Safety and Efficacy of Ganciclovir Ophthalmic Gel for Treatment of Adenovirus Keratoconjunctivitis Utilizing Cell Culture and Animal Models

Abstract

Purpose: : Adenovirus (Ad), associated with significant morbidity, has no approved treatment. A commercial, gel formulation of ganciclovir 0.15% was tested for anti-adenovirus activity both in cell culture as well as in a rabbit model.

Methods: : The biological anti-adenovirus activity of the ganciclovir gel was evaluated by antiviral (effect on previously adsorbed virus) plaque assays on HeLa (human cervical carcinoma) and SIRC (rabbit corneal) cells. Briefly, adenovirus was adsorbed on the two cell lines, then treated with the ganciclovir gel and the antiviral activity of ganciclovir was then quantified by plaque assay.In addition, New Zealand White rabbits were infected by instillation of human Ad-5 into the anterior cul-de-sac of the right eye. After viral propagation and development of active infection, the rabbits were treated binocularly for 21 days with: 1) ganciclovir 0.15%, 5x/day; 2) placebo (formulation without ganciclovir), 5x/day. All animals were monitored via biomicroscopic examination and ocular culture with subsequent plaque assay.

Results: : The in vitro studies demonstrated the ganciclovir ophthalmic gel to be effective against human Ad-5. In the in vivo studies, all eyes (24/24) developed acute conjunctivitis and those receiving the active ganciclovir ophthalmic gel were cleared of active virions more quickly than those receiving the formulation without the active agent. The clinical symptomatology however, lagged behind the viral clearance and did not improve faster than the control to a statistically significant degree.

Conclusions: : Tissue culture efficacy testing of commercial ganciclovir ophthalmic gel demonstrated antiviral activity against Ad-5 in tissue culture, and that it was the active ingredient, not the benzalkonium chloride (BAK), that provided the activity.Animal testing of the ganciclovir ophthalmic gel: 1) Despite viral infection in only the right eye (OD), conjunctivitis developed binocularly in all animals; 2) Few corneal or intra-ocular changes were noted; 3) Clinically, resolution was observed to be similar between the active formulation and the control; 4) Conjunctival plaque assays for adenovirus showed animals treated with the active commercial formulation of ganciclovir ophthalmic gel were cleared of virions more quickly than the control.

Keywords: antiviral drugs • adenovirus • cornea: epithelium