Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Virol ; 69(4): 2637-9, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7533859

RESUMO

A quantitative assessment of human immunodeficiency virus type 1 turnover in patient cell-free virion and infected-cell compartments under the dynamic conditions imposed by an effective antiviral therapy was performed. The turnover was rapid, and following a temporal lag, the extent of viral population replacement was eventually similar in both compartments. Each compartment therefore reflects considerable active virus replication.


Assuntos
DNA Viral/metabolismo , Infecções por HIV/virologia , HIV-1/genética , RNA Viral/metabolismo , Vírion/genética , Replicação Viral , Antivirais/farmacologia , Benzoxazóis/farmacologia , Compartimento Celular , Sistema Livre de Células , Transcriptase Reversa do HIV , HIV-1/enzimologia , Humanos , Piridonas/farmacologia , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa , Replicação Viral/genética
2.
Antimicrob Agents Chemother ; 38(6): 1404-7, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7522428

RESUMO

To evaluate the potential that multiply resistant human immunodeficiency virus type 1 variants may arise during combination nucleoside and nonnucleoside reverse transcriptase inhibitor therapy, we constructed a series of mutant reverse transcriptase enzymes and viruses that coexpressed various combinations of resistance-associated amino acid substitutions. Substitutions at residues 100 (Leu-->Ile) and 181 (Tyr-->Cys), which mediate resistance to the nonnucleosides, suppressed resistance to 3'-azido-3'-deoxythymidine (AZT) when coexpressed with AZT-specific substitutions. However, a number of viral variants that exhibited significantly reduced susceptibilities to both classes of inhibitors were constructed.


Assuntos
HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa , Resistência Microbiana a Medicamentos , Transcriptase Reversa do HIV , Mutação , Relação Estrutura-Atividade , Zidovudina/farmacologia
4.
Arch Virol Suppl ; 9: 11-7, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7518271

RESUMO

The nonnucleoside reverse transcriptase (RT) inhibitors are structurally diverse compounds that are specific inhibitors of the human immunodeficiency virus type 1 RT enzyme. The compounds are largely functionally identical and bind to a common site in the enzyme. HIV-1 variants that exhibit reduced susceptibility to these inhibitors have been derived in cell culture and, more recently, from HIV-1-infected patients undergoing experimental therapy. The variants express amino acid substitutions at RT positions that apparently interact directly with the inhibitors. Effects of specific substitutions at these positions vary among the compounds, suggesting subtle differences in how the compounds physically interact with the enzyme.


Assuntos
Antivirais/farmacologia , Variação Genética , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa , Benzodiazepinas/farmacologia , Benzoxazóis/farmacologia , Ensaios Clínicos como Assunto , Resistência Microbiana a Medicamentos/genética , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV , HIV-1/genética , Humanos , Imidazóis/farmacologia , Nevirapina , Piridinas/farmacologia , Piridonas/farmacologia , DNA Polimerase Dirigida por RNA/genética
5.
N Engl J Med ; 329(15): 1065-72, 1993 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-7690462

RESUMO

BACKGROUND: The non-nucleoside reverse transcriptase inhibitors are novel antiretroviral agents with selective activity in vitro against human immunodeficiency virus type 1 (HIV-1). They act through direct inhibition of reverse transcriptase and are not incorporated into DNA. METHODS: We evaluated a pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661, in separate six-week double-blind trials in patients with HIV-1 infection whose CD4 counts ranged from 200 to 500 cells per cubic millimeter (68 patients) or less than 200 cells per cubic millimeter (67 patients). Eligible patients were randomly assigned to receive L-697,661 orally in one of three doses (25 mg twice a day, 100 mg three times a day, or 500 mg twice a day) or zidovudine (100 mg five times a day). Clinical and laboratory assessments were performed weekly. Viral isolates were obtained from a subgroup of patients before and after treatment and were evaluated for in vitro sensitivity to L-697,661. RESULTS: Both L-697,661 and zidovudine were well tolerated. Transient increases in CD4 counts were noted in the patients with fewer than 200 CD4 cells per cubic millimeter who received the two higher doses of L-697,661, but not in those who received the lowest dose or zidovudine. Patients who received L-697,661 had rapid, dose-related decreases in plasma p24 antigen levels. However, this response virtually disappeared after six weeks in some patients receiving L-697,661, coincidently with the emergence of resistant viruses. This change in susceptibility was more frequent among patients receiving the higher doses of L-697,661 and was associated with amino acid substitutions at positions 103 and 181 in the HIV-1 reverse transcriptase gene. CONCLUSIONS: L-697,661 is safe and well tolerated and has significant dose-related activity against HIV-1. However, resistant strains of the virus emerge rapidly and may limit the effectiveness of non-nucleoside reverse transcriptase inhibitors as monotherapy for HIV-1 infection.


