodaterol showed increased effectiveness regarding lung function and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with the use of its mono-components. Yet, while effectiveness and safety have been shown, the health economic implication of this treatment is still unknown. The aim of this study was to assess the cost–utility and budget impact of tiotropium–olodaterol FDC in patients with moderate to very severe COPD in the Netherlands. Patients and methods A cost–utility study was performed, using an individual-level Markov model. To populate the model, individual patient-level data (age, height, sex, COPD duration, baseline forced expiratory volume in 1 second) were obtained from the tiotropium–olodaterol TOnado trial. In the model, forced expiratory volume in 1 second and patient-level data were extrapolated to utility and survival, and treatment with tiotropium–olodaterol FDC was compared with tiotropium. Cost–utility analysis was performed from the Dutch health care payer’s perspective using a 15-year time horizon in the base-case analysis. The standard Dutch discount rates were applied (costs: 4.0%; effects: 1.5%). Both univariate and probabilistic sensitivity analyses were performed. Budget impact was annually assessed over a 5-year time horizon, taking into account different levels of medication adherence. Results As a result of cost increases, combined with quality-adjusted life-year (QALY) gains, results showed that tiotropium–olodaterol FDC had an incremental cost-effectiveness ratio of €7,004/QALY. Without discounting, the incremental cost-effectiveness ratio was €5,981/QALY. Results were robust in univariate and probabilistic sensitivity analyses. Budget impact was estimated at €4.3 million over 5 years assuming 100% medication adherence. Scenarios with 40%, 60%, and 80% adherence resulted in lower 5-year incremental cost increases of €1.7, €2.6, and €3.4 million, respectively. Conclusion Tiotropium–olodaterol FDC can be considered a cost-effective treatment under current Dutch cost-effectiveness thresholds. PMID:27703341

Cost-effectiveness and budget impact of the fixed-dose dual bronchodilator combination tiotropium-olodaterol for patients with COPD in the Netherlands.

PubMed

van Boven, Job Fm; Kocks, Janwillem Wh; Postma, Maarten J

2016-01-01

The fixed-dose dual bronchodilator combination (FDC) of tiotropium and olodaterol showed increased effectiveness regarding lung function and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with the use of its mono-components. Yet, while effectiveness and safety have been shown, the health economic implication of this treatment is still unknown. The aim of this study was to assess the cost-utility and budget impact of tiotropium-olodaterol FDC in patients with moderate to very severe COPD in the Netherlands. A cost-utility study was performed, using an individual-level Markov model. To populate the model, individual patient-level data (age, height, sex, COPD duration, baseline forced expiratory volume in 1 second) were obtained from the tiotropium-olodaterol TOnado trial. In the model, forced expiratory volume in 1 second and patient-level data were extrapolated to utility and survival, and treatment with tiotropium-olodaterol FDC was compared with tiotropium. Cost-utility analysis was performed from the Dutch health care payer's perspective using a 15-year time horizon in the base-case analysis. The standard Dutch discount rates were applied (costs: 4.0%; effects: 1.5%). Both univariate and probabilistic sensitivity analyses were performed. Budget impact was annually assessed over a 5-year time horizon, taking into account different levels of medication adherence. As a result of cost increases, combined with quality-adjusted life-year (QALY) gains, results showed that tiotropium-olodaterol FDC had an incremental cost-effectiveness ratio of €7,004/QALY. Without discounting, the incremental cost-effectiveness ratio was €5,981/QALY. Results were robust in univariate and probabilistic sensitivity analyses. Budget impact was estimated at €4.3 million over 5 years assuming 100% medication adherence. Scenarios with 40%, 60%, and 80% adherence resulted in lower 5-year incremental cost increases of €1.7, €2.6, and €3.4 million, respectively. Tiotropium-olodaterol FDC can be considered a cost-effective treatment under current Dutch cost-effectiveness thresholds.

Comparison of Pharmacokinetics and Safety of a Fixed-dose Combination of Rosuvastatin and Ezetimibe Versus Separate Tablets in Healthy Subjects.

PubMed

Min, Kyoung Lok; Park, Min Soo; Jung, Jina; Chang, Min Jung; Kim, Choon Ok

2017-09-01

Rosuvastatin and ezetimibe are concomitantly used for dyslipidemia treatment. Compared with separate tablets, fixed-dose combination (FDC) tablets of rosuvastatin/ezetimibe could increase patient compliance. The aim of this study was to compare the pharmacokinetic (PK) profiles of an FDC tablet of rosuvastatin/ezetimibe and co-administration of rosuvastatin and ezetimibe as separate tablets in healthy Korean volunteers. This trial was a randomized, open-label, single-dose, 2-way crossover study. The healthy subjects received an FDC tablet of rosuvastatin 20 mg/ezetimibe 10 mg (test) or co-administration of rosuvastatin 20 mg and ezetimibe 10 mg (reference) in each period (periods 1 and 2), with a 14-day washout period. The blood samples for PK analysis were collected predose and up to 96 hours after administration, and safety was assessed throughout the study. Sixty-four healthy Korean subjects were enrolled, and 57 subjects completed the study. All subjects were men and mean age was 28.52 ± 5.93. The geometric least squares mean ratios (test/reference) and 90% CIs of C max and AUC 0-last were 101.54% (94.03-109.65) and 97.71% (91.86-103.93) for rosuvastatin, 108.93% (98.55-120.40) and 102.90% (96.72-109.47) for free ezetimibe, and 106.74% (98.18-116.05) and 104.24 % (99.53-109.17) for total ezetimibe. Twenty-four adverse events (AEs) were reported in 22 subjects. Three cases were related to the study drugs; 2 cases were mild, and 1 case was severe. However, all AEs were resolved without any sequelae. In addition, there were no serious AEs throughout the study. The FDC tablet of rosuvastatin/ezetimibe was well tolerated and resulted in comparable systemic exposure with co-administration of rosuvastatin and ezetimibe. ClinicalTrials.gov identifier: NCT02941848. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

A retrospective study of treatment persistence and adherence to α-blocker plus antimuscarinic combination therapies, in men with LUTS/BPH in the Netherlands.

PubMed

Drake, Marcus J; Bowditch, Sally; Arbe, Emilio; Hakimi, Zalmai; Guelfucci, Florent; Amri, Ikbel; Nazir, Jameel

2017-05-22

To assess treatment persistence and adherence in men ≥45 years of age with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), using prescription records from the Netherlands IMS Lifelink™ LRx database. In this retrospective, observational cohort study, we identified men who received combination therapy with an α-blocker plus an antimuscarinic (e.g. solifenacin or tolterodine) between 1 November 2013 and 31 October 2014. Treatment could be received as a fixed-dose combination (FDC) tablet or as two drugs administered together (concomitant therapy), if both combination drugs were prescribed within 30 days. The primary objective was to assess treatment persistence, defined as the time from initiation of combination therapy until first discontinuation of the FDC or at least one of the drugs given concomitantly (i.e. ≥30 days without prescription renewal). Subgroup and sensitivity analyses were conducted to assess persistence by antimuscarinic agent, and with different gap lengths used to define discontinuation (45, 60 and 90 days), respectively. A total of 1891 men received an α-blocker plus an antimuscarinic (FDC, N = 665; concomitant therapy, N = 1226). Median time to discontinuation was significantly longer with FDC versus concomitant therapy (414 vs. 112 days; adjusted hazard ratio [HR] 2.04, 95% confidence interval 1.77, 2.35; p < 0.0001). Persistence at 12 months (51.3% vs. 29.9%) was also significantly greater with FDC compared with concomitant therapy. Assessment of antimuscarinic subgroups showed that median time to discontinuation was longest with solifenacin combinations (214 days) compared with other antimuscarinic combinations (range, 47-164 days; adjusted HR range, 1.27-1.77, p = 0.037). No observable impact on treatment persistence was found by adjusting the gaps used to define discontinuation. This study of real-world evidence of men with LUTS/BPH treated with α-blocker plus antimuscarinic combination therapy in the Netherlands showed that treatment persistence was significantly greater in those who received a FDC tablet compared with combination therapy given concomitantly. The study also shows that treatment persistence was extended in men who received combination therapy containing solifenacin compared with other antimuscarinics. Overall, these findings may be useful for prescribers, as improved persistence on-treatment may translate into improved outcomes for men with LUTS/BPH. Further study is warranted to establish the key drivers of persistence in men receiving combination therapy for LUTS/BPH.

The background and rationale for a new fixed-dose combination for first-line treatment of tuberculosis in children.

PubMed

Graham, S M; Grzemska, M; Gie, R P

2015-12-01

In 2010, the World Health Organization revised the recommendations for the treatment of tuberculosis (TB) in children. The major revision was to increase isoniazid, rifampicin and pyrazinamide dosages according to body weight in children. The recommendations for higher dosages are based on consistent evidence from 1) pharmacokinetic studies suggesting that young children require higher dosages than adolescents and adults to achieve desired serum concentrations; and 2) observational studies reporting that the higher dosages would not be associated with increased risk of toxicity in children. However, national tuberculosis programmes faced unforeseen challenges in implementing the revised recommendations. The main difficulty was to adapt the revised dosages for the treatment of children with drug-susceptible TB using available fixed-dose combinations (FDCs). A more suitable FDC for the intensive and continuation phases of treatment has now been developed for planned implementation in 2015. This paper explains the background and rationale for the development of a new FDC tablet for children with drug-susceptible TB.

Asthma control in patients on fixed dose combination evaluated with mannitol challenge test.

PubMed

Romberg, Kerstin A M; Berggren, Anna-Carin; Bjermer, Leif

2014-02-01

Asthma is often difficult to control and it is likely that not all patients are optimally treated. This study aimed to explore asthma control in adults receiving fixed dose combination (FDC) therapy. Control of asthma was assessed using the mannitol challenge test as a monitoring tool to see if this would give additional information compared to the asthma control test (ACT). The study was an open-label, prospective study on 98 adults prescribed with FDC therapies for at least three months. 74 patients considered that their asthma was well controlled. However, 60 patients had a positive mannitol challenge test (PD15 < 635 mg), and when those with a positive response to the short-acting β2-agonist (≥15%) after the mannitol challenge test were included, this increased to 64 patients (65%). Exploratory analysis determined that the spirometry parameters; FEV1/FVC and FEV1% of predicted, were statistically significant predictors of a positive mannitol challenge test. Co-morbid conditions such as concomitant upper airway involvement or eczema did not predict mannitol reactivity. Although most patients rated their asthma as well controlled, many provided a positive mannitol challenge test, suggesting the presence of underlying inflammation, despite treatment with fixed dose combination therapy. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Incidence of oral thrush in patients with COPD prescribed inhaled corticosteroids: Effect of drug, dose, and device.

PubMed

Dekhuijzen, P N Richard; Batsiou, Maria; Bjermer, Leif; Bosnic-Anticevich, Sinthia; Chrystyn, Henry; Papi, Alberto; Rodríguez-Roisin, Roberto; Fletcher, Monica; Wood, Lucy; Cifra, Alessandra; Soriano, Joan B; Price, David B

2016-11-01

Little information is available on real-life occurrence of oral thrush in COPD patients treated with ICS. We investigated oral thrush incidence in COPD patients prescribed FDC ICS/LABA therapies and assessed whether it is modulated by the ICS type, dose, and delivery device. We conducted a historical, observational, matched cohort study (one baseline year before and one outcome year after initiation of therapy) using data from the UK Optimum Patient Care Research Database. We assessed oral thrush incidence in patients initiating long-acting bronchodilators or FDC ICS/LABA therapy. We then compared different combination therapies (budesonide/formoterol fumarate dihydrate [BUD/FOR] and fluticasone propionate/salmeterol xinafoate [FP/SAL]) and devices (DPI and pMDI). Patients prescribed FDC ICS/LABA had significantly greater odds of experiencing oral thrush than those prescribed long-acting bronchodilators alone (adjusted OR 2.18 [95% CI 1.84-2.59]). Significantly fewer patients prescribed BUD/FOR DPI developed oral thrush compared with FP/SAL DPI (OR 0.77 [0.63-0.94]) when allowing for differences in prescribed doses between the drugs. A significantly smaller proportion of patients developed oral thrush in the FP/SAL pMDI arm than in the FP/SAL DPI arm (OR 0.67 [0.55-0.82]). Additionally, in the FP/SAL cohort (both DPI and pMDI), increased risk of oral thrush was significantly associated with high ICS daily dose (OR 1.97 [1.22-3.17] vs low daily dose). ICS use increases oral thrush incidence in COPD and this effect is dose-dependent for FP/SAL therapies. Of the therapies assessed, FP/SAL pMDI and BUD/FOR DPI may be more protective against oral thrush. Copyright © 2016 Elsevier Ltd. All rights reserved.

Assessment of bioequivalence of rifampicin, isoniazid and pyrazinamide in a four drug fixed dose combination with separate formulations at the same dose levels.

PubMed

Agrawal, Shrutidevi; Kaur, Kanwal Jit; Singh, Inderjit; Bhade, Shantaram R; Kaul, Chaman Lal; Panchagnula, Ramesh

2002-02-21

Tuberculosis (TB) needs treatment with three to five different drugs simultaneously, depending on the patient category. These drugs can be given as single drug preparations or fixed dose combinations (FDCs) of two more drugs in a single formulation. World Health Organization and International Union against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. The relative bioavailability of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PYZ) was assessed on a group of 13 healthy male subjects from a four drug FDC versus separate formulations at the same dose levels. The study was designed to be an open, crossover experiment. A total of nine blood samples each of 3 ml volume were collected over a period of 24-h. The concentrations of RIF, its main metabolite desacetyl RIF (DRIF), INH and PYZ in plasma were assessed by HPLC analysis. Pharmacokinetic parameters namely AUC(0-24), AUC(0-inf), C(max), T(max), were calculated and subjected to different statistical tests (Hauschke analysis, two way ANOVA, normal and log transformed confidence interval) at 90% confidence interval. In addition, elimination rate constant (K(el)) and absorption efficiencies for each drug were also calculated. It was concluded that four drugs FDC tablet is bioequivalent for RIF, INH and PYZ to separate formulation at the same dose levels.

Long-term safety and efficacy of single-tablet combinations of solifenacin and tamsulosin oral controlled absorption system in men with storage and voiding lower urinary tract symptoms: results from the NEPTUNE Study and NEPTUNE II open-label extension.

PubMed

Drake, Marcus J; Chapple, Christopher; Sokol, Roman; Oelke, Matthias; Traudtner, Klaudia; Klaver, Monique; Drogendijk, Ted; Van Kerrebroeck, Philip

2015-02-01

Short-term trials have demonstrated the efficacy and safety of combination therapy using antimuscarinics and α-blockers in men with lower urinary tract symptoms (LUTS). The Study of Solifenacin Succinate and Tamsulosin Hydrochloride OCAS (oral controlled absorption system) in Males with Lower Urinary Tract Symptoms (NEPTUNE) II is the first long-term study using solifenacin (Soli) and the oral controlled absorption system formulation of tamsulosin (TOCAS). To evaluate long-term (up to 52 wk) safety and efficacy of flexible dosing of two fixed-dose combinations (FDC) of Soli plus TOCAS in men with moderate to severe storage symptoms and voiding symptoms. Patients with both storage and voiding LUTS, maximum urinary flow rate of 4.0-12.0 ml/s, prostate size <75 ml, and postvoid residuals ≤ 150 ml, who completed the 12-wk, double-blind NEPTUNE study could continue in the 40-wk, open-label NEPTUNE II study. FDC of Soli 6 mg plus TOCAS 0.4 mg, or Soli 9 mg plus TOCAS 0.4mg; patients could switch between doses in NEPTUNE II. Safety and efficacy data from NEPTUNE and NEPTUNE II were combined to cover a 52-wk period. Primary efficacy end points were total International Prostate Symptom Score (IPSS) and total urgency and frequency score (TUFS); secondary end points included IPSS storage and voiding subscores, micturition diary variables, and quality of life parameters. In all, 1066 men completed NEPTUNE and received one dose or more of study medication in NEPTUNE II. Treatment-emergent adverse events were reported in 499 (46.8%) patients who participated in NEPTUNE II; most were mild or moderate. Urinary retention occurred in 13 of 1208 (1.1%) patients receiving one or more FDCs in NEPTUNE and/or NEPTUNE II; 8 (0.7%) required catheterisation (acute urinary retention [AUR]). Reductions in total IPSS and TUFS during NEPTUNE were maintained for up to 52 wk of FDC treatment, with mean reductions of 9.0 (standard deviation [SD]: 5.7) and 10.1 (SD: 9.2), respectively, from baseline to end of treatment. Clinically relevant improvements were also observed for secondary efficacy end points. Long-term treatment with FDC Soli plus TOCAS was well tolerated and efficacious in men with storage and voiding LUTS, with a low incidence of AUR. Treatment with solifenacin plus tamsulosin in a fixed-dose combination tablet was well tolerated by men with lower urinary tract symptoms. Improvements in symptoms were achieved after 4 wk of treatment, with further improvements at week 16 maintained for up to 52 wk throughout the study. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Long-Acting β-Agonist in Combination or Separate Inhaler as Step-Up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids.

PubMed

Turner, Steve; Richardson, Kathryn; Murray, Clare; Thomas, Mike; Hillyer, Elizabeth V; Burden, Anne; Price, David B

Adding a long-acting β 2 -agonist (LABA) to inhaled corticosteroids (ICS) using a fixed-dose combination (FDC) inhaler is the UK guideline recommendation for children aged more than 4 years with uncontrolled asthma. The evidence of benefit of adding an FDC inhaler over a separate LABA inhaler is limited. The objective of this study was to compare the effectiveness of a LABA added as an FDC inhaler, and as a separate inhaler, in children with uncontrolled asthma. Two UK primary care databases were used to create a matched cohort study with a 2-year follow-up period. We included children prescribed their first step-up from ICS monotherapy. Two cohorts were formed for children receiving an add-on LABA as an FDC inhaler, or a separate LABA inhaler. Matching variables and confounders were identified by comparing characteristics during a baseline year of follow-up. Outcomes were examined during the subsequent year. The primary outcome was an adjusted odds ratio for overall asthma control (defined as follows: no asthma-related hospital admission or emergency room visit, prescription for oral corticosteroids or antibiotic with evidence of respiratory consultation, and ≤2 puffs of short-acting β-agonist daily). The final study consisted of 1330 children in each cohort (mean age 9 years; 59% male). In the separate ICS+LABA cohort, the odds of achieving overall asthma control were lower (adjusted odds ratio, 0.77 [95% confidence interval, 0.66-0.91]; P = .001) compared with the FDC cohort. The study demonstrates a small but significant benefit in achieving asthma control from an add-on LABA as an FDC, compared with a separate inhaler and this supports current guideline recommendations. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Quantitative combination of natural anti-oxidants prevents metabolic syndrome by reducing oxidative stress

PubMed Central

Gao, Mingjing; Zhao, Zhen; Lv, Pengyu; Li, YuFang; Gao, Juntao; Zhang, Michael; Zhao, Baolu

2015-01-01

Insulin resistance and abdominal obesity are present in the majority of people with the metabolic syndrome. Antioxidant therapy might be a useful strategy for type 2 diabetes and other insulin-resistant states. The combination of vitamin C (Vc) and vitamin E has synthetic scavenging effect on free radicals and inhibition effect on lipid peroxidation. However, there are few studies about how to define the best combination of more than three anti-oxidants as it is difficult or impossible to test the anti-oxidant effect of the combination of every concentration of each ingredient experimentally. Here we present a math model, which is based on the classical Hill equation to determine the best combination, called Fixed Dose Combination (FDC), of several natural anti-oxidants, including Vc, green tea polyphenols (GTP) and grape seed extract proanthocyanidin (GSEP). Then we investigated the effects of FDC on oxidative stress, blood glucose and serum lipid levels in cultured 3T3-L1 adipocytes, high fat diet (HFD)-fed rats which serve as obesity model, and KK-ay mice as diabetic model. The level of serum malondialdehyde (MDA) in the treated rats was studied and Hematoxylin-Eosin (HE) staining or Oil red slices of liver and adipose tissue in the rats were examined as well. FDC shows excellent antioxidant and anti-glycation activity by attenuating lipid peroxidation. FDC determined in this investigation can become a potential solution to reduce obesity, to improve insulin sensitivity and be beneficial for the treatment of fat and diabetic patients. It is the first time to use the math model to determine the best ratio of three anti-oxidants, which can save much more time and chemical materials than traditional experimental method. This quantitative method represents a potentially new and useful strategy to screen all possible combinations of many natural anti-oxidants, therefore may help develop novel therapeutics with the potential to ameliorate the worldwide metabolic abnormalities. PMID:26262997

3D printed, controlled release, tritherapeutic tablet matrix for advanced anti-HIV-1 drug delivery.

PubMed

Siyawamwaya, Margaret; du Toit, Lisa C; Kumar, Pradeep; Choonara, Yahya E; Kondiah, Pierre P P D; Pillay, Viness

2018-04-12

A 3D-Bioplotter® was employed to 3D print (3DP) a humic acid-polyquaternium 10 (HA-PQ10) controlled release fixed dose combination (FDC) tablet comprising of the anti-HIV-1 drugs, efavirenz (EFV), tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). Chemical interactions, surface morphology and mechanical strength of the FDC were ascertained. In vitro drug release studies were conducted in biorelevant media followed by in vivo study in the large white pigs, in comparison with a market formulation, Atripla®. In vitro-in vivo correlation of results was undertaken. EFV, TDF and FTC were successfully entrapped in the 24-layered rectangular prism-shaped 3DP FDC with a loading of ∼12.5 mg/6.3 mg/4 mg of EFV/TDF/FTC respectively per printed layer. Hydrogen bonding between the EFV/TDF/FTC and HA-PQ10 was detected which was indicative of possible drug solubility enhancement. The overall surface of the tablet exhibited a fibrilla structure and the 90° inner pattern was determined to be optimal for 3DP of the FDC. In vitro and in vivo drug release profiles from the 3DP FDC demonstrated that intestinal-targeted and controlled drug release was achieved. A 3DP FDC was successfully manufactured with the aid of a 3D-Bioplotter in a single step process. The versatile HA-PQ10 entrapped all drugs and achieved an enhanced relative bioavailability of EFV, TDF, and FTC compared to the market formulation for potentially enhanced HIV treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Effectiveness and safety of fixed dose combination of acarbose/metformin in Indian Type 2 diabetes patients: Results from observational GLOBE Study

PubMed Central

Saboo, Banshi; Reddy, Gundam Chandrasekhara; Juneja, Subhashchander; Kedia, Ashok Kumar; Manjrekar, Pravin; Rathod, Rahul

2015-01-01

Primary objective - evaluate effectiveness and safety of acarbose/metformin fixed dose FDC on glycemic control in Indian T2DM patients in real life clinical setting. Secondary objective - evaluate safety and satisfaction of treatment. Materials and Methods: Open-label, prospective, multicentre, single-arm, non-interventional study. Patients included were aged ≥18 years with T2DM on Acarbose (25/50 mg) and Metformin (500 mg) FDC. Glycemic parameters were recorded during observation. Results: Total 9364 patients were enrolled in the study (mean age, 50.7 years and 60.1% were male). Mean (SD) FBG and PPG was significantly reduced by 42.4 (32.6) mg/dl (P < 0.0001) and 80.2 (49.7) mg/dl (P < 0.0001) respectively at the end of observation. Mean (SD) HbA1c reduced by -1.0% (0.8) to 7.3% (0.7) at the last follow-up visit (P <0.0001). Majority of patients (97.5%) and physicians (98.42%) were satisfied with acarbose/metformin FDC treatment. Also, significant reduction in body weight by -1.7 (2.2) kg was observed (P < 0.0001). Patients with known T2DM and newly diagnosed showed a similar glycemic control (P < 0.0001). Drug-related adverse events were reported by only 1.4% patients mostly gastrointestinal. Conclusions: Acarbose/metformin FDC was efficacious, safe well accepted in routine clinical practice. It was well-tolerated without significant risk of hypoglycemia and can be used in early T2DM management PMID:25593840

An 18-week, prospective, randomized, double-blind, multicenter study of amlodipine/ramipril combination versus amlodipine monotherapy in the treatment of hypertension: the assessment of combination therapy of amlodipine/ramipril (ATAR) study.

PubMed

Miranda, Roberto Dischinger; Mion, Décio; Rocha, Joăo Carlos; Kohlmann, Oswaldo; Gomes, Marco Antonio Mota; Saraiva, José Francisco Kerr; Amodeo, Celso; Filho, Bráulio Luna

2008-09-01

A combination of antihypertensive agents of different drug classes in a fixed-dose combination (FDC) may offer advantages in terms of efficacy, tolerability, and treatment compliance. Combination of a calcium channel blocker with an angiotensin-converting enzyme inhibitor may act synergistically to reduce blood pressure (BP). The aim of this study was to compare the efficacy and tolerability of an amlodipine/ramipril FDC with those of amlodipine monotherapy. This 18-week, prospective, randomized, double-blind study was conducted at 8 centers across Brazil. Patients with stage 1 or 2 essential hypertension were enrolled. After a 2-week placebo run-in phase, patients received amlodipine/ramipril 2.5/2.5 mg or amlodipine 2.5 mg, after which the doses were titrated, based on BP, to 5/5 then 10/10 mg (amlodipine/ramipril) and 5 then 10 mg (amlodipine). The primary end point was BP measured in the intent-to-treat (ITT) population. Hematology and serum biochemistry were assessed at baseline and study end. Tolerability was assessed using patient interview, laboratory analysis, and physical examination, including measurement of ankle circumference to assess peripheral edema. A total of 222 patients completed the study (age range, 40-79 years; FDC group, 117 patients [mean dose, 7.60/7.60 mg]; monotherapy, 105 patients [mean dose, 7.97 mg]). The mean (SD) changes in systolic BP (SBP) and diastolic BP (DBP), as measured using 24-hour ambulatory blood pressure monitoring (ABPM) and in the physician's office, were significantly greater with combination therapy than monotherapy, with the exception of office DBP (ABPM, -20.76 [1.25] vs -15.80 [1.18] mm Hg and -11.71 [0.78] vs -8.61 [0.74] mm Hg, respectively [both, P = 0.004]; office, -27.51 [1.40] vs -22.84 [1.33] mm Hg [P = 0.012] and -16.41 [0.79] vs -14.64 [0.75] mm Hg [P = NS], respectively). In the ITT analysis, the mean changes in ambulatory, but not office-based, BP were statistically significant (ABPM: SBP, -20.21 [1.14] vs -15.31 [1.12] mm Hg and DBP, -11.61 [0.72] vs -8.42 [0.70] mm Hg, respectively [both, P = 0.002]; office: SBP, -26.60 [1.34] vs -22.97 [1.30] mm Hg and DBP, -16.48 [0.78] vs -14.48 [0.75] mm Hg [both, P = NS]). Twenty-nine patients (22.1%) treated with combination therapy and 41 patients (30.6%) treated with monotherapy experienced > or =1 adverse event considered possibly related to study drug. The combination-therapy group had lower prevalence of edema (7.6% vs 18.7%; P = 0.011) and a similar prevalence of dry cough (3.8% vs 0.8%; P = NS). No clinically significant changes in laboratory values were found in either group. In this population of patients with essential hypertension, the amlodipine/ramipril FDC was associated with significantly reduced ambulatory and office-measured BP compared with amlodipine monotherapy, with the exception of office DBP. Both treatments were well tolerated.

Quality control of anti-tuberculosis FDC formulations in the global market: part II-accelerated stability studies.

PubMed

Ashokraj, Y; Kohli, G; Kaul, C L; Panchagnula, R

2005-11-01

To determine the quality and performance of rifampicin (RMP) containing fixed-dose combination (FDC) formulations of anti-tuberculosis drugs sourced from the international market with respect to physical, chemical and dissolution properties after storage at accelerated stability conditions (40 degrees C/75% relative humidity) and to identify appropriate storage specifications. Formulations across different companies and combinations were subjected to 6-month accelerated stability testing in packaging conditions recommended by the manufacturer. Various pharmacopeial and nonpharmacopeial tests for tablets were performed for 3- and 6-month samples. All the formulations were found to be stable, where extent of dissolution was within +/- 10% of that of the initial value, and all formulations passed the pharmacopeial limits for assay and content uniformity of 90-110% and +/- 15% of average drug content, respectively. Good quality RMP-containing FDCs that remain stable after 6-month accelerated stability testing are available in the marketplace.

Aclidinium bromide plus formoterol for the treatment of chronic obstructive pulmonary disease.

PubMed

Lal, Chitra; Strange, Charlie

2015-02-01

Drugs that target dynamic hyperinflation such as long-acting β-2 agonists and long-acting antimuscarinic antagonists form a cornerstone of chronic obstructive pulmonary disease (COPD) management. The idea of combining these two medications in a single formulation, which may potentially improve patient compliance, is novel and attractive. The pharmacologic profiles of aclidinium bromide and formoterol fumarate are discussed. However, studies to define drug interactions and alterations in the pharmacodynamics and pharmacokinetics of the fixed dose combination (FDC) of aclidinium bromide/formoterol fumarate in large populations remain unpublished. Results of Phase II and two Phase III pivotal trials, ACLIFORM/COPD and AUGMENT COPD, evaluating the FDC are discussed. Initial data for the aclidinium/formoterol inhaler appears to be promising for impacting the lung function. To define if this benefit translates into improved long-term outcomes of decreased exacerbation frequency, improved quality of life and decreased disease-specific mortality are important. The introduction of this combination will likely have a significant impact on the prescribing habits of physicians across the world.

Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension.

PubMed

Sander, Gary E; Fernandez, Camilo; Giles, Thomas D

2016-01-01

Recent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact "lower is better," with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of β-blockers and renin-angiotensin-aldosterone system inhibitors have previously been deemed "less effective," based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating β1-selective blocker and β3- adrenoceptor agonist; β3-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other β-blockers, and will further support the pharmacological advantages of this particular combination.

Efficacy and Safety of ‘Fixed Dose’ versus ‘Loose’ Drug Regimens for Treatment of Pulmonary Tuberculosis in Two High TB-Burden African Countries: A Randomized Controlled Trial

PubMed Central

2016-01-01

Background There are limited data on the performance of the use of fixed-dose combination (FDC) TB drugs when used under programmatic settings in high TB-endemic countries. We evaluated the efficacy and safety of FDC versus loose formulation (LF) TB treatment regimens for treatment of pulmonary TB (PTB) in the context of actual medical practice in prevailing conditions within programmatic settings in five sites in two high TB-burden African countries. Methods A two-arm, single-blind, randomized clinical trial comparing FDCs with separate LFs involving 1000 adults newly diagnosed with culture positive PTB was conducted at five sites in two African countries between 2007 and 2011. Participants were randomized to receive daily treatment with anti-TB drugs given as either FDC or separate LFs for 24 weeks (intensive phase– 8 weeks of isoniazid, rifampicin, ethambutol and pyrazinamide; continuation phase– 16 weeks of rifampicin and isoniazid). Primary outcome measures were microbiological cure and safety at the end of six months’ treatment; pre-specified non-inferiority margin for difference in cure rate was 4%. The primary efficacy analysis was based on the modified intent to treat (mITT) cohort comprising all randomized patients with a positive baseline culture result for TB and who received at least one dose of study treatment. Patients missing end of treatment culture results were considered failures. Further analyses were done in which mITT patients without an end of treatment (EOT) culture were excluded in a complete case analysis (mITTcc) and a per protocol cohort analysis defined as mITTcc patients who received at least 95% of their intended doses and had an EOT culture result. Results In the mITT analysis, the cure rate in the FDC group was 86.7% (398/459) and in the LF group 85.2% (396/465) (difference 1.5-% (90% confidence interval (CI) (-2.2%– 5.3%)). Per Protocol analysis showed similar results: FDC 98.9% (359/363) versus LF 96.9% (345/356), (difference 2.0% (90% CI: 0.1%– 3.8%)). The two arms showed no significant differences in terms of safety, early culture conversion and patient adherence to treatment. Interpretation The comparison of the two drug regimens satisfied the pre-specified non-inferiority criterion. Our results support the WHO recommendations for the use of FDC in the context of actual medical practice within health services in high TB-endemic countries. Trial Registration ISRCTN Registry 95204603 PMID:27322164

What strategies to boost production of affordable fixed-dose anti-retroviral drug combinations for children in the developing world?

PubMed

Dionisio, Daniele; Gass, Robert; McDermott, Peter; Racalbuto, Vincenzo; Madeo, Marina; Braghieri, Giuseppe; Crowley, Siobhan; Pinheiro, Eloan Dos Santos; Graaff, Peter; Vasan, Ashwin; Eksaengsri, Achara; Moller, Helene; Khanna, Arun Kumar; Kraisintu, Krisana; Juneja, Sandeep; Nicolaou, Stavros; Sengupta, Aloka; Esperti, Francesco; Messeri, Daniela

2007-03-01

No more than 8% of HIV positive children needing treatment in low- and middle-income countries have access to antiretroviral drugs (ARVs). Children presently account for about 4% of all treated patients, while for equitable access they should make up at least 13%. This study explores key issues, implications and interaction dynamics to boost production of easy-to-use and affordable fixed-dose combination (FDC) ARVs for children in the developing world. Potentials for equitable solutions are examined including priority steps and actions, appropriate treatment options and reliable forecasting methods for paediatric ARVs, as well as combination incentives to generic companies against market unattractiveness and enforced intellectual property (IP) rights. Moreover, implementation strategies to enhance the development and production of affordable ARV paediatric formulations and appropriate supply systems to ensure availability are investigated. The current market for FDC paediatric ARVs is already substantial and will only grow with improved and scaled up diagnosis and monitoring of children. This provides an argument for immediate increase of production and development of FDC ARVs for children. These formulations must be low cost and included in the list of Essential Medicines to avoid children continuing to lag behind in access to treatment. Access-oriented, long-term drug policy strategies with the ability to pass muster of governments, the UN system, as well as generic and research-based enterprises are needed to let children gain expanded and sustained access to FDC ARVs. Under the requirements listed above, IP-bound Voluntary License (VL) flexibilities do appear, if coupled with substantial combination incentives to generic firms, as a fitting tool into the needs. Policies must consider enhancing human resource capacity in the area of caregivers and social and health workers aiming to spread correct information and awareness on effectiveness and rationale of FDC ARVs for children. Policies should urge that paediatric ARV treatment programmes entwine with extant interventions on prevention of mother-to-child transmission, as well as with HIV treatment initiatives focused on mothers and household members. Policies, again, should consider centralising functions and pooling resources to help overcome drug supply barriers. WHO's brokering role in VL-based agreements between wealthy and developing country industries, as well as its technical guidance in setting international standards should not be waived while looking for sustained access to optimised ARV treatments for children. Strategies discussed in this paper, while taking unavoidability of marketing and profit rules into account, look closely into the trade and drug policy directions of China and India according to frontier crossing implications of their IP management trends as well as their multi-faceted penetration strategies of both the wealthy and under-served markets the world over.

The physical and chemical stability of anti-tuberculosis fixed-dose combination products under accelerated climatic conditions.

PubMed

Bhutani, H; Mariappan, T T; Singh, S

2004-09-01

To determine the physical and chemical stability of anti-tuberculosis fixed-dose combinations (FDC) of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) sold on the Indian market. The products were stored for 3 months under ICH/WHO accelerated conditions (40 degrees C / 75% RH), with and without the original packaging in the presence and absence of light. The initial RMP, INH and PZA content was found to be within the range of 90-110% of the label claim. However, the products were found to have some chemical instability even initially; one of the tablets also showed physical instability. Under accelerated conditions, the unpackaged products underwent severe changes, whereas both physical and chemical changes were also observed in the packaged formulations. The physical changes were stronger under lighted conditions. A significant finding is that PZA and perhaps EMB may play a catalytic role in the interaction between INH and RMP. This study suggests that, unless they are packed in barrier packaging, anti-tuberculosis FDC formulations should be considered unstable, and due consideration should be given to their development pharmaceutics, packaging and stability testing.

Estimate of the global market for rifampicin-containing fixed-dose combination tablets.

PubMed

Norval, P Y; Blomberg, B; Kitler, M E; Dye, C; Spinaci, S

1999-11-01

Despite WHO and IUATLD recommendations to use fixed-dose combination (FDC) tablets for treatment of tuberculosis, more than 75% of all rifampicin used in the public sector globally is administered as single drug tablets. To estimate the potential global market for rifampicin-containing FDCs in the public and private sectors. The public sector market for FDCs was calculated from the number of tuberculosis cases notified to WHO for 1996 and from information on treatment regimens currently used in each country. The private sector market was calculated from the estimated number of treated tuberculosis cases and the treatment regimens presumed to be used in the private sector. The potential global market for the four-drug FDC tablet (rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol 275 mg) is 305 (90%CI 145-505) million tablets per year, 105 (90%CI 50-160) and 200 (90%CI 95-345) million of which would be distributed in the public and private sectors, respectively. The uncertainty of the estimate remains considerable, as shown by the 90% confidence intervals. The study demonstrated a large potential global market for FDCs that should encourage pharmaceutical manufacturers to produce WHO-recommended dosages of FDCs at affordable prices.

Efficacy and safety profile of combination of tramadol-diclofenac versus tramadol-paracetamol in patients with acute musculoskeletal conditions, postoperative pain, and acute flare of osteoarthritis and rheumatoid arthritis: a Phase III, 5-day open-label study

PubMed Central

Chandanwale, Ajay S; Sundar, Subramanian; Latchoumibady, Kaliaperumal; Biswas, Swati; Gabhane, Mukesh; Naik, Manoj; Patel, Kamlesh

2014-01-01

Objective We aimed to evaluate the safety and efficacy of a fixed-dose combination (FDC) of tramadol and diclofenac versus a standard approved FDC of tramadol and paracetamol, in patients with acute moderate to severe pain. Methods A total of 204 patients with moderate to severe pain due to acute musculoskeletal conditions (n=52), acute flare of osteoarthritis (n=52), acute flare of rheumatoid arthritis (n=50), or postoperative pain (n=50) were enrolled in the study at baseline. Each disease category was then randomized to receive either of two treatments for 5 days: group A received an FDC of immediate-release tramadol hydrochloride (50 mg) and sustained-release diclofenac sodium (75 mg) (one tablet, twice daily), and group B received an FDC of tramadol hydrochloride (37.5 mg) and paracetamol (325 mg) (two tablets every 4–6 hours, up to a maximum of eight tablets daily). The primary efficacy end points were reductions in pain intensity from baseline at day 3 and day 5 as assessed by a Visual Analog Scale (VAS) score. Results Group A showed a significant reduction in the VAS score for overall pain from baseline on day 3 (P=0.001) and day 5 (P<0.0001) as compared with group B. The combination of tramadol-diclofenac resulted in few mild to moderate adverse events (nausea, vomiting, epigastric pain, and gastritis), which required minimal management, without any treatment discontinuation. The number of adverse events in group A was nine (8.82%) compared with 22 (21.78%) in group B, after 5 days of treatment. Conclusion An FDC of tramadol-diclofenac showed a significantly greater reduction in pain intensity and was well tolerated compared with tramadol-paracetamol, resulting in better analgesia in patients suffering from moderate to severe pain due to acute musculoskeletal conditions, postoperative pain following orthopedic surgery, or acute flare of osteoarthritis and rheumatoid arthritis. PMID:25152629

SU-F-T-148: Are the Approximations in Analytic Semi-Empirical Dose Calculation Algorithms for Intensity Modulated Proton Therapy for Complex Heterogeneities of Head and Neck Clinically Significant?

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

Yepes, P; UT MD Anderson Cancer Center, Houston, TX; Titt, U

2016-06-15

Purpose: Evaluate the differences in dose distributions between the proton analytic semi-empirical dose calculation algorithm used in the clinic and Monte Carlo calculations for a sample of 50 head-and-neck (H&N) patients and estimate the potential clinical significance of the differences. Methods: A cohort of 50 H&N patients, treated at the University of Texas Cancer Center with Intensity Modulated Proton Therapy (IMPT), were selected for evaluation of clinical significance of approximations in computed dose distributions. H&N site was selected because of the highly inhomogeneous nature of the anatomy. The Fast Dose Calculator (FDC), a fast track-repeating accelerated Monte Carlo algorithm formore » proton therapy, was utilized for the calculation of dose distributions delivered during treatment plans. Because of its short processing time, FDC allows for the processing of large cohorts of patients. FDC has been validated versus GEANT4, a full Monte Carlo system and measurements in water and for inhomogeneous phantoms. A gamma-index analysis, DVHs, EUDs, and TCP and NTCPs computed using published models were utilized to evaluate the differences between the Treatment Plan System (TPS) and FDC. Results: The Monte Carlo results systematically predict lower dose delivered in the target. The observed differences can be as large as 8 Gy, and should have a clinical impact. Gamma analysis also showed significant differences between both approaches, especially for the target volumes. Conclusion: Monte Carlo calculations with fast algorithms is practical and should be considered for the clinic, at least as a treatment plan verification tool.« less

Dapagliflozin/Saxagliptin Fixed-Dose Tablets: A New Sodium-Glucose Cotransporter 2 and Dipeptidyl Peptidase 4 Combination for the Treatment of Type 2 Diabetes.

PubMed

Coppenrath, Valerie Azzopardi; Hydery, Tasmina

2018-01-01

To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of the fixed-dose combination (FDC) product, QTERN (dapagliflozin/saxagliptin) tablets. Searches of MEDLINE (1946 to July 1, 2017) were conducted using the keywords QTERN, saxagliptin, and dapagliflozin. Additional data were obtained from the prescribing information, the product dossier, and Clinicaltrials.gov . All English language articles related to pharmacology, pharmacokinetics, efficacy, or safety of the combination therapy in human subjects were reviewed. The pharmacokinetics of saxagliptin and dapagliflozin were not affected significantly when administered as an FDC product. Saxagliptin may suppress the increased secretion of glucagon associated with dapagliflozin. The combination dapagliflozin/saxagliptin has been studied as add-on therapy to metformin in patients with uncontrolled type 2 diabetes mellitus (T2DM). The difference in hemoglobin A 1C (A1C) between saxagliptin + dapagliflozin + metformin (triple therapy) and saxagliptin + metformin was -0.59 (95% CI = -0.81 to -0.37, P < 0.0001), and the difference between triple therapy and dapagliflozin + metformin was -0.27 (95% CI = -0.48 to -0.05, P = 0.0166). The combination was well tolerated when added to metformin. QTERN (dapagliflozin/saxagliptin) tablets are a reasonable option for patients with T2DM not controlled on metformin, but cost, insurance coverage, and a lackluster reduction in A1C will likely limit its use until more data regarding its effects on complications of diabetes and cardiovascular outcomes become available.

[Effect of Nano Zeolite on Chemical Fractions of Cd in Soil and Its Uptake by Cabbage].

PubMed

Xiong, Shi-juan; Xu, Wei-hong; Xie, Wen-wen; Chen, Rong; Chen, Yong-qin; Chi, Sun-lin; Chen, Xu- gen; Zhang, Jin-zhong; Xiong, Zhi-ting; Wang, Zheng-yin; Xie, De-ti

2015-12-01

Incubation experiments were carried out to investigate the influence of different nano zeolite (NZ) and ordinary zeolite (OZ) levels(0, 5, 10 and 20 g · kg⁻¹) on the change trends in fraction distribution coefficient (FDC) of Cd when exposed to different Cadmium (Cd) levels (1, 5, 10 and 15 mg · kg⁻¹), and pot experiments were carried out to investigate their influence on soil Cd fraction and Cd uptake by cabbage. The results in incubation experiments showed that the application of nano zeolite as well as ordinary zeolite effectively decreased the FDC of exchangeable Cd and increased the FDC of Fe-Mn oxide fraction. The FDC of soil Cd from 0 d to 28 d was deceased at first, then increased and tended to be stable, and finally increased. At the end of incubation, the FDC of soil exchangeable Cd decreased from 72.0%-88.0% to 30.0%-66.4%. Exchangeable fraction Cd was the most dominant Cd fraction in soil during the whole incubation. The results in pot experiment indicated that the application of nano zeolite and ordinary zeolite decreased the concentration and FDC of soil exchangeable Cd, and concurrently the concentration and FDC of Cd in carbonate, Fe-Mn oxide, organic matter and residual fraction were increased. The lowest EX-Cd was observed in the treatment with high dose of nano zeolite (20 g · kg⁻¹). The FDC of exchangeable Cd showed significant negative relationship with the soil pH (P < 0.05), and was concurrently extremely positively correlated with Cd concentration in shoot and root of cabbage (P < 0.01). Soil pH increased by 1.8%-45.5% and 6.1%-54.3% in the presence of zeolite when exposed to 5 mg · kg⁻¹ 1 and Cd, respectively; FDC of exchangeable Cd decreased by 16.3%-47.7% and 16.2%-46.7%; Cd concentration in each tissues of cabbage decreased by 1.0%-75.0% and 3.8%-53.2%, respectively. Moreover, the reduction effect of nano zeolite on soil and plant Cd was better than that of ordinary zeolite. The growth of cabbage was stimulated by low and medium zeolite doses (≤ 10 g · kg⁻¹), while inhibited by high zeolite doses (20 g · kg⁻¹). Compared to ordinary zeolite, the biomass of Chinese cabbage was significantly increased by Nano zeolite, while the exchangeable Cd in soil as well as Cd concentration and Cd accumulation of cabbage were significantly reduced.

A mathematical approach for the simultaneous in vitro spectrophotometric analysis of rifampicin and isoniazid from modified-release anti-TB drug delivery systems.

PubMed

du Toit, Lisa; Pillay, Viness; Choonara, Yahya

2010-01-01

Dissolution testing with subsequent analysis is considered as an imperative tool for quality evaluation of the combination rifampicin-isoniazid (RIF-INH) combination. Partial least squares (PLS) regression has been successfully undertaken to select suitable predictor variables and to identify outliers for the generation of equations for RIF and INH determination in fixed-dose combinations (FDCs). The aim of this investigation was to ascertain the applicability of the described technique in testing a novel oral FDC anti-TB drug delivery system and currently available two-drug FDCs, in comparison to the United States Pharmacopeial method for analysis of RIF and INH Capsules with chromatographic determination of INH and colorimetric RIF determination. Regression equations generated employing the statistical coefficients satisfactorily predicted RIF release at each sampling point (R(2)>or=0.9350). There was an acceptable degree of correlation between the drug release data, as predicted by regressional analysis of UV spectrophotometric data, and chromatographic and colorimetric determination of INH (R(2)=0.9793 and R(2)=0.9739) and RIF (R(2)= 0.9976 and R(2)=0.9996) for the two-drug FDC and the novel oral anti-TB drug delivery system, respectively. Regressional analysis of UV spectrophotometric data for simultaneous RIF and INH prediction thus provides a simplified methodology for use in diverse research settings for the assurance of RIF bioavailability from FDC formulations, specifically modified-release forms.

Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of fimasartan, amlodipine, and rosuvastatin using partial replicated design in healthy adult subjects.

PubMed

Oh, Minkyung; Ghim, Jong-Lyul; Park, Sung-Eun; Kim, Eun-Young; Shin, Jae-Gook

2018-01-01

The aim of this study was to compare the pharmacokinetics (PK) and safety profiles of a fixed-dose combination (FDC) formulation of fimasartan, amlodipine, and rosuvastatin with the co-administration of the two products by using a replicated crossover study design in healthy male subjects. This was an open-label, randomized, three-sequence, three-period replicated crossover study in healthy male subjects. The replicated crossover design was done because of high coefficient of variation of PK parameter for fimasartan, that is, >30%. With a 14 days washout period, an FDC tablet containing 60 mg fimasartan, 10 mg amlodipine, and 20 mg rosuvastatin was administered only once, and separate formulations of fimasartan/amlodipine 60 mg/10 mg FDC tablet and 20 mg rosuvastatin tablet administered twice. Blood samples were collected up to 72 hours following drug administration. The plasma concentrations of fimasartan, amlodipine, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was assessed by evaluating vital signs, clinical laboratory parameters, physical examinations, and medical interviews. The geometric mean ratios and 90% confidence intervals (CIs) for the maximum plasma concentration (C max ) and area under the curve from time zero to the last measurable sampling time (AUC t ) were 1.0776 (0.9201-1.2622) and 0.9978 (0.9538-1.0439) for fimasartan, 1.0038 (0.9782-1.0301) and 1.0055 (0.9828-1.0288) for amlodipine, and 1.0006 (0.9290-1.0776) and 0.9986 (0.9532-1.0461) for rosuvastatin, respectively. A total of 22 adverse events (AEs) were reported by 60 subjects; there were no significant differences in the incidence of AEs between the two groups. The 90% CI of the C max of fimasartan was within the widened acceptance limit, ln(0.6984)-ln(1.4319). The 90% CIs of the other PK parameters for drugs were between ln(0.8) and ln(1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile, to the co-administration of its three constituent drugs.

