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.

Convulsiones por isoniazida: una causa toxicológica a considerar / Isoniazid seizures: A toxicological cause to consider

La neurotoxicidad de la isoniazida (INH) frecuentemente no es tenida en cuenta por el pediatra ante un paciente con un cuadro convulsivo agudo. La INH es uno de los fármacos más indicados en el tratamiento y quimioprofilaxis de la tuberculosis. Habitualmente se la indica al grupo familiar, debido a las características epidemiológicas de esta enfermedad, lo cual permite una amplia disponibilidad en los hogares, pudiendo originar intoxicaciones accidentales o intencionales. La intoxicación severa se caracteriza por un cuadro neurotóxico agudo, expresado en un síndrome convulsivo o coma, que no cede con el tratamiento habitual. Se presenta un caso clínico de una paciente intoxicada grave con isoniazida, habiendo sido la anamnesis dirigida ampliada junto con un diagnóstico precoz y el tratamiento específico con el antídoto, la base fundamental para la evolución favorable de la paciente.

Pediatricians do not usually considered isoniazid (INH) neurotoxicity in cases of patients with severe seizure disorders. INH is one of the most suitable drugs in the treatment and chemoprophylaxis of tuberculosis. It is usually indicated to the family group, due to the epidemiological characteristics of this disease, allowing a wide availability in homes and being able to cause accidental or intentional poisoning. An acute neurotoxic picture, expressed as a convulsive syndrome or coma, which does not improve with the usual treatments, characterized severe intoxication. A case of a patient with severe intoxication with isoniazid is presented. The extended anamnesis, along with an early diagnosis and the specific antidote treatment, set the fundamental basis for the favorable evolution of the patient.

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.

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

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

[Isoniazid phenotype in a group of Tunisian patients. About 620 patients]

Isoniazid is a first line antituberculosis drug metabolized mainly in the liver by the Nacetyltransferase2. There are differences between individuals in acetylation metabolism. Subjects are thereby characterized as being rapid or slow acetylation. The purpose is to study the distribution pattern of acetylation in patients with tuberculosis followed up the teaching Hospital of La Rabta. The determination of acetylator phenotype was carried out on 620 tuberculosis patients during a period of 12 years. There were 483 men and 137 women with a median age of 40.3 years. The test was investigated before drug regimen administration at the dose of 5 mg/kg. A blood sample was taken three hours after the first administration. The determination of acetylation profile was worked out by Vivien hypothesis. In our population 391 were low and 229 were fast acetylators. The median dose recommended within the test was 3.04 mg/kg/day. 56% of our patients were initially receiving high dose of isoniazid. An increase in serum transaminase was initially observed in 60 patients among whom 47 slow acetylators. After dose adaptation, 53 patients had improved their biological abnormalities. The majority of Tunisian population seem to belong to slow acetylators modal. The frequency of hepatotoxicity suggests reducing the recommended dose of isoniazid from 5 to 3 mg/kg/day

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.