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Gut and Liver Sep 2014The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV), the current therapy for hepatitis C virus (HCV) infection, has saved the lives of many... (Review)
Review
The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV), the current therapy for hepatitis C virus (HCV) infection, has saved the lives of many HCV-infected patients. Direct-acting antivirals (DAAs) target several sites of HCV nonstructural proteins, resulting in the cessation of viral replication. The first NS3/4A protease inhibitors consisted of boceprevir and telaprevir, which have shown superior efficacy against genotype 1 HCV infection when combined with PEG-IFN/RBV compared with the standard therapy in both treatment-naive and -experienced patients. Simeprevir, faldaprevir, and asunaprevir are second-wave, first-generation NS3/4A inhibitors that have already been or will soon be approved. Second-generation protease inhibitors are in clinical trials. Daclatasvir is the first approved DAA belonging to the class of NS5A replication complex inhibitors. The potency of daclatasvir is very high, and this drug is an important and essential component of combination regimens for all genotypes. Sofosbuvir, the first approved NS5B polymerase inhibitor, is characterized by high potency and genetic barriers to resistance. Sofosbuvir combined with RBV achieved an interferon-free regimen in genotype 2 or 3 patients with a reduced treatment duration. It can also be used in combination with PEG-IFN/RBV in genotype 1 patients for 12 weeks. DAAs have provided new hope for curing HCV infections with a short treatment duration and acceptable adverse events.
Topics: Antiviral Agents; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Humans; Protease Inhibitors; Viral Nonstructural Proteins; Virus Replication
PubMed: 25228970
DOI: 10.5009/gnl14083 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jun 2023() is a Gram-positive opportunistic pathogen that often causes hospital infections. With the abuse of antibiotics, the resistance of gradually increases, and drug...
OBJECTIVES
() is a Gram-positive opportunistic pathogen that often causes hospital infections. With the abuse of antibiotics, the resistance of gradually increases, and drug repurposing has become a research hotspot in the treating of refractory drug-resistant bacterial infections. This study aims to study the antimicrobial and antibiofilm effects of simeprevir, an antiviral hepatitis drug, on in vitro.
METHODS
The micro-dilution assay was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of simeprevir against . Crystal violet staining assay was used to detect the biofilm inhibitory effect of simeprevir. The antimicrobial activity of simeprevir against and its biofilm were explored by SYTO9/PI fluorescent staining. The combined effect between simeprevir and gentamycin was assessed by checkerboard assay and was confirmed by time-inhibition assay.
RESULTS
Simeprevir showed significant antimicrobial effects against type strains and clinical isolates with the MIC and MBC at 2-16 μg/mL and 4-32 μg/mL, respectively. The antimicrobial effects of simeprevir were confirmed by SYTO9/PI staining. Simeprevir at MIC could significantly inhibit and break the biofilm on cover slides. Similarly, simeprevir also significantly inhibit the biofilm formation on the surface of urine catheters either in TSB [from (0.700±0.020) to (0.050±0.004)] (=54.03, <0.001), or horse serum [from (1.00±0.02) to (0.13±0.01)] (=82.78, <0.001). Synergistic antimicrobial effect was found between simeprevir and gentamycin against with the fractional inhibitory concentration index of 0.5.
CONCLUSIONS
Simeprevir shows antimicrobial effect and anti-biofilm activities against
Topics: Humans; Simeprevir; Antiviral Agents; Anti-Bacterial Agents; Cross Infection; Gentamicins
PubMed: 37587072
DOI: 10.11817/j.issn.1672-7347.2023.220644 -
World Journal of Hepatology Jun 2015More than twenty years of study has provided a better understanding of hepatitis C virus (HCV) life cycle, including the general properties of viral RNA and proteins.... (Review)
Review
More than twenty years of study has provided a better understanding of hepatitis C virus (HCV) life cycle, including the general properties of viral RNA and proteins. This effort facilitates the development of sensitive diagnostic tools and effective antiviral treatments. At present, serologic screening test is recommended to perform on individuals in the high risk groups and nucleic acid tests are recommended to confirm the active HCV infections. Quantization and genotyping of HCV RNAs are important to determine the optimal duration of anti-viral therapy and predict the likelihood of response. In the early 2000s, pegylated interferon plus ribavirin became the standard anti-HCV treatment. However, this therapy is not ideal. To 2014, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni are approved by Food and Drug Administration for the treat of HCV infections. It is likely that the new all-oral, interferon-free, pan-genotyping anti-HCV therapy will be available within the next few years. Majority of HCV infections will be cured by these anti-viral treatments. However, not all patients are expected to be cured due to viral resistance and the high cost of antiviral treatments. Thus, an efficient prophylactic vaccine will be the next challenge in the fight against HCV infection.
