RESUMO
The hydroxy metabolites of rimantadine (3-5) were synthesized and compared to amantadine (1) and rimantadine (2) for their ability to inhibit the replication of influenza viruses in vitro. All three metabolites were inhibitory to wild-type influenza A viruses (H3N2 and H1N1). In particular, 2-hydroxyrimantadine (3) showed similar activity to amantadine, but the 3- and 4-hydroxy metabolites (4 and 5, respectively), both of which are found in rimantadine-treated patients, showed only modest inhibitory activity. A rimantadine-resistant isolate of influenza A virus exhibited cross-resistance to amantadine and to each of the metabolites 3-5. None of the compounds were effective against influenza B virus.
Assuntos
Adamantano/análogos & derivados , Antivirais/síntese química , Rimantadina/análogos & derivados , Rimantadina/síntese química , Animais , Antivirais/farmacologia , Linhagem Celular , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana/métodos , Estrutura Molecular , Rimantadina/farmacologia , Relação Estrutura-AtividadeRESUMO
The antiviral properties of 2 recombinant DNA-produced interferons, a human hybrid interferon alpha that is active in mice and a murine interferon gamma, were examined in the treatment of mice infected with encephalomyocarditis virus. A single dose of interferon alpha induced a protective state in mice more rapidly than did interferon gamma, but the activity of the latter was more long lasting. When interferon and virus were administered 6 h apart, either intraperitoneally or intravenously, interferons alpha and gamma were equally effective. However, this was not the case when the routes of treatment and infection were different. Interferon alpha showed somewhat reduced activity when the route of administration (intravenous) was different from the route of virus challenge (intraperitoneal) while interferon gamma showed very little activity when tested in this manner. When interferons alpha and gamma were administered in combination to mice, a marked synergistic antiviral effect was observed.
Assuntos
Infecções por Enterovirus/tratamento farmacológico , Interferon Tipo I/uso terapêutico , Interferon gama/uso terapêutico , Animais , Antivirais , Linhagem Celular , Sinergismo Farmacológico , Feminino , Injeções Intraperitoneais , Injeções Intravenosas , Interferon Tipo I/administração & dosagem , Interferon gama/administração & dosagem , Vírus Elberfeld do Camundongo/efeitos dos fármacos , CamundongosRESUMO
Hairless mice were infected intracutaneously with HSV-1 and treated with rHuIFN-alpha A/D, a recombinant DNA-derived hybrid human interferon-alpha that is active on mouse cells in vitro and in vivo. When given alone (1 or 2 X 10(5) units/dose) at times soon after infection, interferon showed some efficacy, reducing disease severity by 20-30% compared to control. Oral acyclovir was also effective in reducing disease severity in a dose-dependent manner, even when treatment was begun 72 h post-infection after herpetic vesicles had become apparent. When used in combination with acyclovir (400 mg/kg/day beginning 72 h post-infection), rHuIFN-alpha A/D (beginning 4 h post-infection) greatly enhanced the therapeutic effect of the nucleoside, giving a 64% reduction in disease severity score relative to control (compared to 14% for acyclovir alone). Furthermore, although interferon treatment alone was ineffective if begun after disease was apparent, it nonetheless potentiated the activity of acyclovir when co-administered with the nucleoside beginning 72 h post-infection. Combination therapy markedly reduced disease severity, limited the progression of the infection to the vesicular stage in 50% of recipient mice and promoted a more rapid onset of healing than was obtained by treatment with acyclovir alone.
Assuntos
Aciclovir/uso terapêutico , Herpes Simples/terapia , Interferon Tipo I/uso terapêutico , Simplexvirus/efeitos dos fármacos , Aciclovir/administração & dosagem , Aciclovir/farmacologia , Animais , Sinergismo Farmacológico , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Feminino , Herpes Simples/tratamento farmacológico , Herpes Simples/microbiologia , Interferon Tipo I/administração & dosagem , Interferon Tipo I/farmacologia , Camundongos , Camundongos Pelados , Proteínas Recombinantes , Fatores de TempoRESUMO
The nucleoside analog acyclovir [9-(2-hydroxyethoxymethyl)guanine] and the hybrid recombinant human alpha interferon (rHuIFN-alpha A/D) were evaluated in weanling mice for their efficacy alone and in combination against a lethal systemic infection with herpes simplex virus type 1. Simultaneous parenteral treatment with combinations of both agents at various doses resulted in a higher percentage of survival than when either agent was administered alone, with a synergistic interaction demonstrated at certain dose combinations. Sequential administration of parenteral rHuIFN-alpha A/D and oral acyclovir, administered by gavage or supplied ad libitum in drinking water, resulted in a synergistic interaction at all dose combinations tested. These results suggest that combinations of interferon and acyclovir may be useful in treating primary herpes simplex virus infections in humans.
Assuntos
Aciclovir/uso terapêutico , Herpes Simples/tratamento farmacológico , Interferon Tipo I/uso terapêutico , Aciclovir/administração & dosagem , Administração Oral , Animais , DNA Recombinante , Esquema de Medicação , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Injeções Intraperitoneais , Interferon Tipo I/administração & dosagem , CamundongosRESUMO
All clinical isolates of influenza A viruses from patients in Huntington, West Virginia, during the decade 1978-1988 were tested, and 65 of 65 H1N1 and 176 of 181 H3N2 viruses were susceptible to the antiviral action of amantadine and rimantadine. The five resistant viruses were obtained from three members of a family undergoing therapy or prophylaxis with rimantadine. Resistant influenza emerged during treatment with rimantadine and spread to two family contacts, causing typical influenza with fever, myalgia, and cough of 5 days' or less duration. Genetic characterization of the resistant viruses when compared to the susceptible virus isolated on day 1 from the index case revealed a single amino acid change in the transmembrane portion of the M2 protein. In vitro studies showed that rimantadine was significantly more active than amantadine against both H1N1 and H3N2 viruses. Although this resistant influenza was transmitted and caused illness in one family, the absence of naturally occurring resistant viruses suggests that the emergence of new strains of influenza A each few years may prevent the widespread emergence of resistant influenza A virus.