Hepatocyte growth factor enhances the clearance of a multidrug-resistant Mycobacterium tuberculosis strain by high doses of conventional chemotherapy, preserving liver function.

Tuberculosis (TB) is one of the deadliest infectious diseases in humankind history. Although, drug sensible TB is slowly decreasing, at present the rise of TB cases produced by multidrug-resistant (MDR) and extensively drug-resistant strains is a big challenge. Thus, looking for new therapeutic options against these MDR strains is mandatory. In the present work, we studied, in BALB/c mice infected with MDR strain, the therapeutic effect of supra-pharmacological doses of the conventional primary antibiotics rifampicin and isoniazid (administrated by gavage or intratracheal routes), in combination with recombinant human hepatocyte growth factor (HGF). This high dose of antibiotics administered for 3 months, overcome the resistant threshold of the MDR strain producing a significant reduction of pulmonary bacillary loads but induced liver damage, which was totally prevented by the administration of HGF. To address the long-term efficiency of this combined treatment, groups of animals after 1 month of treatment termination were immunosuppressed by glucocorticoid administration and, after 1 month, mice were euthanized, and the bacillary load was determined in lungs. In comparison with animals treated only with a high dose of antibiotics, animals that received the combined treatment showed significantly lower bacterial burdens. Thus, treatment of MDR-TB with very high doses of primary antibiotics particularly administrated by aerial route can produce a very good therapeutic effect, and its hepatic toxicity can be prevented by the administration of HGF, becoming in a new treatment modality for MDR-TB.

Modulatory activity of antioxidants against the toxicity of Rifampicin in vivo.

The World Health Organization (WHO) has shown concern about the burden of tuberculosis in the developing countries. Even though rifampicin is an effective drug in the management of tuberculosis, it has been documented to have some toxic effects in humans. Therefore, this study intends to investigate the modulatory effect of vitamins C and E on the hepatotoxicity, sperm quality and brain toxicity of Rifampicin. Forty Wistar albino rats were used, 10 animals per group. Group 1 animals received 0.3 mL of distilled water, the Group 2 animals received the therapeutic dose of rifampicin, Group 3 animals received therapeutic doses of rifampicin plus vitamin E, while Group 4 received therapeutic doses of rifampicin and vitamin C. The administration was performed orally during three months; the animals were sacrificed by cervical dislocation at the end of that period. Blood samples were collected and liver function and lipid profile was analyzed using fully automated clinical chemistry device. The liver, brain and reproductive organs underwent histopathological examination. Sperm samples were collected from the epididymis to achieve count and motility and morphological analysis. Results showed rifampicin alone to raise (p < 0.05) liver function enzymes (Aspartate amino transferase [AST], Serum alanine amino transferase [ALT] and Total Bilirubin) when compared with controls. While the vitamin E treated group showed remarkable protection, the vitamin C treated group showed questionable protection against the rifampicin induced liver damage. Sperm count results showed an important (p < 0.05) increase in the sperm quality in vitamin E and C treated groups. However, the vitamin E plus Rifampicin treated group showed increased lipid peroxidation. The histopathological findings revealed structural damages by rifampicin in liver, brain and epididymis while some remarkable architectural integrity was observed in the antioxidant-treated groups. It can be concluded that vitamin E or C improved sperm quality and protected against the brain damage caused by rifampicin. Moreover, vitamin E demonstrated remarkable hepatoprotection against rifampicin induced damage while vitamin C shows a questionable hepatoprotection.

Modulatory activity of antioxidants against the toxicity of Rifampicin in vivo / Atividade modulatória de anti-oxidantes contra a toxicidade da rifampicina in vivo

The World Health Organization (WHO) has shown concern about the burden of tuberculosis in the developing countries. Even though rifampicin is an effective drug in the management of tuberculosis, it has been documented to have some toxic effects in humans. Therefore, this study intends to investigate the modulatory effect of vitamins C and E on the hepatotoxicity, sperm quality and brain toxicity of Rifampicin. Forty Wistar albino rats were used, 10 animals per group. Group 1 animals received 0.3 mL of distilled water, the Group 2 animals received the therapeutic dose of rifampicin, Group 3 animals received therapeutic doses of rifampicin plus vitamin E, while Group 4 received therapeutic doses of rifampicin and vitamin C. The administration was performed orally during three months; the animals were sacrificed by cervical dislocation at the end of that period. Blood samples were collected and liver function and lipid profile was analyzed using fully automated clinical chemistry device. The liver, brain and reproductive organs underwent histopathological examination. Sperm samples were collected from the epididymis to achieve count and motility and morphological analysis. Results showed rifampicin alone to raise (p < 0.05) liver function enzymes (Aspartate amino transferase [AST], Serum alanine amino transferase [ALT] and Total Bilirubin) when compared with controls. While the vitamin E treated group showed remarkable protection, the vitamin C treated group showed questionable protection against the rifampicin induced liver damage. Sperm count results showed an important (p < 0.05) increase in the sperm quality in vitamin E and C treated groups. However, the vitamin E plus Rifampicin treated group showed increased lipid peroxidation. The histopathological findings revealed structural damages by rifampicin in liver, brain and epididymis while some remarkable architectural integrity was observed in the antioxidant-treated groups. It can be ...

