Effects of ribamidine, a 3-carboxamidine derivative of ribavirin, on experimentally induced Phlebovirus infections.
Ribamidine (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine) was inhibitory in rhesus monkey kidney (LLC-MK2 derivative) cells to Adames and Balliet strains of Punta Toro virus (PTV), a Phlebovirus related to Rift Valley fever and sandfly fever viruses. The 50% effective dose was 8 and 12 micrograms/ml against each respective virus strain; the 50% cytotoxic dose was 320 micrograms/ml, giving selectivity indices of 40 and 27 against each virus strain. The virus ratings were 1.2 and 1.0, respectively. In radiolabel uptake studies, ribamidine had a moderate effect on [3H]leucine uptake at dosages down to 1 microgram/ml, but [3H]thymidine, [32P], and [3H]uridine were inhibited at high (100-1000 micrograms/ml) doses only. Subcutaneous (s.c.) and oral treatments of Adames PTV-infected mice were equally highly effective, as evidenced particularly by 100% survivors. Reduced hepatic icterus, serum oxalic acid transaminase, serum glutamic pyruvic acid transaminase, and recoverable virus titers from livers and sera of infected mice were also seen as a result of ribamidine treatment. Twice daily treatment for 5 days could be started as late as 72 h post-virus inoculation (p.v.i.) with significant inhibition of PTV infection seen. Single s.c. treatments administered as late as 48 h p.v.i. were similarly effective. Using the chronic therapy schedule, the maximum tolerated dose was 1000 mg/kg/day and the minimum effective dose was 31.3 to 62.5 mg/kg/day. Using single treatment, a maximum tolerated dose was greater than 1000 mg/kg, and the minimum effective dose was 125 mg/kg. Ribamidine s.c. treatment of mice infected intracerebrally with the Balliet strain of PTV resulted in a moderate infection-inhibitory effect, seen especially by reduced virus titers in the brains of the infected, treated mice.
Sidwell
R W
RW
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan 84322-5600.
Huffman
J H
JH
Barnard
D L
DL
Pifat
D Y
DY
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D002043:Bunyaviridae / Q000187:drug effects; D002044:Bunyaviridae Infections / Q000188:drug therapy*; D002460:Cell Line; D005260:Female; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D012254:Ribavirin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D012263:Ribonucleosides / Q000627:therapeutic use*; D013047:Specific Pathogen-Free Organisms
D000998:Antiviral Agents; D012263:Ribonucleosides; D012254:Ribavirin; C026956:taribavirin