Research about PY108-068, a New Calcium Antagonist, with Nifedipine in Exercise-Induced Asthma

Many of the pathophysiologic events underlying asthma, including contraction of bronchial smooth muscle and degranulation of mast cells, are calcium-dependent. Because of this, studies have been done to determine the effect of calcium antagonists on pulmonary function in asthmatic subjects. These studies have measured the effect of these drugs on flow rates at rest and after various challenges including antigen histamine, hyperventilation, and exercise. Exercise has frequently been used because it is safe, natural, and reproducible and has short-term effects; however, the reported effects of calcium antagonists on exercise-induced asthma have varied from complete prevention of bronchospasm to only mild attenuation. Similarly, reported effects on resting brorichodilation vary from none to bronchodilation comparable to isoproterenol. Possible reasons for the lack of agreement among these studies include differences in protocols, differences in the severity of underlying disease between groups of subjects, and inherent differences in the various calcium antagonists; for example, the calcium antagonists, nifedipine, verapamil, and diltiazem, each display unique cardiovascular effects. Thus, while it would not be surprising if such agents also exhibited differences in their effect on exercise-induced asthma, there have been no reported comparisons of calcium antagonists in the same individual. The purpose of this study was to compare the effect on resting bronchodilation and on exercise-induced asthma of a new calcium antagonist, PY 108-068, with nifedipine and placebo in the same subjects.

Exercise-induced Asthma

Materials and Methods

We studied 16 asthmatic volunteers (nine women and seven men) ranging in age from 18 to 52 years (mean of 33 years). We obtained approval of the study from the human subject committee at our institution, and each patient gave informed consent. Preliminary evaluation included history and physical examination, complete blood cell count, electrolyte levels, tests of renal and hepatic function, urinalysis, electrocardiogram, and chest roentgenogram to exclude subjects with systemic disease other than asthma. Recent respiratory tract infection or use of corticosteroids or cromolyn sodium within the past three months also served as criteria for exclusion. Physiologic tests included spirometry before and after four breaths of a 0.5 percent solution (1:200) of isoproterenol using a 9-L spirometer (Warren E. Collins) and a six-minute treadmill exercise test to assess exercise-induced asthma. All subjects accepted had both an increase in the forced expired volume in one second (FEVJ of at least 15 percent after isoproterenol, compared to their immediate baseline before isoproterenol, and a fall in FEVt of at least 20 percent after exercise, compared to their baseline before exercise. The baseline FEV1 in percent of predicted for the subjects runged from 105 percent whis a mean ±SB of S3 ±16 percent.

The study consisted of four testing days, each separated by at least 24 hours. Testing occurred at the same time each day for an individual subject and was completed within a three-week period. Throughout the study, subjects were maintained on their prescribed medications for asthma except that all medication was withheld for six hours prior to study. On each testing day, after obtaining blood pressure, pulse rate, and baseline spirometric data, a subject received one of the following four oral drugs in a randomized doubleblind order:

  • (1) 75 mg of PY 108-068;
  • (2) 150 mg in PY 108-068;
  • (3) 30 mg of nifedipine;
  • or (4) placebo.

Measure Blood Pressure

Spirometry was repeated every 30 minutes for two hours, at which time blood pressure and pulse rate were again measured. The subject then ran on the treadmill for six minutes at a work rate estimated to achieve approximately 70 percent of his or her maximum oxygen uptake. The appropriate work rate was determined at each individuals screening test. To ensure standard air conditions and to increase the bronchoconstrictive effect of exercise, dry compressed air was inhaled for two minutes before and throughout the period of exercise. Subjects breathed through a mouthpiece with a small dead space and breathing valve (Koegel). The exhalation port was attached to a pneumotachygraph (Fleisch No. 3) and a flow transducer (Hewlett-Packard 47304A). Gas was sampled at the mouthpiece for continuous measurement of fractional concentrations of exhaled oxygen and carbon dioxide using a mass spectrometer (Perkins-Elmer MGA-1100). A microcomputer (Hewlett-Packard 9825A) was used for on-line measurement and printout of various cardiorespiratory variables as described previously. An ECG continuously measured heart rate and rhythm.

The FEV1 at two hours after the drug was considered the baseline before exercise. Spirometry was repeated at 3, 6,10,15, 20, 25, and 30 minutes after exercise. We reported the amount of exercise-induced asthma as the maximal percentage of foil in FEV1 from baseline before exercise.

At the end of the study, a full evaluation identical to that of the screening was repeated in order to detect any abnormalities which might be caused by the calcium antagonists. Results were analyzed by analysis of variance. If a significant difference was found, then individual mean differences were identified using the Scheflfe test.