Toxicological Sciences 55, 189-194 (2000)
Copyright © 2000 by the Society of Toxicology
Safety Evaluation |
Ocular Changes in Beagle Dogs following Oral Administration of CGS 24565, a Potential Hypolipidemic Agent
Toxicology/Pathology, Preclinical Safety, U.S. Pharmaceuticals Development, Novartis Institute for Biomedical Research, Novartis Pharmaceuticals Corporation, 59 Route 10, East Hanover, New Jersey 07936-1080
(11R)-N,15-dideoxo-1-deoxy-1,15-epoxy-11-hydroxy-4-0methyl-8-0-(2,2-dimethyl-1-oxopropyl)-3-[4-{(2,4,6-trimethylphenyl)methyl}-1-piperazinyl]rifamycin has been evaluated as a potential hypolipidemic agent. As part of a safety 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 and indirect opthalmoscopy) on day 83 (week 12) revealed bilateral adnexal and corneal changes affecting 5 dogs (3 males, 2 females, 300 mg/kg/day). Ophthalmoscopically, 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 posterior stromal edema (cloudy, diffuse opacity usually accompanied by deep neovascularization; the diffuse edema masked the complete evaluation of other ocular 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 clinically in the eyes of other dogs on this experiment. In those dogs affected by the ocular changes caused by CGS 24565, a visual deficit in acuity was suspected. The corneal changes, as manifested, were suggestive of permanent, irreversible corneal damage. Subsequent ophthalmoscopic examinations performed at established intervals during weeks 15 through 26, revealed abatement of the adnexal changes, while the corneal changes, as described above, remained generally unchanged, confirming irreversibility of the corneal changes within the recovery period of 13 weeks. Light microscopy confirmed irreversible corneal neovascularization, vacuolar degeneration of the keratocytes at 300 mg/kg, and polymorphic infiltrates in the region of Decement's membrane. The results demonstrate that the cornea was the target tissue of toxicity for CGS 24565, and indicated that the findings represent a significant toxic effect. The correlation of histopathological findings support the hypothesis 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 compound, further development was terminated.
Key Words: CGS 24565; (11R)-N,15-Didehydro-11,15-dideoxo-1-deoxy-1,15-epoxy-11-hydroxy-4-0-methyl-8-0-(2,2-dimethyl-1-oxopropyl)-3-[4-{ (2,4,6-trimethylphenyl)methyl}-1-piperazinyl]rifamycin; hypolipidemic agent; ocular; adnexal; corneal; toxicity; beagle dogs.