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Abstract Methicillin-resistant Staphylococcus aureus (MRSA) infection poses a severe threat to global public health due to its high mortality. Currently, polymyxins are mainly used for the treatment of Gram-negative bacterial-related infection, while exhibiting limited antibacterial activities against Staphylococcus aureus (S. aureus). However, the combination of antibiotics with antibiotic adjuvants is a feasible strategy for the hard-treated infection and toxicity reducing. We will investigate the antibacterial activity of simeprevir (SIM), which treated for genotype 1 and 4 chronic hepatitis C, combined with polymyxins against MRSA through high-throughput screening technology. In our study, the synergistic antibacterial effect of SIM and polymyxins against S. aureus in vitro was found by checkerboard assay and time-growth curve. The cytotoxicity of SIM combined with polymyxin B sulfate [PB(S)] or polymyxin E (PE) in vitro was evaluated using CCK-8, human RBC hemolysis and scratch assays. In addition, we investigated the eradication of biofilm formation of S. aureus by biofilm inhibition assay and the killing of persister cells. Moreover, we evaluated the therapeutic effect and in vivo toxicity of the combination against MRSA in murine subcutaneous abscess model. Furthermore, it was preliminarily found that SIM significantly enhanced the destruction of MRSA membrane by SYTOX Green and DISC3(5) probes. In summary, these results reveal that the therapy of SIM combined with polymyxins (especially PE) is promising for the treatment of MRSA infection.

Hepatitis C virus (HCV) is an RNA virus with a high mutation rate, making it prone to developing resistance. There is currently no vaccine for this disease, and the existing treatments are often costly. Therefore, this study aimed to provide alternative and complementary antiviral options from plant by evaluating the activity of Piper betle (P. betle) against HCV and its combination with existing antiviral drugs, Ribavirin and Simeprevir. The antiviral inhibition was identified by in vitro culture using Huh7it-1 cells and JFH1a HCV. The phytochemistry profile was also determined by Thin Layer Chromatography (TLC) and High-Performance Liquid Chromatography (HPLC). The result showed that the ethanol extract of P. betle had strong activity with an IC50 value of 0.08 ± 0.028 µg/mL. The mechanism of action showed that the extract dominantly inhibited the post-entry steps. Furthermore, the combination of P. betle extract with simeprevir showed higher anti-HCV activity compared to the single use of the drug, but no effect was observed in the combination with ribavirin. The Western blotting analysis showed that the inhibition of NS3 protein levels was in a dosedependent manner. Based on the phytochemistry evaluation, the extract was found to contain flavonoids, polyphenols, and alkaloids. These results suggested that the ethanolic extract of P. betle could be a good candidate for the development of alternative anti-HCV drugs. [ABSTRACT FROM AUTHOR]

Abstract The present work was developed to create three rapid, simple, eco-friendly, cheap spectrophotometric methods for concurrent assay of Sofosbuvir (SOF) and Simeprevir (SMV) in their pure, laboratory prepared mixture and pharmaceutical dosage form with high degree of accuracy and precision. Three methods were developed including iso-absorptive point, ratio subtraction and dual wavelength. The linear range of the proposed methods was 3.0–50.0 and 2.0–50.0 µg mL−1 for SMV and SOF, respectively. The proposed methods were validated according to ICH guidelines in terms of linearity, accuracy, precision, limit of detection and limit of quantitation. The proposed approach is highly simple and the procedure is environmentally green making it suitable for the drug analysis in routine works.

Methicillin-resistant Staphylococcus aureus (MRSA) infection poses a severe threat to global public health due to its high mortality. Currently, polymyxins are mainly used for the treatment of Gram-negative bacterial-related infection, while exhibiting limited antibacterial activities against Staphylococcus aureus (S. aureus). However, the combination of antibiotics with antibiotic adjuvants is a feasible strategy for the hard-treated infection and toxicity reducing. We will investigate the antibacterial activity of simeprevir (SIM), which treated for genotype 1 and 4 chronic hepatitis C, combined with polymyxins against MRSA through high-throughput screening technology. In our study, the synergistic antibacterial effect of SIM and polymyxins against S. aureus in vitro was found by checkerboard assay and time-growth curve. The cytotoxicity of SIM combined with polymyxin B sulfate [PB(S)] or polymyxin E (PE) in vitro was evaluated using CCK-8, human RBC hemolysis and scratch assays. In addition, we investigated the eradication of biofilm formation of S. aureus by biofilm inhibition assay and the killing of persister cells. Moreover, we evaluated the therapeutic effect and in vivo toxicity of the combination against MRSA in murine subcutaneous abscess model. Furthermore, it was preliminarily found that SIM significantly enhanced the destruction of MRSA membrane by SYTOX Green and DISC3(5) probes. In summary, these results reveal that the therapy of SIM combined with polymyxins (especially PE) is promising for the treatment of MRSA infection. [ABSTRACT FROM AUTHOR]