The evolution of systolic blood pressure as a strong predictor of cardiovascular risk and the effectiveness of fixed-dose ARB/CCB combinations in lowering levels of this preferential target

PubMed Central

Mourad, Jean-Jacques

2008-01-01

Elevated blood pressure is an important cardiovascular risk factor. Although targets for both diastolic blood pressure (DBP) and systolic blood pressure (SBP) are defined by current guidelines, DBP has historically taken precedence in hypertension management. However, there is strong evidence that SBP is superior to DBP as a predictor of cardiovascular events. Moreover, achieving control of SBP is assuming greater importance amongst an aging population. In spite of the growing recognition of the importance of SBP in reducing cardiovascular risk and the emphasis by current guidelines on SBP control, a substantial proportion of patients still fail to achieve SBP targets, and SBP control is achieved much less frequently than DBP control. Thus, new approaches to the management of hypertension are required in order to control SBP and minimize cardiovascular risk. Fixed-dose combination (FDC) therapy is an approach that offers the advantages of multiple drug administration and a reduction in regimen complexity that favors compliance. We have reviewed the latest evidence demonstrating the efficacy in targeting SBP of the most recent FDC products; combinations of the calcium channel blocker (CCB), amlodipine, with angiotensin receptor blockers (ARBs), valsartan or olmesartan. In addition, results from studies with new classes of agent are outlined. PMID:19337545

A pilot stability study on four-drug fixed-dose combination anti-tuberculosis products.

PubMed

Singh, S; Mohan, B

2003-03-01

A pilot stability study was carried out on four fixed-dose combination anti-tuberculosis products at 40 degrees C and 75% RH. The strip-packed products were stable, while the blister-packed products showed both physical and chemical changes. The products in unpacked conditions showed severe (approximately 60%) decomposition of rifampicin and extensive physical changes. The main decomposition product in the solid state was isonicotinyl hydrazone of 3-formylrifamycin and isoniazid. It is suggested that attention should be paid to the detection and quantitation of this product in the marketed formulations. The packing material used in the manufacture of FDC products should also be of the highest quality.

Evaluation of the efficacy and tolerability of fixed-dose combination therapy of azilsartan and amlodipine besylate in Japanese patients with grade I to II essential hypertension.

PubMed

Rakugi, Hiromi; Nakata, Emi; Sasaki, Emma; Kagawa, Tomoya

2014-05-01

Guidelines for the management of hypertension recommend using drugs with different mechanisms of action in antihypertensive regimens that include simple single-pill fixed-dose combination (FDC) products. The objective of this study was to compare the efficacy and tolerability of the FDC of azilsartan (AZI) and amlodipine besylate (AML) with those of AZI monotherapy and AML monotherapy in Japanese patients with grade 1 to 2 essential hypertension. This was a multicenter, randomized, double-blind, parallel-group study. After receiving placebo during a 4-week run-in period in a single-blind manner, patients were randomized to receive 1 of the following 5 treatments for 8 weeks: FDC containing AZI 20 mg and AML 5 mg (AZI/AML 20/5 mg), FDC containing AZI 20 mg and AML 2.5 mg (AZI/AML 20/2.5 mg), AZI 20 mg, AML 5 mg, or AML 2.5 mg once daily in a fasting or fed state. The primary end point was the change from baseline (week 0) in the seated trough diastolic blood pressure at week 8 (last observation carried forward [LOCF]), and the secondary end point was the change from baseline in the seated trough systolic blood pressure at week 8 (LOCF). Tolerability was assessed based on adverse events, vital signs, and physical examination findings. Of the 800 patients who provided informed consent, 603 were randomized to receive AZI/AML 20/5 mg (150 patients), AZI/AML 20/2.5 mg (151 patients), AZI 20 mg (151 patients), AML 5 mg (75 patients), or AML 2.5 mg (76 patients). The mean baseline systolic/diastolic blood pressure was 160.7/100.3 mm Hg. The mean change from baseline in seated blood pressure at week 8 (LOCF) was -35.3/-22.3 mm Hg in the AZI/AML 20/5 mg group and -31.4/-19.2 mm Hg in the AZI/AML 20/2.5 mg group, indicating a reduction significantly greater than that in corresponding monotherapy groups (-21.5/-13.9 mm Hg in the AZI 20 mg group, -26.4/-15.5 mm Hg in the AML 5 mg group, and -19.3/-11.6 mm Hg in the AML 2.5 mg group; p < 0.0001 for all contrast tests). No remarkable difference was found in the incidences of adverse events, vital signs, and physical examination findings among the treatment groups. This study found that the FDC of AZI/AML 20/5 mg and 20/2.5 mg exhibited greater antihypertensive effects compared with each monotherapy. The FDC of AZI/AML had a similar safety profile to that of each monotherapy and was tolerable to Japanese patients with grade 1 to 2 essential hypertension. Japic CTI-111606. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

78 FR 64428 - Draft Qualitative Risk Assessment of Risk of Activity/Animal Food Combinations for Activities...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-29

... Preventive Controls, amends the Federal Food, Drug, and Cosmetic Act (the FD&C Act) to create a new section 418 with the same name. Section 418 of the FD&C Act (21 U.S.C. 350g) contains requirements applicable to food facilities that are required to register under section 415 of the FD&C Act (21 U.S.C. 350d...

SU-E-T-764: Track Repeating Algorithm for Proton Therapy Applied to Intensity Modulated Proton Therapy for Head-And-Neck Patients

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

Yepes, P; Mirkovic, D; Mohan, R

Purpose: To determine the suitability of fast Monte Carlo techniques for dose calculation in particle therapy based on track-repeating algorithm for Intensity Modulated Proton Therapy, IMPT. The application of this technique will make possible detailed retrospective studies of large cohort of patients, which may lead to a better determination of Relative Biological Effects from the analysis of patient data. Methods: A cohort of six head-and-neck patients treated at the University of Texas MD Anderson Cancer Center with IMPT were utilized. The dose distributions were calculated with the standard Treatment Plan System, TPS, MCNPX, GEANT4 and FDC, a fast track-repeating algorithmmore » for proton therapy for the verification and the patient plans. FDC is based on a GEANT4 database of trajectories of protons in a water. The obtained dose distributions were compared to each other utilizing the g-index criteria for 3mm-3% and 2mm-2%, for the maximum spatial and dose differences. The γ-index was calculated for voxels with a dose at least 10% of the maximum delivered dose. Dose Volume Histograms are also calculated for the various dose distributions. Results: Good agreement between GEANT4 and FDC is found with less than 1% of the voxels with a γ-index larger than 1 for 2 mm-2%. The agreement between MCNPX with FDC is within the requirements of clinical standards, even though it is slightly worse than the comparison with GEANT4.The comparison with TPS yielded larger differences, what is also to be expected because pencil beam algorithm do not always performed well in highly inhomogeneous areas like head-and-neck. Conclusion: The good agreement between a track-repeating algorithm and a full Monte Carlo for a large cohort of patients and a challenging, site like head-and-neck, opens the path to systematic and detailed studies of large cohorts, which may yield better understanding of biological effects.« less

The efficacy and safety of valsartan and combination of valsartan and hydrochlorothiazide in the treatment of patients with mild to moderate arterial hypertension - the VICTORY trial.

PubMed

Accetto, Rok; Chazova, Irina Yevgenyevna; Sirenko, Yuriy; Vincelj, Josip; Widimsky, Jiri; Barbič-Žagar, Breda

2017-01-01

The aim of the trial was to establish the efficacy and safety of Valsacor® (valsartan) and Valsacombi® (combination of valsartan and hydrochlorothiazide) in a wide variety of patient populations with mild to moderate arterial hypertension. We performed an international, multicentre, open-label, prospective trial. After one week of washout in previously treated patients, the patients were treated for 16 weeks according to the protocol. Naïve patients entered the treatment period immediately. During the active treatment, four visits were planned for each patient to obtain the data for the primary and secondary efficacy endpoints analysis. The principal methods were blood pressure (BP) measurement, additionally in a subgroup of patients, assessment of erectile function. The initial dosage of valsartan 80 mg/day was titrated up to 320 mg/day to achieve the BP goal, with the addition of hydrochlorothiazide (HCTZ) in a fixed-dose combination (FDC), if needed. Mean ± standard deviation changes from baseline at week 16 were -26.6 ± 10.4 mm Hg (systolic BP) and -14.8 ± 7.6 mm Hg (diastolic BP). A total of 91% of the patients treated with either valsartan or valsartan FDC achieved the BP goal. Adverse reactions were experienced by 7.1% of the patients, with the most common being headache (1.9%), palpitation (1.6%), dizziness (1.6%), and fatigue (1.6%), during the whole trial. The results of the VICTORY trial show that valsartan and valsartan FDC effectively reduce the BP in patients with mild to moderate arterial hypertension and have a good tolerability profile.

Comparison of adherence to generic multi-tablet regimens vs. brand multi-tablet and brand single-tablet regimens likely to incorporate generic antiretroviral drugs by breaking or not fixed-dose combinations in HIV-infected patients.

PubMed

Rwagitinywa, Joseph; Lapeyre-Mestre, Maryse; Bourrel, Robert; Montastruc, Jean-Louis; Sommet, Agnès

2018-03-05

Adherence to antiretroviral (ARV) is crucial to achieve viral load suppression in HIV-infected patients. This study aimed to compare adherence to generic multi-tablet regimens (MTR) vs. brand MTR likely to incorporate ARV drugs without breaking fixed-dose combinations (FDC) and brand single-tablet regimens (STR) likely to incorporate generics by breaking the FDC. Patients aged of 18 years or over exposed to one of the generic or the brand of lamivudine (3TC), zidovudine/lamivudine (AZT/TC), nevirapine (NVP), or efavirenz (EFV), or the brand STR of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Adherence was measured by medication possession ratio (MPR) using both defined daily dose (DDD) and daily number of tablet recommended for adults (DNT). Adherence to generic MTR vs. brand MTR and brand STR was compared using Kruskal-Wallis. The overall median adherence was 0.97 (IQR 0.13) by DNT method and 0.97 (0.14) by DDD method. Adherence in patients exposed to generic MTR (n = 165) vs. brand MTR (n = 481) and brand STR (n = 470) was comparable by DNT and DDD methods. In conclusion, adherence to generic MTR was high and comparable with adherence to brand MTR and to STR. Utilization of DDD instead DNT to measure the MPR led to small but nonsignificant difference that has no clinical impact. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Pharmacokinetic comparison using two tablets of an evogliptin/metformin XR 2.5/500 mg fixed dose combination vs. 1 tablet each of evogliptin 5 mg and metformin XR 1,000 mg
.

PubMed

Yoon, Sumin; Rhee, Su-Jin; Park, Sang-In; Yoon, Seo Hyun; Cho, Joo-Youn; Jang, In-Jin; Lee, SeungHwan; Yu, Kyung-Sang

2017-06-01

The aim of this study was to compare the pharmacokinetic (PK) characteristics of evogliptin and metformin following the administration of 2 evogliptin/metformin extended-release (XR) 2.5/500 mg FDC tablets with the coadministration of separate evogliptin 5-mg and metformin XR 1,000-mg tablets (separate formulations). A randomized, two-period, two-sequence crossover study was conducted. Subjects were randomly assigned to receive 2 FDC tablets or the individual tablets, followed by a 14-day washout period and the administration of the alternate treatment. Blood samples were collected predose and up to 72 hours postdose for each period. PK parameters including C_max and AUC_last were calculated. The geometric mean ratios (GMRs) and the 90% confidence intervals (CIs) between FDC and the separate formulations were calculated for the C_max and AUC_last of evogliptin and metformin. 33 subjects completed the study. The GMR (90% CI) values of C_max and AUC_last for evogliptin were 1.011 (0.959 - 1.066) and 1.010 (0.977 - 1.043), respectively. The GMR (90% CI) values of C_max and AUC_last for metformin were 0.892 (0.827 - 0.963) and 0.893 (0.841 - 0.947), respectively. There was no significant difference between the FDC and separate formulations regarding the occurrence of adverse events. All drug-related adverse events were considered to be mild and resolved without any treatment. Two FDC tablets of evogliptin/metformin XR 2.5/500 mg showed a similar PK profile to the separate formulations of evogliptin 5 mg and metformin XR 1,000 mg. All of the 90% CIs of GMR satisfied the regulatory bioequivalence criteria of 0.800 - 1.250.
.

Management of dyslipidemia and hyperglycemia with a fixed-dose combination of sitagliptin and simvastatin

PubMed Central

Steinberg, Helmut; Anderson, Matt S; Musliner, Thomas; Hanson, Mary E; Engel, Samuel S

2013-01-01

The risk of death due to heart disease and stroke is up to four times higher in individuals with diabetes compared to individuals without diabetes. Most guidelines that address treatment of dyslipidemia in patients with diabetes consider diabetes a cardiovascular disease (CVD) “risk equivalent” and recommend intensive treatment of dyslipidemia for the purpose of CVD prevention. Statins (3-hydroxy 3-methylglutaryl coenzyme A reductase [HMG-CoA reductase] inhibitors) are first-line agents in achieving lipid goals as an adjunct to diet and exercise and should be used in most patients. In addition to lipid management and blood pressure control, glycemic control is a basic component in the management of diabetes. Glycemic control is achieved by combining diabetes self-management education, diet and exercise, and, where required, antihyperglycemic agents (OHAs). Persistence and adherence to therapy are critical in achieving recommended treatment goals. However, overall compliance with concomitantly prescribed OHAs and statins is low in patients with type 2 diabetes. Fixed-dose combination (FDC) therapies have been shown to improve adherence by reducing pill burden, the complexity of treatment regimen, and, potentially, cost. Based on the available evidence regarding the pharmacokinetics and the efficacy and safety profiles of each component drug, the sitagliptin/simvastatin FDC may provide a rational and well-tolerated approach to achieving better adherence to multiple-drug therapy and improved lipid lowering and glycemic control, with consequent reduction in cardiovascular risk, diabetic microvascular disease, and mortality in diabetic patients for whom treatment with both compounds is appropriate. PMID:23761972

The importance of inhaler devices: the choice of inhaler device may lead to suboptimal adherence in COPD patients.

PubMed

Darbà, Josep; Ramírez, Gabriela; Sicras, Antoni; Francoli, Pablo; Torvinen, Saku; Sánchez-de la Rosa, Rainel

2015-01-01

This study aims to identify factors associated with poor adherence to COPD treatment in patients receiving a fixed-dose combination (FDC) of inhaled corticosteroids and long-acting β2-agonist (ICS/LABA), focusing on the importance of inhaler devices. We conducted a retrospective and multicenter study based on a review of medical registries between 2007 and 2012 of COPD patients (n=1,263) treated with ICS/LABA FDC, whose medical devices were either dry powder inhalers (DPIs) or pressurized metered-dose inhalers (pMDI). Medication adherence included persistence outcomes through 18 months and medication possession ratios. Data on exacerbations, comorbidities, demographic characteristics, and health care resource utilization were also included as confounders of adherence. The analyses revealed that COPD patients whose medication was delivered through a DPI were less likely to have medication adherence compared to patients with pMDI, after adjusting for confounding factors, especially active ingredients. Younger groups of patients were less likely to be adherent compared to the oldest group. Smoker men were less likely to be adherent compared to women and non-smokers. Comorbidities decreased the probability of treatment adherence. Those patients that visited their doctor once a month were more likely to adhere to their medication regimen; however, suboptimal adherence was more likely to occur among those patients who visited more than three times per month their doctor. We also found that worsening of COPD is negatively associated with adherence. According to this study, inhaler devices influence patients' adherence to long-term COPD medication. We also found that DPIs delivering ICS/LABA FDC had a negative impact on adherence. Patients' clinic and socioeconomic characteristics were associated with adherence.

ISOLATION OF CHICKEN FOLLICULAR DENDRITIC CELLS

USDA-ARS?s Scientific Manuscript database

The aim of the present study was to isolate chicken follicular dendritic cells (FDC). A combination of methods involving panning, iodixanol density gradient centrifugation, and magnetic cell separation technology made it possible to obtain functional FDC from the cecal tonsils from chickens, which h...

Primary stroke prevention and hypertension treatment: which is the first-line strategy?

PubMed

Ravenni, Roberta; Jabre, Joe F; Casiglia, Edoardo; Mazza, Alberto

2011-07-05

Hypertension (HT) is considered the main classic vascular risk factor for stroke and the importance of lowering blood pressure (BP) is well established. However, not all the benefit of antihypertensive treatment is due to BP reduction per se, as the effect of reducing the risk of stroke differs among classes of antihypertensive agents. Extensive evidences support that angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), dihydropyridine calcium channel blockers (CCB) and thiazide diuretics each reduced risk of stroke compared with placebo or no treatment. Therefore, when combination therapy is required, a combination of these antihypertensive classes represents a logical approach. Despite the efficacy of antihypertensive therapy a large proportion of the population, still has undiagnosed or inadequately treated HT, and remain at high risk of stroke. In primary stroke prevention current guidelines recommend a systolic/diastolic BP goal of <140/<90 mmHg in the general population and <130/80 mmHg in diabetics and in subjects with high cardiovascular risk and renal disease. The recent release in the market of the fixed-dose combination (FDC) of ACEI or ARB and CCB should provide a better control of BP. However to confirm the efficacy of the FDC in primary stroke prevention, clinical intervention trials are needed.

Optimization of a reversed-phase-high-performance thin-layer chromatography method for the separation of isoniazid, ethambutol, rifampicin and pyrazinamide in fixed-dose combination antituberculosis tablets.

PubMed

Shewiyo, D H; Kaale, E; Risha, P G; Dejaegher, B; Smeyers-Verbeke, J; Vander Heyden, Y

2012-10-19

This paper presents the development of a new RP-HPTLC method for the separation of pyrazinamide, isoniazid, rifampicin and ethambutol in a four fixed-dose combination (4 FDC) tablet formulation. It is a single method with two steps in which after plate development pyrazinamide, isoniazid and rifampicin are detected at an UV wavelength of 280 nm. Then ethambutol is derivatized and detected at a VIS wavelength of 450 nm. Methanol, ethanol and propan-1-ol were evaluated modifiers to form alcohol-water mobile phases. Systematic optimization of the composition of each alcohol in the mobile phase was carried out using the window diagramming concept to obtain the best separation. Examination of the Rf distribution of the separated compounds showed that separation of the compounds with the mobile phase containing ethanol at the optimal fraction was almost situated within the optimal Rf-values region of 0.20-0.80. Therefore, ethanol was selected as organic modifier and the optimal mobile phase composition was found to be ethanol, water, glacial acetic acid (>99% acetic acid) and 37% ammonia solution (70/30/5/1, v/v/v/v). The method is new, quick and cheap compared to the actual method in the International Pharmacopoeia for the assay of the 4 FDC tablets, which involves the use of two separate HPLC methods. Copyright © 2012 Elsevier B.V. All rights reserved.

Exposure estimate for FD&C colour additives for the US population.

PubMed

Doell, Diana L; Folmer, Daniel E; Lee, Hyoung S; Butts, Kyla M; Carberry, Susan E

2016-05-01

Dietary exposures to the seven food, drug, and cosmetic (FD&C) colour additives that are approved for general use in food in the United States were estimated for the US population (aged 2 years and older), children (aged 2-5 years) and teenage boys (aged 13-18 years) based on analytical levels of the FD&C colour additives in foods. Approximately 600 foods were chosen for analysis, based on a survey of product labels, for the levels of FD&C colour additives. Dietary exposure was estimated using both 2-day food consumption data from the combined 2007-10 National Health and Nutrition Examination Survey (NHANES) and 10-14-day food consumption data from the 2007-10 NPD Group, Inc. National Eating Trends - Nutrient Intake Database (NPD NET-NID). Dietary exposure was estimated at the mean and 90th percentile using three different exposure scenarios: low exposure, average exposure and high exposure, to account for the range in the amount of each FD&C colour additive for a given food. For all populations and all exposure scenarios, the highest cumulative eaters-only exposures in food were determined for FD&C Red No. 40, FD&C Yellow No. 5 and FD&C Yellow No. 6. In addition, the eaters-only exposure was estimated for individual food categories in order to determine which food categories contributed the most to the exposure for each FD&C colour additive. Breakfast Cereal, Juice Drinks, Soft Drinks, and Frozen Dairy Desserts/Sherbet (also referred to as Ice Cream, Frozen Yogurt, Sherbet (including Bars, Sticks, Sandwiches)) were the major contributing food categories to exposure for multiple FD&C colour additives for all three populations.

Exposure estimate for FD&C colour additives for the US population

PubMed Central

Folmer, Daniel E.; Lee, Hyoung S.; Butts, Kyla M.; Carberry, Susan E.

2016-01-01

Dietary exposures to the seven food, drug, and cosmetic (FD&C) colour additives that are approved for general use in food in the United States were estimated for the US population (aged 2 years and older), children (aged 2–5 years) and teenage boys (aged 13–18 years) based on analytical levels of the FD&C colour additives in foods. Approximately 600 foods were chosen for analysis, based on a survey of product labels, for the levels of FD&C colour additives. Dietary exposure was estimated using both 2-day food consumption data from the combined 2007–10 National Health and Nutrition Examination Survey (NHANES) and 10–14-day food consumption data from the 2007–10 NPD Group, Inc. National Eating Trends – Nutrient Intake Database (NPD NET-NID). Dietary exposure was estimated at the mean and 90th percentile using three different exposure scenarios: low exposure, average exposure and high exposure, to account for the range in the amount of each FD&C colour additive for a given food. For all populations and all exposure scenarios, the highest cumulative eaters-only exposures in food were determined for FD&C Red No. 40, FD&C Yellow No. 5 and FD&C Yellow No. 6. In addition, the eaters-only exposure was estimated for individual food categories in order to determine which food categories contributed the most to the exposure for each FD&C colour additive. Breakfast Cereal, Juice Drinks, Soft Drinks, and Frozen Dairy Desserts/Sherbet (also referred to as Ice Cream, Frozen Yogurt, Sherbet (including Bars, Sticks, Sandwiches)) were the major contributing food categories to exposure for multiple FD&C colour additives for all three populations. PMID:27092991

Simultaneous Determination of First-Line 4-FDC Antituberculosis Drugs by UHPLC-UV and HPLC-UV: A Comparative Study.

PubMed

Franco, Pedro H C; Chellini, Paula R; Oliveira, Marcone A L; Pianetti, Gerson A

2017-07-01

Tuberculosis is the second most deadly infectious disease, surpassed only by HIV/AIDS, and has resulted in over 1 billion deaths in the last 200 years. The World Health Organization estimates that in 2014, 9.6 million people were infected by this disease and 1.5 million had died. First-choice treatment consists of fixed-dose combination tablets containing rifampicin, isoniazid, pyrazinamide, and ethambutol hydrochloride (4-FDC). There are pharmacopeial protocols available to test 4-FDC, but they are prolonged, two-step methods. One single-step method in the literature performs the simultaneous determination by HPLC, but requires a long acquisition time. In this context, an ultra-HPLC (UHPLC) method was developed based on the HPLC method with the objective of reducing analysis time. A C18 column (1.9 µm particle size) was used with UV-diode-array detection at 238 and 282 nm. The method was found to be selective, linear, exact, precise, and robust. Samples from two batches were analyzed and the results compared with those obtained by the HPLC method, with no statistically significant differences observed (P > 0.05). This UHPLC method reduced the analysis time from 17 to 4 min, with a more than 90% reduction in sample and reagent consumption and a financial economy of almost 50-fold.

A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products

PubMed Central

2013-01-01

Background Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as β-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of β-artemether and lumefantrine FDC products. Methods Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30°C, were evaluated. β-artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 μl injection volume. Quantification was performed at 210 nm and 335 nm for β-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0®. Results Both β-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (± RSD) of 99.7 % (± 0.7%) for β-artemether and 99.7 % (± 0.6%) for lumefantrine. All identified β-artemether-related impurities were predicted in Derek Nexus v2.0® to have toxicity risks similar to β-artemether active pharmaceutical ingredient (API) itself. Conclusions A rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of β-artemether and lumefantrine. This method can be applied in the routine regulatory quality control of FDC products. The in-silico toxicological investigation using Derek Nexus® indicated that the overall toxicity risk for β-artemether-related impurities is comparable to that of β-artemether API. PMID:23631682

In vitro and in vivo efficacy of fluorodeoxycytidine analogs against highly pathogenic avian influenza H5N1, seasonal, and pandemic H1N1 virus infections

PubMed Central

Kumaki, Yohichi; Day, Craig W.; Smee, Donald F.; Morrey, John D.; Barnard, Dale L.

2011-01-01

Various fluorodeoxyribonucleosides were evaluated for their antiviral activities against influenza virus infections in vitro and in vivo. Among the most potent inhibitors was 2'-deoxy-2'-fluorocytidine (2'-FdC). It inhibited various strains of low and highly pathogenic avian influenza H5N1 viruses, pandemic H1N1 viruses, an oseltamivir-resistant pandemic H1N1 virus, and seasonal influenza viruses (H3N2, H1N1, influenza B) in MDCK cells, with the 90% inhibitory concentrations ranging from 0.13 µM to 4.6 µM, as determined by a virus yield reduction assay. 2'-FdC was then tested for efficacy in BALB/c mice infected with a lethal dose of highly pathogenic influenza A/Vietnam/1203/2004 H5N1 virus. 2’FdC (60 mg/kg/d) administered intraperitoneally (i.p.) twice a day beginning 24 h after virus exposure significantly promoted survival (80% survival) of infected mice (p=0.0001). Equally efficacious were the treatment regimens in which mice were treated with 2'-FdC at 30 or 60 mg/kg/day (bid × 8) beginning 24 h before virus exposure. At these doses, 70–80% of the mice were protected from death due to virus infection (p=0.0005, p=0.0001; respectively). The lungs harvested from treated mice at day four of the infection displayed little surface pathology or histopathology, lung weights were lower, and the 60 mg/kg dose reduced lung virus titers, although not significantly compared to the placebo controls. All doses were well tolerated in uninfected mice. 2'-FdC could also be administered as late as 72 h post virus exposure and still significantly protect 60% mice from the lethal effects of the H5N1 virus infection (p=0.019). Other fluorodeoxyribonucleosides tested in the H5N1 mouse model, 2’-deoxy-5-fluorocytidine and 2'-deoxy-2', 2'-difluorocytidine, were very toxic at higher doses and not inhibitory at lower doses. Finally, 2'-FdC, which was active in the H5N1 mouse model, was also active in a pandemic H1N1 influenza A infection model in mice. When given at 30 mg/kg/d (bid × 5) beginning 24 h before virus exposure), 2’-FdC also significantly enhanced survival of H1N1-infected mice (50%, p=0.038) similar to the results obtained in the H5N1 infection model using a similar dosing regimen (50%, p<0.05). Given the demonstrated in vitro and in vivo inhibition of avian influenza virus replication, 2’FdC may qualify as a lead compound for the development of agents treating influenza virus infections. PMID:21925541

A comparative study between hot-melt extrusion and spray-drying for the manufacture of anti-hypertension compatible monolithic fixed-dose combination products.

PubMed

Kelleher, J F; Gilvary, G C; Madi, A M; Jones, D S; Li, S; Tian, Y; Almajaan, A; Senta-Loys, Z; Andrews, G P; Healy, A M

2018-07-10

The purpose of this work was to investigate the application of different advanced continuous processing techniques (hot melt extrusion and spray drying) to the production of fixed-dose combination (FDC) monolithic systems comprising of hydrochlorothiazide and ramipril for the treatment of hypertension. Identical FDC formulations were manufactured by the two different methods and were characterised using powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC). Drug dissolution rates were investigated using a Wood's apparatus, while physical stability was assessed on storage under controlled temperature and humidity conditions. Interestingly both drugs were transformed into their amorphous forms when spray dried, however, hydrochlorothiazide was determined, by PXRD, to be partially crystalline when hot melt extruded with either polymer carrier (Kollidon® VA 64 or Soluplus®). Hot melt extrusion was found to result in significant degradation of ramipril, however, this could be mitigated by the inclusion of the plasticizer, polyethylene glycol 3350, in the formulation and appropriate adjustment of processing temperature. The results of intrinsic dissolution rate studies showed that hot-melt extruded samples were found to release both drugs faster than identical formulations produced via spray drying. However, the differences were attributable to the surface roughness of the compressed discs in the Wood's apparatus, rather than solid state differences between samples. After a 60-day stability study spray dried samples exhibited a greater physical stability than the equivalent hot melt extruded samples. Copyright © 2018 Elsevier B.V. All rights reserved.

The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis.

PubMed Central

Blomberg, B.; Spinaci, S.; Fourie, B.; Laing, R.

2001-01-01

There is considerable exigency to take all necessary steps to cure tuberculosis cases and prevent further emergence of drug-resistant tuberculosis. The most important of these steps is to ensure that the treatment, particularly of sputum smear-positive cases, is adequate and that patients adhere to their treatment by supervised, direct observation of drug-taking according to the standardized regimens. Use of fixed-dose combinations (FDCs) of tablets against tuberculosis is now being recommended by WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) as an additional step to ensuring proper treatment. FDCs simplify the prescription of drugs and the management of drug supply, and may also limit the risk of drug-resistant tuberculosis arising as a result of inappropriate drug selection and monotherapy. Only FDCs of proven quality and proven rifampicin bioavailability should be purchased and used. In most situations, blood levels of the drugs are inadequate because of poor drug quality rather than poor absorption. This is true irrespective of the human immunodeficiency virus (HIV) infection status of the tuberculosis patients (other than those with overt acquired immunodeficiency syndrome, with CD4 counts < 200 cells/mm3). Currently, WHO, IUATLD and their partners are developing strategies for ensuring that only quality FDCs are used in tuberculosis programmes. A simplified and effective protocol for assessment of rifampicin bioavailability has been developed, and laboratories are being recruited to form a supranational network for quality assurance of FDCs. Standardization of FDC drug formulations has been proposed, which limits rifampicin-containing preparations to nine (including a four-drug FDC and three paediatric FDCs). PMID:11217670

Designing ARVs Patent Pool Up to Trade & Policy Evolutionary Dynamics

PubMed Central

Dionisio, Daniele; Racalbuto, Vincenzo; Messeri, Daniela

2010-01-01

Patent pools for second and third-line Fixed Dose Combination (FDC) antiretroviral drugs (ARVs) should not be delayed as they are instrumental to urgent public health needs in the under-served markets. Nonetheless, multinational originator companies still seem to perceive patent pooling for ARVs as a minefield that would offer the generic competitors lots of deeply exploitable opportunities, to the detriment of patent owner’s rights. This paper analyses the brand industry concerns, while looking for a strategy up to a really equitable and free world market, without any discrimination between end-users in wealthy and resource-limited countries. This strategy would urge partnerships between originator companies first to make newer FDC ARVs quickly available and allow patent pool agreements with generic counterparts to be negotiated straight afterwards. The patent pool strategy highlighted in this paper would assert the primacy of health over for-profit policies, while aligning with the 61st WHO’s Assembly recommendations and G7, G8 and World Trade Organisation’s warnings and pledges against trade protectionism. PMID:20200604

Fixed-Dose Combinations of Renin–Angiotensin System Inhibitors and Calcium Channel Blockers in the Treatment of Hypertension

PubMed Central

Hsiao, Fu-Chih; Tung, Ying-Chang; Chou, Shing-Hsien; Wu, Lung-Sheng; Lin, Chia-Pin; Wang, Chun-Li; Lin, Yu-Sheng; Chang, Chee-Jen; Chu, Pao-Hsien

2015-01-01

Abstract Fixed-dose combinations (FDCs) of different regimens are recommended in guidelines for the treatment of hypertension. However, clinical studies comparing FDCs of angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) and angiotensin-converting enzyme inhibitor (ACE inhibitor)/CCB in hypertensive patients are lacking. Using a propensity score matching of 4:1 ratio, this retrospective claims database study compared 2 FDC regimens, ARB/CCB and ACE inhibitor/CCB, in treating hypertensive patients with no known atherosclerotic cardiovascular disease. All patients were followed for at least 3 years or until the development of major adverse cardiovascular events (MACEs) during the study period. In addition, the effect of medication adherence on clinical outcomes was evaluated in subgroup analysis based on different portions of days covered. There was no significant difference in MACE-free survival (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.98–1.50; P = 0.08) and survival free from hospitalization for heart failure (HR: 1.15; 95% CI: 082–1.61; P = 0.431), new diagnosis of chronic kidney disease (HR: 0.98; 95% CI: 071–1.36; P = 0.906), and initiation of dialysis (HR: 0.99; 95% CI: 050–1.92; P = 0.965) between the 2 study groups. The results remained the same within each subgroup of patients with different adherence statuses. ARBs in FDC regimens with CCBs in the present study were shown to be as effective as ACE inhibitors at reducing the risks of MACEs, hospitalization for heart failure, new diagnosis of chronic kidney disease, and new initiation of dialysis in hypertensive patients, regardless of the medication adherence status. PMID:26705234

Lack of asthma and rhinitis control in general practitioner-managed patients prescribed fixed-dose combination therapy in Australia.

PubMed

Bosnic-Anticevich, Sinthia; Kritikos, Vicky; Carter, Victoria; Yan, Kwok Yin; Armour, Carol; Ryan, Dermot; Price, David

2018-06-01

The first aim of the study (i) assess the current asthma status of general-practitioner-managed patients receiving regular fixed-dose combination inhaled corticosteroid and long-acting beta 2 agonist (FDC ICS/LABA) therapy and (ii) explore patients' perceptions of asthma control and attitudes/behaviors regarding preventer inhaler use. A cross-sectional observational study of Australian adults with a current physician diagnosis of asthma receiving ≥2 prescriptions of FDC ICS/LABA therapy in the previous year, who were recruited through general practice to receive a structured in-depth asthma review between May 2012 and January 2014. Descriptive statistics and Chi-Square tests for independence were used for associations across asthma control levels. Only 11.5% of the patients had controlled asthma based on guideline-defined criteria. Contrarily, 66.5% of the patients considered their asthma to be well controlled. Incidence of acute asthma exacerbations in the previous year was 26.5% and 45.6% of the patients were without a diagnosis of rhinitis. Asthma medication use and inhaler technique were sub-optimal; only 41.0% of the preventer users reported everyday use. The side effects of medication were common and more frequently reported among uncontrolled and partially controlled patients. The study revealed the extent to which asthma management needs to be improved in this patient cohort and the numerous unmet needs regarding the current state of asthma care. Not only there is a need for continuous education of patients, but also education of health care practitioners to better understand the way in which patient's perceptions impact on asthma management practices, incorporating these findings into clinical decision making.

FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study.

PubMed

Tedesco-Silva, Helio; Szakaly, Peter; Shoker, Ahmed; Sommerer, Claudia; Yoshimura, Norio; Schena, Francesco Paolo; Cremer, Malika; Hmissi, Abdel; Mayer, Hartmut; Lang, Philippe

2007-10-15

FTY720 is a novel immunomodulator that was developed to produce optimal graft protection with improved safety and tolerability. Phase II studies have demonstrated the efficacy of FTY720 up to the doses of 2.5 mg with full-dose cyclosporine (FDC). This multicenter, double-blind, Phase IIb, randomized study evaluated the safety and efficacy of 5 mg FTY720 (n=87; Group 1) vs. 2.5 mg FTY720 (n=90; Group 2) vs. mycophenolate mofetil (MMF; n=94; Group 3) in de novo renal transplant patients receiving FDC and prednisone. The primary efficacy endpoint was the occurrence of treated biopsy-proven acute rejection, graft loss, death, or premature study discontinuation (composite endpoint) within 6 months. The primary endpoint was superior in Group 1 (24%) and statistically noninferior in Group 2 compared to Group 3 (24.1% vs. 29.2% vs. 39.4%; P=0.025 and 0.0039, respectively). FTY720 plus FDC was generally well tolerated, with a similar incidence of adverse events across all groups. FTY720 was associated with higher incidence of bradycardia (Group 1: 26.4%, P=0.0002 and Group 2: 15.6%, P=0.046, vs. Group 3: 6.4%), respiratory disorders (Group 1: 40.2%, not significant [P=NS] and Group 2: 34.4%, P=NS vs. Group 3: 28.7%). One macular edema occurred in Group 2. Lower creatinine clearances were observed with FTY720 versus MMF (Group 1: 52.4 ml/min, P=NS and Group 2: 51.7 ml/min, P=0.039 vs. Group 3: 62.5 ml/min). Although FTY720 with FDC provided adequate protection from acute rejection the safety profile was less favorable for adverse events than current standard immunosuppression in de novo renal transplant patients.

An explanation for the physical instability of a marketed fixed dose combination (FDC) formulation containing isoniazid and ethambutol and proposed solutions.

PubMed

Bhutani, Hemant; Mariappan, T T; Singh, Saranjit

2004-07-01

An investigation was carried out to explore the possible reason for the physical instability of a marketed strip packaged anti-TB fixed dose combination (FDC) tablet containing 300 mg of isoniazid (H) and 800 mg of ethambutol hydrochloride (E). The instability was in the form of distribution of white powder inside the strip pockets. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS-MS) studies confirmed that both H and E were present in the powder. The same was also confirmed through Fourier-transform infrared (FTIR) spectroscopy, which also indicated absence of interaction between the two drugs. No sublimation of the drugs was observed up to 110 degrees C, indicating that the observed instability was not due to this reason. Subsequently, attention was paid to the possibility of moisture gain by the tablets through defective packaging (which was established) due to hygroscopicity of E. To understand the phenomenon further, pure drugs and their mixtures were stored under accelerated conditions of temperature and humidity [40 degrees C/75% relative humidity (RH)] and both increase in weight and physical changes were recorded periodically. The mixtures gained moisture at a higher rate than pure E and those with higher content of E became liquid, which on withdrawal from the chambers, became crystallized. The drug mixture containing H:E at a ratio of 30:70 w/w, which was similar to the ratio of the drugs in the tablets (27:73 w/w), crystallized fastest, indicating formation of a rapid crystallizing saturated system at this ratio of the drugs. It is postulated that the problem of instability arises because of the formation of a saturated layer of drugs upon moisture gain through the defective packaging material and drying of this layer with time. The study suggests that barrier packaging free from defects and alternatively (or in combination) film coating of the tablets with water-resistant polymers are essential for this formulation.

Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial.

PubMed

Thom, Simon; Poulter, Neil; Field, Jane; Patel, Anushka; Prabhakaran, Dorairaj; Stanton, Alice; Grobbee, Diederick E; Bots, Michiel L; Reddy, K Srinath; Cidambi, Raghu; Bompoint, Severine; Billot, Laurent; Rodgers, Anthony

2013-09-04

Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment. To assess whether FDC delivery of aspirin, statin, and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C). The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe. The trial follow-up concluded in July 2012. Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) containing either (1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol or (2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide or to usual care (n=1002). Adherence to medication (defined as self-reported use of antiplatelet, statin, and ≥2 BP-lowering medications) and changes in SBP and LDL-C from baseline. At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P < .001) with concurrent reductions in SBP (-2.6 mm Hg; 95% CI, -4.0 to -1.1 mm Hg; P < .001) and LDL-C (-4.2 mg/dL; 95% CI, -6.6 to -1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74-4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3-2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P=.09) between the groups. Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C. clinicaltrials.gov Identifier: NCT01057537.

Behavioural responses of Frankliniella occidentalis Pergande larvae to methyl jasmonate and cis-jasmone.

PubMed

Egger, Barbara; Koschier, Elisabeth H

2014-01-01

The larval stages of Frankliniella occidentalis Pergande (Thysanoptera: Thripidae) cause more direct feeding damage to plants than the adults. We, therefore, investigated the behaviour-modifying effects on second instar larvae of two jasmonic acid derivatives. The artificial application of methyl jasmonate and cis -jasmone, both at 1 % concentration, deterred the larvae from settling in a dual choice bean leaf disc assay. We observed a dose-dependent feeding deterrence of both jasmonates and calculated the concentration required to reduce the feeding damage by 50 % relative to the control treatment (FDC 50 ) for each jasmonate. The feeding damage was reduced by the application of cis -jasmone at 1 % concentration, but not by the jasmonates at the respective FDC 50 in no-choice leaf disc bioassays. However, significantly more larvae left jasmonate-treated whole potted bean plants by migrating to the soil compared with control plants. Our results may be exploited extending behavioural manipulation by using plant compounds in thrips control programmes to the full lifecycle of the pest. Plant compounds could be used in integrated and biological pest management strategies against F. occidentalis in combination with the application of various above and below ground control measures.

Estimated rates of recurrence, cure, and treatment abandonment in patients with pulmonary tuberculosis treated with a -four-drug fixed-dose combination regimen at a tertiary health care facility in the city of Rio de Janeiro, Brazil.

PubMed

Silva, Vangie Dias da; Mello, Fernanda Carvalho de Queiroz; Figueiredo, Sonia Catarina de Abreu

2017-01-01

To estimate the rates of recurrence, cure, and treatment abandonment in patients with pulmonary tuberculosis treated with a four-drug fixed-dose combination (FDC) regimen, as well as to evaluate possible associated factors. This was a retrospective observational study involving 208 patients with a confirmed diagnosis of pulmonary tuberculosis enrolled in the Hospital Tuberculosis Control Program at the Institute for Thoracic Diseases, located in the city of Rio de Janeiro, Brazil. Between January of 2007 and October of 2010, the patients were treated with the rifampin-isoniazid-pyrazinamide (RHZ) regimen, whereas, between November of 2010 and June of 2013, the patients were treated with the rifampin-isoniazid-pyrazinamide-ethambutol FDC (RHZE/FDC) regimen. Data regarding tuberculosis recurrence and mortality in the patients studied were retrieved from the Brazilian Case Registry Database and the Brazilian Mortality Database, respectively. The follow-up period comprised two years after treatment completion. The rates of cure, treatment abandonment, and death were 90.4%, 4.8%, and 4.8%, respectively. There were 7 cases of recurrence during the follow-up period. No significant differences in the recurrence rate were found between the RHZ and RHZE/FDC regimen groups (p = 0.13). We identified no factors associated with the occurrence of recurrence; nor were there any statistically significant differences between the treatment groups regarding adverse effects or rates of cure, treatment abandonment, or death. The adoption of the RHZE/FDC regimen produced no statistically significant differences in the rates of recurrence, cure, or treatment abandonment; nor did it have any effect on the occurrence of adverse effects, in comparison with the use of the RHZ regimen. Estimar as taxas de recidiva, cura e abandono de tratamento em pacientes com tuberculose pulmonar tratados com o esquema de dose fixa combinada (DFC) de quatro drogas e avaliar possíveis fatores associados. Estudo observacional retrospectivo com 208 pacientes com diagnóstico confirmado de tuberculose pulmonar registrados no Programa de Controle da Tuberculose Hospitalar do Instituto de Doenças do Tórax, localizado na cidade do Rio de Janeiro. Os pacientes tratados entre janeiro de 2007 e outubro de 2010 receberam o esquema rifampicina-isoniazida-pirazinamida (RHZ), e aqueles tratados entre novembro de 2010 e junho de 2013 receberam o esquema rifampicina-isoniazida-pirazinamida-etambutol em DFC (RHZE/DFC). Os dados dos pacientes sobre recidiva e óbito foram obtidos no Sistema de Informação de Agravos de Notificação e no Sistema de Informação de Mortalidade, respectivamente. O período de acompanhamento foi de dois anos após o encerramento do tratamento. As taxas de cura, abandono e óbito foram de 90,4%, 4,8% e 4,8%, respectivamente. Houve 7 casos de recidivas durante o período de acompanhamento. Não houve diferenças significativas na taxa de recidiva entre os grupos de tratamento RHZ e RHZE/DFC (p = 0,13). Não foram identificados fatores associados com a ocorrência de recidiva, nem houve diferenças estatisticamente significativas na ocorrência dos efeitos adversos ou nas taxas de cura, abandono e óbito entre os grupos de tratamento. A adoção do esquema de tratamento RHZE/DFC não produziu diferenças estatisticamente significativas nas taxas de recidiva, cura e abandono nem na ocorrência de efeitos adversos em comparação com o esquema RHZ.

Improved consistency in dosing anti-tuberculosis drugs in Taipei, Taiwan.

PubMed

Chiang, Chen-Yuan; Yu, Ming-Chih; Shih, Hsiu-Chen; Yen, Muh-Yong; Hsu, Yu-Ling; Yang, Shiang-Lin; Lin, Tao-Ping; Bai, Kuan-Jen

2012-01-01

It was reported that 35.5% of tuberculosis (TB) cases reported in 2003 in Taipei City had no recorded pre-treatment body weight and that among those who had, inconsistent dosing of anti-TB drugs was frequent. Taiwan Centers for Disease Control (CDC) have taken actions to strengthen dosing of anti-TB drugs among general practitioners. Prescribing practices of anti-TB drugs in Taipei City in 2007-2010 were investigated to assess whether interventions on dosing were effective. Lists of all notified culture positive TB cases in 2007-2010 were obtained from National TB Registry at Taiwan CDC. A medical audit of TB case management files was performed to collect pretreatment body weight and regimens prescribed at commencement of treatment. Dosages prescribed were compared with dosages recommended. The proportion of patients with recorded pre-treatment body weight was 64.5% in 2003, which increased to 96.5% in 2007-2010 (p<0.001). The proportion of patients treated with consistent dosing of a 3-drug fixed-dose combination (FDC) increased from 73.9% in 2003 to 87.7% in 2007-2010 (p<0.001), and that for 2-drug FDC from 76.0% to 86.1% (p = 0.024), for rifampicin (RMP) from 62.8% to 85.5% (p<0.001), and for isoniazid from 87.8% to 95.3% (p<0.001). In 2007-2010, among 2917 patients treated with either FDCs or RMP in single-drug preparation, the dosage of RMP was adequate (8-12 mg/kg) in 2571(88.1%) patients, too high in 282(9.7%), too low in 64(2.2%). In multinomial logistic regression models, factors significantly associated with adequate dosage of RMP were body weight and preparations of RMP. Patients weighting <40 kg (relative risk ratio (rrr) 6010.5, 95% CI 781.1-46249.7) and patients weighting 40-49 kg (rrr 1495.3, 95% CI 200.6-11144.6) were more likely to receive higher-than-recommended dose of RMP. Prescribing practice in the treatment of TB in Taipei City has remarkably improved after health authorities implemented a series of interventions.

The Adjuvant LT-K63 Can Restore Delayed Maturation of Follicular Dendritic Cells and Poor Persistence of Both Protein- and Polysaccharide-Specific Antibody-Secreting Cells in Neonatal Mice

PubMed Central

Bjarnarson, Stefania P.; Adarna, Brenda C.; Benonisson, Hreinn; Del Giudice, Giuseppe

2012-01-01

Ab responses in early life are low and short-lived; therefore, induction of protective immunity requires repeated vaccinations. One of the major limitations in early-life immunity is delayed maturation of follicular dendritic cells (FDCs), which play a central role in mediating the germinal center (GC) reaction leading to production of Ab-secreting cells (AbSCs). We assessed whether a nontoxic mutant of Escherichia coli heat-labile enterotoxin (LT-K63) and CpG1826 as model adjuvants could accelerate FDC maturation and immune response in neonatal mice, using a pneumococcal polysaccharide of serotype 1 conjugated to tetanus toxoid (Pnc1-TT) as a model vaccine. In neonatal NMRI mice, a single dose of Pnc1-TT coadministered with LT-K63 enhanced Pnc1-TT–induced GC reaction. In contrast, CpG1826 had no effect. Accordingly, LT-K63, but not CpG1826, accelerated the maturation of FDC networks, detected by FDC-M2+ staining, characteristic for adult-like FDCs. This coincided with migration of MOMA-1+ macrophages into the GCs that can enhance GC reaction and B cell activation. The FDC-M2+ FDC networks colocalized with enhanced expression of TNF-α, which is critical for the maintenance of mature FDCs and is poorly expressed in neonates. The accelerated maturation of FDC networks correlated with increased frequency and prolonged persistence of polysaccharide- and protein-specific IgG+ AbSCs in spleen and bone marrow. Our data show for the first time, to our knowledge, that an adjuvant (LT-K63) can overcome delayed maturation of FDCs in neonates, enhance the GC reaction, and prolong the persistence of vaccine-specific AbSCs in the BM. These properties are attractive for parenteral vaccination in early life. PMID:22753937

Enhanced inactivation of foodborne pathogenic and spoilage bacteria by FD&C Red no. 3 and other xanthene derivatives during ultrahigh pressure processing.

