Effect of a calcium antagonist, nifedipine, in exercise-induced asthma

The nifedipine effect was studied in 8 extrinsic asthmatic subjects with exercise-induced asthma. Before the exercise the patients received, in a randomized double-blind manner, either 20 mg nifedipine, sublingually or sodium cromoglycate by inhalation on 2 separate days. Nifedipine and sodium cromoglycate in all patients inhibited the exercise fall in FEV1. No differences were found between the two drugs. Nifedipine is a potent antagonist of calcium ion influx in smooth muscle and secretory cells, and these studies suggest that it may inhibit release of mast cell mediators and reduce bronchial smooth muscle contractility in asthma.     

Comparison of PY 108-068, a new calcium antagonist, with nifedipine in exercise-induced asthma

Several calcium antagonists, each with significantly different chemical structures, have demonstrated variable attenuation of exercise-induced asthma. Quantitative comparisons have been hampered by differences in the intensity of challenge and the severity of the underlying disease between groups of patients. In 12 asthmatic adults with relatively severe exercise-induced asthma, we compared the effect of a new calcium antagonist, PY 108-068, in doses of 75 mg and 150 mg with nifedipine (30 mg) and placebo on resting flow rates and flow rates after exercise. Over a three-week period, each patient completed a four-day, randomized, double-blind Latin-square study. After receiving one of four oral drugs, spirometry was repeated every 30 minutes for two hours, followed by a six-minute treadmill exercise test breathing dry air. The exercise tests were well matched for work rate, ventilation, heart rate, and oxygen uptake. Spirometry was then repeated seven times over the next 30 minutes after exercise. Though both 150 mg of PY 108-068 and nifedipine were associated with mild bronchodilation before exercise, only the latter was significant (p less than 0.05). Exercise-induced asthma (expressed as maximal percent fall in the forced expiratory volume in one second from before baseline) was significantly attenuated only by 150 mg of PY 108-068 compared to placebo (24 +/- 13 vs 40 +/- 16; p less than 0.05). Headache, which occurred in six subjects after nifedipine, five after 150 mg of PY 108-068, one after 75 mg of PY 108-068, and none after placebo, was subjectively more severe after nifedipine. We conclude that in these patients, there was a tendency for mild bronchodilation before exercise with both 150 mg of PY 108-068 and nifedipine, but only the 150-mg dose provided significant protection against exercise-induced asthma two hours after the drug.     

Bronchodilatation and attenuation of exercise-induced bronchospasm by PY 108-068, a new calcium antagonist

The effect of a new dihydropyridine-derivative calcium antagonist, PY 108-068, on resting and postexercise flow rates was evaluated in 12 adult asthmatic subjects in a double-blind, randomized, placebo-controlled, cross-over study. The study consisted of 2 periods, each lasting for 3 days. For a given period a single dose of PY 108-068 (or placebo) was given orally, 75 mg on the first day and 150 mg on the second and third day. Spirometry was obtained at 30-min intervals thereafter. On Day 3, 75 min after the medication was given, a 6-min treadmill exercise test was performed breathing dry air. The mean maximal FEV1 recorded after 150 mg of PY 108-068 on Day 2 was 15 +/- 4% higher than the daily baseline (p less than 0.05), whereas after placebo the maximal FEV1 value was not different from the daily baseline. Also, the mean FEV1 values, expressed as percent of the daily predrug baseline, were significantly higher at 2 and 3 h after 150 mg of PY 108-068 than the respective values after placebo (110 +/- 4 compared with 95 +/- 1, and 106 +/- 5 compared with 91 +/- 3, respectively). Exercise-induced bronchospasm (EIB), expressed as maximal percent fall in FEV1 from preexercise baseline, was attenuated by PY 108-068 as compared with placebo (% delta FEV1 of 20 +/- 6 and 40 +/- 4, respectively; p less than 0.001). Protection against EIB did not correlate with the resting bronchodilation induced by PY 108-068, but was more likely if the patient had eosinophilia. Thus, PY 108-068 not only attenuates EIB but also causes resting bronchodilation, a unique finding for calcium channel blockers.     

Inhibition of exercise-induced asthma by oral procaterol, a new beta 2-adrenergic drug

8 asthmatics were studied for 2 consecutive days in order to assess the preventive effect of a new oral beta 2-sympathomimetic, procaterol hydrochloride, against exercise-induced asthma. Statistical analysis of the resulting data showed that this preparation, unlike other oral beta 2-sympathomimetics, affords good protection against exercise-induced asthma.     

