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M. Kumar, H. W. Thompson, E. D. Varnell, H. E. Kaufman; In vitro Combination Efficacies of Antiviral Drugs Against Hsv-1. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5131.
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To determine if combinations of newer antivirals with commercially available agents are synergistic in activity, and whether the combinations are toxic. Combination therapy has been used in the treatment of many infections including herpes simplex virus (HSV), especially for long term management. Acyclovir is commonly used for treating HSV but emergence of resistance is a big problem with this drug. To overcome resistance, many combination studies have been performed, however none of the combinations are in common clinical use. Recently helicase-primase inhibitors, especially BAY 57-1293, have shown promising in vitro and in vivo activity against HSV-1. Trifluridine ophthalmic solution is used to treat ocular HSV virus infections in the United States, but can be toxic, especially with long term use. Ganciclovir (Virgan) is available in Europe for the treatment of ocular viral infections and is claimed to have a safety profile superior to trifluridine.
We evaluated the possibility of synergistic activity of BAY 57-1293 and acyclovir using the fluorescence based cytopathogenicity (FBC) assay and the conventional plaque reduction assay. We evaluated the in vitro interaction of trifluridine and ganciclovir by same methods. The combination effect of the drugs was analyzed by using the Loewe additivity drug interaction model.
The IC50 for BAY 57-1293, acyclovir, ganciclovir and trifluridine were 4.5 ng/ml, 1.8 µg/ml, 61.65 ng/ml and 8.47 µg/ml respectively against McKrae HSV-1, while 90% inhibition was observed with 3 µg/ml, 25 ng/ml, 195 ng/ml and 15 µg/ml respectively. The antiviral activity obtained by FBC assay was compared with the plaque reduction assay and the results were similar by both methods except for trifluridine. We were unable to get IC90 for trifluridine with the FBC assay because of its toxicity against Vero cells. We also analyzed the in vitro toxicities of these drugs either alone or in combination and only trifluridine was found toxic even at its IC50 concentration. The Loewe additivity index was less than 1.0 for both the combinations.
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