© 1993 Oxford University Press
research-article |
Tapetal Effect of an Azalide Antibiotic Following Oral Administration in Beagle Dogs1
Drug Safety Evaluation, Pfizer Inc Groton, Connecticut 06340
Received December 30, 1992; accepted April 23, 1993
An azalide antibiotic (CP-62,993) was administered at 100 mg/kg by oral gavage once daily for 35 consecutive days to 3 normal Beagle dogs (tapetal) and 3 Beagle dogs lacking a clinically apparent ocular tapetum (atapetal). The total dose delivered was approximately 100-fold the recommended clinical dose. Bilateral ophthalmoscopic changes were observed in the treated tapetal dogs on Day 36, consisting of mild to moderate tapetal decoloration with loss of the normal color change at the junction with the nontapetal fundus and muting of reflectivity of the normally highly reflective tapetum; treated atapetal and all control tapetal and atapetal dogs had no ophthalmoscopic changes. Microscopic examination of ocular tissue revealed rudimentary tapetal cell layers in the correct location in untreated, clinically atapetal eyes. Tapetal cells from treated tapetal and atapetal dogs were swollen and vacuolated, and contained intracytoplasmic, electron-dense debris but no recognizable tapetal rodlets. Lysosomal lamellar bodies were observed in the retinal ganglion cells of both treated groups and were neither enhanced nor reduced by the presence of a functional tapetum. Necrosis and inflammation were not observed in any ocular tissue. The altered ophthalmoscopic appearance of treated tapetal dogs was not influenced by the retinal changes because any effect on retinal transparency would have been seen in treated atapetal dogs. The decoloration and muting of reflectivity observed clinically in the tapetal fundus of dogs following prolonged exposure to high levels of CP-62,993 result from unique changes within the ocular tapetum itself and cannot be interpreted to be of consequence to nontapetal species including humans.