piperidines and cerivastatin

Endothelin blocking drugs have vasodilator effects mediated at least in part via the nitric oxide system. Hypercholesterolaemia is associated with vascular dysfunction manifest as impaired nitric oxide-mediated vasodilatation and arterial stiffness. Treatment with HMG CoA reductase inhibitors (statins) has proven mortality benefits in a range of patient populations. Subjects (n = 5) received either placebo or 800 mug cerivastatin for an 8-week period in a double-blind, placebo-controlled, cross-over study. Cerivastatin reduced the total plasma cholesterol compared with baseline by 27% (5.4 +/- 0.4 mmol/L versus 7.3 +/- 0.4 mmol/L, P = 0.04). Selective endothelin-A receptor blockade caused an increase in forearm blood flow (FBF) (18.0 +/- 7.2%, P = 0.04). Compared with placebo, cerivastatin therapy caused a trend towards a further increase in FBF (18.0 +/- 7.2% versus 52.0 +/- 19.0%, P = 0.06). Selective endothelin-B receptor blockade reduced FBF (-11.0 +/- 3.9%, P = 0.02) with no difference between placebo and cerivastatin therapy (-11.0 +/- 3.9% versus -13.0 +/- 3.6%, P = 0.9). Combined endothelin-A/endothelin-B receptor blockade increased FBF (39.8 +/- 13.4%, P < 0.01) with no difference between placebo and cerivastatin therapy (39.8 +/- 13.4% versus 42.4 +/- 19.0%, P = 0.7). There was a trend towards a reduction in the augmentation index between cerivastatin and placebo (6.2 +/- 2.7 versus 9.1 +/- 2.4, n = 5, P = 0.4) compared with baseline (7.2 +/- 1.0). In conclusion, statin therapy may decrease large artery stiffness and increase the vasodilating effects of endothelin-A receptor blockade.

Topics: Cholesterol, LDL; Compliance; Cross-Over Studies; Double-Blind Method; Down-Regulation; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Forearm; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Oligopeptides; Peptides, Cyclic; Piperidines; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

Topics: Antipsychotic Agents; Cyclooxygenase 2 Inhibitors; Dibenzocycloheptenes; Evidence-Based Medicine; Heterocyclic Compounds, 4 or More Rings; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoindoles; Isoxazoles; Lactones; Lurasidone Hydrochloride; Piperidines; Psychotic Disorders; Pyridines; Serotonin Receptor Agonists; Sulfones; Thiazoles

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.

Topics: Animals; Biomarkers; Cholesterol; Creatine Kinase; Drug Antagonism; Drug Therapy, Combination; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Guinea Pigs; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mevalonic Acid; Muscle, Skeletal; Muscular Diseases; Oxazepines; Piperidines; Pyridines