A Organização Mundial da Saúde tem mostrado preocupação acerca da eclosão da tuberculose nos países em desenvolvimento. Embora a rifampicina seja droga efetiva para o controle da tuberculose têm sido documentados seus efeitos tóxicos em pacientes. Portanto este estudo tem a intenção de investigar o efeito modulador das vitaminas C e E na hepatotoxicidade, qualidade de esperma e a toxicidade cerebral da rifampicina. Quarenta ratos albinos da raça Wistar foram usados, 10 animais por grupo. O grupo 1 de animais recebeu 0,3 mL de água destilada. O grupo 2 recebeu a dose terapêutica de rifampicina. O grupo 3 recebeu doses terapêuticas de rifampicina mais vitamina E, enquanto o grupo 4 recebeu doses terapêuticas de rifampicina e vitamina C. A administração foi feita por via oral durante três meses; os animais foram sacrificados por deslocação cervical após este período. Amostras sanguíneas foram coletadas e função hepática e o perfil lipídico foram analisados usando aparelho automático de química clínica. O fígado, o cérebro e os órgãos reprodutivos foram submetidos a análise histopatológica. As amostras de esperma foram coletadas do epidídimo para contagem, motilidade e análise morfológica. Resultados revelaram que a rifampicina isoladamente aumenta (p < 0,05) os enzimas de função hepática (aspartato amino transferase {AST], alanino amino transferase sérica [ALT] e bilirrubina total) quando comparados com os controles. Embora o grupo tratado com vitamina E mostrasse marcada proteção, o grupo tratado com vitamina C mostrou proteção questionável contra a lesão hepática induzida pela rifampicina. Resultados da contagem espermática mostraram importante (p < 0,05) aumento na qualidade do esperma no grupo tratado com vitamina E e C. Entretanto, o grupo tratado com vitamina E e rifampicina mostrou aumento da peroxidação lipídica. Os achados histopatológicos revelaram danos estruturais pela rifampicina ao fígado, cérebro e epidídimo enquanto uma notável ...

Toxicidad hepática por medicamentos antituberculosos / Hepatotoxicity induced by antituberculosis drugs

El fenómeno de la toxicidad hepática inducida por medicamentos cobró relevancia hace algunos años con el estudio de las reacciones adversas a medicamentos. El daño producido en el hígado por un xenobiótico que altera su función es lo que se conoce como toxicidad hepática. La importancia de reconocer y diagnosticar la toxicidad hepática por medicamentos estriba en su gravedad potencial; no en vano es la causa más frecuente por la que la industria farmacéutica retira medicamentos. La tuberculosis es una pandemia que afecta a gran parte de la población mundial y junto con el VIH es una enfermedad cada vez más frecuente en Colombia. Esta enfermedad se puede considerar como una situación especial porque para su tratamiento es preciso suministrar, por largos períodos, medicamentos con potencial tóxico para el hígado.El objetivo de este artículo es revisar algunos aspectos relacionados con la toxicidad hepática secundaria a medicamentos antituberculosos, tales como: epidemiología, factores de riesgo, mecanismos de toxicidad, manifestaciones clínicas, diagnóstico, tratamiento y seguimiento.

Hepatotoxicity is the alteration of liver structure and function induced by either drugs or other substances. The importance of its proper diagnosisrests on its potential severity. It is the most frequent reason by which the pharmaceutical industry withdraws its products. Tuberculosis is a pandemicinfection affecting a large proportion of the world population. Together with HIV infection it is becoming ever more frequent in Colombia. Tuberculosisposes a special challenge because itstreatment requires the administration, during long periods, of drugs with the potential of inducing liver injury. In this article some aspects of hepatotoxicity induced by antituberculosis drugs are reviewed, namely: epidemiology, risk factors, mechanisms, clinical manifestations, diagnosis, treatment and follow-up.

Investigacion sobre toxicidad hepatica de medicacion antituberculosa / Study of the hepatic toxicity of antituberculouis drugs treatment

El presente trabajo fue realizado en el hospital San Gabriel entre enero a marzo de 1990, con 47 pacientes que fueron estudiados durante su tratamiento en diferentes etapas, y muestra el grado de tolerancia hepatica a medicamentos que deben ser utilizados por largo tiempo y que de acuerdo a reaccion individual es imprevisible el grado de toxicidad que pueda esperarse. Los resultados son alentadores porque no se tuvieron que lamentar grados extremos de toxicidad y solo en tres casos, la suspension temporal del tratamiento