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.

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.

Hepatoprotective and therapeutic effect of Muravvaq of Mako on rifampicin-induced hepatotoxicity in rats just after rainy season [August-September]

The efficacy of Muravvaq of Mako [Frothless juice of Aolanum nigrum leaves] to control hepatic damage induces by Rifampicin was studied in Wistar albino rats. Rifampicin was administered orally as suspension to rats with a daily dose of 50 mg/kg body weight till 30 days with Muravvaq of Mako in concurrent group. In the second phase of study the effect of Muravvaq on established hepatotoxicity was studied by giving it for 20 days after withdrawal of Rifampicin. Hepatic dysfunction was assessed by biochemical and histological parameters. A significant increase observed in serum bilirubin, SGOT, SGPT and Alkaline phosphatase levels in negative control groups. However, there was a significant reduction in increased enzymatic levels in concurrent and treated group of rats, which received Muravvaq alongwith Rifampicin for 30 and 50 days, respectively. Histopathological analysis of liver samples also confirmed the hepatoprotective effect of Muravvaq. These results suggest that Muravvaq of Mako shows hepatoprotective effect against Rifampicin-induced hepatic damage in rats. The study was done in two different seasons, just after rainy [August-September] and in autumn season, to assess the efficacy of seasonal variation

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 ...

hepato-protective effect of cassia fistula [amaltas] leaves in isoniazid and rifampicin induced hepatotoxicity in rodents

Certain medicinal plants have been reported to have their effect on various experimentally induced diseases. Drug induced hepatitis [DIH] is one of them. The purpose of this study was to assess the effect of ethanolic extract of Cassia fistula leaves in experimentally induced drug hepatitis [DIH] in rodents. The rats were divided into four groups, i.e. a control group [A], antituberculous [ATT] group [B], and the remaining two groups [C and D] served as experimental therapy groups. They received Cassia fistula extract as hepatoprotective agent. Rats having normal liver functions were included in this study. Group C experimental rats received [INH/RIF] [50 mg/kg] each and ethanolic extract of Cassia fistula at 400 mg/kg of body weight. On the other hand group D experimental rats received [INH/RIF] [50 mg/kg] each and ethanolic extract of Cassia fistula at 500 mg/kg of body weight. Blood samples were taken at 30[th] day and liver in each was taken out for microscopical examination on day 30[th]. The [ATT] group rats showed variable increase in serum ALT, AST, ALP and total bilirubin levels. Group C treated with 400 mg/kg of body weight Cassia fistula treatment decreased the level of these parameters in rats. On the other hand group D rats treated with 500 mg/kg body weight of Cassia fistula dose significantly decreased levels of these biochemical parameters. The morphological examination of experimental group C rats showed slight recovery whereas the rats in experimental group D showed a significant recovery. Cassia fistula constituents, especially flavonoids and anthraquinones have strong anti-oxidant activity which provides hepato-protection against drug-induced hepatitis [DIH]. In conclusion, high dose of Cassia fistula ethanolic leaves extract [500 mg/kg] body weight showed hepatoprotection against INH/RIF induced hepatitis in rats

Effect of Muravvaq of Mako, Muravvaq of Kasni and Muravvaqain on hepatotoxicity induced by rifampicin in rats just after rainy season [August-September]

To assess the hepatoprotective activity of Muravvaq of Mako, Muravvaq of Kasni and Muravvaqain frothless juice of Mako [Solanum nigrum] leaves, and Kasni [Cichorium intybus] leaves and collectively leaves of both plants on Rifampicin-induced hepatotoxicity in Wistar albino rats. Hepatotoxicity was induced in rats by Rifampicin given orally as suspension for 30 days. Concurrent group received Muravvaq of Mako, Muravvaq of Kasni and Muravvaqain alongwith Rifampicin. In the second phase of study the effect of Muravvaq of Mako, Muravvaq of Kasni and Muravvaqain on established hepatotoxicity was studied by giving the Muravvaq of Mako, Muravvaq of Kasni and Muravvaqain for 20 days after withdrawal of Rifampicin. Hepatic dysfunction was assessed by biochemical and histological parameters. Muravvaq of Mako, Muravvaq of Kasni and Muravvaqain significantly [p<0.05] prevented changes in the serum levels of bilirubin, SGOT, SGPT and SALP. Similarly it significantly prevented the histological changes as compared to the group receiving Rifampicin. It also significantly reversed the biochemical and histological changes

Hepatoprotective effect of tocopherol against isoniazid and rifampicin induced hepatotoxicity in albino rabbits.

Antitubercular drug induced hepatotoxicity is a major hurdle for an effective treatment of tuberculosis. The present study was undertaken to assess the hepatoprotective potential of tocopherol (50 mg/kg and 100 mg/kg, ip) and to compare it with cimetidine (120 mg/kg, ip). Hepatotoxicity was produced by giving isoniazid (INH, 50 mg/kg, po) and rifampicin (RMP, 100 mg/kg, po) combination to albino rabbits for 7 days. Assessment of liver injury was done by estimating levels of alanine transaminase (ALT) and argininosuccinic acid lyase (ASAL) in serum and by histopathological examination of liver. Results revealed that pretreatment with high dose of tocopherol (100 mg/kg) prevented both biochemical as well as histopathological evidence of hepatic damage induced by INH and RMP combination. Moreover, tocopherol (100 mg/kg) was found to be a more effective hepatoprotective agent as compared to cimetidine.

