Preclinical safety evaluation of cerivastatin, a novel HMG-CoA reductase inhibitor

Keutz, Eckhard von; Schlüter, G.

doi:10.1016/s0002-9149(98)00424-x

Cited by 51 publications

(30 citation statements)

References 20 publications

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“…Mice were treated with CEV (0.5 and 2.5 mg · kg Ϫ1 · d Ϫ1 ) in drinking water or with daily subcutaneous injections of ATV (0.5 and 2.5 mg/kg). The dose range was based on biotransformation studies with CEV in mice 15,16 and on our studies of the lipid-lowering effects of statins in apoE Ϫ/Ϫ mice (Ϸ35% and 15% reduction in cholesterol levels after 7 days' treatment with 2.5 or 0.5 mg · kg Ϫ1 · d Ϫ1 CEV). Serum cholesterol and triglyceride levels were determined by the Department of Comparative Medicine, Stanford University.…”

Section: Animalsmentioning

confidence: 99%

Statins Have Biphasic Effects on Angiogenesis

et al. 2002

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Background-Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo. Methods and Results-Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 mol/L) but significantly inhibited at high statin concentrations (0.05 to 1 mol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg · kg Ϫ1 · d Ϫ1 ) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg · kg Ϫ1 · d

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Section: Animalsmentioning

confidence: 99%

Statins Have Biphasic Effects on Angiogenesis

et al. 2002

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“…A low incidence of testicular changes has been noted in dogs given statins Gerson, 1989;Walsh et al, 1996;von Keutz and Schluter, 1998). The findings include decreased testicular weights, atrophy/degeneration of seminiferous epithelial cells, disruption of spermatocyte maturation and an increased incidence of multinucleated giant cells.…”

Section: Testicular Effectsmentioning

confidence: 99%

The Toxicology of HMG—CoA Reductase Inhibitors: Prediction of Human Risk

Macdonald¹,

Halleck

2004

Toxicol Pathol

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The discovery that 3-hydroxy-3-methyglutaryl coenzyme A reductase was a rate-determining step in the biosynthesis of cholesterol led to the discovery of inhibitors of this enzyme. To support the development of these agents (statins) as potential hypocholesterolemic drugs, a variety of preclinical studies were conducted in several animal species. Not unexpectedly due to the central role played by mevalonic acid and its products including cholesterol in development and maintenance of cellular homeostasis, administration of high dosage levels of these agents led to the expression of a broad variety of adverse effects in many different tissues. Using the tools of toxicologic pathology and classical risk assessment, these varied toxicities were evaluated by many groups relative to the conditions of use in human therapy and a perspective was developed on potential human risk. These approaches of mechanism-based risk assessment predicted that most of the adverse effects observed in animals would not be seen under conditions of human use and supported the successful introduction of one of the most important classes of human medicines.

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“…Cerivastatin was orally administered to rats, dogs, minipigs, and monkeys in studies with a duration up to one year (73 alkaline phosphatase [AP] in the plasma, pleomorphic hepatocytes, karyo-and cytomegaly, hepatocellular foci, proliferation of the smooth endoplasmatic reticulum), in the skeletal muscle (degeneration of muscle fibers), and in the nonglandular forestomach (hyperkeratosis). The no-effect level for rats after chronic treatment was 0.05 mgkg.…”

Section: Repeated-dose Toxicity Studiesmentioning

confidence: 99%