Therapeutic Effects of Ribavirin Given by the Intraperitoneal or Aerosol Route Against Influenza Virus Infections in Mice

Abstract

Ribavirin (1-,8--ribofuranosyl-1,2,4-triazole-3-carboxamide) is an effective antiviral agent against type A influenza infection of mice. Therapy was most effective when administered as a small-particle aerosol early in the infection. Treatment was also effective by either the intraperitoneal or aerosol route in mice with histological evidence of pneumonia. Ribavirin increased the percent survival, lowered lung virus titers, and decreased the development of lung pathology when therapy was initiated at 6 h as a small-particle aerosol. There was no evidence of pulmonary toxicity or immunosuppressive effects.Virus diseases of man and animals represent an important group of disease entities. Notwithstanding the influenza pandemic of 1918 to 1919, which was accompanied by great loss of life, influenza, like most virus diseases, is usually self-limiting and not associated with high mortality unless complicated by bacterial pneumonia. In 1957, Horsfall estimated that man suffers with viral diseases for 7 years of a 70-year life span (5). Loosli has stated that influenza is the major incapacitating viral disease not adequately controlled by vaccines (9).Ribavirin has antiviral activity against both ribonucleic and deoxyribonucleic acid viruses (6,13,17). The demonstration that small-particle aerosols containing rimantadine or amantadine-hydrochloride were effective for the treatment of influenza virus-infected mice (15,16) and the reported efficacy of parenterally injected ribavirin against lethal influenza infections in mice (1, 7) suggested that aerosols of ribavirin might be useful for the treatment of influenza. This report describes the therapeutic efficacy of ribavirin given in small-particle aerosols to treat experimental influenza virus infection in mice.MATERIALS AND METHODS Mice. Five-week-old outbred, female mice, Tac:(SW)fBR, were used for all experiments. Upon arrival, mice were housed 15 to a cage in random order. Each group of mice contained a separate subgroup destined for the same treatment, but reserved for serial sacrifice studies in addition to those recorded for survival. Groups contained 55 mice except that continuously treated groups contained 40 mice.Virus. The mouse-adapted variant of the A/Aichi/ 2/68 (H3N2) strain of influenza virus used to infect the mice has been previously described (12, 15).Lung virus titers. Lung samples were homogenized in 4.5 ml of heart infusion broth and assayed in 10-to 12-day-old embryonated eggs (15). Lung titers, expressed as the mean egg infective dose per lung, are the geometric mean of three individual mouse lungs at the indicated times postexposure. When no virus was detected in a lung sample, a value of 1.0 was assigned to calculate the geometric mean titer.Aerosol sampling and dissemination system. The dissemination system used to infect the mice and for intermittent therapy has been previously described (15). The aerosols for continuous therapy were generated by a modified Collison system developed in our laboratory. The particles generated by this system h...

Response of Influenza Virus-Infected Mice to Selected Doses of Ribavirin Administered Intraperitoneally or by Aerosol

“…These experiments indicated that small-particle aerosols (mass median diameter, 1.4 gm) of ribavirin were more effective in reducing mortality, lesions in the lung, and virus concentrations in the lungs than approximately equivalent doses of drug given intraperitoneally (i.p.) (4). However, the data did not indicate how much better aerosol administration was than i.p.…”

“…Recently, ribavirin (1-3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was found to be effective for the treatment of type A influenza virus infections in mice (1,(3)(4)(5). These experiments indicated that small-particle aerosols (mass median diameter, 1.4 gm) of ribavirin were more effective in reducing mortality, lesions in the lung, and virus concentrations in the lungs than approximately equivalent doses of drug given intraperitoneally (i.p.)…”

“…A virus control group received no treatment. The degree of gross pathology in the lungs (lung lesion score) was evaluated in three mice on day 4 and in five mice on day 7 by 1 Present address: Plum Island Animal Disease Center, P.O. Box 848, Greenport, NY 11944. methods that have been described previously (4).…”

“…The degree of gross pathology in the lungs (lung lesion score) was evaluated in three mice on day 4 and in five mice on day 7 by 1 Present address: Plum Island Animal Disease Center, P.O. Box 848, Greenport, NY 11944. methods that have been described previously (4). The concentration of virus in the lungs was also determined on day 4 by previously described methods (5).…”

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

“…Amantadine, rmantadine, and ribavirin have demonstrated activity against disease caused by several strains of type A influenza virus (6,8,9,12,13). This paper reports results of studies on the efficacy of these three drugs given by the oral route for the prevention and/or treatment of type A/New Jersey (swine) influenza virus infections in mice.…”