Ocular changes in beagle dogs following oral administration of CGS 24565, a potential hypolipidemic agent

Dm. Schiavo et P. Bentley, Ocular changes in beagle dogs following oral administration of CGS 24565, a potential hypolipidemic agent, TOXICOL SCI, 55(1), 2000, pp. 189-194
Citations number
Categorie Soggetti
Pharmacology & Toxicology
Journal title
ISSN journal
1096-6080 → ACNP
Year of publication
189 - 194
SICI code
(11R)-N,15-dideoxo-1-deoxy-1,15-epoxy-11-hydroxy-4-0-methyl-8-0-(2,2-dimeth yl-1-oxopropyl)-3-[4-{(2,4,6-trimethyl-phenyl)methyl}-1-piperazinyl]rifamyc in has been evaluated as a potential hypolipidemic agent. As part of a safe ty evaluation program, a 3-month oral toxicity study was performed in which CGS 24565 was administered to beagle dogs via gelatin capsules at 10, 50, or 300 mg/kg/day. Ophthalmoscopic examinations (using focal illumination an d indirect opthalmoscopy) on day 83 (week 12) revealed bilateral adnexal an d corneal changes affecting 5 dogs (3 males, 2 females, 300 mg/kg/day). Oph thalmoscopically, dogs from the 300 mg/kg dose level exhibited the adnexal changes characterized as ptosis, conjunctivitis, episcleritis, and relaxed membrane nictitans, while the corneal changes were characterized as posteri or stromal edema (cloudy, diffuse opacity usually accompanied by deep neova scularization; the diffuse edema masked the complete evaluation of other oc ular structures) and stromal infiltrates in the area of Decement's membrane (appeared to be multifocal, polymorphic changes/alterations in Decement's membrane, or endothelial swelling). No changes from normal were seen clinic ally in the eyes of other dogs on this experiment. In those dogs affected b y the ocular changes caused by CGS 24565, a visual deficit in acuity was su spected. The corneal changes, as manifested, were suggestive of permanent, irreversible corneal damage. Subsequent ophthalmoscopic examinations perfor med at established intervals during weeks 15 through 26, revealed abatement of the adnexal changes, while the corneal changes, as described above, rem ained generally unchanged, confirming irreversibility of the corneal change s within the recovery period of 13 weeks. Light microscopy confirmed irreve rsible corneal neovascularization, vacuolar degeneration of the keratocytes at 300 mg/kg, and polymorphic infiltrates in the region of Decement's memb rane. The results demonstrate that the cornea was the target tissue of toxi city for CGS 24565, and indicated that the findings represent a significant toxic effect. The correlation of histopathological findings support the hy pothesis of the diagnosis of interstitial stromal degeneration/atrophy. The potential for a similar result to the cornea of humans does exist. Due to these changes and other toxic effects associated with this class of compoun d, further development was terminated.