PubMed

Waite, Joy G; Yousef, Ahmed E

2008-09-01

Variability among microorganisms in barotolerance has been demonstrated at genus, species, and strain levels. Identification of conditions and additives that enhance the efficacy of ultrahigh pressure (UHP) against important foodborne microorganisms is crucial for maximizing product safety and stability. Preliminary work indicated that FD&C Red No. 3 (Red 3), a xanthene derivative, was bactericidal and acted synergistically with UHP against Lactobacillus spp. The objective of this study was to determine the antimicrobial efficacy of Red 3 and other xanthene derivatives, alone and combined with UHP, against spoilage and pathogenic bacteria in citrate-phosphate buffer (pH 7.0). Xanthene derivatives tested were fluorescein, Eosin Y, Erythrosin B, Phloxine B, Red 3, and Rose Bengal. Halogenated xanthene derivatives (10 ppm) were effective at reducing Listeria monocytogenes survivors but ineffective against Escherichia coli O157:H7. When combined with UHP (400 MPa, 3 min), the presence of derivatives enhanced inactivation. Because Red 3 was the only xanthene derivative to produce synergistic inactivation of both pathogens, further studies using this colorant were warranted. Efficacy of Red 3 against gram-positive bacteria (Lactobacillus plantarum and L. monocytogenes) was concentration dependent (1 to 10 ppm). E. coi O157: H7 strains were resistant to Red 3 concentrations up to 300 ppm. When Red 3 was combined with UHP, the lethality against gram-positive and gram-negative bacteria was dose dependent, with synergy being significant for most strains at > or = 3 ppm. Additional gram-positive and gram-negative bacteria showed lethalities similar to those observed for L. plantarum or L. monocytogenes, and E. coli O157:H7, respectively. Red 3 is a potentially useful additive to enhance the safety and stability of UHP-treated food products.

Improved Consistency in Dosing Anti-Tuberculosis Drugs in Taipei, Taiwan

PubMed Central

Chiang, Chen-Yuan; Yu, Ming-Chih; Shih, Hsiu-Chen; Yen, Muh-Yong; Hsu, Yu-Ling; Yang, Shiang-Lin; Lin, Tao-Ping; Bai, Kuan-Jen

2012-01-01

Background It was reported that 35.5% of tuberculosis (TB) cases reported in 2003 in Taipei City had no recorded pre-treatment body weight and that among those who had, inconsistent dosing of anti-TB drugs was frequent. Taiwan Centers for Disease Control (CDC) have taken actions to strengthen dosing of anti-TB drugs among general practitioners. Prescribing practices of anti-TB drugs in Taipei City in 2007–2010 were investigated to assess whether interventions on dosing were effective. Methodology/Principal Findings Lists of all notified culture positive TB cases in 2007–2010 were obtained from National TB Registry at Taiwan CDC. A medical audit of TB case management files was performed to collect pretreatment body weight and regimens prescribed at commencement of treatment. Dosages prescribed were compared with dosages recommended. The proportion of patients with recorded pre-treatment body weight was 64.5% in 2003, which increased to 96.5% in 2007–2010 (p<0.001). The proportion of patients treated with consistent dosing of a 3-drug fixed-dose combination (FDC) increased from 73.9% in 2003 to 87.7% in 2007–2010 (p<0.001), and that for 2-drug FDC from 76.0% to 86.1% (p = 0.024), for rifampicin (RMP) from 62.8% to 85.5% (p<0.001), and for isoniazid from 87.8% to 95.3% (p<0.001). In 2007–2010, among 2917 patients treated with either FDCs or RMP in single-drug preparation, the dosage of RMP was adequate (8–12 mg/kg) in 2571(88.1%) patients, too high in 282(9.7%), too low in 64(2.2%). In multinomial logistic regression models, factors significantly associated with adequate dosage of RMP were body weight and preparations of RMP. Patients weighting <40kg (relative risk ratio (rrr) 6010.5, 95% CI 781.1–46249.7) and patients weighting 40–49 kg (rrr 1495.3, 95% CI 200.6–11144.6) were more likely to receive higher-than-recommended dose of RMP. Conclusions/Significance Prescribing practice in the treatment of TB in Taipei City has remarkably improved after health authorities implemented a series of interventions. PMID:22952900

Isoniazid, Pyrazinamide and Rifampicin Content Variation in Split Fixed-Dose Combination Tablets

PubMed Central

Pouplin, Thomas; Phuong, Pham Nguyen; Toi, Pham Van; Nguyen Pouplin, Julie; Farrar, Jeremy

2014-01-01

Setting In most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets. Objective To determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis. Design Drug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high performance liquid chromatography. The content uniformity was assessed by comparing drug content measured in split portions with their expected amounts and the quality of split portions was assessed applying qualitative specifications for whole tablets. Results All whole tablets measurements fell into the USP proxy for the three drugs. But a significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity. To correct for the inaccuracy of splitting the tablets into equal portions, a weight-adjustment strategy was used but this did not improve the findings. Conclusion In split tablets the content of the three drugs is non-uniform and exceeded the USP recommendations. There is an absolute need to make child-friendly formulations available for the treatment of childhood tuberculosis. PMID:25004128

Isoniazid, pyrazinamide and rifampicin content variation in split fixed-dose combination tablets.

PubMed

Pouplin, Thomas; Phuong, Pham Nguyen; Toi, Pham Van; Nguyen Pouplin, Julie; Farrar, Jeremy

2014-01-01

In most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets. To determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis. Drug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high performance liquid chromatography. The content uniformity was assessed by comparing drug content measured in split portions with their expected amounts and the quality of split portions was assessed applying qualitative specifications for whole tablets. All whole tablets measurements fell into the USP proxy for the three drugs. But a significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity. To correct for the inaccuracy of splitting the tablets into equal portions, a weight-adjustment strategy was used but this did not improve the findings. In split tablets the content of the three drugs is non-uniform and exceeded the USP recommendations. There is an absolute need to make child-friendly formulations available for the treatment of childhood tuberculosis.

Chemical genomic guided engineering of gamma-valerolactone tolerant yeast.

PubMed

Bottoms, Scott; Dickinson, Quinn; McGee, Mick; Hinchman, Li; Higbee, Alan; Hebert, Alex; Serate, Jose; Xie, Dan; Zhang, Yaoping; Coon, Joshua J; Myers, Chad L; Landick, Robert; Piotrowski, Jeff S

2018-01-12

Gamma valerolactone (GVL) treatment of lignocellulosic bomass is a promising technology for degradation of biomass for biofuel production; however, GVL is toxic to fermentative microbes. Using a combination of chemical genomics with the yeast (Saccharomyces cerevisiae) deletion collection to identify sensitive and resistant mutants, and chemical proteomics to monitor protein abundance in the presence of GVL, we sought to understand the mechanism toxicity and resistance to GVL with the goal of engineering a GVL-tolerant, xylose-fermenting yeast. Chemical genomic profiling of GVL predicted that this chemical affects membranes and membrane-bound processes. We show that GVL causes rapid, dose-dependent cell permeability, and is synergistic with ethanol. Chemical genomic profiling of GVL revealed that deletion of the functionally related enzymes Pad1p and Fdc1p, which act together to decarboxylate cinnamic acid and its derivatives to vinyl forms, increases yeast tolerance to GVL. Further, overexpression of Pad1p sensitizes cells to GVL toxicity. To improve GVL tolerance, we deleted PAD1 and FDC1 in a xylose-fermenting yeast strain. The modified strain exhibited increased anaerobic growth, sugar utilization, and ethanol production in synthetic hydrolysate with 1.5% GVL, and under other conditions. Chemical proteomic profiling of the engineered strain revealed that enzymes involved in ergosterol biosynthesis were more abundant in the presence of GVL compared to the background strain. The engineered GVL strain contained greater amounts of ergosterol than the background strain. We found that GVL exerts toxicity to yeast by compromising cellular membranes, and that this toxicity is synergistic with ethanol. Deletion of PAD1 and FDC1 conferred GVL resistance to a xylose-fermenting yeast strain by increasing ergosterol accumulation in aerobically grown cells. The GVL-tolerant strain fermented sugars in the presence of GVL levels that were inhibitory to the unmodified strain. This strain represents a xylose fermenting yeast specifically tailored to GVL produced hydrolysates.

Pharmacokinetic drug evaluation of saxagliptin plus dapagliflozin for the treatment of type 2 diabetes.

PubMed

Scheen, André J

2017-05-01

Combining a dipeptidyl peptidase-4 inhibitor and a sodium-glucose cotransporter type 2 inhibitor is an attractive option to treat hyperglycaemia in type 2 diabetes. Areas covered: The saxagliptin plus dapagliflozin combination is carefully analysed, focusing on: 1) pharmacokinetic properties, 2) pharmacodynamics data, and 3) results of randomised controlled trials (dual combination versus either monotherapy, sequential therapy saxagliptin added to dapagliflozin or dapagliflozin added to saxagliptin). Expert opinion: Pharmacokinetic findings demonstrate the absence of drug-drug interaction and the bioequivalence of the FDC compared with separated tablets. Pharmacodynamic observations confirm a complementary mode of action of the two agents. Dual saxagliptin-dapagliflozin therapy is more potent than either monotherapy. It may be used as an initial combination, although this approach remains debatable and should probably be reserved in case of high glycated hemoglobin, or a stepwise strategy, according to a personalized approach. The developed saxagliptin-dapagliflozin FDC may simplify anti-hyperglycemic therapy and improve drug compliance.

Antituberculosis Drug-Induced Fixed Drug Eruption: A Case Report.

PubMed

Vaghela, Jitendra H; Nimbark, Vivek; Barvaliya, Manish; Mehta, Hita; Chavada, Bhavesh

2018-05-21

Fixed drug eruption (FDE) was caused by fixed-dose combination (FDC) of antituberculosis drugs in the form of tablet Forecox ® (rifampicin [rifampin] 225 mg + isoniazid 150 mg + pyrazinamide 750 mg + ethambutol 400 mg) in a 40-year-old male patient with a history of drug allergy. The patient developed FDE after taking the third dose of tablet Forecox ® for pulmonary tuberculosis. Tablet Forecox ® was withdrawn and the patient recovered from the reaction after 15 days of treatment for FDE. As per World Health Organization-Uppsala Monitoring Centre (WHO-UMC) and Naranjo causality assessment criteria, the association between the reaction and tablet Forecox ® was possible and probable, respectively. The reaction was moderately (Level 4b) severe according to the Modified Hartwig and Siegel scale. As there is an increased risk of allergic reaction in patients with a history of drug allergy, FDCs should not be used in order to avoid complexity in identifying the culprit drug.

Pharmacodynamic effects of a new fixed-dose clopidogrel-aspirin combination compared with separate administration of clopidogrel and aspirin in patients treated with coronary stents: The ACCEL-COMBO trial.

PubMed

Koh, Jin-Sin; Park, Yongwhi; Tantry, Udaya S; Ahn, Jong-Hwa; Kang, Min Gyu; Kim, Kyehwan; Jang, Jeong Yoon; Park, Hyun Woong; Park, Jeong Rang; Hwang, Seok-Jae; Kwak, Choong Hwan; Hwang, Jin-Yong; Gurbel, Paul A; Jeong, Young-Hoon

2017-03-01

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely prescribed regimen to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI). A fixed-dose combination (FDC) capsule (HCP0911) has been developed to provide dosing convenience and improve adherence. We compared the antiplatelet effects of single daily dose HCP0911 with separate treatment with daily 75 mg clopidogrel plus 100 mg aspirin. This was a randomized, open-label, two-period, crossover, non-inferiority study conducted in stented patients who had been treated for at least 6 months with clopidogrel and aspirin. Thirty patients were randomly assigned to receive either daily 75 mg clopidogrel plus 100 mg aspirin treatment or HCP0911 for 2 weeks and then were crossed over to the other treatment for 2 weeks. Pharmacodynamic effects were measured with VerifyNow, light transmittance aggregometry (LTA), and thromboelastography (TEG ® ). The primary endpoint was P2Y12 Reaction Units (PRU) measured by VerifyNow. PRUs during treatment with HCP0911 were not inferior to those during separate treatment (202 ± 52 vs. 207 ± 60 PRU; mean difference, -5 PRU; 90% confidence interval of difference, -23 to 13 PRU; P for non-inferiority = 0.015 for predetermined limit). "BASE" and Aspirin Reaction Units by VerifyNow did not differ between the two treatments. During each treatment, there were no differences in maximal and final platelet aggregations by LTA (all P values ≥0.822) and TEG ® measurements. In conclusion, in stented patients, the antiplatelet effect of a fixed-dose clopidogrel-aspirin combination, HCP0911, was not inferior to separate administration of clopidogrel and aspirin.

21 CFR 74.2203 - FD&C Green No. 3.

Code of Federal Regulations, 2010 CFR

2010-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2203 FD&C Green No. 3. (a) Identity and specifications. The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements of § 74.203(a)(1) and (b). (b) Uses and restrictions. The color additive FD&C Green No. 3 may be...

21 CFR 74.2203 - FD&C Green No. 3.

Code of Federal Regulations, 2014 CFR

2014-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2203 FD&C Green No. 3. (a) Identity and specifications. The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements of § 74.203(a)(1) and (b). (b) Uses and restrictions. The color additive FD&C Green No. 3 may be...

21 CFR 74.2203 - FD&C Green No. 3.

Code of Federal Regulations, 2013 CFR

2013-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2203 FD&C Green No. 3. (a) Identity and specifications. The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements of § 74.203(a)(1) and (b). (b) Uses and restrictions. The color additive FD&C Green No. 3 may be...

21 CFR 74.2203 - FD&C Green No. 3.

Code of Federal Regulations, 2012 CFR

2012-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2203 FD&C Green No. 3. (a) Identity and specifications. The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements of § 74.203(a)(1) and (b). (b) Uses and restrictions. The color additive FD&C Green No. 3 may be...

Common elements in interleukin 4 and insulin signaling pathways in factor-dependent hematopoietic cells.

PubMed

Wang, L M; Keegan, A D; Li, W; Lienhard, G E; Pacini, S; Gutkind, J S; Myers, M G; Sun, X J; White, M F; Aaronson, S A

1993-05-01

Interleukin 4 (IL-4), insulin, and insulin-like growth factor I (IGF-I) efficiently induced DNA synthesis in the IL-3-dependent murine myeloid cell lines FDC-P1 and FDC-P2. Although these factors could not individually sustain long-term growth of these lines, a combination of IL-4 with either insulin or IGF-I did support continuous growth. The principal tyrosine-phosphorylated substrate observed in FDC cells stimulated with IL-4, previously designated 4PS, was of the same size (170 kDa) as the major substrate phosphorylated in response to insulin or IGF-I. These substrates had phosphopeptides of the same size when analyzed by digestion with Staphylococcus aureus V8 protease, and each tightly associated with the 85-kDa component of phosphatidylinositol 3-kinase after factor stimulation. IRS-1, the principal substrate phosphorylated in response to insulin or IGF-I stimulation in nonhematopoietic cells, is similar in size to 4PS. However, anti-IRS-1 antibodies failed to efficiently precipitate 4PS, and some phosphopeptides generated by V8 protease digestion of IRS-1 were distinct in size from the phosphopeptides of 4PS. Nevertheless, IL-4, insulin, and IGF-I were capable of stimulating tyrosine phosphorylation of IRS-1 in FDC cells that expressed this substrate as a result of transfection. These findings indicate that (i) IL-4, insulin, and IGF-I use signal transduction pathways in FDC lines that have at least one major feature in common, the rapid tyrosine phosphorylation of 4PS, and (ii) insulin and IGF-I stimulation of hematopoietic cell lines leads to the phosphorylation of a substrate that may be related to but is not identical to IRS-1.

Common elements in interleukin 4 and insulin signaling pathways in factor-dependent hematopoietic cells.

PubMed Central

Wang, L M; Keegan, A D; Li, W; Lienhard, G E; Pacini, S; Gutkind, J S; Myers, M G; Sun, X J; White, M F; Aaronson, S A

1993-01-01

Interleukin 4 (IL-4), insulin, and insulin-like growth factor I (IGF-I) efficiently induced DNA synthesis in the IL-3-dependent murine myeloid cell lines FDC-P1 and FDC-P2. Although these factors could not individually sustain long-term growth of these lines, a combination of IL-4 with either insulin or IGF-I did support continuous growth. The principal tyrosine-phosphorylated substrate observed in FDC cells stimulated with IL-4, previously designated 4PS, was of the same size (170 kDa) as the major substrate phosphorylated in response to insulin or IGF-I. These substrates had phosphopeptides of the same size when analyzed by digestion with Staphylococcus aureus V8 protease, and each tightly associated with the 85-kDa component of phosphatidylinositol 3-kinase after factor stimulation. IRS-1, the principal substrate phosphorylated in response to insulin or IGF-I stimulation in nonhematopoietic cells, is similar in size to 4PS. However, anti-IRS-1 antibodies failed to efficiently precipitate 4PS, and some phosphopeptides generated by V8 protease digestion of IRS-1 were distinct in size from the phosphopeptides of 4PS. Nevertheless, IL-4, insulin, and IGF-I were capable of stimulating tyrosine phosphorylation of IRS-1 in FDC cells that expressed this substrate as a result of transfection. These findings indicate that (i) IL-4, insulin, and IGF-I use signal transduction pathways in FDC lines that have at least one major feature in common, the rapid tyrosine phosphorylation of 4PS, and (ii) insulin and IGF-I stimulation of hematopoietic cell lines leads to the phosphorylation of a substrate that may be related to but is not identical to IRS-1. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:7683417

The impact of dual bronchodilation on cardiovascular serious adverse events and mortality in COPD: a quantitative synthesis

PubMed Central

Rogliani, Paola; Matera, Maria Gabriella; Ora, Josuel; Cazzola, Mario; Calzetta, Luigino

2017-01-01

Objective Long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are burdened by the potential risk of inducing cardiovascular serious adverse events (SAEs) in COPD patients. Since the risk of combining a LABA with a LAMA could be greater, we have carried out a quantitative synthesis to investigate the cardiovascular safety profile of LABA/LAMA fixed-dose combinations (FDCs). Methods A pair-wise and network meta-analysis was performed by using the data of the repository database ClinicalTrials.gov concerning the impact of approved LABA/LAMA FDCs versus monocomponents and/or placebo on cardiovascular SAEs in COPD. Results Overall, LABA/LAMA FDCs did not significantly (P>0.05) modulate the risk of cardiovascular SAEs versus monocomponents. However, the network meta-analysis indicated that aclidinium/formoterol 400/12 µg and tiotropium/olodaterol 5/5 µg were the safest FDCs, followed by umeclidinium/vilanterol 62.5/25 µg which was as safe as placebo, whereas glycopyrronium/formoterol 14.9/9.6, glycopyrronium/indacaterol 15.6/27.5 µg, and glycopyrronium/indacaterol 50/110 µg were the least safe FDCs. No impact on mortality was detected for each specific FDC. Conclusion This meta-analysis indicates that LABA/LAMA FDC therapy is characterized by an excellent cardiovascular safety profile in COPD patients. However, the findings of this quantitative synthesis have been obtained from populations that participated in randomized clinical trials, and were devoid of major cardiovascular diseases. Thus, post-marketing surveillance and observational studies may help to better define the real impact of specific FDCs with regard to the cardiovascular risk. PMID:29255354

21 CFR 74.1101 - FD&C Blue No. 1

Code of Federal Regulations, 2010 CFR

2010-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1101 FD&C Blue No. 1 (a) Identity. (1) For ingested drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of § 74.101(a)(1). (2) For externally applied drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of...

21 CFR 74.1303 - FD&C Red No. 3.

Code of Federal Regulations, 2010 CFR

2010-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1303 FD&C Red No. 3. (a) Identity and specifications. (1) The color additive FD&C Red No. 3 shall conform in identity and specifications to the requirements of § 74.303(a)(1) and (b). (2) Color additive mixtures for ingested drug used made with FD&C Red No. 3 may...

21 CFR 74.1303 - FD&C Red No. 3.

Code of Federal Regulations, 2014 CFR

2014-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1303 FD&C Red No. 3. (a) Identity and specifications. (1) The color additive FD&C Red No. 3 shall conform in identity and specifications to the requirements of § 74.303(a)(1) and (b). (2) Color additive mixtures for ingested drug used made with FD&C Red No. 3 may...

21 CFR 74.1303 - FD&C Red No. 3.

Code of Federal Regulations, 2013 CFR

2013-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1303 FD&C Red No. 3. (a) Identity and specifications. (1) The color additive FD&C Red No. 3 shall conform in identity and specifications to the requirements of § 74.303(a)(1) and (b). (2) Color additive mixtures for ingested drug used made with FD&C Red No. 3 may...

21 CFR 74.1303 - FD&C Red No. 3.

Code of Federal Regulations, 2012 CFR

2012-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1303 FD&C Red No. 3. (a) Identity and specifications. (1) The color additive FD&C Red No. 3 shall conform in identity and specifications to the requirements of § 74.303(a)(1) and (b). (2) Color additive mixtures for ingested drug used made with FD&C Red No. 3 may...

Habituation in Frankliniella occidentalis to deterrent plant compounds and their blends.

PubMed

Egger, Barbara; Spangl, Bernhard; Koschier, Elisabeth Helene

2014-06-01

Feeding and oviposition deterrence of three secondary plant compounds and their 1:1 blends to adult female Frankliniella occidentalis Pergande (Thysanoptera: Thripidae) and the potential for habituation of the thrips to the pure compounds and the 1:1 blends at various concentrations were investigated. In choice assays, we tested dose-dependent feeding and oviposition deterrence of the two fatty acid derivatives methyl jasmonate and cis -jasmone, the phenylpropanoid allylanisole, and their blends when directly applied to bean leaf discs. The concentration required to reduce the feeding damage by 50% relative to the control treatment (FDC 50 ) was lowest for cis -jasmone and highest for allylanisole. The feeding deterrent effect of both jasmonates was increased when blended with allylanisole. Feeding deterrence and oviposition deterrence were strongly correlated. In no-choice assays conducted over four consecutive days, we discovered that dilutions at low concentrations (FDC 15 ) applied to bean leaves resulted in habituation to the deterrents, whereas no habituation occurred at higher concentrations (FDC 50 ). We observed a tendency that the 1:1 blends reduce the probability that thrips habituate to the deterrent compounds. Our results may be useful in the development of integrated crop protection strategies with the implementation of allelochemicals as pest behaviour-modifying agents.

Pharmacokinetics and bioequivalence study of a fixed dose combination of rabeprazole and itopride in healthy Indian volunteers.

PubMed

Sahoo, Bijay Kumar; Das, Ayan; Agarwal, Sangita; Bhaumik, Uttam; Bose, Anirbandeep; Ghosh, Debotri; Roy, Bikash; Pal, Tapan Kumar

2009-01-01

The aim of the present study was to compare the pharmacokinetics of rabeprazole (CAS 117976-89-3) and itopride (CAS 122898-67-3) after oral administration of a rabeprazole (20 mg)-itopride (150 mg) fixed dose combination (FDC) in healthy human volunteers. The bioequivalence of two formulations (test and reference) was determined in 12 healthy Indian male volunteers (age: 25.25 +/- 4.69 years; weight: 60.50 +/- 5.04 kg) in a randomized, single-dose, two-period, two-treatment crossover study. Both formulations were administered orally as a single dose, with the treatments separated by a washout period of 1 week. Rabeprazole and itopride plasma levels were determined by a validated HPLC method using UV detection. The formulations were compared using the pharmacokinetic parameters area under the plasma concentration-time curve (AUC(0-t)), area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) and peak plasma concentration (Cmax). General linear model (GLM) procedures were used in which sources of variation were subject, treatment and period. The results indicated that there were no statistically significant differences (P > 0.05) between the logarithmically transformed AUC(0-infinity) and Cmax values between test and reference formulation. The 90% confidence interval for the ratio of the logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax were within the bioequivalence limits of 0.8-1.25 and the relative bioavailability of rabeprazole and itopride test and reference formulations was 98.24 and 93.65%, respectively.

21 CFR 74.1101 - FD&C Blue No. 1

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Blue No. 1 74.1101 Section 74.1101 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1101 FD&C Blue No. 1 (a) Identity. (1) For ingested drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of § 74.101(a)(1). (2) For...

21 CFR 82.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

21 CFR 82.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color additive FD&C Blue No. 1 shall conform in identity and specifications to the requirements of § 74.101(a)(1...

21 CFR 74.1102 - FD&C Blue No. 2.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Blue No. 2. 74.1102 Section 74.1102 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1102 FD&C Blue No. 2. (a) Identity. (1) The color additive FD&C Blue No. 2 shall conform in identity to the requirements of § 74.102(a)(1). (2) Color additive...

21 CFR 74.1101 - FD&C Blue No. 1

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Blue No. 1 74.1101 Section 74.1101 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1101 FD&C Blue No. 1 (a) Identity. (1) For ingested drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of § 74.101(a)(1). (2) For...

21 CFR 82.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

21 CFR 74.1102 - FD&C Blue No. 2.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Blue No. 2. 74.1102 Section 74.1102 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1102 FD&C Blue No. 2. (a) Identity. (1) The color additive FD&C Blue No. 2 shall conform in identity to the requirements of § 74.102(a)(1). (2) Color additive...

21 CFR 74.1101 - FD&C Blue No. 1

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Blue No. 1 74.1101 Section 74.1101 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1101 FD&C Blue No. 1 (a) Identity. (1) For ingested drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of § 74.101(a)(1). (2) For...

21 CFR 82.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color additive FD&C Blue No. 1 shall conform in identity and specifications to the requirements of § 74.101(a)(1...

21 CFR 82.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

21 CFR 82.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color additive FD&C Blue No. 1 shall conform in identity and specifications to the requirements of § 74.101(a)(1...

21 CFR 82.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

21 CFR 82.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

21 CFR 74.1102 - FD&C Blue No. 2.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Blue No. 2. 74.1102 Section 74.1102 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1102 FD&C Blue No. 2. (a) Identity. (1) The color additive FD&C Blue No. 2 shall conform in identity to the requirements of § 74.102(a)(1). (2) Color additive...

40 CFR 180.1074 - F.D.&C. Blue No. 1; exemption from the requirement of a tolerance.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 24 2011-07-01 2011-07-01 false F.D.&C. Blue No. 1; exemption from the... Exemptions From Tolerances § 180.1074 F.D.&C. Blue No. 1; exemption from the requirement of a tolerance. F.D.&C. Blue No. 1 is exempted from the requirement of a tolerance when used as an aquatic plant control...

40 CFR 180.1074 - F.D.&C. Blue No. 1; exemption from the requirement of a tolerance.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 25 2013-07-01 2013-07-01 false F.D.&C. Blue No. 1; exemption from the... Exemptions From Tolerances § 180.1074 F.D.&C. Blue No. 1; exemption from the requirement of a tolerance. F.D.&C. Blue No. 1 is exempted from the requirement of a tolerance when used as an aquatic plant control...

40 CFR 180.1074 - F.D.&C. Blue No. 1; exemption from the requirement of a tolerance.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 25 2012-07-01 2012-07-01 false F.D.&C. Blue No. 1; exemption from the... Exemptions From Tolerances § 180.1074 F.D.&C. Blue No. 1; exemption from the requirement of a tolerance. F.D.&C. Blue No. 1 is exempted from the requirement of a tolerance when used as an aquatic plant control...

40 CFR 180.1074 - F.D.&C. Blue No. 1; exemption from the requirement of a tolerance.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false F.D.&C. Blue No. 1; exemption from the... Exemptions From Tolerances § 180.1074 F.D.&C. Blue No. 1; exemption from the requirement of a tolerance. F.D.&C. Blue No. 1 is exempted from the requirement of a tolerance when used as an aquatic plant control...

40 CFR 180.1074 - F.D.&C. Blue No. 1; exemption from the requirement of a tolerance.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 24 2014-07-01 2014-07-01 false F.D.&C. Blue No. 1; exemption from the... Exemptions From Tolerances § 180.1074 F.D.&C. Blue No. 1; exemption from the requirement of a tolerance. F.D.&C. Blue No. 1 is exempted from the requirement of a tolerance when used as an aquatic plant control...

Behavior of decomposition of rifampicin in the presence of isoniazid in the pH range 1-3.

PubMed

Sankar, R; Sharda, Nishi; Singh, Saranjit

2003-08-01

The extent of decomposition of rifampicin in the presence of isoniazid was determined in the pH range 1-3 at 37 degrees C in 50 min, the mean stomach residence time. With increase in pH, the degradation initially increased from pH 1 to 2 and then decreased, resulting in a bell-shaped pH-decomposition profile. This showed that rifampicin degraded in the presence of isoniazid to a higher extent at pH 2, the maximum pH in the fasting condition, under which antituberculosis fixed-dose combination (FDC) products are administered. At this pH and in 50 min, rifampicin decomposed by approximately 34%, while the fall of isoniazid was 10%. The extent of decomposition for the two drugs was also determined in marketed formulations, and the values ranged between 13-35% and 4-11%, respectively. The extents of decomposition at stomach residence times of 15 min and 3 h were 11.94% and 62.57%, respectively, for rifampicin and 4.78% and 11.12%, respectively, for isoniazid. The results show that quite an extensive loss of rifampicin and isoniazid can occur as a result of interaction between them in fasting pH conditions. This emphasizes that antituberculosis FDC formulations, which contain both drugs, should be designed in a manner that the interaction of the two drugs is prevented when the formulations are administered on an empty stomach.

77 FR 71006 - Sodium Nitrite Injection and Sodium Thiosulfate Injection Drug Products Labeled for the Treatment...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-28

... 505(b) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 355(b)): Division of.... Methemoglobinemia can lead to neurological and cardiac symptoms due to lack of adequate oxygen in body tissues. The... discrepancies in dosing may lead to underdosing of sodium thiosulfate in children. III. Legal Status of Products...

Dapagliflozin and saxagliptin tablets for adults with type 2 diabetes.

PubMed

Scheen, André J

2017-12-01

Saxagliptin (a dipeptidyl peptidase-4 inhibitor, DPP-4i) and dapagliflozin (a sodium-glucose cotransporter type 2 inhibitor, SGLT2i) improve glucose control in type 2 diabetes (T2D) through different potentially complementary mechanisms, thus offering the opportunity for a combined therapy. Area covered: The characteristics of the saxagliptin/dapagliflozin combination are analysed, focusing on: 1) pharmacokinetic and pharmacodynamic properties; 2) efficacy and safety in phase III trials with concurrent and sequential add-on therapy; and 3) potential use in clinical practice, including in special populations (cardiovascular disease, heart failure, chronic kidney disease, elderly). Expert commentary: Conclusions drawn from clinical trials investigating combination with the separate drugs are considered to apply to the fixed-dose combination (FDC) that demonstrates bioequivalence. Dual saxagliptin/dapagliflozin therapy is more potent than either monotherapy and can be used as an initial combination or a stepwise sequential approach. Dual therapy is generally well tolerated and may be used in special populations, with some limitations because of the presence of dapagliflozin. However, the latter may offer some advantages because of multiple effects attributed to SGLT2i. The best place of this dual combination for the management of T2D and the profile of patients who will make the most of this combined therapy remains to be defined.

Population Pharmacokinetics and Exposure-Response of a Fixed-Dose Combination of Azilsartan Medoxomil and Chlorthalidone in Patients With Stage 2 Hypertension.

PubMed

Tsai, Max C; Wu, Jingtao; Kupfer, Stuart; Vakilynejad, Majid

2016-08-01

Population pharmacokinetic and exposure-response models for azilsartan medoxomil (AZL-M) and chlorthalidone (CLD) were developed using data from an 8-week placebo-controlled phase 3, factorial study of 20, 40, and 80 mg AZL-M every day (QD) and 12.5 and 25 mg CLD QD in fixed-dose combination (FDC) in subjects with moderate to severe essential hypertension. A 2-compartment model with first-order absorption and elimination was developed to describe pharmacokinetics. An Emax model for exposure-response analysis evaluated AZL-M/CLD effects on ambulatory systolic blood pressure (SBP). Estimated oral clearance and apparent volume of distribution (central compartment) were 1.47 L/h and 3.98 L for AZL, and 4.13 L/h and 62.1 L for CLD. Age as a covariate had the largest effect on AZL and CLD exposure (±20% change). Predicted maximal SBP responses (Emax ) were -15.6 and -23.9 mm Hg for AZL and CLD. Subgroup analysis identified statistically significant Emax differences for black vs nonblack subjects, whereby the reduced AZL response in black subjects was offset by greater response to CLD. The estimated Emax for AZL and CLD was generally greater in subjects with higher baseline BP. In conclusion, no dose adjustments to AZL-M or CLD are warranted based on identified covariates, and antihypertensive efficacy of AZL-M/CLD combination therapy is comparable in black and nonblack subjects. © 2015, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Follicular Dendritic Cells Retain Infectious HIV in Cycling Endosomes

PubMed Central

Heesters, Balthasar A.; Lindqvist, Madelene; Vagefi, Parsia A.; Scully, Eileen P.; Schildberg, Frank A.; Altfeld, Marcus; Walker, Bruce D.; Kaufmann, Daniel E.; Carroll, Michael C.

2015-01-01

Despite the success of antiretroviral therapy (ART), it does not cure Human Immunodeficiency Virus (HIV) and discontinuation results in viral rebound. Follicular dendritic cells (FDC) are in direct contact with CD4+ T cells and they retain intact antigen for prolonged periods. We found that human FDC isolated from patients on ART retain infectious HIV within a non-degradative cycling compartment and transmit infectious virus to uninfected CD4 T cells in vitro. Importantly, treatment of the HIV+ FDC with a soluble complement receptor 2 purges the FDC of HIV virions and prevents viral transmission in vitro. Our results provide an explanation for how FDC can retain infectious HIV for extended periods and suggest a therapeutic strategy to achieve cure in HIV-infected humans. PMID:26623655

Human FDC express PrPc in vivo and in vitro

PubMed Central

Thielen, Caroline; Antoine, Nadine; Mélot, France; Cesbron, Jean-Yves; Heinen, Ernst

2001-01-01

Prion diseases are fatal neurodegenerative disorders caused by accumulation of abnormal prion protein (protease-resistant prion, PrPres). PrPres accumulation is also detected in lymphoid organs after peripheral infection. Several studies suggest that follicular dendritic cells (FDC) could be the site of PrPres retention and amplification. Here we show that human follicular dendritic cells can express normal cellular prion protein (PrPc) both in situ and in vitro. When tonsillar cryosections were treated with anti-PrP antibody, the label was found on some very delicate cell extensions inside the lymphoid follicles, especially in the germinal centres. These extensions react with DRC1 antibody, used frequently to label FDC. Other structures labelled with anti-PrP antibody were the keratinocytes. To confirm the ability of FDC to synthesise PrPc, we isolated FDC by a non-enzymatic procedure and cultured them. By cytochemistry and flow cytometry it was clearly shown that FDC do produce PrPc. PMID:11785675

21 CFR 74.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.101 FD&C Blue No. 1. (a) Identity. (1) The color additive FD&C...] (o-sulfobenzyl) ammonium hydroxide inner salt. (2) Color additive mixtures for food use (including...

21 CFR 74.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.101 FD&C Blue No. 1. (a) Identity. (1) The color additive FD&C...] (o-sulfobenzyl) ammonium hydroxide inner salt. (2) Color additive mixtures for food use (including...

21 CFR 74.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.101 FD&C Blue No. 1. (a) Identity. (1) The color additive FD&C...] (o-sulfobenzyl) ammonium hydroxide inner salt. (2) Color additive mixtures for food use (including...

21 CFR 74.1203 - FD&C Green No. 3.

Code of Federal Regulations, 2010 CFR

2010-04-01

... manufacturing practice. (c) Labeling. The label of the color additive and any mixtures prepared therefrom... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1203 FD&C Green No. 3. (a) Identity and specifications. (1) The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements...

21 CFR 74.2706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2010 CFR

2010-04-01

... COLOR ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2706 FD&C Yellow No. 6. (a) Identity and specifications. The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

21 CFR 74.2706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2012 CFR

2012-04-01

... COLOR ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2706 FD&C Yellow No. 6. (a) Identity and specifications. The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

21 CFR 74.1203 - FD&C Green No. 3.

Code of Federal Regulations, 2013 CFR

2013-04-01

... manufacturing practice. (c) Labeling. The label of the color additive and any mixtures prepared therefrom... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1203 FD&C Green No. 3. (a) Identity and specifications. (1) The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements...

21 CFR 74.2706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2013 CFR

2013-04-01

... COLOR ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2706 FD&C Yellow No. 6. (a) Identity and specifications. The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

21 CFR 74.2706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2014 CFR

2014-04-01

... COLOR ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2706 FD&C Yellow No. 6. (a) Identity and specifications. The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

21 CFR 74.1203 - FD&C Green No. 3.

Code of Federal Regulations, 2012 CFR

2012-04-01

... manufacturing practice. (c) Labeling. The label of the color additive and any mixtures prepared therefrom... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1203 FD&C Green No. 3. (a) Identity and specifications. (1) The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements...

21 CFR 74.1203 - FD&C Green No. 3.

Code of Federal Regulations, 2014 CFR

2014-04-01

... manufacturing practice. (c) Labeling. The label of the color additive and any mixtures prepared therefrom... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1203 FD&C Green No. 3. (a) Identity and specifications. (1) The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements...

Retrieval of water vapor mixing ratios from a laser-based sensor

NASA Technical Reports Server (NTRS)

Tucker, George F.

1995-01-01

Langley Research Center has developed a novel external path sensor which monitors water vapor along an optical path between an airplane window and reflective material on the plane's engine. An infrared tunable diode laser is wavelength modulated across a water vapor absorption line at a frequency f. The 2f and DC signals are measured by a detector mounted adjacent to the laser. The 2f/DC ratio depends on the amount of wavelength modulation, the water vapor absorption line being observed, and the temperature, pressure, and water vapor content of the atmosphere. The present work concerns efforts to quantify the contributions of these factors and to derive a method for extracting the water vapor mixing ratio from the measurements. A 3 m cell was fabricated in order to perform laboratory tests of the sensor. Measurements of 2f/DC were made for a series of pressures and modulation amplitudes. During my 1994 faculty fellowship, a computer program was created which allowed 2f/DC to be calculated for any combination of the variables which effect it. This code was used to generate 2f/DC values for the conditions measured in the laboratory. The experimental and theoretical values agreed to within a few percent. As a result, the laser modulation amplitude can now be set in the field by comparing the response of the instrument to the calculated response as a function of modulation amplitude. Once the validity of the computer code was established, it was used to investigate possible candidate absorption lines. 2f/DC values were calculated for pressures, temperatures, and water vapor mixing ratios expected to be encountered in future missions. The results have been incorporated into a database which will be used to select the best line for a particular mission. The database will also be used to select a retrieval technique. For examples under some circumstances there is little temperature dependence in 2f/DC so temperature can be neglected. In other cases, there is a dependence with temperature for a particular pressure, requiring a more complicated retrieval algorithm. Future experimental work is necessary to test agreement with the theoretical values over a range of temperatures and mixing ratios. Additionally, retrieval algorithms for forthcoming missions must be incorporated into the software package which controls the instrument.

Pharmacokinetic Interaction Between Rosuvastatin, Telmisartan, and Amlodipine in Healthy Male Korean Subjects: A Randomized, Open-label, Multiple-dose, 2-period Crossover Study.

PubMed

Son, Mijeong; Guk, Jinju; Kim, Yukyung; Woo Chae, Dong; Heo, Young-A; Soh, Dongjun; Park, Kyungsoo

2016-08-01

Rosuvastatin, a hydroxy methylglutaryl coenzyme A reductase inhibitor; telmisartan, an angiotensin receptor blocker; and amlodipine, a calcium channel inhibitor, are commonly prescribed together for the treatment of hypertension nonresponsive to monotherapy and accompanied by dyslipidemia. However, the pharmacokinetic interactions among these 3 substances are not well understood. The aim of this study was to investigate the pharmacokinetic drug-drug interactions among rosuvastatin, telmisartan, and amlodipine in a healthy Korean male population. In both parts of this randomized, open-label, multiple-dose, 2-part, 2-period crossover study, subjects aged 19 to 55 years were enrolled. In part 1, each subject received rosuvastatin 20 mg with and without 2 fixed-dose combination (FDC) tablets of telmisartan/amlodipine 40/5 mg, once daily for 9 consecutive days. In part 2, each subject received 2 FDC tablets of telmisartan/amlodipine 40/5 mg with and without rosuvastatin 20 mg, once daily for 9 consecutive days. In both parts, there was a 13-day washout period between treatments. Pharmacokinetic samples were collected up to 72 hours after the last dose in subjects who received rosuvastatin only, and up to 144 hours after the last dose in subjects who received telmisartan/amlodipine with or without rosuvastatin. Adverse events (AEs) were assessed via interviews and physical examinations. Forty-eight subjects were enrolled, of whom 19 in part 1 and 22 in part 2 completed the study. In Part 1, the 90% CIs of the geometric mean ratios (GMRs) (coadministration of rosuvastatin and telmisartan/amlodipine to monotherapy with rosuvastatin) of the primary pharmacokinetic parameters (AUCτ and Cmax,ss) were: rosuvastatin, 1.1436 to 1.3059 and 1.8970 to 2.3514, respectively; and N-desmethyl rosuvastatin, 0.8441 to 1.0200 and 1.1971 to 1.5457. In part 2, the 90% CIs of the GMRs (coadministration to monotherapy with telmisartan/amlodipine) were: telmisartan, 1.1204 to 1.4228 and 0.9940 to 1.5940; amlodipine, 0.9705 to 1.0636 and 0.9813 to 1.0779. There were no significant differences in the prevalences of AEs between the treatments, and all reported AEs were mild or moderate. These results demonstrate that when rosuvastatin, telmisartan, and amlodipine are coadministered to healthy male subjects, pharmacokinetic exposure increases with respect to rosuvastatin and telmisartan, whereas no change occurs with respect to amlodipine. However, based on previous analyses, the degree of increase in the exposure observed was not regarded as clinically significant. All treatments were well-tolerated. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

21 CFR 74.340 - FD&C Red No. 40.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.340 FD&C Red No. 40. (a) Identity. (1) The color additive FD&C...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

21 CFR 74.203 - FD&C Green No. 3.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.203 FD&C Green No. 3. (a) Identity. (1) The color additive FD... mixtures for coloring food. (b) Specifications. The color additive FD&C Green No. 3 shall conform to the...

21 CFR 74.706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

21 CFR 74.203 - FD&C Green No. 3.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.203 FD&C Green No. 3. (a) Identity. (1) The color additive FD... mixtures for coloring food. (b) Specifications. The color additive FD&C Green No. 3 shall conform to the...

21 CFR 74.705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.705 FD&C Yellow No. 5. (a) Identity. (1) The color additive FD... salt. (2) Color additive mixtures for food use made with FD&C Yellow No. 5 may contain only those...

21 CFR 74.706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

21 CFR 74.706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

21 CFR 74.706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

21 CFR 74.340 - FD&C Red No. 40.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.340 FD&C Red No. 40. (a) Identity. (1) The color additive FD&C...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

21 CFR 74.705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.705 FD&C Yellow No. 5. (a) Identity. (1) The color additive FD... salt. (2) Color additive mixtures for food use made with FD&C Yellow No. 5 may contain only those...

21 CFR 74.340 - FD&C Red No. 40.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.340 FD&C Red No. 40. (a) Identity. (1) The color additive FD&C...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

21 CFR 74.203 - FD&C Green No. 3.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.203 FD&C Green No. 3. (a) Identity. (1) The color additive FD... mixtures for coloring food. (b) Specifications. The color additive FD&C Green No. 3 shall conform to the...

21 CFR 74.706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

21 CFR 74.705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.705 FD&C Yellow No. 5. (a) Identity. (1) The color additive FD... salt. (2) Color additive mixtures for food use made with FD&C Yellow No. 5 may contain only those...

21 CFR 74.1706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2010 CFR

2010-04-01

... manufacturing practice. (c) Labeling requirements. (1) The label of the color additive and any mixtures intended... COLOR ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1706 FD&C Yellow No. 6. (a) Identity and specifications. (1) The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the...

21 CFR 74.2304 - FD&C Red No. 4.

Code of Federal Regulations, 2010 CFR

2010-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2304 FD&C Red No. 4. (a) Identity and specifications. The color additive FD&C Red No. 4 shall conform in identity and specifications to the requirements of § 74... externally applied cosmetics in amounts consistent with good manufacturing practice. (c) Labeling. The label...

21 CFR 74.1340 - FD&C Red No. 40.

Code of Federal Regulations, 2010 CFR

2010-04-01

... amounts consistent with current good manufacturing practice. (c) Labeling. The label of the color additive... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of § 74...

21 CFR 74.2340 - FD&C Red No. 40.

Code of Federal Regulations, 2010 CFR

2010-04-01

... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

21 CFR 74.2304 - FD&C Red No. 4.

Code of Federal Regulations, 2013 CFR

2013-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2304 FD&C Red No. 4. (a) Identity and specifications. The color additive FD&C Red No. 4 shall conform in identity and specifications to the requirements of § 74... externally applied cosmetics in amounts consistent with good manufacturing practice. (c) Labeling. The label...

21 CFR 74.2340 - FD&C Red No. 40.

Code of Federal Regulations, 2014 CFR

2014-04-01

... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

21 CFR 74.2340 - FD&C Red No. 40.

Code of Federal Regulations, 2012 CFR

2012-04-01

... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

21 CFR 74.1340 - FD&C Red No. 40.

Code of Federal Regulations, 2012 CFR

2012-04-01

... amounts consistent with current good manufacturing practice. (c) Labeling. The label of the color additive... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of § 74...

21 CFR 74.1706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2014 CFR

2014-04-01

... manufacturing practice. (c) Labeling requirements. (1) The label of the color additive and any mixtures intended... COLOR ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1706 FD&C Yellow No. 6. (a) Identity and specifications. (1) The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the...

21 CFR 74.2304 - FD&C Red No. 4.

Code of Federal Regulations, 2014 CFR

2014-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2304 FD&C Red No. 4. (a) Identity and specifications. The color additive FD&C Red No. 4 shall conform in identity and specifications to the requirements of § 74... externally applied cosmetics in amounts consistent with good manufacturing practice. (c) Labeling. The label...

21 CFR 74.1706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2012 CFR

2012-04-01

... manufacturing practice. (c) Labeling requirements. (1) The label of the color additive and any mixtures intended... COLOR ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1706 FD&C Yellow No. 6. (a) Identity and specifications. (1) The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the...

21 CFR 74.2340 - FD&C Red No. 40.

Code of Federal Regulations, 2013 CFR

2013-04-01

... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

21 CFR 74.1706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2013 CFR

2013-04-01

... manufacturing practice. (c) Labeling requirements. (1) The label of the color additive and any mixtures intended... COLOR ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1706 FD&C Yellow No. 6. (a) Identity and specifications. (1) The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the...

21 CFR 74.2304 - FD&C Red No. 4.

Code of Federal Regulations, 2012 CFR

2012-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2304 FD&C Red No. 4. (a) Identity and specifications. The color additive FD&C Red No. 4 shall conform in identity and specifications to the requirements of § 74... externally applied cosmetics in amounts consistent with good manufacturing practice. (c) Labeling. The label...