Effect of cimetidine on hepatotoxicity induced by isoniazid-rifampicin combination in rabbits.

OBJECTIVE: To evaluate the hepatoprotective potential of cimetidine in hepatotoxicity induced by isoniazid-rifampicin combination in albino rabbits. METHODS: Six groups of six rabbits each were studied. Three groups received saline (control), isoniazid (50 mg/Kg/d) alone or isoniazid with rifampicin (100 mg/Kg/d) daily orally for 7 days. Other groups received intraperitoneal cimetidine (50 mg/Kg/d) alone or cimetidine (50 or 120 mg/Kg/d) along with isoniazid-rifampicin combination. Serum levels of liver enzymes were measured at baseline and on day 8 and liver histology was studied on day 8. RESULTS: Rabbits receiving isoniazid alone for 7 days showed no increase in serum ALT and AST levels, whereas those receiving isoniazid-rifampicin combination had a 3-4-fold increase in these levels (p=0.02). Animals receiving cimetidine pre-treatment did not show a significant increase in ALT and AST levels. Histological changes in the liver were more common with isoniazid-rifampicin combination than with isoniazid only. These changes were reduced in animals receiving low-dose cimetidine and prevented in those receiving high-dose cimetidine. CONCLUSION: Cimetidine in high dose can prevent hepatotoxicity induced by isoniazid-rifampicin combination.

Hepatotoxicity of antituberculous drugs: incidence, severity and risk factors

Antituberculous drug [ATD]-induced hepatotoxicity can cause permanent injury and death. It is significantly more frequent and more severe in patients with hepatotoxicity risk factors. Early recognition and immediate withdrawal of offending agent is very important to arrest its development and allow liver to heal. Surveillance studies are needed to determine the local incidence of ATD-induced hepatotoxicity and define the possible associated risk factors. The aim of this study is to assess the incidence, severity and some risk factors associated with hepatotoxicity of ATD. A prospective cohort study including patients with active tuberculosis, receiving ATD regimens with at least Isoniazid [INH], Rifampicin [RMP] and Pyrazinamide [PZA], who were following at a tuberculosis clinic in Taif, Saudi Arabia, between January 2004 and December 2006. Patients were subjected to clinical and laboratory investigations to assess hepatotoxicity of ATD and to find out the possible risk factors. The diagnosis, severity and management of ATD-induced hepatotoxicity followed the AASLD recommendations on 2004. Out of 214 patients included in the study, ATD-induced hepatotoxicity was diagnosed in 31[14.2%] of patients, which is relatively common and deserves further investigation. Hepatotoxicity was more common in females than males [18.75% vs. 11.86% respectively], and in older patients than younger ones [15% vs. 13.26% respectively]. It was also more frequent in patients with low hemoglobin, albumin levels and/or malnutrition [BMI < 18.5 kg/m2]. Alcohol intake was considered a risk factor in 11% [1/9] of patients. One hundred and twenty-one [56.5%] patients had one or more of the defined hepatotoxicity risk factors; 86 [40.2%] had one risk factor, 95 [44.4%] had two, and 33 [15.4%] had three or more. The site of disease was pulmonary in 138 [64.5%] cases, abdominal in 35 [16.4%], lymph nodes in 22 [10.3%], spine in 9 [4.2] and other sites in 10 [4.7%]. Hepatotoxicity was most frequently reported [42.9%] in patients with abdominal tuberculosis. All patients showed aminotransferase elevations; the majority of them [93.5%] had mild/moderate hepatotoxicity. Serum bilirubin >3 mg% was reported in 4 patients, who had moderate-severe hepatotoxicity. Hepatotoxicity was reported in 21[67.7%] patients within 2 weeks of starting treatment, 8 [25.8%] patients between 2 and 4 weeks and in the other two patients after one month of treatment. Patients with identified risk factor[s] were more liable to develop hepatotoxicity and more liable for progression from mild to moderate degree. Hepatotoxicity was related to INH in 17 patients [54.8%], to RMF in 10 patients [32.3%] and to PZA in 4 patients [12.9%]. Most cases of INH hepatotoxicity appeared early, while late hepatotoxicity appeared more with PZA. Twenty-two [71%] of these patients had normalization of their liver function tests within two weeks of drug discontinuation. The reported ATD-induced hepatotoxicity is relatively common. It is significantly more frequent and more severe in patients with hepatotoxicity risk factors. Hepatotoxicity occurs most commonly within the first two weeks of therapy. Early recognition with immediate withdrawal of offending agent is very important to arrest its development and allow liver to heal

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

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.

Hepatic and renal toxicity of rifampicin and isoniazid in albino rats

Antituberculous drugs, rifampicin and isoniazid proved to be toxic to the liver and kidneys both biochemically and histopathologically when given singly in a dose of 5.4 mg/l00 gm body weight [b.wt] Intra peritoneally [I.P] twice weekly for two months and their toxic effect became more pronounced when given in combination.Isoniazid proved to be more toxic to the liver as reflected on hepatic enzymes [aspartate aminotransferase AST and alanine aminotransferase ALT] and kidney functions [serum creatinine and blood urea] compared to rifampicin Significant decrease in animals body weights compared to that of the controls was also pronounced with the combination, less with isoniazid and least with rifampicin but internal organs weights were not affected.After termination of therapy recovery of liver and kidney functions occured with rifampicin after one month, with isoniazid after two months and more than two months with the combination therapy