Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs
| Autor: | Tomoyuki Nishimoto, Hitomi Hamajyo, Hisashi Anayama, Masao Hirakata, Eiichiro Ishikawa, Ryuichi Tozawa, Hirofumi Nagai |
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| Rok vydání: | 2007 |
| Předmět: |
Male
medicine.medical_specialty Statin Pyridines medicine.drug_class Guinea Pigs Mevalonic Acid Reductase Biology Toxicology Lapaquistat Acetate Squalene chemistry.chemical_compound Muscular Diseases Piperidines In vivo Internal medicine medicine Animals Enzyme Inhibitors Muscle Skeletal Creatine Kinase Pharmacology Skeletal muscle Cerivastatin Oxazepines Cholesterol Farnesyl-Diphosphate Farnesyltransferase Endocrinology medicine.anatomical_structure chemistry Drug Therapy Combination Hydroxymethylglutaryl-CoA Reductase Inhibitors Drug Antagonism Biomarkers Lapaquistat medicine.drug |
| Zdroj: | Toxicology and Applied Pharmacology. 223:39-45 |
| ISSN: | 0041-008X |
| Popis: | High-dose statin treatment has been recommended as a primary strategy for aggressive reduction of LDL cholesterol levels and protection against coronary artery disease. The effectiveness of high-dose statins may be limited by their potential for myotoxic side effects. There is currently little known about the molecular mechanisms of statin-induced myotoxicity. Previously we showed that T-91485, an active metabolite of the squalene synthase inhibitor lapaquistat acetate (lapaquistat: a previous name is TAK-475), attenuated statin-induced cytotoxicity in human skeletal muscle cells [Nishimoto, T., Tozawa, R., Amano, Y., Wada, T., Imura, Y., Sugiyama, Y., 2003a. Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A. Biochem. Pharmacol. 66, 2133-2139]. In the current study, we investigated the effects of lapaquistat administration on statin-induced myotoxicity in vivo. Guinea pigs were treated with either high-dose cerivastatin (1 mg/kg) or cerivastatin together with lapaquistat (30 mg/kg) for 14 days. Treatment with cerivastatin alone decreased plasma cholesterol levels by 45% and increased creatine kinase (CK) levels by more than 10-fold (a marker of myotoxicity). The plasma CK levels positively correlated with the severity of skeletal muscle lesions as assessed by histopathology. Co-administration of lapaquistat almost completely prevented the cerivastatin-induced myotoxicity. Administration of mevalonolactone (100 mg/kg b.i.d.) prevented the cerivastatin-induced myotoxicity, confirming that this effect is directly related to HMG-CoA reductase inhibition. These results strongly suggest that cerivastatin-induced myotoxicity is due to depletion of mevalonate derived isoprenoids. In addition, squalene synthase inhibition could potentially be used clinically to prevent statin-induced myopathy. |
| Databáze: | OpenAIRE |
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