Antiviral Activity of a bis-Benzimidazole Against Experimental Rhinovirus Infections in Chimpanzees1

Abstract

The marked antiviral activity of (S,S-1,2-bis(5-methoxy-2-benzimidazolyl)-1, 2-ethanediol (Abbott 36683) against rhinoviruses in tissue culture warranted investigation of its antiviral activity in vivo. Antiviral levels in mouse sera were attained with an oral dose as small as 10 mg/kg and detectable antiviral levels of drug were also found in lung, liver, kidney, intestinal contents, and urine of mice given a single 300 mg/kg oral dose. Antiviral serum levels were also obtained when monkeys were given a single oral dose of Abbott 36683. Six chimpanzees were infected with 100 median tissue culture infective dose units (TCID50) of rhinovirus 30. Three of the animals were treated with Abbott 36683, 100 mg/kg daily for 4 consecutive days. Virus shedding occurred in the infected controls but could not be demonstrated in the treated animals from postinfection days 1 to 8. Two of the treated animals did, however, shed virus on day 9. The compound was retested in chimpanzees at dosage levels of 15 and 50 mg/kg daily for 4 days. Each animal was challenged with 100 TCIDO of rhinovirus 49. Partial protection was obtained. In a third trial, a single 100 mg/kg dose of the compound was administered to chimpanzees infected with rhinovirus 44. Virus was isolated from all throat smears taken from treated animals, indicating that at the lowest drug level no protection occurred.

In vivo experimental models of infection and disease

“…200 Subsequent studies in chimpanzees and gibbons assessed the antiviral effects of drug treatments on RV infection, using bis-benzimidazole and triazinoindole, respectively. 201,202 Administration of soluble truncated form of human ICAM-1 can prevent subsequent infection in chimpanzees. 203 However, it has been noted that neither chimpanzees nor gibbons develop "cold" symptoms following RV infection and the high costs and logistics of these studies has limited further progress.…”

Diagnosis of viral disease and the advent of antiviral drugs

“…This drug may also have a significant impact on viral excretion and hence contagion (Schulman, 1968). Bis-benzimidazoles also are not being pursued for use in rhinovirus infections (Shipkowitz et al, 1972). Hydroxybenzylbenzimidazole and guanidine, inhibitors of certain picornaviruses, have long been rejected as having no in vivo activity, a rejection based on very little data.…”

“…Although certain drugs may be useful to treat only the symptoms of the common cold when produced by rhinoviruses and coronaviruses, this too may not be enough when these viruses produce more serious lower respiratory tract illnesses in children. Since rhinoviruses are related to the enteroviruses it could well be that drugs inhibitory for one group will work against all picornavirus and there are a number of antiviral compounds that suggest this possibility, including hydroxybenzimadazole (Gwaltney, 1968), the bisbenzimidazoles (Schleicher et al, 1972), the triazinoindoles (Gwaltney, 1970) and AR-336 (DeLong et al, 1978).…”