- Part 1: Research about PY108-068, a New Calcium Antagonist, with Nifedipine in Exercise-Induced Asthma
- Part 2: PY108-068, a New Calcium Antagonist, with Nifedipine in Exercise-Induced Asthma Outcomes
Bronchodilation and prevention of exercise-induced asthma are separate and useful goals of therapy for asthma. We studied a class of drugs that may have potential for meeting either or both of these goals.
We found some resting bronchodilation associated with both 150 mg of PY 108-068 and nifedipine, although only the latter was significant. Some studies on calcium antagonists in asthma have not shown resting bronchodilation; however, measurements were only made up to 30 minutes and 45 minutes after dosing. Patakas et al extended measurements up to two hours and did find significant resting bronchodilation with nifedipine. PY 108-068, which, according to some, is the most potent calcium antagonist presently known, has recently been studied by Ben-Dov et al. They found a significant increase in resting FEVX (15 percent with 150 mg of PY 108-068 vs 3 percent with placebo), which occurred at a mean of 143 ± 20 minutes after the 150 mg. These data plus the increasing FEV1 after 150 mg of PY 108-068 shown in Figure 1 suggest that bronchodilation after 150 mg of PY 108-068 may have become apparent in our study if the time of measurement had been extended.
Another possibility is that the differences in resting flow rates found between placebo and calcium antagonists represent not bronchodilation by calcium antagonists but rather inhibition of deep inspiration-induced bronchospasm. Bronchospasm caused by repeated deep breaths would explain both the progressive fall in FEV1 before exercise with placebo and the initial decrease in FEVx seen with 75 mg and 150 mg of PY 108-068. Because nifedipine has a more rapid onset of action, the deep inspiration-induced bronchospasm could have been prevented altogether. Three subjects did complain that the maneuvers made them wheeze. Of note, nifedipine has been shown previously to inhibit deep inspiration-induced bronchospasm in asthmatic subjects. The mechanism underlying this type of bronchospasm is not known, but one theory is that pulmonary irritant receptors, which are abnormally sensitive in asthmatic subjects, are stimulated by nonspecific irritants, such as deep inspiration, resulting in cholinergic bronchoconstriction. It is known that calcium antagonists block influx of calcium into the tracheal smooth muscle, thus inhibiting the constriction induced by low doses of acetylcholine; however, whether or not the protective effect of the calcium antagonists resides at the level of the bronchial smooth muscle is not known.
Video below shows doctor’s point of view about Exercise-Induced Asthma:
In regard to the protection against exercise-induced asthma, both nifedipine and 150 mg of PY 108-068 have been shown to attenuate exercise-induced asthma in previous studies; however, comparison of these drugs is hampered by differences in protocols and in the severity of underlying disease between groups of subjects. We attempted to control for all variables except the drugs, thereby allowing direct comparison of their effects on exercise-induced asthma. Carefully standardized conditions in which the degree of exercise was matched closely for each subject on all four testing days assured that the stimuli for bronchospasm were always the same. Because placebo itself can significantly reduce exercise-induced asthma, nifedipine and PY 108-068 were compared to placebo. Each subject served as his own control, thus eliminating individual differences among subjects which might alter a drugs effect. Both nifedipine and PY 108-068 were given at the recommended therapeutic dosage. The high incidence of headache associated with nifedipine would limit any increase in dosage.
The calcium antagonists are a heterogeneous group of drugs, both in their structure and their pharmacologic effects; for example, nifedipine, a potent vasodilator, is very effective in relieving angina caused by coronary vasospasm but has little effect on the atrioventricular node. Verapamil, on the other hand, significantly prolongs conduction through the atrioventricular node and is the drug of choice for reentrant supraventricular tachycardias. The calcium antagonists diverse structures and their stereoselectivity suggest that they may bind to different sites in the calcium channel and have different modes of action. Nifedipine may act by “plugging” the calcium channels, whereas verapamil may be “use-dependent;” that is, as the use or frequency of contraction of the muscle increases, the force of contraction decreases. Much remains to be learned about how these drugs block the calcium channels, but considering their dissimilar cardiovascular effects, one might also expect differences in their effect on the airways.
Indeed, we found that 150 mg of PY 108-068 was superior to nifedipine in protection against exercise-induced asthma; however, surprisingly, nifedipine was not significantly better than placebo. This result differs from that of several other published studies. A possible explanation for nifedipines lack of protection in our study involves the timing of exercise. In order to assure a double-blind protocol, all exercise testing was done two hours after dosing. If nifedipine s peak effect occurred 30 minutes after the dose, the time when most of the studies showing significant protection were done, then its maximal protection may have been missed. Unfortunately, the time at which maximal effect occurs for these drugs is not known. The time for each drugs maximal effect may vary among individuals, depending on their rates of absorption.
In conclusion, only nifedipine produced significant resting bronchodilation and only 150 mg of PY 108-068 provided significant protection against exercise-induced asthma. The time of testing may have contributed to both results. In either case, the effects of these calcium antagonists on both resting bronchodilation and protection against exercise-induced asthma are mild. Based on the physiologic role of calcium in asthma, the calcium antagonists may still eventually play a role in therapy. Because (i-sympathomimetics are more effective in exercise-induced asthma by inhalation than by the oral route, the effect of inhaled calcium antagonists should be assessed. As more calcium antagonists are developed, one that is more capable of preventing exercise-induced asthma may be found.
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