methylcellulose and Rift-Valley-Fever

The prophylactic efficacy of poly(ICLC) (stabilized, synthetic, double-stranded polyriboinosinic-polyribocytidylic acid) against Rift Valley fever virus infection in Swiss-Webster mice was dependent on the treatment schedule. The treatment schedule was optimized by ranking the results of various treatments by the Cox proportional-hazard model based on the incremental relative risk of death. With this ranking procedure, the schedule of choice was three doses of 20 micrograms each given 5 days apart. This regimen yielded a 90% survival rate. Additional parameters were determined, including the timing of the first and second drug dose, the temporal relationship of these treatments to the day of challenge, and the minimal effective dose (1 microgram per mouse).

Topics: Animals; Carboxymethylcellulose Sodium; Drug Administration Schedule; Female; Injections, Subcutaneous; Interferon Inducers; Methylcellulose; Mice; Poly I-C; Polylysine; Rift Valley Fever; Risk; Time Factors

The therapeutic efficacy of polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine and carboxymethyl cellulose [poly(ICLC)] given alone or in combination with ribavirin was evaluated in Swiss Webster mice infected with Rift Valley fever virus. Four or more 20-micrograms doses of poly(ICLC) given at various intervals beginning 24 h after infection protected all mice against death. On the other hand, a treatment regimen consisting of only three doses of poly(ICLC) given 24 h postinfection resulted in a 50% survival rate. When initiated 48 h postinfection, an extended treatment regimen with the same dose was required to yield 40% survivors. Lower doses (5 micrograms) of poly(ICLC) per mouse were only marginally effective even when six injections were given between days 1 and 9 postinfection. The combined administration of ribavirin and poly(ICLC) initiated as late as 48 h postinfection was effective even when treatment consisted of doses that were ineffective when either drug was used alone.

Topics: Animals; Carboxymethylcellulose Sodium; Drug Administration Schedule; Drug Therapy, Combination; Female; Interferon Inducers; Methylcellulose; Mice; Poly I-C; Polylysine; Ribavirin; Ribonucleosides; Rift Valley Fever

Rift Valley fever virus (RVFV), a member of the family Bunyaviridae, extended its range from sub-Saharan Africa into Egypt in 1977. Its clinical spectrum is recognized to include severe manifestations such as hemorrhagic fever and encephalitis. For these reasons, as well as the limited knowledge of specific therapy for Bunyaviridae infections, we investigated several prophylactic regimens for RVF in a mouse model. Rimantadine, thiosemicarbazone, and inosiplex were ineffective. Pretreatment with glucan was of some use, but the most encouraging results were obtained with the antiviral drug ribavirin, passive antibody, or an interferon inducer polyriboinosinic-polyribocytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly[ICLC]). Ribavirin and poly(ICLC) were also shown to be efficacious in preventing disease in hamsters. Ribavirin (loading dose of 50 mg/kg followed by 10 mg/kg at 8-h intervals for 9 days) suppressed viremia in RVF-infected rhesus monkeys. Ribavirin also reduced virus yield in infected cell cultures; sensitivity varied markedly with cell type but not with virus strain. Immune mouse ascitic fluid, with a plaque reduction neutralization titer of 1:1024, was effective in a dose of 4 ml/kg, a volume approximately equivalent to administration of a unit of convalescent plasma to a human. Poly(ICLC) may well have functioned through interferon induction, since RVFV was shown to be sensitive to interferon in cell culture, and since another macrophage activator (glucan) was only marginally effective. These studies suggest that ribavirin, poly(ICLC), and convalescent plasma may have a role in prevention or therapy of human RVF.

Topics: Animals; Antiviral Agents; Carboxymethylcellulose Sodium; Cell Line; Cricetinae; Female; Glucans; Humans; Immunization, Passive; Interferon Inducers; Interferons; Macaca mulatta; Macrophage Activation; Male; Mesocricetus; Methylcellulose; Mice; Mice, Inbred Strains; Poly I-C; Polylysine; Ribavirin; Rift Valley Fever; Rift Valley fever virus

The prophylactic and therapeutic efficacy of polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose [poly(I,C)-LC] was evaluated in female Swiss Webster mice against a lethal infection of Rift Valley fever virus (RVFV). Prophylactically, the best effect was obtained with 2-3 doses of 1-20 micrograms poly(I,C)-LC, which fully protected the mice in a schedule-dependent fashion against an LD100 RVFV challenge. Multiple intermittent therapeutic administration of 20 micrograms poly(I,C)-LC 24 or 48 h after infection protected 100% and 50% of the mice, respectively. When given as late as 48 h after infection, 20 micrograms poly(I,C)-LC prevented viremia, and single or multiple doses induced high levels of serum interferon that peaked 24 h after administration of the compound. As late as 48 h postinfection, a high degree of therapeutic synergism was achieved with the combined administration of poly(I,C)-LC and the antiviral compound ribavirin, using doses that were not effective alone.

Topics: Animals; Carboxymethylcellulose Sodium; Drug Evaluation, Preclinical; Female; Interferon Inducers; Interferons; Methylcellulose; Mice; Poly I-C; Polylysine; Rift Valley Fever; Rift Valley fever virus