PubMed: 26052383
DOI: 10.4254/wjh.v7.i10.1377 -
Clinical Pharmacokinetics Feb 2016Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the... (Review)
Review
Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug-drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.
Topics: Drug Interactions; Humans; Protease Inhibitors; Simeprevir; Viral Nonstructural Proteins
PubMed: 26353895
DOI: 10.1007/s40262-015-0314-y -
Australian Prescriber Apr 2015
Review
PubMed: 26648621
DOI: 10.18773/austprescr.2015.026 -
International Journal of Molecular... Mar 2015The current treatments for chronic hepatitis C virus (HCV) genotype 1 infection are combinations of direct-acting antivirals, and faldaprevir is one of the new... (Review)
Review
The current treatments for chronic hepatitis C virus (HCV) genotype 1 infection are combinations of direct-acting antivirals, and faldaprevir is one of the new generation of HCV NS3/4A protease inhibitors. At the end of 2013, the US Food and Drug Administration (FDA) approved the HCV NS3/4A protease inhibitor simeprevir and the HCV NS5B polymerase inhibitor sofosbuvir. Simeprevir or sofosbuvir in combination with pegylated interferon and ribavirin are available for clinical use. Faldaprevir, another HCV NS3/4A protease inhibitor that also has fewer adverse events than telaprevir or boceprevir, is under development. Of interest, faldaprevir in combination with pegylated interferon and ribavirin, and interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin provides high sustained virological response rates for HCV genotype 1 infection. The aim of this article is to review these data concerning faldaprevir. Faldaprevir in combination with pegylated interferon and ribavirin treatment appears to be associated with fewer adverse events than telaprevir or boceprevir in combination with pegylated interferon and ribavirin, and may be one of the therapeutic options for treatment-naive patients with HCV genotype 1. The interferon-free combination of faldaprevir and deleobuvir with ribavirin was effective for HCV genotype 1 infection and may hold promise for interferon-ineligible and interferon-intolerant patients.
Topics: Aminoisobutyric Acids; Antiviral Agents; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Leucine; Oligopeptides; Polyethylene Glycols; Proline; Quinolines; Thiazoles; Viral Nonstructural Proteins
PubMed: 25749475
DOI: 10.3390/ijms16034985 -
British Journal of Clinical Pharmacology Feb 2017Several direct-acting antiviral agents (DAAs) have marketing authorization in Europe and in the USA and have changed the landscape of hepatitis C treatment: each DAA has... (Review)
Review
Several direct-acting antiviral agents (DAAs) have marketing authorization in Europe and in the USA and have changed the landscape of hepatitis C treatment: each DAA has its own metabolism and drug-drug interactions (DDIs), and managing them is a challenge. To compile the pharmacokinetics and DDI data of the new DAA and to provide a guide for management of DDI. An indexed MEDLINE search was conducted using the keywords: DAA, hepatitis C, simeprevir, daclatasvir, ledipasvir, sofosbuvir, 3D regimen (paritaprevir/ritonavir, ombitasvir, dasabuvir), DDI and pharmacokinetics. Data were also collected from hepatology, and infectious disease and clinical pharmacology conferences abstracts. Food can play a role in the absorption of DAAs. Most of the interactions are linked to metabolism (cytochrome P450-3 A4 [CYP3A4]) or hepatic and/or intestinal transporters (organic anion-transporting polypeptide and P-glycoprotein [P-gp]). To a lesser extent other pathways can be involved such as breast cancer resistance protein transporter or UDP-glucuronosyltransferase metabolism. DDI are more likely to occur with 3D regimen, daclatasvir, simeprevir and ledipasvir, as they are all both substrates and inhibitors of P-gp and/or CYP3A4, than with sofosbuvir. They can increase concentrations of coadministered drugs and their concentrations may be influenced by P-gp or CYP3A4 inducers or inhibitors. Overdosage or low dosage can be encountered with potent inducers or inhibitors of CYP3A4 or drugs with a narrow therapeutic range. The key to interpret DDI data is a good understanding of the pharmacokinetic profiles of the drugs involved. Their ability to inhibit CYP450-3A4 and transporters (hepatic and/or intestinal) can have significant clinical consequences.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antiviral Agents; Cytochrome P-450 CYP3A; Drug Interactions; Food-Drug Interactions; Hepatitis C, Chronic; Humans; Organic Anion Transporters
