Effects of Solanum lycopersicum L. (tomato) against isoniazid and rifampicin induced hepatotoxicity in wistar albino rats.

Anti-tuberculosis drugs are reported to cause hepatotoxicity, which varies from asymptomatic rise of the hepatic enzymes. Hepatoprotective plants plays important role to protect liver. This study investigated the hepatoprotective potential of the Solanum lycopersicum in rats intoxicated with Isoniazid and Rifampicin (INH+RIF) to induce hepatotoxicity. Thirty wistar albino rats were divided into five groups of six animals each. Group 1 rats were kept control while groups II, III, IV and V were administered with INH+RIF (75+150 mg/kg) orally, for seven consecutive days. For treatment, rats in group III received silymarin while animals in group IV and V were provided with 40 mg/kg and 80 mg/kg of Solanum lycopersicum extract, respectively. On day 0 and 8th blood samples were collected for the analysis of hepatic biomarkers. The data were subjected to one-way ANOVA and Bonferroni's post hoc test for statistical analysis. Hepatotoxicity induced by INH+RIF resulted in significant elevation of serum hepatic enzymes including Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), and total bilirubin while decreased the albumin level. The Solanum lycopersicum at dose of 80 mg/kg significantly reduced the hepatic enzymes AST, ALT, ALP and bilirubin while the albumin level was significantly increased. The treatment had non-significant effect on body and liver weight. Drug induced hepatotoxicity can be effectively treated with Solanum lycopersicum at 80 mg/kg dose.

The protective effect of lycopene against oxidative kidney damage associated with combined use of isoniazid and rifampicin in rats.

It is known that the combined use of antibiotics, such as isoniazid and rifampicin, in the treatment of tuberculosis causes oxidative kidney damage. The aim of this study was to biochemically and histopathologically investigate the effect of lycopene on oxidative kidney damage due to the administration of isoniazid and rifampicin in albino Wistar male rats. Lycopene at a dose of 5 mg/kg was orally administered to lycopene+isoniazid+rifampicin (LIR) rats, and normal sunflower oil (0.5 mL) was orally administered to isoniazid+rifampicin (IR) and healthy control (HG) rats as vehicle by gavage. One hour after the administration of lycopene and vehicle, 50 mg/kg isoniazid and rifampicin were given orally to the LIR and IR groups. This procedure was performed once a day for 28 days. Rats were sacrificed by a high dose of anesthesia at the end of this period, and oxidant-antioxidant parameters were measured in the removed kidney tissues. Creatinine and blood urea nitrogen (BUN) levels were measured in blood samples, and kidney tissues were also evaluated histopathologically. The combined administration of isoniazid and rifampicin changed the oxidant-antioxidant balance in favor of oxidants, and it increased blood urea nitrogen and creatinine levels, which are indicators of kidney function. Co-administration of isoniazid and rifampicin also caused oxidative kidney damage. Lycopene biochemically and histopathologically decreased oxidative kidney damage induced by isoniazid and rifampicin administration. These results suggested that lycopene may be beneficial in the treatment of nephrotoxicity due to isoniazid and rifampicin administration.

Exploring the Toxicity, Lung Distribution, and Cellular Uptake of Rifampicin and Ascorbic Acid-Loaded Alginate Nanoparticles as Therapeutic Treatment of Lung Intracellular Infections.

Nanotechnology is a very promising technological tool to combat health problems associated with the loss of effectiveness of currently used antibiotics. Previously, we developed a formulation consisting of a chitosan and tween 80-decorated alginate nanocarrier that encapsulates rifampicin and the antioxidant ascorbic acid (RIF/ASC), intended for the treatment of respiratory intracellular infections. Here, we investigated the effects of RIF/ASC-loaded NPs on the respiratory mucus and the pulmonary surfactant. In addition, we evaluated their cytotoxicity for lung cells in vitro, and their biodistribution on rat lungs in vivo after their intratracheal administration. Findings herein demonstrated that RIF/ASC-loaded NPs display a favorable lung biocompatibility profile and a uniform distribution throughout lung lobules. RIF/ASC-loaded NPs were mainly uptaken by lung macrophages, their primary target. In summary, findings show that our novel designed RIF/ASC NPs could be a suitable system for antibiotic lung administration with promising perspectives for the treatment of pulmonary intracellular infections.