21 CFR 74.1340 - FD&C Red No. 40.

Code of Federal Regulations, 2014 CFR

2014-04-01

... amounts consistent with current good manufacturing practice. (c) Labeling. The label of the color additive... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of § 74...

21 CFR 74.2340 - FD&C Red No. 40.

Code of Federal Regulations, 2011 CFR

2011-04-01

... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

21 CFR 74.1340 - FD&C Red No. 40.

Code of Federal Regulations, 2013 CFR

2013-04-01

... amounts consistent with current good manufacturing practice. (c) Labeling. The label of the color additive... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of § 74...

Overexpression of PAD1 and FDC1 results in significant cinnamic acid decarboxylase activity in Saccharomyces cerevisiae.

PubMed

Richard, Peter; Viljanen, Kaarina; Penttilä, Merja

2015-01-01

The S. cerevisiae PAD1 gene had been suggested to code for a cinnamic acid decarboxylase, converting trans-cinnamic acid to styrene. This was suggested for the reason that the over-expression of PAD1 resulted in increased tolerance toward cinnamic acid, up to 0.6 mM. We show that by over-expression of the PAD1 together with the FDC1 the cinnamic acid decarboxylase activity can be increased significantly. The strain over-expressing PAD1 and FDC1 tolerated cinnamic acid concentrations up to 10 mM. The cooperation of Pad1p and Fdc1p is surprising since the PAD1 has a mitochondrial targeting sequence and the FDC1 codes for a cytosolic protein. The cinnamic acid decarboxylase activity was also seen in the cell free extract. The activity was 0.019 μmol per minute and mg of extracted protein. The overexpression of PAD1 and FDC1 resulted also in increased activity with the hydroxycinnamic acids ferulic acid, p-coumaric acid and caffeinic acid. This activity was not seen when FDC1 was overexpressed alone. An efficient cinnamic acid decarboxylase is valuable for the genetic engineering of yeast strains producing styrene. Styrene can be produced from endogenously produced L-phenylalanine which is converted by a phenylalanine ammonia lyase to cinnamic acid and then by a decarboxylase to styrene.

21 CFR 74.303 - FD&C Red No. 3.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.303 FD&C Red No. 3. (a) Identity. (1) The color additive FD&C... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods...

21 CFR 74.303 - FD&C Red No. 3.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.303 FD&C Red No. 3. (a) Identity. (1) The color additive FD&C... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods...

21 CFR 74.303 - FD&C Red No. 3.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.303 FD&C Red No. 3. (a) Identity. (1) The color additive FD&C... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods...

21 CFR 74.1706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Yellow No. 6. 74.1706 Section 74.1706 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... safe for use in color additive mixtures for coloring drugs. (b) Uses and restrictions. FD&C Yellow No...

21 CFR 74.1203 - FD&C Green No. 3.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Green No. 3. 74.1203 Section 74.1203 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... use in color additive mixtures for coloring drugs. (b) Uses and restrictions. The color additive FD&C...

21 CFR 74.1303 - FD&C Red No. 3.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Red No. 3. 74.1303 Section 74.1303 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... use in color additive mixtures for coloring ingested drugs. (b) Uses and restrictions. FD&C Red No. 3...

21 CFR 74.1101 - FD&C Blue No. 1

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Blue No. 1 74.1101 Section 74.1101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... mixtures for coloring drugs. (b) Specifications. (1) The color additive FD&C Blue No. 1 for use in coloring...

21 CFR 82.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF CERTIFIED PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color...

21 CFR 82.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF CERTIFIED PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color...

Family Day Care in Australia: A Systematic Review of Research (1996-2010)

ERIC Educational Resources Information Center

Bohanna, India; Davis, Elise; Corr, Lara; Priest, Naomi; Tan, Huong

2012-01-01

Family Day Care (FDC) is a distinctive form of child care chosen by many Australian families. However, there appears to be little empirical research on FDC conducted in Australia. The aim of this study was to systematically review the recent published literature on FDC research in Australia, assess its quality, and identify pertinent topics for…

Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data.

PubMed

2016-05-24

Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.

21 CFR 74.1102 - FD&C Blue No. 2.

Code of Federal Regulations, 2010 CFR

2010-04-01

... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1102 FD&C Blue No. 2. (a) Identity. (1) The color additive FD&C Blue No. 2 shall conform in identity to the requirements of § 74.102(a)(1). (2) Color additive... suitable and that are listed in part 73 of this chapter as safe for use in color additive mixtures for...

21 CFR 74.1102 - FD&C Blue No. 2.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Blue No. 2. 74.1102 Section 74.1102 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... coloring drugs. (b) The color additive FD&C Blue No. 2 for use in coloring ingested drugs shall conform to...

21 CFR 74.2304 - FD&C Red No. 4.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Red No. 4. 74.2304 Section 74.2304 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR....1304(a)(1) and (b). (b) Uses and restrictions. FD&C Red No. 4 may be safely used for coloring...

76 FR 60055 - Draft Guidance for Industry: Applications for Premarket Review of New Tobacco Products...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-28

... Tobacco Control Act amends the FD&C Act and grants FDA authority to regulate the manufacture, marketing... (PMTA) under section 910(b) of the FD&C Act and receive a marketing authorization order under section 910(c)(1)(A)(i) of the FD&C Act prior to marketing the product. The draft guidance is intended to...

Variations on the "Blue-Bottle" Demonstration Using Food Items That Contain FD&C Blue #1

ERIC Educational Resources Information Center

Staiger, Felicia A.; Peterson, Joshua P.; Campbell, Dean J.

2015-01-01

Erioglaucine dye (FD&C Blue #1) can be used instead of methylene blue in the classic "blue-bottle" demonstration. Food items containing FD&C Blue #1 and reducing species such as sugars can therefore be used at the heart of this demonstration, which simply requires the addition of strong base such as sodium hydroxide lye.

Adequacy of clinical trial evidence of metformin fixed-dose combinations for the treatment of type 2 diabetes mellitus in India

PubMed Central

Evans, Valerie; Roderick, Peter; Pollock, Allyson M

2018-01-01

There is growing national and international concern about the drug regulatory system in India. Parliamentary reports have highlighted the presence of high numbers of unapproved medicines and irrational combinations of both approved and unapproved drugs in the Indian market-place. Fixed-dose combinations (FDCs) are a peculiar feature of the Indian pharmaceutical landscape. Although metformin is a first-line treatment, FDCs for diabetes in India account for two-thirds of all diabetes medicine sales, and some have not been approved by the Central Drugs Standard Control Organization (CDSCO). This study examines the basis of efficacy and safety of top-selling metformin FDCs in India against four WHO criteria from clinical trials guidelines for the approval of FDCs. Data from a commercial drug sales database (PharmaTrac) were combined with searches through published literature, clinical trial registries, and published and unpublished trial websites of metformin FDCs in adults with type 2 diabetes mellitus. Five metformin FDCs in India from November 2011 to October 2012 accounted for 80% of all metformin FDC sales by value and volume. Although all five had obtained CDSCO approval, three had been sold and marketed prior to receiving this approval. Evaluation of published and unpublished clinical trials of these five FDCs found none provided robust evidence of safety and efficacy for the treatment of type 2 diabetes. Recommendations are made for publishing evidence that underpins drug approvals, marketing bans, greater transparency through updated clinical trials databases and legislative reform in order to prevent irrational FDCs from entering the market. PMID:29527355

Adequacy of clinical trial evidence of metformin fixed-dose combinations for the treatment of type 2 diabetes mellitus in India.

PubMed

Evans, Valerie; Roderick, Peter; Pollock, Allyson M

2018-01-01

There is growing national and international concern about the drug regulatory system in India. Parliamentary reports have highlighted the presence of high numbers of unapproved medicines and irrational combinations of both approved and unapproved drugs in the Indian market-place. Fixed-dose combinations (FDCs) are a peculiar feature of the Indian pharmaceutical landscape. Although metformin is a first-line treatment, FDCs for diabetes in India account for two-thirds of all diabetes medicine sales, and some have not been approved by the Central Drugs Standard Control Organization (CDSCO). This study examines the basis of efficacy and safety of top-selling metformin FDCs in India against four WHO criteria from clinical trials guidelines for the approval of FDCs. Data from a commercial drug sales database (PharmaTrac) were combined with searches through published literature, clinical trial registries, and published and unpublished trial websites of metformin FDCs in adults with type 2 diabetes mellitus. Five metformin FDCs in India from November 2011 to October 2012 accounted for 80% of all metformin FDC sales by value and volume. Although all five had obtained CDSCO approval, three had been sold and marketed prior to receiving this approval. Evaluation of published and unpublished clinical trials of these five FDCs found none provided robust evidence of safety and efficacy for the treatment of type 2 diabetes. Recommendations are made for publishing evidence that underpins drug approvals, marketing bans, greater transparency through updated clinical trials databases and legislative reform in order to prevent irrational FDCs from entering the market.

Bacterioplankton in antarctic ocean waters during late austral winter: abundance, frequency of dividing cells, and estimates of production.

PubMed

Hanson, R B; Shafer, D; Ryan, T; Pope, D H; Lowery, H K

1983-05-01

Bacterioplankton productivity in Antarctic waters of the eastern South Pacific Ocean and Drake Passage was estimated by direct counts and frequency of dividing cells (FDC). Total bacterioplankton assemblages were enumerated by epifluorescent microscopy. The experimentally determined relationship between in situ FDC and the potential instantaneous growth rate constant (mu) is best described by the regression equation ln mu = 0.081 FDC - 3.73. In the eastern South Pacific Ocean, bacterioplankton abundance (2 x 10 to 3.5 x 10 cells per ml) and FDC (11%) were highest at the Polar Front (Antarctic Convergence). North of the Subantarctic Front, abundance and FDC were between 1 x 10 to 2 x 10 cells per ml and 3 to 5%, respectively, and were vertically homogeneous to a depth of 600 m. In Drake Passage, abundance (10 x 10 cells per ml) and FDC (16%) were highest in waters south of the Polar Front and near the sea ice. Subantarctic waters in Drake Passage contained 4 x 10 cells per ml with 4 to 5% FDC. Instantaneous growth rate constants ranged between 0.029 and 0.088 h. Using estimates of potential mu and measured standing stocks, we estimated productivity to range from 0.62 mug of C per liter . day in the eastern South Pacific Ocean to 17.1 mug of C per liter . day in the Drake Passage near the sea ice.

The role of physicians in prescribing irrational fixed-dose combination medicines in India.

PubMed

Bhaskarabhatla, Ajay; Chatterjee, Chirantan

2017-02-01

Many irrational fixed-dose combination (FDC) medicines have been approved by the state and central regulatory authorities in India and their use is promoted extensively by pharmaceutical firms. In this study, we examine the previously-neglected role of physicians in India, as their prescriptions are essential for the continued proliferation of FDCs. Primarily using longitudinal data on prescriptions by 4600 physicians spanning 19 disciplinary categories for 48 months between 2008 and 2011 provided by IMS Medical Audit, we study 201 medicines in the cardiovascular and oral-antidiabetic markets. We find that 129.6 million (8.1%) prescriptions for irrational FDCs were written by the sample of physicians in India during the study period, half of which were written by cardiologists and consulting physicians. A further analysis of the regional markets reveals that cardiologists prescribe more irrational FDCs in the richer, metropolitan cities of western India. We also document the role of medical practitioners without an undergraduate degree in medicine in generating prescriptions for irrational FDCs. Our results suggest that an effective government strategy to curb irrational FDCs must recognize that spreading greater awareness about the perils of irrational FDCs is at best an incomplete solution to the problem in India as many who prescribe them are specialists. Organizations such as the Indian Medical Association must develop clear guidelines to stop prescribing such FDCs. Copyright © 2016 Elsevier Ltd. All rights reserved.

FAMILY DEVELOPMENT CREDENTIAL TRAINING IMPACT ON SELF-EFFICACY BELIEFS OF HUMAN SERVICE WORKERS.

PubMed

Smith, Deborah B; Day, Nancy E

2015-01-01

The Family Development Credential (FDC) Training offers an innovative interagency training for human service workers within a community. We use a mixed-methods approach to evaluate the impact of FDC on work-related self-efficacy beliefs. Quantitative data found FDC participants increased their levels of positive self-efficacy beliefs and had no change in negative self-efficacy beliefs; a comparison group saw no change in positive self-efficacy beliefs but increased their levels of negative self-efficacy beliefs. Qualitative data indicated training increased work-related self-efficacy beliefs. Overall, findings suggest that FDC training improved self-efficacy in human service workers and that no training allowed negative self-efficacy beliefs to grow.

Regional variation of flow duration curves in the eastern United States: Process-based analyses of the interaction between climate and landscape properties

NASA Astrophysics Data System (ADS)

Chouaib, Wafa; Caldwell, Peter V.; Alila, Younes

2018-04-01

This paper advances the physical understanding of the flow duration curve (FDC) regional variation. It provides a process-based analysis of the interaction between climate and landscape properties to explain disparities in FDC shapes. We used (i) long term measured flow and precipitation data over 73 catchments from the eastern US. (ii) We calibrated the Sacramento model (SAC-SMA) to simulate soil moisture and flow components FDCs. The catchments classification based on storm characteristics pointed to the effect of catchments landscape properties on the precipitation variability and consequently on the FDC shapes. The landscape properties effect was pronounce such that low value of the slope of FDC (SFDC)-hinting at limited flow variability-were present in regions of high precipitation variability. Whereas, in regions with low precipitation variability the SFDCs were of larger values. The topographic index distribution, at the catchment scale, indicated that saturation excess overland flow mitigated the flow variability under conditions of low elevations with large soil moisture storage capacity and high infiltration rates. The SFDCs increased due to the predominant subsurface stormflow in catchments at high elevations with limited soil moisture storage capacity and low infiltration rates. Our analyses also highlighted the major role of soil infiltration rates on the FDC despite the impact of the predominant runoff generation mechanism and catchment elevation. In conditions of slow infiltration rates in soils of large moisture storage capacity (at low elevations) and predominant saturation excess, the SFDCs were of larger values. On the other hand, the SFDCs decreased in catchments of prevalent subsurface stormflow and poorly drained soils of small soil moisture storage capacity. The analysis of the flow components FDCs demonstrated that the interflow contribution to the response was the higher in catchments with large value of slope of the FDC. The surface flow FDC was the most affected by the precipitation as it tracked the precipitation duration curve (PDC). In catchments with low SFDCs, this became less applicable as surface flow FDC diverged from PDC at the upper tail (> 40% of the flow percentile). The interflow and baseflow FDCs illustrated most the filtering effect on the precipitation. The process understanding we achieved in this study is key for flow simulation and assessment in addition to future works focusing on process-based FDC predictions.

Single nucleotide polymorphisms of PAD1 and FDC1 show a positive relationship with ferulic acid decarboxylation ability among industrial yeasts used in alcoholic beverage production.

PubMed

Mukai, Nobuhiko; Masaki, Kazuo; Fujii, Tsutomu; Iefuji, Haruyuki

2014-07-01

Among industrial yeasts used for alcoholic beverage production, most wine and weizen beer yeasts decarboxylate ferulic acid to 4-vinylguaiacol, which has a smoke-like flavor, whereas sake, shochu, top-fermenting, and bottom-fermenting yeast strains lack this ability. However, the factors underlying this difference among industrial yeasts are not clear. We previously confirmed that both PAD1 (phenylacrylic acid decarboxylase gene, YDR538W) and FDC1 (ferulic acid decarboxylase gene, YDR539W) are essential for the decarboxylation of phenylacrylic acids in Saccharomyces cerevisiae. In the present study, single nucleotide polymorphisms (SNPs) of PAD1 and FDC1 in sake, shochu, wine, weizen, top-fermenting, bottom-fermenting, and laboratory yeast strains were examined to clarify the differences in ferulic acid decarboxylation ability between these types of yeast. For PAD1, a nonsense mutation was observed in the gene sequence of standard top-fermenting yeast. Gene sequence analysis of FDC1 revealed that sake, shochu, and standard top-fermenting yeasts contained a nonsense mutation, whereas a frameshift mutation was identified in the FDC1 gene of bottom-fermenting yeast. No nonsense or frameshift mutations were detected in laboratory, wine, or weizen beer yeast strains. When FDC1 was introduced into sake and shochu yeast strains, the transformants exhibited ferulic acid decarboxylation activity. Our findings indicate that a positive relationship exists between SNPs in PAD1 and FDC1 genes and the ferulic acid decarboxylation ability of industrial yeast strains. Copyright © 2013 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Abacavir + dolutegravir + lamivudine for the treatment of HIV.

PubMed

Comi, Laura; Maggiolo, Franco

2016-10-01

Since the last revision of both European and American guidelines (EACS and DHHS), new data from clinical trials and cohort studies, as well as experience in clinical practice, have prompted significant changes to the list of recommended/preferred options for the treatment of HIV infected patients, highlighted the role of INSTI-based regimens. Dolutegravir (DTG) in combination with abacavir/lamivudine (ABC/3TC) is one of these preferred regimens in multiple clinical scenarios, including treatment-naive and treatment-experienced patients. In this article we describe the coformulation of ABC/3TC/DTG in a fixed-dose combination (FDC) approved in September 2014 for the treatment of HIV infection. We focused our research on the efficacy and safety data resulting from phase 2 and 3 clinical study, particularly on the results of both SPRING (1 and 2) and SINGLE studies. Triple combination therapy with ABC/3TC/DTG should be considered among the initial options for treatment-naive patients, being effective, well tolerated, with a high genetic barrier to resistance along with a convenient once-daily administration. In treatment-experienced patients the single-tablet regimen (STR) based on ABC/3TC/DTG could be used as simplification strategy in subjects with sustained viral suppression, as the high genetic barrier of DTG should ensure a safe switch from both NNRTI or PI based regimens.

Calibrations for Charged Particle Tracking with the GlueX Detector

NASA Astrophysics Data System (ADS)

Staib, Michael; GlueX Collaboration

2015-10-01

Two gas detectors comprise the tracking system for the GlueX experiment, the Central Drift Chamber (CDC) and the Forward Drift Chamber (FDC). The CDC is a cylindrical straw-tube detector covering polar angles between 6° and 168°, delivering spatial resolution of ~150 μm. The FDC is a Cathode Strip Chamber consisting of four packages, each with six alternating layers of anode wires and cathode strips. The FDC is designed to track forward-going charged particles with polar angles between 1° and 20° with a spatial resolution of ~200 μm. Both tracking detectors record timing information and energy loss measurements useful for particle identification. During Fall 2014 and Spring 2015, the first photon beam was delivered on target for commissioning of the GlueX detector in Hall-D at Jefferson Lab. These data are currently being used in a large effort to calibrate the individual detector subsystems to achieve design performance. Methods and results for calibrations of each of the tracking detectors are presented. Techniques for alignment of the tracking system using a combination of cosmic rays and beam data is discussed. Finally, some early results of physics measurements including charged final-state particles are presented. This material is based upon work supported by the U.S. Department of Energy, Office of Science, Office of Nuclear Physics under Contract DE-AC05-06OR23177.

Rapid removal of nitrobenzene in a three-phase ozone loaded system with gas-liquid-liquid

USGS Publications Warehouse

Li, Shiyin; Zhu, Jiangpeng; Wang, Guoxiang; Ni, Lixiao; Zhang, Yong; Green, Christopher T.

2015-01-01

This study explores the removal rate of nitrobenzene (NB) using a new gas-liquid-liquid (G-L-L) three-phase ozone loaded system consisting of a gaseous ozone, an aqueous solvent phase, and a fluorinated solvent phase (perfluorodecalin, or FDC). The removal rate of NB was quantified in relation to six factors including 1) initial pH, 2) initial NB dosage, 3) gaseous ozone dosage, 4) free radical scavenger, 5) FDC pre-aerated gaseous ozone, and 6) reuse of FDC. The NB removal rate is positively affected by the first three factors. Compared with the conventional gas-liquid (water) (G-L) two-phase ozonation system, the free radical scavenger (tertiary butyl alcohol) has much less influence on the removal rate of NB in the G-L-L system. The FDC loaded ozone acts as an ozone reservoir and serves as the main reactive phase in the G-L-L three-phase system. The reuse of FDC has little influence on the removal rate of NB. These experimental results suggest that the oxidation efficiency of ozonation in the G-L-L three-phase system is better than that in the conventional G-L two-phase system.

Altered regulation of Fc gamma RII on aged follicular dendritic cells correlates with immunoreceptor tyrosine-based inhibition motif signaling in B cells and reduced germinal center formation.

PubMed

Aydar, Yüksel; Balogh, Péter; Tew, John G; Szakal, Andras K

2003-12-01

Aging is associated with reduced trapping of Ag in the form of in immune complexes (ICs) by follicular dendritic cells (FDCs). We postulated that this defect was due to altered regulation of IC trapping receptors. The level of FDC-M1, complement receptors 1 and 2, FcgammaRII, and FDC-M2 on FDCs was immunohistochemically quantitated in draining lymph nodes of actively immunized mice for 10 days after Ag challenge. Initially, FDC FcgammaRII levels were similar but by day 3 a drastic reduction in FDC-FcgammaRII expression was apparent in old mice. FDC-M2 labeling, reflecting IC trapping, was also reduced and correlated with a dramatic reduction in germinal center (GC) B cells as indicated by reduced GC size and number. Nevertheless, labeling of FDC reticula with FDC-M1 and anti-complement receptors 1 and 2 was preserved, indicating that FDCs were present. FDCs in active GCs normally express high levels of FcRs that are thought to bind Fc portions of Abs in ICs and minimize their binding to FcRs on B cells. Thus, cross-linking of B cell receptor and FcR via IC is minimized, thereby reducing signaling via the immunoreceptor tyrosine-based inhibition motif. Old FDCs taken at day 3, when they lack FcgammaRII, were incapable of preventing immunoreceptor tyrosine-based inhibition motif signaling in wild-type B cells but old FDCs stimulated B cells from FcgammaRIIB(-/-) mice to produce near normal levels of specific Ab. The present data support the concept that FcR are regulated abnormally on old FDCs. This abnormality correlates with a reduced IC retention and with a reduced capacity of FDCs to present ICs in a way that will activate GC B cells.

21 CFR 74.3102 - FD&C Blue No. 2.

Code of Federal Regulations, 2012 CFR

2012-04-01

... copolymer of adipic acid and hexamethylene diamine) surgical sutures for use in general surgery subject to... Food, Drug, and Cosmetic Act with respect to the medical device in which the color additive FD&C Blue...

21 CFR 74.3102 - FD&C Blue No. 2.

Code of Federal Regulations, 2011 CFR

2011-04-01

... copolymer of adipic acid and hexamethylene diamine) surgical sutures for use in general surgery subject to... Food, Drug, and Cosmetic Act with respect to the medical device in which the color additive FD&C Blue...

21 CFR 74.3102 - FD&C Blue No. 2.

Code of Federal Regulations, 2014 CFR

2014-04-01

... copolymer of adipic acid and hexamethylene diamine) surgical sutures for use in general surgery subject to... Food, Drug, and Cosmetic Act with respect to the medical device in which the color additive FD&C Blue...

21 CFR 74.3102 - FD&C Blue No. 2.

Code of Federal Regulations, 2013 CFR

2013-04-01

... copolymer of adipic acid and hexamethylene diamine) surgical sutures for use in general surgery subject to... Food, Drug, and Cosmetic Act with respect to the medical device in which the color additive FD&C Blue...

Precision Control and Randomized Benchmarking of a 12-us Class Superconducting Qubit

DTIC Science & Technology

2013-03-28

well potential profile. The  diabatic  ground state of the left (right) well corresponds to a persistent  current Iq with clockwise (counterclockwise...circulation. The two  diabatic  energy levels have an energy  separation  = 2 Iq fdc linear in the flux detuning fdc = fdc ‐  0/2. Higher‐excited states...is:  ⁄ ∆ . At detuning  fdc=0, the double‐well potential is symmetric and the  diabatic ‐state energies are degenerate. At this  ``degeneracy point

FdC1 and Leaf-Type Ferredoxins Channel Electrons From Photosystem I to Different Downstream Electron Acceptors.

PubMed

Guan, Xiaoqian; Chen, Shuai; Voon, Chia Pao; Wong, Kam-Bo; Tikkanen, Mikko; Lim, Boon L

2018-01-01

Plant-type ferredoxins in Arabidopsis transfer electrons from the photosystem I to multiple redox-driven enzymes involved in the assimilation of carbon, nitrogen, and sulfur. Leaf-type ferredoxins also modulate the switch between the linear and cyclic electron routes of the photosystems. Recently, two novel ferredoxin homologs with extra C-termini were identified in the Arabidopsis genome (AtFdC1, AT4G14890; AtFdC2, AT1G32550). FdC1 was considered as an alternative electron acceptor of PSI under extreme ferredoxin-deficient conditions. Here, we showed that FdC1 could interact with some, but not all, electron acceptors of leaf-type Fds, including the ferredoxin-thioredoxin reductase (FTR), sulfite reductase (SiR), and nitrite reductase (NiR). Photoreduction assay on cytochrome c and enzyme assays confirmed its capability to receive electrons from PSI and donate electrons to the Fd-dependent SiR and NiR but not to the ferredoxin-NADP + oxidoreductase (FNR). Hence, FdC1 and leaf-type Fds may play differential roles by channeling electrons from photosystem I to different downstream electron acceptors in photosynthetic tissues. In addition, the median redox potential of FdC1 may allow it to receive electrons from FNR in non-photosynthetic plastids.

FdC1 and Leaf-Type Ferredoxins Channel Electrons From Photosystem I to Different Downstream Electron Acceptors

PubMed Central

Guan, Xiaoqian; Chen, Shuai; Voon, Chia Pao; Wong, Kam-Bo; Tikkanen, Mikko; Lim, Boon L.

2018-01-01

Plant-type ferredoxins in Arabidopsis transfer electrons from the photosystem I to multiple redox-driven enzymes involved in the assimilation of carbon, nitrogen, and sulfur. Leaf-type ferredoxins also modulate the switch between the linear and cyclic electron routes of the photosystems. Recently, two novel ferredoxin homologs with extra C-termini were identified in the Arabidopsis genome (AtFdC1, AT4G14890; AtFdC2, AT1G32550). FdC1 was considered as an alternative electron acceptor of PSI under extreme ferredoxin-deficient conditions. Here, we showed that FdC1 could interact with some, but not all, electron acceptors of leaf-type Fds, including the ferredoxin-thioredoxin reductase (FTR), sulfite reductase (SiR), and nitrite reductase (NiR). Photoreduction assay on cytochrome c and enzyme assays confirmed its capability to receive electrons from PSI and donate electrons to the Fd-dependent SiR and NiR but not to the ferredoxin-NADP+ oxidoreductase (FNR). Hence, FdC1 and leaf-type Fds may play differential roles by channeling electrons from photosystem I to different downstream electron acceptors in photosynthetic tissues. In addition, the median redox potential of FdC1 may allow it to receive electrons from FNR in non-photosynthetic plastids. PMID:29670639

A randomized titrate-to-target study comparing fixed-dose combinations of azilsartan medoxomil and chlorthalidone with olmesartan and hydrochlorothiazide in stage-2 systolic hypertension.

PubMed

Cushman, William C; Bakris, George L; White, William B; Weber, Michael A; Sica, Domenic; Roberts, Andrew; Lloyd, Eric; Kupfer, Stuart

2018-04-01

Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD). We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160-190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured. Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P < 0.001) in both AZL-M/CTD arms (-37.6 and -38.2 mmHg) versus OLM/HCTZ (-31.5 mmHg), despite greater dose titration in the OLM/HCTZ group. At 8 weeks, both AZL-M/CTD FDCs reduced 24-h SBP more than OLM/HCTZ (-26.4 and -27.9 versus -20.7 mmHg; both P < 0.001), and higher proportions in both AZL-M/CTD groups achieved target BP compared with the OLM/HCTZ group (69.4 and 68.9 versus 54.7%, both P < 0.001). Adverse events leading to drug discontinuation occurred in 6.2, 9.5, and 3.1% with the AZL-M/CTD lower and higher doses, and OLM/HCTZ, respectively. This large, titration-to-target BP study demonstrated AZL-M/CTD FDCs to have superior antihypertensive efficacy compared with the maximum approved dose of OLM/HCTZ.

A randomized titrate-to-target study comparing fixed-dose combinations of azilsartan medoxomil and chlorthalidone with olmesartan and hydrochlorothiazide in stage-2 systolic hypertension

PubMed Central

Cushman, William C.; Bakris, George L.; White, William B.; Weber, Michael A.; Sica, Domenic; Roberts, Andrew; Lloyd, Eric; Kupfer, Stuart

2018-01-01

Background: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD). Objective/methods: We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160–190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured. Results: Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P < 0.001) in both AZL-M/CTD arms (−37.6 and −38.2 mmHg) versus OLM/HCTZ (−31.5 mmHg), despite greater dose titration in the OLM/HCTZ group. At 8 weeks, both AZL-M/CTD FDCs reduced 24-h SBP more than OLM/HCTZ (−26.4 and −27.9 versus −20.7 mmHg; both P < 0.001), and higher proportions in both AZL-M/CTD groups achieved target BP compared with the OLM/HCTZ group (69.4 and 68.9 versus 54.7%, both P < 0.001). Adverse events leading to drug discontinuation occurred in 6.2, 9.5, and 3.1% with the AZL-M/CTD lower and higher doses, and OLM/HCTZ, respectively. Conclusion: This large, titration-to-target BP study demonstrated AZL-M/CTD FDCs to have superior antihypertensive efficacy compared with the maximum approved dose of OLM/HCTZ. PMID:29334491

Prescribing Pattern of Oral Antihyperglycaemic Drugs, Rationality and Adherence to American Diabetes Association (ADA) Treatment Guidelines among Type 2 Diabetes Mellitus (T2DM) Postmenopausal Women.

PubMed

Sharma, Sudhaa; Tandon, Vishal R; Roshi; Mahajan, Annil

2016-01-01

Oral antihyperglycaemic prescription trends keep on changing and thus the drug prescription trend study may prove to be powerful exploratory tool for health care providers. To investigate trends in prescriptions of oral antihyperglycaemic drugs (OHDs) among postmenopausal women suffering from T2DM in India and evaluate the rationality and adherence to ADA treatment guidelines. An observational, cross-sectional descriptive prescription audit (n=500) was carried. Postmenopausal women were interviewed in their local language using pre-tested pre validated questionnaire after verbal informed consent at a teaching tertiary care hospital of north India. Oral antihyperglycaemic drugs (OHDs) drugs were categorized as per the pharmacological classification. Adherence to available clinical practice guidelines/recommendations issued under American Diabetes Association (ADA) 2015 Guidelines as well as rationality of these prescriptions were assessed using WHO Guide to Good Prescribing. Mean age of the study population was 58.14±12.86. Mean duration since menopause was 5.3 years and of T2DM was 9.5 years. A 93.4% of the prescriptions had only OHDs whereas 6.6% of the prescriptions had various insulin preprations + OHDs (p<0.0001). Biguanides followed by sulfonylureas, thiazolidinediones, DPP-inhibitors and alpha-glucosidases inhibitor were prescribed in 85.6%, 59.8%, 26.6%, 26% and 12.2% respectively as monotherapy or in combination. Among biguanides, metformin was the most frequently prescribed OHDs. In spite of black box warning on pioglitazone, it was prescribed in 26.6% as FDC. However, clear increase use of vidagliptine was noticed upto 26%. Among combinations most frequent was metformin plus glimipride followed by voglibose plus metformin, whereas, among FDC, metformin plus glimipride followed by metformin plus vidagliptine were most frequently prescribed. Metformin was the most common OHDs to be prescribed followed by glimepiride. Although pioglitazone still continues to be prescribed after safety alert but apparently it appears that the share of pioglitazone has been shifted to vidagliptin or combinations like metformin plus glimipride. Polypharmacy, high use of FDC, & prescription by brand names were some of the irrationalities. Relatively low adherence to ADA treatment guidelines was observed.

76 FR 52237 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-22

... SIAPs, their complex nature, and the need for a special format make their verbatim publication in the... Publication AIRAC Date State City Airport FDC No. FDC Date Subject 22-Sep-11 MN RED WING RED WING RGNL...

Obesity prevention in the family day care setting: impact of the Romp & Chomp intervention on opportunities for children's physical activity and healthy eating.

PubMed

de Silva-Sanigorski, A; Elea, D; Bell, C; Kremer, P; Carpenter, L; Nichols, M; Smith, M; Sharp, S; Boak, R; Swinburn, B

2011-05-01

The Romp & Chomp intervention reduced the prevalence of overweight/obesity in pre-school children in Geelong, Victoria, Australia through an intervention promoting healthy eating and active play in early childhood settings. This study aims to determine if the intervention successfully created more health promoting family day care (FDC) environments. The evaluation had a cross-sectional, quasi-experimental design with the intervention FDC service in Geelong and a comparison sample from 17 FDC services across Victoria. A 45-item questionnaire capturing nutrition- and physical activity-related aspects of the policy, socio-cultural and physical environments of the FDC service was completed by FDC care providers (in 2008) in the intervention (n= 28) and comparison (n= 223) samples. Select results showed intervention children spent less time in screen-based activities (P= 0.03), organized active play (P < 0.001) and free inside play (P= 0.03) than comparison children. There were more rules related to healthy eating (P < 0.001), more care provider practices that supported children's positive meal experiences (P < 0.001), fewer unhealthy food items allowed (P= 0.05), higher odds of staff being trained in nutrition (P= 0.04) and physical activity (P < 0.001), lower odds of having set minimum times for outside (P < 0.001) and organized (P= 0.01) active play, and of rewarding children with food (P < 0.001). Romp & Chomp improved the FDC service to one that discourages sedentary behaviours and promotes opportunities for children to eat nutritious foods. Ongoing investment to increase children's physical activity within the setting and improving the capacity and health literacy of care providers is required to extend and sustain the improvements. © 2011 Blackwell Publishing Ltd.

HISPASAT launch and early operations phases: Computation and monitoring of geostationary satellite positioning

NASA Technical Reports Server (NTRS)

Brousse, Pascal; Desprairies, Arnaud

1993-01-01

Since 1974, CNES, the French National Space Agency, has been involved in the geostationary launch and early operations phases (LEOP) of moving satellites from a transfer orbit delivered by a launcher to a geostationary point. During the operations and their preparation, the Flight Dynamics Center (FDC), part of CNES LEOP facilities, is in charge of the space mechanics aspects. What is noteworthy about the Spanish HISPASAT satellite positioning is that all the operations were performed on the customer's premises, and consequently the FDC was duplicated in Madrid, Spain. The first part of this paper is the FDC presentation: its role, its hardware configuration, and its space dynamics ground control system called MERCATOR. The second part of this paper details the preparation used by the FDC for the HISPASAT mission: hardware and software installation in Madrid, integration with the other entities, and technical and operational qualifications. The third part gives results concerning flight dynamics aspects and operational activities.

Synthesis and characterization of polymorphs of photoluminescent Eu(III)-(2,5-furandicarboxylic acid, oxalic acid) MOFs

NASA Astrophysics Data System (ADS)

Shi, Fa-Nian; Ananias, Duarte; Yang, Ting-Hai; Rocha, João

2013-08-01

A novel metal organic framework (MOF) formulated as [Eu(H2O)2(fdc)(ox)0.5·(H2O)]n (1, fdc2-=2,5-furandicarboxylate, ox2-=oxalate), was hydrothermally synthesized via in situ ox2- generation from the partial decomposition of the fdc2- ligand. This material crystallizes in the monoclinic space group C2/c, unit cell parameters of 1: a=16.7570(10), b=10.5708(7), c=13.5348(14) Å, β=116.917(2)° (Z=8), and exhibits a three-dimensional (3D)-porous framework, with guest water molecules residing in the channel linking all other ligands (H2O, ox2-and fdc2-) via hydrogen bonding interactions. Compound 2 is a polymorph of 1 crystallizing in monoclinic P21/c space group. The photoluminescence properties of 1 and 2 were studied at room temperature. The spectra show the typical Eu3+ red emission and the differences observed reflects the slightly different structures of these polymorphs.

21 CFR 74.2101 - FD&C Blue No. 1.

Code of Federal Regulations, 2012 CFR

2012-04-01

...-[(ethylphenylamino)methyl] benzenesulfonic acid, and smaller amounts of 4-[(ethylphenylamino)methyl] benzenesulfonic acid and 2-[(ethylphenylamino)methyl] benzenesulfonic acid to form the leuco base. The leuco base is... inner salt. Additionally, FD&C Blue No. 1 is manufactured by the acid catalyzed condensation of one mole...

21 CFR 74.2101 - FD&C Blue No. 1.

Code of Federal Regulations, 2013 CFR

2013-04-01

...-[(ethylphenylamino)methyl] benzenesulfonic acid, and smaller amounts of 4-[(ethylphenylamino)methyl] benzenesulfonic acid and 2-[(ethylphenylamino)methyl] benzenesulfonic acid to form the leuco base. The leuco base is... inner salt. Additionally, FD&C Blue No. 1 is manufactured by the acid catalyzed condensation of one mole...

21 CFR 74.2101 - FD&C Blue No. 1.

Code of Federal Regulations, 2014 CFR

2014-04-01

...-[(ethylphenylamino)methyl] benzenesulfonic acid, and smaller amounts of 4-[(ethylphenylamino)methyl] benzenesulfonic acid and 2-[(ethylphenylamino)methyl] benzenesulfonic acid to form the leuco base. The leuco base is... inner salt. Additionally, FD&C Blue No. 1 is manufactured by the acid catalyzed condensation of one mole...

Oral Prion Disease Pathogenesis Is Impeded in the Specific Absence of CXCR5-Expressing Dendritic Cells

PubMed Central

Bradford, Barry M.; Reizis, Boris

2017-01-01

ABSTRACT After oral exposure, the early replication of certain prion strains upon stromal cell-derived follicular dendritic cells (FDC) in the Peyer's patches in the small intestine is essential for the efficient spread of disease to the brain. However, little is known of how prions are initially conveyed from the gut lumen to establish infection on FDC. Our previous data suggest that mononuclear phagocytes such as CD11c+ conventional dendritic cells play an important role in the initial propagation of prions from the gut lumen into Peyer's patches. However, whether these cells conveyed orally acquired prions toward FDC within Peyer's patches was not known. The chemokine CXCL13 is expressed by FDC and follicular stromal cells and modulates the homing of CXCR5-expressing cells toward the FDC-containing B cell follicles. Here, novel compound transgenic mice were created in which a CXCR5 deficiency was specifically restricted to CD11c+ cells. These mice were used to determine whether CXCR5-expressing conventional dendritic cells propagate prions toward FDC after oral exposure. Our data show that in the specific absence of CXCR5-expressing conventional dendritic cells the early accumulation of prions upon FDC in Peyer's patches and the spleen was impaired, and disease susceptibility significantly reduced. These data suggest that CXCR5-expressing conventional dendritic cells play an important role in the efficient propagation of orally administered prions toward FDC within Peyer's patches in order to establish host infection. IMPORTANCE Many natural prion diseases are acquired by oral consumption of contaminated food or pasture. Once the prions reach the brain they cause extensive neurodegeneration, which ultimately leads to death. In order for the prions to efficiently spread from the gut to the brain, they first replicate upon follicular dendritic cells within intestinal Peyer's patches. How the prions are first delivered to follicular dendritic cells to establish infection was unknown. Understanding this process is important since treatments which prevent prions from infecting follicular dendritic cells can block their spread to the brain. We created mice in which mobile conventional dendritic cells were unable to migrate toward follicular dendritic cells. In these mice the early accumulation of prions on follicular dendritic cells was impaired and oral prion disease susceptibility was reduced. This suggests that prions exploit conventional dendritic cells to facilitate their initial delivery toward follicular dendritic cells to establish host infection. PMID:28275192

An analysis of volumes, prices and pricing trends of the pediatric antiretroviral market in developing countries from 2004 to 2012.

PubMed

Lee, Janice Soo Fern; Sagaon Teyssier, Luis; Dongmo Nguimfack, Boniface; Collins, Intira Jeannie; Lallemant, Marc; Perriens, Joseph; Moatti, Jean-Paul

2016-03-15

The pediatric antiretroviral (ARV) market is poorly described in the literature, resulting in gaps in understanding treatment access. We analyzed the pediatric ARV market from 2004 to 2012 and assessed pricing trends and associated factors. Data on donor funded procurements of pediatric ARV formulations reported to the Global Price Reporting Mechanism database from 2004 to 2012 were analyzed. Outcomes of interest were the volume and mean price per patient-year ARV formulation based on WHO ARV dosing recommendations for a 10 kg child. Factors associated with the price of formulations were assessed using linear regression; potential predictors included: country income classification, geographical region, market segment (originator versus generic ARVs), and number of manufacturers per formulation. All analyses were adjusted for type of formulations (single, dual or triple fixed-dose combinations (FDCs)) Data from 111 countries from 2004 to 2012 were included, with procurement of 33 formulations at a total value of USD 204 million. Use of dual and triple FDC formulations increased substantially over time, but with limited changes in price. Upon multivariate analysis, prices of originator formulations were found to be on average 72 % higher than generics (p < 0.001). A 10 % increase in procurement volume was associated with a 1 % decrease (p < 0.001) in both originator and generic prices. The entry of one additional manufacturer producing a formulation was associated with a decrease in prices of 2 % (p < 0.001) and 8 % (p < 0.001) for originator and generic formulations, respectively. The mean generic ARV price did not differ by country income level. Prices of originator ARVs were 48 % (p < 0.001) and 14 % (p < 0.001) higher in upper-middle income and lower-middle income countries compared to low income countries respectively, with the exception of South Africa, which had lower prices despite being an upper-middle income country. The donor funded pediatric ARV market as represented by the GPRM database is small, and lacks price competition. It is dominated by generic drugs due to the lower prices offered and the practicality of FDC formulations. This market requires continued donor support and the current initiatives to protect it are important to ensure market viability, especially if new formulations are to be introduced in the future.

Size and usage patterns of private TB drug markets in the high burden countries.

PubMed

Wells, William A; Ge, Colin Fan; Patel, Nitin; Oh, Teresa; Gardiner, Elizabeth; Kimerling, Michael E

2011-05-04

Tuberculosis (TB) control is considered primarily a public health concern, and private sector TB treatment has attracted less attention. Thus, the size and characteristics of private sector TB drug sales remain largely unknown. We used IMS Health data to analyze private TB drug consumption in 10 high burden countries (HBCs), after first mapping how well IMS data coverage overlapped with private markets. We defined private markets as any channels not used or influenced by national TB programs. Private markets in four countries--Pakistan, the Philippines, Indonesia and India--had the largest relative sales volumes; annually, they sold enough first line TB drugs to provide 65-117% of the respective countries' estimated annual incident cases with a standard 6-8 month regimen. First line drug volumes in five countries were predominantly fixed dose combinations (FDCs), but predominantly loose drugs in the other five. Across 10 countries, these drugs were available in 37 (loose drug) plus 74 (FDCs) distinct strengths. There were 54 distinct, significant first line manufacturers (range 2-11 per country), and most companies sold TB drugs in only a single study country. FDC markets were, however, more concentrated, with 4 companies capturing 69% of FDC volume across the ten countries. Among second line drugs, fluoroquinolones were widely available, with significant volumes used for TB in India, Pakistan and Indonesia. However, certain WHO-recommended drugs were not available and in general there were insufficient drug volumes to cover the majority of the expected burden of multidrug-resistant TB (MDR-TB). Private TB drug markets in several HBCs are substantial, stable, and complicated. This calls for appropriate policy and market responses, including expansion of Public-Private Mix (PPM) programs, greater reach, flexibility and appeal of public programs, regulatory and quality enforcement, and expansion of public MDR-TB treatment programs.

Size and Usage Patterns of Private TB Drug Markets in the High Burden Countries

PubMed Central

Wells, William A.; Ge, Colin Fan; Patel, Nitin; Oh, Teresa; Gardiner, Elizabeth; Kimerling, Michael E.

2011-01-01

Background Tuberculosis (TB) control is considered primarily a public health concern, and private sector TB treatment has attracted less attention. Thus, the size and characteristics of private sector TB drug sales remain largely unknown. Methodology/Principal Findings We used IMS Health data to analyze private TB drug consumption in 10 high burden countries (HBCs), after first mapping how well IMS data coverage overlapped with private markets. We defined private markets as any channels not used or influenced by national TB programs. Private markets in four countries – Pakistan, the Philippines, Indonesia and India – had the largest relative sales volumes; annually, they sold enough first line TB drugs to provide 65–117% of the respective countries' estimated annual incident cases with a standard 6–8 month regimen. First line drug volumes in five countries were predominantly fixed dose combinations (FDCs), but predominantly loose drugs in the other five. Across 10 countries, these drugs were available in 37 (loose drug) plus 74 (FDCs) distinct strengths. There were 54 distinct, significant first line manufacturers (range 2–11 per country), and most companies sold TB drugs in only a single study country. FDC markets were, however, more concentrated, with 4 companies capturing 69% of FDC volume across the ten countries. Among second line drugs, fluoroquinolones were widely available, with significant volumes used for TB in India, Pakistan and Indonesia. However, certain WHO-recommended drugs were not available and in general there were insufficient drug volumes to cover the majority of the expected burden of multidrug-resistant TB (MDR-TB). Conclusions/Significance Private TB drug markets in several HBCs are substantial, stable, and complicated. This calls for appropriate policy and market responses, including expansion of Public-Private Mix (PPM) programs, greater reach, flexibility and appeal of public programs, regulatory and quality enforcement, and expansion of public MDR-TB treatment programs. PMID:21573227

The influence of mutation gene rpoB of Mycobacterium tuberculosis cluster I (507-534) on the elimination 25-desacetyl rifampicin in urine of tuberculosis subjects

NASA Astrophysics Data System (ADS)

Lily; Sinaga, B. Y. M.; Ardinata, D.; Siregar, Y.

2018-03-01

The study aimed to evaluate the influence of mutation gene rpoB of Mycobacterium (M.) tuberculosis cluster I (507-534) on the elimination of 25-Desacetyl Rifampicin (25-DR) in the urine of tuberculosis (TB) subjects. Early morning sputum took from patient TB before treatment. Urine collected after 2 hours taken Fixed-Dose Combination (FDC) at days 7th treatment. All sputum were sequencing at Macrogen Korea Laboratory. Urine was analyzed by high-Performance Liquid Chromatography (HPLC) using the method of Lily et al. Mean (standard deviation) for mutation and non-mutation of rpoB M. tuberculosis group were 7.6147 (4.4478) and 4.5772 (1.7532) μg/ml, respectively. Shapiro-Wilk test showed normally distributed data, with significance 0.3. Independent t-test performed p-value 0.167 and confidence interval (CI) from -1.648 to 7.723. The mutation gene rpoB of M. tuberculosis cluster, I (507-534) in this study, did not affect elimination 25-DR in theurine of TB subjects statistically and clinically.

Advanced Infantry Training: An Empirical Analysis Of (0341) Mortarman Success While Attending Advanced Mortarman Course

DTIC Science & Technology

2017-12-01

13 Table 2. TFDW File Descriptions ... evaluation FO Forward Observer FY Fiscal year GT General technical HLZ Helicopter landing zone ID Identification ITB Infantry Training...survive during AMCs most difficult training phases, to include FDC and advanced FDC evaluations . These events require a heightened degree of cognitive

21 CFR 74.2706 - FD&C Yellow No. 6.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Yellow No. 6. 74.2706 Section 74.2706 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

21 CFR 74.2203 - FD&C Green No. 3.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Green No. 3. 74.2203 Section 74.2203 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... safely used for coloring cosmetics generally in amounts consistent with current good manufacturing...

21 CFR 74.1304 - FD&C Red No. 4.

Code of Federal Regulations, 2011 CFR

2011-04-01

...-insoluble matter, not more than 0.2 percent. 5-Amino-2,4-dimethyl-1-benzenesulfonic acid, sodium salt, not... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...-naphthalenesulfonic acid. (2) Color additive mixtures for use in externally applied drugs made with FD&C Red No. 4 may...

