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Clinical Nephrology Jan 2021Hepatitis C virus (HCV) infection has been associated with several extrahepatic adverse clinical outcomes, including an accelerated rate of loss of kidney function in...
Hepatitis C virus (HCV) infection has been associated with several extrahepatic adverse clinical outcomes, including an accelerated rate of loss of kidney function in patients with chronic kidney disease (CKD) and an increased mortality in patients with CKD and kidney failure on hemodialysis. Clinical trials using direct-acting antiviral (DAA) agents have uniformly achieved sustained viral response at 12 weeks (SVR) rates of > 90% in the general population as well as in patients with CKD/kidney failure on hemodialysis. Sofosbuvir is a DAA prodrug that is phosphorylated into the active metabolite GS-461203, with subsequent dephosphorylation into the inactive metabolite GS-331007. The kidneys clear both sofosbuvir and GS-331007, and its use has been associated with worsening kidney function in some studies. In the HCV-TARGET study, patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min at the initiation of sofosbuvir-based therapy had higher rates of deterioration of kidney function compared to patients with higher eGFR [1]. However, based on recent data demonstrating safety in patients with advanced CKD, the US Food and Drug Administration (FDA) approved the use of sofosbuvir-containing regimens in patients with CKD 4/5 (eGFR of less than 30 mL/min/1.73m) and end-stage renal disease (ESRD) in late 2019. The current report describes 8 HCV-infected patients who developed acute kidney injury (AKI) with biopsy-proven acute interstitial nephritis (AIN) temporally associated with the use of DAAs. The mean age of the group was 61.3 (± 6 years). The most common HCV genotype (GT) was 1a (n = 7). The DAA formulations were sofosbuvir/ledipasvir (n = 5), elbasvir/grazoprevir (n = 2), and sofosbuvir/simeprevir (n = 1). All patients achieved an SVR. The mean serum creatinine at the initiation of DAA treatment was 1.5 mg/dL (± 0.6) and increased to 2.03 mg/dL (± 0.7) by the last day of DAA administration. The kidney biopsies were performed at a mean of 320 days (± 247) after achieving an SVR, at which point the mean creatinine had increased to 2.3 mg/dL (± 1.4). All patients received a course of high-dose corticosteroids after the diagnosis of AIN was confirmed by biopsy. Serum creatinine levels at 3 and 6 months following the completion of steroid therapy were 2.8 (± 1.2) and 3.1 mg/dL (± 1.5), respectively. Three patients had worsening CKD and progressed to kidney failure requiring hemodialysis. These results are consistent with earlier studies demonstrating the efficacy of the DAAs in HCV-infected CKD patients. Of note, the demonstration of AIN in these patients may explain some of the AKI events reported with the use of DAAs in patients with CKD.
Topics: Acute Disease; Acute Kidney Injury; Aged; Antiviral Agents; Drug Therapy, Combination; Female; Hepatitis C; Humans; Male; Middle Aged; Nephritis, Interstitial; Retrospective Studies; Sofosbuvir
PubMed: 32909545
DOI: 10.5414/CN110276 -
Journal of Chromatographic Science May 2021A high-performance thin-layer chromatographic method was developed and validated for the concurrent determination of simeprevir (SMV) and sofosbuvir (SOF). The...
Feasible TLC-Spectro-Densitometry Technique for Simultaneous Determination of Two Hepatitis C Antiviral Drugs, Sofosbuvir and Simeprevir: Application to Combined Pharmaceutical Dosage Forms and Human Plasma.
A high-performance thin-layer chromatographic method was developed and validated for the concurrent determination of simeprevir (SMV) and sofosbuvir (SOF). The chromatographic separation was attained on silica gel 60 F254 as stationary phase and ethyl acetate-hexane-methanol (5.0:4.0:1.0, v/v/v) as developing solvent with UV detection at 273 nm. The RF values were 0.67±0.02 and 0.43±0.02 for SMV and SOF, respectively. The method has been validated in respect to the guidelines of the International Conference on Harmonization. Linearity was maintained between 60-1,000 and 70-1,200 ng/band for SMV and SOF, respectively, with good correlation coefficients (0.9993-0.9997) for both drugs. The suggested method was highly sensitive as the calculated detection limits were 15 and 22 ng/band, while the quantitation limits were 44 and 66 ng/ band for SMV and SOF, respectively. The suggested methodology has been effectively employed for the determination of the mentioned drugs in their pure forms and their pharmaceutical dosage forms as well as human plasma without significant interference of the pharmaceutical excipients or plasma components.
