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1.
Antiviral Res ; 79(2): 105-13, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18423639

RESUMO

Phenothiazine and derivatives were tested for inhibition of SARS-CoV replication. Phenothiazine slightly inhibited SARS-CoV replication in a neutral red (NR) uptake assay. Adding a propylamino group to give promazine reduced virus yields (VYR assay) with an EC(90)=8.3+/-2.8 microM, but without selectivity. Various substitutions in the basic phenothiazine structure did not promote efficacy. Phenazine ethosulfate was the most potent compound by VYR assay (EC(90)=6.1+/-4.3 microM). All compounds were toxic (IC(50)=6.6-74.5 microM) except for phenoxathiin (IC(50)=858+/-208 microM) and 10-(alpha-diethylamino-propionyl) phenothiazine.HCl (IC(50)=195+/-71.2 microM). Consequently, none were selective inhibitors of SARS-CoV replication (SI values <1-3.3 microM). These data portended the poor efficacy of promazine in a SARS-CoV mouse lung replication model. Intraperitoneal treatment with promazine using a prophylactic (-4h)/therapeutic regimen of 1, 10, or 50mg/(kg day) did not reduce virus lung titers at day 3, yet prolonged virus replication to 14 days. Similar therapeutic promazine doses were not efficacious. Thus, promazine did not affect SARS-CoV replication in vitro or in vivo, nor were any other phenothiazines efficacious in reducing virus replication. Therefore, treating SARS infections with compounds like promazine is not warranted.


Assuntos
Antivirais/farmacologia , Fenotiazinas/farmacologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Replicação Viral , Animais , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Antivirais/toxicidade , Sobrevivência Celular , Quimioprevenção , Chlorocebus aethiops , Citocinas/análise , Feminino , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Vermelho Neutro/metabolismo , Fenotiazinas/administração & dosagem , Fenotiazinas/uso terapêutico , Fenotiazinas/toxicidade , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/prevenção & controle , Células Vero
2.
Antiviral Res ; 71(1): 53-63, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16621037

RESUMO

Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572-3577). Ribavirin given at 75 mg/kg 4 h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1alpha, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the infection. Our data do not support the use of ribavirin or other IMP dehydrogenase inhibitors for treating SARS infections in humans.


Assuntos
Antivirais/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Ribavirina/farmacologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/fisiologia , Replicação Viral/efeitos dos fármacos , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Citocinas/metabolismo , Efeito Citopatogênico Viral/efeitos dos fármacos , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Ácido Micofenólico/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Ribonucleosídeos/farmacologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/enzimologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/patogenicidade , Organismos Livres de Patógenos Específicos , Células Vero
3.
Antivir Chem Chemother ; 17(5): 275-84, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17176632

RESUMO

Compounds approved for therapeutic use and in vitro inhibitors of severe acute respiratory syndrome coronavirus (SARS-CoV) were evaluated for inhibition in the mouse SARS-CoV replication model. A hybrid interferon, interferon alpha (IFN-alpha) B/D, and a mismatched double-stranded (ds) RNA interferon (IFN) inducer, Ampligen (poly I:poly C124), were the only compounds that potently inhibited virus titres in the lungs of infected mice as assessed by CPE titration assays. When mice were dosed intraperitoneally (i.p.) with IFN-alpha B/D once daily for 3 days beginning 4 h after virus exposure, SARS-CoV replication in the lungs of infected mice was reduced by 1 log10 at 10,000 and 32,000 IU; at the highest dose of 100,000 IU, virus lung titres were below detectable limits. Ampligen used i.p. at 10 mg/kg 4 h prior to virus exposure also reduced virus lung titres to below detectable limits. Nelfinavir, beta-D-N4-hydroxycytidine, calpain inhibitor VI, 3-deazaneplanocin A and Alferon (human leukocyte IFN-alpha-n3) did not significantly reduce lung virus titres in mice. Anti-inflammatory agents, chloroquine, amodiaquin and pentoxifylline, were also inactive in vivo, suggesting that although they may be useful in ameliorating the hyperinflammatory response induced by the virus infection, they will not significantly reduce the replication of the virus, the inducer of inflammatory response. Thus, anti-inflammatory agents may only be useful in treating virus lung infections if used in combination with agents that inhibit virus replication. In summary, the data suggest that induction of IFN by mismatched dsRNA or actual treatment with exogenous IFN-alpha can inhibit SARS-CoV replication in the lungs of mice.


Assuntos
Antivirais/administração & dosagem , Fatores Imunológicos/administração & dosagem , Interferons/administração & dosagem , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Administração Intranasal , Animais , Antivirais/farmacologia , Chlorocebus aethiops , Efeito Citopatogênico Viral/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Fatores Imunológicos/farmacologia , Infusões Parenterais , Interferons/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade , Células Vero
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