The protective effect of lycopene against oxidative kidney damage associated with combined use of isoniazid and rifampicin in rats

It is known that the combined use of antibiotics, such as isoniazid and rifampicin, in the treatment of tuberculosis causes oxidative kidney damage. The aim of this study was to biochemically and histopathologically investigate the effect of lycopene on oxidative kidney damage due to the administration of isoniazid and rifampicin in albino Wistar male rats. Lycopene at a dose of 5 mg/kg was orally administered to lycopene+isoniazid+rifampicin (LIR) rats, and normal sunflower oil (0.5 mL) was orally administered to isoniazid+rifampicin (IR) and healthy control (HG) rats as vehicle by gavage. One hour after the administration of lycopene and vehicle, 50 mg/kg isoniazid and rifampicin were given orally to the LIR and IR groups. This procedure was performed once a day for 28 days. Rats were sacrificed by a high dose of anesthesia at the end of this period, and oxidant-antioxidant parameters were measured in the removed kidney tissues. Creatinine and blood urea nitrogen (BUN) levels were measured in blood samples, and kidney tissues were also evaluated histopathologically. The combined administration of isoniazid and rifampicin changed the oxidant-antioxidant balance in favor of oxidants, and it increased blood urea nitrogen and creatinine levels, which are indicators of kidney function. Co-administration of isoniazid and rifampicin also caused oxidative kidney damage. Lycopene biochemically and histopathologically decreased oxidative kidney damage induced by isoniazid and rifampicin administration. These results suggested that lycopene may be beneficial in the treatment of nephrotoxicity due to isoniazid and rifampicin administration.

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.

Efecto protector del extracto acuoso de las hojas de Peumus boldus Boldo en la toxicidad hepática inducida por rifampicina en ratas Holtzman hembra / Protective effect of aqueous extract of the leaves of Peumus boldus, Boldo, in liver toxicity induced by rifampicin in female Holtzman rats

Objetivo: Determinar el efecto protector del extracto acuoso de las hojas de Peumus boldus "Boldo" en la toxicidad hepática inducida por rifampicina en ratas Holtzman hembra. Materiales y métodos: Se realizó un estudio experimental completo. Se adquirieron 24 ratas Holtzman hembra, y fueron divididas, aleatoriamente, en 4 grupos: A (control), B (rifampicina 100 mg/kg), C (silimarina 200 mg/kg y rifampicina 100 mg/kg) y D (boldo 160 mg/kg y rifampicina 100 mg/kg). Dicho protocolo se realizó por 14 días. Se analizaron variables clínica, bioquímicas (se realizó perfil hepático antes y después del experimento) y morfológica. Se compararon las medias de los grupos mediante la prueba de Kruskall Wallis y se consideró significativo p<0,05. Resultados: Al finalizar el experimento, las ratas del grupo B perdieron más peso (16,41+/-17,94 gr), tuvieron mayor elevación de bilirrubinas totales (0,25+/-0,13), bilirrubina directa (0,21+/-0,12), TGP (48,83+/-17,72) y sus hígados fueron más congestivos, pesaron y midieron más. Las proteínas totales (0,66+/-0,38) y albúmina (0,33+/-0,35) del grupo B fueron menores comparado con los grupos C y D. No se halló diferencia significativa en cuanto a la bilirrubina indirecta, globulina y TGP. Los hígados del grupo B mostraron mayores cambios histopatológicos (5,33+/-0,51) en comparación con los demás grupos. Conclusiones: el extracto acuoso de las hojas de Peumus boldus posee efecto protector en la toxicidad hepática inducida por rifampicina en ratas Holtzman hembra.