Topics: Antiviral Agents; Capsules; Chromatography, Thin Layer; Densitometry; Hepatitis C; Humans; Limit of Detection; Simeprevir; Sofosbuvir
PubMed: 33822903
DOI: 10.1093/chromsci/bmab034 -
Immunologic Research Jun 2020Anti-rods and rings (anti-RR) antibody induction is related to the combination of interferon and ribavirin in the treatment of hepatitis C virus (HCV) infection. If the... (Observational Study)
Observational Study
Anti-rods and rings (anti-RR) antibody induction is related to the combination of interferon and ribavirin in the treatment of hepatitis C virus (HCV) infection. If the main factor leading to this autoimmune reaction is the combination of these drugs, is not well known, but in vitro studies shows that ribavirin alone can induce rods and rings structures. New direct-acting antivirals (DAAs) permit HCV treatment without needing interferon but may be associated with ribavirin in the most difficult-to-treat patients. The aim of this study is to evaluate the occurrence of anti-RR in patients with chronic HCV infection, before and after 12 weeks of treatment with DAAs, with and without ribavirin. From Jun 2016 to Oct 2017, 52 HCV-infected patients were screened for anti-RR before and after DAA therapy, including sofosbuvir, daclatasvir, simeprevir, and ribavirin. Serum samples were analyzed using indirect immunofluorescence. The anti-RR was present in 11 (21%) of the 52 patients (51.9% male and mean age of 59.1 years) before using DAAs. All of them had been previously treated and previous exposed to interferon/ribavirin, with exposure time to ribavirin associated with the presence of anti-RR. After 12 weeks of DAA treatment, 3 patients (5.7%) developed the antibody in low titers, and two of them (66%) were interferon/ribavirin experienced. Only one of the 29 naïve patients (3.44%) developed anti-RR during the current treatment. Anti-RR was present in patients previously treated with interferon/ribavirin and can emerge after DAA treatment probably at a lower frequency than after interferon/ribavirin treatment.
Topics: Aged; Antibodies, Antinuclear; Antiviral Agents; Carbamates; Drug Therapy, Combination; Female; Fluorescent Antibody Technique, Indirect; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferon-alpha; Male; Middle Aged; Pyrrolidines; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response; Valine
PubMed: 32537670
DOI: 10.1007/s12026-020-09136-6 -
Journal of Biomolecular Structure &... 2023The use of US FDA-approved drugs is preferred due to the need for lower costs and less time. In medicine, repurposing is a quick and accurate way to screen US...
The use of US FDA-approved drugs is preferred due to the need for lower costs and less time. In medicine, repurposing is a quick and accurate way to screen US FDA-approved medications to find a therapeutic option for COVID-19 infection. Dual inhibitors possess dual inhibitory activity, which may be due to the inhibition of two different enzymes, and are considered better than combination therapy from the developmental and clinical perspectives. In this study, a molecular docking simulation was performed to identify the interactions of antiviral drugs with the critical residues in the binding site of the main SARS-CoV-2 protease, spike glycoprotein, and papain-like protease receptors compared to the angiotensin-converting enzyme-related carboxypeptidase (ACE2) receptor of host cells. Each of the receptors was docked with 70 US FDA-approved antiviral drugs using AutoDock Vina. A molecular dynamics (MD) simulation study was also used for 100 ns to confirm the stability behaviour of the ligand receptor complexes. Among the drugs that had the strongest interaction with the SARS-CoV-2 main protease, spike glycoprotein and papain-like protease receptors, and host cell ACE2 receptors, Simeprevir, Maraviroc and Saquinavir had dual inhibitory effects. The MD simulation study confirmed the stability of the strongest interactions between the antiviral drugs and the main protease, ACE2, spike glycoprotein, and papain-like protease receptors to 100 ns. However the results of MMPBSA analysis showed that the bond between Saquinavir and the ACE2 receptor was weak. Simeprevir and Maraviroc drugs had acceptable binding energies with dual receptors, especially the Simeprevir.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Antiviral Agents; Simeprevir; SARS-CoV-2; Saquinavir; Angiotensin-Converting Enzyme 2; Molecular Dynamics Simulation; Maraviroc; Molecular Docking Simulation; Papain; COVID-19; Peptide Hydrolases; Glycoproteins; Protease Inhibitors
PubMed: 35876061
DOI: 10.1080/07391102.2022.2103735 -
Physical Chemistry Chemical Physics :... Jun 2021The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell after the receptor binding domain (RBD) of the virus spike (S) glycoprotein...
