RESUMEN
A series of acyclovir-resistant mutants of varicella zoster virus (VZV) were selected in vitro by serial passage of VZV-infected human fibroblasts in increasing drug concentrations, or by continuous exposure of cultures infected at high multiplicity to 100 microM acyclovir. The in vitro susceptibility of these mutants to several antiherpetic agents was measured by the plaque-reduction assay. The capacity of extracts of cells infected with these mutants to phosphorylate acyclovir was examined and compared with that of their acyclovir-sensitive parent strains. Based on these studies, VZV could be shown to acquire resistance to acyclovir through diminished acyclovir phosphorylation. This was presumable due to loss of viral specific thymidine kinase (TK) function. Two acyclovir-resistant mutants remained TK competent but demonstrated phenotypic changes in sensitivity to antiviral agents known to act at the herpes simplex virus (HSV)-specific DNA polymerase level. These results suggest that the resistance of VZV to acyclovir results from qualitative or quantitative alterations in the virus-specified TK or DNA polymerase.
Asunto(s)
Antivirales/farmacología , Guanina/análogos & derivados , Herpesvirus Humano 3/efectos de los fármacos , Aciclovir , ADN Polimerasa Dirigida por ADN/metabolismo , Farmacorresistencia Microbiana , Guanina/metabolismo , Guanina/farmacología , Herpesvirus Humano 3/enzimología , Herpesvirus Humano 3/genética , Mutación , Fosforilación , Timidina Quinasa/metabolismoRESUMEN
The uptake, distribution, and anabolism of the nucleoside analog 9-(2-hydroxyethoxymethyl) guanine (acyclovir) were compared in herpes simplex virus-infected and uninfected mice. Analyses of tissue distribution and the concentration of acyclovir after either a single dose or multiple doses failed to reveal significant differences between drug levels in infected and uninfected animals. Extracts of tissues from [8-14C] acyclovir-treated animals were examined by high-performance liquid chromatography to detect the presence of any phosphorylated forms of the drug. The sensitivity of this method did not allow a reproducible demonstration of acyclovir anabolism in herpes simplex virus-infected tissues owing to the low numbers of infected cells per organ.
Asunto(s)
Antivirales/metabolismo , Guanina/análogos & derivados , Herpes Simple/metabolismo , Aciclovir , Animales , Encéfalo/metabolismo , Femenino , Guanina/metabolismo , Herpes Simple/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos , Distribución TisularRESUMEN
Carteolol, a nonselective beta-adrenergic antagonist with intrinsic sympathomimetic activity, was compared in 1% and 2% topical solutions with 0.5% timolol in 105 patients with primary open-angle glaucoma. In this double-masked, randomized 3-month trial, all three preparations significantly lowered intraocular pressure throughout the study, with no significant differences being observed. There were also no significant differences among the three preparations with regard to ocular or systemic adverse reactions, including heart rate and blood pressure.