Objective: To determinate the protective effect the aqueous extract of the leaves of Peumus boldus "Boldo" on rifampicin-induced liver toxicity in female Holtzman rats. Materials and methods: A complete experimental study was conducted 24 female Holtzman rats were used. They were divided in 4 groups: A (control), B (rifampicin 100 mg/kg), grupo C (silimarina 200 mg/kg and rifampicin 100 mg/kg) y D (boldo 160 mg/kg and rifampicin 100 mg/kg). Rifampicin was administrated one hour after treatment in groups C and D. This protocol was carried out for 14 days. Clinical, biochemical (liver function test were performed before and after the experiment) and morphological variables were analyzed. Means were compared using the Kruskall Wallis test and results were considered significant when p<0.05. Results: At the end of the experiment, rats from group B were the ones who lost more weight, (16.41+/-17.94 g), showed grater elevation of total bilirubin (0.25+/-0.13), direct bilirubin (0.21+/-0.12), TGP (48.83+/-17.72), and whose livers were found to be more congestive, were bigger and weighed more. Whereas leaves of total proteins (0.66+/-0.38) and albumin (0.33+/-0.35) in group B were lower than in other groups. No significant difference was found in levels of indirect bilirubin, globulin and TGO. More intense morphological changes were found in livers of the group B (5.33+/-0.51) compared with other groups. Conclusions: After analyzing clinical, biochemical and morphological parameter, it can be concluded that the aqueous extract of leaves of Peumus boldus has protective effect on rifampicin-induced liver toxicity in female Holtzman rats.

Hepatocyte growth factor protects against isoniazid/rifampicin-induced oxidative liver damage.

The worldwide increment of multidrug- and extensively drug-resistant tuberculosis has emphasized the importance of looking for new options in therapeutics. Long-time usage or higher doses of isoniazid and rifampicin have been considered for the treatment of multidrug-resistant tuberculosis; however, the risk of liver failure is proportionally increased. Hepatocyte growth factor (HGF) is a multitask growth factor that stimulates both antiapoptotic and antioxidant responses that counteract the toxic effects of drug metabolism in the liver. The present work was focused to address the antioxidant and antiapoptotic effects of HGF on isoniazid- and rifampicin-induced hepatotoxicity. BALB/c mice were subjected to rifampicin (150mg/kg, intragavage [ig]) plus isoniazid (75mg/kg, ig) for 7 days. Increments in alanine aminotransferase activity, steatosis, apoptosis, and oxidative stress markers were found in animals. Recombinant HGF (iv) prevented all the harmful effects by increasing the activation of Erk1/2 and PKCδ signaling pathways and glutathione (GSH) synthesis. Furthermore, inhibition of endogenous HGF with anti-HGF antibody (iv) enhanced the isoniazid- and rifampicin-induced oxidative stress damage and decreased the GSH content, aggravating liver damage. In conclusion, HGF demonstrated to be a good protective factor against antituberculosis drug-induced hepatotoxicity and could be considered a good adjuvant factor for the use of high doses of or the reintroduction of these antituberculosis drugs.

Hígado y terapia antituberculosa / Hepatotoxicity of antituberculosis therapy

La toxicidad hepática en pacientes tratados con drogas antituberculosas es relativamente infrecuente, probablemente debido a este hecho no contamos con una buena definición de toxicidad hepática. Existen algunas condiciones de los enfermos en que la hepatotoxicidad es más frecuente, tales como pacientes envejecidos, bebedores de alcohol, desnutrición, uso de ciertas drogas e hipoalbuminemia. Las drogas antituberculosas más frecuentemente involucradas en hepatotoxicidad son la pirazinamida, la isoniacida y la rifampicina. En este artículo analizamos el problema clínico de la hepatotoxicidad de la terapia antituberculosa y proponemos el manejo de diferentes situaciones. Discutimos cuando se debe suspender la administración de una droga, cómo se debe evaluar el daño hepático y qué drogas alternativas pueden usarse durante el tratamiento de la tuberculosis.

Liver toxicity in patients being treated with antituberculosis drugs is relatively uncommon, although transient elevation of liver enzymes is very common. Probably because of this there is not a good definition for liver toxicity. There are conditions in which hepatotoxicity is more frequent, such as elderly patients, alcohol consumption, malnutrition, use of certain drugs, and hypoalbuminemia. Pirazinamide, isoniazid and rifampicin are the antituberculosis drugs more commonly involved in liver toxicity. In this article we analyze the clinical problem of hepatotoxicity of antituberculosis therapy and propose the management of different situations. We discuss when a drug administration should be discontinued, how liver damage should be assesed and which alternative drugs should be used during the antituberculosis treatment.

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 ...

