AN ANIMAL-MODEL FOR CIDOFOVIR (HPMPC) TOXICITY - INTRAOCULAR-PRESSUREAND HISTOPATHOLOGIC EFFECTS

Intravitreal cidofovir has been shown to be a long acting and highly e fficacious treatment for CMV retinitis: however decrease in IOP is an adverse effect. We wanted to determine the effect of cidofovir on intr aocular pressure (IOP) ih the guinea pig, and rabbit eye to develop an animal model of cidofovir induced ocular hypotony and to study the hi stopathology of this toxicity. Twenty-eight guinea pig eyes were injec ted with cidofovir yielding final intravitreal concentrations of 25, 2 00, 625 and 2000 mu g ml(-1). Eighteen eyes of pigmented rabbits were injected with cidofovir yielding final intravitreal concentrations of 625 and 2000 mu g ml(-1). A carefully calibrated low volume displaceme nt manometer system using a micro-transducer was used to determine the IOP measurements in the guinea pig and rabbit eyes. Histology was eva luated using light and electron microscopy. Injection of 6.25 mu g of cidofovir intravitreally (vitreous concentration of 25 mu g ml(-1)) is the highest non-toxic dose in the guinea pig; the IOP was unchanged a t two and four weeks after injection with this dose; histologically th e eyes were normal. A single injection of 50 mu g of cidofovir intravi treally (vitreous concentration of 200 mu g ml(-1)) caused a long last ing (9.3 mmHg) decrease in IOP (approximately 50% of baseline). At thi s dose there were only mild and variable histologic changes in the cil iary body and the retina. Higher doses of 156.25 mu g and 500 mu g of cidofovir (vitreous concentrations of 625, and 2000 mu g ml(-1), respe ctively) caused moderate to severe ciliary body and retinal changes, I n rabbit eyes there was a mild but statistically insignificant pressur e drop with doses of 875 mu g cidofovir intravitreally (vitreous conce ntration of 625 mu g ml(-1)); retina was within normal limits after in jection with this dose, there were mild changes in the ciliary body. T here was a total destruction of ciliary body and loss of nonpigmented epithelial cells with injections of 2800 mu g of cidofovir intravitrea lly (vitreous concentration of 2000 mu g ml(-1)); retina was relativel y well preserved. The guinea pig eye shows similar reduction in IOP an d ciliary body changes as are seen in the human eye after intravitreal cidofovir and also appears to have a similar dose-response curve. How ever, the reduction of IOP caused by cidofovir occurs in the guinea pi g eye at a concentration 40 times higher than was observed in the huma n eye. (C) 1997 Academic Press Limited.