Effect of Treatment with 5-Ethyl-2′-Deoxyuridine on Herpes Simplex Virus Encephalitis in Normal and Immunosuppressed Mice

Abstract

5-Ethyl-2'-deoxyuridine (5-ethyl-dUrd), an analog of thymidine, was evaluated for its capacity to inhibit herpes simplex virus (HSV) replication in vitro and in vivo. The 50% effective dose concentration of 5-ethyl-dUrd for HSV types 1 and 2 (HSV-1 and -2) cultured in Vero cells was 6 and 9 mug/ml, respectively. Levels of 5-ethyl-dUrd 14-fold in excess of the 50% effective dose for HSV-1 did not inhibit the formation of confluent monolayers by Vero cells, suggesting that the compound was not cytotoxic or inhibitory for mammalian cells. In vivo studies showed that 5-ethyl-dUrd was effective in significantly reducing mortality when administered to young adult mice after subcutaneous infection with HSV-2. Intraperitoneal and intravenous inoculation of drug (250 mg/kg per day) resulted in a 50% survivor rate at 15 days. Comparative studies with adenine arabinoside at 250 mg/kg per day gave a 40% survivor rate. Intramuscular injection of 5-ethyl-dUrd at a concentration as high as 2,000 mg/kg per day for 10 days was well tolerated by uninfected animals, and HSV-2-infected mice treated at this dosage had a 100% survival rate. Treatment with 5-ethyl-dUrd at a concentration of 500 mg/kg per day significantly increased the mean survival times of HSV-1- and HSV-2-infected mice immunosuppressed by irradiation; however, the fatal course of the infection was not altered. Assay for virus in tissues showed that 5-ethyl-dUrd treatment delayed progression of the infection into the central nervous system, indicating suppression of virus replication in the tissues.