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An animal model for cidofovir (HPMPC) toxicity: intraocular pressure and histopathologic effects
I Taskintuna1, A S Banker, N A Rao
1Department of Ophthalmology, Shiley Eye Center, University of California at San Diego, La Jolla 92093-0946, USA.
Abstract:
Intravitreal cidofovir has been shown to be a long acting and highly efficacious treatment for CMV retinitis; however decrease in IOP is an adverse effect. We wanted to determine the effect of cidofovir on intraocular pressure (IOP) in the guinea pig, and rabbit eye to develop an animal model of cidofovir induced ocular hypotony and to study the histopathology of this toxicity. Twenty-eight guinea pig eyes were injected with cidofovir yielding final intravitreal concentrations of 25, 200, 625 and 2000 micrograms ml-1. Eighteen eyes of pigmented rabbits were injected with cidofovir yielding final intravitreal concentrations of 625 and 2000 micrograms ml-1. A carefully calibrated low volume displacement manometer system using a micro-transducer was used to determine the IOP measurements in the guinea pig and rabbit eyes. Histology was evaluated using light and electron microscopy. Injection of 6.25 micrograms of cidofovir intravitreally (vitreous concentration of 25 micrograms ml-1) is the highest non-toxic dose in the guinea pig; the IOP was unchanged at two and four weeks after injection with this dose; histologically the eyes were normal. A single injection of 50 micrograms of cidofovir intravitreally (vitreous concentration of 200 micrograms ml-1) caused a long lasting (9.3 mmHg) decrease in IOP (approximately 50% of baseline). At this dose there were only mild and variable histologic changes in the ciliary body and the retina. Higher doses of 156.25 micrograms and 500 micrograms of cidofovir (vitreous concentrations of 625, and 2000 micrograms ml-1, respectively) caused moderate to severe ciliary body and retinal changes. In rabbit eyes there was a mild but statistically insignificant pressure drop with doses of 875 micrograms cidofovir intravitreally (vitreous concentration of 625 micrograms ml-1); retina was within normal limits after injection with this dose, there were mild changes in the ciliary body. There was a total destruction of ciliary body and loss of nonpigmented epithelial cells with injections of 2800 micrograms of cidofovir intravitreally (vitreous concentration of 2000 micrograms ml-1): retina was relatively well preserved. The guinea pig eye shows similar reduction in IOP and ciliary body changes as are seen in the human eye after intravitreal cidofovir and also appears to have a similar dose-response curve. However, the reduction of IOP caused by cidofovir occurs in the guinea pig eye at a concentration 40 times higher than was observed in the human eye.
Insights
Intravitreal cidofovir effectively treats CMV retinitis but can lower intraocular pressure (IOP). This study developed animal models to understand cidofovir-induced ocular hypotony and toxicity, finding guinea pigs mimic human responses.
Area of Science:
- Ophthalmology
- Toxicology
- Pharmacology
Background:
- Intravitreal cidofovir is a potent treatment for cytomegalovirus (CMV) retinitis.
- A known adverse effect of cidofovir treatment is a decrease in intraocular pressure (IOP).
Purpose of the Study:
- To establish animal models (guinea pig and rabbit) of cidofovir-induced ocular hypotony.
- To investigate the histopathological effects of cidofovir on ocular tissues.
Main Methods:
- Intravitreal injections of varying cidofovir concentrations were administered to guinea pig and rabbit eyes.
- Intraocular pressure (IOP) was measured using a low volume displacement manometer system.
- Ocular tissues were evaluated using light and electron microscopy.
Main Results:
- In guinea pigs, a vitreous concentration of 200 µg/mL caused a sustained IOP decrease (~50%) with mild ciliary body and retinal changes.
- Higher doses in guinea pigs and rabbits led to moderate to severe ciliary body damage and retinal alterations.
- The guinea pig model demonstrated similar IOP reduction and ciliary body changes to humans, but at a higher effective concentration.
Conclusions:
- The guinea pig eye serves as a viable model for studying cidofovir-induced ocular hypotony and toxicity.
- Cidofovir's ocular hypotensive effects are dose-dependent, associated with ciliary body pathology.
- Understanding these mechanisms is crucial for managing adverse effects in patients treated with intravitreal cidofovir.