Abstract
Purpose: :
To reduce the number of animals used in drug safety testing, toxicologic and toxicokinetic data are obtained from the same animals whenever possible. Unexpected findings in control rabbits in two unrelated ocular drug safety studies were attributed to medial ear artery catheters used to obtain multiple toxicokinetic blood samples. These findings are reported here to raise awareness of the potential untoward consequences of this study design.
Methods: :
In Study A, a control article was applied topically 10X daily to the right eye of Dutch Belted (DB) rabbits for 29 days and a medial ear artery catheter was taped in place for 24 hours on Days 1 and 28. In Study B, a control article was applied 4X daily to the right eye of New Zealand White (NZW) rabbits for 28 days and a medial ear artery catheter taped in place for 6 hours on Day 4. Left eyes were untreated in both studies.
Results: :
In Study A, indirect ophthalmoscopy revealed white lesions in the superior peripheral retina in the right eye of 1/10 animals on Day 2 and the left eye of 3/10 on Day 29. Histopathology revealed multifocal outer retinal degeneration/necrosis (left eye of 4/10 animals, right of 2/10), and multifocal degeneration/necrosis and acute inflammation of the lacrimal gland (left of 5/10, right of 3/10) and/or harderian gland (left of 6/10, right of 6/10). In Study B, there was minimal focal outer retinal degeneration/necrosis in the left eye of 1/8 animals and multifocal degeneration/necrosis and acute inflammation of the left lacrimal and/or harderian glands in 4/8 animals.
Conclusions: :
Paraocular gland lesions in both studies were most likely infarcts resulting from embolism of microthrombi from the arterial catheters. Retinal lesions were interpreted as commotio retinae induced when heavily taped catheterized pinnae caused blunt globe trauma during episodes of vigorous head-shaking. The lower incidence of retinal lesions in Study B was attributed to the more upright pinnae of NZW compared to DB rabbits, modification of the taping procedure to maintain the upright position subsequent to the identification of commotio retinae in Study A, and a shorter catheterization period.
Keywords: pathology: experimental • retina • lacrimal gland