The present work was developed to create three rapid, simple, eco-friendly, cheap spectrophotometric methods for concurrent assay of Sofosbuvir (SOF) and Simeprevir (SMV) in their pure, laboratory prepared mixture and pharmaceutical dosage form with high degree of accuracy and precision. Three methods were developed including iso-absorptive point, ratio subtraction and dual wavelength. The linear range of the proposed methods was 3.0–50.0 and 2.0–50.0 µg mL−1 for SMV and SOF, respectively. The proposed methods were validated according to ICH guidelines in terms of linearity, accuracy, precision, limit of detection and limit of quantitation. The proposed approach is highly simple and the procedure is environmentally green making it suitable for the drug analysis in routine works. [ABSTRACT FROM AUTHOR]

Background and aimsThe advent of direct-acting antiviral agents promises to change the management of hepatitis C virus infection (HCV) in patients with chronic kidney disease (CKD), a patient group in which the treatment of hepatitis C was historically challenging. We investigated the safety and efficacy of all-oral, interferon-free direct-acting antiviral agents for the treatment of hepatitis C in a 'real-world' cohort of patients with CKD.MethodsWe performed an observational single-arm multi-centre study in a large (n=198) cohort of patients with stage 1-3 CKD who underwent antiviral therapy with DAAs for the treatment of HCV. The primary end-point was sustained virologic response (serum HCV RNA

[Display omitted] • Spectrofluorimetric approach resolve velpatasvir and simeprevir overlapped spectra. • The method was validated using ICH guidelines. • Greenness evaluation using AGREE and GAPI metrics. Velpatasvir and simeprevir are two direct acting antivirals that are often used in combination with sofosbuvir to treat HCV infections. Herein, an environmentally benign spectrofluorimetric method was developed for simultaneous quantification of velpatasvir and simeprevir in pharmaceutical and plasma samples. To address the issue of overlapping fluorescence spectra presented by these compounds, this method integrates synchronous fluorescence and second-derivative spectroscopy. By employing the second derivative of the synchronous fluorescence spectra measured at Δλ of 140 nm, the accurate determination of velpatasvir at 400 nm and simeprevir at 426 nm was achieved without any interference. Different experimental parameters affecting the synchronous fluorescence of the studied drugs were carefully optimized. The plots of second-derivative amplitudes against concentrations showed linearity in the range of 5–400 ng/mL for velpatasvir and 80–800 ng/mL for simeprevir. The method was very sensitive, with lower detection limits of 1.11 ng/mL and 25.40 ng/mL, and quantification limits of 3.36 ng/mL and 76.96 ng/mL for velpatasvir and simeprevir, respectively. The method was effectively used to determine velpatasvir and simeprevir simultaneously in their pure forms, pharmaceutical dosage forms, and human plasma with no interference. The suggested technique was additionally evaluated for its eco-friendliness through the utilization of the Analytical GREEnness (AGREE) and Green Analytical Procedure Index (GAPI) evaluation metrics, revealing that the method is indeed sustainable. [ABSTRACT FROM AUTHOR]

