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Ying-Hong Wang, Dapeng Chen, Georgy Hartmann, Carolyn R Cho, Karsten Menzel
Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. In vitro, letermovir is a time-dependent inhibitor and an inducer of cytochrome P450 (CYP)3A, and an inhibitor of CYP2C8 and organic anion transporting polypeptide (OATP)1B. A stepwise approach was taken to qualify the interaction model of an existing letermovir physiologically-based pharmacokinetic (PBPK) model to predict letermovir interactions with CYP3A and OATP1B...
June 14, 2018: Clinical Pharmacology and Therapeutics
Q Wang, H Y Rao, N Yu, S Q Gao, L Wei
Objective: To analyze the comorbidity and concomitant medications use in adult patients with chronic hepatitis C. Methods: A descriptive epidemiological methods was carried out in adult patients with chronic hepatitis C and data from 2013 to 2015 were accessed through the China Medical Insurance database. Results: Among a chronic HCV cohort of 2 958 cases, the top five comorbidities were diabetes, hypertension, ischemic heart disease, gastroduodenitis, and co-infection with HBV and HCV. The three most common concomitant medications prescribed for mentioned comorbidities were acarbose, metformin and repaglinide (Diabetes), nifedipine, amlodipine and metoprolol (Hypertension), aspirin, nifedipine and amlodipine (Ischemic heart disease), omeprazole, pantoprazole and levolfoxacin (Gastroduodenitis), ribavirin, pegylated interferon alpha-2a and alpha-2b ( Co- infected with hepatitis B and C virus)...
March 20, 2018: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
Md Shamsir Alam, Abdul Ahad, Lubna Abidin, Mohd Aqil, Showkat Rasool Mir, Mohd Mujeeb
Embelin is a natural compound possessing a plethora of pharmacological activities, including antidiabetic activity. When formulated as niosomes, embelin offers additional advantages of nanoformulations and can be further exploited for clinical use. An oral niosome formulation of embelin was developed using a thin-film hydration technique, and its antidiabetic activity was studied. The formulation was characterized in terms of entrapment efficiency, vesicle size and morphology, in vitro release profile, and stability...
January 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Yasuyuki Ishii, Yuko Ito, Shunji Matsuki, Kasumi Sanpei, Osamu Ogawa, Kenji Takeda, Edgar L Schuck, Naoto Uemura
BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug-drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2...
May 16, 2018: Clinical and Translational Science
Masahiko Gosho
Hypoglycemia is the most important complication of antidiabetic medications. Most patients with diabetes mellitus take multiple medications. In this study, we explored clinical drug-drug interactions that result in hypoglycemia by analyzing the Japanese Adverse Drug Event Report (JADER) database. The primary outcome was the report of hypoglycemia. The Norén and Gosho methods, which quantitatively measure the discrepancy between the observed and expected number of adverse events under the combination of 2 drugs, were used as the criteria for detecting drug-drug interactions...
May 15, 2018: Journal of Clinical Pharmacology
Qi Pei, Jun-Yan Liu, Ji-Ye Yin, Guo-Ping Yang, Shi-Kun Liu, Yi Zheng, Pan Xie, Cheng-Xian Guo, Mi Luo, Hong-Hao Zhou, Xi Li, Zhao-Qian Liu
PURPOSE: On account of the potential inhibition of OATP1B1 (organic anion transporting polypeptide) by angiotensin II receptor blockers (ARBs) and the effects of SLCO1B1 (solute carrier organic anion transporter family member) polymorphism, the aim of current study is to assess the impact of ARBs on the pharmacokinetics (PK) and pharmacodynamics (PD) of repaglinide in Chinese healthy volunteers with different SLCO1B1 genotypes. METHODS: The in vitro study was conducted on irbesartan, valsartan, olmesartan, and losartan by using HEK293 cells transfected with OATP1B1...
May 11, 2018: European Journal of Clinical Pharmacology
C Purna Chander, B Raju, M Ramesh, G Shankar, R Srinivas
RATIONALE: Stress stability studies of drugs have been recognized as an essential part of the drug development process. These studies are used to investigate the intrinsic stability of the drugs and for the development of a selective stability indicating assay method (SIAM). Stress testing is also useful for the formulation and packaging development, shelf-life determination and designing of manufacturing processes. As per regulatory guidelines, stress degradation studies and structural characterization should be carried out to establish degradation pathways of the drug, which is essential from both efficacy and safety point of view...
