Intranasal Treatment of Picornavirus and Coronavirus Respiratory Infections in Rodents Using 7-Thia-8-Oxoguanosine

Abstract

SummarySince common cold viruses are responsive to interferon, we developed two animal models to test the efficacy of the interferon inducer 7-thia-8-oxoguano'" sine: (i) an intranasal coronavirus infection in suckling rats; and (ii) an intranasal encephalomyocarditis (EMC) virus infection in adult mice. Concentrations of 0.3 and 1% 7-thia-8-oxoguanosine delivered intranasally to rats 24 and 18 hours before virus inoculation were highly protective against the otherwise lethal coronavirus infection. A 1% concentration of drug administered 4 and 8 hours after virus challenge increased mean survival times of rats but did not increase numbers of survivors. Intranasal treatment of an EMC infection produced moderate improvements in mean survival times and survival. Titrations of EMC virus indicated >300-fold reductions in nasal titres in drug-treated relative to placebo control animals on days 2-4 following virus challenge. The distribution of r 4 C]-7-thia-8-oxoguanosine was determined shortly after intranasal delivery to mice and rats. Approximately 50% of total doses were deposited in the inner noses and mouths of both species. Most of the rest was found on/in the outer noses, stomachs, tracheas, oesophagi, and lungs. By analogy, the infecting viruses were deposited on/in the same organs and tissues of each species. The results suggest that containment of the viruses primarily occurred in the nasopharyngeal area prior to their spread to the lungs (rat coronavirus) or the brain (EMC), where fatal pathologies were manifest. Intranasal application of an interferon-inducing nucleoside analogue represents a new approach for the study of treatment of the common cold.

Effects of Plant-Derived Polysaccharides on Murine Cytomegalovirus and Encephalomyocarditis Virus Infections in Mice

“…The fact that the polysaccharides are inhibitory to these viruses in a prophylactic but not a therapeutic manner and do not inhibit the viruses in vitro is consistent with them being immune-enhancing agents. This is in agreement with other published work (Stringfellow et a/., 1977;Morahan and Pinto, 1992;Smee et a/., 1989Smee et a/., , 1990aSmee et a/., , 1990bSmee et a/., , 1992Smee et a/., , 1995a.…”

“…ECMV was passaged in mouse L929 cells (ATCC). In vitro titration of MCMV was conducted in mouse embryo fibroblasts (MEF cells;Freitas et al, 1985); EMCV was titrated in L929 cells (Smee et al, 1990a). Each virus was later titrated for lethality in mice.…”

“…Plaque reduction assays against MCMV were performed in mouse C1271 cells (Smee et al, 1995b), whereas cytopathic effect inhibition tests against EMCV were conducted in mouse L929 cells (Smee et al, 1990a), as described. Compounds were evaluated in half-log 1o increments varying from 1 to 100 Ilg/ml.…”

“…Although immune-stimulating antiviral agents may affect a number of virus infections in vivo (Smee et al, 1992), their effects on only two viral systems which are relevant to human disease were focussed upon in this paper. These include murine cytomegalovirus (MCMV), which is an animal model for human cytomegalovirus disease (Kern, 1991); and encephalomyocarditis virus (EMCV), a picornavirus related to human common cold viruses (rhinoviruses) that may be predictive of activity against the common cold (Smee et al, 1990a).…”

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

“…Guanosine analogs of the thiazolo [4,5-d]pyrimidine ring system, such as 7-thia-8-oxoguanosine, have been reported to possess in vivo activity against a variety of RNA and DNA viruses (17,26,28). Surprisingly, no direct in vitro antiviral activity in virus-infected cells was observed with these compounds (5).…”