Potentiating effect of dextran sulphate on the antiviral activity of acyclovir and BVDU in the treatment of herpetic keratitis in rabbits

199 Potentiating Effect of Dextran Sulphate on the Antiviral Activity o f A c y c l o v i r a n d B V D U in t h e T r e a t m e n t o f H e r p e t i c K e r a t i t i s i n R a b b i t s . S.N. Paneheva. I n s t i t u t e of Microbiology, B u l g a r i a n A c a d e m y of Sciences, Sofia, Bulgaria. D e x t r a n s u l p h a t e (DS, MW 5000) h a s been shown to be a p o t e n t a n d selective i n h i b i t o r of various enveloped viruses in vitro (Baba et al., 1988). Recently we have r e p o r t e d t h a t DS is effective also in vivo a g a i n s t HSV-1 keratoconjunctivitis in r a b b i t s (Pancheva, 1992, 1993). We have i n v e s t i g a t e d now t h e effect of DS in the t r e a t m e n t of HSV-1 k e r a t i t i s w i t h acyclovir a n d BVDU. DS w a s a d m i n i s t e r e d before virus inoculation a n d continued for 10 days. T r e a t m e n t w i t h ACV a n d BVDU (parallel e x p e r i m e n t s ) s t a r t e d 72 h after v i r u s inoculation a n d applied for 7 consecutive days. DS p o t e n t i a t e d t h e a n t i v i r a l action of ACV a n d of BVDU m a n i f e s t e d by decrease in both severity of corneal lesions a n d virus s h e d d i n g in the t e a r film. The a n t i h e r p e s activity of DS a n d a p p a r e n t lack of toxicity, d e m o n s t r a t e d in r a b b i t eye after local a d m i n i s t r a t i o n of the drug, m a k e s it a p r o m i s i n g compound for the exploration of its a n t i h e r p e s p o t e n t i a l s in h u m a n as prophylactic a n d t h e r a p e u t i c a g e n t alone or in combination w i t h others a n t i h e r p e s drugs.

200 Peptidomimetic Ribonucleotide Reductase Inhibitors in the Treatment of Herpes Simplex Keratitis in Mice. M. Garneau, M.-C. Par~, S. Nawoot, J. Jaramillo and R. D~ziel. Bio-M~ga/Boehringer Ingelheim Research Inc., 2100 Cunard Street, Laval, Qut. Canada, H7S 2G5. Herpetic keratitis is the leading cause of blindness due to infectious disease in developed countries. Current antiviral therapy consists mainly of nucleoside analogs. We investigated the in vivo antiviral effects of two ribonucleotide reductase (RR) inhibitors, BILD 733 and BILD 1263. These inhibitors are peptidomimetic compounds that act by blocking the association of the two subunits of the virally encoded RR. BILD 1263 is approximately 10 times more potent than BILD 733 in inhibiting herpes simplex virus (HSV-1) growth in cell culture (EC50 of 3 and 32 ~tM respectively). Starting 3 hr post inoculation (PI), Balb/C mice inoculated with 106 plaque forming units of HSV-1 strain KOS were treated 6 times a day for 3 days and subsequently 4 times a day for 4 days with either ophthalmic cream or ophthalmic cream plus inhibitor. Animals were examined microscopically for signs of stromal keratitis and corneal vascularization, up to 21 days PI. Under the present experimental conditions, BILD 733 failed to show activity at a concentration of 5%. In contrast, BILD 1263 dosedependently reduced the mean keratitis and mean neovascularization disease scores when administered topically at doses of 1% and 5%. Further development of peptidomirnetic RR inhibitors could lead to a valuable alternative to nucleoside analogs in the treatment of herpes simplex infections.

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