Drug Development against Viral Diseases.
Annual rept. 1 Feb 88-31 Jan 89,
YALE UNIV NEW HAVEN CT SCHOOL OF MEDICINE
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Two hundred and ninety-four drugs have been tested for efficacy against CCHF strain 10200. Geometric mean times to death were calculated for control mice VC and for drug-treated mice VR. Tests with 294 drugs resulted in a mean VR score of 1.0, and 75th and 90th percentile scores of 1.1 and 1.2 respectively. Thirty drugs had VR scores greater than 1.2. Ribavirin efficacy is inversely dependent upon virus dose. After multiple doses of drug, efficacy is significantly higher than that observed after single dose treatment. CCHF virus antigen occurs very early in Kupffer cells lining the liver sinusoids. Animals treated with a single dose of ribavirin have very little or no demonstrable CCHF antigen in these cells. Infected Kupffer cells have been positively identified by immunoperoxidase staining on serial sections of paraffin embedded liver tissue sections using either anti-MAC-1 antibody or anti-CCHF antibody. Ribavirin-resistant CCHF virus has been isolated from the livers of ribavirin-treated mice showing no clinical signs of illness and necropsied on the seventh day after infection. Virus was isolated from the liver and was used as source in a ribavirin drug test. The VR score in mice treated with 50 mgkg was 1.0 and the VR score in mice treated with 100 mgkg was 0.9. Keywords Anti-viral drug, Lymphocytic choriomeningitis virus, Crimean-Congo hemorrhagic fever virus, Yellow fever virus. sdw