OPHTHALMOSCOPIC & GROSS PATHOLOGY RESULTS:
Other gross findings in the dog included discoloration of the mucous membranes, skin and/or toenails, dull, coarse faded haircoat, and a thin appearance.
Electrocardiographic findings in the dog included changes in T waves (increased amplitude, altered polarity, and spiked or dome-dart appearance), increased amplitude of the Q and R waves and increased amplitude of the S waves.
MORPHOLOGIC DIAGNOSI(E)S AND ETIOLOGY:
The lesions in the rat and the dog are consistent with degeneration of the outer layers of retina. The different stages of lesions (acute in rat, chronic in dog) can be explained with species variation in pharmacokinetics. The high energy requirements and rapid turnover of the photoreceptors in the outer retina make them susceptible to injury via toxins, light, etc. (Stone et al., 1999, Wilcock, 1993). In the developed mammalian retina, the ability to switch energy sources from aerobic to anaerobic metabolism makes the retina resistent to changes in energy supply (Stone et al., 1999).
Research indicates that ATP-sensitive potassium channels are protective during an ischemic episode (Ettaiche et al., 2001), making it unlikely that the degenerative changes are mechanistically associated with the given compound.
In these studies, the main drug-related change in the retina is thought to be degeneration of photoreceptors. Increased photoreceptor turnover was supported by the membranous inclusions evident in retinal pigmented epithelium (RPE) using transmission electron microscopy in the dog. The combination of photoreceptor degeneration and increased demand on the phagocytic capacity of the RPE may have resulted in focal areas of retinal detachment, hypertrophy of the RPE and further atrophy and disorganization of the outer layers of the retina.
The cause of fundic discoloration evident during the ophthalmoscopic examination was undetermined; one consideration was the accumulation of a drug metabolite which may have resulted in damage to photoreceptors. Tissue distribution studies indicated that compound concentrations in several tissues, including eye, were substantially higher than in plasma for up to 24 hours after administration.
40X H&E. Treated rat with focal degeneration of outer retina.
40X H&E. Control canine nontapetal retina