Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Scand J Gastroenterol ; 43(9): 1122-7, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18609142

RESUMO

OBJECTIVE: Neopterin is a marker of monocyte/macrophage activity. Alanine aminotransferase (ALAT) is a marker of hepatocyte injury. The aim of this study was to determine changes in neopterin and ALAT levels, as markers of inflammation, in two ancillary studies during two-phase 1b trials of hepatitis C virus (HCV) NS3.4A protease inhibitor telaprevir (VX-950), with or without peginterferon alfa-2a (Peg-IFN). MATERIAL AND METHODS: Fifty-four chronic hepatitis C patients (genotype 1) received placebo or telaprevir, with or without Peg-IFN, for 14 days in two multiple-dose studies. RESULTS: During administration of telaprevir, every patient demonstrated a >2-log decrease in HCV RNA. Mean neopterin and ALAT levels decreased in all four groups receiving telaprevir alone. In contrast, mean neopterin levels increased and ALAT levels decreased in the Peg-IFN plus telaprevir and Peg-IFN plus placebo groups. CONCLUSIONS: These data suggest that treatment of chronic hepatitis C patients with an HCV NS3.4A protease inhibitor ameliorates inflammation. The increase in neopterin levels and the decrease in ALAT levels during administration of Peg-IFN with or without telaprevir are in accordance with earlier observations showing that IFN reduces hepatocyte injury but increases monocyte/macrophage activity. The IFN-mediated immunomodulatory effects appear to remain intact when IFN is combined with telaprevir.


Assuntos
Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Mediadores da Inflamação/sangue , Interferon-alfa/administração & dosagem , Oligopeptídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Alanina Transaminase/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C Crônica/diagnóstico , Humanos , Interferon alfa-2 , Testes de Função Hepática , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neopterina/sangue , Proteínas Recombinantes , Valores de Referência , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Resultado do Tratamento , Proteínas não Estruturais Virais
2.
Hepatology ; 46(3): 640-8, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17879366

RESUMO

UNLABELLED: Telaprevir (VX-950), an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, substantially decreased plasma HCV RNA levels in a prior clinical study. The present study evaluated viral kinetics and safety during dosing with telaprevir alone and in combination with peginterferon alfa-2a for 14 days. Previously untreated patients with genotype 1 hepatitis C were randomized to receive placebo and peginterferon alfa-2a (n = 4); telaprevir (n = 8); or telaprevir and peginterferon alfa-2a (n = 8). Telaprevir was given as 750 mg oral doses every 8 hours; peginterferon alfa-2a was given as weekly 180 mug subcutaneous injections. The median change in HCV RNA from baseline to day 15 was -1.09 log(10) (range, -2.08 to -0.46) in the placebo and peginterferon alfa-2a group; -3.99 log(10) (range, -5.28 to -1.26) in the telaprevir group, and -5.49 log(10) (range, -6.54 to -4.30) in the telaprevir and peginterferon alfa-2a group. Day 15 HCV RNA levels were undetectable in 4 patients who received telaprevir and peginterferon alfa-2a and in 1 patient who received telaprevir alone. No viral breakthrough occurred in patients who received telaprevir and peginterferon alfa-2a. The majority of adverse events were mild. There were no serious adverse events or premature discontinuations. Twelve weeks after starting off-study standard therapy, HCV RNA was undetectable in all 8 patients in the telaprevir and peginterferon alfa-2a group, 5 patients in the telaprevir group, and 1 patient in the placebo and peginterferon alfa-2a group. CONCLUSION: This study confirmed the substantial antiviral effects of telaprevir and showed an increased antiviral effect of telaprevir combined with peginterferon alfa-2a.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Oligopeptídeos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adolescente , Adulto , Alanina Transaminase/sangue , Antivirais/efeitos adversos , Antivirais/farmacocinética , Feminino , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interferon-alfa/farmacocinética , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacocinética , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , RNA Viral/sangue , Proteínas Recombinantes , Transaminases/sangue
3.
J Hepatol ; 47(4): 476-83, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17629590

