cHepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n ؍ 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n ؍ 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUC) or maximum concentration in plasma (C max ) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R-and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUC for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUC was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments.
Alzheimer's (AD) is a progressive neurodegenerative disease and the most common cause of dementia; 4 million Americans currently suffer from AD. Approved therapies for AD offer modest benefits by enhancing memory and learning, but do not change the course of the disease. A focus on etiology has shifted efforts in drug development from symptomatic treatments to targets that could change the course of the disease. AD is characterized pathologically by the presence of senile plaques, neurofibrillary tangles and neuronal degeneration in specific brain regions. The major component of plaques is a 40-42 amino acid ß-amyloid peptide (Aß). Pathogenic mutations in the β-amyloid precursor protein (β-APP) and presenilin genes, that alter Aβ production and cause AD, provide genetic evidence that ß-APP processing leading to Aß accumulation is an early event in the etiology of the disease. Pharmaceutical companies including Bristol-Myers Squibb have developed drug discovery programs for disease modifying treatments based on lowering Aβ production or accumulation.The generation of Aβ requires cleavage from β-APP by at least two novel proteases. Inhibitors of one of these targets γ-secretase lowers Aβ in vitro and in transgenic animal model. An inhibitor that is potent, orally bioavailable, brain penetrable and nontoxic in vivo is a candidate for clinical development. Successful clinical development of a γ-secretase inhibitor will permit definitive testing of the hypothesis that amyloid causes neurodegeneration in AD. This presentation will focus on the model systems we have used to characterize γ-secretase inhibitors and some examples of compounds that have been discovered. I will also discuss the use of inhibitors in characterizing γ-secretase, a novel membrane bound protease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.