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Publications and source records attributed to Peter V Dicpinigaitis.
The publisher regrets that this is an accidental duplication of an article that has already been published inPulm. Pharmacol. Ther., 16 (2003) 61-65, doi:10.1016/S1094-5539(02)00149-9. The duplicate article has therefore been withdrawn.
The experimental induction of cough has become an important component of clinical cough research. Measurement of cough reflex sensitivity allows the evaluation of the effect of pharmacological and other interventions on the cough reflex, as well as the performance of epidemiological studies relevant to cough. The most commonly used tussive agents include capsaicin, citric acid and ultrasonically nebulized distilled water (fog). Methodological considerations are vital to the performance of high quality, reproducible cough challenge, which is especially important when measuring the effect of an experimental intervention on cough reflex sensitivity. For the optimal execution of clinical trials employing inhalation cough challenge, the subject population must be carefully selected, and the usefulness and potential limitations of data obtained from cough challenge studies need to be appreciated.
Previous studies have shown that healthy cigarette smokers have diminished cough reflex sensitivity compared to healthy nonsmokers. We have recently demonstrated that cough reflex sensitivity is enhanced soon after smoking cessation, suggesting that diminished cough sensitivity in smokers results from chronic cigarette smoke-induced desensitization of airway cough receptors. In this study, we evaluated cough reflex sensitivity to capsaicin (C(5)) in 11 chronic smokers who had discontinued smoking for at least 2 weeks, and then resumed smoking. Two weeks after smoking cessation there was a significant enhancement of cough reflex sensitivity; mean (+/-SEM) log C(5) decreased from 1.77+/-0.18 to 1.47+/-0.14 (p=0.01). All subjects resumed smoking after 2-12 weeks of abstinence. Repeat capsaicin cough challenge was performed 14-23 days after resumption of smoking. Mean log C(5) increased compared to the last value obtained during the smoking cessation period: 1.42+/-0.15 vs. 1.77+/-0.16 (p=0.0004). Mean log C(5) after resumption of smoking returned to almost exactly the baseline value. Our findings suggest that the sensitivity of airway cough receptors is a dynamic phenomenon, promptly affected and modulated by changes in environmental conditions, such as the presence or absence of cigarette smoke.
Cough is among the most common complaints for which medical evaluation is sought. The clinical significance of this problem is evidenced by the enormous financial expenditure on prescription and non-prescription cough remedies worldwide. Centrally-acting antitussive agents, such as opiates, are often associated with undesirable or intolerable side effects, including sedation, nausea, and constipation. Therefore, safe and effective peripherally-acting antitussive agents are particularly desirable. Relatively few commercially-available products suppress cough through a peripheral mechanism of action. Recent research in the field of cough has resulted in the development of several new classes of compounds that may prove to be clinically useful peripherally-acting antitussives.
BACKGROUND: A dry, persistent cough is a well-described class effect of the angiotensin-converting enzyme (ACE) inhibitor medications. The mechanism of ACE inhibitor-induced cough remains unresolved, but likely involves the protussive mediators bradykinin and substance P, agents that are degraded by ACE and therefore accumulate in the upper respiratory tract or lung when the enzyme is inhibited, and prostaglandins, the production of which may be stimulated by bradykinin. METHODS: Data for this review were obtained from a National Library of Medicine (PubMed) search, which was performed in May 2004, of the literature published in the English language from 1985 to 2004, using the search terms "angiotensin-converting enzyme," "angiotensin converting enzyme inhibitors," and "cough." RESULTS: The incidence of ACE inhibitor-induced cough has been reported to be in the range of 5 to 35% among patients treated with these agents. However, a much lower incidence has been described in studies of patients presenting for the evaluation of chronic cough. The onset of ACE inhibitor-induced cough ranges from within hours of the first dose to months after the initiation of therapy. Resolution typically occurs within 1 to 4 weeks after the cessation of therapy, but cough may linger for up to 3 months. The only uniformly effective treatment for ACE inhibitor-induced cough is the cessation of treatment with the offending agent. The incidence of cough associated with therapy with angiotensin-receptor blockers appears to be similar to that of the control drug. In a minority of patients, cough will not recur after the reintroduction of ACE inhibitor therapy. CONCLUSIONS: In a patient with chronic cough, ACE inhibitors should be considered as wholly or partially causative, regardless of the temporal relation between the initiation of ACE inhibitor therapy and the onset of cough. Although the cessation of therapy is the only uniformly effective treatment for ACE inhibitor-induced cough, some pharmacologic agents have been shown to attenuate the cough.