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell after the receptor binding domain (RBD) of the virus spike (S) glycoprotein binds to the human angiotensin-converting enzyme 2 (hACE2). This binding requires the RBD to undergo a conformational change from a closed to an open state. In the present study, a key pair of salt bridges formed by the side chains of K537 and E619, residues at the interfaces of SD1 and SD2, respectively, was identified to promote the opening of the RBD. Mutations of K537Q and E619D reduced their side chain lengths and eliminated this pair of salt bridges; as a result, the opening of the RBD was not observed in the MD simulations. Thus, blocking the formation of this pair of salt bridges is a promising approach for treating novel coronavirus disease 2019 (COVID-19). FDA approved drug molecules were screened by their capabilities of blocking the formation of the key pair of salt bridges, achieved by their positional stabilities in the cavity containing the side chains of K537 and E619 formed in the interface between SD1 and SD2. Simeprevir, imatinib, and naldemedine were identified to possess the desired capability with the most favorable interaction energies.
Topics: Antiviral Agents; Drug Design; Drug Evaluation, Preclinical; Humans; Imatinib Mesylate; Molecular Docking Simulation; Naltrexone; Protein Domains; SARS-CoV-2; Simeprevir; Spike Glycoprotein, Coronavirus
PubMed: 34008647
DOI: 10.1039/d1cp01045j -
Scientific Reports Aug 2020The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread...
The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.
Topics: Aminopyridines; Angiotensin-Converting Enzyme 2; Benzodioxoles; Betacoronavirus; Binding Sites; COVID-19; Computational Biology; Coronavirus Infections; Drug Discovery; Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Protein Conformation; Protein Domains; Protein Interaction Maps; SARS-CoV-2; Simeprevir; Spike Glycoprotein, Coronavirus
PubMed: 32807895
DOI: 10.1038/s41598-020-70863-9 -
Journal of Gastroenterology and... Sep 2020Various all-oral direct-acting antiviral (DAA) regimens are being widely used in the treatment of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIM
Various all-oral direct-acting antiviral (DAA) regimens are being widely used in the treatment of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients; however, the comparative efficacy and safety of different types and combinations of DAAs are not completely clear. There is still a lack of integration of evidence for optimized therapies for HIV/HCV co-infection.
METHODS
We conducted a systematic literature search in several databases up to January 1, 2020. All the studies that reported the sustained virologic response (SVR) and adverse events of DAAs in HIV/HCV co-infected patients were included. The Bayesian Markov Chain Monte Carlo method was used for the pooled estimates of network meta-analysis.
RESULTS
We identified 33 eligible articles with 7 combinations of all-oral DAAs for the analyses of efficacy and safety. Grazoprevir-elbasvir ± ribavirin (GZR/EBR ± RBV: 95.6%; 95% CrI, 91.7-98.1%), ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin (3D ± RBV: 95.3%; 95% CrI, 93.4-96.9%), sofosbuvir-ledipasvir ± ribavirin (SOF/LDV ± RBV: 95.2%; 95% CrI, 93.7-96.6%), and sofosbuvir-daclatasvir ± ribavirin (SOF/DCV ± RBV: 94.8%; 95% CrI, 92.5-96.6%) were the most effective combinations for HIV/HCV co-infected patients, with SVR rates of approximately 94% and above while severe adverse events were rare. However, the SVR rates of sofosbuvir-ribavirin (SOF/RBV) and sofosbuvir-simeprevir ± ribavirin (SOF/SMV ± RBV) both failed to reach 90%, and the incidences of adverse events were higher than 5%.
CONCLUSIONS
Efficacy and safety of all-oral DAAs were in prospect for HIV/HCV co-infection patients. GZR/EBR ± RBV was the optimal combination recommended for HIV/HCV co-infected patients based on the excellent treatment effects and insignificant adverse events.
Topics: Administration, Oral; Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Ribavirin; Safety; Sulfonamides; Sustained Virologic Response; Treatment Outcome
PubMed: 32246857
DOI: 10.1111/jgh.15051 -
F1000Research 2022Medicinal plants are potential resources for isolating drug candidates. Various plants have been reported to possess pharmacological effects including anti-hepatitis C...