21 CFR 74.340 - FD&C Red No. 40.

Code of Federal Regulations, 2011 CFR

2011-04-01

... more than 0.3 percent. 4-Amino-5-methoxy-o- toluenesulfonic acid, not more than 0.2 percent. Disodium... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

21 CFR 74.340 - FD&C Red No. 40.

Code of Federal Regulations, 2010 CFR

2010-04-01

... more than 0.3 percent. 4-Amino-5-methoxy-o- toluenesulfonic acid, not more than 0.2 percent. Disodium... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

21 CFR 74.1304 - FD&C Red No. 4.

Code of Federal Regulations, 2010 CFR

2010-04-01

...-insoluble matter, not more than 0.2 percent. 5-Amino-2,4-dimethyl-1-benzenesulfonic acid, sodium salt, not... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...-naphthalenesulfonic acid. (2) Color additive mixtures for use in externally applied drugs made with FD&C Red No. 4 may...

77 FR 56646 - Wayne E. Spencer: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-13

..., including the process for development or approval, of a drug product under the FD&C Act. Dr. Spencer was..., including the process for development or approval, of a drug product under the FD&C Act. On March 7, 2012... to the development or approval, including the process for development or approval, of a drug product...

21 CFR 201.20 - Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for human...

Code of Federal Regulations, 2014 CFR

2014-04-01

..., or rectally, or for use in the area of the eye, the labeling required by § 201.100(d) shall bear the... patients who also have aspirin hypersensitivity.” This warning statement shall appear in the “Precautions...

21 CFR 201.20 - Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for human...

Code of Federal Regulations, 2013 CFR

2013-04-01

..., or rectally, or for use in the area of the eye, the labeling required by § 201.100(d) shall bear the... patients who also have aspirin hypersensitivity.” This warning statement shall appear in the “Precautions...

21 CFR 201.20 - Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for human...

Code of Federal Regulations, 2012 CFR

2012-04-01

..., or rectally, or for use in the area of the eye, the labeling required by § 201.100(d) shall bear the... patients who also have aspirin hypersensitivity.” This warning statement shall appear in the “Precautions...

21 CFR 201.20 - Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for human...

Code of Federal Regulations, 2010 CFR

2010-04-01

..., or rectally, or for use in the area of the eye, the labeling required by § 201.100(d) shall bear the... patients who also have aspirin hypersensitivity.” This warning statement shall appear in the “Precautions...

21 CFR 201.20 - Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for human...

Code of Federal Regulations, 2011 CFR

2011-04-01

..., or rectally, or for use in the area of the eye, the labeling required by § 201.100(d) shall bear the... patients who also have aspirin hypersensitivity.” This warning statement shall appear in the “Precautions...

ModABa Model: Annual Flow Duration Curves Assessment in Ephemeral Basins

NASA Astrophysics Data System (ADS)

Pumo, Dario; Viola, Francesco; Noto, Leonardo V.

2013-04-01

A representation of the streamflow regime for a river basin is required for a variety of hydrological analyses and engineering applications, from the water resource allocation and utilization to the environmental flow management. The flow duration curve (FDC) represents a comprehensive signature of temporal runoff variability often used to synthesize catchment rainfall-runoff responses. Several models aimed to the theoretical reconstruction of the FDC have been recently developed under different approaches, and a relevant scientific knowledge specific to this topic has been already acquired. In this work, a new model for the probabilistic characterization of the daily streamflows in perennial and ephemeral catchments is introduced. The ModABa model (MODel for Annual flow duration curves assessment in intermittent BAsins) can be thought as a wide mosaic whose tesserae are frameworks, models or conceptual schemes separately developed in different recent studies. Such tesserae are harmoniously placed and interconnected, concurring together towards a unique final aim that is the reproduction of the FDC of daily streamflows in a river basin. Two separated periods within the year are firstly identified: a non-zero period, typically characterized by significant streamflows, and a dry period, that, in the cases of ephemeral basins, is the period typically characterized by absence of streamflow. The proportion of time the river is dry, providing an estimation of the probability of zero flow occurring, is empirically estimated. Then, an analysis concerning the non-zero period is performed, considering the streamflow disaggregated into a slow subsuperficial component and a fast superficial component. A recent analytical model is adopted to derive the non zero FDC relative to the subsuperficial component; this last is considered to be generated by the soil water excess over the field capacity in the permeable portion of the basin. The non zero FDC relative to the fast streamflow component is directly derived from the precipitation duration curve through a simple filter model. The fast component of streamflow is considered to be formed by two contributions that are the entire amount of rainfall falling onto the impervious portion of the basin and the excess of rainfall over a fixed threshold, defining heavy rain events, falling onto the permeable portion. The two obtained FDCs are then overlapped, providing a unique non-zero FDC relative to the total streamflow. Finally, once the probability that the river is dry and the non zero FDC are known, the annual FDC of the daily total streamflow is derived applying the theory of total probability. The model is calibrated on a small catchment with ephemeral streamflows using a long period of daily precipitation, temperature and streamflow measurements, and it is successively validated in the same basin using two different time periods. The high model performances obtained in both the validation periods, demonstrate how the model, once calibrated, is able to accurately reproduce the empirical FDC starting from easily derivable parameters arising from a basic ecohydrological knowledge of the basin and commonly available climatic data such as daily precipitation and temperatures. In this sense, the model reveals itself as a valid tool for streamflow predictions in ungauged basins.

21 CFR 74.303 - FD&C Red No. 3.

Code of Federal Regulations, 2010 CFR

2010-04-01

... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods... coloring foods generally (including dietary supplements) in amounts consistent with good manufacturing... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FD&C Red No. 3. 74.303 Section 74.303 Food and...

21 CFR 74.303 - FD&C Red No. 3.

Code of Federal Regulations, 2011 CFR

2011-04-01

... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods... coloring foods generally (including dietary supplements) in amounts consistent with good manufacturing... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Red No. 3. 74.303 Section 74.303 Food and...

21 CFR 74.1340 - FD&C Red No. 40.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Red No. 40. 74.1340 Section 74.1340 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... additive mixtures for coloring drugs. (3) The listing of this color additive includes lakes prepared as...

21 CFR 74.2705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Yellow No. 5. 74.2705 Section 74.2705 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... ethyl ester, or a salt of this carboxylic acid. The resulting dye is purified and isolated as the sodium...

21 CFR 74.2705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Yellow No. 5. 74.2705 Section 74.2705 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... ethyl ester, or a salt of this carboxylic acid. The resulting dye is purified and isolated as the sodium...

21 CFR 74.2705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Yellow No. 5. 74.2705 Section 74.2705 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... ethyl ester, or a salt of this carboxylic acid. The resulting dye is purified and isolated as the sodium...

21 CFR 74.2705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Yellow No. 5. 74.2705 Section 74.2705 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... ethyl ester, or a salt of this carboxylic acid. The resulting dye is purified and isolated as the sodium...

Family Day Care Educators: An Exploration of Their Understanding and Experiences Promoting Children's Social and Emotional Wellbeing

ERIC Educational Resources Information Center

Davis, Elise; Priest, Naomi; Davies, Belinda; Smyth, Lisa; Waters, Elizabeth; Herrman, Helen; Sims, Margaret; Harrison, Linda; Cook, Kay; Marshall, Bernie; Williamson, Lara

2012-01-01

This study aimed to explore family day care (FDC) educators' knowledge of child social and emotional wellbeing and mental health problems, the strategies used to promote children's wellbeing, and barriers and opportunities for promoting children's social and emotional wellbeing. Thirteen FDC educators participated in individual semi-structured…

Investigations of DC power supplies with optoelectronic transducers and RF energy converters

NASA Astrophysics Data System (ADS)

Guzowski, B.; Gozdur, R.; Bernacki, L.; Lakomski, M.

2016-04-01

Fiber Distribution Cabinets (FDC) monitoring systems are increasingly popular. However it is difficult to realize such system in passive FDC, due to lack of source of power supply. In this paper investigation of four different DC power supplies with optoelectronic transducers is described. Two converters: photovoltaic power converter and PIN photodiode can convert the light transmitted through the optical fiber to electric energy. Solar cell and antenna RF-PCB are also tested. Results presented in this paper clearly demonstrate that it is possible to build monitoring system in passive FDC. During the tests maximum obtained output power was 11 mW. However all converters provided enough power to excite 32-bit microcontroller with ARM-cores and digital thermometer.

Fixed-dose combination drugs for tuberculosis: application in standardised treatment regimens.

PubMed

Blomberg, Bjørn; Fourie, Bernard

2003-01-01

Short-course chemotherapy is highly efficacious in treating tuberculosis (TB). However, the length (>/=6 months) and complexity (three or four different drugs) of the treatment makes adherence difficult. Erratic treatment not only fails to cure patients but also creates chronically contagious cases, who may excrete drug-resistant TB bacteria. The Directly Observed Treatment Short-course (DOTS) strategy recommended by WHO provides a comprehensive organisational and infrastructural framework for the rational use of diagnosis, drug supply, as well as case and programme management services, in TB control. WHO and other organisations recommend fixed-dose combination formulations (FDCs) as a further step to facilitate the optimal drug treatment of TB. Using FDCs in TB control will simplify the doctor's prescription and patient's drug intake, as well as the drug supply management of the programme. By preventing monotherapy and facilitating the ingestion of adequate doses of the constituent anti-TB drugs, FDCs are expected to help prevent the emergence of drug resistance. This article presents the international recommendations for the use of FDCs in TB programmes. The fundamental issue is to obtain drug supplies of good quality. A laboratory network for quality testing, including bioavailability testing of FDCs exists, and the recently established Global TB Drug Facility (GDF) supplies quality TB drugs, including 4-drug FDCs, to countries requesting assistance. This articles deals with the requirements for a successful transition to FDC-based treatment. It emphasises the need for appropriately revised programme documentation (programme manual, training modules, treatment guidelines and forms), training of staff at all levels, carefully calculated drug needs, and a plan for the exhaustion of existing stocks of loose tablets and the phasing-in of FDCs at all levels of the programme at the same time. Loose drugs for individualised treatment of patients with adverse effects should be kept at district or central health institutions.

The index gage method to develop a flow duration curve from short-term streamflow records

NASA Astrophysics Data System (ADS)

Zhang, Zhenxing

2017-10-01

The flow duration curve (FDC) is one of the most commonly used graphical tools in hydrology and provides a comprehensive graphical view of streamflow variability at a particular site. For a gaged site, an FDC can be easily estimated with frequency analysis. When no streamflow records are available, regional FDCs are used to synthesize FDCs. However, studies on how to develop FDCs for sites with short-term records have been very limited. Deriving representative FDC when there are short-term hydrologic records is important. For instance, 43% of the 394 streamflow gages in Illinois have records of 20 years or fewer, and these short-term gages are often distributed in headwaters and contain valuable hydrologic information. In this study, the index gage method is proposed to develop FDCs using short-term hydrologic records via an information transfer technique from a nearby hydrologically similar index gage. There are three steps: (1) select an index gage; (2) determine changes of FDC; and (3) develop representative FDCs. The approach is tested using records from 92 U.S. Geological Survey streamflow gages in Illinois. A jackknife experiment is conducted to assess the performance. Bootstrap resampling is used to simulate various periods of records, i.e., 1, 2, 5, 10, 15, and 20 years of records. The results demonstrated that the index gage method is capable of developing a representative FDC using short-term records. Generally, the approach performance is improved when more hydrologic records are available, but the improvement appears to level off when the short-term gage has 10 years or more records.

Extraction and Quantitation of FD&C Red Dye #40 from Beverages Containing Cranberry Juice: A College-Level Analytical Chemistry Experiment

ERIC Educational Resources Information Center

Rossi, Henry F., III; Rizzo, Jacqueline; Zimmerman, Devon C.; Usher, Karyn M.

2012-01-01

A chemical separation experiment can be an interesting addition to an introductory analytical chemistry laboratory course. We have developed an experiment to extract FD&C Red Dye #40 from beverages containing cranberry juice. After extraction, the dye is quantified using colorimetry. The experiment gives students hands-on experience in using solid…

77 FR 25 - Amendments to Regulations on Citizen Petitions, Petitions for Stay of Action, and Submission of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-03

... FD&C Act). Section 505(q) of the FD&C Act also includes certification and verification requirements... petition unless the submission is in writing and signed and contains a specific verification (section 505(q... Sec. 10.31(c) and (d) would codify the certification and verification requirements of section 505(q)(1...

78 FR 18803 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-28

... region in which the affected airport is located; 3. The National Flight Procedures Office, 6500 South... Policies and Procedures (44 FR 11034; February 26, 1979); and (3) does not warrant preparation of a... City Airport FDC No. FDC date Subject 2-May-13 IL Decatur Decatur 3/8961 2/25/13 This NOTAM, published...

77 FR 61003 - Stephen C. Delaney, Jr.: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-05

...] Stephen C. Delaney, Jr.: Debarment Order AGENCY: Food and Drug Administration, HHS. ACTION: Notice... Cosmetic Act (the FD&C Act) debarring Stephen C. Delaney, Jr. for a period of 5 years from importing... INFORMATION: I. Background Section 306(b)(1)(C) of the FD&C Act (21 U.S.C. 335a(b)(1)(C)) permits FDA to debar...

76 FR 25231 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-04

..., and the need for a special format make their verbatim publication in the Federal Register expensive... AIRAC date State City Airport FDC No. FDC date Subject 2-Jun-11 IN Terre Haute Terre Haute Intl-- 1/2732 4/1/11 VOR/DME RWY 5, Amdt 17C Hulman Field. 2-Jun-11 LA Lake Charles Lake Charles Rgnl.... 1/2810 4...

78 FR 40385 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-05

... regulatory evaluation as the anticipated impact is so minimal. For the same reason, the FAA certifies that... Airport FDC No. FDC Date Subject 7/25/13 AL Birmingham...... Birmingham- 3/0061 6/13/13 ILS OR LOC RWY Shuttlesworth 6, ILS RWY 6 Intl. (CAT II), Amdt 42. 7/25/13 FL Daytona Beach... Daytona Beach 3/0406 6/13/13...

Successful international collaboration improves family donation conversations resulting in increased organ donation.

PubMed

Mulvania, P; Mehakovic, E; Wise, C; Cass, Y; Daly, T A; Nathan, H M

2014-01-01

Australian donation leaders recognized that to increase organ donation outcomes, health professionals conducting family donation conversations (FDCs) required support and specialist training. An international training institute with programs based on proven results was engaged to create and implement a customized training program to influence change in FDC practice and culture. The goal was to increase donation rates by developing and implementing a customized, self-sustaining training program to enhance FDC practices of health professionals. Other goals included providing training and communications skills to lead FDC, supporting families in making decisions, and influencing health professionals to adopt FDC practices. To gain support and determine program suitability, two 1-day pilot training sessions were provided to 45 Australian donation leaders in 2011. Training was further customized with an emphasis on creating changes to achieve and sustain desired results. A comprehensive national training plan was implemented over 18 months. Twenty-six 2-day FDC training workshops were held in 8 cities (646 participants). Program evaluations and debriefings showed distinct shifts in perspectives and an enthusiasm to implement new processes. In 2012 to 2013, an instructor program was developed to transition training facilitation. The training institute remains involved in development and training to build and sustain skill and expertise. There was a 58% increase in organ donors in Australia from 2009 to 2013 (data reflect 2013 Australian end-of-year organ donation information). This represents a 36% increase in organ donors (2009-2011); the remaining 22% increase was achieved in the 2 years since the FDC training was implemented in Australia (2011-2013). Improved skills training in the conduct of FDCs seem to have contributed to improved donation outcomes in national identification, request, and consent rates. The integration of another organization's process poses distinct challenges; thoughtful collaboration, sensitive to cultural aspects and family care, communication, and donation practices, can result in successful customized training that shifts perspectives, provides new skills, and achieves and sustains an increase in organ donation rates. Copyright © 2014 Elsevier Inc. All rights reserved.

Real World Experience With Ion Implant Fault Detection at Freescale Semiconductor

NASA Astrophysics Data System (ADS)

Sing, David C.; Breeden, Terry; Fakhreddine, Hassan; Gladwin, Steven; Locke, Jason; McHugh, Jim; Rendon, Michael

2006-11-01

The Freescale automatic fault detection and classification (FDC) system has logged data from over 3.5 million implants in the past two years. The Freescale FDC system is a low cost system which collects summary implant statistics at the conclusion of each implant run. The data is collected by either downloading implant data log files from the implant tool workstation, or by exporting summary implant statistics through the tool's automation interface. Compared to the traditional FDC systems which gather trace data from sensors on the tool as the implant proceeds, the Freescale FDC system cannot prevent scrap when a fault initially occurs, since the data is collected after the implant concludes. However, the system can prevent catastrophic scrap events due to faults which are not detected for days or weeks, leading to the loss of hundreds or thousands of wafers. At the Freescale ATMC facility, the practical applications of the FD system fall into two categories: PM trigger rules which monitor tool signals such as ion gauges and charge control signals, and scrap prevention rules which are designed to detect specific failure modes that have been correlated to yield loss and scrap. PM trigger rules are designed to detect shifts in tool signals which indicate normal aging of tool systems. For example, charging parameters gradually shift as flood gun assemblies age, and when charge control rules start to fail a flood gun PM is performed. Scrap prevention rules are deployed to detect events such as particle bursts and excessive beam noise, events which have been correlated to yield loss. The FDC system does have tool log-down capability, and scrap prevention rules often use this capability to automatically log the tool into a maintenance state while simultaneously paging the sustaining technician for data review and disposition of the affected product.

Coding Sequence Mutations Identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 Patients with Familial or Idiopathic Dilated Cardiomyopathy

PubMed Central

Hershberger, Ray E.; Parks, Sharie B.; Kushner, Jessica D.; Li, Duanxiang; Ludwigsen, Susan; Jakobs, Petra; Nauman, Deirdre; Burgess, Donna; Partain, Julie; Litt, Michael

2008-01-01

Abstract Background: More than 20 genes have been reported to cause idiopathic and familial dilated cardiomyopathy (IDC/FDC), but the frequency of genetic causation remains poorly understood. Methods and Results: Blood samples were collected and DNA prepared from 313 patients, 183 with FDC and 130 with IDC. Genomic DNA underwent bidirectional sequencing of six genes, and mutation carriers were followed up by evaluation of additional family members. We identified in 36 probands, 31 unique protein‐altering variants (11.5% overall) that were not identified in 253 control subjects (506 chromosomes). These included 13 probands (4.2%) with 12 β‐myosin heavy chain (MYH7) mutations, nine probands (2.9%) with six different cardiac troponin T (TNNT2) mutations, eight probands (2.6%) carrying seven different cardiac sodium channel (SCN5A) mutations, three probands (1.0%) with three titin‐cap or telethonin (TCAP) mutations, three probands (1.0%) with two LIM domain binding 3 (LDB3) mutations, and one proband (0.3%) with a muscle LIM protein (CSRP3) mutation. Four nucleotide changes did not segregate with phentoype and/or did not alter a conserved amino acid and were therefore considered unlikely to be disease‐causing. Mutations in 11 probands were assessed as likely disease‐causing, and in 21 probands were considered possibly disease‐causing. These 32 probands included 14 of the 130 with IDC (10.8%) and 18 of the 183 with FDC (9.8%) Conclusions: Mutations of these six genes each account for a small fraction of the genetic cause of FDC/IDC. The frequency of possible or likely disease‐causing mutations in these genes is similar for IDC and FDC. PMID:19412328

Examining the Relationships between Family Drug Court Program Compliance and Child Welfare Outcomes.

PubMed

Child, Holly; McIntyre, Dara

2015-01-01

Although the evidence is accumulating to substantiate the successes of Family Drug Courts (FDC), there is little research on the relationship between parent compliance and successful reunification of children with their parent(s). This study looked at data from 206 families participating in a FDC in Sacramento County, California. Four compliance measures were examined individually and collectively, after controlling for participant characteristics, using logistic regression models to determine how FDC participation benchmarks impact child reunification. This study found the best predictors of reunification was participation in support group meetings and negative tests for substance use. These findings indicate that initiatives designed to address the needs of families affected by child maltreatment and substance use should take into account and support engagement in informal, community-based activities as well as formal, clinically focused interventions.

Axial strength test for round flat faced versus capsule shaped bilayer tablets.

PubMed

Franck, Jason; Abebe, Admassu; Keluskar, Rekha; Martin, Kyle; Majumdar, Antara; Kottala, Niranjan; Stamato, Howard

2015-03-01

There has been increasing interest in fixed dose combination (FDC) therapy. Multi-layer tablets are a popular choice among various technologies to deliver FDCs. In most cases, round flat faced tooling is used in testing tablets as they have the simplest geometry. However, shaped tooling is more common for commercial products and may have an effect on bilayer tablet strength. Capsule shaped bilayer tablets, similar to a commercial image, and holders conforming to the tablet topology, were compared with similar round flat faced bilayer tablets and their corresponding holders. Bilayer tablets were subjected to an axial test device, until fracture and the quantitative breaking force value was recorded. As the second layer compression force increases, regardless of holder design, an increase in breaking force occurs as expected. This consistent trend provides insight regarding the breaking force of capsule shaped bilayer tablets. The results of this study show that at lower second layer compression forces, tablet geometry does not significantly impact the results. However, at higher compression forces, a significant difference in breaking force between tablet geometries exists. Therefore, using a test geometry close to the final commercial tablet image is recommended to have the most accurate prediction for tablet breakage.

Evaluation of the recently reported USP gradient HPLC method for analysis of anti-tuberculosis drugs for its ability to resolve degradation products of rifampicin.

PubMed

Mohan, Bhavika; Sharda, Nishi; Singh, Saranjit

2003-03-10

The recently notified USP gradient HPLC method for quantitative determination of rifampicin, isoniazid and pyrazinamide in fixed dose combination (FDC) formulations was evaluated to determine its ability to resolve major degradation products of rifampicin, viz. 3-formylrifamycin SV, rifampicin N-oxide, 25-desacetyl rifampicin, rifampicin quinone, and the newly reported isonicotinyl hydrazone, an interaction product of 3-formylrifamycin and isoniazid. The first observation was that the requirements of theoretical plates listed in the given method were met for rifampicin, but not for isoniazid and pyrazinamide, even on columns of different makes. The resolving power of the method was also dependent upon make of the column. On two of the three columns of the three tested, it was able to resolve most degradation products, except rifampicin N-oxide and 25-desacetylrifampicin, which were overlapping. The method was modified and an overall satisfactory resolution for all components was obtained by changing the buffer: organic modifier ratio of solution B in the gradient from 45:55 to 55:45 and decreasing the flow rate from 1.5 to 1.0 ml/min, keeping all other conditions constant.

Regional variation of flow duration curves in the eastern United States: Process-based analyses of the interaction between climate and landscape properties

Treesearch

Wafa Chouaib; Peter V. Caldwell; Younes Alila

2018-01-01

This paper advances the physical understanding of the flow duration curve (FDC) regional variation. It provides a process-based analysis of the interaction between climate and landscape properties to explain disparities in FDC shapes. We used (i) long term measured flow and precipitation data over 73 catchments from the eastern US. (ii) We calibrated the...

78 FR 7652 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-04

... a regulatory evaluation as the anticipated impact is so minimal. For the same reason, the FAA... Airport FDC No. FDC Date Subject 7-Mar-13 MI Detroit Coleman A. Young 2/7262 01/11/13 RNAV (GPS) RWY 33, Orig Muni. 7-Mar-13 TX Graford Possum Kingdom...... 3/0511 01/11/13 RNAV (GPS) RWY 20, Orig 7-Mar-13 TX...

78 FR 54562 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-05

... regulatory evaluation as the anticipated impact is so minimal. For the same reason, the FAA certifies that... City Airport FDC No. FDC Date Subject 9/19/13 OR Aurora Aurora State........ 3/0113 8/7/13 RNAV (GPS) RWY 17, Orig-B. 9/19/13 OR Aurora Aurora State........ 3/0114 8/7/13 RNAV (GPS) RWY 35, Orig-C. 9/19...

78 FR 34561 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-10

... regulatory evaluation as the anticipated impact is so minimal. For the same reason, the FAA certifies that... Airport FDC No. FDC Date Subject 6/27/13 NE Alliance Alliance Muni...... 2/3777 5/22/13 NDB RWY 12, Orig. 6/27/13 AK McGrath McGrath 2/7217 5/13/13 Takeoff Minimums and (Obstacle) DP, Amdt 2. 6/27/13 OR...

Regional flow duration curves: Geostatistical techniques versus multivariate regression

USGS Publications Warehouse

Pugliese, Alessio; Farmer, William H.; Castellarin, Attilio; Archfield, Stacey A.; Vogel, Richard M.

2016-01-01

A period-of-record flow duration curve (FDC) represents the relationship between the magnitude and frequency of daily streamflows. Prediction of FDCs is of great importance for locations characterized by sparse or missing streamflow observations. We present a detailed comparison of two methods which are capable of predicting an FDC at ungauged basins: (1) an adaptation of the geostatistical method, Top-kriging, employing a linear weighted average of dimensionless empirical FDCs, standardised with a reference streamflow value; and (2) regional multiple linear regression of streamflow quantiles, perhaps the most common method for the prediction of FDCs at ungauged sites. In particular, Top-kriging relies on a metric for expressing the similarity between catchments computed as the negative deviation of the FDC from a reference streamflow value, which we termed total negative deviation (TND). Comparisons of these two methods are made in 182 largely unregulated river catchments in the southeastern U.S. using a three-fold cross-validation algorithm. Our results reveal that the two methods perform similarly throughout flow-regimes, with average Nash-Sutcliffe Efficiencies 0.566 and 0.662, (0.883 and 0.829 on log-transformed quantiles) for the geostatistical and the linear regression models, respectively. The differences between the reproduction of FDC's occurred mostly for low flows with exceedance probability (i.e. duration) above 0.98.

75 FR 63710 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-18

...: * * * Effective Upon Publication AIRAC date State City Airport FDC No. FDC date Subject 18-Nov-10 CQ SAIPAN ISLAND...... FRANCISCO C. ADA/ 0/1358 9/29/10 ILS OR LOC/DME RWY 7, AMDT 5B. SAIPAN INTL. 18-Nov-10 CQ SAIPAN ISLAND...... FRANCISCO C. ADA/ 0/1359 9/29/10 NDB/DME RWY 25, AMDT 2A SAIPAN INTL. 18-Nov-10 CQ SAIPAN ISLAND...

76 FR 28173 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-16

..., and the need for a special format make their verbatim publication in the Federal Register expensive... Airport FDC No. FDC date Subject 2-Jun-11 IN New Castle New Castle-Henry Co 1/5020 4/6/11 NDB RWY 27, Amdt 5A Muni. 2-Jun-11 OH Akron Akron-Canton Rgnl... 1/5370 4/12/11 RNAV (GPS) RWY 5, Orig 2-Jun-11 OH...

New physicochemical interpretations for the adsorption of food dyes on chitosan films using statistical physics treatment.

PubMed

Dotto, G L; Pinto, L A A; Hachicha, M A; Knani, S

2015-03-15

In this work, statistical physics treatment was employed to study the adsorption of food dyes onto chitosan films, in order to obtain new physicochemical interpretations at molecular level. Experimental equilibrium curves were obtained for the adsorption of four dyes (FD&C red 2, FD&C yellow 5, FD&C blue 2, Acid Red 51) at different temperatures (298, 313 and 328 K). A statistical physics formula was used to interpret these curves, and the parameters such as, number of adsorbed dye molecules per site (n), anchorage number (n'), receptor sites density (NM), adsorbed quantity at saturation (N asat), steric hindrance (τ), concentration at half saturation (c1/2) and molar adsorption energy (ΔE(a)) were estimated. The relation of the above mentioned parameters with the chemical structure of the dyes and temperature was evaluated and interpreted. Copyright © 2014 Elsevier Ltd. All rights reserved.

Designating Additions to the Current List of Tropical Diseases in the Federal Food, Drug, and Cosmetic Act. Final order.

PubMed

2015-08-20

The Federal Food, Drug, and Cosmetic Act (the FD&C Act) authorizes the Food and Drug Administration (FDA or Agency) to award priority review vouchers (PRVs) to tropical disease product applicants when the applications meet certain criteria. The FD&C Act lists the diseases that are considered to be tropical diseases for purposes of obtaining PRVs, and also provides for Agency expansion of that list to include other diseases that satisfy the definition of ``tropical diseases'' as set forth in the FD&C Act. FDA has determined that Chagas disease and neurocysticercosis satisfy this definition, and therefore is adding them to the list of designated tropical diseases whose product applications may result in the award of PRVs. Sponsors submitting certain applications for the treatment of Chagas disease and neurocysticercosis may be eligible to receive a PRV if such applications are approved by FDA.

Effect of operating conditions on performance of silica gel-water air-fluidised desiccant cooler

NASA Astrophysics Data System (ADS)

Rogala, Zbigniew; Kolasiński, Piotr; Gnutek, Zbigniew

2017-11-01

Fluidised desiccant cooling is reported in the literature as an efficient way to provide cooling for air-conditioning purposes. The performance of this technology can be described by electric and thermal Coefficients of Performance (COP) and Specific Cooling Power (SCP). In this paper comprehensive theoretical study was carried out in order to assess the effect of operating conditions such as: superficial air velocity, desiccant particle diameter, bed switching time and desiccant filling height on the performance of fluidised desiccant cooler (FDC). It was concluded that FDC should be filled with as small as possible desiccant particles featuring diameters and should not be operated with shorter switching times than optimum. Moreover in order to efficiently run such systems superficial air velocities during adsorption and desorption should be similar. At last substantial effect of desiccant filling height on performance of FDC was presented.

An Integration, Long Range Planning, and Migration Guide for the Stock Point Logistics Integrated Communications Project.

DTIC Science & Technology

1986-03-01

and universal terminal/printer interface mapping ( TMAP ) software. When the Burroughs HYPERchannel software package (i.e., Burroughs NETEX) provided...and terminal device and security functions placed under the control of the FDC’s SAS/ TMAP processes. Without processing efficiency enhancements, TAPS...FDC’s SAS/ TMAP processes. As was also previously indicated, the performance of TAPS II on TANDEM is poor today, and there are questions as whether

Impacts analysis regarding partially hydrogenated oils

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

Smith, Ellen D.; Turhollow, Jr., Anthony F.; Zimmerman, Gregory P..

The U.S. Food and Drug Administration (FDA) has the responsibility under the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 United States Code (U.S.C.) 301 et seq.] for assuring that the U.S. food supply is safe, sanitary, wholesome, and honestly labeled. Toward that end, FDA exercised approval authority over substances permitted for use as food additives. Substances that are generally recognized as safe (GRAS) are not subject to regulation as food additives under the FD&C Act.

Use of Gene Expression Programming in regionalization of flow duration curve

NASA Astrophysics Data System (ADS)

Hashmi, Muhammad Z.; Shamseldin, Asaad Y.

2014-06-01

In this paper, a recently introduced artificial intelligence technique known as Gene Expression Programming (GEP) has been employed to perform symbolic regression for developing a parametric scheme of flow duration curve (FDC) regionalization, to relate selected FDC characteristics to catchment characteristics. Stream flow records of selected catchments located in the Auckland Region of New Zealand were used. FDCs of the selected catchments were normalised by dividing the ordinates by their median value. Input for the symbolic regression analysis using GEP was (a) selected characteristics of normalised FDCs; and (b) 26 catchment characteristics related to climate, morphology, soil properties and land cover properties obtained using the observed data and GIS analysis. Our study showed that application of this artificial intelligence technique expedites the selection of a set of the most relevant independent variables out of a large set, because these are automatically selected through the GEP process. Values of the FDC characteristics obtained from the developed relationships have high correlations with the observed values.

Characteristics of newly diagnosed COPD patients treated with triple inhaled therapy by general practitioners: a real world Italian study.

PubMed

Di Marco, Fabiano; Santus, Pierachille; Terraneo, Silvia; Peruzzi, Elena; Muscianisi, Elisa; Ripellino, Claudio; Pegoraro, Valeria

2017-09-07

Factors predicting prescriptions of triple therapy were investigated in a large group of general practitioners in Italy. In the population treated by identified general practitioners, a cohort of newly diagnosed chronic obstructive pulmonary disease patients was extracted from IMS Health Longitudinal Database during the period 2010-2013. From the diagnosis, 1-year follow-up was evaluated. Thirty-two thousand forty-six newly diagnosed chronic obstructive pulmonary disease patients were evaluated (57.7% male, mean age 67 years). During 2 years prior to diagnosis less than 13% of patients were requested with a pulmonology evaluation and less than 5% with a spirometry; 65.1% cases were prescribed with a respiratory drug, which in 9.6% of cases was inhaled corticosteroid/long-acting β 2 -agonist fixed-dose combination. Two thousand and twenty eight patients (6.3% of the newly diagnosed chronic obstructive pulmonary disease patients) were treated with triple therapy during the first year of follow-up, whose 858 (42.3%) starting immediately, and 762 (37.6%) following an initial treatment with inhaled corticosteroid/long-acting β 2 -agonist fixed-dose combination. Being older, being requested with pulmonologist evaluation or spirometry, being prescribed with a inhaled corticosteroid/long-acting β 2 -agonist fixed-dose combination at diagnosis resulted independent predictors of triple therapy use. ENSURING CORRECT PRESCRIPTIONS FOR EARLY-STAGE DISEASE: An improved education program for doctors promoting correct use of medication for chronic lung disease is needed in Italy. Current guidelines state that inhaled corticosteroids (ICSs) should be reserved for patients with severe chronic obstructive pulmonary disease (COPD), but it appears that doctors do not always follow this advice. Fabiano Di Marco, at San Paolo Hospital-Università degli Studi di Milano, and co-workers analyzed data from 32,046 COPD patients newly-diagnosed by family doctors in Italy between 2010 and 2013. When the researchers followed up on patients after 1 year, 2028 (6.3%) of newly-diagnosed patients were being treated with triple inhaled therapy incorporating ICSs-42% of these patients had started triple therapy immediately upon diagnosis. Being an older male and having been prescribed with a ICS/LABA FDC at diagnosis were strong predictors of triple therapy use within 1 year from the diagnosis.

Comparison of Monte Carlo and analytical dose computations for intensity modulated proton therapy

NASA Astrophysics Data System (ADS)

Yepes, Pablo; Adair, Antony; Grosshans, David; Mirkovic, Dragan; Poenisch, Falk; Titt, Uwe; Wang, Qianxia; Mohan, Radhe

2018-02-01

To evaluate the effect of approximations in clinical analytical calculations performed by a treatment planning system (TPS) on dosimetric indices in intensity modulated proton therapy. TPS calculated dose distributions were compared with dose distributions as estimated by Monte Carlo (MC) simulations, calculated with the fast dose calculator (FDC) a system previously benchmarked to full MC. This study analyzed a total of 525 patients for four treatment sites (brain, head-and-neck, thorax and prostate). Dosimetric indices (D02, D05, D20, D50, D95, D98, EUD and Mean Dose) and a gamma-index analysis were utilized to evaluate the differences. The gamma-index passing rates for a 3%/3 mm criterion for voxels with a dose larger than 10% of the maximum dose had a median larger than 98% for all sites. The median difference for all dosimetric indices for target volumes was less than 2% for all cases. However, differences for target volumes as large as 10% were found for 2% of the thoracic patients. For organs at risk (OARs), the median absolute dose difference was smaller than 2 Gy for all indices and cohorts. However, absolute dose differences as large as 10 Gy were found for some small volume organs in brain and head-and-neck patients. This analysis concludes that for a fraction of the patients studied, TPS may overestimate the dose in the target by as much as 10%, while for some OARs the dose could be underestimated by as much as 10 Gy. Monte Carlo dose calculations may be needed to ensure more accurate dose computations to improve target coverage and sparing of OARs in proton therapy.

Tuberculosis drug issues: prices, fixed-dose combination products and second-line drugs.

PubMed

Laing, R O; McGoldrick, K M

2000-12-01

Access to tuberculosis drugs depends on multiple factors. Selection of a standard list of TB drugs to procure is the first step. This paper reviews the advantages and disadvantages of procuring and using fixed-dose combination (FDC) products for both the intensive and continuation phases of treatment. The major advantages are to prevent the emergence of resistance, to simplify logistic management and to reduce costs. The major disadvantage is the need for the manufacturers to assure the quality of these FDCs by bioavailability testing. The paper reports on the inclusion of second-line TB drugs in the 1999 WHO Essential Drug List (EDL). The need to ensure that these drugs are used within established DOTS-Plus programs is stressed. The price of TB drugs is determined by many factors, including producer prices, local taxes and duties as well as mark-ups and fees. TB drug prices for both the public and private sectors from industrialized and developing countries are reported. Price trends over time are also reported. The key findings of this study are that TB drug prices have generally declined in developing countries while they have increased in developed countries, both for the public and private sectors. Prices vary between countries, with the US paying as much as 95 times the price paid in a specific developing country. The prices of public sector first-line TB drugs vary little between countries, although differences do exist due to the procurement methods used. The price of tuberculin, a diagnostic agent, has increased dramatically in the US, with substantial inter-country variations in price. The paper suggests that further research is necessary to identify the reasons for the price disparities and changes over time, and suggests methods which can be used by National Tuberculosis Programme managers to ensure availability of quality assured TB drugs at low prices.

Lifespan psychomotor behaviour profiles of multigenerational prenatal stress and artificial food dye effects in rats.

PubMed

Erickson, Zachary T; Falkenberg, Erin A; Metz, Gerlinde A S

2014-01-01

The consumption of artificial food dye (AFD) during childhood and adolescence has been linked to behavioural changes, such as hyperactivity. It is possible that the vulnerability to AFDs is modified by prenatal stress. Common consequences of prenatal stress include hyperactivity, thus potentially leading to synergistic actions with AFDs. Here, we investigated the compounding effect of multigenerational prenatal stress (MPS) and AFD consumption on the development of hyperactivity and anxiety-related behaviours across the lifespan in male rats. MPS treatment involved a family history of four consecutive generations of prenatal stress (F4 generation). AFD treatment included a 4%-concentration of FD&C Red 40, FD&C Yellow 5, FD&C Yellow 6, and FD&C Blue 1 in the drinking water from postnatal days 22 to 50 to resemble juvenile and adolescent dietary exposure. Using several exploration tasks, animals were tested in motor activity and anxiety-like behaviours from adolescence to 13 months of age. MPS resulted in hyperactivity both early (50 days) and later in life (13 months), with normalized activity patterns at reproductive age. AFD consumption resulted in hyperactivity during consumption, which subsided following termination of treatment. Notably, both MPS and AFD promoted risk-taking behaviour in young adults (3 months). There were few synergistic effects between MPS and AFD in this study. The findings suggest that AFDs exert the most noticeable effects at the time of exposure. MPS, however, results in a characteristic lifespan profile of behavioural changes, indicating that development and aging represent particularly vulnerable periods in life during which a family history of prenatal stress may precipitate.

78 FR 3646 - Current Good Manufacturing Practice and Hazard Analysis and Risk-Based Preventive Controls for...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-16

...The Food and Drug Administration (FDA) is proposing to amend its regulation for Current Good Manufacturing Practice In Manufacturing, Packing, or Holding Human Food (CGMPs) to modernize it and to add requirements for domestic and foreign facilities that are required to register under the Federal Food, Drug, and Cosmetic Act (the FD&C Act) to establish and implement hazard analysis and risk- based preventive controls for human food. FDA also is proposing to revise certain definitions in FDA's current regulation for Registration of Food Facilities to clarify the scope of the exemption from registration requirements provided by the FD&C Act for ``farms.'' FDA is taking this action as part of its announced initiative to revisit the CGMPs since they were last revised in 1986 and to implement new statutory provisions in the FD&C Act. The proposed rule is intended to build a food safety system for the future that makes modern, science-, and risk-based preventive controls the norm across all sectors of the food system.

High-Resolution Free-GIS operations to assist hydropower potential assessment

NASA Astrophysics Data System (ADS)

Ganora, Daniele; Gallo, Enrico; Masoero, Alessandro; Laio, Francesco; Claps, Pierluigi

2013-04-01

Even in regions with mature hydropower development, needs for renewable energy suggest to revise plans of exploitation of water resources, according to EU and national environmental regulations. High resolution hydrological analysis is then needed to comply with the effects of existing hydropower plants and of other water withdrawals. Flow duration curves (FDC) are the tool usually adopted to represent water availability and variability for hydropower purposes. For this study, developed within the RENERFOR-ALCOTRA Project, a regional "spatially smooth" model has been developed for FDC estimation: the procedure adopted relates the L-moments of the FDC to several geomorphoclimatic parameters (more than 100), with the purpose to directly reconstruct a "naturalized" FDC. The proposed procedure is systematically extended to all the gauged basins located in Northwestern Italy, which is an area characterized by the presence of a large number of dams. For each basin, the annual average FDC is computed, its L-moments are calculated and corrected using a simplified model that takes into account the effect of upstream reservoirs and power plants. Then, each corrected L-moment is regionalized using multiple regressions techniques, allowing one to reconstruct the L-moments at any ungauged basin. Finally, the "naturalized" FDC is reconstructed at the ungauged site on the basis of the predicted L-moments. Due to necessity of obtaining high-resolution estimates, the method has been designed to keep the estimates of mean annual runoff congruent in the confluences. This feature is obtained considering only raster-summable explanatory variables, which are only a subset of the available descriptors. The residual hydropower potential is evaluated by mapping the mean naturalized flow estimated for each pixel of a DEM-derived river network raster model in two mountain basins used as case studies. Applying extensively the proposed methodology, the mean annual flow is reconstructed not only in some significant sections, but in all the about 25000 sections defined by each network pixel. We used a 50 m DEM to compute, for each network pixel, the upstream watershed and all the morpho-climatic characteristics needed in the regional model. Maps obtained can return flow-altitude relations for each pixel along a drainage path assuming different possible headrace length (1, 2.5 and 5 km). Spatial algorithms and data management are developed by the use of the Free&OpenSource software GRASS GIS and PostgreSQL as database manager, integrated with PostGIS elaboration to create the outputs. The large number of data and the complexity of the information derived required some thinking about the best way to access and represent the data, that has to be easy-to-use also for no-expert GIS users.

The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children.

PubMed

Waning, Brenda; Diedrichsen, Ellen; Jambert, Elodie; Bärnighausen, Till; Li, Yun; Pouw, Mieke; Moon, Suerie

2010-10-17

Important advances in the development and production of quality-certified pediatric antiretroviral (ARV) formulations have recently been made despite significant market disincentives for manufacturers. This progress resulted from lobbying and innovative interventions from HIV/AIDS activists, civil society organizations, and international organizations. Research on uptake and dispersion of these improved products across countries and international organizations has not been conducted but is needed to inform next steps towards improving child health. We used information from the World Health Organization Prequalification Programme and the United States Food and Drug Administration to describe trends in quality-certification of pediatric formulations and used 7,989 donor-funded, pediatric ARV purchase transactions from 2002-2009 to measure uptake and dispersion of new pediatric ARV formulations across countries and programs. Prices for new pediatric ARV formulations were compared to alternative dosage forms. Fewer ARV options exist for HIV/AIDS treatment in children than adults. Before 2005, most pediatric ARVs were produced by innovator companies in single-component solid and liquid forms. Five 2-in1 and four 3-in-1 generic pediatric fixed-dose combinations (FDCs) in solid and dispersible forms have been quality-certified since 2005. Most (67%) of these were produced by one quality-certified manufacturer. Uptake of new pediatric FDCs outside of UNITAID is low. UNITAID accounted for 97-100% of 2008-2009 market volume. In total, 33 and 34 countries reported solid or dispersible FDC purchases in 2008 and 2009, respectively, but most purchases were made through UNITAID. Only three Global Fund country recipients reported purchase of these FDCs in 2008. Prices for pediatric FDCs were considerably lower than liquids but typically higher than half of an adult FDC. Pediatric ARV markets are more fragile than adult markets. Ensuring a long-term supply of quality, well-adapted ARVs for children requires ongoing monitoring and improved understanding of global pediatric markets, including country-based research to explain and address low uptake of new, improved formulations. Continued innovation in pediatric ARV development may be threatened by outdated procurement practices failing to connect clinicians making prescribing decisions, supply chain staff dealing with logistics, donors, international organizations, and pharmaceutical manufacturers. Perceptions of global demand must be better informed by accurate estimates of actual country-level demand.

Intervening in global markets to improve access to HIV/AIDS treatment: an analysis of international policies and the dynamics of global antiretroviral medicines markets

PubMed Central

2010-01-01

Background Universal access to antiretroviral therapy (ART) in low- and middle-income countries faces numerous challenges: increasing numbers of people needing ART, new guidelines recommending more expensive antiretroviral (ARV) medicines, limited financing, and few fixed-dose combination (FDC) products. Global initiatives aim to promote efficient global ARV markets, yet little is known about market dynamics and the impact of global policy interventions. Methods We utilize several data sources, including 12,958 donor-funded, adult first-line ARV purchase transactions, to describe the market from 2002-2008. We examine relationships between market trends and: World Health Organization (WHO) HIV/AIDS treatment guidelines; WHO Prequalification Programme (WHO Prequal) and United States (US) Food and Drug Administration (FDA) approvals; and procurement policies of the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM), US President's Emergency Plan for AIDS Relief (PEPFAR) and UNITAID. Results WHO recommended 7, 4, 24, and 6 first-line regimens in 2002, 2003, 2006 and 2009 guidelines, respectively. 2009 guidelines replaced a stavudine-based regimen ($88/person/year) with more expensive zidovudine- ($154-260/person/year) or tenofovir-based ($244-465/person/year) regimens. Purchase volumes for ARVs newly-recommended in 2006 (emtricitabine, tenofovir) increased >15-fold from 2006 to 2008. Twenty-four generic FDCs were quality-approved for older regimens but only four for newer regimens. Generic FDCs were available to GFATM recipients in 2004 but to PEPFAR recipients only after FDA approval in 2006. Price trends for single-component generic medicines mirrored generic FDC prices. Two large-scale purchasers, PEPFAR and UNITAID, together accounted for 53%, 84%, and 77% of market volume for abacavir, emtricitabine, and tenofovir, respectively, in 2008. PEPFAR and UNITAID purchases were often split across two manufacturers. Conclusions Global initiatives facilitated the creation of fairly efficient markets for older ARVs, but markets for newer ARVs are less competitive and slower to evolve. WHO guidelines shape demand, and their complexity may help or hinder achievement of economies of scale in pharmaceutical manufacturing. Certification programs assure ARV quality but can delay uptake of new formulations. Large-scale procurement policies may decrease the numbers of buyers and sellers, rendering the market less competitive in the longer-term. Global policies must be developed with consideration for their short- and long-term impact on market dynamics. PMID:20500827

The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children

PubMed Central

2010-01-01

Background Important advances in the development and production of quality-certified pediatric antiretroviral (ARV) formulations have recently been made despite significant market disincentives for manufacturers. This progress resulted from lobbying and innovative interventions from HIV/AIDS activists, civil society organizations, and international organizations. Research on uptake and dispersion of these improved products across countries and international organizations has not been conducted but is needed to inform next steps towards improving child health. Methods We used information from the World Health Organization Prequalification Programme and the United States Food and Drug Administration to describe trends in quality-certification of pediatric formulations and used 7,989 donor-funded, pediatric ARV purchase transactions from 2002-2009 to measure uptake and dispersion of new pediatric ARV formulations across countries and programs. Prices for new pediatric ARV formulations were compared to alternative dosage forms. Results Fewer ARV options exist for HIV/AIDS treatment in children than adults. Before 2005, most pediatric ARVs were produced by innovator companies in single-component solid and liquid forms. Five 2-in1 and four 3-in-1 generic pediatric fixed-dose combinations (FDCs) in solid and dispersible forms have been quality-certified since 2005. Most (67%) of these were produced by one quality-certified manufacturer. Uptake of new pediatric FDCs outside of UNITAID is low. UNITAID accounted for 97-100% of 2008-2009 market volume. In total, 33 and 34 countries reported solid or dispersible FDC purchases in 2008 and 2009, respectively, but most purchases were made through UNITAID. Only three Global Fund country recipients reported purchase of these FDCs in 2008. Prices for pediatric FDCs were considerably lower than liquids but typically higher than half of an adult FDC. Conclusion Pediatric ARV markets are more fragile than adult markets. Ensuring a long-term supply of quality, well-adapted ARVs for children requires ongoing monitoring and improved understanding of global pediatric markets, including country-based research to explain and address low uptake of new, improved formulations. Continued innovation in pediatric ARV development may be threatened by outdated procurement practices failing to connect clinicians making prescribing decisions, supply chain staff dealing with logistics, donors, international organizations, and pharmaceutical manufacturers. Perceptions of global demand must be better informed by accurate estimates of actual country-level demand. PMID:20950492

Optimising research to speed up availability of paediatric antiretroviral drugs and formulations

PubMed Central

Penazzato, M; Gnanashanmugam, D; Rojo, P; Lallemant, M; Lewis, L; Rocchi, F; Saint Raymond, A; Ford, N; Hazra, R; Giaquinto, C; Gibb, D; Abrams, Elaine J

2018-01-01

Globally 1.8 million children are estimated to be living with HIV, yet only 51% of those eligible actually start treatment. The completion of research and development (R&D) for paediatric antiretrovirals (ARVs) is a lengthy process and licensing of new paediatric ARVs continues to lag considerably behind adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up of paediatric treatment globally. In this manuscript we review current approaches to R&D for paediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including enrolment of multiple age-cohorts concurrently and the early introduction of dosing approaches for both single and fixed-dose combination (FDC) drug formulations (preferably scored and dispersible) that match WHO weight-bands. Efforts to speed up development of optimal drugs and formulations for children should focus on a limited number of prioritised formulations. This work should build upon existing partnerships and collaborations to ensure that paediatric investigation plans are developed early in the drug development process but can be modified in a streamlined manner as more information becomes available. In addition, simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more efficient and sustainable. Registration, implementation, and strategic use of drugs should not be seen as a sequential process, with research designed to address multiple questions simultaneously to respond to the needs of HIV-infected children where they live. It is imperative that lessons learned from HIV should be shared to support progress in developing paediatric formulations for other diseases with similar treatment challenges, including tuberculosis and viral hepatitis. PMID:29190337

Overview of regulation of dietary supplements in the USA and issues of adulteration with phenethylamines (PEAs).

