Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) develops persistent infection in most infected patients, and eventually cause chronic hepatitis, liver cirrhosis and then hepatocellular carcinoma. The combination therapy of PEG-IFN and ribavirin improves the efficacy in many patients, while it does not lead to sufficient achievements in genotype1b patients. To invent new anti-HCV reagent, we focused on host factors which HCV take advantage of in its life-cycle. We identified serine palmitoyltransferase inhibitor as anti-HCV reagent through high-through put screenig using HCV replicon cells. Moreover, we evaluate the anti-HCV effect of SPT-inhibitor in vivo with humanized chimeric mice. SPT-inhibitor led to rapid decline in serum HCV-RNA of about 1-2log within 8 day, futhermore the combination therapy of SPT-inhibitor and PEG-IFN achieved about 3log reduction in serum HCV-RNA. At last, we investigated the mechanism of anti-HCV effect of SPT-inhibitor. It has been reported that sphingolipids and cholesterol compose the lipid raft, in which the replication of HCV occur. We investigated the influence of SPT-inhibitor to lipid rafts by analysing the detergent resistant membrane (DRM). The analysis proved that SPT inhibitor got HCV RNA dependent RNA polymerase (NS5B) to move to detergent soluble fraction from DRM, and Biacore analysis indicated the binding of sphingomyelin to NS5B. These results suggested SPT inhibitor got NS5B to release from replication complex.
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PMID:[Suppression of hepatitis C virus with the reagent targetting host factors]. 1937 99

Previous studies provided a direct experimental evidence for the contribution of HCV core protein in the development of insulin resistance (IR), but the clinical impact of HCV core region on IR is still not clear. The present study evaluated the impact of Amino acid (aa) substitutions of HCV-1b core region on IR in 123 Japanese patients infected with HCV-1b without cirrhosis and diabetes mellitus, and investigated the treatment efficacy of 48-week pegylated interferon (PEG-IFN) plus ribavirin (RBV) according to HOMA-IR values. Patients with IR (HOMA-IR > or = 2.5) and severe IR (HOMA-IR > or = 3.5) were present in 51.2% and 27.6%, respectively. Multivariate analysis identified body mass index (> or = 25 kg/m(2)) and hepatocyte steatosis (> or = 5%) as significant determinants of IR. Furthermore, multivariate analysis identified hepatocyte steatosis (> or = 5%), aa substitutions of the core region (Gln70 (His70) and/or Met91), and age (> or = 55 years) as significant determinants of severe IR. Especially, significantly lower proportions of patients with Gln70 (His70) and/or Met91 were noted among those without severe IR (59.6%) than those with severe IR (82.4%). The rates of sustained virological response in patients with IR (50.0%) were not significantly different from those without IR (52.9%). Furthermore, the rates of non-virological response in patients with IR (28.9%) were not significantly also different from those without IR (20.6%). In conclusion, the present study indicated that substitutions of HCV-1b core region were the important predictor of severe IR in patients without cirrhosis and diabetes mellitus, but HOMA-IR values might be not useful as predictors of 48-week PEG-IFN plus RBV therapy.
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PMID:Amino acid substitutions in the hepatitis C virus core region of genotype 1b are the important predictor of severe insulin resistance in patients without cirrhosis and diabetes mellitus. 1938 70

Data concerning the efficacy of PEG-IFN alpha 2a plus ribavirin treatment in treatment-naive, genotype 4-infected chronic hepatitis C (CHC) patients from Europe are limited. Hence the aim of this study was to investigate the viral kinetics as well as the sustained virological response (SVR) rates and their predictors, in these patients. One hundred and twenty-three patients were retrospectively analysed. Early (EVR) and late virological response (LVR) was confirmed by undetectable (<50 IU/mL) serum HCV-RNA at week 12 and week 24 of treatment, respectively. SVR was confirmed by undetectable serum HCV-RNA at the end of treatment as well as 6 months later. Overall, 43.5% of patients exhibited SVR, 42.6% were nonresponders and 13.9% were relapsers. EVR was observed in 40.74% and LVR in 59.25% of them. The positive predictive values of EVR and LVR were 72.97% and 86.27% whereas their negative predictive values were 64.29% and 92.85%, respectively. EVR independently predicted SVR in Caucasian patients (P < 0.001) but not in Egyptian patients (P = 0.613), in whom the only independent predictor of SVR was the absence of cirrhosis (P = 0.004). LVR seems to be a better predictor of SVR than EVR in the vast majority of genotype 4-infected CHC patients, irrespective of ethnicity and all the other baseline parameters.
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PMID:Differential viral kinetics in treated genotype 4 chronic hepatitis C patients according to ethnicity. 1941 97

Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 200 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or PEG-interferon alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only approximately 50% of the patients showing sustained virological response. We recently disclosed the discovery of Boceprevir, SCH 503034 (1), which is a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been shown to be efficacious in humans and is currently undergoing clinical trials. As second generation compounds, we have further explored various novel structures with the aim of improving enzyme and cellular binding activities of 1. Herein, we disclose our efforts toward the identification of a novel P(3) sulfonamide-capped inhibitor that demonstrated improved binding and cellular activity compared to 1. X-ray structure of one of these inhibitors bound to the enzyme revealed a hydrogen bond of the P(3) sulfonamide group to Cys-159 which resulted in improved binding and cellular potency.
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PMID:Discovery of novel P3 sulfonamide-capped inhibitors of HCV NS3 protease. Inhibitors with improved cellular potencies. 1948 46

Hepatitis C virus (HCV) infection remains a large-scale and significant health concern. The combination of subcutaneously administered pegylated interferon and oral ribavirin is the FDA-approved regimen for the treatment of chronic HCV infection. Combination therapy may result in a sustained virologic response leading to HCV eradication, with a reduction in risk for cirrhosis, hepatic decompensation, and hepatocellular carcinoma. However, the combination of PEG-IFN and ribavirin does not universally result in cure in all patients who undergo treatment. In this article, the authors discuss immunomodulatory therapies and clinical trials in the treatment of HCV infection.
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PMID:Hepatitis C virus infection and immunomodulatory therapies. 1962 56

TMC-435, being developed by Tibotec Pharmaceuticals Ltd, is an orally administered, macrocyclic inhibitor of the HCV NS3/4A serine protease. HCV infection can cause chronic hepatitis, cirrhosis of the liver and hepatocellular carcinoma. The HCV NS3/4A enzyme is an essential component for viral replication, suggesting that this protein is a key therapeutic target. Biochemical assays demonstrated potent inhibition of HCV NS3/4A by TMC-435 in all HCV genotypes tested, with the exception of HCV-3. In cellular replicon models, the compound selectively inhibited HCV-1 replication and displayed additive effects with ribavirin, and had synergistic activity with IFNalpha and an NS5B polymerase inhibitor. Pharmacokinetic data demonstrated high exposure and good oral bioavailability, supporting once-daily dosing of TMC-435 in humans. In phase I and II clinical trials, the administration of TCM-435 to patients infected with HCV-1, alone or in combination with PEG-IFNalpha and ribavirin, produced significant reductions in HCV-RNA without any significant adverse effects, thus providing a basis for further development of this compound as an anti-HCV therapeutic agent. At the time of publication, phase II trials with TMC-435 were ongoing.
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PMID:TMC-435, an NS3/4A protease inhibitor for the treatment of HCV infection. 1964 31

Consensus interferon (CIFN) is an artificially engineered interferon that reflects most of the human genotype 1 interferons and shows a higher biological and antiviral capacity in vitro. It has been used internationally to treat patients with chronic hepatitis C (HCV) infection before pegylated IFN became available. To mimic the half-life of PEG-IFN it has to be administered on a daily basis. The gold standard in the treatment of hepatitis C is well established and recommended. Today patients are being treated with a combination therapy of pegylated IFN and ribavirin. Length and dosage of therapy depends on the genotype of the virus. Patients with genotype 1 and 4 and high viral load should be treated for 48 weeks; for patients with these genotypes along with either low viral load or early virological response, therapy for 24 weeks is sufficient. Patients with genotype 2 and 3 should be treated for up to 24 weeks. However, daily dosing of IFN-alpha, eg, CIFN, resulting in a higher cumulative dosage, might be beneficial and more efficacious in some chronic HCV-infected patients. Patients with genotype 1, having initially high viral load (>800,000 IU/mL) and showing advanced liver disease with progressive fibrosis or even cirrhosis comprise the difficult-to-treat in order to overcome the infection. This review summarizes and critically discusses the published data on the treatment of HCV with CIFN.
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PMID:Review of consensus interferon in the treatment of chronic hepatitis C. 1970 44

