Toxicologic lesions associated with two related inhibitors of oxidosqualene cyclase in the dog and mouse.
Two novel hypolipidaemic agents, both members of the aminopyrimidine series, with a mode of action of inhibition of oxidosqualene cyclase (OSC), were administered orally to dogs and mice for 14 and 28 days. Both compounds produced a similar spectrum of pathologic changes. In dogs, the agents produced equatorial single cell necrosis and cataract in the lens (also observed clinically); atrophy, ulceration, and inflammation of the cornea; hyperkeratosis, acanthosis, hair papillary atrophy, and inflammation of the skin; and epithelial degeneration and sperm granuloma in the epididymides. One female dog showed signs of liver toxicity. In mice, severe cataract formation was seen with both compounds, and liver toxicity was produced by one of the compounds. The severity and speed of onset of the cataract formation were very marked. The changes seen were dissimilar to those reported with the most commonly used class of hypolipidaemic agents in the clinic, the hydroxymethyl glutaryl coenzyme A (HMGCoA) reductase inhibitors but were reminiscent of those reported for the hypolipidaemic agent Triparanol. which was predictive of toxicity seen in man.
Pyrah
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Safety Assessment, Alderley, AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
Kalinowski
A
A
Jackson
D
D
Davies
W
W
Davis
S
S
Aldridge
A
A
Greaves
P
P
D000284:Administration, Oral; D000818:Animals; D003315:Cornea / Q000187:drug effects / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D004822:Epididymis / Q000187:drug effects / Q000473:pathology; D005260:Female; D006201:Hair Diseases / Q000139:chemically induced / Q000473:pathology; D007420:Intestine, Large / Q000187:drug effects / Q000473:pathology; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D007908:Lens, Crystalline / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011743:Pyrimidines / Q000008:administration & dosage / Q000633:toxicity*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013045:Species Specificity; D018675:Toxicity Tests
D004791:Enzyme Inhibitors; D011743:Pyrimidines; C438964:ZD7851; C438963:ZD9720; D019751:Intramolecular Transferases; C021924:lanosterol synthase