Introduction Cirrhosis is a condition in which the liver becomes fibrotic following damage to the liver and transforms the architecture of the organ into regenerative nodules. The disease is caused 30% by HCV infection, resulting in a risk of severe complications and death. Since the use of direct-acting antivirals ( DAAs) for the treatment of chronic HCV, sustained virological response (SVR) rates have begun to increase, even in treatment-resistant cases. Studies have also shown that DAAs may have applications in other viral diseases and even In the treatment of breast cancer. Aim of the study The purpouse of our study was to review scientific articles to show the efficiency and potential use of DAAs in the treatment of chronic HCV, and to identify possible directions for further research. Methods and materials We reviewed the English literature in the PubMed, using the key words: "simeprevir" ; "sofosbuvir" ; "velpatasvir" ; "telaprevir" ; "chronic hepatitis C". Results Studies have shown that the therapeutic regimens currently being designed with (DAAs) offer the possibility of treating almost the entire population with hepatitis C, while reducing side effects of interferon therapy such as increased AST, ALT activities, diarrhoea, vomiting, nausea and depression. They remain effective and tolerable, regardless of the stage of cirrhosis and associated serious co-morbidities. Analysis of studiem shows, that DAAs also show efficacy against other disease such as breast cancer, MRSA infections, SARS-CoV-2 or flavivirus infection. Conclusion All (DAAs) are effective in the treatment of patients with HCV, including cirrhosis. They result in significant improvements in prognosis and clinical outcomes. Promising results have been obtained in published data on the effect of DAAs against disease entities other than HCV, suggesting the rationale for future clinical trials to further the hypothesis of the increased potential of these drugs.

Baseline resistance-associated substitutions (RASs) have variable impacts in clinical trials but their prevalence and impact in real-world patients remains unclear. We performed baseline resistance testing using a commercial assay (10% cutoff) for 486 patients treated with LDV/SOF or SMV/SOF, with or without ribavirin, in the multi-center, observational HCV-TARGET cohort. Linkage of RASs was evaluated in selected samples using a novel quantitative single variant sequencing assay. Our results showed that the prevalence of NS3, NS5A, NS5B RASs was 45%, 13%, and 8%, respectively, and 10% of patients harbored RASs in 2 or more drug classes. Baseline LDV RASs in GT1a, TE, and cirrhosis LDV/SOF subgroup was associated with 2-4% lower SVR12 rates. SMV RASs was associated with lower SVR12 rates in GT1a, treatment-experienced, cirrhotics SMV/SOF subgroup. Pooled analysis of all patients with baseline RASs revealed that SVR12 was 100% (19/19) in patients treated for longer than 98 days but was 87% (81/93) in patients treated for shorter than 98 days. These results demonstrate that RASs prevalence and their impact in real world practice are in general agreement with registration trials, and suggest that longer treatment duration may overcome the negative impact of baseline RASs on SVR12 rates in clinical practice.

Background & aimsRenal clearance is the major elimination pathway for sofosbuvir (SOF). We assessed the safety and efficacy of SOF-containing regimens in patients with varying baseline estimated glomerular filtration rate (eGFR).MethodsHCV-TARGET database is a multicentre, longitudinal 'real-world' treatment cohort.ResultsA total of 1789 patients [genotypes 1 (72%), 2 (17%) 3 (9%), 4-6 (2%)] had baseline eGFR determination: 73 with eGFR≤45 (18 with eGFR≤30, 5 on dialysis) were compared to 1716 with eGFR>45 ml/min/1.73 m(2) . Patients with baseline eGFR≤45 vs. >45 differed in being female (55% vs. 36%), age ≥65 years (24% vs. 16%), Black race (22% vs. 12%), having cirrhosis with decompensation (73% vs. 24%) and being post-transplant (49% vs. 10%), all P < 0.05. All patients with eGFR≤45 were treated with SOF 400 mg/day (including those on haemodialysis) and had median starting ribavirin (RBV) dose of 800 mg (IQR: 400-1200). Sustained virologic response (SVR) frequencies were similar across eGFR groups, ranging from 82-83%. Patients with eGFR ≤45 more frequently experienced anaemia, worsening renal function and serious AEs (all P < 0.05), and these associations persisted when limiting analysis to RBV-free regimens. Patients with baseline eGFR≤30 and eGFR 31-45 had similar frequencies of efficacy and safety outcomes.ConclusionsSustained viral clearance was achieved in 83% of patients with renal impairment (eGFR ≤45 ml/min/1.73 m(2) ) treated with SOF-containing regimens. However, these patients had higher rates of anaemia, worsening renal dysfunction and serious adverse events regardless of use of RBV. Patient with renal impairment require close monitoring and should be treated by providers extensively experienced with SOF-containing regimens.

