DISCOVERY AND DEVELOPMENT OF NEW ANTIVIRALS FOR SMALLPOX in VS .NET

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DISCOVERY AND DEVELOPMENT OF NEW ANTIVIRALS FOR SMALLPOX
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Cidofovir, which is licensed for use in treatment of cytomegalovirus retinitis in AIDS patients, was rst reported to have activity against VV in vitro by De Clercq et al.15 and has been the subject of a number of reviews.18,32,37,38 In our studies, we have con rmed the in vitro ef cacy of CDV21,30,39 and utilized CV and VV infections in normal and immunocompromised mice to determine the in vivo ef cacy of CDV.26 Viruses were administered systemically by intraperitoneal (i.p.) inoculation or by the respiratory route using intranasal instillation. Treatments were administered 24 96 h after virus inoculation by using several dosage levels of CDV in order to determine its effectiveness under suboptimal conditions. To determine if CDV could be utilized prophylactically or as postexposure therapy, we evaluated single-dose administration given at various time intervals either prior to infection or postinfection and also determined the ef cacy of multiple interval dose administration. In our initial experiments, three-week-old BALB/c mice were inoculated intranasally with CV and treated i.p. once daily for 7 days with 60, 20, or 6.7 mg of CDV/kg of body weight beginning 24, 48, or 72 h after infection. The effect of treatment on the mortality of these mice is summarized in Table 14.2. Placebo-treated animals had a 93% mortality rate and 6.7 mg/kg of CDV signi cantly reduced mortality even if treatment was delayed until 48 72 h postinfection. When mice were inoculated with VV, results similar to those described above for CV were obtained; however, signi cant protection against mortality was
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TABLE 14.2 Effect of Treatment with CDV on Mortality of BALB/c Mice Inoculated with Cowpox or Vaccinia Virus Virus Cowpox Treatment Placebo saline CDV 6.7 mg/kg 48 h 2.2 mg/kg 48 h 6.7 mg/kg 72 h 2.2 mg/kg 72 h Vaccinia Placebo Saline CDV 2.2 mg/kg 48 h 0.7 mg/kg 48 h 2.2 mg/kg 72 h 0.7 mg/kg 72 h 6.7 mg/kg 96 h 2.2 mg/kg 96 h
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Mortality Rate (%) 14/15 (93) 6/15 (40) 14/15 (93) 8/15 (53) 10/15 (67) 15/15 (100) 1/15 (7) 6/15 (40) 6/15 (40) 10/15 (67) 6/15 (40) 15/15 (100)
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MDD, mean day of death. NS, not signi cant when compared to the placebo control. Source: Adapted from Quenelle et al.26
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TABLE 14.3 Effect of Interval Treatment with CDV on Mortality of BALB/c Mice Inoculated with Cowpox Virus Treatment Placebo 48 h 72 h CDV once daily 6.7 mg/kg 72 h 2 mg/kg 72 h CDV every 48 h 6.7 mg/kg 72 h 2 mg/kg 72 h CDV every 72 h 6.7 mg/kg 72 h 2 mg/kg 72 h
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Mortality Rate (%) 14/15 (93) 14/14 (100) 1/15 (7) 5/15 (33) 1/15 (7) 8/15 (53) 0/15 (0) 11/15 (79)
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NS, not signi cant when compared to the placebo control. Source: Adapted from Quenelle et al.26
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observed at concentrations of CDV as low as 0.7 6.7 mg/kg. Signi cant protection could be obtained even if therapy was delayed until 72 96 h postinfection (Table 14.2). Since daily intravenous administration of CDV under emergency conditions would be logistically dif cult and is associated with nephrotoxicity, we also determined if dosing two to three times weekly would be effective. BALB/c mice were inoculated intranasally with CV and treated with CDV either once daily for 7 days, every other day, or every third day to determine the ef cacy of interval treatments with lower dosages of CDV. The results in Table 14.3 clearly indicate the protective effects of interval dosing, even with suboptimal levels of CDV and even when delayed up to 72 h postinfection. Since CDV has the unique property of having a long intracellular half-life of about 15 65 h, we next determined how long a single dose of CDV would retain ef cacy when given either 5, 3, or 1 day prior to CV infection or if administered 1 or 3 days after infection. The results summarized in Table 14.4 indicate that a single dose of 100 mg of CDV/kg provided signi cant protection when given any time from day 5 to day 3. The 30 mg/kg dose was highly effective when given at day 3 to day 3. The 10 mg/kg dose was most effective when given at day 1 to day 3, and the 3 mg/kg dose was most effective when given at day 1. Similar results were obtained when mice were infected with VV and treated as described above (Table 14.4). These results indicate that the effectiveness of CDV in these animal models is retained for at least 5 days after a single treatment and is dose related. Acquisition of smallpox or vaccination with VV in an immunocompromised host can result in serious morbidity and even mortality. As a model for the immunocompromised host with disseminated orthopoxvirus disease, we have used SCID mice inoculated i.p. with either CV or VV. Groups of 6- to 8-week-old SCID mice