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BACKGROUND: When the etiology of a patient's chronic cough is established, specific antitussive therapy that is aimed at a particular cause of cough is highly effective. Nevertheless, in certain situations, therapy with cough suppressants, which previously were classified as nonspecific antitussive therapy, and which aim at suppressing the cough reflex regardless of the cause of cough, will be necessary. METHODOLOGY: The data for this review were obtained with the aid of a National Library of Medicine (PubMed) search, which was performed in June 2004, of literature published in the English language from 1966 to 2004, using the search terms "cough," "antitussive," "pharmacotherapy," "future therapies, " and "potential therapies." RESULTS/CONCLUSIONS: Currently available cough-suppressant therapy is severely limited by a dearth of effective agents and/or their unacceptable side effects. Several classes of pharmacologic agents are currently under investigation in an attempt to develop clinically useful cough suppressants.
BACKGROUND: Asthma is among the most common causes of chronic cough in adult nonsmokers. Although cough usually accompanies dyspnea and wheezing, it may present in isolation as a precursor of typical asthmatic symptoms, or it may remain the predominant or sole symptom of asthma. The latter condition is known as cough-variant asthma (CVA). METHODS: Data for this review were obtained from a National Library of Medicine (PubMed) search, performed in April 2004, of the English language literature from 1975 to 2004, limited to human studies, using the search terms "cough" and "asthma." RESULTS: The diagnosis of cough not associated with typical asthmatic symptoms (ie, CVA) presents a challenge, because physical examination and spirometry findings may be entirely normal. Methacholine inhalation challenge testing can demonstrate the presence of bronchial hyperresponsiveness; however, the diagnosis of cough due to asthma is only confirmed after the resolution of cough with antiasthmatic therapy. In general, the therapeutic approach to asthmatic cough is similar to that of the typical form of asthma. Most patients will respond to inhaled bronchodilators and inhaled corticosteroids. A subgroup of patients will require the addition of leukotriene receptor antagonists and/or a short course of oral corticosteroids. CONCLUSIONS: Asthma should be considered as a potential etiology in any patient with chronic cough, because asthma is a common condition that is commonly associated with cough. Because the subgroup of asthmatic patients with CVA presents with no other symptoms of asthma, clinical suspicion must remain high. Cough due to asthma responds to standard antiasthmatic therapy.
STUDY OBJECTIVES: Cough is the most common complaint for which patients in the United States seek medical attention. Although the significant effect of cough on quality of life has been reported, the association of chronic cough with depressive symptomatology has not previously been investigated. DESIGN: Prospective, nonrandomized evaluation. SETTING: Outpatient department of academic medical center. PATIENTS: Representative sample of patients presenting to a specialty center seeking evaluation and treatment of chronic cough. INTERVENTIONS: Participants completed the Center for Epidemiologic Studies Depression Scale (CES-D), a 20-item self-report questionnaire designed to measure depressive symptomatology and risk for clinical depression, on initial evaluation and again after 3 months. Patients also provided subjective cough scores reflecting the severity of their cough. MEASUREMENTS AND RESULTS: Of 100 patients undergoing initial evaluation, 53% scored positive (>/= 16) on the CES-D. Mean CES-D score was 18.3 +/- 13.2 (+/- SD). Among 81 subjects followed up at 3 months, mean CES-D score fell to 7.4 +/- 10.4, and subjective cough score decreased from 10 to 4.9 +/- 3.1. There was a statistically significant improvement in both cough and depression scores after 3 months (p < 0.001). Improvement in cough score correlated significantly with improvement in depression score (p = 0.003; Spearman rho = 0.323). CONCLUSION: Depressive symptomatology is very common in patients with chronic cough. Physicians and other caregivers must be aware of the significant risk of clinical depression in this patient population.
