RESUMO
Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile.
Assuntos
Antituberculosos/farmacologia , Ésteres/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pirazinamida/análogos & derivados , Animais , Antituberculosos/síntese química , Antituberculosos/toxicidade , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/toxicidade , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Estrutura Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , Pirazinamida/síntese química , Pirazinamida/farmacologia , Pirazinamida/toxicidade , Relação Estrutura-Atividade , Células VeroRESUMO
BACKGROUND: Chagas disease, which is caused by Trypanosoma cruzi, is a major health problem in Latin America, and there are currently no drugs for the effective treatment of this disease. The energy metabolism of T. cruzi is an attractive target for drug design, and we previously reported that inhibitors of α-hydroxy acid dehydrogenase (HADH)-isozyme II exhibit trypanocidal activity. N-Propyl oxamate (NPOx) is an inhibitor of HADH-isozyme II, and its non-polar ethyl ester (Et-NPOx) is cytotoxic to T. cruzi. A new derivative of NPOx has been developed in this study with higher trypanocidal activity, which could be used for the treatment of Chagas disease. METHODS: The benzyl ester of NPOx (B-NPOx) was synthesized and its activity evaluated towards epimastigotes and bloodstream trypomastigotes (in vitro), as well as mice infected with T. cruzi (in vivo). The activity of B-NPOx was also compared with those of Et-NPOx, benznidazole (Bz) and nifurtimox (Nx). NINOA, Miguz, Compostela, Nayarit and INC-5 T. cruzi strains were used in this study. RESULTS: Polar NPOx did not penetrate the parasites and exhibited no trypanocidal activity. In contrast, the hydrophobic ester B-NPOx exhibited trypanocidal activity in vitro and in vivo. B-NPOx exhibited higher trypanocidal activity than Et-NPOx, Bz and Nx towards all five of the T. cruzi strains. The increased activity of B-NPOx was attributed to its hydrolysis inside the parasites to give NPOx and benzyl alcohol, which is an antimicrobial compound with trypanocidal effects. B-NPOx was also effective against two strains of T. cruzi that are resistant to Bz and Nx. CONCLUSION: B-NPOx exhibited higher in vitro (2- to 14.8-fold) and in vivo (2.2- to 4.5-fold) trypanocidal activity towards T. cruzi than Et-NPOx. B-NPOx also exhibited higher in vitro (2- to 24-fold) and in vivo (1.9- to 15-fold) trypanocidal activity than Bz and Nx. B-NPOx is more lipophilic than Et-NPOx, allowing for better penetration into T. cruzi parasites, where the enzymatic cleavage of B-NPOx would give NPOx and benzyl alcohol, which are potent trypanocidal agents. Taken together with its low toxicity, these results suggest that B-NPOx could be used as a potent prodrug for the treatment of Chagas disease.
Assuntos
Doença de Chagas/tratamento farmacológico , Ésteres/síntese química , Ácido Oxâmico/análogos & derivados , Pró-Fármacos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Oxirredutases do Álcool/antagonistas & inibidores , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Isoenzimas/antagonistas & inibidores , Masculino , Camundongos , Nifurtimox/farmacologia , Nitroimidazóis/farmacologia , Ácido Oxâmico/síntese química , Ácido Oxâmico/farmacologia , Ácido Oxâmico/uso terapêutico , Pró-Fármacos/síntese química , Pró-Fármacos/uso terapêutico , Pró-Fármacos/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/uso terapêutico , Tripanossomicidas/toxicidade , Trypanosoma cruzi/enzimologiaRESUMO
Objetivo: Identificar na literatura indicações e controvérsias do ATP bioluminescência para avaliação da efetividade da limpeza de superfícies em estabelecimentos de saúde. Método: Revisão integrativa da literatura, entre 2000 e 2012, nas bases de dados MEDLINE, LILACS, Science Direct, SCOPUS e Isi Web of Knowledge. Resultados: Selecionou-se para esta revisão 15 artigos. O ATP bioluminescência foi apontado como importante recurso educacional e método complementar à inspeção visual e às análises microbiológicas na avaliação da efetividade da limpeza. A impossibilidade de indicar a contaminação da superfície por micro-organismos viáveis, a interferência por substâncias químicas e a dificuldade de interpretação dos resultados constituem as principais controvérsias para o uso deste nos serviços de saúde. Conclusão: Apesar de constituir importante recurso na avaliação da limpeza de superfícies, mais estudos são necessários para incorporação efetiva do método nos serviços de saúde. .
Objective: To identify indications and controversies in the literature of the use of ATP bioluminescence to evaluate the effectiveness of surface cleaning in healthcare facilities. Method: Integrative literature review between 2000 and 2012 in the following databases: MEDLINE, LILACS, Science Direct, SCOPUS and Isi Web of Knowledge. Results: were selected for this review 15 articles. The ATP bioluminescence was considered an important educational resource and complementary method to visual inspection and microbiological evaluation of the effectiveness of cleaning. The impossibility to indicate surface contamination by microorganisms, interference by chemicals and the difficulty of interpreting the results constitute the main controversies in the use of ATP in health services. Conclusion: Although this is an important resource in the evaluation of surface cleaning, more studies are necessary for effective incorporation of the method in health services. .