May 3, 2018: Rapid Communications in Mass Spectrometry: RCM
Tom de Bruyn, Ayse Ufuk, Carina Cantrill, Rachel E Kosa, Yi-An Bi, Mark Niosi, Sweta Modi, A David Rodrigues, Larry M Tremaine, Manthena Vs Varma, Aleksandra Galetin, J Brian Houston
This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV, respectively...
May 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Zhenhai Shang, Feifei Han, Xueyan Zhou, Zejun Bao, Jing Zhu, Tao Wang, Qian Lu, Lei Du, Wei Li, Dongmei Lv, Xiaoxing Yin
Post-Market Research We aimed to investigate the impact of G protein-coupled receptor kinase 5 (GRK5) rs10886471 polymorphism on repaglinide efficacy in Chinese patients with type 2 diabetes mellitus (T2DM). A total of 300 T2DM patients and 210 healthy controls were genotyped for GRK5 rs10886471 on a three-dimensional polyacrylamide gel-based DNA microarray. Eighty-five patients with the same genotypes of cytochrome P450 (CYP) 2C8*3 139Arg and organic anion-transporting polypeptide 1B1 (OATP1B1) 521TT were randomly selected to orally take repaglinide for eight consecutive weeks...
May 2018: Drug Development Research
Hea-Young Cho, Lien Ngo, Sang-Ki Kim, Yoonho Choi, Yong-Bok Lee
OBJECTIVE: 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. MATERIALS AND METHODS: 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...
June 2018: International Journal of Clinical Pharmacology and Therapeutics
Harumi Takahashi, Shihomi Hidaka, Chihiro Seki, Norihide Yokoi, Susumu Seino
The dynamics of insulin secretion stimulated by repaglinide, a glinide, and the combinatorial effects of repaglinide and incretin were investigated. At 4.4 mM glucose, repaglinide induced insulin secretion with a gradually increasing first phase, showing different dynamics from that induced by glimepiride, a sulfonylurea. In the presence of glucagon-like peptide-1 (GLP-1), insulin secretion by repaglinide was augmented significantly but to lesser extent and showed different dynamics from that by glimepiride...
June 5, 2018: European Journal of Pharmacology
Alejandro López-Hurtado, Daniel F Burgos, Paz González, Xose M Dopazo, Valentina González, Alberto Rábano, Britt Mellström, Jose R Naranjo
The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a multifunctional neuronal calcium sensor (NCS) that controls Ca2+ and protein homeostasis through gene regulation and protein-protein interactions. Downregulation of DREAM is part of an endogenous neuroprotective mechanism that improves ATF6 (activating transcription factor 6) processing, neuronal survival in the striatum, and motor coordination in R6/2 mice, a model of Huntington's disease (HD). Whether modulation of DREAM activity can also ameliorate cognition deficits in HD mice has not been studied...
March 9, 2018: Molecular Brain
Antonio Rodriguez-Poncelas, Joan Barrot-de la-Puente, Gabriel Coll de Tuero, Carles López-Arpí, Bogdan Vlacho, Flora Lopéz-Simarro, Xavier Mundet Tudurí, Josep Franch-Nadal
AIM: The aim of this study was to assess glycaemic control and prescribing practices of antihyperglycaemic treatment in patients with diabetes mellitus type 2 aged 75 years or older. METHODS: We analysed data from health electronic records from 4,581 persons attended at primary healthcare centres of the Institut Català de la Salut (ICS), in the Girona Sud area of Catalonia, Spain, during 2013 and 2016. Variables such as age, gender, body mass index (BMI), diabetes duration, age at diabetes diagnosis, glycated haemoglobin (HbA1c), creatinine, glomerular filtrate rate and the albumin/creatinine ratio in urine were collected...
March 2018: International Journal of Clinical Practice
Jade Huguet, Fleur Gaudette, Veronique Michaud, Jacques Turgeon
1. The objective of our study was to develop and validate a cocktail approach to allow the simultaneous characterization of various CYP450-mediated oxidations by human heart microsomes for nine probe drug substrates, namely, 7-ethoxyresorufin, bupropion, repaglinide, tolbutamide, bufuralol, chlorzoxazone, ebastine, midazolam and dodecanoic acid. 2. The first validation step was conducted using recombinant human CYP450 isoenzymes by comparing activity measured for each probe drug as a function of (1) buffer used, (2) selectivity towards specific isoenzymes and (3) drug interactions between probes...