Aberrant squamous cell carcinoma antigen (SCCA) expression is an early event in hepatocarcinogenesis, and increasing serum levels of SCCA variants IgM immune complexes (SCCA-IgM IC) have been found in cirrhotic patients developing hepatocellular carcinoma (HCC). We longitudinally evaluated a cohort of cirrhotic patients with hepatitis C virus infection (HCV) who underwent pegylated interferon (PEG-IFN) and ribavirin treatment. SCCA-IgM IC levels were assessed in the sera of 33 cirrhotic patients with HCV (21 males, median age 57 years) before, at the end and at 6-month and 1-year follow-up after treatment with PEG-IFN and ribavirin. SCCA-IgM IC serum levels (arbitrary units/mL, AU/mL) were evaluated according to treatment outcome: sustained virological response (SVR) vs nonresponse (NR). Overall, 15 patients obtained a SVR to antiviral therapy (45%). There was no significant difference in baseline SCCA-IgM IC serum levels between SVR and NR patients. When compared to baseline (451.2 AU/mL), SVR patients showed a significant decrease in median SCCA-IgM IC serum levels at the end of treatment (186.8 AU/mL, P = 0.013) and at both 6-month (96.8 AU/mL, P < 0.001) and 1-year follow-up (52.4 AU/mL, P < 0.001), while no significant modification was observed in NR patients. In patients with HCV-related liver cirrhosis, successful antiviral therapy is associated with a dramatic and significant decrease in SCCA-IC serum levels. Because of the pathophysiological correlation between SCCA and liver carcinogenesis, it is hypothesized that in patients with liver cirrhosis, SVR may be accompanied by a decreased proliferative stimulation.
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PMID:Successful antiviral therapy determines a significant decrease in squamous cell carcinoma antigen-associated (SCCA) variants' serum levels in anti-HCV positive cirrhotic patients. 1984 Mar 64

Hepatitis C virus (HCV) persists chronically in most infected patients, eventually causing chronic hepatitis, liver cirrhosis, and in some cases hepatocellular carcinoma. The combination therapy of PEG-IFN and ribavirin improves efficacy in many patients, although it does not lead to sufficient achievements in genotype 1b patients. To aid in invention of new anti-HCV reagents, we focused on host factors that contributed to HCV lifecycle. We identified serine palmitoyltransferase inhibitor as an anti-HCV reagent through high-throughput screening using HCV replicon cells. We investigated the mechanism of anti-HCV effect of SPT inhibitor. It has been reported that sphingolipids and cholesterol compose the lipid raft where replication of HCV occurs. We investigated the influence of SPT inhibitor to lipid rafts by analyzing the detergent-resistant membrane (DRM). The analysis showed that SPT inhibitor moved HCV RNA-dependent RNA polymerase (NS5B) to detergent-soluble fraction from DRM, and Biacore analysis indicated binding of sphingomyelin to NS5B. These results suggest that SPT inhibitor disrupts the interaction between NS5B and sphingomyelin. Moreover, we evaluated the anti-HCV effect of SPT inhibitor in vivo with humanized chimeric mice. SPT inhibitor led to rapid decline in serum HCV-RNA of about 1-2 log within 8 days. Furthermore, combination therapy of SPT inhibitor and PEG-IFN achieved about 3 log reduction in serum HCV-RNA.
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PMID:[Suppression of hepatitis C virus (HCV) replication with serine palmitoyltransferase inhibitor]. 2011 37

Treatment results of hepatitis C have improved markedly during the last years with the combination pegylated interferons and ribavirin. The indications for evaluation for therapy is positive HCV-PCR and lack of contraindications for treatment. Liver biopsy is considered only for those with suspicion of other concomitant liver disease or in patients, where retreatment is considered. The length of therapy is individualised and based on rapid virological response in both genotype 2/3 and in genotype 1. Patients with genotype 2/3 with negative HCV-PCR at week 4 and younger than 40 years are treated for 12 weeks only with 80-90 % response rate. In Finland some 70 % of the patients with genotype 2/3 can successfully be treated with 12 weeks therapy. In genotype 1 patients with rapid virological response, regardless of age are treated for 24 weeks. Treatment is discontinued for those, who are still positive at week 24. Early intervention with tailored combination therapy before cirrhosis has developed improves treatment results, patient's overall prognosis and reduces cost of medication and surveillance. New protease inhibitors, telaprevir and boceprevir combined with PEG-interferons and ribavirin might be a future option for those not achieving early virological response.
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PMID:[When and how should hepatitis C be treated?]. 2040 8


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