RESUMO
Type III phosphatidylinositol-4-kinase beta (PI4KIIIß) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIß inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIIIß in lymphocyte proliferation. Previously proposed functions of PI4KIIIß in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIß inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.
Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Animais , Antivirais/efeitos adversos , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Camundongos , Ratos , Ratos Sprague-DawleyRESUMO
Effects of steady-state rifabutin on the pharmacokinetics of steady-state maraviroc were investigated in fourteen healthy adult female and male volunteers. Maraviroc 300 mg twice daily (BID) was given orally with food for fifteen days. On day six, rifabutin 300 mg once daily (QD, P.O.) was added to the regimen. Formal pharmacokinetic (PK) sampling was performed on days five and fifteen. Individual plasma drug concentration-time data for maraviroc, and rifabutin on day fifteen, were obtained using validated High Performance Liquid Chromatography (HPLC) tandem Mass Spectrometry (MS/MS). Rifabutin steady state exposure was comparable to data in the literature. Maraviroc area under the curve (AUC) and minimum plasma concentration (Clast or Cmin) were reduced by 17% and 30% respectively when co-administered with rifabutin. No unexpected or serious adverse eventsoccurred. Based on the reduced exposure of maraviroc observed in this study, increasing the dose of maraviroc may be studied to normalize its moderately reduced exposure following rifabutin co-administration, a moderate inducer of CYP3A4.
Assuntos
Antibacterianos/farmacocinética , Interações Medicamentosas , Inibidores da Fusão de HIV/farmacocinética , Maraviroc/farmacocinética , Rifabutina/farmacocinética , Adolescente , Adulto , Idoso , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Tecidual , Adulto JovemRESUMO
An atp gene cluster from the extreme acidophile Thiobacillus ferrooxidans was able to complement Escherichia coli F1 unc mutants for growth on minimal medium plus succinate. Complementation with all four E. coli F1 mutants tested was observed and subunits for the F1 portion of the T. ferrooxidans ATP synthase formed a functional association with the F0 subunits of the E. coli enzyme. In addition, a hybrid F1 enzyme in which some units were derived from E. coli and some from T. ferrooxidans was partially functional. No clones capable of complementing E. coli F0 unc mutants were isolated. The nucleotide sequence of the gene cluster was determined and the genes for the F0 and the F1 ATP synthase subunits were found to be physically linked.