RESUMO

BACKGROUND/AIMS: While combination of peginterferon-alpha (PEG-IFN) and ribavirin (RBV) therapy is the current standard of care for chronic hepatitis C (CHC), only 44-51% of genotype-1 patients achieve a sustained virological response (SVR), and both agents produce treatment-limiting toxicities. In the hepatitis C virus (HCV) replicon system, merimepodib (MMPD), a novel, selective inhibitor of inosine monophosphate dehydrogenase, has shown potent antiviral effects. METHODS: This randomized, placebo-controlled, double-blind study evaluated the safety and antiviral activity of PEG-IFN-alpha2b and RBV combined with either placebo, 25mg MMPD every 12h (q12h), or 50mg MMPD q12h in interferon-alpha (IFN) and RBV nonresponders. After 24 weeks of treatment, subjects with undetectable HCV RNA were proposed to continue assigned treatment for up to 24 additional weeks. RESULTS: The PEG-IFN-alpha, RBV, and MMPD combination was well tolerated at both doses. After 24 weeks, the proportion of HCV RNA undetectable subjects was 8/11 (73%) in the 50-mg MMPD group, 2/10 (20%) in the 25-mg MMPD group, and 3/10 (30%) in the placebo group (P=0.02, Jonckheere-Terpstra test for increasing dose response). Ten subjects entered and completed an extension study, at Week 48, 2 of 2 (100%) of the 25-mg and 3 of 5 (60%) of the 50-mg subjects remained HCV RNA undetectable, compared with 3 of 3 (100%) of the placebo subjects. At Follow-up Week 24, 2 (100%) of the 25-mg , and 1 (25%) of the 50-mg subjects remained undetectable, compared with 1 (33%) of the placebo subjects. Pharmacokinetic and pharmacodynamic analyses showed a correlation between MMPD exposure and early virological response at week 12, but not with hemoglobin decreases often associated with RBV. CONCLUSIONS: In conclusion, PEG-IFN-alpha2b and RBV combined with 50 mg MMPD q12h was well tolerated and induced virological response with undetectable HCV RNA in IFN-alpha and RBV nonresponders.


Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Carbamatos/farmacocinética , Carbamatos/farmacologia , Quimioterapia Combinada , Feminino , Hepacivirus/isolamento & purificação , Humanos , Interferon alfa-2 , Interferon-alfa/farmacocinética , Interferon-alfa/farmacologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Placebos , Polietilenoglicóis , RNA Viral/sangue , Proteínas Recombinantes , Ribavirina/farmacocinética , Ribavirina/farmacologia , Resultado do Tratamento
4.
Gastroenterology ; 131(4): 997-1002, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17030169

RESUMO

BACKGROUND & AIMS: VX-950 specifically inhibits the NS3.4A protease of hepatitis C and has antiviral activity in vitro. This phase I, placebo-controlled, double-blind study evaluated the antiviral activity, pharmacokinetics, and safety of VX-950 in patients with chronic hepatitis C (CHC). METHODS: Thirty-four patients with genotype 1 CHC were randomized to receive placebo or VX-950 at doses of 450 mg or 750 mg every 8 hours or 1250 mg every 12 hours for 14 days. Of the 34 participants, 27 (79%) had failed prior treatment. Patients were monitored for safety and tolerability of VX-950. Plasma VX-950 concentrations and HCV RNA levels were measured. RESULTS: VX-950 was well tolerated and had substantial antiviral effects: viral loads dropped > or =2 log(10) in all 28 patients treated with VX-950 and > or =3 log(10) in 26 (93%) of the 28 patients. In the 750-mg-dose group, which had the highest trough plasma drug concentrations, the median reduction of HCV RNA was 4.4 log(10) after 14 days. In the 450-mg and 1250-mg groups, the maximal effect was seen between days 3 and 7 of dosing, and median HCV RNA increased between days 7 and 14; median reductions at day 14 were 2.4 log(10) and 2.2 log(10), respectively. Median alanine aminotransferase levels decreased during dosing in all VX-950 groups. CONCLUSIONS: VX-950 was well tolerated and demonstrated substantial antiviral activity. Some patients had viral breakthrough during dosing, related to selection of variants with decreased sensitivity to VX-950. The results support further studies of VX-950 in patients with CHC.


Assuntos
Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/administração & dosagem , RNA Viral/sangue , Inibidores de Serina Proteinase/administração & dosagem , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Feminino , Hepacivirus/genética , Hepatite C Crônica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacocinética , Placebos , Inibidores de Serina Proteinase/efeitos adversos , Inibidores de Serina Proteinase/farmacocinética , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...