Background: Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is universal and associated with an accelerated disease course. Second-generation direct-acting antivirals dramatically improve viral clearance. Their use in the Egyptian population in the post-transplant setting needs further evaluation. Objectives: To evaluate the safety and efficacy of sofosbuvir-based regimens in the treatment of HCV recurrence after LT in the Egyptian population. Patients and methods: Sixty patients with HCV recurrence after LT were included. Twenty patients received sofosbuvir (SOF) in combination with ribavirin (RBV) for 24 weeks, 21 patients received SOF and simeprevir (SIM) for 12 weeks and 19 patients received SOF and daclatasvir (DCV) with or without RBV for 12 or 24 weeks according to the stage of liver fibrosis and eligibility for ribavirin. Treatment response and adverse events were analyzed. Results: The mean age was 52.5±7.9 years. Most of patients were males (91.7%). Sustained virological response at week 12 after treatment (SVR12) was achieved in all patients who received SIM/SOF and SOF/DCV±RBV regimens and in 85% of patients who received SOF/RBV regimen. The most common reported adverse events were fatigue, anemia and hyperbilirubinemia. Fatigue was reported in 75% of patients in SOF/RBV group and in 85.7% of patients in SIM/SOF group. Anemia was reported in 15, 4.8 and 10.5% of patients in SOF/RBV, SIM/SOF and SOF/DCV±RBV groups respectively, whereas hyperbilirubinemia was documented in 10% of patients in SOF/SIM group and in 9.5% of patients in SIM/SOF group. Conclusion: Sofosbuvir-based combinations are safe and effective in the treatment of recurrent HCV after LT, especially when combined with another directly acting antiviral. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is a major human pathogen, and the appearance of methicillin-resistant S. aureus (MRSA) renders S. aureus infections more challenging to treat. Therefore, new antimicrobial drugs are urgently needed to combat MRSA infections. Drug repurposing is an effective and feasible strategy. Here, we reported that the clinically approved anti-hepatitis C virus drug simeprevir had strong antibacterial activity against MRSA, with a minimum inhibitory concentration of 2–8 µg/mL. Simeprevir did not easily induce in vitro resistance. In addition, simeprevir significantly prevented S. aureus biofilm formation. Furthermore, simeprevir displayed limited toxicity in in vitro and in vivo assays. Moreover, simeprevir showed synergistic antimicrobial effects against both type and clinical strains of S. aureus. Simeprevir combined with gentamicin effectively reduced the bacterial burden in an MRSA–infected subcutaneous abscess mouse model. Results from a series of experiments, including membrane permeability assay, membrane potential assay, intracellular ATP level assay, and electron microscope observation, demonstrated that the action of simeprevir may be by disrupting bacterial cell membranes. Collectively, these results demonstrated the potential of simeprevir as an antimicrobial agent for the treatment of MRSA infections. Key points: • Simeprevir showed strong antibacterial activity against MRSA. • The antibacterial mechanism of simeprevir was mediated by membrane disruption and intracellular ATP depletion. • In vitro and in vivo synergistic antimicrobial efficacy between simeprevir and gentamicin was found. [ABSTRACT FROM AUTHOR]

Abstract In addition to liver disease, the hepatitis C virus (HCV) has been associated with autoimmune phenomena, such as mixed cryoglobulin and glomerulonephritis (GN). Until recently, both chronic hepatitis and HCV extra-hepatic manifestations were treated with peg-interferon plus ribavirin, however these drugs presented low efficacy and induced severe side effects. Nowadays, the HCV chronic hepatitis has been treated with direct acting antivirals (DAA), but studies on the DAA therapy for HCV-associated glomerulonephritis are scarce. Here, we describe two cases of HCV-associated glomerulonephritis that were treated with DAAs. In these two cases, previously experienced to peg-interferon plus ribavirin, the sofosbuvir plus simeprevir therapy was effective, without significant side effects, and interrupted the evolution of at least 20 years of both hepatic and renal diseases. These cases join the seven previously described cases that were treated with this DAAs association.

HBV/HCV coinfection Viral hepatitis kills over 1 million people annually worldwide, and the majority of these deaths are attributable to chronic infection from either hepatitis B virus (HBV) or hepatitis [...], Treatment for hepatitis C virus (HCV) with direct-acting antivirals (DAAs) in hepatitis B virus (HBV) coinfection can result in HBV reactivation. In this issue of the JCI, Cheng and colleagues explored the role of interferon signaling in the complex interaction between HBV and HCV using cell lines, mouse models, and samples from people with coinfection. Notably, HCV enhanced interferon signaling, as measured by interferon-stimulated gene (ISG) expression, and decreased HBV transcription and replication. Blockade of interferon signaling reversed the effects on HBV replication. Further, pharmacologic inhibition of HCV replication in vitro and in coinfected humanized mice also reduced interferon signaling and, correspondingly, increased HBV replication. Intriguingly, baseline serum levels of the ISG CXCL10 predicted HBV reactivation in a cohort of coinfected people taking DAAs. Determining how interferon signaling silences HBV transcription and whether serum CXCL10 predicts HBV reactivation in a clinical setting are questions that warrant further investigation.

