SUB-ACUTE ORAL TOXICITY STUDY OF ATORVASTATIN ALONE AND IN COMBINATION WITH VERAPAMIL FOLLOWING REPEATED ADMINISTRATION IN HYPERLIPIDEMIC RATS
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Date
2012
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AAU, Anand
Abstract
Atorvastatin, a second-generation potent inhibitor of 3-Hydroxy 3- Methylglutaryl coenzyme A reductase is indicated for the treatment of dyslipidemia. The present study was conducted to evaluate the toxicity potential of Atorvastatin alone and in combination with Verapamil in hyperlipidemic rats. The study was conducted on 48 male Wistar rats dividing them in various groups having six rats in each group. Group I served as vehicle control and received 1.0 ml of 0.5% sodium bicarbonate solution orally for 28 days of dosing period. Group II served as hyperlipidemic control. Atorvastatin was given orally at dose rate of 0.5, 2.5 and 5.0 mg/kg body weight in poloxamer-407 induced hyperlipidemic rats of group III, IV and V respectively. Poloxamer-407 induced hyperlipidemic rats of group VI, VII and VIII received Atorvastatin at dose rate of 0.5, 2.5 and 5.0 mg/kg body weight respectively and additionally received Verapamil orally at dose rate of 10 mg/kg body weight. Animals were observed daily for clinical signs and mortality, if any. Body weight and feed consumption were recorded at weekly interval. On 29th of study, animals were subjected to blood collection; blood and serum sample were analyzed for haematological and biochemical parameters respectively. At the end of study period, animals were sacrificed and necropsy was performed; tissues (cerebrum, cerebellum, lung, liver, kidney, heart, aorta, spleen and muscle) were collected for histopathological studies. Hyperlipidemic rat model was developed by intra-peritoneal injection of poloxamer-407 at the dose rate of 500 mg/kg body weight on day prior to start of study and subsequently at every third day throughout the study period. In this dyslipidemic rat model serum concentration of triglycerides, total cholesterol and low density lipoprotein cholesterol level was increased by 15.1, 5.2 and 8.7 fold respectively; whereas high density lipoprotein cholesterol level was decreased by 1.5 fold as compared to vehicle control rats. Hjperlipidemic rats treated with Atorvastatin alone at 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight demonstrated hunched posture and piloerection along with dullness and sluggishness in the last week of experiment. Feed consumption was significantly reduced in hyperlipidemic rats treated with Atorvastatin at doses of 2.5 and 5.0 mg/kg body weight in combination with Verapamil at 10 mg/kg body weight in 3rd and 4th week of experiment. During 3rd and 4th week of study, there was also significant reduction in body weight gain of hyperlipidemic rats treated with Atorvastatin at doses of 2.5 and 5.0 mg/kg body weight in combination with Verapamil at 10 mg/kg body weight Significant neutrophilia, thrombocytopenia and lymphocytopenia have been observed in hyperlipidemic rats treated with Atorvastatin at 5.0 mg/kg body weight in combination with Verapamil at 10 mg/kg body weight. Atorvastatin alone at 2.5 and 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight produced significant hypotriglyceridemia in dyslipidemic rats. Atorvastatin alone at 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight; and Atorvastatin at 2.5 mg/kg body weight in combination with Verapamil at 10 mg/kg body weight produced significant hypocholesterolemia in dyslipidemic rats. Daily oral administration of Atorvastatin alone at 2.5 and 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight for 28 days produced significant reduction in low density lipoprotein cholesterol and significant rise in high density lipoprotein cholesterol in dyslipidemic rats. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin level were significantly increased in hyperlipidemic rats treated with Atorvastatin alone at 2.5 and 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight. Daily oral administration of Atorvastatin alone at 5.0 mg/kg body weight; at 2.5 and 5.0 mg/kg body weight in combination with Verapamil at 10 mg/kg body weight for 28 days caused significant rise in serum creatinine level in hyperlipidemic rats. Atorvastatin alone at 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight; and Atorvastatin at 2.5 mg/kg body weight in combination with Verapamil at 10 mg/kg body weight caused significant elevation in serum creatine kinase and lactate dehydrogenase level in hyperlipidemic rats. Rats of all treatment groups along with hyperlipidemic control group showed pale liver grossly. In poloxamer-407 induced hyperlipidemic rats, Atorvastatin alone at 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight showed noticeable muscle wasting condition Microscopically, fatty changes were observed in liver sections of hyperlipidemic control rats. Microscopic changes observed in liver were necrosis of hepatocytes, mild fatty changes and mild degeneration in hyperlipidemic rats treated with Atorvastatin alone at 2.5 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight. While hyperlipidemic rats treated with Atorvastatin alone at 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight revealed multifocal areas of necrosis, congestion in sections of liver; and bile duct proliferation was evident. Skeletal muscle showed loss of striations in myofibers, segmental muscle fiber necrosis, mild mononuclear cell infiltration and focal muscle fiber necrosis in hyperlipidemic rats treated with Atorvastatin alone at 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight; and Atorvastatin at 2.5 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight. Variable extent of degenerative lesions were observed in myocardium in hyperlipidemic rats treated with Atorvastatin alone at 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight; and Atorvastatin at 2.5 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight. Kidney sections showed varying extent of degenerative and necrotic lesion in renal tubules in hyperlipidemic rats treated with Atorvastatin alone at 5.0 mg/kg body weight and in combination with Verapamil at 10 mg/kg body weight. Based on serum profile as well as microscopic lesions, it was clearly observed that Atorvastatin in combination with Verapamil exhibited pronounced hepatotoxic, myotoxic and nephrotoxic potential.
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VETERINARY PHARMACOLOGY & TOXICOLOGY, A STUDY