Activity of Amantadine, Rimantadine, and Ribavirin Against Swine Influenza in Mice and Squirrel Monkeys

The activities and toxicities of amantadine hydrochloride and rimantadine hydrochloride against influenza A/Alaska/6/77 (H3N2) and A/Bangkok/l/79 (H3N2) viruses were compared in organ cultures of ferret tracheal ciliated epithelium. Pretreatment of cultures with concentrations (0.5 and 1 ,ug/ml) comparable to those found in human serum after oral administration of amantadine revealed that rimantadine produced significantly longer protection than amantadine against virus-induced cytopathic effects. Correspondingly, rimantadine produced a comparable protective effect at four-to eight-fold-lower concentrations than amantadine. Both drugs produced increasing and similar effects at higher concentrations, which were comparable to those reported in nasal washings after aerosol administration of amantadine. At the concentrations tested, amantadine was nontoxic. However, at concentrations of 16 and 32 ,ug/ml, rimantadine was toxic to the ciliated epithelium after 10 to 21 days of continuous exposure. When the drugs were added 24 h or more after infection, protection against cytopathic effects decreased markedly. Both drugs moderately suppressed virus production at concentrations of 0.5 to 16 ,ug/ml. However, no dose response or difference between the drugs was observed. Because of comparable antiviral activity at lower concentrations and greater activity at similar concentrations, rimantadine may be more useful than amantadine for oral prophylaxis and therapy of influenza.

“…This may explain why in intact animals both amantadine and rimantadine are effective later after the initiation of infection (30,34) than observed in this study.…”

Section: Discussionmentioning

confidence: 60%

Anti-influenza A virus activity of amantadine hydrochloride and rimantadine hydrochloride in ferret tracheal ciliated epithelium

Meiklejohn¹,

Mostow²

1982

“…Although ribavirin inhibits replication of some viruses by specifically interfering with RNA polymerases or by preventing the 5'-terminal modification of viral mRNA, several observations suggest the possibility that some of the effectiveness of the drug in vivo may stem from its immunosuppressive activity. For example, ribavirin is most beneficial against influenza and vaccinia virus infections, diseases in which hypersensitivity responses to viral antigens may contribute significantly to pathogenicity (2,23,30). Ribavirin is also active in the treatment of murine systemic lupus erythematosus (10,11).…”

mentioning

confidence: 99%

Selective inhibition of functional lymphocyte subpopulations by ribavirin

Powers¹,

Peavy²,

Knight³

1982

The present studies were designed to examine the effects of ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a broad-spectrum antiviral agent, on the generation of murine antibody responses in vitro. Whereas primary and secondary sheep erythrocyte-specific, plaque-forming cell responses by normal murine spleen cells were enhanced by low concentrations of ribavirin (1 microgram per culture), they were strongly inhibited by higher concentrations of ribavirin (5 to 10 micrograms per culture). Both phenomena occurred with the greatest magnitude when spleen cells were exposed to ribavirin 48 to 72 h after culture initiation. Enhancement appeared to result from selective interference with suppressor T cells, since ribavirin failed to augment lipopolysaccharide-specific plaque-forming cell responses in T cell-depleted spleen cell cultures but inhibited concanavalin A-induced lymphocyte proliferation and suppressor T cell generation in cultures of normal spleen cells. The immunosuppressive properties of ribavirin were mediated by a direct antiproliferative effect and, at higher concentrations, a cytotoxic effect for B lymphocytes, since the drug inhibited plaque-forming cell responses in T cell-depleted spleen cell cultures, suppressed lipopolysaccharide-induced lymphocyte proliferation and reduced viable spleen cell recoveries.

“…or oral dosing of tritium-labeled ribavirin in rats have suggested that this drug was rapidly lost from all tissues of the body (7,17). Based on these observations, multiple-dose schedules have been utilized to test the efficacy of ribavirin therapy in humans and in rhesus and squirrel monkeys (2,4,6,9,15,18). Since the tritium label was in both the triazole ring and ribose components of ribavirin, its disappearance after injection into rats may not reflect the true tissue uptake and retention of the drug.…”

mentioning

confidence: 99%

“…Therefore, the studies have been repeated in rats to measure tissue distribution and disappearance rates of ribavirin labeled with 14C in the 3 position of the triazole ring. Since there is little evidence for in vivo degradation of the triazole ring (7), the radioactivity measured in tissues represents at Recent observations have suggested that ribavirin therapy is an effective antiviral drug for the treatment of several viral infections ofrhesus and squirrel monkeys (4,9,14,15). Therefore, disappearance rates and tissue distribution following a single dose of "C-labeled ribavirin were measured in rhesus monkeys to determine whether there were differences in the way these monkeys and rats metabolized this drug.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Plasma disappearance, urine excretion, and tissue distribution of ribavirin in rats and rhesus monkeys

Ferrara¹,

Oishi²,

Wannemacher³

et al. 1981

Ribavirin has been shown to have broad-spectrum antiviral activity. To study its tissue distribution and disappearance rate, a single dose of 10 mg/kg which contained 10 ,uCi of ['4C]ribavirin was injected intravenously into rhesus monkeys and intramuscularly into monkeys and rats. Except for peak plasma concentrations and the initial phases of the plasma disappearance and urine excretion curves, no significant difference was observed between plasma, tissue, or urine values for intramuscularly or intravenously injected monkeys. Plasma disappearance curves were triphasic; plasma concentrations of ribavirin were similar for both monkeys and rats. Rats excreted ribavirin in the urine more rapidly and to a greater extent (82% excreted in 24 h) than did monkeys (60% excreted in 72 h). In the rat, only 3% of the injected ['40]ribavirin was detected in expired C02. Therefore, for both species, urine was the major route for the elimination of labeled ribavirin and its metabolites from the body. In monkeys, the amount of parent drug in blood cells increased through 48 h and remained stable for 72 h, whereas in rats, ribavirin decreased at a rate similar to the plasma disappearance curve. Concentrations of ribavirin at 8 h were consistently higher in monkeys than in rats for all tissues except the brain. Thus, these differences in blood cellular components and organ content and in urine excretion suggested that there was greater tissue retention of ribavirin in monkeys than in rats.