PubMed

Pawar, Rahul S; Grundel, Erich

2017-03-01

The multi-billion dollar dietary supplement industry is global in reach. The industry has been criticized for problems related to poor quality control, safety, misbranding, and adulteration. In this review, we describe how the US Food and Drug Administration (FDA) regulates dietary supplements within the framework of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The Dietary Supplement Health and Education Act of 1994 (DSHEA), which amended the FD&C Act, gave the FDA the authority to promulgate Good Manufacturing Practices for dietary supplements and required that manufacturers provide the FDA information supporting a conclusion that the ingredients are reasonably expected to be safe if the dietary ingredients were not marketed in the USA before 15 October 1994. Recent amendments to the FD&C Act require that serious dietary-supplement-related adverse events be reported to the FDA and provide the agency with mandatory recall authority. We discuss the presence of naturally occurring (e.g. Ephedra, Citrus aurantium, Acacia) and synthetic (e.g. β-methylphenethylamines, methylsynephrine, α-ethyl-phenethylamine) biologically active phenethylamines (PEAs) in dietary supplements and of PEA drugs (e.g. clenbuterol, fenfluramine, sibutramine, lorcaserin) in weight-loss products. Regulatory actions against manufacturers of products labelled as dietary supplements that contain the aliphatic amines 1,3-dimethylamine and 1,3-dimethylbutylamine, and PEAs such as β-methylphenethylamine, aegeline, and Dendrobium illustrate the FDA's use of its authority under the FD&C Act to promote dietary supplement safety. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Coverage and Preventive Screening

PubMed Central

Meeker, Daniella; Joyce, Geoffrey F; Malkin, Jesse; Teutsch, Steven M; Haddix, Anne C; Goldman, Dana P

2011-01-01

Context Preventive care has been shown as a high-value health care service. Many employers now offer expanded coverage of preventive care to encourage utilization. Objective To determine whether expanding coverage is an effective means to encourage utilization. Design Comparison of screening rates before and after introduction of deductible-free coverage. Setting People insured through large corporations between 2002 and 2006. Patients or Other Participants Preferred Provider Organization (PPO) enrollees from an employer introducing deductible-free coverage, and a control group enrolled in a PPO from a second employer with no policy change. Main Outcome Measures Adjusted probability of endoscopy, fecal occult blood test (FOBT), lipid screens, mammography, and Papanicolaou (pap) smears. Intervention Introduction of first-dollar coverage (FDC) of preventive services in 2003. Results After adjusting for demographics and secular trends, there were between 23 and 78 additional uses per 1,000 eligible patients of covered preventive screens (lipid screens, pap smears, mammograms, and FOBT), with no significant changes in the control group or in a service without FDC (endoscopy). Conclusions FDC improves utilization modestly among healthy individuals, particularly those in lower deductible plans. Compliance with guidelines can be encouraged by lowering out-of-pocket costs, but patients' predisposing characteristics merit attention. PMID:21029084

Zone specific fractal dimension of retinal images as predictor of stroke incidence.

PubMed

Aliahmad, Behzad; Kumar, Dinesh Kant; Hao, Hao; Unnikrishnan, Premith; Che Azemin, Mohd Zulfaezal; Kawasaki, Ryo; Mitchell, Paul

2014-01-01

Fractal dimensions (FDs) are frequently used for summarizing the complexity of retinal vascular. However, previous techniques on this topic were not zone specific. A new methodology to measure FD of a specific zone in retinal images has been developed and tested as a marker for stroke prediction. Higuchi's fractal dimension was measured in circumferential direction (FDC) with respect to optic disk (OD), in three concentric regions between OD boundary and 1.5 OD diameter from its margin. The significance of its association with future episode of stroke event was tested using the Blue Mountain Eye Study (BMES) database and compared against spectrum fractal dimension (SFD) and box-counting (BC) dimension. Kruskal-Wallis analysis revealed FDC as a better predictor of stroke (H = 5.80, P = 0.016, α = 0.05) compared with SFD (H = 0.51, P = 0.475, α = 0.05) and BC (H = 0.41, P = 0.520, α = 0.05) with overall lower median value for the cases compared to the control group. This work has shown that there is a significant association between zone specific FDC of eye fundus images with future episode of stroke while this difference is not significant when other FD methods are employed.

Preparative separation of two subsidiary colors of FD&C Yellow No. 5 (Tartrazine) using spiral high-speed counter-current chromatography◊

PubMed Central

Roque, Jose A.; Mazzola, Eugene P.; Ito, Yoichiro

2014-01-01

Specifications in the U.S. Code of Federal Regulations for the color additive FD&C Yellow No. 5 (Colour Index No. 19140) limit the level of the tetrasodium salt of 4-[(4',5-disulfo[1,1'-biphenyl]-2-yl)hydrazono]-4,5-dihydro-5-oxo-1-(4-sulfophenyl)-1H-pyrazole-3-carboxylic acid and that of the trisodium salt of 4,4'-[4,5-dihydro-5-oxo-4-[(4-sulfophenyl)hydrazono]-1H-pyrazol-1,3-diyl]bis[benzenesulfonic acid], which are subsidiary colors abbreviated as Pk5 and Pk7, respectively. Small amounts of Pk5 and Pk7 are needed by the U.S. Food and Drug Administration for confirmatory analyses and for development of analytical methods. The present study describes the use of spiral high-speed counter-current chromatography (HSCCC) with the recently introduced highly polar organic/high-ionic strength aqueous solvent systems to separate Pk5 and Pk7 from a sample of FD&C Yellow No. 5 containing ~3.5% Pk5 and ~0.7% Pk7. Multiple ~1.0 g portions of FD&C Yellow No. 5 (totaling 6.4 g dye) were separated, using the upper phase of the solvent system 1-BuOH/EtOHabs/saturated ammonium sulfate/water, 1.7:0.3:1:1, v/v/v/v, as the mobile phase. After applying a specially developed method for removing the ammonium sulfate from the HSCCC-collected fractions, these separations resulted in an enriched mixture (~160 mg) of Pk5 and Pk7 (~46% and ~21%, respectively). Separation of the enriched mixture, this time using the lower phase of that solvent system as the mobile phase, resulted in ~ 61 mg of Pk5 collected in fractions whose purity ranged from 88.0% to 92.7% (by HPLC at 254 nm). Pk7 (20.7 mg, ~83% purity) was recovered from the upper phase of the column content. Application of this procedure also resulted in purifying the major component of FD&C Yellow No. 5 to >99% purity. The separated compounds were characterized by high-resolution mass spectrometry and several 1H and 13C nuclear magnetic resonance spectroscopic techniques (COSY, NOESY, HSQC, and HMBC). PMID:24755184

Estimating flow duration curve in the humid tropics: a disaggregation approach in Hawaiian catchments

NASA Astrophysics Data System (ADS)

Chris, Leong; Yoshiyuki, Yokoo

2017-04-01

Islands that are concentrated in developing countries have poor hydrological research data which contribute to stress on hydrological resources due to unmonitored human influence and negligence. As studies in islands are relatively young, there is a need to understand these stresses and influences by building block research specifically targeting islands. The flow duration curve (FDC) is a simple start up hydrological tool that can be used in initial studies of islands. This study disaggregates the FDC into three sections, top, middle and bottom and in each section runoff is estimated with simple hydrological models. The study is based on Hawaiian Islands, toward estimating runoff in ungauged island catchments in the humid tropics. Runoff estimations in the top and middle sections include using the Curve Number (CN) method and the Regime Curve (RC) respectively. The bottom section is presented as a separate study from this one. The results showed that for majority of the catchments the RC can be used for estimations in the middle section of the FDC. It also showed that in order for the CN method to make stable estimations, it had to be calibrated. This study identifies simple methodologies that can be useful for making runoff estimations in ungauged island catchments.

Synergistic Effects of Ethanol and Isopentenyl Pyrophosphate on Expansion of γδ T Cells in Synovial Fluid from Patients with Arthritis

PubMed Central

Laurent, Agneta J.; Bindslev, Niels; Johansson, Björn; Berg, Louise

2014-01-01

Low to moderate ethanol consumption has been associated with protective effects in autoimmune diseases such as rheumatoid arthritis, RA. An expansion of γδ T cells induced by isopentenyl pyrophosphate, IPP, likewise seems to have a protective role in arthritis. The aim of this project was to test the hypothesis that low doses of ethanol can enhance IPP-induced expansion of synovial fluid γδ T cells from patients with arthritis and may thereby potentially account for the beneficial effects of ethanol on symptoms of the arthritic process. Thus, mononuclear cells from synovial fluid (SF) from 15 patients with arthritis and from peripheral blood (PB) from 15 healthy donors were stimulated with low concentrations of ethanol and IPP for 7 days in vitro. IPP in combination with ethanol 0.015%, 2.5 mM, equivalent to the decrease per hour in blood ethanol concentration due to metabolism, gave a significantly higher fractional expansion of SF γδ T cells compared with IPP alone after 7 days (ratio 10.1+/−4.0, p<0.0008, n = 12) in patients with arthritis. Similar results were obtained for PB γδ T cells from healthy controls (ratio 2.0+/−0.4, p<0.011, n = 15). The augmented expansion of γδ T cells in SF is explained by a higher proliferation (p = 0.0034, n = 11) and an increased survival (p<0.005, n = 11) in SF cultures stimulated with IPP plus ethanol compared to IPP alone. The synergistic effects of IPP and ethanol indicate a possible allosteric effect of ethanol. Similar effects could be seen when stimulating PB with ethanol in presence of risedronate, which has the ability to increase endogenous levels of IPP. We conclude that expansion of γδ T cells by combinatorial drug effects, possibly in fixed-dose combination, FDC, of ethanol in the presence of IPP might give a protective role in diseases such as arthritis. PMID:25090614

77 FR 51030 - Kelly Dean Shrum: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-23

...The Food and Drug Administration (FDA) is issuing an order under the Federal Food, Drug, and Cosmetic Act (the FD&C Act) permanently debarring Kelly Dean Shrum, from providing services in any capacity to a person that has an approved or pending drug product application. FDA bases this order on a finding that Dr. Shrum was convicted of a felony under Federal law for conduct relating to the regulation of a drug product under the FD&C Act. Dr. Shrum was given notice of the proposed permanent debarment and an opportunity to request a hearing within the timeframe prescribed by regulation. Dr. Shrum failed to respond. Dr. Shrum's failure to respond constitutes a waiver of his right to a hearing concerning this action.

Relationship of periodontal infection to serum antibody levels to periodontopathic bacteria and inflammatory markers in periodontitis patients with coronary heart disease

PubMed Central

Yamazaki, K; Honda, T; Domon, H; Okui, T; Kajita, K; Amanuma, R; Kudoh, C; Takashiba, S; Kokeguchi, S; Nishimura, F; Kodama, M; Aizawa, Y; Oda, H

2007-01-01

Several reports have demonstrated a possible association of periodontal infections with coronary heart disease (CHD) by elevated antibody titre to periodontopathic bacteria in CHD patients compared with non-diseased controls. Although each periodontopathic bacterium may vary in virulence for periodontitis and atherosclerosis, antibody response to multiple bacteria in CHD patients has not been understood fully. Therefore, serum levels of antibody to 12 periodontopathic bacteria together with other atherosclerotic risk markers were compared among 51 patients with CHD, 55 patients with moderate to severe chronic periodontitis and 37 healthy individuals. The antibody response was the most prevalent for Porphyromonas gingivalis, a major causative organism, in CHD as well as periodontitis patients. However, antibody positivity was different between CHD and periodontitis if the response was analysed for two different strains of P. gingivalis, namely FDC381 and Su63. While periodontitis patients were positive for both P. gingivalis FDC381 and Su63, a high frequency of antibody positivity for P. gingivalis Su63 but not for FDC381 was observed in CHD patients. The results indicate that the presence of particular periodontopathic bacteria with high virulence may affect atherogenesis. Identifying the virulence factors of P. gingivalis Su63 may gain insight into the new therapeutic modality for infection-induced deterioration of atherosclerosis. PMID:17645769

Refractive index and extinction coefficient of NH2CH  =  NH2PbI3 perovskite photovoltaic material.

PubMed

Xie, Ziang; Sun, Shuren; Yan, Yu; Zhang, Lili; Hou, Ruixiang; Tian, Fuyang; Qin, G G

2017-06-21

Very recently, the NH 2 CH  =  NH 2 PbI 3 (FAPbI 3 ) perovskite material has attracted considerable attention in fabricating solar cells (SCs). For a photovoltaic material, its refractive index and extinction coefficient, n(λ) and k(λ), as functions of λ, are important to study its optical properties and to estimate the power conversion efficiency potential for the SCs made of it. As far as we know, to date there has been no reports of n(λ) and k(λ) for FAPbI 3 material. In this article, with spectroscopic ellipsometry (SE) measurements, the n(λ) and k(λ), as well as E g   =  1.45 eV for FAPbI 3 , are acquired. The fast deposition crystallization (FDC) procedure combined with the slowed down annealing (SDA) process is applied to fabricate smooth and uniform FAPbI 3 film on quartz substrate. Several kinds of organic solvents were tried as the second solvent in the FDC procedure, and it is found that when petroleum ether is used, the smallest surface roughness and good FAPbI 3 material purity of the FAPbI 3 film can be acquired. The k(λ) results for FAPbI 3 obtained by SE, calculated from the n(λ) using the Kramers-Kronig relationship, by absorbance, and by first-principles calculations, are compared. The n(λ) and k(λ) for FAPbI 3 are also compared with those for CH 3 NH 3 PbI 3 , GaAs and c-Si.

Refractive index and extinction coefficient of NH2CH  =  NH2PbI3 perovskite photovoltaic material

NASA Astrophysics Data System (ADS)

Xie, Ziang; Sun, Shuren; Yan, Yu; Zhang, Lili; Hou, Ruixiang; Tian, Fuyang; Qin, G. G.

2017-06-01

Very recently, the NH2CH  =  NH2PbI3 (FAPbI3) perovskite material has attracted considerable attention in fabricating solar cells (SCs). For a photovoltaic material, its refractive index and extinction coefficient, n(λ) and k(λ), as functions of λ, are important to study its optical properties and to estimate the power conversion efficiency potential for the SCs made of it. As far as we know, to date there has been no reports of n(λ) and k(λ) for FAPbI3 material. In this article, with spectroscopic ellipsometry (SE) measurements, the n(λ) and k(λ), as well as E g  =  1.45 eV for FAPbI3, are acquired. The fast deposition crystallization (FDC) procedure combined with the slowed down annealing (SDA) process is applied to fabricate smooth and uniform FAPbI3 film on quartz substrate. Several kinds of organic solvents were tried as the second solvent in the FDC procedure, and it is found that when petroleum ether is used, the smallest surface roughness and good FAPbI3 material purity of the FAPbI3 film can be acquired. The k(λ) results for FAPbI3 obtained by SE, calculated from the n(λ) using the Kramers-Kronig relationship, by absorbance, and by first-principles calculations, are compared. The n(λ) and k(λ) for FAPbI3 are also compared with those for CH3NH3PbI3, GaAs and c-Si.

Functional and taxonomic plant diversity for riverbank protection works: bioengineering techniques close to natural banks and beyond hard engineering.

PubMed

Cavaillé, Paul; Ducasse, Léon; Breton, Vincent; Dommanget, Fanny; Tabacchi, Eric; Evette, André

2015-03-15

Erosion control is a major issue in the Prealps region since piedmont is subject to both intense flood hazards and anthropic pressure. Riverbank protections may have major impacts on local ecosystem functioning and ecological corridor continuity. This study aimed to estimate the effects of the types of riverbank protection technique (from pure riprap to pure bioengineering) on the taxonomic and ecological composition of plant communities in comparison with unmanaged riverbanks as the referential system. Thirty-eight embankments were sampled in the foothills of the French and Swiss Alps. Four distinct riverbank techniques were analyzed and natural young willow stands were chosen as the referential system. At each site, vegetation was sampled along three transects from the waterline to the top of the riverbank. Plant communities were characterized using biological group composition (growth forms and life history, life strategies and distribution in space and time) and functional diversity indices (MFAD, FDc and wFDc). We identified 177 distinct plant species on 38 sites. Higher species richness levels were observed on bioengineered banks (from an average of 12 species recorded on ripraps to 27 species recorded on bioengineered banks) strongly dominated by Salicaceae species, especially for fascine and cribwall banks. Functional analyses of plant communities highlighted significant differences among bank types (p-value: 0.001) for all selected biological groups. Competitive - ruderal strategy, rooting shoots, stems or leaves that lie down or break off, and unisexual - dioecious, as well as pioneer plants and low shrubs (<4 m tall) distinguished bioengineered bank types. Functional diversity indices confirmed these differences among bank types (MFAD: p-value: 0.002; FDc: p-value: 0.003; wFDc: p-value: 0.005). Riprap always showed the lowest levels on functional diversity indices, fascine and cribwall banks were at the medium level and finally mixed and natural banks the highest level. These results confirm the low ecological potential of purely hard engineering techniques and highlight the similarity of bioengineered techniques and unmanaged riverbanks. Copyright © 2014 Elsevier Ltd. All rights reserved.

A web tool for STORET/WQX water quality data retrieval and Best Management Practice scenario suggestion.

PubMed

Park, Youn Shik; Engel, Bernie A; Kim, Jonggun; Theller, Larry; Chaubey, Indrajeet; Merwade, Venkatesh; Lim, Kyoung Jae

2015-03-01

Total Maximum Daily Load is a water quality standard to regulate water quality of streams, rivers and lakes. A wide range of approaches are used currently to develop TMDLs for impaired streams and rivers. Flow and load duration curves (FDC and LDC) have been used in many states to evaluate the relationship between flow and pollutant loading along with other models and approaches. A web-based LDC Tool was developed to facilitate development of FDC and LDC as well as to support other hydrologic analyses. In this study, the FDC and LDC tool was enhanced to allow collection of water quality data via the web and to assist in establishing cost-effective Best Management Practice (BMP) implementations. The enhanced web-based tool provides use of water quality data not only from the US Geological Survey but also from the Water Quality Portal for the U.S. via web access. Moreover, the web-based tool identifies required pollutant reductions to meet standard loads and suggests a BMP scenario based on ability of BMPs to reduce pollutant loads, BMP establishment and maintenance costs. In the study, flow and water quality data were collected via web access to develop LDC and to identify the required reduction. The suggested BMP scenario from the web-based tool was evaluated using the EPA Spreadsheet Tool for the Estimation of Pollutant Load model to attain the required pollutant reduction at least cost. Copyright © 2014 Elsevier Ltd. All rights reserved.

Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl.

PubMed Central

Cleveland, J L; Dean, M; Rosenberg, N; Wang, J Y; Rapp, U R

1989-01-01

Retroviral expression vectors carrying the tyrosine kinase oncogenes abl, fms, src, and trk abrogate the requirements of murine myeloid FDC-P1 cells for interleukin-3 (IL-3). Factor-independent clones constitutively express c-myc in the absence of IL-3, whereas in parental cultures c-myc transcription requires the presence of the ligand. To directly test the effect of a tyrosine kinase oncogene on c-myc expression, retroviral constructs containing three different temperature-sensitive mutants of v-abl were introduced into myeloid IL-3-dependent FDC-P1 and 32D cells. At the permissive temperature, clones expressing temperature-sensitive abl behaved like wild-type abl-containing cells in their growth properties and expressed c-myc constitutively. Temperature shift experiments demonstrated that both IL-3 abrogation and the regulation of c-myc expression correlated with the presence of functional v-abl. Induction of c-myc expression by reactivation of temperature-sensitive v-abl mimicked c-myc induction by IL-3 in that it did not require protein synthesis and occurred at the level of transcription, with effects on both initiation and a transcription elongation block. However, v-abl-regulated FDC-P1 cell growth differed from IL-3-regulated growth in that c-fos and junB, which are normally induced by IL-3, were not induced by activation of v-abl. Images PMID:2555703

75 FR 12555 - Prescription Drug User Fee Act; Public Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-16

... negotiations with the regulated industry on PDUFA reauthorization, we publish a notice in the Federal Register...)(2)) of the FD&C Act requires that before FDA begins negotiations with the regulated industry on...

FDC Mentor-Mentee Mixer Breaks the Ice Between Investigators and Trainees | Poster

Cancer.gov

The Frederick Diversity Committee’s mentor-mentee mixer gave research trainees, senior investigators, scientists, and administrative staff a chance to meet and mingle over refreshments and games following the Spring Research Festival.

75 FR 49502 - Medical Device User Fee Act; Public Meeting; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-13

... Federal Food, Drug, and Cosmetic Act (FD&C Act) requires that before FDA begins negotiations with the...)) requires that, before FDA begins negotiations with the regulated industry on user fee reauthorization, we...

Administrative Destruction of Certain Drugs Refused Admission to the United States. Final rule.

PubMed

2015-09-15

The Food and Drug Administration (FDA or Agency) is implementing its authority to destroy a drug valued at $2,500 or less (or such higher amount as the Secretary of the Treasury may set by regulation) that has been refused admission into the United States under the Federal Food, Drug, and Cosmetic Act (the FD&C Act), by issuing a rule that provides to the owner or consignee notice and an opportunity to appear and introduce testimony to the Agency prior to destruction. This regulation is authorized by amendments made to the FD&C Act by the Food and Drug Administration Safety and Innovation Act (FDASIA). Implementation of this authority will allow FDA to better protect the public health by providing an administrative process for the destruction of certain refused drugs, thus increasing the integrity of the drug supply chain.

THE USE OF QUENCHING IN A LIQUID SCINTILLATION COUNTER FOR QUANTITATIVE ANALYSIS

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

Foster, G.V.

1963-01-01

Quenching was used to quantitatively determine the amonnt of quenching agent present. A sealed promethium147 source was prepared to be used for the count rate determinations. Two methods to determine the amount of quenching agent present in a sample were developed. One method related the count rate of a sample containing a quenching agent to the amount of quenching agent present. Calibration curves were plotted using both color and chemical quenchers. The quenching agents used were: F.D.C. Orange No. 2, F.D.C. Yellow No. 3, F.D.C. Yellow No. 4, Scarlet Red, acetone, benzaldehyde, and carbon tetrachloride. the color quenchers gave amore » linear-relationship, while the chemical quenchers gave a non-linear relationship. Quantities of the color quenchers between about 0.008 mg and 0.100 mg can be determined with an error less than 5%. The calibration curves were found to be usable over a long period of time. The other method related the change in the ratio of the count rates in two voltage windows to the amount of quenching agent present. The quenchers mentioned above were used. Calibration curves were plotted for both the color and chemical quenchers. The relationships of ratio versus amount of quencher were non-linear in each case. It was shown that the reproducibility of the count rate and the ratio was independent of the amount of quencher present but was dependent on the count rate. At count rates above 10,000 counts per minute the reproducibility was better than 1%. (TCO)« less

Deeming Tobacco Products To Be Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act; Restrictions on the Sale and Distribution of Tobacco Products and Required Warning Statements for Tobacco Products. Final rule.

PubMed

2016-05-10

The Food and Drug Administration (FDA) is issuing this final rule to deem products meeting the statutory definition of "tobacco product,'' except accessories of the newly deemed tobacco products, to be subject to the Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act). The Tobacco Control Act provides FDA authority to regulate cigarettes, cigarette tobacco, roll-your-own tobacco, smokeless tobacco, and any other tobacco products that the Agency by regulation deems to be subject to the law. With this final rule, FDA is extending the Agency's "tobacco product'' authorities in the FD&C Act to all other categories of products that meet the statutory definition of "tobacco product" in the FD&C Act, except accessories of such newly deemed tobacco products. This final rule also prohibits the sale of "covered tobacco products" to individuals under the age of 18 and requires the display of health warnings on cigarette tobacco, roll-your own tobacco, and covered tobacco product packages and in advertisements. FDA is taking this action to reduce the death and disease from tobacco products. In accordance with the Tobacco Control Act, we consider and intend the extension of our authorities over tobacco products and the various requirements and prohibitions established by this rule to be severable.

Estimated daily intake and safety of FD&C food-colour additives in the US population.

PubMed

Bastaki, Maria; Farrell, Thomas; Bhusari, Sachin; Bi, Xiaoyu; Scrafford, Carolyn

2017-06-01

A refined exposure assessment was undertaken to calculate the estimated daily intake (EDI) of the seven FD&C straight-colour additives and five FD&C colour lakes ('synthetic' food colours) approved in the United States. The EDIs were calculated for the US population as a whole and specific age groups, including children aged 2-5 and 6-12 years, adolescents aged 13-18 years, and adults aged 19 or more y. Actual use data were collected from an industry survey of companies that are users of these colour additives in a variety of products, with additional input from food colour manufacturers. Food-consumption data were obtained from the National Health and Nutrition Examination Survey (NHANES). The assessment was further refined by adjusting the intake to more realistic scenarios based on the fraction of products containing colour within specific food categories using data provided by the Mintel International Group Ltd. The results of the analysis indicate that (1) the use levels reported by the industry are consistent with the concentrations measured analytically by the US Food and Drug Administration; and (2) exposure to food-colour additives in the United States by average and high-intake consumers is well below the acceptable daily intake (ADI) of each colour additive as published by the Joint WHO/FAO Committee on Food Additives (JECFA) and allows wide margins of safety. It is concluded that food colour use as currently practised in the United States is safe and does not result in excessive exposure to the population, even at conservative ranges of food consumption and levels of use.

75 FR 67981 - Agency Information Collection Activities; Proposed Collection; Comment Request; Importer's Entry...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-04

... under the Family Smoking Prevention and Tobacco Control Act (the Tobacco Control Act). DATES: Submit... United States meet the same requirements of the FD&C Act as do domestic products, and for preventing...

Notices to airmen : domestic/international, September 10, 1998.

DOT National Transportation Integrated Search

1998-09-10

Table of contents: Airway notams; Airports, facilities, and procedural Notams; General FDC Notams; Part 95 Revisions to minimum en route IFR altitudes and changeover points; International Notices to Airmen; Graphic notices.;See also PB99-104317.;pg 2...

21 CFR 74.1705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2014 CFR

2014-04-01

..., nasally, vaginally, or rectally, or for use in the area of the eye, the labeling required by § 201.100(d... seen in patients who also have aspirin hypersensitivity.” This warning statement shall appear in the...

21 CFR 74.1705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2013 CFR

2013-04-01

..., nasally, vaginally, or rectally, or for use in the area of the eye, the labeling required by § 201.100(d... seen in patients who also have aspirin hypersensitivity.” This warning statement shall appear in the...

21 CFR 74.1705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., nasally, vaginally, or rectally, or for use in the area of the eye, the labeling required by § 201.100(d... seen in patients who also have aspirin hypersensitivity.” This warning statement shall appear in the...

21 CFR 74.1705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2011 CFR

2011-04-01

..., nasally, vaginally, or rectally, or for use in the area of the eye, the labeling required by § 201.100(d... seen in patients who also have aspirin hypersensitivity.” This warning statement shall appear in the...

21 CFR 74.1705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2012 CFR

2012-04-01

..., nasally, vaginally, or rectally, or for use in the area of the eye, the labeling required by § 201.100(d... seen in patients who also have aspirin hypersensitivity.” This warning statement shall appear in the...

77 FR 59926 - Agency Information Collection Activities; Proposed Collection; Comment Request; Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-01

... by the Project BioShield Act of 2004 (Pub. L. 108-276). The FD&C Act permits the Commissioner of Food... variability based on whether there is an active manufacturer respondent, other factors also inject significant...

76 FR 9023 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-16

... Control Number 0910-0046)--Revision On June 22, 2009, the President signed the Family Smoking Prevention... requirements of the FD&C Act as do domestic products, and for preventing products from entering the country if...

78 FR 1221 - Notice of Issuance of Final Determination Concerning Ponstel® (Mefenamic Acid) Capsules

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-08

... inactive ingredients are lactose monohydrate, D&C Yellow No. 10, FD&C Yellow No. 6, gelatin, titanium dioxide, and food-grade inks. The mefenamic acid is added to a tumbler and blended. Lactose monohydrate, a...

The Fulldome Curriculum for the Spitz SciDome Digital Planetarium: Volume 2

NASA Astrophysics Data System (ADS)

Bradstreet, David H.; Sanders, S. J.; Huggins, S.

2014-01-01

The Spitz Fulldome Curriculum (FDC) for the SciDome digital planetarium ushered in a new and innovative way to present astronomical pedagogy via its use of the unique teaching attributes of the digital planetarium. In the case of the FDC, which uses the ubiquitous Starry Night planetarium software as its driving engine, these engaging and novel teaching techniques have also been made usable to desktop computers and flat-screen video projectors for classroom use. Volume 2 of the FDC introduces exciting new classes and mini-lessons to further enlighten and invigorate students as they struggle with often difficult three dimensional astronomical concepts. Additionally, other topics with related astronomical ties have been created to integrate history into planetarium presentations. One of the strongest advantages of the SciDome is its use of Starry Night as its astronomical engine. With it students can create their own astronomical configurations in the computer lab or at home, using the PC or Mac version. They can then simply load their creations onto the SciDome planetarium system and display them for their classmates on the dome. This poster will discuss and illustrate some of the new content that has been developed for Volume 2. Topics covered in Volume 2 include eclipses, plotting planet locations on a curtate orbit chart by observing their positions in the sky, time and timekeeping (including sidereal day, hour angles, sidereal time, LAST, LMST, time zones and the International Date Line), teaching to the Boy Scout Merit Badge requirements, plotting scale analemmas on the surface of planets and interpreting them, precession, astronomical events in revolutionary Boston, the Lincoln Almanac Trial, eclipsing binaries, lunar librations, a trip through the universe, watching the speed of light move in real time, stellar sizes and the Milky Way.

77 FR 75171 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-19

..., and Cosmetic Act (the FD&C Act) (21 U.S.C. 360bbb-3), which was amended by the Project BioShield Act... relevant activities. In addition to variability based on whether there is an active manufacturer respondent...

Instrumental Analysis in the High School Classroom: UV-Vis Spectroscopy

ERIC Educational Resources Information Center

Erhardt, Walt

2007-01-01

Note is presented on the standard lab from a second year chemistry course. The lab "Determining which of the Seven FD&C Food-Approved Dyes are Used in Making Green Skittles", familiarizes students with the operation of the CHEM2000 UV-Vis spectrophorometer.

Anchored and soluble gangliosides contribute to myelosupportivity of stromal cells

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

Ziulkoski, Ana L.; Departamento de Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS; Instituto de Ciencias da Saude, Centro Universitario Feevale, Novo Hamburgo, RS

2009-10-09

Stroma-mediated myelopoiesis depends upon growth factors and an appropriate intercellular microenvironment. Previous studies have demonstrated that gangliosides, produced by hepatic stromal cell types, are required for optimal myelosupportive function. Here, we compared the mielossuportive functions of a bone marrow stroma (S17) and skin fibroblasts (SF) regarding their ganglioside pattern of synthesis and shedding. The survival and proliferation of a myeloid precursor cell (FDC-P1) were used as reporter. Although the ganglioside synthesis of the two stromal cells was similar, their relative content and shedding were distinct. The ganglioside requirement for mielossuportive function was confirmed by the decreased proliferation of FDC-P1 cellsmore » in ganglioside synthesis-inhibited cultures and in presence of an antibody to GM3 ganglioside. The distinct mielossuportive activities of the S17 and SF stromata may be related to differences on plasma membrane ganglioside concentrations or to differences on the gangliosides shed and their subsequent uptake by myeloid cells, specially, GM3 ganglioside.« less

Biosorption of food dyes onto Spirulina platensis nanoparticles: equilibrium isotherm and thermodynamic analysis.

PubMed

Dotto, G L; Lima, E C; Pinto, L A A

2012-01-01

The biosorption of food dyes FD&C red no. 40 and acid blue 9 onto Spirulina platensis nanoparticles was studied at different conditions of pH and temperature. Four isotherm models were used to evaluate the biosorption equilibrium and the thermodynamic parameters were estimated. Infra red analysis (FT-IR) and energy dispersive X-ray spectroscopy (EDS) were used to verify the biosorption behavior. The maximum biosorption capacities of FD&C red no. 40 and acid blue 9 were found at pH 4 and 298 K, and the values were 468.7 mg g(-1) and 1619.4 mg g(-1), respectively. The Sips model was more adequate to fit the equilibrium experimental data (R2>0.99 and ARE<5%). Thermodynamic study showed that the biosorption was exothermic, spontaneous and favorable. FT-IR and EDS analysis suggested that at pH 4 and 298 K, the biosorption of both dyes onto nanoparticles occurred by chemisorption. Copyright © 2011 Elsevier Ltd. All rights reserved.

Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium.

PubMed

Humby, Frances; Bombardieri, Michele; Manzo, Antonio; Kelly, Stephen; Blades, Mark C; Kirkham, Bruce; Spencer, Jo; Pitzalis, Costantino

2009-01-13

Follicular structures resembling germinal centres (GCs) that are characterized by follicular dendritic cell (FDC) networks have long been recognized in chronically inflamed tissues in autoimmune diseases, including the synovium of rheumatoid arthritis (RA). However, it is debated whether these ectopic structures promote autoimmunity and chronic inflammation driving the production of pathogenic autoantibodies. Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific markers of RA, predict a poor prognosis, and have been suggested to be pathogenic. Therefore, the main study objectives were to determine whether ectopic lymphoid structures in RA synovium: (i) express activation-induced cytidine deaminase (AID), the enzyme required for somatic hypermutation and class-switch recombination (CSR) of Ig genes; (ii) support ongoing CSR and ACPA production; and (iii) remain functional in a RA/severe combined immunodeficiency (SCID) chimera model devoid of new immune cell influx into the synovium. Using immunohistochemistry (IHC) and quantitative Taqman real-time PCR (QT-PCR) in synovial tissue from 55 patients with RA, we demonstrated that FDC+ structures invariably expressed AID with a distribution resembling secondary lymphoid organs. Further, AID+/CD21+ follicular structures were surrounded by ACPA+/CD138+ plasma cells, as demonstrated by immune reactivity to citrullinated fibrinogen. Moreover, we identified a novel subset of synovial AID+/CD20+ B cells outside GCs resembling interfollicular large B cells. In order to gain direct functional evidence that AID+ structures support CSR and in situ manufacturing of class-switched ACPA, 34 SCID mice were transplanted with RA synovium and humanely killed at 4 wk for harvesting of transplants and sera. Persistent expression of AID and Igamma-Cmu circular transcripts (identifying ongoing IgM-IgG class-switching) was observed in synovial grafts expressing FDCs/CD21L. Furthermore, synovial mRNA levels of AID were closely associated with circulating human IgG ACPA in mouse sera. Finally, the survival and proliferation of functional B cell niches was associated with persistent overexpression of genes regulating ectopic lymphoneogenesis. Our demonstration that FDC+ follicular units invariably express AID and are surrounded by ACPA-producing plasma cells provides strong evidence that ectopic lymphoid structures in the RA synovium are functional and support autoantibody production. This concept is further confirmed by evidence of sustained AID expression, B cell proliferation, ongoing CSR, and production of human IgG ACPA from GC+ synovial tissue transplanted into SCID mice, independently of new B cell influx from the systemic circulation. These data identify AID as a potential therapeutic target in RA and suggest that survival of functional synovial B cell niches may profoundly influence chronic inflammation, autoimmunity, and response to B cell-depleting therapies.

Assessment of nonsteroidal anti-inflammatory drug use pattern using World Health Organization indicators: A cross-sectional study in a tertiary care teaching hospital of Chhattisgarh.

PubMed

R Vaishnavi, P R; Gaikwad, Nitin; Dhaneria, S P

2017-01-01

The objective of this study is to assess drug utilization pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) in a tertiary care teaching hospital, Raipur, Chhattisgarh. A prospective, cross-sectional observational study was conducted in the outpatient department during 2-month period. After informed consent, the patients visiting pharmacy shop with a prescription were enrolled in the study. Their demographic details and prescription data were recorded in a case record form. The data were analyzed to determine the drug utilization pattern of NSAIDs, using the World Health Organization (WHO) prescribing indicators. A total of 600 prescriptions were analyzed. Of them, NSAIDs were prescribed in 30.83% encounters. In general, nonselective COX inhibitors were most commonly prescribed. The most commonly prescribed form of NSAID was paracetamol (39.45%). The percentage of NSAIDs prescribed with generic names were almost identical (91.15%), whereas the percentage of NSAIDs prescribed from the National List of Essential Medicine (India) - 2015 (49.72%) was not identical with the WHO standard (100%) which serves as an ideal. In 13.51% encounters, a fixed-dose combination (FDC) of NSAIDs was prescribed. Co-administration of gastroprotective agent with NSAIDs was observed in 24.32% encounters. The prescribing practices of NSAIDs indicate some deviation from the WHO standard. In addition, FDCs of NSAIDs with gastroprotective agents as well as other NSAIDs was also prescribed, which are irrational. This baseline data will be useful to plan further targeted research and to improve prescribing practices at the center. Various strategies such as face-to-face periodic training programs of prescribers, establishing drug and therapeutic committee; drug information centers; and drug bulletins can serve beneficial in improving prescribing practices.

78 FR 17086 - Public Hearing Before a Public Advisory Committee; Technical Amendments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-20

... Administrative practice and procedure, Advisory committees, Color additives, Drugs, Foods, Medical Devices... device good manufacturing practice advisory committees established under section 520(f)(3) of the FD&C...) Color additive advisory committees are required to be established under the circumstances specified in...

Guiding Principles for the use of Fluroquinolones in Out-patient Community Settings of India: Panel Consensus.

PubMed

Vora, Agam; Krishnaprasad, K

2017-08-01

Respiratory tract infections have been an important cause of morbidity and mortality worldwide that is looming large especially in context of antibiotic resistance that is confronted both by a pulmonologist as well as a general practitioner. A reflection to this trend has been the rising phenomenon of MICs as shown the respiratory pathogens towards conventional antibiotics including macrolides or β lactam/β lactamase inhibitor combinations. Respiratory fluoroquinolones offer broad yet potent cover of respiratory pathogens leading to their obvious choice for empirical therapy for clinical persisters or high risk cases with prior history of antibiotics not-withstanding the clinical concerns in tropical countries. To further assess the clinical role of respiratory quinolones in outpatient settings of India especially in line with the known endemicity of chronic infections or tuberculosis. Cross-sectional, national survey questionnaire survey to explore the clinical perceptions, attitude and insights on the clinical use of respiratory fluoroquinolones was rolled out amongst pulmonologists and consultant physicians practicing respiratory medicine in India. Descriptive statistics was utilized to describe the numerical and categorical data. Nationwide representative sample of fourteen pulmonologists provided response and clinical insight on the current management strategies for community acquired pneumonia (CAP) with 'respiratory' fluoroquinolones. Each of the doctor in the panel agreed that the ideal antibiotic for the treatment in CAP or lower respiratory tract infection (LRTI) should be highly effective with lesser side effects and broader spectrum covering atypical bacteria. Doctors agreed that most the fixed dose combination (FDC) has gone into disrepute probably because of pharmacokinetic incompatibility that could have further fuelled the epidemic of antibiotic resistance. 9 (64%) doctors suggested that there is omnipresence if not overwhelming presence of patient poor response to beta-lactam or fluoroquinolones in clinical practice. It was agreed that fluoroquinolones would be the rightful choice for patients with prior history of antibiotic use with or without comorbidities. Amongst the newer fluoroquinolones available, Garenoxacin offers broad and potent action against resistant strains for CAP. Despite the overwhelming concern of tropical infection in Indian context, Garenoxacin could be considered for mono- or add-on therapy in moderate to severe yet stable cases of CAP. Short course therapy of 5 to 10 days should offer no complimentary masking of anti-mycobacterial activity since the relevant minimum inhibitory concentration (MIC90) are high that are beyond the comprehension of suggested therapeutic dose of 400 mg tablets. The growing incidence of Macrolide resistance suggests the clinical role of new generation fluoroquinolones including Garenoxacin as a clinically useful therapeutic strategy for moderate to severe CAP as monotherapy or in combination.

76 FR 18556 - Maja S. Ruetschi: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-04

...] Maja S. Ruetschi: Debarment Order AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY... Act (the FD&C Act) debarring Maja S. Ruetschi, MD for 5 years from providing services in any capacity... failed to respond. Dr. Ruetschi's failure to respond constitutes a waiver of her right to a hearing...

Inert Reassessment Document for D & C Green No. 6

EPA Pesticide Factsheets

Based upon the reasonable certainty of no harm safety findings, D&C Green No. 6, D&C Red No. 17, D&C Red No. 33, D&C Violet No. 2, and FD&C Yellow No. 6 Aluminum Lake can each be classified as L ist 4B inert ingredients.

21 CFR 74.203 - FD&C Green No. 3.

Code of Federal Regulations, 2011 CFR

2011-04-01

...-aminobenzenesulfonic acid) to sodium 5-amino-2-formylbenzenesulfonate. This amine is diazotized and the resulting...-formylbenzenesulfonic acids, sodium salts, not more than 0.5 percent. Sum of 3- and 4-[[ethyl(4-sulfophenyl)amino]methyl... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...

21 CFR 74.203 - FD&C Green No. 3.

Code of Federal Regulations, 2010 CFR

2010-04-01

...-aminobenzenesulfonic acid) to sodium 5-amino-2-formylbenzenesulfonate. This amine is diazotized and the resulting...-formylbenzenesulfonic acids, sodium salts, not more than 0.5 percent. Sum of 3- and 4-[[ethyl(4-sulfophenyl)amino]methyl... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...

21 CFR 74.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2010 CFR

2010-04-01

... subjected to purification procedures. The indigo (or indigo paste) used above is manufactured by the fusion... purification procedures prior to sulfonation. (2) Color additive mixtures for food use (including dietary... (calculated as sodium salts), not more than 15 percent. Water insoluble matter, not more than 0.4 percent...

21 CFR 74.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2012 CFR

2012-04-01

... subjected to purification procedures. The indigo (or indigo paste) used above is manufactured by the fusion... purification procedures prior to sulfonation. (2) Color additive mixtures for food use (including dietary... (calculated as sodium salts), not more than 15 percent. Water insoluble matter, not more than 0.4 percent...

21 CFR 74.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2013 CFR

2013-04-01

... subjected to purification procedures. The indigo (or indigo paste) used above is manufactured by the fusion... purification procedures prior to sulfonation. (2) Color additive mixtures for food use (including dietary... (calculated as sodium salts), not more than 15 percent. Water insoluble matter, not more than 0.4 percent...

21 CFR 74.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2014 CFR

2014-04-01

... subjected to purification procedures. The indigo (or indigo paste) used above is manufactured by the fusion... purification procedures prior to sulfonation. (2) Color additive mixtures for food use (including dietary... (calculated as sodium salts), not more than 15 percent. Water insoluble matter, not more than 0.4 percent...

21 CFR 74.102 - FD&C Blue No. 2.

Code of Federal Regulations, 2011 CFR

2011-04-01

... subjected to purification procedures. The indigo (or indigo paste) used above is manufactured by the fusion... purification procedures prior to sulfonation. (2) Color additive mixtures for food use (including dietary... (calculated as sodium salts), not more than 15 percent. Water insoluble matter, not more than 0.4 percent...

76 FR 17136 - Medical Devices; Availability of Safety and Effectiveness Summaries for Premarket Approval...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-28

... section 515(d)(4) and (e)(2) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 360e(d......... Dako Denmark A/S..... HercepTest kit Approved October 20, 2010. P080009 Ethicon Endo-Surgery, SEDASYS...

76 FR 21910 - Ivyl W. Wells: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-19

...] Ivyl W. Wells: Debarment Order AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The... (the FD&C Act) permanently debarring Ivyl W. Wells, MD from providing services in any capacity to a... Dr. Wells was convicted of multiple felonies under Federal law for conduct relating to the regulation...

75 FR 79005 - Ehigiator O. Akhigbe: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-17

...] Ehigiator O. Akhigbe: Debarment Order AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY... Act (the FD&C Act) debarring Ehigiator O. Akhigbe, MD for 25 years from providing services in any... delegated to him (Staff Manual Guide 1410.35), finds that Ehigiator O. Akhigbe has been convicted of...

76 FR 30947 - Stephen Lee Seldon: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-27

...] Stephen Lee Seldon: Debarment Order AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY... Act (the FD&C Act) permanently debarring Stephen Lee Seldon, M.D. from providing services in any... authority delegated to the Director (Staff Manual Guide 1410.35), finds that Stephen Lee Seldon has been...

Multifunctional Metal-Organic Frameworks Based on Redox-Active Rhenium Octahedral Clusters.

PubMed

Litvinova, Yulia M; Gayfulin, Yakov M; Kovalenko, Konstantin A; Samsonenko, Denis G; van Leusen, Jan; Korolkov, Ilya V; Fedin, Vladimir P; Mironov, Yuri V

2018-02-19

The redox-active rhenium octahedral cluster unit [Re 6 Se 8 (CN) 6 ] 4- was combined with Gd 3+ ions and dicarboxylate linkers in novel types of metal-organic frameworks (MOFs) that display a set of functional properties. The hydrolytically stable complexes [{Gd(H 2 O) 3 } 2 (L)Re 6 Se 8 (CN) 6 ]·nH 2 O (1, L = furan-2,5-dicarboxylate, fdc; 2, L = thiophene-2,5-dicarboxylate, tdc) exhibit a 3D framework of trigonal symmetry where 1D chains of [{Gd(H 2 O) 3 } 2 (L)] 4+ are connected by [Re 6 Se 8 (CN) 6 ] 4- clusters. Frameworks contain spacious channels filled with H 2 O. Solvent molecules can be easily removed under vacuum to produce permanently porous solids with high volumetric CO 2 uptake and remarkable CO 2 /N 2 selectivity at room temperature. The frameworks demonstrate an ability for reversible redox transformations of the cluster fragment. The orange powders of compounds 1 and 2 react with Br 2 , yielding dark-green powders of [{Gd(H 2 O) 3 } 2 (L)Re 6 Se 8 (CN) 6 ]Br·nH 2 O (3, L = fdc; 4, L = tdc). Compounds 3 and 4 are isostructural with 1 and 2 and also have permanently porous frameworks but display different optical, magnetic, and sorption properties. In particular, oxidation of the cluster fragment "switches off" its luminescence in the red region, and the incorporation of Br - leads to a decrease of the solvent-accessible volume in the channels of 3 and 4. Finally, the green powders of 3 and 4 can be reduced back to the orange powders of 1 and 2 by reaction with hydrazine, thus displaying a rare ability for fully reversible chemical redox transitions. Compounds 1-4 are mentioned as a new class of redox-active cluster-based MOFs with potential usage as multifunctional materials for gas separation and chemical contamination sensors.