BACKGROUND: Capsaicin, the pungent extract of red peppers, has achieved widespread use in clinical research because it induces cough in a dose-dependent and reproducible manner. Although > 2 decades of experience has led investigators to consider capsaicin cough challenge testing a safe diagnostic modality, this issue has not been specifically addressed in the literature. STUDY OBJECTIVES: To review the published experience with capsaicin inhalation challenge testing in terms of safety. DESIGN: Literature review and personal communication with study authors. SETTING: Academic medical center. RESULTS: One hundred twenty-two published studies since 1984 described 4,833 subjects (4,374 adults, 459 children) undergoing capsaicin cough challenge, with no serious adverse events reported. Subjects included healthy volunteers as well as patients with asthma, COPD, pathologic cough, and other respiratory conditions. Minor complaints described in a small fraction of studies consisted mainly of transient throat irritation. Personal communication with the authors of > 90% of the studies confirmed an absence of any serious adverse events. Furthermore, these investigators have performed thousands of additional capsaicin challenge studies not reported in the literature, also without any associated serious adverse events. CONCLUSIONS: A review of the 20-year clinical experience has failed to uncover a single serious adverse event associated with capsaicin cough challenge testing in humans. Given the need for better antitussive therapies, capsaicin represents a vital component of future scientific inquiry in the field of cough.
Cough is among the most common complaints for which patients seek medical attention. Consequently, enormous expenditures are made worldwide on prescription and non-prescription cough remedies. Multiple prospective studies have shown that specific antitussive therapy aimed at the underlying aetiology of cough is highly successful. The greatest current need therefore is for more effective nonspecific antitussive therapy, whose purpose is to suppress the cough reflex and provide symptomatic relief regardless of the underlying mechanism. Such therapy is particularly required for prolonged cough following upper respiratory tract infection, cough whose underlying aetiology is not easily treated, and idiopathic cough. Many areas of inquiry are currently ongoing that may lead to the development of novel and effective antitussive drugs.
The tussive agent capsaicin has achieved common usage in clinical research because it induces cough in a safe, dose-dependent, and reproducible manner. However, the reproducibility of capsaicin challenge testing has been demonstrated only in the short term (study intervals of 20 min to 14 days). In the present study, evaluation of data from several hundred cough challenges performed in the author's laboratory yielded two groups of 40 subjects. In the short-term reproducibility group, subjects underwent cough challenge at an interval of 14 days. Subjects in the long-term reproducibility group were challenged at intervals of at least 6 months (mean 16.7+/-2.4 months, range 6-62 months). All subjects were healthy adult volunteers who underwent identical cough challenge testing, which involved inhalation of incremental, doubling concentrations (microM) of capsaicin until the concentrations inducing two or more (C(2)) and five or more coughs (C(5)) were reached. Results were evaluated in terms of the percentage of subjects whose repeat studies yielded C(2) and C(5) values within one and two doubling concentrations of the initial values. Overall, reproducibility was quite good, with 90-100% of challenges yielding C(2) and C(5) values within two doubling concentrations. Short-term reproducibility of C(5) was superior to that of C(2), suggesting that C(5) is the preferred end point for trials involving serial cough challenges performed within a 14-day period.
AIMS: Current guidelines recommend the use of first-generation antihistamines for the treatment of cough due to rhinitis/postnasal drip syndrome. The antitussive activity of the second-generation antihistamine, fexofenadine, has not been investigated. Therefore, we evaluated the effect of fexofenadine on capsaicin-induced cough in healthy volunteers and in subjects with acute viral upper respiratory tract infection (URI). METHODS: Twelve healthy volunteers and 12 subjects with URI underwent pulmonary function testing and capsaicin cough challenge on two separate days, 2 h after ingesting 180 mg fexofenadine or matched placebo. Subjects inhaled single, vital-capacity breaths of capsaicin aerosol, administered in incremental doubling concentrations, until the concentration inducing five or more coughs (C5) was determined. RESULTS: In both subject groups, C5 was not significantly different after fexofenadine compared to placebo. In subjects with URI, pulmonary function studies were also similar. In healthy volunteers, however, FEV1 and FEF(25-75), pulmonary function parameters reflecting the degree of airway dilatation, were significantly increased after fexofenadine. Mean (95% CI) values for FEV1(L) after fexofenadine and placebo were 3.16 (2.77, 3.55) and 3.08 (2.69, 3.47), respectively (P = 0.017). Mean values for FEF(25-75)(L/s) were 3.49 (3.10, 3.88) and 3.26 (2.79, 3.72), respectively (P = 0.029). CONCLUSIONS: Fexofenadine demonstrated no antitussive activity against capsaicin-induced cough in healthy volunteers and subjects with URI. The ineffectiveness of fexofenadine in suppressing cough probably reflects the lack of anticholinergic activity and central nervous system penetrance that is characteristic of first-generation antihistamines. The mild bronchodilation induced by fexofenadine in healthy volunteers is of unclear clinical significance and requires further investigation.
