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E. D. Varnell, H. E. Kaufman, B. M. Gebhardt, G. Kleymann, H. W. Thompson, E. S. Atwal; Efficacy of a Helicase-Primase Inhibitor in Animal Models of Ocular HSV-1 Infection. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2665.
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© ARVO (1962-2015); The Authors (2016-present)
Helicase-primase inhibitors have been described as a new class of potent antiviral compounds which inhibit herpes simplex virus (HSV) multiplication by a mechanism of action that is different from the antiviral compounds in use today. BAY 57-1293 has been reported to be more potent than valacyclovir when administered shortly after infection. Our purpose was to confirm the initial reports and to test efficacy on well established disease in rabbits and mice.
Animals were handled according to the ARVO Statement on the Use of Animals in Ophthalmic and Vision Research and the NIH Guidelines on the Care and Use of Animals in Research. Female BALB/c mice were infected with HSV and the infection allowed to become latent. The mice were then stressed and treated with the BAY 57-1293. Twenty-four hours later, the mice were euthanized and the corneas cultured for HSV. NZW white rabbits were infected with the McKrae strain of HSV-1 in both corneas. Three days later when infection was clinically apparent, the animals were randomized to coded treatments with BAY 57-1293, trifluridine 1% or placebo. The severity of the herpetic keratitis was graded daily in a masked fashion daily.
Orally administered BAY 57-1293 statistically supressed herpes viral reactivation more effectively than acyclovir in mice, however, intraperitoneal administration of the inhibitor did not suppress viral reactivation. In one study utilizing a 2% suspension of BAY 57-1293 in Murocel given five times a day to rabbits, the therapeutic efficacy was similar to that of trifluridine although the helicase-primase inhibitor was difficult to solubilize and the final preparation was not entirely satisfactory. Additional studies with BAY 57-1293 that had been dissolved first in either cremophor or cyclodextrin, then diluted with balanced salt solution and administered twice a day were not as effective as twice-a-day trifluridine treatment, however efficacy was increased with four-times-a-day treatment. Once daily oral treatment with 500 mg/kg of BAY 57-1293 was as effective as twice a day treatment with trifluridine.
Our results suggest that it may be possible to effectively treat herpetic keratitis without the cytotoxicity or potential healing retardation seen with trifluridine and more effectively than acyclovir.
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