Efficacy and Safety of Oral Pleconaril for Treatment of Colds Due to Picornaviruses in Adults: Results of 2 Double-Blind, Randomized, Placebo-Controlled Trials

Hayden, Frederick G.; Herrington, Darrell T.; Coats, Teresa L.; Kim, Kenneth; Cooper, Ellen C.; Villano, Stephen; Liu, Siyu; Hudson, Spencer; Pevear, Daniel C.; Collett, Marc S.; McKinlay, Mark A.

doi:10.1086/375069

Cited by 279 publications

(184 citation statements)

References 31 publications

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“…This model has major advantages as it permits investigations of exacerbations in a controlled manner with a single etiological agent, and facilitates longitudinal sampling, allowing investigation of temporal and quantitative relationships between virus infection, inflammatory mediators, and biological and physiological markers in a manner not possible with cross-sectional studies of naturally occurring exacerbations. The evidence we provide linking rhinovirus infection to COPD exacerbations should stimulate research into both existing and novel antiviral therapies as potential therapies in COPD (44). Therapies targeting neutrophilic inflammation (45) and neutrophil elastase inhibitors (46) or augmentation of IFN-b may also have potential in the treatment or prevention of COPD exacerbations.…”

Section: Discussionmentioning

confidence: 93%

Experimental Rhinovirus Infection as a Human Model of Chronic Obstructive Pulmonary Disease Exacerbation

Mallia

Message²,

Gielen³

et al. 2011

Am J Respir Crit Care Med

352

416

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Rationale: Respiratory virus infections are associated with chronic obstructive pulmonary disease (COPD) exacerbations, but a causative relationship has not been proven. Studies of naturally occurring exacerbations are difficult and the mechanisms linking virus infection to exacerbations are poorly understood. We hypothesized that experimental rhinovirus infection in subjects with COPD would reproduce the features of naturally occurring COPD exacerbations and is a valid model of COPD exacerbations. Objectives: To evaluate experimental rhinovirus infection as a model of COPD exacerbation and to investigate the mechanisms of virusinduced exacerbations. Methods: We used experimental rhinovirus infection in 13 subjects with COPD and 13 nonobstructed control subjects to investigate clinical, physiologic, pathologic, and antiviral responses and relationships between virus load and these outcomes. Measurements and Main Results: Clinical data; inflammatory mediators in blood, sputum, and bronchoalveolar lavage; and viral load in nasal lavage, sputum, and bronchoalveolar lavage were measured at baseline and after infection with rhinovirus 16. After rhinovirus infection subjects with COPD developed lower respiratory symptoms, airflow obstruction, and systemic and airway inflammation that were greater and more prolonged compared with the control group. Neutrophil markers in sputum related to clinical outcomes and virus load correlated with inflammatory markers. Virus load was higher and IFN production by bronchoalveolar lavage cells was impaired in the subjects with COPD. Conclusions: We have developed a new model of COPD exacerbation that strongly supports a causal relationship between rhinovirus infection and COPD exacerbations. Impaired IFN production and neutrophilic inflammation may be important mechanisms in virusinduced COPD exacerbations.

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Section: Discussionmentioning

confidence: 93%

Experimental Rhinovirus Infection as a Human Model of Chronic Obstructive Pulmonary Disease Exacerbation

Mallia

Message²,

Gielen³

et al. 2011

Am J Respir Crit Care Med

352

416

View full text Add to dashboard Cite

show abstract

“…At the first study visit, subjects were taught to collect samples of their own nasal mucus, using a nose-blowing technique as previously described (10,11). These samples were analyzed for common respiratory viruses by multiplex polymerase chain reaction (respiratory MultiCode assay; EraGen Biosciences, Madison, WI) (12) and by seminested polymerase chain reaction specific for the hemagglutinin gene of the 2009 H1N1 influenza virus (see the online supplement for details).…”