STUDY OBJECTIVES: To evaluate cough reflex sensitivity in a population of young, healthy, male cigarette smokers. DESIGN: Cross-sectional comparison. SETTING: Academic medical center. PARTICIPANTS: Twenty healthy, male current-smokers (mean [+/- SEM] age, 32.2 +/- 1.2 years). MEASUREMENTS: Subjects underwent baseline spirometry followed by capsaicin cough challenge testing, which involved the inhalation of capsaicin in ascending, doubling concentrations until the concentrations inducing two or more coughs (C(2)) and those inducing five or more coughs (C(5)) were reached. The data were compared to those from a group of 50 healthy, male nonsmokers who had undergone identical cough challenge testing. RESULTS: The two groups did not differ in terms of age or baseline pulmonary function. Cough sensitivity was significantly diminished in the current-smokers compared to control subjects. The mean (+/- SEM) log C(2) values in smokers and nonsmokers were 1.26 +/- 0.13 and 0.81 +/- 0.08, respectively (p = 0.004). The mean log C(5) values in smokers and nonsmokers were 2.03 +/- 0.10 and 1.20 +/- 0.08, respectively (p < 0.000001). CONCLUSIONS: Cough reflex sensitivity is significantly diminished in young, healthy, male current-smokers compared to a similar population of nonsmokers. The mechanism of cough suppression in smokers remains speculative but may involve long-term tobacco smoke-induced desensitization of the cough receptors within the airway epithelium.
BACKGROUND: Guaifenesin, a commonly used agent for the treatment of cough, is termed an expectorant since it is believed to alleviate cough discomfort by increasing sputum volume and decreasing its viscosity, thereby promoting effective cough. Despite its common usage, relatively few studies, yielding contrasting results, have been performed to investigate the action and efficacy of guaifenesin. STUDY OBJECTIVES: To evaluate the effect of guaifenesin on cough reflex sensitivity. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Academic medical center. PARTICIPANTS: Fourteen subjects with acute viral upper respiratory tract infection (URI) and 14 healthy volunteers. INTERVENTIONS: On 2 separate days, subjects underwent capsaicin cough challenge 1 to 2 h after receiving a single, 400-mg dose (capsules) of guaifenesin or matched placebo. MEASUREMENTS AND RESULTS: The concentration of capsaicin inducing five or more coughs (C(5)) was determined. Among subjects with URI, mean (+/- SEM) log C(5) after guaifenesin and placebo were 0.92 +/- 0.17 and 0.66 +/- 0.14, respectively (p = 0.028). No effect on cough sensitivity was observed in healthy volunteers. CONCLUSIONS: Our results demonstrate that guaifenesin inhibits cough reflex sensitivity in subjects with URI, whose cough receptors are transiently hypersensitive, but not in healthy volunteers. Possible mechanisms include a central antitussive effect, or a peripheral effect by increased sputum volume serving as a barrier shielding cough receptors within the respiratory epithelium from the tussive stimulus.
Cough-variant asthma (CVA) occurs in a subgroup of asthmatics whose sole or predominant respiratory symptom is cough. Although bronchodilators are often sufficient to treat CVA, refractory cough may require therapy with inhaled or systemic corticosteroids. In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of a 14-day course of the leukotriene receptor antagonist zafirlukast on subjective cough score and cough-reflex sensitivity to inhaled capsaicin in eight subjects with CVA refractory to inhaled beta agonists, and in five subjects refractory to inhaled corticosteroids. Seven of eight subjects experienced significant subjective and objective improvement in cough after treatment with zafirlukast. Mean (+/- SEM) cough score improved from 7.75 +/- 0.56 to 3.25 +/- 0.84 (p = 0.0006). Cough sensitivity to capsaicin was suppressed by zafirlukast in all subjects. Patients with CVA may represent a distinct subgroup of asthmatics whose afferent cough receptors within the respiratory epithelium are hypersensitive relative to those of patients with the typical form of asthma. Zafirlukast appears to be particularly effective in treating CVA by inhibiting the sensitivity of these receptors. Leukotriene receptor antagonists may offer an alternative to corticosteroids for the treatment of CVA refractory to inhaled bronchodilators.