piperidines and Common-Cold

A randomized, double-blind, placebo-controlled trial assessed the therapeutic efficacy of intranasal pirodavir in naturally occurring rhinovirus colds. Adults with symptoms of < or = 2 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.

Topics: Administration, Intranasal; Adolescent; Adult; Aged; Antiviral Agents; Common Cold; Double-Blind Method; Female; Humans; Male; Middle Aged; Patient Compliance; Piperidines; Pyridazines; Rhinovirus

Pirodavir (R77975) is a capsid-binding, antipicornaviral agent with in vitro activity against most rhinovirus (RV) serotypes. We conducted four double-blind, controlled trials to assess the efficacy of intranasal pirodavir in experimentally induced RV infection of susceptible volunteers. Intranasal pirodavir (2 mg per dose) or the hydroxypropyl-beta-cyclodextrin vehicle as a placebo was given by metered pump spray. In three prophylaxis trials, subjects were inoculated with RV within 10 min of the second and third doses. When sprays were given six times per day for a total of 25 doses, infection, detected by either virus shedding or seroconversion, developed in 100% of the 13 placebo-treated subjects and 58% of the 12 pirodavir-treated subjects (P = 0.015). Clinical colds developed in 54% of placebo-treated subjects and 8% of pirodavir-treated subjects during drug administration (efficacy = 85%, P = 0.03), although late-developing colds developed in several subjects in both groups. Significant reductions in morning symptom scores and in the frequency of abnormal middle-ear pressures were also found in the pirodavir group. In contrast, in two prophylaxis studies using three doses daily, no significant antiviral or clinical benefits were observed. When frequent sprays were initiated at 24 h after RV challenge, significant reductions in virus shedding but no clinical benefits were found. Intranasal pirodavir was generally well tolerated but was associated with an excess rate of transient unpleasant taste. The findings indicated that frequent intranasal sprays of pirodavir were effective in preventing experimentally induced RV illness.

Topics: Administration, Intranasal; Adolescent; Adult; Common Cold; Double-Blind Method; Humans; Middle Aged; Piperidines; Pyridazines

Topics: Ascorbic Acid; Benzhydryl Compounds; Clinical Trials as Topic; Common Cold; Delayed-Action Preparations; Histamine H1 Antagonists; Humans; Piperidines

Human rhinovirus type C (HRV-C) is a newly discovered enterovirus species frequently associated with exacerbation of asthma and other acute respiratory conditions. Until recently, HRV-C could not be propagated in vitro, hampering in-depth characterization of the virus replication cycle and preventing efficient testing of antiviral agents. Herein we describe several subgenomic RNA replicon systems and a cell culture infectious model for HRV-C that can be used for antiviral screening. The replicon constructs consist of genome sequences from HRVc15, HRVc11, HRVc24, and HRVc25 strains, with the P1 capsid region replaced by a Renilla luciferase coding sequence. Following transfection of the replicon RNA into HeLa cells, the constructs produced time-dependent increases in luciferase signal that can be inhibited in a dose-dependent manner by known inhibitors of HRV replication, including the 3C protease inhibitor rupintrivir, the nucleoside analog inhibitor MK-0608, and the phosphatidylinositol 4-kinase IIIβ (PI4K-IIIβ) kinase inhibitor PIK93. Furthermore, with the exception of pleconaril and pirodavir, the other tested classes of HRV inhibitors blocked the replication of full-length HRVc15 and HRVc11 in human airway epithelial cells (HAEs) that were differentiated in the air-liquid interface, exhibiting antiviral activities similar to those observed with HRV-16. In summary, this study is the first comprehensive profiling of multiple classes of antivirals against HRV-C, and the set of newly developed quantitative HRV-C antiviral assays represent indispensable tools for the identification and evaluation of novel panserotype HRV inhibitors.

Topics: Antiviral Agents; Common Cold; Dose-Response Relationship, Drug; HeLa Cells; Humans; In Vitro Techniques; Isoxazoles; Oxadiazoles; Oxazoles; Phenylalanine; Piperidines; Pyridazines; Pyrrolidinones; Replicon; Rhinovirus; RNA, Viral; Tubercidin; Valine; Virus Replication