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Protease, Polymerase, and Assembly Inhibitors for the Treatment of Hepatitis C Virus Infection
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Marianne Martinello, Jason Grebely, Gregory Dore
CYP3A is involved in the elimination of asunaprevir. Therefore, moderate or strong inducers of CYP3A may decrease the plasma levels of asunaprevir, and moderate or strong inhibitors of CYP3A may increase the plasma levels of asunaprevir. Asunaprevir is also a substrate of PGP. OATP1B1 and OATP2B1 are involved in the liver distribution of asunaprevir. Therefore, strong inhibitors of OATP-mediated transport may increase the plasma concentrations of asunaprevir and may decrease its therapeutic effect by reducing distribution to the liver. Clinically relevant examples of OATP inhibitors include ritonavir (OATPB1/B3/A2), atazanavir (OATPB1/B3), cyclosporine A (OATP1B1/B3/A2, OATP2B1), rifampicin (OATP1B1/B3, OATP2B1), lovastatin (OATP1BI), pravastatin (OATP1BI), and simvastatin (OATP1BI) (International Transporter, et al., 2010; Karlgren et al. 2012). Up-to-date drug–drug interaction information can be accessed via hep-druginteractions.org.
An overview of the recent progress in Middle East Respiratory Syndrome Coronavirus (MERS-CoV) drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Several broad-spectrum anti-CoV drugs were repurposed from hepatitis C (HCV) agents [84]. Asunaprevir had IC50 values of 31 to 53.9 µM against different strains of CoVs, suggesting a broad-spectrum application for the drug. F0213 was found to be a broad-spectrum inhibitor that inhibited the PLpro of MERS-CoV and SARS-CoV1 and 2 [32]. F0213 is a competitive inhibitor of MERS-PLpro and binds to the 271E position. F0213 inserts itself into the shallow gap between the α7 and β8 residues of MERS-PLpro, leading to a change in the conformation. In addition to its inhibitory properties, it promoted host immunity by suppressing the deubiquitinating activity of PLpro. However, in the case of SARS-2-PLpro, F0213 became bound to the BL2 loop instead of the cleft between the α7 and β8 residues of MERS-PLpro. Therefore, it blocked the entrance of the substrate at the active site. Hence, F0213 could be utilized as a potential antiviral drug against a broad range of CoVs.
Effectiveness and safety of chronic hepatitis C treatment with direct-acting antivirals in patients with rheumatic diseases: A case-series
Published in Modern Rheumatology, 2020
Takashi Kida, Atsushi Umemura, Shunya Kaneshita, Risa Sagawa, Takuya Inoue, Shogo Toyama, Makoto Wada, Masataka Kohno, Ryo Oda, Tohru Inaba, Yoshito Itoh, Yutaka Kawahito
The SVR rate at EoT24 for the first course of DAA therapy was 89% (16/18). After starting DAAs, all patients showed undetectable HCV-RNA by week 8; however, the reappearance of HCV-RNA was observed in two patients treated with daclatasvir + asunaprevir against HCV genotype 1b. Reappearance in one patient occurred during treatment (a patient with RA treated with sulfasalazine; DAAs were discontinued at week 16), so-called ‘virological breakthrough’, and reappearance in the other patient occurred 4 weeks after EoT (a patients with systemic lupus erythematosus (SLE) treated with tacrolimus and prednisolone), so-called ‘virological relapse’. Both patients received a second course of DAA therapy using a different regimen, and achieved SVR during the study period (see Supplementary Table S1, available with the online version of this article). Regarding these two patients, data from the second course of DAA therapy were used for analyses when evaluating the effect of HCV elimination.
Managing HCV treatment failure and the potential of resistance testing in informing second-line therapy options
Published in Expert Review of Anti-infective Therapy, 2018
Elisabetta Loggi, Ranka Vukotic, Pietro Andreone
More specifically, first-generation NS3 inhibitors (asunaprevir, paritaprevir, simeprevir) showed high antiviral potency, but low genetic barrier to resistance. Both these features have been significantly improved by the most recent NS3/4 inhibitors, such as grazoprevir, glecaprevir and voxilaprevir. From the experience gained on first-generation protease inhibitors (PI), we learned that crucial sites with low barrier to resistance are located in certain aminoacidic positions (V36, T54, S122, R155, A156, D168). The individual resistance profile of the new PI showed that they became more effective against some of the variants known to have resistance to first-generation PI. However, NS3 RASs have been observed at failure with the second-generation drugs, particularly in genotype 1a [6,10].