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

Al‐Nakib, W.; Higgins, P. G.; Barrow, G. I.; Tyrrell, D. A. J.; Andries, Koen; Bussche, G. Van Den; Taylor, Norman E.; Janssen, P. A. J.

doi:10.1128/aac.33.4.522

Cited by 85 publications

(42 citation statements)

References 8 publications

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“…The findings of the present study were predicted by results obtained in experimentally infected volunteers (9) and help to confirm the validity of the human challenge model with regard to the evaluation of antirhinoviral agents. Previous studies of pirodavir and its narrower-spectrum predecessor, R61,837, found that intranasal administration was protective against rhinovirus illness when it was begun prior to viral challenge with a susceptible serotype (1,9) and, in the case of R61,837, when administration was begun during the incubation period before symptom onset (5). In contrast, when pirodavir (six sprays per day) administration was begun at 1 day after viral challenge, when the subjects were symptomatic, reductions in the frequency of viral shedding but no clinical benefits were found (9).…”

Section: Discussionmentioning

confidence: 99%

Intranasal pirodavir (R77,975) treatment of rhinovirus colds

Hayden

Hipskind

Woerner

et al. 1995

Antimicrob Agents Chemother

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A randomized, double-blind, placebo-controlled trial assessed the therapeutic efficacy of intranasal pirodavir in naturally occurring rhinovirus colds. Adults with symptoms of Յ2 days' duration were randomly assigned to intranasal sprays of pirodavir (2 mg per treatment) or placebo six times daily for 5 days. In people with laboratory-documented rhinovirus colds (53 in the pirodavir group, 55 in the placebo group), no significant differences in the resolution of respiratory symptoms were apparent between the groups. The median duration of illness was 7 days in each group. Similarly, scores for individual symptoms found no differences in favor of pirodavir during or after treatment. In contrast, reduced frequencies of rhinovirus shedding were observed in the pirodavir group on day 3 (70 versus 23%; P < 0.001) and day 5 (38 versus 12%; P ‫؍‬ 0.002) but not after the cessation of treatment, on day 7 (19 versus 21%). No pirodavir-resistant viruses were recovered from treated individuals. The pirodavir group had higher rates of nasal dryness, blood in mucus, or unpleasant taste on several study days. In summary, intranasal sprays of pirodavir were associated with significant antiviral effects but no clinical benefit in treating naturally occurring rhinovirus colds.

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Section: Discussionmentioning

confidence: 99%

Intranasal pirodavir (R77,975) treatment of rhinovirus colds

Hayden

Hipskind

Woerner

et al. 1995

Antimicrob Agents Chemother

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“…The literature on the common cold contains many studies on prophylactic use of such agents as interferons [19][20][21][22][23][24][25][26] and synthetic drugs 8,27,28 in attempts to prevent colds or shorten their duration. Interferon, for example has demonstrated varying degrees of prophylactic efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…Interferon, for example has demonstrated varying degrees of prophylactic efficacy. [20][21][22]24,26 Success with such agents has proven to be elusive to date, 8,[19][20][21][22][23][24][25][26][27][28] as most treatments either have had limited efficacy or have had side-effects, such as nasal irritation, that are more severe than the symptoms of the cold. Very few agents have been found to have any effect once the symptoms have developed, i.e.…”

Section: Discussionmentioning

confidence: 99%

Zinc Gluconate and the Common Cold: A Controlled Clinical Study

et al. 1992

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A report in 1984 on the success of zinc gluconate against common cold symptoms could not be confirmed in three subsequent studies, which are now known to have used formulations that inactivated zinc. A non-chelating formulation including glycine, which releases 93% of contained zinc into saliva, was tested in a randomized, placebo-controlled, double-blind trial in 73 young adults. Efficacy was recorded in symptom diaries using a symptom severity rating. Patients' symptoms first appeared 1.34 days prior to entry to the study in both groups. Disappearance of symptoms occurred after an additional 4.9 days for zinc-treated patients versus 6.1 days for placebo-treated patients. A difference was noted in the efficacy of treatment if it was started 1 day after symptom onset: cold duration was an additional 4.3 days in zinc-treated patients compared with 9.2 days for placebo-treated patients. Cough, nasal drainage and congestion were the symptoms most affected, and only mild side-effects were noted.

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“…Several compounds of the WIN series have proved to be efficacious in various animal models of enteroviral disease (16,25). R 61837, the prototype compound of the pyridazinamine series, has shown clinical efficacy in humans (1). A pilot clinical trial of pirodavir under double-blind, placebo-controlled conditions indicated that the compound has a clinical effect in humans (13).…”

Section: Methodsmentioning

confidence: 99%

In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity

Andries

Dewindt

Snoeks

et al. 1992

Antimicrob Agents Chemother

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Pirodavir (R 77975) is the prototype of a novel class of broad-spectrum antipicornavirus compounds. Although its predecessor, R 61837, a substituted phenyl-pyridazinamine, was effective in inhibiting 80% of 100 serotypes tested (EC.) at concentrations above 32 ,ug/ml, pirodavir inhibits the same percentage of viruses at 0.064 ,ug/ml. Whereas R 61837 was active almost exclusively against rhinovirus serotypes of antiviral group B, pirodavir is broad spectrum in that it is highly active against both group A and group B rhinovirus serotypes.Pirodavir is also effective in inhibiting 16 enteroviruses, with an ECgo of 1.3 ,ug/ml. Susceptible rhinovirus serotypes were rendered noninfectious by direct contact with the antiviral compound. Their infectivity was not restored by dilution of virus-drug complexes, but was regained by organic solvent extraction of the compound for most serotypes. Neutralized viruses became stabilized to acid and heat, strongly suggesting a direct interaction of the compounds with viral capsid proteins. Mutants resistant to R 61837 (up to 85 times the MIC) were shown to bear some cross-resistance (up to 23 times the MIC) to the new compound, indicating that pirodavir also binds into the hydrophobic pocket beneath the canyon floor of rhinoviruses. Pirodavir acts at an early stage of the viral replication cycle (up to 40 min after infection) and reduces the yield of selected rhinoviruses 1,000-to 100,000-fold in a single round of replication. The mode of action appears to be serotype specific, since pirodavir was able to inhibit the adsorption of human rhinovirus 9 but not that of human rhinovirus 1A. Pirodavir is a novel capsid-binding antipicornavirus agent with potent in vitro activity against both group A and group B rhinovirus serotypes.

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

Cited by 85 publications

References 8 publications

Intranasal pirodavir (R77,975) treatment of rhinovirus colds

Intranasal pirodavir (R77,975) treatment of rhinovirus colds

Zinc Gluconate and the Common Cold: A Controlled Clinical Study

In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity

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