Bitolterol mesylate aerosol in adults with steroid-dependent asthma: a comparison with isoproterenol hydrochloride aerosol.

A double-blind randomized study of 29 patients was conducted to evaluate the efficacy, safety, and possible subsensitivity of bitolterol mesylate aerosol and isoproterenol hydrochloride aerosol in the treatment of patients with moderate to severe steroid-dependent asthma. Patients received two sprays, three times a day, of either bitolterol or isoproterenol for 3 months. There were four 8-hour office visits at approximately 30-day intervals to assess pulmonary function. On days when pulmonary functions were evaluated, electrocardiogram and laboratory analysis were performed to help assess safety. Both medications gave bronchodilatation within five minutes. Bitolterol had a maximum effect within 60 minutes while isoproterenol was within 15 minutes. The magnitude of peak effect was consistently greater for bitolterol, but not statistically different from isoproterenol. The mean FEV1 (forced expiratory volume in one second) remained at least 15% or greater above baseline for four to eight hours postmedication for bitolterol on the four monthly pulmonary function test days, compared with one to two hours postmedication for isoproterenol. Both medications were well tolerated, with no significant changes in pulse rate, blood pressure, or respiratory rate. Adverse reactions were mild to moderate in nature and were typical sympathomimetic effects. There were no clinically significant laboratory changes or electrocardiographic findings. During the 3-month study, there was no evidence of subsensitivity. Bitolterol mesylate aerosol was shown to be an effective bronchodilator with a prolonged duration of action in steroid-dependent asthma.

Comparison of bronchodilator responses with bitolterol mesylate solution with the use of two different nebulizer systems in asthma.

Bitolterol mesylate is a beta 2-adrenergic bronchodilator that has been studied in a metered-dose inhaler formulation and as an aerosol in a closed, intermittent-flow nebulizer system. The optimum dose was found to be 1.0 mg in the closed system. In this dose-response study, 1.0 mg by closed-system nebulizer was compared with different doses delivered by an open, continuous-flow nebulizer system. Treatment with 2.5 mg of bitolterol mesylate in the open system is comparable to 1.0 mg in a closed system. Onset of bronchodilator activity occurred within 5 minutes for most patients, and median duration of action with different doses was 8 hours or longer. Mean maximum percent increases in FEV1 with 2.5, 3.5, and 4.5 mg of bitolterol mesylate with the open system were approximately 50% and comparable with that obtained with 1.0 mg with the closed system. Treatments with doses up to 3.5 mg in the open system were well tolerated with few side effects. We conclude that bitolterol mesylate is an effective, long-lasting bronchodilator when it is used as a nebulized aerosol by both open and closed delivery systems; a larger dose is optimal for the former system than for the latter. We believe that manufacturers' recommended doses should take into account the different efficiencies of open and closed nebulizer systems.

Bitolterol mesylate in exercise-induced asthma.

Exercise-induced asthma is a useful model for evaluating the activity and duration of action of pharmacologic agents of asthma. The main objective of this double-blind, crossover study was to determine the effect of the aerosolized beta-adrenergic agent, bitolterol mesylate, on exercise-induced asthma while its efficacy was being compared with isoproterenol and placebo. Twelve subjects with exercise-induced asthma performed cycloergometer exercise 45 minutes after three inhalations of bitolterol mesylate aerosol (1050 micrograms), or isoproterenol (255 micrograms), or placebo in random sequence. Bitolterol mesylate aerosol was very effective in protecting against exercise-induced asthma. The mean percent maximal decrease of FEV1 after exercise was 5.0% for bitolterol, 22.2% for isoproterenol, and 23.2% for placebo. Subjects experienced skeletal muscle tremor with both bitolterol mesylate (four subjects) and isoproterenol (three subjects), but not with placebo. No other side effects were noted.

Concomitant bitolterol mesylate aerosol and theophylline for asthma therapy, with 24 hr electrocardiographic monitoring.

A higher incidence of fatal asthma after increased use of combined inhaled beta 2-agonists and theophylline has been attributed to additive cardiac toxicity of these agents. This study had three major objectives: first, to evaluate the efficacy and safety of a new long-acting beta 2-agonist, bitolterol mesylate, given as metered-dose aerosol in a regular "round-the-clock" asthma medication regimen; second, to compare the efficacy and safety of bitolterol with those of sustained-release theophylline alone and of the combination of bitolterol and theophylline; third, to use 24 hr Holter monitoring to evaluate cardiac toxicity of the three medication regimens. This was a 6 wk double-blind study of regular, daily medication in 36 young non-steroid-dependent and 37 older steroid-dependent stable asthmatic patients. All patients had two 24 hr Holter ECG monitorings during the 2 wk baseline period when all patients received theophylline only and four further 24 hr Holter monitorings during the double-blind period. All Holter recordings from the study groups showed no significant abnormalities in any treatment group. Pulmonary function studies were performed on 4 study days in the 6 wk double-blind period. The largest increase in bronchodilator effect was obtained with combined medication and the smallest with theophylline alone. Mean duration of action was markedly longer in the combined treatment group (greater than 7 hr) than with bitolterol mesylate aerosol or theophylline alone (greater than 5 and greater than 4 hr, respectively) in the non-steroid-dependent patients. Degree of bronchodilation and duration of action was less in the steroid-dependent patients in all treatment groups. There is no evidence from cardiac monitoring that therapeutic doses of bitolterol mesylate or theophylline alone or in combination have cardiotoxic effects.

Bitolterol mesylate (WIN 32784) aerosol. A new long-acting bronchodilator with reduced chronotropic effects.

Bitolterol mesylate (WIN 37284) is alpha-[tert-butylaminomethyl]-3,4-dihydroxybenzyl alcohol 3,4-di(p-toluate) methanesulfonate, a diester sympathomimetic amine bronchodilator. Bitolterol mesylate represents a new concept in sympathomimetic amine therapy. It is "prodrug" which is inactive until altered in the body. The intact 3,4-diester molecule is metabolized by esterase hydrolysis to release the active catecholamine, N-t-butylarterenol. Because the level of esterase is greater in the pulmonary tissue than in the heart, bitolterol mesylate aerosol was shown to be an effective bronchodilator drug, without any significant cardic side effects. The onset of action was rapid and lasted more than six hours. The improvement over baseline values in the forced expiratory volume in the first second and the mean forced expiratory flow during the middle half of the forced vital capacity was greater than 15 percent and 30 percent, respectively.