Assuntos
Antivirais/uso terapêutico , Benzoxazóis/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Piridonas/uso terapêutico , Inibidores da Transcriptase Reversa , Adulto , Antivirais/efeitos adversos , Sequência de Bases , Benzoxazóis/efeitos adversos , Linfócitos T CD4-Positivos , DNA Viral , Método Duplo-Cego , Feminino , Seguimentos , Infecções por HIV/imunologia , Transcriptase Reversa do HIV , HIV-1/genética , Humanos , Contagem de Leucócitos , Masculino , Dados de Sequência Molecular , Piridonas/efeitos adversos , Zidovudina/uso terapêutico
7.
Antimicrob Agents Chemother ; 37(8): 1576-9, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7692811

RESUMO

The nonnucleoside reverse transcriptase (RT) inhibitors comprise a class of structurally diverse compounds that are functionally related and specific for the human immunodeficiency virus type 1 RT. Viral variants resistant to these compounds arise readily in cell culture and in treated, infected human. Therefore, the eventual clinical usefulness of the nonnucleoside inhibitors will rely on a thorough understanding of the genetic and biochemical bases for resistance. A study was performed to assess the effects of substitutions at each RT amino acid residue that influences the enzyme's susceptibility to the various nonnucleoside compounds. Single substitutions were introduced into both purified enzyme and virus. The resulting patterns of resistance were markedly distinct for each of the tested inhibitors. For instance, a > 50-fold loss of enzyme susceptibility to BI-RG-587 was engendered by any of four individual substitutions, while the same level of relative resistance to the pyridinone derivatives was mediated only by substitution at residue 181. Similarly, substitution at residue 181. Similarly, substitution at residue 106 had a noted effect on virus resistance to BI-RG-587 but not to the pyridinones. The opposite effect was mediated by a substitution at residue 179. Such knowledge of nonucleoside inhibitor resistance profiles may help in understanding the basis for resistant virus selection during clinical studies of these compounds.


Assuntos
Antivirais/farmacologia , HIV-1/genética , Mutação/genética , Nucleosídeos/farmacologia , DNA Polimerase Dirigida por RNA/genética , Inibidores da Transcriptase Reversa , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Antivirais/uso terapêutico , Benzoxazóis/uso terapêutico , DNA Viral/genética , Variação Genética , Transcriptase Reversa do HIV , HIV-1/enzimologia , Humanos , Piridonas/uso terapêutico , Relação Estrutura-Atividade
8.
Antimicrob Agents Chemother ; 37(5): 947-9, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-7685996

RESUMO

Pyridinone derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and HIV-1 replication in cell culture. However, the potential clinical usefulness of these compounds as monotherapeutic agents may be limited by the selection of inhibitor-resistant viral variants. Resistance in cell culture is due primarily to mutational alterations at RT amino acid residues 103 and 181. A recombinant HIV-1 RT containing both of these mutations was used to screen a panel of pyridinone analogs for inhibitory activity. L-696,229 and L-697,661, pyridinones currently undergoing clinical evaluation, were more than 4,000-fold weaker against the mutant enzyme than against the wild-type enzyme. In contrast, one derivative of L-696,229, L-702,019 (3-[2-(4,7-dichlorobenzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyrid in-2(1H)-thione), showed only three-fold different potencies against the two enzymes. L-702,019 was also a potent inhibitor of the replication of mutant HIV-1 containing the individual mutations at amino acid 103 or 181 as well as of clinical isolates resistant to L-697,661 and L-696,229. Isolation and analysis of resistant viral variants in cell culture showed that significant resistance to L-702,019 could be engendered only by multiple amino acid substitutions in RT. Accordingly, these studies demonstrated the potential of identifying second-generation specific HIV-1 RT inhibitors that can overcome the viral resistance selected by the first generation of inhibitors.


Assuntos
Antivirais/farmacologia , Benzoxazóis/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Piridonas/análogos & derivados , Piridonas/farmacologia , Inibidores da Transcriptase Reversa , Antivirais/síntese química , Resistência Microbiana a Medicamentos , Transcriptase Reversa do HIV , HIV-1/genética , Humanos , DNA Polimerase Dirigida por RNA/genética , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...