title: Juvenile toxicity assessment of open-acid lovastatin in rats.
abstract: BACKGROUND
  Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, reduces de novo cholesterol biosynthesis primarily in the liver. Since cholesterol is a major component of brain myelin and peak periods of brain myelination occurs after birth, this study was designed to encompass this period in rats and evaluate the potential neurotoxic effects.
  
  
  METHODS
  The pharmacologically active, open-acid form of lovastatin was administered to groups of 50 Sprague-Dawley rats per sex subcutaneously once daily at dose levels of 0 (vehicle), 2.5, 5, or 10 mg/kg/day beginning on postnatal day 4 and continuing until termination on postnatal day 41 to 51. Physical signs and body weights were monitored during the study. Animals were assessed in a battery of behavioral tests, and at termination a set of animals were examined for gross and histological changes.
  
  
  RESULTS
  There were no test article-related deaths, physical signs, or effects on preweaning and postweaning body weights during the study. In the behavior tests there were no test article-related effects in the passive avoidance, auditory startle habituation, open-field motor activity, or FOB. No test article-related postmortem findings were observed, including brain weights and histomorphology of brain, spinal cord, eye, optic nerve, or peripheral nerve.
  
  
  CONCLUSIONS
  Based on these results, the no-effect level for general and neurobehavioral toxicity in neonatal rats was ≥10 mg/kg/day for open-acid lovastatin.
authors: Safety Assessment, Merck Research Laboratories, West Point, PA 19486, USA. ld.wise@merck.com
authors: L David
authors: LD
authors: Wise
authors: Dana A
authors: DA
authors: Stoffregen
authors: Chao-Min
authors: CM
authors: Hoe
authors: George R
authors: GR
authors: Lankas