Altered regulation of intracellular calcium is probably the final common pathway for the pathogenesis of asthma. However, the role of calcium channel blockers in this disease has not been defined. This study proposes to investigate, in a logical and systematic manner, the potential efficacy and safety of this group of drugs in controlling the symptoms of chronic asthma, and to evaluate the usefulness of methacholine-induced bronchoconstriction for selecting a clinically effective member of this class, route, dose and frequency of administration. In the first phase, three groups of ten patients with chronic asthma will receive, on seven separate days, placebo and graded doses of either inhaled verapamil, inhaled diltiazem or oral diltiazem;one drug per group. A bronchial provocation test with methacholine will be performed before and after each dose. ECG, blood pressure and the presence of subjective complaints of side effects will be monitored at intervals to determine the safety of each dose. Blood samples will be obtained at intervals to measure verapamil, diltiazem and metabolite serum concentrations. The dose of each drug that produces maximum blocking effect without toxicity will be used for Phase II. In this phase, the effect of inhaled verapamil, oral and inhaled diltiazem and placebo in blocking the bronchoconstrictor response to methacholine will be determined in a double-blind randomized cross-over manner in 40 patients with chronic asthma. On four separate days serial methacholine challenges will be performed, serum concentrations measured, and toxicity assessed at 2 hour intervals for a 12 hour period after the dose. The area under the response-time curve will be used to determine the relative intensity and durationof each regimen. In the third phase, 40 patients will be treated for three one month periods with placebo and the two active drug regimens in Phase II that were judged least effective and most effective, in a randomized double-blind cross-over manner. The dose and frequency of administration will be the same as those used in Phase II. The frequency of asthmatic symptoms, adverse effects, peak expiratory flow rate, and the need for inhaled beta agonists and additional medicatons for acute symptoms will be recorded by the patinets in a diary twice daily. In addition, patients will be seen at two week intervals for evaluation, spirometry, a standardized exercise stress test, serum level measurements, and compliance check.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Pharmacology A Study Section (PHRA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
Schools of Pharmacy
United States
Zip Code
Ann Twiss, Mary; Harman, Eloise; Chesrown, Sarah et al. (2002) Efficacy of calcium channel blockers as maintenance therapy for asthma. Br J Clin Pharmacol 53:243-9
Hoppe, M; Harman, E; Hendeles, L (1992) The effect of inhaled gallopamil, a potent calcium channel blocker, on the late-phase response in subjects with allergic asthma. J Allergy Clin Immunol 89:688-95
Harman, E; Hill, M; Pieper, J A et al. (1991) Inhaled verapamil-induced bronchoconstriction in mild asthma. Chest 100:17-22
Christopher, M A; Harman, E; Hendeles, L (1989) Clinical relevance of the interaction of theophylline with diltiazem or nifedipine. Chest 95:309-13
Massey, K L; Hill, M; Harman, E et al. (1988) Dose response of inhaled gallopamil (D600), a calcium channel blocker, in attenuating airway reactivity to methacholine and exercise. J Allergy Clin Immunol 81:912-8
Blake, K V; Massey, K L; Hendeles, L et al. (1988) Relative efficacy of phenytoin and phenobarbital for the prevention of theophylline-induced seizures in mice. Ann Emerg Med 17:1024-8
Massey, K L; Harman, E; Hendeles, L (1988) Duration of effect of gallopamil, a calcium channel blocker, on methacholine-induced bronchoconstriction. Pharmacotherapy 8:189-92
Hendeles, L; Hill, M; Harman, E et al. (1988) Dose-response of inhaled diltiazem on airway reactivity to methacholine and exercise in subjects with mild asthma. Clin Pharmacol Ther 43:387-92
Massey, K L; Harman, E; Hendeles, L (1988) Duration of protection of calcium channel blockers against exercise-induced bronchospasm: comparison of oral diltiazem and inhaled gallopamil. Eur J Clin Pharmacol 34:555-9
Christopher, M A; Wyzan, D; Harman, E et al. (1988) The effects of nalmefene, a potent oral opiate antagonist, on exercise-induced bronchospasm. J Allergy Clin Immunol 82:1037-41

Showing the most recent 10 out of 13 publications