78 FR 76838 - Agency Information Collection Activities; Proposed Collection; Comment Request; Tobacco Products...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-19

...) by adding a chapter granting FDA important authority to regulate the manufacture, marketing, and... introduced or delivered for introduction into interstate commerce, a manufacturer must submit a premarket... for introduction into interstate commerce (section 910 of the FD&C Act (21 U.S.C. 387j)). An order...

77 FR 7165 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-10

... Request; Medical Device Recall Authority AGENCY: Food and Drug Administration, HHS. ACTION: Notice... Recall Authority--21 CFR Part 810 (OMB Control Number 0910-0432)--Extension This collection of...)) and part 810 (21 CFR part 810), medical device recall authority provisions. Section 518(e) of the FD&C...

75 FR 75677 - Agency Information Collection Activities; Proposed Collection; Comment Request; Exports...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-06

... requirements for persons exporting human drugs, biological products, devices, animal drugs, food, and cosmetics... Control Number 0910-0482)--Extension The respondents to this information collection are exporters who have... States as allowed under section 801(e) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S...

78 FR 67038 - FD&C Green No. 3; Exemption From the Requirement of a Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-08

... antimicrobial formulations, for use on food contact surfaces in public eating places, dairy processing equipment, and food processing equipment and utensils. The firm Exponent, on behalf of Ecolab submitted a petition to EPA under the Federal Food, Drug, and Cosmetic Act (FFDCA), requesting establishment of an...

77 FR 27236 - Daphne I. Panagotacos; Denial of Hearing; Final Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0475] Daphne I. Panagotacos; Denial of Hearing; Final Debarment Order AGENCY: Food and Drug Administration, HHS... (the FD&C Act) debarring Panagotacos for 5 years from providing services in any capacity to a person...

21 CFR 74.705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2010 CFR

2010-04-01

...-sulfophenyl-azo]-1H-pyrazole-3-carboxylic acid (CAS Reg. No. 1934-21-0). To manufacture the additive, 4-amino-benzenesulfonic acid is diazotized using hydrochloric acid and sodium nitrite. The diazo compound is coupled with... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...

21 CFR 74.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... Blue No. 1 is principally the disodium salt of ethyl [4-[p-[ethyl (m-sulfobenzyl) amino]-α-(o... with smaller amounts of the isomeric disodium salts of ethyl [4-[p-[ethyl(p-sulfobenzyl) amino]-α-(o...

21 CFR 74.2101 - FD&C Blue No. 1.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...&C Blue No. 1 is principally the disodium salt of ethyl[4-[p-[ethyl(m-sulfobenzyl)amino]-α-(o... amounts of the isomeric disodium salts of ethyl[4-[p-[ethyl(p-sulfobenzyl)amino]-α-(o-sulfophenyl...

21 CFR 74.2101 - FD&C Blue No. 1.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...&C Blue No. 1 is principally the disodium salt of ethyl[4-[p-[ethyl(m-sulfobenzyl)amino]-α-(o... amounts of the isomeric disodium salts of ethyl[4-[p-[ethyl(p-sulfobenzyl)amino]-α-(o-sulfophenyl...

21 CFR 74.101 - FD&C Blue No. 1.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... Blue No. 1 is principally the disodium salt of ethyl [4-[p-[ethyl (m-sulfobenzyl) amino]-α-(o... with smaller amounts of the isomeric disodium salts of ethyl [4-[p-[ethyl(p-sulfobenzyl) amino]-α-(o...

21 CFR 74.705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2011 CFR

2011-04-01

...-sulfophenyl-azo]-1H-pyrazole-3-carboxylic acid (CAS Reg. No. 1934-21-0). To manufacture the additive, 4-amino-benzenesulfonic acid is diazotized using hydrochloric acid and sodium nitrite. The diazo compound is coupled with... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...

76 FR 32215 - Agency Information Collection Activities; Proposed Collection; Comment Request; Substantiation...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-03

... Dietary Supplement Claims Made Under the Federal Food, Drug, and Cosmetic Act AGENCY: Food and Drug... of information technology. Substantiation for Dietary Supplement Claims Made Under the Federal Food...) of the FD&C Act (21 U.S.C. 343(r)(6)) requires that a manufacturer of a dietary supplement making a...

78 FR 68453 - Agency Information Collection Activities; Proposed Collection; Comment Request; Petition to...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-14

... Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements AGENCY: Food and Drug... Dietary Supplements--21 CFR 111.75(a)(1)(ii) (OMB Control Number 0910-0608)-- Extension The Dietary... supplements. Section 402(g)(1) of the FD&C Act states that a dietary supplement is adulterated if ``it has...

Information-Seeking in Family Day Care: Access, Quality and Personal Cost

ERIC Educational Resources Information Center

Corr, L.; Davis, E.; Cook, K.; Mackinnon, A.; Sims, M.; Herrman, H.

2014-01-01

Family day-care (FDC) educators work autonomously to provide care and education for children of mixed ages, backgrounds and abilities. To meet the demands and opportunities of their work and regulatory requirements, educators need access to context-relevant and high quality information. No previous research has examined how and where these workers…

76 FR 12971 - David E. Berman: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-09

... Cosmetic Act (the FD&C Act) debarring David E. Berman, MD, for 3 years from providing services in any... medical doctor licensed by the Virginia Department of Health Professions, specializing in plastic surgery..., and used it on, thirty of his patients as BOTOX Cosmetic. Dr. Berman did not disclose to his patients...

76 FR 48168 - Andrew K. Choi: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-08

...] Andrew K. Choi: Debarment Order AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The... (the FD&C Act) debarring Andrew K. Choi, M.D. for 4 years from providing services in any capacity to a... delegated to him (Staff Manual Guide 1410.35), finds that Andrew K. Choi has been convicted of a misdemeanor...

77 FR 40366 - Glen R. Justice: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-09

...] Glen R. Justice: Debarment Order AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY... Act (the FD&C Act) debarring Glen R. Justice, M.D. from providing services in any capacity to a person... 1410.35), finds that Glen R. Justice has been convicted of five counts of a felony under Federal law...

78 FR 46962 - Biosimilar User Fee Rates for Fiscal Year 2014

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-02

...] Biosimilar User Fee Rates for Fiscal Year 2014 AGENCY: Food and Drug Administration, HHS. ACTION: Notice... fiscal year (FY) 2014. The Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the... October 1, 2013, and will remain in effect through September 30, 2014. FOR FURTHER INFORMATION CONTACT...

77 FR 2552 - Agency Information Collection Activities; Proposed Collection; Comment Request; Substances...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-18

... Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 348) establishes a premarket approval... statutory premarket approval requirements based on a determination that such use is GRAS. The proposed... GRAS determination, and the notifier would maintain a record of such data and information. FDA would...

78 FR 42387 - Draft Guidance for Industry on Circumstances That Constitute Delaying, Denying, Limiting, or...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-15

... Guidance for Industry on Circumstances That Constitute Delaying, Denying, Limiting, or Refusing a Drug... Drug Administration (FDA) is announcing the availability of a draft guidance for industry entitled... Administration Safety and Innovation Act (FDASIA) added a new provision to the Food, Drug, and Cosmetic Act (FD&C...

76 FR 45261 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-28

... Request; Guidance for Industry: Fast Track Drug Development Programs: Designation, Development, and... information to OMB for review and clearance. Guidance for Industry: Fast Track Drug Development Programs... to industry on fast track policies and procedures outlined in section 506 of the FD&C Act. The...

76 FR 737 - Tobacco Products, Exemptions From Substantial Equivalence Requirements

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-06

... tobacco additive, or increasing or decreasing the quantity of an existing tobacco additive, from the... provision by July 1, 2011. ``Additive'' is defined at section 900(1) of the FD&C Act, as ``any substance the... substances intended for use as a flavoring or coloring or in producing, manufacturing, packing, processing...

78 FR 59265 - FD&C Yellow No. 5; Exemption From the Requirement of a Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-26

... (NAICS code 112). Food manufacturing (NAICS code 311). Pesticide manufacturing (NAICS code 32532). B. How.... 5 is a FDA permanently listed color additive used in food, drugs and cosmetics, including drugs and cosmetics for the eye area. FDA's color additive evaluation included the consideration of an extensive set...

The Quantitative Determination of Food Dyes in Powdered Drink Mixes: A High School or General Science Experiment

ERIC Educational Resources Information Center

Sigmann, Samuella B.; Wheeler, Dale E.

2004-01-01

The development of a simple spectro photometric method to quantitatively determine the quantity of FD&C color additives present in powdered drink mixes, are focused by the investigations. Samples containing single dyes of binary mixtures of dyes can be analyzed using this method.

78 FR 38349 - Draft Guidance for Industry on Expedited Programs for Serious Conditions-Drugs and Biologics...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-26

... approval, and priority review designation. DATES: Although you can comment on any guidance at any time (see... designation, (3) accelerated approval, and (4) priority review designation. The draft guidance describes... (the FD&C Act) (Enhancement of Accelerated Approval Access to New Medical Treatments) within 1 year of...

76 FR 25542 - Information Required in Prior Notice of Imported Food

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-05

..., Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 381(m)) to require that additional information be provided... Subjects in 21 CFR Part 1 Cosmetics, Drugs, Exports, Food labeling, Imports, Labeling, Reporting and recordkeeping requirements. Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority...

Zebularine: A Novel DNL Methylation Inhibitor that Forms a Covalent Complex with DNA Methyltransferases

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

Zhou, L.; Cheng, X; Connolly, B

2009-01-01

Mechanism-based inhibitors of enzymes, which mimic reactive intermediates in the reaction pathway, have been deployed extensively in the analysis of metabolic pathways and as candidate drugs. The inhibition of cytosine-[C5]-specific DNA methyltransferases (C5 MTases) by oligodeoxynucleotides containing 5-azadeoxycytidine (AzadC) and 5-fluorodeoxycytidine (FdC) provides a well-documented example of mechanism-based inhibition of enzymes central to nucleic acid metabolism. Here, we describe the interaction between the C5 MTase from Haemophilus haemolyticus (M.HhaI) and an oligodeoxynucleotide duplex containing 2-H pyrimidinone, an analogue often referred to as zebularine and known to give rise to high-affinity complexes with MTases. X-ray crystallography has demonstrated the formation ofmore » a covalent bond between M.HhaI and the 2-H pyrimidinone-containing oligodeoxynucleotide. This observation enables a comparison between the mechanisms of action of 2-H pyrimidinone with other mechanism-based inhibitors such as FdC. This novel complex provides a molecular explanation for the mechanism of action of the anti-cancer drug zebularine.« less

Designing an orientation program for new faculty.

PubMed

Holyfield, Lavern J; Berry, Charles W

2008-12-01

The Faculty Development Committee (FDC) at Baylor College of Dentistry (BCD) is charged with providing programs and activities that facilitate the success of existing faculty in the constantly changing environment of academia. In response to concerns regarding the challenges wrought by current and projected shortages of dental faculty across the nation, the FDC was prompted to assess development opportunities available to BCD faculty. A professional development resource that we found deficient was a formal, comprehensive orientation program for newly hired faculty. To guide the efforts of the committee in developing this program, a survey was designed and administered during an annual faculty retreat. Respondents were new and junior faculty, senior faculty, and some administrators. The results of the survey to determine requirements for new faculty orientation became the basis for formalizing BCD's new faculty orientation program. This article provides an overview of the new faculty orientation process from design to program implementation and describes the development and use of a faculty survey to determine the fundamental elements of a faculty development program, identification of essential individuals for designing/implementing the program, and implementation of a new faculty orientation program at BCD.

Estimation of Flow Duration Curve for Ungauged Catchments using Adaptive Neuro-Fuzzy Inference System and Map Correlation Method: A Case Study from Turkey

NASA Astrophysics Data System (ADS)

Kentel, E.; Dogulu, N.

2015-12-01

In Turkey the experience and data required for a hydrological model setup is limited and very often not available. Moreover there are many ungauged catchments where there are also many planned projects aimed at utilization of water resources including development of existing hydropower potential. This situation makes runoff prediction at locations with lack of data and ungauged locations where small hydropower plants, reservoirs, etc. are planned an increasingly significant challenge and concern in the country. Flow duration curves have many practical applications in hydrology and integrated water resources management. Estimation of flood duration curve (FDC) at ungauged locations is essential, particularly for hydropower feasibility studies and selection of the installed capacities. In this study, we test and compare the performances of two methods for estimating FDCs in the Western Black Sea catchment, Turkey: (i) FDC based on Map Correlation Method (MCM) flow estimates. MCM is a recently proposed method (Archfield and Vogel, 2010) which uses geospatial information to estimate flow. Flow measurements of stream gauging stations nearby the ungauged location are the only data requirement for this method. This fact makes MCM very attractive for flow estimation in Turkey, (ii) Adaptive Neuro-Fuzzy Inference System (ANFIS) is a data-driven method which is used to relate FDC to a number of variables representing catchment and climate characteristics. However, it`s ease of implementation makes it very useful for practical purposes. Both methods use easily collectable data and are computationally efficient. Comparison of the results is realized based on two different measures: the root mean squared error (RMSE) and the Nash-Sutcliffe Efficiency (NSE) value. Ref: Archfield, S. A., and R. M. Vogel (2010), Map correlation method: Selection of a reference streamgage to estimate daily streamflow at ungaged catchments, Water Resour. Res., 46, W10513, doi:10.1029/2009WR008481.

Estimation of daily mean streamflow for ungaged stream locations in the Delaware River Basin, water years 1960–2010

USGS Publications Warehouse

Stuckey, Marla H.

2016-06-09

The ability to characterize baseline streamflow conditions, compare them with current conditions, and assess effects of human activities on streamflow is fundamental to water-management programs addressing water allocation, human-health issues, recreation needs, and establishment of ecological flow criteria. The U.S. Geological Survey, through the National Water Census, has developed the Delaware River Basin Streamflow Estimator Tool (DRB-SET) to estimate baseline (minimally altered) and altered (affected by regulation, diversion, mining, or other anthropogenic activities) and altered streamflow at a daily time step for ungaged stream locations in the Delaware River Basin for water years 1960–2010. Daily mean baseline streamflow is estimated by using the QPPQ method to equate streamflow expressed as a percentile from the flow-duration curve (FDC) for a particular day at an ungaged stream location with the percentile from a FDC for the same day at a hydrologically similar gaged location where streamflow is measured. Parameter-based regression equations were developed for 22 exceedance probabilities from the FDC for ungaged stream locations in the Delaware River Basin. Water use data from 2010 is used to adjust the baseline daily mean streamflow generated from the QPPQ method at ungaged stream locations in the Delaware River Basin to reflect current, or altered, conditions. To evaluate the effectiveness of the overall QPPQ method contained within DRB-SET, a comparison of observed and estimated daily mean streamflows was performed for 109 reference streamgages in and near the Delaware River Basin. The Nash-Sutcliffe efficiency (NSE) values were computed as a measure of goodness of fit. The NSE values (using log10 streamflow values) ranged from 0.22 to 0.98 (median of 0.90) for 45 streamgages in the Upper Delaware River Basin and from -0.37 to 0.98 (median of 0.79) for 41 streamgages in the Lower Delaware River Basin.

The food dye FD&C Blue No. 1 is a selective inhibitor of the ATP release channel Panx1.

PubMed

Wang, Junjie; Jackson, David George; Dahl, Gerhard

2013-05-01

The food dye FD&C Blue No. 1 (Brilliant Blue FCF [BB FCF]) is structurally similar to the purinergic receptor antagonist Brilliant Blue G (BBG), which is a well-known inhibitor of the ionotropic P2X7 receptor (P2X7R). The P2X7R functionally interacts with the membrane channel protein pannexin 1 (Panx1) in inflammasome signaling. Intriguingly, ligands to the P2X7R, regardless of whether they are acting as agonists or antagonists at the receptor, inhibit Panx1 channels. Thus, because both P2X7R and Panx1 are inhibited by BBG, the diagnostic value of the drug is limited. Here, we show that the food dye BB FCF is a selective inhibitor of Panx1 channels, with an IC50 of 0.27 µM. No significant effect was observed with concentrations as high as 100 µM of BB FCF on P2X7R. Differing by just one hydroxyl group from BB FCF, the food dye FD&C Green No. 3 exhibited similar selective inhibition of Panx1 channels. A reverse selectivity was observed for the P2X7R antagonist, oxidized ATP, which in contrast to other P2X7R antagonists had no significant inhibitory effect on Panx1 channels. Based on its selective action, BB FCF can be added to the repertoire of drugs to study the physiology of Panx1 channels. Furthermore, because Panx1 channels appear to be involved directly or indirectly through P2X7Rs in several disorders, BB FCF and derivatives of this "safe" food dye should be given serious consideration for pharmacological intervention of conditions such as acute Crohn's disease, stroke, and injuries to the central nervous system.

Functional Inactivation of Putative Photosynthetic Electron Acceptor Ferredoxin C2 (FdC2) Induces Delayed Heading Date and Decreased Photosynthetic Rate in Rice

PubMed Central

Ruan, Banpu; Kang, Shujing; He, Lei; Zhang, Sen; Dong, Guojun; Hu, Jiang; Zeng, Dali; Zhang, Guangheng; Gao, Zhenyu; Ren, Deyong; Hu, Xingming; Chen, Guang; Guo, Longbiao; Qian, Qian; Zhu, Li

2015-01-01

Ferredoxin (Fd) protein as unique electron acceptor, involved in a variety of fundamental metabolic and signaling processes, which is indispensable for plant growth. The molecular mechanisms of Fd such as regulation of electron partitioning, impact of photosynthetic rate and involvement in the carbon fixing remain elusive in rice. Here we reported a heading date delay and yellowish leaf 1 (hdy1) mutant derived from Japonica rice cultivar “Nipponbare” subjected to EMS treatment. In the paddy field, the hdy1 mutant appeared at a significantly late heading date and had yellow-green leaves during the whole growth stage. Further investigation indicated that the abnormal phenotype of hdy1 was connected with depressed pigment content and photosynthetic rate. Genetic analysis results showed that the hdy1 mutant phenotype was caused by a single recessive nuclear gene mutation. Map-based cloning revealed that OsHDY1 is located on chromosome 3 and encodes an ortholog of the AtFdC2 gene. Complementation and overexpression, transgenic plants exhibited the mutant phenotype including head date, leaf color and the transcription levels of the FdC2 were completely rescued by transformation with OsHDY1. Real-time PCR revealed that the expression product of OsHDY1 was detected in almost all of the organs except root, whereas highest expression levels were observed in seeding new leaves. The lower expression levels of HDY1 and content of iron were detected in hdy1 than WT’s. The FdC2::GFP was detected in the chloroplasts of rice. Real-time PCR results showed that the expression of many photosynthetic electron transfer related genes in hdy1 were higher than WT. Our results suggest that OsFdC2 plays an important role in photosynthetic rate and development of heading date by regulating electron transfer and chlorophyll content in rice. PMID:26598971

"One-stop-shop" ultrasound diagnosis of functional, structural and physicomechanical properties of the brachial artery.

PubMed

Balzer, J; Boos, M; Rassaf, T; Heiss, Ch; Preik, M; Matern, S; Schoebel, F; Kelm, M; Lauer, T

2007-05-01

The pathogenesis of atherosclerosis comprises endothelial dysfunction, thickening as well as impaired compliance of the arterial vessel wall. Early assessment of these alterations of the vessel wall at the same site of the vascular tree has yet been hampered by the lack of highly sensitive diagnostic approaches suitable for clinical routine. We therefore aimed to develop and validate a single non-invasive examination of the brachial artery for simultaneous and highly accurate measurement of functional, structural and physicomechanical parameters of the brachial artery. 20 healthy individuals were investigated using high resolution ultrasound. Flow-mediated dilation (FMD), fractional diameter changes (FDC) and intima-media-thickness (IMT) were measured in the same segment of the brachial artery. Coefficients of variation, day-to-day-variability, between- and within-observer-variability were investigated in 5 individuals. All measurements were performed manually and by an automated PC-based analyzing system. Mean values for all measured parameters were 7.65 +/- 0.8% for FMD, 0.02 +/- 0.002 for FDC, 0.351 +/- 0.007 mm for IMT and followed an even distribution throughout the study population. Automated analysis of coefficient of variation, day-to-day-, between- and within-observer variabilities were: 0. 78%, 1.3%, 0.8%, 0.8% (FMD); 4.7%, 2.8%, 4.2%, 2.7% (FDC); 1.8%, 1.1%, 1.9%, 1.1% (IMT). Coefficient of variation, day-to-day-, between- and within-observer variabilities for the manual readings were significantly higher. Functional, structural and physicomechanical parameters of the brachial artery can be quantified consecutively, time-saving and highly reproducibly as an "one-stop-shop" in a single session using high resolution ultrasound with digitized post-processing. This highlights the future possibility of early, sensitive and non-invasive diagnostic testing of vascular function in patients prone to vascular disease.

Strength in Amalgamation: Newer Combination Agents for HIV and Implications for Practice.

PubMed

McCoy, Christopher; Badowski, Melissa; Sherman, Elizabeth; Crutchley, Rustin; Smith, Ethan; Chastain, Daniel B

2018-01-01

Antiretroviral (ART) therapy for the treatment of human immunodeficiency virus (HIV) infection has undergone significant changes over the past 30 years. Many single-tablet regimens (STRs), including newer fixed-dose combination (FDC) tablets, are available, offering patients several options for choosing a treatment regimen that works best for them. Given these changes, patients are more likely to adhere to treatment, achieve better clinical outcomes, and experience both fewer side effects and drug-drug interactions. Newer STRs include dolutegravir (DTG)/lamivudine (3TC)/abacavir (ABC) (Triumeq; Viiv Healthcare, Research Triangle Park, NC), rilpivirine (RPV)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (Odefsey; Gilead, Foster City, CA), RPV/FTC/tenofovir disoproxil fumarate (TDF) (Complera; Gilead), elvitegravir (EVG)/cobicistat (COBI)/FTC/TDF (Stribild; Gilead), and EVG/COBI/FTC/TAF (Genvoya; Gilead). Recently approved FDCs, such as atazanavir (ATV)/COBI (Evotaz; Bristol-Myers Squibb, Princeton, NJ), darunavir (DRV)/COBI (Prezcobix; Janssen Products, Titusville NJ), and FTC/TAF (Descovy; Gilead), are also now available. The Department of Health and Human Services treatment guidelines for HIV recommend many of these integrase strand transfer inhibitor (INSTI) STRs as a preferred choice for initiation of treatment in both ART-naive and -experienced patients because they offer comparably faster rates of virologic suppression, reduced rates of resistance development (especially with DTG), and overall better adherence than protease inhibitors or NNRTIs. Numerous phase 3 clinical trials support these recommendations including several switch or simplification clinical trials. Notably, the novel pharmacokinetic booster COBI, with its water soluble properties, has enabled the development and coformulation of a few of these STRs and FDCs. Also, a newer tenofovir salt formulation, TAF, has an advantageous pharmacokinetic profile, contributing to better overall renal and bone tolerability compared with TDF. Further simplification regimens comprising dual ART therapies are currently being explored. This review provides an overview of the clinical efficacy and safety data for these coformulated agents, highlighting the relative impact on comparative adverse events, assessing the potential for experiencing fewer drug-drug interactions, and discussing the clinical implications regarding adherence to treatment. © 2017 Pharmacotherapy Publications, Inc.

76 FR 58277 - Animal Generic Drug User Fee Act; Public Meeting; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-20

... including specific suggestions for changes to the goals referred to in section 740A(a) of FD&C Act; (3... performance goals for certain submissions over 5 years from fiscal year (FY) 2009 through FY 2013. These review performance goals strive to expedite the review of abbreviated new animal drug applications...

9 CFR 325.13 - Denaturing procedures.

Code of Federal Regulations, 2011 CFR

2011-01-01

...) Tripe may be denatured by dipping it in a 6 percent solution of tannic acid for 1 minute followed by... coloring; (4) Meat may be denatured by dipping it in a solution of 0.0625 percent tannic acid, followed by... carbolic acid; cresylic disinfectant; a formula consisting of 1 part FD&C green No. 3 coloring, 40 parts...

9 CFR 325.13 - Denaturing procedures.

Code of Federal Regulations, 2010 CFR

2010-01-01

...) Tripe may be denatured by dipping it in a 6 percent solution of tannic acid for 1 minute followed by... coloring; (4) Meat may be denatured by dipping it in a solution of 0.0625 percent tannic acid, followed by... carbolic acid; cresylic disinfectant; a formula consisting of 1 part FD&C green No. 3 coloring, 40 parts...

75 FR 69093 - Prescription Drug User Fee Act; Reopening of the Comment Period

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-10

... review program after negotiations with the regulated industry conclude. FDA expects that this additional...)(2) (21 U.S.C. 379h-2(d)(2)) of the FD&C Act requires that before FDA begins negotiations with the... requires public review of the recommendations for the human drug review program after negotiations with the...

77 FR 34955 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-12

...'' as ``any substance intended for use as a component of materials used in manufacturing, packing... premarket review of a food additive petition (FAP) under section 409(b) of the FD&C Act is necessary to... notification. Currently, interested persons transmit an FCN submission to the Office of Food Additive Safety in...

77 FR 19670 - Agency Information Collection Activities; Proposed Collection; Comment Request; Food Contact...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-02

... intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or... additive petition (FAP) under section 409(b) of the FD&C Act is necessary to provide adequate assurance of... transmit an FCN submission to the Office of Food Additive Safety in the Center for Food Safety and Applied...

76 FR 55919 - Agency Information Collection Activities; Proposed Collection; Comment Request; MedWatch: The...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-09

...; dietary supplements and other special nutritional products (e.g., infant formula and medical foods); and... regulates the safety (i.e., adulteration) of dietary supplements under section 402 of the FD&C Act (21 U.S.C. 342). Dietary supplements do not require premarket approval by FDA and the Agency bears the burden to...

78 FR 71621 - Agency Information Collection Activities; Proposed Collection; Comment Request; Eye Tracking...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-29

... notice. This notice solicits comments on research entitled, ``Eye Tracking Study of Direct-to-Consumer... the FDA to conduct research relating to health information. Section 1003(d)(2)(C) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 393(b)(2)(c)) authorizes FDA to conduct research...

76 FR 47085 - Effective Date of Requirement for Premarket Approval for a Pacemaker Programmer

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-04

.... FDA-2011-N-0526] Effective Date of Requirement for Premarket Approval for a Pacemaker Programmer... programmers. The agency is also summarizing its proposed findings regarding the degree of risk of illness or.... Background--Regulatory Authorities The Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the...

77 FR 74485 - Request for Comments and Information on Initiating a Risk Assessment for Establishing Food...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-14

...-mediated sensitivity to foods that can lead to life-threatening adverse reactions. Because there is no cure... Cosmetic Act (the FD&C Act) by defining the term ``major food allergen'' and stating that foods regulated... ingredient ``does not contain allergenic protein'' or that a determination has previously been made through a...

78 FR 61991 - Schedules of Controlled Substances: Temporary Placement of Three Synthetic Phenethylamines Into...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-10

... the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355, for the substance. 21 U.S.C. 811(h... Institute on Drug Abuse (NIDA), FDA acts as the lead agency within HHS in carrying out the Assistant... grounds for his determination that it is [[Page 61993

77 FR 39924 - Effective Date of Requirement for Premarket Approval for Cardiovascular Permanent Pacemaker...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-06

.... FDA-2011-N-0505] Effective Date of Requirement for Premarket Approval for Cardiovascular Permanent... application (PMA) or a notice of completion of a product development protocol (PDP) for the cardiovascular...) of the FD&C Act of a PMA or notice of completion of a PDP for the cardiovascular permanent pacemaker...

78 FR 33842 - Determination and Declaration Regarding Emergency Use of In Vitro Diagnostics for Detection of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-05

... In Vitro Diagnostics for Detection of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) AGENCY... Middle East respiratory syndrome coronavirus (MERS-CoV). On the basis of this determination, she also... detection of Middle East respiratory syndrome coronavirus (MERS-CoV) pursuant to section 564 of the FD&C Act...

An International Perspective on Regulated Family Day Care Systems

ERIC Educational Resources Information Center

Davis, Elise; Freeman, Ramona; Doherty, Gillian; Karlsson, Malene; Everiss, Liz; Couch, Jane; Foote, Lyn; Murray, Patricia; Modigliani, Kathy; Owen, Sue; Griffin, Sue; Friendly, Martha; McDonald, Grace; Bohanna, India; Corr, Lara; Smyth, Lisa; Morkeseth, Elisabeth Ianke; Morreaunet, Sissel; Ogi, Mari; Fukukawa, Sumi; Hinke-Rahnau, Jutta

2012-01-01

Despite emerging evidence of the contributors to high-quality family day care, a comprehensive comparison of international family day care systems has not been undertaken. The aim of this paper is to compare regulated family day care (FDC) in Australia, Canada, England and Wales, Germany, Ireland, Japan, Norway, New Zealand, Sweden, and the USA,…

9 CFR 325.13 - Denaturing procedures.

Code of Federal Regulations, 2012 CFR

2012-01-01

... water, 40 parts liquid detergent, and 40 parts oil of citronella, or other proprietary substance... immersion in a water bath, then immersing it for 1 minute in a solution of 0.022 percent FD&C yellow No. 5... immersion in a water bath, then dipping it in a solution of 0.0625 percent ferric acid; and (5) When meat...

9 CFR 325.13 - Denaturing procedures.

Code of Federal Regulations, 2013 CFR

2013-01-01

... water, 40 parts liquid detergent, and 40 parts oil of citronella, or other proprietary substance... immersion in a water bath, then immersing it for 1 minute in a solution of 0.022 percent FD&C yellow No. 5... immersion in a water bath, then dipping it in a solution of 0.0625 percent ferric acid; and (5) When meat...

9 CFR 325.13 - Denaturing procedures.

Code of Federal Regulations, 2014 CFR

2014-01-01

... water, 40 parts liquid detergent, and 40 parts oil of citronella, or other proprietary substance... immersion in a water bath, then immersing it for 1 minute in a solution of 0.022 percent FD&C yellow No. 5... immersion in a water bath, then dipping it in a solution of 0.0625 percent ferric acid; and (5) When meat...

78 FR 58886 - FD&C Blue No. 1; Exemption From the Requirement of a Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-25

... infants and children. Specific information on the studies received and the nature of the adverse effects... consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to ``ensure that there is a reasonable certainty that no harm will result to infants and children...

75 FR 42308 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-21

... previously by the FAA in a Flight Data Center (FDC) Notice to Airmen (NOTAM) as an emergency action of immediate flight safety relating directly to published aeronautical charts. The circumstances which created... Locks, CT, Bradley Intl, RNAV (RNP) Z RWY 15, Orig-A Orlando, FL, Kissimmee Gateway, ILS OR LOC RWY 15...

78 FR 60288 - Agency Information Collection Activities: Proposed Collection; Comment Request; Guidance for...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-01

..., and Cosmetic Act AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug... Cosmetic Act (FD&C Act). DATES: Submit either electronic or written comments on the collection of... Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act--(OMB...

76 FR 33309 - Guidance for Industry on Citizen Petitions and Petitions for Stay of Action Subject to Section...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-08

... the Federal Food, Drug, and Cosmetic Act; Availability AGENCY: Food and Drug Administration, HHS... to Section 505(q) of the Federal Food, Drug, and Cosmetic Act.'' The Food and Drug Administration Amendments Act (FDAAA) added new provisions to the Federal Food, Drug, and Cosmetic Act (the FD&C Act...

76 FR 40376 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-08

... should be identified with the OMB control number 0910-0482. Also include the FDA docket number found in...:. Exports: Notification and Recordkeeping Requirements--21 CFR Part 1 (OMB Control Number 0910-0482... section 801(e) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act (21 U.S.C. 381)). In general, the...

9 CFR 327.25 - Disposition procedures for product condemned or ordered destroyed under import inspection.

Code of Federal Regulations, 2010 CFR

2010-01-01

... dipping it in a solution of 0.0625 percent tannic acid, followed by immersion in a water bath, then... tannic acid for 1 minute followed by immersion in a water bath, then immersing it for 1 minute in a... establishment: Crude carbolic acid; cresylic disinfectant; a formula consisting of 1 part FD&C green No. 3...

9 CFR 327.25 - Disposition procedures for product condemned or ordered destroyed under import inspection.

Code of Federal Regulations, 2011 CFR

2011-01-01

... dipping it in a solution of 0.0625 percent tannic acid, followed by immersion in a water bath, then... tannic acid for 1 minute followed by immersion in a water bath, then immersing it for 1 minute in a... establishment: Crude carbolic acid; cresylic disinfectant; a formula consisting of 1 part FD&C green No. 3...

76 FR 45811 - Animal Drug User Fee Rates and Payment Procedures for Fiscal Year 2012

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-01

... Lisa Kable, Center for Veterinary Medicine (HFV-10), Food and Drug Administration, 7529 Standish Pl... Medicine (CVM) at: [email protected] . SUPPLEMENTARY INFORMATION: I. Background Section 740 of the FD&C... from the base years in column 3. At the bottom right of the table the sum of the values in column 5 is...

76 FR 76417 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-07

...); biologics; medical devices; dietary supplements and other special nutritional products (e.g., infant formula... supplements under section 402 of the FD&C Act (21 U.S.C. 342). Dietary supplements do not require premarket approval by FDA and the Agency bears the burden to gather and review evidence that a dietary supplement may...

78 FR 42082 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-15

... Request; Agreement for Shipment of Devices for Sterilization AGENCY: Food and Drug Administration, HHS... review and clearance. Agreement for Shipment of Devices for Sterilization--21 CFR 801.150(e) (OMB Control... (the FD&C Act) (21 U.S.C. 351(c) and 352(a)), nonsterile devices that are labeled as sterile but are in...

Development and Application of Flow Duration Curves for Stream Restoration

DTIC Science & Technology

2016-02-01

hydrograph (TNC 2009). Colorado State University’s GeoTools offers an FDC computation focusing on the geomorphic implications of hydrology (Bledsoe...processes • Assessment of changes in stream metabolism using temperature duration curves • Evaluation of pollutant or contaminant transport using...major concern associated with stream restoration projects, due to the many chemical, ecological, and geomorphic advantages a robust riparian buffer

78 FR 64220 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-28

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0804... Section 510(k) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 360(k)) and the... sheet form, assists respondents in categorizing administrative 510(k) information for submission to FDA...

78 FR 2998 - Food and Drug Administration Modernization Act of 1997: Modifications to the List of Recognized...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-15

... on FDA's Internet site at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Standards..., and Cosmetic Act (the FD&C Act) (21 U.S.C. 360d). Amended section 514 allows FDA to recognize... accessible at the Agency's Internet site. See section VI of this document for electronic access information...

An Inexpensive Kinetic Study: The Reaction of FD&C Red #3 (Erythrosin B) with Hypochlorite

ERIC Educational Resources Information Center

Henary, Maher M.; Russell, Arlene A.

2007-01-01

Kinetics constitutes a core topic in both the lecture and laboratory components of lower- level chemistry courses. While textbook examples can ignore issues of time, temperature and safety, the laboratory can not. Reactions must occur slowly enough to be detected by students, occur rapidly enough for data collection in the few hours assigned to a…

78 FR 72901 - Draft Guidance; Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-04

... the Drug Quality and Security Act to remove the unconstitutional advertising, promotion, and... 503A are met. The conditions of section 503A of the FD&C Act included restrictions on the advertising or promotion of the compounding of any particular drug, class of drug, or type of drug, and the...

75 FR 61497 - Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing; Request...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-05

..., whereas small molecule drugs are typically manufactured through chemical synthesis. Section 351(k) of the... provision for protein products that have been or will be approved under section 505 of the FD&C Act (21 U.S... certain protein products during the 10-year transition period following enactment of the BPCI Act; and the...

76 FR 35098 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-16

... North Bend Southwest Rgnl...... 1/9838 5/2/11 RNAV (RNP) Z RWY 4, Orig 30-Jun-11 MT Bozeman Gallatin... City, OK. 73169 (Mail Address: P.O. Box 25082 Oklahoma City, OK 73125) telephone: (405) 954-4164... appropriate FAA Form 8260, as modified by the National Flight Data Center (FDC)/Permanent Notice to Airmen (P...

21 CFR 74.3102 - FD&C Blue No. 2.

Code of Federal Regulations, 2010 CFR

2010-04-01

... impurities may be avoided by current good manufacturing practice: Sum of volatile matter at 135 °C (275 °F... bone cement shall be prepared in accordance with the requirements of § 82.51 of this chapter. (c) Uses... No. 2-Aluminum Lake on alumina may be safely used for coloring bone cement at a level not to exceed 0...

77 FR 14811 - Draft Guidance for Industry on Direct-to-Consumer Television Advertisements-the Food and Drug...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-13

... 503B of the FD&C Act and on the submission process for these ads. It does not create or confer any...), Federal Agencies must obtain approval from the Office of Management and Budget (OMB) for each collection... for each proposed collection of information before submitting the collection to OMB for approval. To...

21 CFR 74.2705 - FD&C Yellow No. 5.

Code of Federal Regulations, 2010 CFR

2010-04-01

... salt, not more than 0.2 percent. 4,5-Dihydro-5-oxo-1-(4-sulfophenyl)-1H-pyrazole-3-carboxylic acid, disodium salt, not more than 0.2 percent. Ethyl or methyl 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-1H-pyrazole-3...-sulfophenyl)azo]-1H-pyrazole-3-carboxylic acid (CAS Reg. No. 1934-21-0). To manufacture the additive, 4...

An Analysis of Alternatives to Verbal FM Radio Tactical Command and Control Communications

DTIC Science & Technology

1975-06-06

specialist’s ,, , nwarted by these means even more reliablv than by conventional weapons.16 renaoiy an enemy attack can be th1 Marshal Vasili ...Mort Pit Squad(4) FDC F0(3) LDR FAC Bn LN0(2) Conmel Cff Survl Sec Sgt Commo Pit Gnd Survl Sec(6) Spt Pit Co Maint Sec AVLB Sec Med Sec Bn

78 FR 66748 - Smith Miller and Patch Inc. et al.; Proposal to Withdraw Approval of 14 New Drug Applications...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-06

... Ave., Glendale, CA 91201. NDA 017861 Acthar Gel Synthetic Armour (seractide acetate) Pharmaceutical Co... the Center for Drug Evaluation and Research proposes to issue an order under section 505(e) of the... reports required under Sec. 314.81. In accordance with section 505 of the FD&C Act and part 314 (21 CFR...

Aerial Observation; A Bibliography of Periodical Articles.

DTIC Science & Technology

1982-04-01

99,90, Jan 1944. ’If not an Air OP why not locatinc7," 2CRA, ?0:115-123, Apr 1953. Jackson , I-ian E. "FDC an- the Artillery Air Observer," FM, 34...194, 1886. Thom.pson, Percy N;. "Organization and ’aneuver of Ficld Artillery Observation," .*IL RVW, 25:53-60, Apr 1945. "To See or not to see," JORA

78 FR 59810 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-30

... appropriate FAA Form 8260, as modified by the National Flight Data Center (FDC)/Permanent Notice to Airmen (P... published aeronautical charts. The circumstances which created the need for all these SIAP amendments... 8/29/13 ILS OR LOC RWY 4, Amdt 3B 10/17/13 IA Sioux City Sioux Gateway/Col. 3/6352 9/10/13 ILS OR...

Effects of a Red Marker Dye on Aedes and Culex Larvae: Are There Implications for Operational Mosquito Control?

PubMed

Unlu, Isik; Leisnham, Paul T; Williams, Gregory M; Klingler, Kim; Dow, Garrett W; Kirchoff, Nicole; Jin, Sophie; Delisi, Nicholas; Montenegro, Katherine; Faraji, Ary

2015-12-01

Marker dyes are often mixed with liquid insecticide formulations prior to field applications to accurately determine the characteristics and penetration of droplets into targeted habitats. We have been using FD&C Red 40 Granular DM food dye at the rate of 20 g/liter in liquid solutions of Bacillus thuringiensis israelensis (Bti) for area-wide larvicide applications against the Asian tiger mosquito, Aedes albopictus. The Bti and dye mix ratio has been recommended by pesticide manufacturers for testing under operational conditions, but no data exist on the effects of the dye itself on mosquito larvae. We tested the effects of the FD&C Red 40 food dye in laboratory bioassays against different strains of Ae. albopictus (New Jersey and Maryland) and Culex pipiens pipiens (Utah) at rates of 0.039 to 80.0 g/liter. We also conducted field application trials to measure dye concentrations up to 100 m downwind when mixed and applied according to manufacturer instructions. In laboratory bioassays, we found that mean survival in cups with dye were significantly different from the controls beginning at 10.0 g/liter for New Jersey Ae. albopictus and at 20.0 g/liter for Maryland Ae. albopictus and Utah Cx. p. pipiens. In field application trials, we recorded a maximum volume density of 1,152.8 nl/cm(2) and calculated the maximum concentration of dye at 9.09 × 10(-3) g/liter. Our results showed that although we detected greater effects of dye on Ae. albopictus in New Jersey experiments than Ae. albopictus in Maryland and Cx. p. pipiens from Utah, concentrations of the dye during operational applications were at least 1,100 times below concentrations that exhibited toxic effects for either species in the laboratory, suggesting that the dye will not interfere with accuracy of field bioassays. Our results conclusively demonstrate that the addition of the FD&C Red 40 marker dye does not alter the efficacy of the pesticide formulation by skewing results, but rather provides a valuable addition to accurately determine pesticide penetration and spectrum by discriminating between intended pesticide and other potential pollutants.

Integrating Hydrology, Ecology, and Biogeochemistry in Stormwater Management: the Vermont Experience

NASA Astrophysics Data System (ADS)

Bowden, W. B.

2005-12-01

Although Vermont has had a stormwater management program since the 1970's, support for the program languished during a period intense suburban development in several counties in the state, most notably Chittenden County next to Lake Champlain. Beginning in 2000, the state renewed efforts to address concerns that stormwater runoff from suburban developments had significantly degraded streams in the area and threatened the health of the Lake. The state employs an extensive, EPA-approved biomonitoring program (based on macroinvertebrates and fish) to assess the health of streams. However, it is difficult to translate these data into targets for stormwater management or to predict how and especially when they will change as a result of future management practices. The challenge of managing stormwater in this area is further compounded by a complete lack of historical hydrologic monitoring data. Ultimately a stakeholder-driven process developed that has lead to an innovative partnership among state agencies, resource managers, NGO's, the US-EPA and scientists. Through this partnership a unique consensus evolved that management for hydrologic targets by themselves would address most of the stakeholders' concerns. The new regulations that are emerging are based on two components. The first component relies on flow-duration curves (FDC's) derived from a simple, widely-used stormwater model (P-8) for which adequate input data are available. The model was calibrated for streams in other areas for which long-term hydrologic data were available and then used to generate `synthetic' FDC's for the stormwater impaired and a suite of `attainment' (developing, but currently un-impaired) watersheds in Vermont. Statistical (cluster) analyses of synthetic FDC's provide watershed-wide targets for hydrologic reduction. Sub-watershed mapping linked to further multivariate analysis of the flow data identify specific locations to implement best management practices (BMP's) that will achieve these targets. This approach is firmly grounded in first principles of stormwater hydrology and recognition of the impacts of altered hydrology on stream ecology and biogeochemistry. Stakeholders have accepted the approach because it is objective, defensible, and subject to future, quantitative analysis and adjustment (adaptive management). This approach is not specific to Vermont and could be employed in any region.

A Bayesian Dose-finding Design for Oncology Clinical Trials of Combinational Biological Agents

PubMed Central

Cai, Chunyan; Yuan, Ying; Ji, Yuan

2013-01-01

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. PMID:24511160

Strategic Performance Management Evaluation for the Navy’s Splice Local Area Networks.

DTIC Science & Technology

1985-04-01

Communications Agency (DCA)/Federal Data Corporation (FDC) literature; an extensive survey of academic and professional book and article literature... interesting closing note on strategic planning characteristics is that the period during which collapse or disaster develops is of the same order as the...accepted set of standards. In computer performance, such things as paging rates , throughput, input/output channel usage, turnaround * 32 EM-. time

Dye to use with virus challenge for testing barrier materials.

PubMed Central

Lytle, C D; Felten, R P; Truscott, W

1991-01-01

Can FD&C Blue no. 1 dye photoinactivate bacteriophages phi X174, T7, PRD1, and phi 6 under laboratory lighting conditions? At high levels of light, the dye (500 microM) photoinactivated only phi 6. Thus, this dye can be used at concentrations up to 500 microM with bacteriophages phi X174, T7, and PRD1 to test barrier material integrity. PMID:1872612

78 FR 46977 - Generic Drug User Fee-Abbreviated New Drug Application, Prior Approval Supplement, Drug Master...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-02

... costs to total FDA costs of the review of human generic drug activities for the first 3 of the preceding... review of human generic drug activities. Since the first year of the Generic Drug User Fee Program has... activities other than PC&B (see section 744B(c)(1)(C) of the FD&C Act). Table 3 of this document provides the...

Assessment of DoD and Industry Networks for Computer Aided Logistics Support (CALS) Telecommunications.

DTIC Science & Technology

1987-06-01

International Business Machines ( IBM ) Corporation compatible synchronous terminals (2780/3780/327X), and the Federal Data Corporation (FDC) has developed...the interfaces for Burroughs look-alike asynchronous and synchronous terminals. Basically, this means that the IBM and Burroughs protocols are...and other vendor computers, such as IBM , UNIVAC, and Honeywell. The Navy has developed file transfer capabilities between Tandem and Burroughs. These

An Anomalous Force on the Map Spacecraft

NASA Technical Reports Server (NTRS)

Starin, Scott R.; ODonnell, James R., Jr.; Ward, David K.; Wollack, Edward J.; Bay, P. Michael; Fink, Dale R.; Bauer, Frank (Technical Monitor)

2002-01-01

The Microwave Anisotropy Probe (MAP) orbits the second Earth-Sun libration point (L2)-about 1.5 million kilometers outside Earth's orbit-mapping cosmic microwave background radiation. To achieve orbit near L2 on a small fuel budget, the MAP spacecraft needed to swing past the Moon for a gravity assist. Timing the lunar swing-by required MAP to travel in three high-eccentricity phasing loops with critical maneuvers at a minimum of two, but nominally all three, of the perigee passes. On the approach to the first perigee maneuver, MAP telemetry showed a considerable change in system angular momentum that threatened to cause on-board Failure Detection and Correction (FDC) to abort the critical maneuver. Fortunately, the system momentum did not reach the FDC limit; however, the MAP team did develop a contingency strategy should a stronger anomaly occur before or during subsequent perigee maneuvers, Simultaneously, members of the MAP team developed and tested various hypotheses for the cause of the anomalous force. The final hypothesis was that water was outgassing from the thermal blanketing and freezing to the cold side of the solar shield. As radiation from Earth warmed the cold side of the spacecraft, the uneven sublimation of frozen water created a torque on the spacecraft.

Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for "vertical" and "lateral" combination strategies.

