No abstract

The protection of mice against MM virus infection and the induction of circulating interferon by tilorone hydrochloride were determined. Whereas protection was evident with doses of 0.15 and 1.5 mg/kg, interferon was not detected with doses lower than 150 mg/kg. Protection was apparently not dependent on interferon induction.Tilorone hydrochloride, the orange, watersoluble dihydrochloride salt of 2,7-bis[2-(diethylamino) ethoxy] fluoren-9-one, is a broadspectrum antiviral agent (5). In mice, it is effective against Semliki Forest virus by the oral, subcutaneous, and intraperitoneal treatment routes. It has also been shown to be effective against intranasal infection by vesicular stomatis virus (VSV; 2). Its mode of action is presumably interferon stimulation (2, 6). We have investigated the protection elicited by different doses of tilorone given intraperitoneally against MM virus infection in mice. At the same time, the amount of circulating interferon induced by each dose of tilorone was determined.Female Swiss Webster mice weighing about 14 g were treated intraperitoneally with different doses of tilorone diluted in Hanks balanced salt solution. Ten mice from each group were bled at 6, 12, and 24 hr after the administration of tilorone. The blood was pooled, and the plasma was collected and assayed for interferon activity. At 24 hr after the injection of tilorone, the mice remaining in each group were challenged intraperitoneatly with about 100 plaque-forming units of MM virus (2 LD50). Deaths were recorded daily for 20 days. The results (Table 1) show that, in terms of mortality and mean survival time, a tilorone dose of 7.5 mg/kg was sufficient to protect mice. They also suggest that doses as low as 0.15 and 1.5 mg/kg can have a protective effect, although at these doses the results were variable. Circulating interferon, however, was not detected with tilorone doses of less than 150 mg/kg. As these data show, in our system there was no correlation between the protection of mice against MM virus infection and the amount of circulating interferon induced by tilorone.These results are not in agreement with those of De Clercq and Merigan (2), who reported that the degree of protection of mice against intranasal infection with VSV was directly related to the titers of interferon induced by different doses of tilorone. Their interferon titers in response to tilorone were much higher than those in the present study. Since the 50% reduction in plaque count as a method for assay of interferon is more sensitive when MM virus is the challenge agent than when VSV is used (1), we must conclude that the differences in interferon titers in the two studies are real. This discrepancy could be due to a genotypic difference in the animals.

The effect of interferon inducers and exogenous L-cell interferon on the infection of mice by Pasteurella tularensis or Diplococcus pneumoniae was investigated. The results indicate that the degree of protection is dependent on the type of inducer used.

Mice receiving statolon intraperitoneally were 1,000 times more resistant to intraperitoneal challenge with mengovirus than were untreated controls. Protection was afforded when statolon was administered 1 day before or 1 day after intraperitoneal inoculation with the virus. No therapeutic effect was observed when treatment with statolon was delayed for 2 days or more after virus infection. Exposure of mice to a simulated space cabin environment did not increase their susceptibility to the lethal effects of mengovirus infection or eliminate the protective effect of statolon.

A single intraperitoneal injection of statolon was shown to exert a therapeutic effect on mice previously injected with the large plaque-forming variant of mengovirus. The LD50 and survival time data demonstrated that such treatment was effective when given 2 to 48 hr after infection. No protective effect was apparent when statolon was administered 3, 4, or 5 days after the viral challenge. It was concluded that statolon, or other similar interferon inducers, may be of therapeutic value in instances of accidental or other known exposure to hazardous viral agents.