PubMed: 27530469
DOI: 10.1111/bcp.13095 -
Transplant International : Official... Feb 2016The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently... (Review)
Review
The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to liver cirrhosis leading to liver transplantation or death, and HCV recurrence still constitutes a major challenge for the transplant team. Antiviral therapy is the only available instrument to slow down this process, although its actual impact on liver histology, in responders and nonresponders, is still controversial. We are now facing a "new era" of direct antiviral agents that is already changing the approach to HCV burden both in the pre- and in the post-liver transplantation settings. Available data on sofosbuvir/ledipasvir and sofosbuvir/simeprevir in patients with decompensated cirrhosis sustain a SVR12 of 89% , but one-third of patients do not clinically improved. The sofosbuvir/ribavirin treatment in stable cirrhotic patients with HCC before liver transplantation is associated with 2% recurrence rate if liver transplantation is performed at least one month after undetectable HCV-RNA is achieved. The treatment of recurrence with the new antiviral drugs is associated with a SVR that ranges between 60 and 90%. In this review, we have focused on the evolution of antiviral therapy for HCV recurrence from the "old" interferon-based therapy to the "new" interferon-free regimens, highlighting useful information to aid the transplant hepatologist in the clinical practice.
Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; RNA, Viral; Recurrence; Tissue Donors
PubMed: 26199060
DOI: 10.1111/tri.12642 -
Revista Espanola de Enfermedades... Oct 2015A simeprevir (SMV)-based regimen has shown promising results in treating chronic hepatitis C virus (HCV) infection. This meta-analysis aimed to assess the efficacy and... (Meta-Analysis)
Meta-Analysis Review
Efficacy and safety of simeprevir in combination with peginterferon and ribavirin for patients with hepatitis C genotype 1 infection: a meta-analysis of randomized trials.
BACKGROUND AND AIM
A simeprevir (SMV)-based regimen has shown promising results in treating chronic hepatitis C virus (HCV) infection. This meta-analysis aimed to assess the efficacy and safety of simeprevir for treating HCV genotype 1 infection.
METHODS
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched, along with the reference lists of retrieved articles. The meta-analysis only included randomized controlled trials (RCTs) that compared the efficacy and safety of addition of SMV to peginterferon (PegIFN) and ribavirin (RBV) (triple regimen) with PegIFN/RBV alone (dual regimen) in treating chronic HCV genotype 1 infection.
RESULTS
A total of seven RCTs involving 2,301 patients were included. The triple regimen had a higher pooled sustained virologic response (SVR) rate [odds ratio (OR) = 4.57; 95% confidence interval (CI): 3.34-6.27; p < 0.001)] and lower pooled relapse rate [relative risk (RR) = 0.41; 95% CI: 0.33-0.50; p < 0.001] than the dual regimen had. The pooled incidence of adverse events (AEs) was comparable between the two regimens (RR = 1.01; 95% CI: 0.99-1.03; p = 0.339), whereas the incidence of serious AEs in the triple regimen was lower (RR = 0.7; 95% CI: 0.50-0.98; p < 0.05).
CONCLUSIONS
The meta-analysis demonstrates that the addition of SMV to pegIFN and RBV is effective and well-tolerated in treating chronic HCV genotype 1 infection, with a low incidence of AEs.
Topics: Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Randomized Controlled Trials as Topic; Ribavirin; Simeprevir
PubMed: 26437977
DOI: 10.17235/reed.2015.3840/2015 -
ACS Central Science May 2021The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health....
The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir . Mechanistically, we showed that simeprevir not only inhibits the main protease (M) and unexpectedly the RNA-dependent RNA polymerase (RdRp) but also modulates host immune responses. Our results thus reveal the possible anti-SARS-CoV-2 mechanism of simeprevir and highlight the translational potential of optimizing simeprevir as a therapeutic agent for managing COVID-19 and future outbreaks of CoV.
PubMed: 34075346
DOI: 10.1021/acscentsci.0c01186