Insuficiencia renal aguda por rifampicina en dos pacientes de hanseniasis multibacilar / Acute renal insufficienc secondary to rifampicin for the treatment of multibacillary leprosyy

Se presentan dos pacientes de hanseniasis multibacilar (LL y BB), con terapia multidroga, que se trataron con rifampicina diaria y al instaurarle el régimen intermitente se les produjo una insuficiencia renal aguda. Un paciente requirió un breve tiempo de hemodiálisis; el otro superó la insuficiencia renal aguda con tratamiento médico conservador. Siendo la rifampicina un antibiótico de primera importancia en el tratamiento de la enfermedad de Hansen, se alerta sobre esta reacción adversa

Insuficiencia renal aguda por rifampicina en dos pacientes de hanseniasis multibacilar / Acute renal insufficienc secondary to rifampicin for the treatment of multibacillary leprosyy

Se presentan dos pacientes de hanseniasis multibacilar (LL y BB), con terapia multidroga, que se trataron con rifampicina diaria y al instaurarle el régimen intermitente se les produjo una insuficiencia renal aguda. Un paciente requirió un breve tiempo de hemodiálisis; el otro superó la insuficiencia renal aguda con tratamiento médico conservador. Siendo la rifampicina un antibiótico de primera importancia en el tratamiento de la enfermedad de Hansen, se alerta sobre esta reacción adversa (AU)

Risk factors for hepatotoxicity induced by antituberculosis drugs

To evaluate the risk factors involved in antituberculosis treatment-induced hepatotoxicity. In a retrospective study we analyzed the rate of drug-induced hepatotoxicity in a sample of 456 patients. Patients received a combination of drugs including isoniazid, rifampin, pirazinamide and streptomycinor or ethambutol. The association among hepatotoxicity and several risk factors (age, sex, alcoholism and HIV infection) was studied by univariate methods, stratified analysis and the multiple logistic regression model. Signs of liver injury were found in 9.86 percent of the treated patients. In the logistic model, the adjusted odds ratios (OR) and significance were found as follows: a) for alcoholism, OR=17.31 (95 percent CI:6.35-47.16), p<0.001; b) for HIV infection, OR=3.23 (95 percent CI:1.47-7.11), p=0.003 and c) for female Sex, OR=2.44 (95 percent CI:1.22-4.86), p=0.011. Age was not significantly associated with hepatotoxicity. Alcoholism, HIV infection and female sex were associated with an increased risk of hepatotoxicity in this study.

Risk factors for hepatotoxicity induced by antituberculosis drugs

To evaluate the risk factors involved in antituberculosis treatment-induced hepatotoxicity. In a retrospective study we analyzed the rate of drug-induced hepatotoxicity in a sample of 456 patients. Patients received a combination of drugs including isoniazid, rifampin, pirazinamide and streptomycinor or ethambutol. The association among hepatotoxicity and several risk factors (age, sex, alcoholism and HIV infection) was studied by univariate methods, stratified analysis and the multiple logistic regression model. Signs of liver injury were found in 9.86 percent of the treated patients. In the logistic model, the adjusted odds ratios (OR) and significance were found as follows: a) for alcoholism, OR=17.31 (95 percent CI:6.35-47.16), p<0.001; b) for HIV infection, OR=3.23 (95 percent CI:1.47-7.11), p=0.003 and c) for female Sex, OR=2.44 (95 percent CI:1.22-4.86), p=0.011. Age was not significantly associated with hepatotoxicity. Alcoholism, HIV infection and female sex were associated with an increased risk of hepatotoxicity in this study. (AU)

Efectos secundarios y toxicidad de la rifampicina en el tratamiento de la lepra

Se analisa la toxicidad y los efectos de la rifampicina en el tratamiento de la lepra. En una experiencia terapéutica sobre 131 enfermos se ha observado una buena tolerancia general citándose algunas alteraciones gastro-intestinales y únicamente cuando se empleó como monoterapia la aparición de reacción lepromatosa en un 60%. Cuando se utilizó asociada a la clofazimina fueron escasos los episódios reaccionales. La tolerancia fue buena incluso asociada al isoprodian. En administración intermitente, mensual o semanal, hubo aparición del "Flu síndrome" en un 25% y 2 casos graves de insuficiencias renales agudas y una hepatitis tóxica.