Section: Procedures and Definitionsmentioning

confidence: 99%

Increased H1N1 Infection Rate in Children with Asthma

Kloepfer¹,

Olenec²,

Lee³

et al. 2012

Am J Respir Crit Care Med

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Rationale: The 2009 H1N1 flu appeared to cause more severe cold symptoms during the 2009-2010 flu season. Objectives: We evaluated H1N1 infections during peak viral season in children with and without asthma to determine whether the H1N1 infectivity rate and illness severity were greater in subjects with asthma. Methods: One hundred and eighty children, 4-12 years of age, provided eight consecutive weekly nasal mucus samples from September 5 through October 24, 2009, and scored cold and asthma symptoms daily. Viral diagnostics were performed for all nasal samples. Measurements and Main Results: One hundred and sixty-one children (95 with asthma, 66 without asthma) completed at least 6 of the 8 nasal samples. The incidence of H1N1 infection was significantly higher in children with asthma (41%) than in children without asthma (24%; odds ratio, 4; 95% confidence interval, 1.8-9; P , 0.001), but rates of human rhinovirus infection (90% each) and other viral infections (47 vs. 41%) were similar. In children with asthma, there was a nonsignificant trend for increased loss of asthma control during H1N1 infections compared with human rhinovirus infections (38 vs. 21%; odds ratio, 2.6; 95% confidence interval, 0.9-7.2; P ¼ 0.07). Conclusions: During peak 2009 H1N1 flu season, children with asthma were infected almost twice as often with H1N1 compared with other respiratory viruses. H1N1 infection also caused increased severity of cold symptoms compared with other viral infections. Given the increased susceptibility of children with asthma to infection, these findings reinforce the need for yearly influenza vaccination to prevent infection, and raise new questions about the mechanism for enhanced susceptibility to influenza infection in asthma.Keywords: asthma; viral infection; influenza 2009 H1N1 Flu was first reported in the United States in the spring of 2009, and eventually affected 61 million people (1), one-third of them children. Morbidity was high, with 87,000 children requiring hospitalization. The most common comorbidity for patients hospitalized as a result of H1N1 infection was asthma (2), and the percentage of children with asthma hospitalized because of the 2009 H1N1 virus was two-to fivefold higher than previous reports of hospitalization due to seasonal influenza (3, 4). Despite the observation that subjects with asthma suffer H1N1 illness with increased severity, it remains unclear at what rate they are infected and whether their symptom severity is greater than those of their nonasthmatic counterparts. Previous studies of H1N1 infectivity reflect symptomatic infections with limited reporting of mild or asymptomatic infection (5-7).A study by our group demonstrated that 90% of children with asthma are infected with human rhinoviruses (HRVs) during the month of September, and that the severity of clinical illness varies from no symptoms to severe wheezing illnesses (8). This study provided the foundation on which we designed a larger cohort to prospectively examine the relationship between illness symptom...

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“…The agent that came furthest in clinical development was pleconaril. In two large phase II, placebo-controlled, natural cold trials, pleconaril was demonstrated to reduce the time to alleviation of illness in patients with an onset of a typical cold within 36 hours of respiratory symptoms during the months between July and December; this clinical response was noted in subjects who were HRV positive (121). Furthermore, subsequent analyses confirmed that clinical response to pleconaril was limited to those infected with pleconaril-sensitive HRV strains (122).…”

Section: Pathogen-specific Therapymentioning

confidence: 91%

“…Induction of reduced pleconaril susceptibility in HRV isolates was seen in greater than 10% of patients, although the clinical course of illness in these subjects was less protracted than in the overall group. A subsequent 6-week prophylaxis study documented that pleconaril induced CYP3A4, which led to intermenstrual bleeding and related menstrual abnormalities in women taking estrogenbased oral contraceptives (121,123). In March 2002, a U.S. Food and Drug Administration Antiviral Drugs Advisory Committee voted to not recommend pleconaril approval based on these drug interactions and possible transmission of resistance isolates.…”

Section: Pathogen-specific Therapymentioning

confidence: 99%

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Pathogen-directed Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Martínez

2007

Proceedings of the American Thoracic Society

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Acute exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the natural history of this chronic lung disorder. These events can be caused by a large number of infectious and noninfectious agents and are associated with an increased local and systemic inflammatory response. Their frequency and severity have been linked to progressive deterioration in lung function and health status. Infectious pathogens ranging from viral to atypical and typical bacteria have been implicated in the majority of episodes. Most therapeutic regimens to date have emphasized broad, nonspecific approaches to bronchoconstriction and pulmonary inflammation. Increasingly, therapy that targets specific etiologic pathogens has been advocated. These include clinical and laboratory-based methods to identify bacterial infections. Further additional investigation has suggested specific pathogens within this broad class. As specific antiviral therapies become available, better diagnostic approaches to identify specific pathogens will be required. Furthermore, prophylactic therapy for at-risk individuals during high-risk times may become a standard therapeutic approach. As such, the future will likely include aggressive diagnostic algorithms based on the combination of clinical syndromes and rapid laboratory modalities to identify specific causative bacteria or viruses.

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Efficacy and Safety of Oral Pleconaril for Treatment of Colds Due to Picornaviruses in Adults: Results of 2 Double-Blind, Randomized, Placebo-Controlled Trials

Cited by 279 publications

References 31 publications

Experimental Rhinovirus Infection as a Human Model of Chronic Obstructive Pulmonary Disease Exacerbation

Experimental Rhinovirus Infection as a Human Model of Chronic Obstructive Pulmonary Disease Exacerbation

Increased H1N1 Infection Rate in Children with Asthma

Pathogen-directed Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

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