Introduction: In chronic hepatitis C virus (HCV) patients in whom prior direct-acting antiviral agent (DAA) treatment had failed, outcomes after retreatment are optimal. Combination of sofosbuvir (SOF), daclatasvir (DCV), simeprevir (SIM), and ribavirin (RBV) in treatment experienced patients is recommended in current guidelines despite insufficient data. Our aim is to determine the efficacy and safety of SOF, DCV, SIM plus RBV in HCV infected patients who failed prior DAA treatment. Material and methods: One hundred and seventeen patients who failed to respond to SOF containing regimens were randomized according to previous response to therapy to non-responders and relapsers. Duration of therapy depends on fibrosis stages. SOF, DCV, SIM and weight based RBV 12 weeks for F1 and F2 (group I) and 24 weeks for F3 and F4 (group II). Results: In the non-responder group, a sustained virologic response (SVR) occurred in 100% in group I (F1 and F2) and 97% in group II (F3 and F4). Relapse was 3% in group II (F3 and F4). No patients from either group had breakthrough or non-response. In relapsers SVR was 100% in group I (F1 and F2) and 96% in group II (F3 and F4). Breakthrough, relapse and non-response were 2%, 4%, 2% respectively only in group II (F3 and F4). Conclusions: Combining multiple DAAs with different viral targets may be effective treatment protocol in previous non-responders and relapsers with short durations of treatment. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a vector‐borne disease caused by around 20 species of Leishmania. The main clinical forms of leishmaniasis are cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). VL is caused by Leishmania infantum in Central and South America, Mediterranean Basin, Middle East, and by L. donovani in Asia and Africa. Sterol C‐24 methyltransferase (LdSMT) of L. donovani is a transferase enzyme of the sterol biosynthesis pathway. This pathway is one of the major targets for drug developments in Leishmania. Due to insufficient evidence about the exact function of SMT inside the cell and the uniqueness of the SMT enzyme in the Leishmania parasites made it a significant target for an effective drug development approach. We performed virtual screening of the Food and Drug Administration (FDA)‐approved drug library against LdSMT and found simeprevir, an antiviral drug on top in the binding score. It showed a significant binding affinity with LdSMT. The binding was supported by hydrogen bonds and several other interactions. Simeprevir inhibited L. donovani growth of promastigotes with 50% inhibitory concentration (IC50) of 51.49 ± 5.87 μM. Further studies showed that simeprevir induced ROS generation in 44.7% of parasites at 125‐μM concentration. Here, we for the first time reported simeprevir as an antileishmanial lead molecule using a drug repurposing approach. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infection currently remains the leading indication for liver transplant in the United States. However, recurrent HCV infection after transplant is universal in those who enter transplant with viremia resulting in reduced posttransplant graft and patient survival rates, caused in large part by progressive recurrent HCV disease. Therefore, successful treatment of HCV in the peri-transplant period, either before or after transplant, is paramount in ensuring improved posttransplant outcomes. This article reviews the experience to date treating HCV in wait-listed patients and liver transplant recipients and the unique challenges encountered when treating this population.

UnlabelledRisks and benefits of simeprevir plus sofosbuvir (SIM+SOF) in patients with advanced cirrhosis are unknown. We assessed the safety and sustained virological responses (SVR) of SIM+SOF with and without ribavirin (RBV) in patients with Child-Pugh (CP)-B/C versus CP-A cirrhosis and compared to matched untreated controls. This study was of a multicenter cohort of adults with hepatitis C virus genotype 1 and cirrhosis treated with SIM+SOF with/without RBV for 12 weeks. Controls were matched on treatment center, age, CP class, and Model for End-Stage Liver Disease (MELD) score. Of 160 patients treated with SIM+SOF with/without RBV, 35% had CP-B/C and 64% had CP-A, with median baseline MELD 9 (interquartile range, 8-11). Sustained virological response at week 12 (SVR12) was achieved by 73% of CP-B/C versus 91% of CP-A (P