Antitussive effect of the GABA-agonist baclofen.

BACKGROUND: gamma-Aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in peripheral tissues, including the lung. The GABA-agonist baclofen has been shown, in animal studies, to inhibit cough via a central mechanism, but has not been investigated in humans (to our knowledge). STUDY OBJECTIVE: To evaluate the antitussive effect of baclofen in normal human subjects. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Academic medical center. PARTICIPANTS: Twenty healthy, adult volunteers. INTERVENTIONS: Subjects underwent cough challenge with inhaled capsaicin before and after a 14-day course of baclofen, 10 mg three times daily, or placebo. Capsaicin cough threshold (C5) was defined as the concentration of inhaled capsaicin inducing five or more coughs. RESULTS: Subjects receiving baclofen (n=10) demonstrated a significant elevation of capsaicin cough threshold compared with placebo subjects (n=10). Mean delta log C5 after treatment was 0.48+/-0.19 (SEM) for the baclofen group, and -0.06+/-0.12 for the placebo group (p=0.024). Six of 10 subjects receiving baclofen, but none of the 10 subjects receiving placebo, demonstrated a fourfold or greater increase in capsaicin cough threshold (p=0.0054). CONCLUSION: The antitussive activity of low-dose, oral baclofen demonstrated in this study supports further investigation of this drug, or other GABA-agonists, for a potential therapeutic role in the treatment of pathologic cough.

Effect of angiotensin-converting enzyme inhibition on bronchial responsiveness.

The effect of angiotensin-converting enzyme (ACE) inhibition on bronchial responsiveness has not been clearly established. Because ACE degrades bradykinin and substance P, inhibition of the enzyme may lead to accumulation of these potent bronchoconstrictors in the lung, potentially leading to enhanced bronchial reactivity or bronchospasm. Previous studies of the effect of ACE inhibition on airway responsiveness have yielded conflicting results. A randomized, double-blind, placebo-controlled study was therefore conducted to evaluate the effect of a 14-day course of oral lisinopril (10 mg for days 1-3, 20 mg for days 4-14) on bronchial responsiveness to inhaled methacholine in a group of healthy volunteers. No significant change in methacholine responsiveness occurred in any of the participants receiving lisinopril. The mean ( +/- SD) concentration of methacholine producing a decrease in FEV1 of 20% from baseline (PC20; mg/mL) was 23.3 +/- 5.0 before the study and 23.5 +/- 4.5 at the end of the study for the lisinopril group, and 23.0 +/- 4.6 before the study and 21.8 +/- 6.9 after the study for the placebo group. The 14-day course of ACE inhibitor therapy did not enhance nonspecific bronchial responsiveness in healthy volunteers.

Inhibition of capsaicin-induced cough by the gamma-aminobutyric acid agonist baclofen.

Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in the lungs. The GABA-agonist baclofen has been shown to have antitussive activity via a central mechanism in animals. Recently it was demonstrated that a 14-day course of baclofen given three times daily significantly inhibits the cough reflex in healthy volunteers. Because of the prolonged antitussive effect of baclofen that has been previously observed, the present study was conducted to evaluate the antitussive effect of low-dose, oral baclofen given once daily. Forty-one healthy volunteers were randomly assigned in a double-blind manner to receive a 28-day course of baclofen, either 10 mg or 20 mg once daily, or placebo. Subjects underwent cough challenge testing with inhaled capsaicin to establish baseline cough reflex sensitivity, and subsequently after 14 and 28 days of therapy. Subjects receiving baclofen 20 mg daily demonstrated significant inhibition of cough sensitivity after 14 days and after 28 days of therapy compared with baseline. Neither placebo nor baclofen 10 mg daily had a significant effect on cough sensitivity. No serious side effects were experienced by any study participant. These results confirm the recent observation that baclofen has significant antitussive activity in humans. Further, once-daily administration of a relatively low dose of baclofen is sufficient to achieve significant cough inhibition, although at least 14 to 28 days of therapy may be required to attain maximal antitussive effect. These results support further investigation of baclofen or other GABA-agonists as potential therapeutic agents for chronic, nonproductive cough.

Effect of zafirlukast on cough reflex sensitivity in asthmatics.

In patients with asthma, increased sensitivity of airway sensory nerves may be involved in producing bronchospasm and cough. To evaluate the effect of a leukotriene-modifying agent on cough reflex sensitivity, we measured the cough response to inhaled capsaicin before and after a 1 4-day course of therapy with zafirlukast, a cysteinyl leukotriene receptor antagonist, in a group of stable asthmatics. The concentration of capsaicin inducing two or more (C2) and five or more (C5) coughs was not altered by zafirlukast, even in those subjects demonstrating a significant change (increment or decrement) in forced expiratory volume in 1 sec (FEV1). These findings support previous evidence that cough and bronchoconstriction are modulated by distinct neural pathways.