PubMed

Ricciardi, Maria Rosaria; Scerpa, Maria Cristina; Bergamo, Paola; Ciuffreda, Ludovica; Petrucci, Maria Teresa; Chiaretti, Sabina; Tavolaro, Simona; Mascolo, Maria Grazia; Abrams, Stephen L; Steelman, Linda S; Tsao, Twee; Marchetti, Antonio; Konopleva, Marina; Del Bufalo, Donatella; Cognetti, Francesco; Foà, Robin; Andreeff, Michael; McCubrey, James A; Tafuri, Agostino; Milella, Michele

2012-10-01

In hematological malignancies, constitutive activation of the RAF/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Here, we investigated the molecular and functional effects of pharmacological MEK inhibition in cell line models of acute myeloid leukemia (AML) and freshly isolated primary AML samples. The small-molecule, ATP-non-competitive, MEK inhibitor PD0325901 markedly inhibited ERK phosphorylation and growth of several AML cell lines and approximately 70 % of primary AML samples. Growth inhibition was due to G(1)-phase arrest and induction of apoptosis. Transformation by constitutively active upstream pathway elements (HRAS, RAF-1, and MEK) rendered FDC-P1 cells exquisitely prone to PD0325901-induced apoptosis. Gene and protein expression profiling revealed a selective effect of PD0325901 on ERK phosphorylation and compensatory upregulation of the RAF/MEK and AKT/p70( S6K ) kinase modules, potentially mediating resistance to drug-induced growth inhibition. Consequently, in appropriate cellular contexts, both "vertical" (i.e., inhibition of RAF and MEK along the MAPK pathway) and "lateral" (i.e., simultaneous inhibition of the MEK/ERK and mTOR pathways) combination strategies may result in synergistic anti-leukemic effects. Overall, MEK inhibition exerts potent growth inhibitory and proapoptotic activity in preclinical models of AML, particularly in combination with other pathway inhibitors. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective targeted strategies for the treatment of AML.

Implementation of a Proposed System for Automated Microcode Generation.

DTIC Science & Technology

1984-12-01

Marcia Elaine Provance 6 . PERFORMING ORGANIZATION NAME AND ADDRESS t0. PROGRAM ELEMENT, PROJECT, TASK AREA 6 WORK UNIT NUMBERS * Naval Postgraduate...The proposed microprogramming system is organized around a series of menus which are presented to a microprograrmuer so that she can build FDC 1473... organization is not affected. A computer can also respond more easily to new performance demands and problem solutions. A richer or a larger instruction set

Technology Readiness Assessment (TRA) Deskbook

DTIC Science & Technology

2005-05-01

information such as expiration date and lot number. DoD will probably be in a position to use a commercially proven technology with an inherently low...federal regulations, DoD was able to gain approval of pyridostigmine bromide for prophylaxis against the lethal effects of the soman nerve agent . H...www.fda.gov/cber/ H.4 ADDITIONAL INFORMATION Federal Food, Drug, and Cosmetic (FD&C) Act United States Code, Title 21 – Food and Drugs (21USC

10 CFR 835.203 - Combining internal and external equivalent doses.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Combining internal and external equivalent doses. 835.203 Section 835.203 Energy DEPARTMENT OF ENERGY OCCUPATIONAL RADIATION PROTECTION Standards for Internal and External Exposure § 835.203 Combining internal and external equivalent doses. (a) The total effective dose...

Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations.

PubMed

Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian

2016-05-01

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Hydropower potential mapping in mountain basins by high-resolution hydrological and GIS analysis

NASA Astrophysics Data System (ADS)

Claps, P.; Gallo, E.; Ganora, D.; Laio, F.; Masoero, A.

2013-12-01

Even in regions with mature hydropower development, needs for stable renewable power sources suggest to revise plans of exploitation of water resources, in compliance to the framework of international and national environmental regulations. This goal requires high-resolution hydrological analysis, that allows to : i) comply with the effects of existing hydropower plants or of other types of water withdrawals; ii) to assist the planner to figure out potential of new plants with still high marginal efficiency; iii) to assist the regulator in the process of comparing projects based on different solutions and different underlying hydrologic estimation methods. Flow duration curves (FDC) are the tool usually adopted to represent water availability and variability for hydropower purposes. They are usually determined in ungauged basins by means of regional statistical analysis. For this study, a 'spatially smooth' regional estimation method (SSEM) has been developed for FDC estimation, with some evolutions from a previous version: i) the method keeps the estimates of mean annual runoff congruent in the confluences by considering only raster-summable explanatory variables; ii) the presence of existing reservoirs and hydropower plants is taken into account by restoring the ';natural' statistics of the curve. The SSEM reconstructs the the FDC in ungauged basins using its L-moments from regressions on geomorphoclimatic descriptors. Relations are obtained on more than 100 gauged basins located in Northwestern Italy. To support the assessment of residual hydropower potential on two specific mountain watersheds the model has been applied extensively (Hi-Res) by mapping the estimated mean flow for each pixel of a DEM-derived river network raster model. 25000 sections were then identified over the network extracted from a 50m-resolution DTM. Spatial algorithms and data management were developed using Free&OpenSource Software (FOSS) (GRASS GIS and PostgreSQL/PostGIS), with the spatial database required to store perimeters and other descriptors needed for the hydrological estimation. Specific efforts have been devoted to spatial representation of the available potential using different flow-(elevation drop) relations for each pixel (along-river path, straight within floating window, in-valley constrained, etc.). This representation expands the information content and the domain of application of the classical hydrodynamic curve ( elevation-drop/ contributing area). Specific and abrupt changes due to existing plants are then clearly represented to provide a complete picture of the available potential for planning and regulation purposes.

Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy.

PubMed

Svensson, Elin M; Yngman, Gunnar; Denti, Paolo; McIlleron, Helen; Kjellsson, Maria C; Karlsson, Mats O

2018-05-01

Fixed-dose combination formulations where several drugs are included in one tablet are important for the implementation of many long-term multidrug therapies. The selection of optimal dose ratios and tablet content of a fixed-dose combination and the design of individualized dosing regimens is a complex task, requiring multiple simultaneous considerations. In this work, a methodology for the rational design of a fixed-dose combination was developed and applied to the case of a three-drug pediatric anti-tuberculosis formulation individualized on body weight. The optimization methodology synthesizes information about the intended use population, the pharmacokinetic properties of the drugs, therapeutic targets, and practical constraints. A utility function is included to penalize deviations from the targets; a sequential estimation procedure was developed for stable estimation of break-points for individualized dosing. The suggested optimized pediatric anti-tuberculosis fixed-dose combination was compared with the recently launched World Health Organization-endorsed formulation. The optimized fixed-dose combination included 15, 36, and 16% higher amounts of rifampicin, isoniazid, and pyrazinamide, respectively. The optimized fixed-dose combination is expected to result in overall less deviation from the therapeutic targets based on adult exposure and substantially fewer children with underexposure (below half the target). The development of this design tool can aid the implementation of evidence-based formulations, integrating available knowledge and practical considerations, to optimize drug exposures and thereby treatment outcomes.

On the Role of Built-in Electric Fields on the Ignition of Oxide Coated NanoAluminum: Ion Mobility versus Fickian Diffusion

DTIC Science & Technology

2010-01-01

on Al ion diffu- sion can be computed using the Nernst –Planck equation . The Nernst –Plank equation is given in Eq. 4,22 J = − D dC dx − zFDC RT d dx...The use of the bulk diffusion equation is reason- able since during the time scales considered the movement of only the atoms initially on the surface

Threshold Voltage Instability in A-Si:H TFTS and the Implications for Flexible Displays and Circuits

DTIC Science & Technology

2008-12-01

and negative gate voltages with and without elevated drain voltages for FDC TFTs. Extending techniques used to localize hot electron degradation...in MOSFETs, experiments in our lab have localized the degradation of a-Si:H to the gate dielectric/a-Si:H channel interface [Shringarpure, et al...saturation, increased drain source current measured with the source and drain reversed indicates localization of ΔVth to the gate dielectric/amorphous

MERCATOR: Methods and Realization for Control of the Attitude and the Orbit of spacecraft

NASA Technical Reports Server (NTRS)

Tavernier, Gilles; Campan, Genevieve

1993-01-01

Since 1974, CNES has been involved in geostationary positioning. Among different entities participating in operations and their preparation, the Flight Dynamics Center (FDC) is in charge of performing the following tasks: orbit determination; attitude determination; computation, monitoring, and calibration of orbit maneuvers; computation, monitoring, and calibration of attitude maneuvers; and operational predictions. In order to fulfill this mission, the FDC receives telemetry from the satellite and localization measurements from ground stations (e.g., CNES, NASA, INTELSAT). These data are processed by space dynamics programs integrated in the MERCATOR system which is run on SUN workstations (UNIX O.S.). The main features of MERCATOR are redundancy, modularity, and flexibility: efficient, flexible, and user friendly man-machine interface; and four identical SUN stations redundantly linked in an Ethernet network. Each workstation can perform all the tasks from data acquisition to computation results dissemination through a video network. A team of four engineers can handle the space mechanics aspects of a complete geostationary positioning from the injection into a transfer orbit to the final maneuvers in the station-keeping window. MERCATOR has been or is to be used for operations related to more than ten geostationary positionings. Initially developed for geostationary satellites, MERCATOR's methodology was also used for satellite control centers and can be applied to a wide range of satellites and to future manned missions.

IS1598 (IsPg4) distributed to abscess-forming strains of Porphyromonas gingivalis may enhance virulence through upregulation of nrdD-like gene expression.

PubMed

Sonoi, Norihiro; Maeda, Hiroshi; Murauchi, Toshimitsu; Yamamoto, Tadashi; Omori, Kazuhiro; Kokeguchi, Susumu; Naruishi, Koji; Takashiba, Shogo

2018-01-01

An insertion sequence, IS1598 (IsPg4) has been found in virulent strains of Porphyromonas gingivalis in a murine abscess model. The present study was performed to investigate the effects of genetic rearrangements by IS1598 on the phenotypic characteristics of the virulent strains. For this purpose, we searched for a common insertion site of IS1598 among the virulent strains. Through cloning and database search, a common insertion site was identified beside an nrdD-like gene in the virulent FDC 381, W83 and W50 strains. In this region, predicted promoters of the nrdD-like gene and IS1598 are located in tandem, and accumulation of nrdD-like gene mRNA was 5-fold higher in virulent strains (W83, W50, FDC 381) than avirulent strains (ATCC33277, SU63, SUNY1021, ESO59 without IS1598). The role of the nrdD-like gene in virulence of P. gingivalis was investigated by constructing a nrdD-deficient mutant. In the murine abscess model, the parental W83 strain produced necrotic abscesses, while the nrdD-deficient mutant had almost lost this ability. Insertion of IS1598 into the nrdD-like gene promoter region may be related to the phenotypic differences in virulence among P. gingivalis strains through upregulation of the expression of this gene.

No longer "if," but "when": the coming abbreviated approval pathway for follow-on biologics.

PubMed

Kelly, Jeremiah J; David, Michael

2009-01-01

Abbreviated approval of follow-on biologics involves answering complex scientific, legal, and policy questions. The Food and Drug Administration (FDA or the Agency) asserts that it lacks the statutory authority to approve follow-on versions of biologics licensed under Section 351 of the Public Health Service Act (PHSA). Despite persuasive arguments to the contrary the one hundred and tenth Congress entertained four legislative proposals to give FDA this authority, each markedly different. It is no longer a question of "if," but "when" FDA will receive authority to review and license abbreviated applications for follow-on biologics. Any legislation in the one hundred and eleventh Congress must determine: (1) if FDA should be granted authority to develop an abbreviated pathway through rulemaking or guidance; (2) if human clinical trials should be mandatory or discretionary; (3) the feasibility of interchangeability determinations in light of patient safety concerns; (4) the duration of marketing exclusivity for associated products; (5) which products are eligible for follow-on approval; and (6) the degree to which uniformity is achievable between the FD&C Act and the PHSA. This paper recommends the one hundred and eleventh Congress strike a balance between patient safety, incentives for product innovation, price competition, and the need for a flexible, transparent process that capitalizes on FDA's growing expertise with follow-on biologics approvals under Section 505(b)(2) of the FD&C Act.

Quantitative LC-MS Provides No Evidence for m6 dA or m4 dC in the Genome of Mouse Embryonic Stem Cells and Tissues.

PubMed

Schiffers, Sarah; Ebert, Charlotte; Rahimoff, René; Kosmatchev, Olesea; Steinbacher, Jessica; Bohne, Alexandra-Viola; Spada, Fabio; Michalakis, Stylianos; Nickelsen, Jörg; Müller, Markus; Carell, Thomas

2017-09-04

Until recently, it was believed that the genomes of higher organisms contain, in addition to the four canonical DNA bases, only 5-methyl-dC (m 5 dC) as a modified base to control epigenetic processes. In recent years, this view has changed dramatically with the discovery of 5-hydroxymethyl-dC (hmdC), 5-formyl-dC (fdC), and 5-carboxy-dC (cadC) in DNA from stem cells and brain tissue. N 6 -methyldeoxyadenosine (m 6 dA) is the most recent base reported to be present in the genome of various eukaryotic organisms. This base, together with N 4 -methyldeoxycytidine (m 4 dC), was first reported to be a component of bacterial genomes. In this work, we investigated the levels and distribution of these potentially epigenetically relevant DNA bases by using a novel ultrasensitive UHPLC-MS method. We further report quantitative data for m 5 dC, hmdC, fdC, and cadC, but we were unable to detect either m 4 dC or m 6 dA in DNA isolated from mouse embryonic stem cells or brain and liver tissue, which calls into question their epigenetic relevance. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Estimated cardiovascular relative risk reduction from fixed-dose combination pill (polypill) treatment in a wide range of patients with a moderate risk of cardiovascular disease.

PubMed

Lafeber, Melvin; Webster, Ruth; Visseren, Frank Lj; Bots, Michiel L; Grobbee, Diederick E; Spiering, W; Rodgers, Anthony

2016-08-01

Recent data indicate that fixed-dose combination (FDC) pills, polypills, can produce sizeable risk factor reductions. There are very few published data on the consistency of the effects of a polypill in different patient populations. It is unclear for example whether the effects of the polypill are mainly driven by the individuals with high individual risk factor levels. The aim of the present study is to examine whether baseline risk factor levels modify the effect of polypill treatment on low-density lipoprotein (LDL)-cholesterol, blood pressure (BP), calculated cardiovascular relative risk reduction and adverse events. This paper describes a post-hoc analysis of a randomised, placebo-controlled trial of a polypill (containing aspirin 75 mg, simvastatin 20 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated five-year risk for cardiovascular disease ≥7.5%. The outcomes considered were effect modification by baseline risk factor levels on change in LDL-cholesterol, systolic BP, calculated cardiovascular relative risk reduction and adverse events. The mean LDL-cholesterol in the polypill group was 0.9 mmol/l (95% confidence interval (CI): 0.8-1.0) lower compared with the placebo group during follow-up. Those with a baseline LDL-cholesterol >3.6 mmol/l achieved a greater absolute LDL-cholesterol reduction with the polypill compared with placebo, than patients with an LDL-cholesterol ≤3.6 mmol/l (-1.1 versus -0.6 mmol/l, respectively). The mean systolic BP was 10 mm Hg (95% CI: 8-12) lower in the polypill group. In participants with a baseline systolic BP >135 mm Hg the polypill resulted in a greater absolute systolic BP reduction with the polypill compared with placebo, than participants with a systolic BP ≤ 135 mm Hg (-12 versus -7 mm Hg, respectively). Calculated from individual risk factor reductions, the mean cardiovascular relative risk reduction was 48% (95% CI: 43-52) in the polypill group. Both baseline LDL-cholesterol and estimated cardiovascular risk were significant modifiers of the estimated cardiovascular relative risk reduction caused by the polypill. Adverse events did not appear to be related to baseline risk factor levels or the estimated cardiovascular risk. This study demonstrated that the effect of a cardiovascular polypill on risk factor levels is modified by the level of these risk factors. Groups defined by baseline LDL-cholesterol or systolic BP had large differences in risk factor reductions but only moderate differences in estimated cardiovascular relative risk reduction, suggesting also that patients with mildly increased risk factor levels but an overall raised cardiovascular risk benefit from being treated with a polypill. © The European Society of Cardiology 2016.

Experimental design and statistical analysis for three-drug combination studies.

PubMed

Fang, Hong-Bin; Chen, Xuerong; Pei, Xin-Yan; Grant, Steven; Tan, Ming

2017-06-01

Drug combination is a critically important therapeutic approach for complex diseases such as cancer and HIV due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. One of the key issues is to identify which combinations are additive, synergistic, or antagonistic. While the value of multidrug combinations has been well recognized in the cancer research community, to our best knowledge, all existing experimental studies rely on fixing the dose of one drug to reduce the dimensionality, e.g. looking at pairwise two-drug combinations, a suboptimal design. Hence, there is an urgent need to develop experimental design and analysis methods for studying multidrug combinations directly. Because the complexity of the problem increases exponentially with the number of constituent drugs, there has been little progress in the development of methods for the design and analysis of high-dimensional drug combinations. In fact, contrary to common mathematical reasoning, the case of three-drug combinations is fundamentally more difficult than two-drug combinations. Apparently, finding doses of the combination, number of combinations, and replicates needed to detect departures from additivity depends on dose-response shapes of individual constituent drugs. Thus, different classes of drugs of different dose-response shapes need to be treated as a separate case. Our application and case studies develop dose finding and sample size method for detecting departures from additivity with several common (linear and log-linear) classes of single dose-response curves. Furthermore, utilizing the geometric features of the interaction index, we propose a nonparametric model to estimate the interaction index surface by B-spine approximation and derive its asymptotic properties. Utilizing the method, we designed and analyzed a combination study of three anticancer drugs, PD184, HA14-1, and CEP3891 inhibiting myeloma H929 cell line. To our best knowledge, this is the first ever three drug combinations study performed based on the original 4D dose-response surface formed by dose ranges of three drugs.

Comparison of consolidation strategies in acute myeloid leukemia: high-dose cytarabine alone versus intermediate-dose cytarabine combined with anthracyclines.

PubMed

Kim, Dae Sik; Kang, Ka-Won; Lee, Se Ryeon; Park, Yong; Sung, Hwa Jung; Kim, Seok Jin; Choi, Chul Won; Kim, Byung Soo

2015-09-01

We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard induction regimen (idarubicin and cytarabine 3 + 7). Postremission therapy was performed for three or four cycles according to one of the following regimens: high-dose cytarabine (3 g/m(2)) or combination of intermediate-dose cytarabine (1 g/m(2)) with anthracyclines (idarubicin or mitoxantrone). Among the 443 AML patients enrolled in the registry, 145 patients received consolidation chemotherapy. The median overall survival (OS) and relapse-free survival (RFS) in the high-dose cytarabine group were significantly longer than those in the anthracycline combination group (OS, not reached vs. 16.6 months, p = 0.045; RFS, 38.6 months vs. 11.0 months, p = 0.011). The median duration of neutropenia was longer in the anthracycline combination group than in the high-dose cytarabine group (8 vs. 10 days, p = 0.001). This study suggests that high-dose cytarabine consolidation may produce superior outcomes than combination treatment with intermediate-dose cytarabine and anthracyclines and that the addition of anthracyclines during AML consolidation has limited value as compared to cytarabine intensification.

Effect of combined doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea using rat (Sprague- Dawley) models of conditioned gaping.

PubMed

Rock, Erin M; Limebeer, Cheryl L; Parker, Linda A

2015-12-01

Δ(9)-Tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) found in cannabis both reduce the distressing symptom of nausea, but their combined effects are not understood. The potential of combined doses of THC and CBDA to reduce acute nausea and anticipatory nausea in rodent models was assessed. For acute nausea, the potential of cannabinoid pretreatment(s) to reduce LiCl-induced nausea paired with saccharin was evaluated in a subsequent drug free taste reactivity test, followed by a taste avoidance test. For anticipatory nausea, the potential of the cannabinoid pretreatment(s) to reduce the expression of LiCl-induced contextually elicited conditioned gaping was evaluated. Combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) reduced acute nausea. Higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses also reduced acute nausea. THC (10 mg/kg) interfered with conditioned taste avoidance, an effect attenuated by CBDA (10 μg/kg). On the other hand, combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) did not suppress contextually elicited conditioned gaping in a test for anticipatory nausea. However, higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses, also reduced anticipatory nausea. Only at the highest dose (10 mg/kg) did THC impair locomotor activity, but CBDA did not at any dose. Combined subthreshold doses of THC:CBDA are particularly effective as a treatment for acute nausea. At higher doses, CBDA may attenuate THC-induced interference with learning.

Project C-018H, 242-A Evaporator/PUREX Plant Process Condensate Treatment Facility, functional design criteria. Revision 3

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

Sullivan, N.

1995-05-02

This document provides the Functional Design Criteria (FDC) for Project C-018H, the 242-A Evaporator and Plutonium-Uranium Extraction (PUREX) Plant Condensate Treatment Facility (Also referred to as the 200 Area Effluent Treatment Facility [ETF]). The project will provide the facilities to treat and dispose of the 242-A Evaporator process condensate (PC), the Plutonium-Uranium Extraction (PUREX) Plant process condensate (PDD), and the PUREX Plant ammonia scrubber distillate (ASD).

Assessment of knowledge, attitude, and practices on fixed dose combinations among postgraduate dental students.

PubMed

Vinnakota, Narayana R; Krishna, V; Viswanath, V; Ahmed, Zaheer; Shaik, Kamal S; Boppana, Naveen K

2016-12-01

To assess the knowledge, attitude, and practices of fixed dose combination drugs among postgraduate dental students. A cross-sectional study was carried out among postgraduate dental students of dental colleges in coastal Andhra Pradesh. Three colleges were randomly selected and students of all the three years were included. Data was collected from the specialities of oral medicine and radiology, oral surgery, endodontics, pedodontics, periodontics, and public health dentistry. The total sample was 90 postgraduate students; informed consent was obtained from the participants, and a pretested questionnaire was distributed to them. Data was analyzed using the Statistical Package for the Social Sciences version 20 software. Out of 90 postgraduates, 33 were males and 57 were females. Thirty-five percent were aware of the essential medical list (EML), among them 11% were from oral medicine and radiology and 6.7% were from pedodontics. However, most of them were unaware of the number of fixed dose combination drugs present in the World Health Organization EML. None of them were able to name at least a single banned fixed dose combination drug. Most of them were unaware of the advantages and disadvantages of using fixed dose combination drugs. Amoxicillin with clavulanic acid was the most common drug prescribed by students (73.3%) followed by ofloxacin with ornidazole (54.4%), ibuprofen with paracetamol (53.3%), and sulfamethoxazole with trimethoprim (6%). Most of them were unaware of the rationality in using fixed dose combination drugs. Common sources of information were medical representatives 43 (47.8%), internet 39 (43.3%), and 12 (13.3%) reported using WHO EML. There is an urgent need to improve knowledge on the rationality for using fixed dose combination, EML, and banned fixed dose combination in India to the promote rational use of fixed dose combination.

[Fixed-dose combination fluticasone propionate/formoterol for the treatment of asthma: a review of its pharmacology, efficacy and tolerability].

PubMed

Quintano Jiménez, J A; Ginel Mendoza, L; Entrenas Costa, L M; Polo García, J

2016-02-01

The fixed-dose combination fluticasone propionate/formoterol (FPF) is a novel combination of a widely known and used inhaled glucocorticoid (IGC) and a long-acting β2-adrenergic agonist (LABA), available for the first time in a single device. This fixed-dose combination of FPF has a demonstrated efficacy and safety profile in clinical trials compared with its individual components and other fixed-dose combinations of IGC/LABA and is indicated for the treatment of persistent asthma in adults and adolescents. FPF is available in a wide range of doses that can adequately cover the therapeutic steps recommended by treatment guidelines, constituting a fixed-dose combination of GCI/LABA that is effective, rapid, well tolerated and with a reasonable acquisition cost. Various assessment agencies of the Spanish Autonomous Communities consider this combination to be an appropriate alternative therapy for asthma in the primary care setting. Copyright © 2016 Elsevier España, S.L.U. y Sociedad Española de Medicina Rural y Generalista (SEMERGEN). All rights reserved.

Effectiveness of Ivermectin and Albendazole against Haemonchus contortus in Sheep in West Java, Indonesia.

PubMed

Puspitasari, Silvia; Farajallah, Achmad; Sulistiawati, Erni; Muladno

2016-02-01

Administering a half dose of an anthelmintic is a simple method for detecting resistance in parasites infesting small ruminants. When a single anthelmintic fails in native sheep from Indonesia, a combination of anthelmintics from different chemical classes with different modes of action are administered as an alternative parasite-control strategy. This study compared the anthelmintic efficacy of ivermectin (IVM) and albendazole (ABZ) given either separately as a single dose or half dose or co-administered to sheep naturally infected with Haemonchus contortus. Twelve sheep from Bogor, West Java, Indonesia were divided into the following six treatment groups: half-dose IVM, full-dose IVM, half-dose ABZ, full-dose ABZ, combined IVM + ABZ, and control. The treatment efficacy was determined using the faecal egg count reduction test (FECRT) at day 0 (pre-treatment) and post-treatment at days 7, 14, 21, 28, 35, and 42. The efficacies of half-dose IVM, full-dose IVM, half-dose ABZ, full-dose ABZ, and the combination treatment ranged from -1900% to 100%, 99% to 100%, -167% to 100%, -467% to 89%, and -200% to 100%, respectively. The FECRT for the half-dose IVM, half-dose ABZ, full-dose ABZ showed that H. contortus is resistant to half-dose IVM and ABZ. Full-dose IVM was effective against H. contortus. The combined treatment was more effective against H. contortus than ABZ alone.

Effectiveness of Ivermectin and Albendazole against Haemonchus contortus in Sheep in West Java, Indonesia

PubMed Central

Puspitasari, Silvia; Farajallah, Achmad; Sulistiawati, Erni; Muladno

2016-01-01

Administering a half dose of an anthelmintic is a simple method for detecting resistance in parasites infesting small ruminants. When a single anthelmintic fails in native sheep from Indonesia, a combination of anthelmintics from different chemical classes with different modes of action are administered as an alternative parasite-control strategy. This study compared the anthelmintic efficacy of ivermectin (IVM) and albendazole (ABZ) given either separately as a single dose or half dose or co-administered to sheep naturally infected with Haemonchus contortus. Twelve sheep from Bogor, West Java, Indonesia were divided into the following six treatment groups: half-dose IVM, full-dose IVM, half-dose ABZ, full-dose ABZ, combined IVM + ABZ, and control. The treatment efficacy was determined using the faecal egg count reduction test (FECRT) at day 0 (pre-treatment) and post-treatment at days 7, 14, 21, 28, 35, and 42. The efficacies of half-dose IVM, full-dose IVM, half-dose ABZ, full-dose ABZ, and the combination treatment ranged from −1900% to 100%, 99% to 100%, −167% to 100%, −467% to 89%, and −200% to 100%, respectively. The FECRT for the half-dose IVM, half-dose ABZ, full-dose ABZ showed that H. contortus is resistant to half-dose IVM and ABZ. Full-dose IVM was effective against H. contortus. The combined treatment was more effective against H. contortus than ABZ alone. PMID:27019686

[The best noise index combined with ASIR weighting selection in low-dose chest scanning].

PubMed

Xiao, Huijuan; Hou, Ping; Liu, Jie; Gao, Jianbo; Tan, Hongna; Liang, Pan; Pu, Shi

2015-10-06

To discuss the best noise index combined with ASIR weighting selection in low-dose chest scanning based on BMI. 200 patients collected from May to December 2014 underwent non-contrast chest CT examinations, they were randomly assigned into standard dose group (Group A, NI15 combined with 30% ASIR) and low-dose groups (Group B, NI25 combined with 40% ASIR, Group C, NI30 combined with 50% ASIR, Group D, NI35 combined with 60% ASIR), 50 cases in each group; the patients were assigned into three groups based on BMI (kg/m2): BMI<18.5; 18.5≤BMI≤25; BMI>25. Signal-to-nosie ratio (SNR), contrast-to noise ratio (CNR), CT dose index volume (CTDIvol), dose-length product (DLP), effective dose (ED) and subjective scoring between the standard and low-dose groups were compared and analyzed statistically. Differences of SNR, CNR, CTDIvol, DLP and ED among groups were determined with ANOVA analysis and the consistency of diagnosis with Kappa test. SNR, CTDIvol, DLP and ED reduced with the increase of nosie index, the differences among the groups were statistically significant (P<0.05). Kappa value of the two reviewers were 0.888. Subjective scoring of four groups were all above 3 points in BMI<18.5 kg/m2 group; subjective scoring of ABC groups were all above 3 points in 18.5 kg/m2≤BMI≤25 kg/m2 group and subjective scoring of AB groups were all above 3 points in BMI>25 kg/m2 group. NI35 combined with 60% ASIR in BMI<18.5 kg/m2 group; NI30 combined with 50% ASIR in 18.5 kg/m2≤BMI≤25 kg/m2 group; NI25 combined with 40% ASIR in 18.5 kg/m2≤BMI≤25 kg/m2 group were the best parameters combination which both can significantly reduce the radiation dose and ensure the image quality.

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

PubMed

Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

2014-08-01

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

Orbit Determination and Navigation of the Time History of Events and Macroscale Interactions during Substorms (THEMIS)

NASA Technical Reports Server (NTRS)

Morinelli, Patrick; Cosgrove, Jennifer; Blizzard, Mike; Robertson, Mike

2007-01-01

This paper provides an overview of the launch and early orbit activities performed by the NASA Goddard Space Flight Center's (GSFC) Flight Dynamics Facility (FDF) in support of five probes comprising the Time History of Events and Macroscale Interactions during Substorms (THEMIS) spacecraft. The FDF was tasked to support THEMIS in a limited capacity providing backup orbit determination support for validation purposes for all five THEMIS probes during launch plus 30 days in coordination with University of California Berkeley Flight Dynamics Center (UCB/FDC)2. The FDF's orbit determination responsibilities were originally planned to be as a backup to the UCB/FDC for validation purposes only. However, various challenges early on in the mission and a Spacecraft Emergency declared thirty hours after launch placed the FDF team in the role of providing the orbit solutions that enabled contact with each of the probes and the eventual termination of the Spacecraft Emergency. This paper details the challenges and various techniques used by the GSFC FDF team to successfully perform orbit determination for all five THEMIS probes during the early mission. In addition, actual THEMIS orbit determination results are presented spanning the launch and early orbit mission phase. Lastly, this paper enumerates lessons learned from the THEMIS mission, as well as demonstrates the broad range of resources and capabilities within the FDF for supporting critical launch and early orbit navigation activities, especially challenging for constellation missions.

Orbit Determination and Navigation of the Time History of Events and Macroscale Interactions during Substorms (THEMIS)

NASA Technical Reports Server (NTRS)

Morinelli, Patrick; Cosgrove, jennifer; Blizzard, Mike; Nicholson, Ann; Robertson, Mika

2007-01-01

This paper provides an overview of the launch and early orbit activities performed by the NASA Goddard Space Flight Center's (GSFC) Flight Dynamics Facility (FDF) in support of five probes comprising the Time History of Events and Macroscale Interactions during Substorms (THEMIS) spacecraft. The FDF was tasked to support THEMIS in a limited capacity providing backup orbit determination support for validation purposes for all five THEMIS probes during launch plus 30 days in coordination with University of California Berkeley Flight Dynamics Center (UCB/FDC). The FDF's orbit determination responsibilities were originally planned to be as a backup to the UCB/FDC for validation purposes only. However, various challenges early on in the mission and a Spacecraft Emergency declared thirty hours after launch placed the FDF team in the role of providing the orbit solutions that enabled contact with each of the probes and the eventual termination of the Spacecraft Emergency. This paper details the challenges and various techniques used by the GSFC FDF team to successfully perform orbit determination for all five THEMIS probes during the early mission. In addition, actual THEMIS orbit determination results are presented spanning the launch and early orbit mission phase. Lastly, this paper enumerates lessons learned from the THEMIS mission, as well as demonstrates the broad range of resources and capabilities within the FDF for supporting critical launch and early orbit navigation activities, especially challenging for constellation missions.

Rapid detection of ciprofloxacin effects on Fusarium graminearum and F. avenaceum cells in modulating environmental pH using a reactive, non-toxic food-dye indicator.

PubMed

Yuan, Xiakun; Goh, Yit Kheng; Low, Nicholas; Vujanovic, Vladimir

2011-09-01

The objective of the study was to assess the effect of ciprofloxacin antibiotic on the physiological or phenotypic characteristics of food-borne toxigenic Fusarium graminearum and F. avenaceum molds under in vitro conditions. In the presence of ciprofloxacin, Fusarium mycelia growth and morphology were altered based on the antibiotic concentration range used. Results showed that ciprofloxacin in concentrations ≥40μg/mL induced chlamydospore formation in Fusaria and as such, this antibiotic should be considered as an important abiotic stress factor and growth inhibitor. A novel method was investigated to correlate chlamydospore formation with the colour changes observed in FD&C Green Number 3, a common water soluble food dye. The antibiotic-treated F. graminearum and F. avenaceum isolates produced chamydospores, which in turn altered environmental pH with concomitant changes in the colour and intensity of the dye. The colour changes observed as a function of environmental pH were supported by instrumental methods (pH meter and spectroscopy), and a commercial pH indicator (thymol blue) results. In conclusion, we propose that FD&C Green Number 3 can be used as an accurate indicator for the rapid assessment of Fusarium molds when grown on ciprofloxacin antibiotic-containing substrate. Special emphasis should be given to an indirect risk assessment of antibiotic effects on toxic molds. Copyright © 2011 Elsevier B.V. All rights reserved.

S-Fms signalobody enhances myeloid cell growth and migration.

PubMed

Kawahara, Masahiro; Hitomi, Azusa; Nagamune, Teruyuki

2014-07-01

Since receptor tyrosine kinases (RTKs) control various cell fates in many types of cells, mimicry of RTK functions is promising for artificial control of cell fates. We have previously developed single-chain Fv (scFv)/receptor chimeras named signalobodies that can mimic receptor signaling in response to a specific antigen. While the RTK-based signalobodies enabled us to control cell growth and migration, further extension of applicability in another cell type would underlie the impact of the RTK-based signalobodies. In this study, we applied the scFv-c-Fms (S-Fms) signalobody in a murine myeloid progenitor cell line, FDC-P1. S-Fms transduced a fluorescein-conjugated BSA (BSA-FL)-dependent growth signal and activated downstream signaling molecules including MEK, ERK, Akt, and STAT3, which are major constituents of Ras/MAPK, PI3K/Akt, and JAK/STAT signaling pathways. In addition, S-Fms transduced a migration signal as demonstrated by the transwell-based migration assay. Direct real-time observation of the cells further confirmed that FDC/S-Fms cells underwent directional cell migration toward a positive gradient of BSA-FL. These results demonstrated the utility of the S-Fms signalobody for controlling growth and migration of myeloid cells. Further extension of our approach includes economical large-scale production of practically relevant blood cells as well as artificial control of cell migration for tissue regeneration and immune response. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rational and combinatorial approaches to engineering styrene production by Saccharomyces cerevisiae.

PubMed

McKenna, Rebekah; Thompson, Brian; Pugh, Shawn; Nielsen, David R

2014-08-21

Styrene is an important building-block petrochemical and monomer used to produce numerous plastics. Whereas styrene bioproduction by Escherichia coli was previously reported, the long-term potential of this approach will ultimately rely on the use of hosts with improved industrial phenotypes, such as the yeast Saccharomyces cerevisiae. Classical metabolic evolution was first applied to isolate a mutant capable of phenylalanine over-production to 357 mg/L. Transcription analysis revealed up-regulation of several phenylalanine biosynthesis pathway genes including ARO3, encoding the bottleneck enzyme DAHP synthase. To catalyze the first pathway step, phenylalanine ammonia lyase encoded by PAL2 from A. thaliana was constitutively expressed from a high copy plasmid. The final pathway step, phenylacrylate decarboxylase, was catalyzed by the native FDC1. Expression of FDC1 was naturally induced by trans-cinnamate, the pathway intermediate and its substrate, at levels sufficient for ensuring flux through the pathway. Deletion of ARO10 to eliminate the competing Ehrlich pathway and expression of a feedback-resistant DAHP synthase encoded by ARO4K229L preserved and promoted the endogenous availability precursor phenylalanine, leading to improved pathway flux and styrene production. These systematic improvements allowed styrene titers to ultimately reach 29 mg/L at a glucose yield of 1.44 mg/g, a 60% improvement over the initial strain. The potential of S. cerevisiae as a host for renewable styrene production has been demonstrated. Significant strain improvements, however, will ultimately be needed to achieve economical production levels.

The soil water characteristic as new class of closed-form parametric expressions for the flow duration curve

NASA Astrophysics Data System (ADS)

Sadegh, M.; Vrugt, J. A.; Gupta, H. V.; Xu, C.

2016-04-01

The flow duration curve is a signature catchment characteristic that depicts graphically the relationship between the exceedance probability of streamflow and its magnitude. This curve is relatively easy to create and interpret, and is used widely for hydrologic analysis, water quality management, and the design of hydroelectric power plants (among others). Several mathematical expressions have been proposed to mimic the FDC. Yet, these efforts have not been particularly successful, in large part because available functions are not flexible enough to portray accurately the functional shape of the FDC for a large range of catchments and contrasting hydrologic behaviors. Here, we extend the work of Vrugt and Sadegh (2013) and introduce several commonly used models of the soil water characteristic as new class of closed-form parametric expressions for the flow duration curve. These soil water retention functions are relatively simple to use, contain between two to three parameters, and mimic closely the empirical FDCs of 430 catchments of the MOPEX data set. We then relate the calibrated parameter values of these models to physical and climatological characteristics of the watershed using multivariate linear regression analysis, and evaluate the regionalization potential of our proposed models against those of the literature. If quality of fit is of main importance then the 3-parameter van Genuchten model is preferred, whereas the 2-parameter lognormal, 3-parameter GEV and generalized Pareto models show greater promise for regionalization.

The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis

PubMed Central

Donaldson, David S.; Else, Kathryn J.

2015-01-01

ABSTRACT Prion diseases are infectious neurodegenerative disorders characterized by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally, and following exposure, the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, the relative contributions of the small and large intestinal GALT to oral prion pathogenesis were unknown. To address this issue, we created mice that specifically lacked FDC-containing GALT only in the small intestine. Our data show that oral prion disease susceptibility was dramatically reduced in mice lacking small intestinal GALT. Although these mice had FDC-containing GALT throughout their large intestines, these tissues were not early sites of prion accumulation or neuroinvasion. We also determined whether pathology specifically within the large intestine might influence prion pathogenesis. Congruent infection with the nematode parasite Trichuris muris in the large intestine around the time of oral prion exposure did not affect disease pathogenesis. Together, these data demonstrate that the small intestinal GALT are the major early sites of prion accumulation and neuroinvasion after oral exposure. This has important implications for our understanding of the factors that influence the risk of infection and the preclinical diagnosis of disease. IMPORTANCE Many natural prion diseases are acquired orally. After exposure, the accumulation of some prion diseases in the gut-associated lymphoid tissues (GALT) is important for efficient spread of disease to the brain. However, the relative contributions of GALT in the small and large intestines to oral prion pathogenesis were unknown. We show that the small intestinal GALT are the essential early sites of prion accumulation. Furthermore, congruent infection with a large intestinal helminth (worm) around the time of oral prion exposure did not affect disease pathogenesis. This is important for our understanding of the factors that influence the risk of prion infection and the preclinical diagnosis of disease. The detection of prions within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, our data suggest that using these biopsy specimens may miss individuals in the early stages of oral prion infection and significantly underestimate the disease prevalence. PMID:26157121

Bupropion-varenicline interactions and nicotine self-administration behavior in rats.

PubMed

Hall, Brandon J; Slade, Susan; Wells, Corinne; Rose, Jed E; Levin, Edward D

2015-03-01

Varenicline and bupropion each have been shown to significantly improve cessation of tobacco addiction in humans. They act through different mechanisms and the question about the potential added efficacy with their combined used has arisen. Preclinical animal models of nicotine addiction can help with the evaluation of this combined approach and what dose combinations of varenicline and bupropion may be useful for enhancing tobacco cessation. In this study, we investigated the interacting dose-effect functions of varenicline and bupropion in a rat model of nicotine self-administration. Young adult female Sprague-Dawley rats were allowed to self-administer nicotine in 1-h sessions under an FR1 reinforcement schedule. Varenicline (0.3, 1. 3 mg/kg) and bupropion (8.33, 25, 75 mg/kg) were administered alone or together 15 min before each session. The vehicle saline was the control. Higher doses of each drug alone reduced nicotine self-administration compared to control with reductions of 62% and 75% with 3 mg/kg varenicline and 75 mg/kg bupropion respectively. Lower dose varenicline which does not by itself reduce nicotine self-administration, significantly augmented bupropion effects. The 0.3 mg/kg varenicline dose combined with the 25 and 75 mg/kg bupropion doses caused greater reductions of nicotine self-administration than either dose of bupropion given alone. However, higher dose varenicline did not have this effect. Lower dose bupropion did not augment varenicline effects. Only the high bupropion dose significantly enhanced the varenicline effect. Likewise, combining 1 mg/kg varenicline with 75 mg/kg bupropion reduced self-administration to a greater extent than either dose alone. These results demonstrate that combination therapy with varenicline and bupropion may be more beneficial than monotherapy with either drug alone. Copyright © 2015 Elsevier Inc. All rights reserved.

Synergistic interaction between fentanyl and bupivacaine given intrathecally for labor analgesia.

PubMed

Ngan Kee, Warwick D; Khaw, Kim S; Ng, Floria F; Ng, Karman K L; So, Rita; Lee, Anna

2014-05-01

Lipophilic opioids and local anesthetics are often given intrathecally in combination for labor analgesia. However, the nature of the pharmacologic interaction between these drugs has not been clearly elucidated in humans. Three hundred nulliparous women randomly received 1 of 30 different combinations of fentanyl and bupivacaine intrathecally using a combined spinal-epidural technique for analgesia in the first stage of labor. Visual analogue scale pain scores were recorded for 30 min. Response was defined by percentage decrease in pain score from baseline at 15 and 30 min. Dose-response curves for individual drugs were fitted to a hyperbolic dose-response model using nonlinear regression. The nature of the drug interaction was determined using dose equivalence methodology to compare observed effects of drug combinations with effects predicted by additivity. The derived dose-response models for individual drugs (doses in micrograms) at 15 min were: Effect = 100 × dose / (13.82 + dose) for fentanyl, and Effect = 100 × dose / (1,590 + dose) for bupivacaine. Combinations of fentanyl and bupivacaine produced greater effects than those predicted by additivity at 15 min (P < 0.001) and 30 min (P = 0.015) (mean differences, 9.1 [95% CI, 4.1-14.1] and 6.4 [95% CI, 1.2-11.5] units of the normalized response, respectively), indicating a synergistic interaction. The pharmacologic interaction between intrathecal fentanyl and bupivacaine is synergistic. Characterization and quantification of this interaction provide a theoretical basis and support for the clinical practice of combining intrathecal opioids and local anesthetics.

Efficacy and safety of combination therapy of high-dose losartan and hydrochlorothiazide in patients with hypertension.

PubMed

Shiga, Yuhei; Miura, Shin-Ichiro; Norimatsu, Kenji; Hitaka, Yuka; Nagata, Itsuki; Koyoshi, Rie; Morii, Joji; Kuwano, Takashi; Uehara, Yoshinari; Inoue, Asao; Shirotani, Tetsuro; Fujisawa, Kazuaki; Matsunaga, Eiyu; Saku, Keijiro

2015-12-01

We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day). Forty hypertensive patients who received a combination of high-dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis. The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143±12 mmHg to 126±11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects. Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients. © The Author(s) 2014.

Low-dose atorvastatin, losartan, and particularly their combination, provide cardiovascular protection in isolated rat heart and aorta.

PubMed

Lunder, Mojca; Ziberna, Lovro; Janić, Miodrag; Jerin, Aleš; Skitek, Milan; Sabovič, Mišo; Drevenšek, Gorazd

2013-03-01

Statins and angiotensin receptor blockers at therapeutic doses have beneficial cardiovascular effects, which can be applied for cardiovascular protection. We explored whether low doses of atorvastatin, losartan, and particularly their combination, possess important pleiotropic vasodilatory effects. Wistar rats were treated daily with low-dose atorvastatin (2 mg/kg, n = 15), low-dose losartan (5 mg/kg, n = 15), their combination (n = 15), or saline (n = 15). After 4, 6, or 8 weeks the animals were anesthetized, blood samples taken, and their hearts and thoracic aortas isolated. Two kinds of experiments were performed: the measurement of coronary flow rate after ischemia/reperfusion myocardial injury and endothelium-dependent relaxation of thoracic aorta. In both models, maximal vasodilation activity was obtained in rats treated for 6 weeks. In the ischemia/reperfusion myocardial injury model, coronary flow increased (atorvastatin or losartan 1.9-fold, P < 0.01; combination 2.4-fold, P < 0.001) compared with controls. In the thoracic aorta model, endothelium-dependent relaxation significantly increased only in the combination group compared with the control group (up to 1.4-fold; P < 0.01). Simultaneously, we detected increased anti-inflammatory activity and increased nitric oxide concentration, but no changes in lipids and blood pressure. In a rat model we showed important vasodilatory activity of low-dose atorvastatin, losartan, and particularly their combination. The effects of the low-dose combination were accompanied by, and probably at least partly achieved by, anti-inflammatory and nitric oxide pathways. Overall, these results could be valuable for the development of new vascular protective strategies focusing on a low-dose regimen of statins and sartans, and particularly their combination.

Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe).

PubMed

Kim, Kyung-Jin; Kim, Sang-Hyun; Yoon, Young Won; Rha, Seung-Woon; Hong, Soon-Jun; Kwak, Choong-Hwan; Kim, Weon; Nam, Chang-Wook; Rhee, Moo-Yong; Park, Tae-Ho; Hong, Taek-Jong; Park, Sungha; Ahn, Youngkeun; Lee, Namho; Jeon, Hui-Kyung; Jeon, Dong-Woon; Han, Kyoo-Rok; Moon, Keon-Woong; Chae, In-Ho; Kim, Hyo-Soo

2016-10-01

We aimed to compare the effects of fixed-dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS). This multicenter eight-week randomized double-blind phase III study evaluated the safety and efficacy of fixed-dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid-lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed-dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily). Fixed-dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed-dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%-63%, 37%-43%, and 19%-24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non-DM or non-MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non-DM or MetS vs non-MetS patients. Fixed-dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS. © 2016 The Authors Cardiovascular Therapeutics Published by John Wiley & Sons Ltd.

Phase I/II adaptive design for drug combination oncology trials

PubMed Central

Wages, Nolan A.; Conaway, Mark R.

2014-01-01

Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose–toxicity and dose–efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents. PMID:24470329

Effects of Different Doses of Irbesartan Combined With Spironolactone on Urinary Albumin Excretion Rate in Elderly Patients With Early Type 2 Diabetic Nephropathy.

PubMed

Chen, Yingying; Liu, Peng; Chen, Xia; Li, Yanan; Zhang, Fengmei; Wang, Yangang

2018-05-01

There is a lack of research on the effect of low dose of angiotensin receptor blockers combined with spironolactone, and the effect of high dose of angiotensin receptor blockers alone on the urinary albumin excretion rate (UAER) in elderly patients with early type 2 diabetic nephropathy (DN). We conducted a prospective, randomized, open-label, parallel-controlled study that included 244 elderly patients with early DN and mild-to-moderate essential hypertension. Patients were randomly divided into 4 groups: low-dose irbesartan (group A), high-dose irbesartan (group B), low-dose irbesartan combined with spironolactone (group C) and high-dose irbesartan combined with spironolactone (group D). Changes in UAER, serum potassium and blood pressure were compared. There were no statistical differences in the baseline characteristics among groups. Furthermore, no significant difference in blood pressure before and after treatment was found among different groups. After 72-week treatment, UAER in group D was lower compared to group A and B (P < 0.05). Meanwhile, compared with group B, UAER in group C decreased significantly (P < 0.05). Additionally, significantly higher serum potassium was found in group D compared to other groups (P < 0.05). Also, group D had the highest count of patients who withdrew from the study due to hyperkalemia compared to other groups (P < 0.05). Our results indicate high-dose irbesartan combined with spironolactone may be more efficient in reducing UAER in elderly patients with early DN, but this treatment could cause hyperkalemia. Low-dose irbesartan combined with spironolactone was shown to be safer and more effective in decreasing UAER compared to high-dose irbesartan. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.