Cataracts in Dogs following Subchronic Administration of the Phenylpiperazine Antihypertensive Agent PD 78787

Abstract

Cataracts in Dogs following Subchronic Administration of the Phenylpiperazine Anhihypertensive Agent PD 78787. SUSICK R. L. JR., JORDAN, R. A., AND WATKINS, J. R. (1991). Fundam. Appl. Toxicol. 17, 593–600. PD 78787, 3-[4-[4-(3-methylpbenyl)-1-piperazinyl]butyl]-2,4-imidazolinedione, was an antihypertensive drug candidate with α1 adrenoreceptor blockade identified as one of its pharmacologic activities. Beagle dogs were administered daily doses of 0, 1, 5, or 10 mg/kg for 41 weeks. During the study, periodic ophthalmic examinations were performed in addition to electrocardiography, blood pressure measurements, and hematological, clinical biochemical, and urinalysis assessments. At study termination, animals were euthanatized and the following procedures conducted; complete gross pathological examinations; histopathologic examination of lens; biochemical analysis of aqueous humor, and measurements of drug concentration in plasma, aqueous humor, and lens. Clinical signs observed included miosis, relaxed membrane nictitans, and somnolence. Ophthalmic examinations at Week 13 revealed unilateral posterior lenticular opacities at the dose of 10 mg/kg in two of four females. At Week 41, mature bilateral cataracts were observed in four of four females and three of four males administered the 10 mg/kg dose. The opacities appeared to develop from the posterior suture lines. No adverse effects on aqueous humor composition were observed. Significant concentrations of PD 78787 were found in lens and aqueous humor from all dose groups 24 hr following the last dose. These concentrations increased with increasing dose averaging 4 μg/ml in the lenses of dogs administered 10 mg/kg. Histopathologically, swelling, vacuolation, and dissolution of the lenticular fibers were observed at 10 mg/kg. All other study parameters were unaffected by drug treatment. The clinical progression of the opacities, nature of the histopathological lesions, lack of adverse systemic effects or effects on the aqueous humor, and accumulation of drug in the lens, indicate a direct effect of the drug on the lenticular fibers as the cause of the cataracts.