WIN 54954 Treatment of Mice Infected with a Diabetogenic Strain of Group B Coxsackievirus

The therapeutic efficacy of an experimental antiviral agent, WIN 54954, was evaluated in a mouse model in which infection by coxsackievirus B4 (CVB4) strain E2 was followed by diabetes mellitus. Male CD1 mice (age, 5 weeks) were inoculated with 10(4) PFU of CVB4. WIN 54954 was administered orally via gavage tube in a dose of either 5 or 50 mg/kg of body weight per day. Treatment was initiated on the day of inoculation and was continued for 10 days. Control animals received the xanthan gum carrier only. At 3 days postinoculation (p.i.), the mean titer of virus in the pancreas was found to be significantly lower in both the high-dose (P < 0.001) and low-dose (P < 0.05) treatment groups compared with that in the controls. Furthermore, islet histologic abnormalities were significantly less common in the high-dose group (P < 0.02) than in the controls. At 7 weeks p.i., both fasting and 1-h postprandial glucose levels in blood were significantly lower for both the high-dose (P < 0.001) and the low-dose (P < 0.01) treatment groups than in controls. The proportion of mice with persistent viral RNA in the pancreas at this time, as detected by polymerase chain reaction, was significantly reduced in the high-dose treatment group (4 of 11 mice) compared with that in the controls (7 of 8 mice). When mice received 50 mg of WIN 54954 per kg daily beginning at either 48 or 72 h postinoculation, the titers in the pancreas were again significantly reduced at 3 days p.i. compared with those in the controls (P < 0.01 and P < 0.05, respectively). Thus, WIN 54954 effectively reduces virus replication and islet histologic changes acutely and decreases, at 7 weeks, both the metabolic alteration associated with diabetes mellitus and the incidence of detectable viral RNA in the pancreas.