Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats.

Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca(2+) has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid-rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses.

A 90 day chronic toxicity study of Nigerian herbal preparation DAS-77 in rats.

BACKGROUND: The herbal preparation DAS-77, used for the treatment of various ailments in Nigeria, contains the milled bark of Mangifera indica L. and root of Carica papaya L. Toxicological assessment of the preparation was carried out in this study. METHODS: In the acute toxicity study, DAS-77 was administered to mice p.o. up to 20 g/kg in divided doses and i.p. at 250-3000 mg/kg. Mortality within 24 h was recorded. In the chronic toxicity study, rats were treated p.o. for 90 days at doses of 80, 400 (therapeutic dose, TD) and 2000 mg/kg. By 90 days, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination, antioxidants and histopathological assessments. RESULTS: DAS-77 did not produce any lethality administered p.o. up to 20 g/kg in divided doses but the i.p. LD50 was 1122.0 mg/kg. At TD, DAS-77 produced significant (p < 0.05) reductions in body weight, food intake and K+, and increases in ovary weight, neutrophils and HDL, which were reversible. Histopathological presentations were generally normal. Effects at the other doses were comparable to those at TD except for reversible increases in antioxidants in the liver, kidney and testes, and sperm abnormality, and reductions in liver enzymes, sperm motility and count. CONCLUSIONS: Findings in this study revealed that DAS-77 is relatively safe with the potential for enhancing in vivo antioxidant activity. However, possibly reversible side-effects include electrolyte imbalance and sterility in males.

Hepatoprotective and in vivo antioxidant effects of Byrsocarpus coccineus Schum. and Thonn. (Connaraceae).

ETHNOPHARMACOLOGICAL RELEVANCE: The leaf decoction of Byrsocarpus coccineus (Connaraceae) is drunk for the treatment of jaundice in West African traditional medicine. AIM OF THE STUDY: To investigate the hepatoprotective and in vivo antioxidant effects of Byrsocarpus coccineus in carbon tetrachloride (CCl(4))-induced hepatotoxicity in rats. MATERIALS AND METHODS: Group allotment in this study included vehicle, CCl(4), Byrsocarpus coccineus 1000 mg/kg alone, Byrsocarpus coccineus 200, 400, and 1000 mg/kg+CCl(4) and Livolin((R)) 20mg/kg+CCl(4), and treatment was carried out accordingly. On the 7th day, rats were sacrificed and blood was withdrawn by cardiac puncture. The levels and activities of serum biochemical parameters and antioxidant enzymes were then assayed using standard procedures. RESULTS: CCl(4) significantly (P<0.05) increased the levels of ALT and AST and reduced total protein. In CCl(4) treated animals, Byrsocarpus coccineus (200, 400, and 1000 mg/kg) dose-dependently and significantly decreased ALT, AST and ALP levels with peak effect produced at the highest dose. Conversely, Byrsocarpus coccineus produced significant increases in albumin and total protein levels. The standard drug produced significant effects in respect of ALT (downward arrow), albumin (upward arrow), and total protein (upward arrow). CCl(4) also produced significant (P<0.05) reductions in the activity of catalase, SOD, peroxidase and GSH, and conversely increased MDA level. Byrsocarpus coccineus produced significant and dose-dependent reversal of CCl(4)-diminished activity of the antioxidant enzymes and reduced CCl(4)-elevated level of MDA. The standard drug also significantly increased CCl(4)-diminished antioxidant enzymes activity and reduced CCl(4)-elevated MDA level. In general, the effects of the standard drug were comparable and not significantly different from those of Byrsocarpus coccineus. CONCLUSION: The results obtained in this study suggest that the aqueous leaf extract of Byrsocarpus coccineus possesses hepatoprotective and in vivo antioxidant effects. This finding justifies the use of this preparation in West African traditional medicine for the treatment of liver disease.