Objetivo: Identificar en la literatura las indicaciones y controversias sobre el uso de la bioluminiscencia ATP para evaluar la eficacia de la limpieza de superficies en los servicios de salud. Método: Revisión integrativa de la literatura, entre 2000 y 2012, en las siguientes bases de datos: MEDLINE, LILACS, Science Direct, SCOPUS e ISI Web of Knowledge. Resultados: Se seleccionaron para esta revisión 15 artículos. La bioluminiscencia del ATP se considera un importante recurso educativo y método complementario a la inspección visual y la análisis microbiológica de la evaluación de la efectividad de la limpieza. La imposibilidad de indicar contaminación de la superficie por los microorganismos, la interferencia por los productos químicos y la dificultad de interpretar los resultados constituyen las principales controversias en la utilización de ATP en los servicios de salud. Conclusión: Aunque esto es un elemento importante en la evaluación de limpieza de superficies, se necesitan más estudios para incorporación eficaz del método en los servicios de salud. .
Assuntos
Animais , Masculino , Camundongos , Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Floxuridina/farmacologia , Intestinos/efeitos dos fármacos , Pró-Fármacos/farmacologia , Desoxicitidina/farmacologia , Floxuridina/metabolismo , Floxuridina/toxicidade , Fluoruracila/metabolismo , Fluoruracila/farmacologia , Fluoruracila/toxicidade , Camundongos Endogâmicos , Neoplasias Experimentais/tratamento farmacológico , Pró-Fármacos/toxicidadeRESUMO
Gastrotoxicity is a major problem for long-term therapy with non-steroidal anti-inflammatory drugs (NSAIDs). DICCIC (1-(2,6-dichlorophenyl)indolin-2-one) is a new diclofenac prodrug, which has proven anti-inflammatory activity without gastroulcerogenic effect. The aim of this work was to compare the pharmacokinetic profiles of diclofenac from DICCIC (7.6 mg/kg equivalent to 8.1 mg/kg diclofenac) and diclofenac (8.1 mg/kg) administration in Wistar rats weighing 250-300 g (n=20). The doses were calculated by interspecific allometric scaling based on the 2 mg/kg from diary human dose of diclofenac. Blood samples were collected in heparinized tubes via the femoral artery through the implanted catheter. The plasma was separated and quantitation was made in a HPLC system with a UV-Vis detector. The confidence limits of the bioanalytical method were appropriate for its application in a preclinical pharmacokinetic study. The AUC of diclofenac from DICCIC (53.7± 5.8 ug/mL.min) was significantly less (Mann Whitney test, p<0.05) than that of diclofenac from diclofenac administration (885.9 ± 124,8 ug/mL.min). Terminal half-life of diclofenac from DICCIC (50.1 ± 17.2 min) was significantly less (Mann Whitney test, p<0.05) than that of diclofenac from diclofenac administration (247.4 ± 100.9 min). Still the parameters clearance and distribution volume were calculated for diclofenac from diclofenac, whose results were 9.2 ±1.2 mL/min.kg and 3.3 ±1.2 L/kg, respectively. The results of DICCIC from DICCIC administration were 108.9 ± 19.6 mL/min.kg and 7.8 ± 2.4 L/kg for clearance and distribution volume, respectively. The pharmacokinetic profile demonstrated that there was an increase in diclofenac elimination and a lower exposure to diclofenac with administration of DICCIC compared to diclofenac.
Assuntos
Indóis/farmacocinética , Pró-Fármacos/farmacocinética , Animais , Diclofenaco/farmacocinética , Diclofenaco/toxicidade , Indóis/toxicidade , Masculino , Pró-Fármacos/toxicidade , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamenteRESUMO
In therapeutics research, the nitro compounds are part of an important group of drugs with multiple pharmacological activities. However, in drug design, the inclusion of a nitro group in a molecule changes the physico-chemical and electronic properties and is associated with increased mutagenicity and carcinogenicity. In addition, several studies have related the relationship between the antimicrobial and/or anti-protozoal activity and the mutagenic effect to reduction of the nitro group. This work reviews the toxicity of nitro compounds and shows how the use of prodrugs can increase the biological activity and decrease the genotoxicity of nitro compounds, without any modification in nitro reduction behavior, but rather by physico-chemical improvement. Examples are given of metronidazole and nitrofurazone prodrugs.
Assuntos
Anti-Infecciosos , Dano ao DNA , Desenho de Fármacos , Nitrocompostos , Pró-Fármacos , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/toxicidade , Fenômenos Químicos , Humanos , Metronidazol/química , Metronidazol/metabolismo , Metronidazol/toxicidade , Estrutura Molecular , Nitrocompostos/química , Nitrocompostos/metabolismo , Nitrocompostos/toxicidade , Nitrofurazona/química , Nitrofurazona/metabolismo , Nitrofurazona/toxicidade , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/toxicidade , Relação Estrutura-AtividadeRESUMO
We report here the synthesis of a novel series of 5'-O-carbonates of 3TC, using different aliphatic alcohols and N,N-carbonyldiimidazol. Its antiviral activity was determined in peripheral blood mononuclear cells (PBMCs) showing some carbonate derivatives with an activity similar to or better than 3TC, except 3TC-Metha and 3TC-2Pro with less activity. In vitro assays in PBMCs have demonstrated that cytotoxicity increases as the carbon chain length of the alcohol moiety increases, showing compounds with a normal chain length of n=2-5 good selective index, compared to the parent drug. Thus, this work is an important contribution leading to the suppression of HIV replication.