Histopathologic findings after treatment with different oxidosqualene cyclase (OSC) inhibitors in hamsters and dogs.
In order to investigate the toxicity of oxidosqualene cyclase (OSC) inhibitors, hamsters and dogs were treated up to 13 weeks with three different agents of this compound class. Subacute treatment (< or = 4 weeks) of hamsters and dogs with OSC inhibitors produced a similar spectrum of histopathologic lesions, which have previously been described for compounds of this pharmacological class. In the hamster, other lesions were produced only after subchronic treatment (13 weeks). After subacute treatment, histopathologic findings were observed in the eye, skin and forestomach. Lesions in the eye were characterized as proliferation, swelling and degeneration of lens fiber cells. This finding was considered to be an early stage in cataract development. In the skin and forestomach, squamous cell hyperplasia and hyperkeratosis accompanied by a mixed inflammation was observed. After subchronic treatment of hamsters, histopathologic findings were observed in the eye, skin, forestomach, testes, epididymides, prostate gland, seminal vesicles and long bones. Lesions in the eye were characterized as cataracts. Squamous cell hyperplasia accompanied by a diffuse hyperkeratosis and a mixed inflammation was seen in the skin and forestomach epithelium. In addition, testes lesions were characterized as testicular atrophy, generalized germ cell depletion, germ cell degeneration and tubular collapse. Atrophy, oligospermia and lumenal germ cells/cell debris were found in the epididymides. The prostate gland and seminal vesicles were decreased in size (atrophy). The bone lesions were characterized as a failure of enchondral ossification causing variable widening of the growth plate and a failure to form primary bone trabecula (lesions resemble those found in rickets). To our knowledge, this is the first study describing the toxicity of OSC inhibitors after subchronic treatment in hamsters and dogs. As all adverse effects described in this report are considered to be due to an exaggeration of the desired biochemical mechanism of action at high dose levels, a decrease of the systemic exposure by the use of more hepatoselective OSC inhibitors is expected to reduce the probability of these adverse effects in humans.
Funk
J
J
F. Hoffmann-La Roche Ltd., Pharma Research Basel Non-Clinical Drug Safety, CH-4070 Basel, Switzerland. juergen.funk@roche.com
Landes
C
C
D000818:Animals; D006224:Cricetinae; D004285:Dogs; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005123:Eye / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D005837:Genitalia, Male / Q000187:drug effects* / Q000473:pathology; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D007908:Lens, Crystalline / Q000187:drug effects / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013270:Stomach / Q000187:drug effects* / Q000473:pathology; D018675:Toxicity Tests
D004791:Enzyme Inhibitors; D019751:Intramolecular Transferases; C021924:lanosterol synthase