Naringenin protects hepato-renal tissues against antituberculosis drugs induced toxic manifestations by modulating interleukin-6, insulin like growth factor-1, biochemical and ultra-structural integrity.

BACKGROUND: The antituberculosis drugs (ATDs), isoniazid, rifampicin, pyrazinamide and ethambutol prompt extreme hepatic and renal damage during treatment of tuberculosis. The present study aimed to investigate protective potential of naringenin against ATDs induced hepato-renal injury. METHODS: Rats were administered with ATDs (pyrazinamide; 210, ethambutol; 170, isoniazid; 85, rifampicin; 65 mg/kg b.wt) orally for 8 weeks (3 days/week) followed by naringenin at three different doses (10, 20 and 40 mg/kg b.wt) conjointly for 8 weeks (3 days/week alternately to ATDs administration) and silymarin (50 mg/kg b.wt) as positive control. RESULTS: Exposure to ATDs caused significant increase in interleukin-6 (IL-6), triglycerides, cholesterol, bilirubin whereas depletion in insulin like growth factor-1 (IGF-1), albumin and glucose in serum. Endogenous antioxidant enzymes glutathione reductase (GR), glutathione peroxidase (GPx) and glucose-6-phosphate-dehydrogenase (G-6-PDH) were diminished in liver and kidney tissues with parallel increase in triglycerides, cholesterol, microsomal LPO and aniline hydroxylase (CYP2E1 enzyme). Ultra-structural observations of liver and kidney showed marked deviation in plasma membranes of various cellular and sub-cellular organelles after 8 weeks of exposure to ATDs. CONCLUSIONS: Conjoint treatment of naringenin counteracted ATDs induced toxic manifestations by regulating IL-6, IGF-1, CYP2E1, biochemical and ultra-structural integrity in a dose dependent manner. Naringenin has excellent potential to protect ATDs induced hepato-renal injury by altering oxidative stress, modulation of antioxidant enzymes, serum cytokines and ultra-structural changes.

Ameliorative Effects of Kolaviron, a Biflavonoid Fraction from Garcinia Kola Seed, on Hepato-renal Toxicity of Anti-tuberculosis Drugs in Wistar Rats.

BACKGROUND: Tuberculosis (TB) is an infectious disease of international health priority. The combination of anti-TB drugs (4-Tabs)- isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (ETB) are effective in the management of the disease, however, their toxic effect is a major concern. PURPOSE: The study was designed to evaluate the toxicity of anti-TB drugs in male Wistar rats and possible ameliorative effects of kolaviron (KV), a biflavonoid from Garcinia kola seeds. METHODS: Twenty-eight rats were assigned into four groups; Group 1 (Control) received corn oil, Group 2 (4-Tabs) received therapeutic doses of INH (5 mg/kg), RIF (10 mg/kg), PZA (15 mg/kg) and ETB (15 mg/kg) in combination, Group 3 (4-Tabs + KV) received INH, RIF, PZA, ETB and KV (200 mg/kg) and Group 4 (KV) received KV (200 mg/kg) by oral gavage three times per week for 8 consecutive weeks. RESULTS: Administration of 4-Tabs caused oxidative stress resulting in significant (p = 0.031, 0.027) increase in malondialdehyde levels in the liver and kidney of rats by 101% and 34%, respectively. Also, 4-Tabs caused significant (p = 0.023-0.035) elevation of serum alanine and aspartate aminotransferases by 41% and 48%, creatinine by 252% and total bilirubin by 89%, respectively. In contrast, hepatic and renal antioxidant indices- reduced glutathione, glutathione peroxidase, glutathione-s-transferase and superoxide dismutase were significantly (p = 0.028-0.039) decreased in 4-Tabs-treated rats. Co-administration of KV with 4-Tabs significantly restored the antioxidant parameters and biochemical indices to near normal. CONCLUSION: These findings suggest that anti-TB drugs elicit oxidative damage in liver and kidney of rats while KV protects against the adverse effects via antioxidative mechanism.

Caspase inhibitors block zinc-chelator induced death of retinal ganglion cells.

Zinc-chelating agents, including ethambutol and its metabolite 2,2'(ethylenediamino)-dibutyric acid (EDBA) are toxic to retinal ganglion cells through a glutamate dependent mechanism. We explored whether such cell death was mediated through the caspase family of cysteine proteases. Retinal cultures were treated with EDBA alone, or EDBA plus a variety of known caspase inhibitors, and ganglion cell viability was assayed. EDBA killed 20-30% of ganglion cells. A general caspase inhibitor, BAF, prevented EDBA induced ganglion cell death. Specific inhibitors of caspase-3 and caspase-6 showed a similar ability to BAF in preventing EDBA mediated ganglion cell loss, whereas inhibitors of caspase-8 and caspase-9 were not able to rescue EDBA treated ganglion cells. A caspase-1,4 inhibitor was less effective than BAF. These studies show that a caspase mediated mechanism of apoptosis accents for a portion of EDBA mediated retinal ganglion cell death. This toxicity was mediated by downstream effector caspases, 3 and 6. Caspase inhibitors may prevent ganglion cell death secondary to ethambutol treatment.

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.