March 8, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
James Harrison, Tom De Bruyn, Adam S Darwich, J Brian Houston
Hepatocyte drug depletion-time assays are well established for determination of metabolic clearance in vitro. The present study focuses on the refinement and evaluation of a "media loss" assay, an adaptation of the conventional depletion assay involving centrifugation of hepatocytes prior to sampling, allowing estimation of uptake in addition to metabolism. Using experimental procedures consistent with a high throughput, a selection of 12 compounds with a range of uptake and metabolism characteristics (atorvastatin, cerivastatin, clarithromycin, erythromycin, indinavir, pitavastatin, repaglinide, rosuvastatin, saquinavir, and valsartan, with two control compounds-midazolam and tolbutamide) were investigated in the presence and absence of the cytochrome P450 inhibitor 1-aminobenzotriazole and organic anion transporter protein inhibitor rifamycin SV in rat hepatocytes...
April 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Kosuke Doki, Adam S Darwich, Brahim Achour, Aleksi Tornio, Janne T Backman, Amin Rostami-Hodjegan
AIMS: Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolizing enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 intercorrelation on the predicted interindividual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically based pharmacokinetic (PBPK) modelling. METHODS: PBPK modelling and simulation were employed using Simcyp Simulator (v15.1). Virtual populations were generated assuming intercorrelations between hepatic CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers...
May 2018: British Journal of Clinical Pharmacology
Wafaa S Abo-Elseoud, Mohammad L Hassan, Magdy W Sabaa, Mona Basha, Enas A Hassan, Shaimaa M Fadel
The aim of the present work was to study the use of cellulose nanocrystals (CNC) and chitosan nanoparticles (CHNP) for developing controlled-release drug delivery system of the anti-hyperglycemic drug Repaglinide (RPG). CNC was isolated from palm fruit stalks by sulfuric acid hydrolysis; the dimensions of the isolated nanocrystals were 86-237 nm in length and 5-7 nm in width. Simple and economic method was used for the fabrication of controlled release drug delivery system from CNC and CHNP loaded with RPG drug via ionic gelation of chitosan in the presence of CNC and RPG...
May 2018: International Journal of Biological Macromolecules
Manfred Ballmann, Dominique Hubert, Baroukh M Assael, Doris Staab, Alexandra Hebestreit, Lutz Naehrlich, Tanja Nickolay, Nicole Prinz, Reinhard W Holl
BACKGROUND: As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. METHODS: We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy...
February 2018: Lancet Diabetes & Endocrinology
Charles E Leonard, Xu Han, Colleen M Brensinger, Warren B Bilker, Serena Cardillo, James H Flory, Sean Hennessy
PURPOSE: To examine and compare risks of serious hypoglycemia among antidiabetic monotherapy-treated adults receiving metformin, a sulfonylurea, a meglitinide, or a thiazolidinedione. METHODS: We performed a retrospective cohort study of apparently new users of monotherapy with metformin, glimepiride, glipizide, glyburide, pioglitazone, rosiglitazone, nateglinide, or repaglinide within a dataset of Medicaid beneficiaries from California, Florida, New York, Ohio, and Pennsylvania...
January 2018: Pharmacoepidemiology and Drug Safety
Shao-Lian Wang, Wen-Bin Dong, Xiao-Lin Dong, Wen-Min Zhu, Fang-Fang Wang, Fang Han, Xin Yan
We performed a network meta-analysis to compare the efficacy of 12 single-drug regimens (Glibenclamide, Glimepiride, Pioglitazone, Rosiglitazone, Repaglinide, Metformin, Sitaglitin, Exenatide, Liraglutide, Acarbose, Benfluorex, and Glipizide) in the treatment of type 2 diabetes mellitus (T2DM). Fifteen relevant randomized controlled trials (RCTs) were included; direct and indirect evidence from these studies was combined, and weighted mean difference (WMD) and surface under the cumulative ranking curves (SUCRAs) were examined to evaluate the monotherapies...
September 22, 2017: Oncotarget
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