Failure of intranasally administered 4?, 6-dichloroflavan to protect against rhinovirus infection in man

Abstract

4',6-Dichloroflavan, a potent inhibitor of rhinovirus replication in tissue culture systems was tested in a double-blind, placebo-controlled volunteer trial for its protective efficacy against experimental rhinovirus infection. Dichloroflavan was administered intranasally as a 5 per cent w/v aqueous suspension (40 mg; 5 times per day) for 5 doses before and 21 doses after intranasal challenge with rhinovirus type 9, a virus type known to be highly sensitive to the drug when tested in tissue culture. A total of 49 volunteers were included in the efficacy analysis. Dichloroflavan did not produce any consistent or significant reduction in clinical or laboratory parameters of infection. Indeed there was some indication that treatment with the drug may have been associated with increased severity of clinical signs and symptoms. Dichloroflavan administered intranasally is not, therefore, of value in the prevention of human rhinovirus infection.

Safety and efficacy of intranasal pirodavir (R77975) in experimental rhinovirus infection

“…The calculated efficacy of pirodavir in preventing infection was 42%. Similarly, the overall number of days of virus shedding was reduced in the pirodavir group, and significant differences in the proportion of virus-positive subjects in the pirodavir and placebo groups were found on days 2 (0 versus 69%, P < 0.001), 3 (17% versus 85%, P = 0.005), and 4 (17% versus 62%, P = 0.04) of drug administration. At 48 or 72 h after cessation of drug administration, 33% of pirodavirtreated subjects and 69% of placebo-treated subjects continued to shed virus on one or both days (P = 0.12).…”

“…These agents appear to bind into a specific hydrophobic pocket within the capsid protein VP1, beneath the canyon floor of rhinoviruses, and prevent viral attachment and/or uncoating, depending on the serotype involved (13,15). However, clinical trials in which several of the agents were administered orally or intranasally yielded negative results (2,3,14,18). The first of these agents to show clinical activity in studies with humans was the pyridazinamine R61837 (1,7).…”

Suppression of colds in human volunteers challenged with rhinovirus by a new synthetic drug (R61837)

“…Treatment continued for a period of about 4 days, depending on how soon symptoms had developed after virus challenge. Each volunteer was assessed daily by a clinician who was unaware of the medication and challenge that they had received and who allotted a clinical score as described previously (2). Paper tissues were collected daily and sealed in tared plastic bags which were weighed to determine the amount of nasal secretion they contained.…”

Chemotherapy of rhinovirus colds

“…However, nasal drops of dichloroflavan, 40 mg five times daily, failed to reduce infection rates or protect against illness after experimental rhinoviral infection. These findings suggest that despite high levels in nasal washings, adequate levels were not achieved in nasal mucosal cells (6).…”

“…Despite adequate levels in plasma, drug was not detected in nasal washings, and no antiviral effect was found (91). A subsequent study determined that intranasal administration of dichloroflavan was tolerated and resulted in high nasal wash concentrations for 3 to 3.5 h after administration (6). However, nasal drops of dichloroflavan, 40 mg five times daily, failed to reduce infection rates or protect against illness after experimental rhinoviral infection.…”