Medicinal plants are potential resources for isolating drug candidates. Various plants have been reported to possess pharmacological effects including anti-hepatitis C activities. The current study examined the anti-hepatitis C virus (HCV) activities of extracts in solvents with various polarities and further evaluated the mechanism of action of the extracts using Western blotting and combination treatment models. The leaves of were extracted in two phases, first in ethanol and then in solvents with different polarities (n-hexane, dichloromethane, and methanol). HCV-infected Huh7it-1 cells were treated with the extracts at concentrations of 0.01, 0.1, 1, 10, 50, and 100 µg/mL. The results revealed the strong anti-HCV activities of the extracts. The 50% inhibition concentrations (IC s) of the ethanol, n-hexane, dichloromethane and methanol extracts were of 4.6 ± 0.3, 2.9 ± 0.2, 0.2 ± 0.3, and 2.8 ± 0.2 μg/mL, respectively, and no cytotoxic effect was detected. These extracts displayed stronger effects than the positive control ribavirin. The mode of action of the ethanol extract was evaluated at 30 µg/mL, revealing that the inhibitory effect was stronger on the post-entry step than on the entry step. Western blotting revealed that the extracts decreased NS3 protein expression, indicating that virus replication was suppressed. Further evaluation illustrated that combined treatment with the ethanol extract enhanced the anti-viral activity of simeprevir. These results indicated that leaves could represent sources of anti-HCV agents.
Topics: Plant Extracts; Acacia; Hepacivirus; Methanol; Methylene Chloride; Solvents; Hepatitis C; Ethanol
PubMed: 38046541
DOI: 10.12688/f1000research.124947.3 -
Journal of Gastroenterology Jun 2020The efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and...
JNJ-4178 (adafosbuvir, odalasvir, and simeprevir) in Japanese patients with chronic hepatitis C virus genotype 1 or 2 infection with or without compensated cirrhosis: the Phase IIa OMEGA-3 study.
BACKGROUND
The efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis.
METHODS
In this Phase IIa, open-label, multicenter study-OMEGA-3 (NCT02993250)-patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs).
RESULTS
Overall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%) experienced AEs compared with Cohort 1 (68.2%), but the incidence of treatment-related AEs was similar. Most AEs were mild-to-moderate in severity and no patients discontinued due to an AE. There was one serious AE (cataract) in a patient in Cohort 2, which was not considered related to treatment. All patients achieved sustained virologic response 12 weeks after EOT (SVR12). No incidences of viral relapse were observed during follow-up.
CONCLUSIONS
In HCV GT1- and GT2-infected Japanese patients, treatment with JNJ-4178 was well tolerated and resulted in 100% of patients achieving SVR12.
Topics: Adult; Aged; Alanine; Antiviral Agents; Benzimidazoles; Carbamates; Drug Combinations; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Japan; Liver Cirrhosis; Male; Middle Aged; Phosphoramides; Simeprevir; Sustained Virologic Response; Treatment Outcome; Uridine
PubMed: 32065330
DOI: 10.1007/s00535-020-01672-0 -
Spectrochimica Acta. Part A, Molecular... Oct 2020Simeprevir (SMV) is commonly co-administered with ledipasvir (LDS) and sofosbuvir (SOF) as an effective combination regimen for treatment naive hepatitis C virus...
Micelle sensitized synchronous spectrofluorimetric approaches for the simultaneous determination of simeprevir and ledipasvir: Application to pharmaceutical formulations and human plasma.
Simeprevir (SMV) is commonly co-administered with ledipasvir (LDS) and sofosbuvir (SOF) as an effective combination regimen for treatment naive hepatitis C virus infected patients. In the present study, two spectrofluorimetric approaches were combined together for the development of highly sensitive, rapid, simple and accurate method for simultaneous quantification of SMV and LDS. The native fluorescence intensity values of SMV and LDS were enhanced by the addition of Tween-80 micellar system, while second derivative of the synchronous fluorescence intensity of the drugs at Δλ = 120 nm enabled the determination of both drug concomitantly. Different experimental parameters affecting the synchronous fluorescence of the cited drugs were carefully evaluated for their optimization. The peak amplitudes of the second derivative synchronous fluorimetry were measured at 429 nm for SMV and at 417 nm for LDS. The fluorescence-concentration plots were rectilinear over the range of 60-1500 and 36-540 ng mL with lower detection limits of 9.0 and 6.0 ng mL and quantification limits of 27.0 and 17.0 ng mL for SMV and LDS respectively. The method was successfully applied for the determination of both drugs in their pure forms as well as their pharmaceutical products and human plasma without any significant interference. Statistical comparison with the reported method revealed excellent accuracy and precision of the proposed method.
Topics: Benzimidazoles; Drug Compounding; Fluorenes; Humans; Micelles; Simeprevir; Spectrometry, Fluorescence
PubMed: 32474370
DOI: 10.1016/j.saa.2020.118471