Amlodipine, a new 1,4-dihydropyridine calcium antagonist with a particularly strong antihypertensive profile

The effects of a new 1,4-dihydropyridine derivative amlodipine have been compared with results from our previous work. Application of amlodipine at a concentration of 1.6 X 10(-6) M to isolated guinea-pig papillary muscle for 120 minutes produced a 50% reduction in tension development compared with a concentration of 3.7 X 10(-7) M nifedipine needed to produce the same result under identical conditions. This suggests that amlodipine has even weaker negative inotropic effects than nifedipine. In isolated porcine coronary strips, the K+-induced contractions were approximately 10,000 times more sensitive to the relaxing effects of nisoldipine, nitrendipine and nicardipine than to those of papaverine, whereas nifedipine and amlodipine were 3,000 times more potent than papaverine. However, in comparison with these in vitro actions, the efficacy of amlodipine appears to be greater in vivo: Simultaneous subcutaneous injection of nifedipine (20 mg/kg) and of equimolar doses of nisoldipine and felodipine attenuated the myocardial calcium uptake by rat hearts in situ (stimulated with a single subcutaneous dose of 30 mg/kg isoproterenol) with the same efficacy, whereas the actions of nitrendipine and nimodipine were considerably weaker. In contrast, amlodipine antagonized isoproterenol-stimulated myocardial calcium accumulation more effectively. Furthermore, amlodipine exhibited a high antihypertensive potency combined with rapid onset and long duration of action: Amlodipine (10 mg/kg orally [p.o.]) reduced the blood pressure of spontaneously hypertensive rats almost to the same extent as nifedipine, nitrendipine, verapamil and felodipine administered at the much higher doses of 100 mg/kg p.o. Amlodipine (20 mg/kg/day p.o.) maintained normal blood pressure during the whole life span of Dahl-S rats (5 months), but this dose is considerably lower than that reported for other 1,4-dihydropyridines. The survival of NaCl-loaded Dahl-S rats increased from 20 to 100% after administration of amlodipine (20 mg/kg/day p.o.) over 10 weeks: The effective dose of other calcium antagonists is approximately 5 times higher, but well tolerated as, e.g., demonstrated in long-term studies on Dahl-S rats with nitrendipine over 12 months. Increases in systemic arteriolar tone can be visualized in the ocular fundus of spontaneously hypertensive rats. After amlodipine (10 mg/kg p.o.) arteriolar spasm declines. Prophylaxis with 2 doses of 20 mg/kg amlodipine daily in NaCl-loaded Dahl-S rats abolished the macroscopic and histologic changes that are normally seen in branches of the mesenteric artery. With use of electron microscopy, calcium accumulation in the lamina elastica interna was demonstrated by the potassium-pyr-oantimonate technique.(ABSTRACT TRUNCATED AT 400 WORDS)     

Hypotensive effect of a new calcium antagonist, SR 33557 in conscious rats

SR 33557 (SR) is a new calcium channel blocker belonging to the chemical class of indolizinsulfones (IC50 = 0.6 nM, 3H-nitrendipine). Its hypotensive effects were studied in conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, and compared to those of Nitrendipine (Nit) (IC50 = 0.8 nM, 3H-nitrendipine). SR was given intravenously (IV) at 0.3, 1 and 3 mg/kg (n = 4 to 6) and orally (PO) at 3, 10, 30 and 60 mg/kg (n = 4 to 7). Nitrendipine was studied at 0.3 mg/kg (IV) and 10 mg/kg (PO). Blood pressure (BP) and heart rate (HR) were measured for 120 min, and for 24 h at 30 mg/kg. The IV injection of SR induced an immediate and dose-dependent decrease in BP. The maximal diastolic hypotension was situated between 11 p. 100 at 0.3 mg/kg and 45 p. 100 at 3 mg/kg (basal values: 133 +/- 6 and 131 +/- 5 mmHg). These effects lasted between 30 min and over 2 hours. The oral administration of SR induced a dose-dependent fall in BP at 3 mg/kg and upwards. The maximal diastolic hypotension appeared within 60 and 120 min and were situated between 8 p. 100 at 3 mg/kg and 28 p. 100 at 60 mg/kg (basal values: 130 +/- 7 and 133 +/- 2 mmHg). At 30 mg/kg, the hypotension lasted for 8 hours. SR was roughly 10 times less hypotensive in WKY than in SHR. HR did not change.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of exercise-induced asthma

In a previous review in this journal McFadden eloquently presented the findings which led him and his colleagues to propose that respiratory heat loss and the subsequent cooling of the airways are the initial reaction sequence leading to airway obstruction in hyperventilation and exercise-induced asthma [62]. He further concluded that: “Exercise per se is not essential and serves only as means to increase ventilation”. Our interpretation of currently available data has led us to conclude that while respiratory heat loss may play an important permissive role in initiating the bronchoconstriction which follows exercise, the weight of evidence indicates that exercise per se serves as the trigger mechanism and is not just a tool to increase ventilation. Moreover, we believe that the role of exercise in releasing chemical mediators has been established, although pathways by which the airway smooth muscle is affected are still uncertain.     

孟鲁司特钠治疗运动诱发性支气管收缩的临床研究

目的　观察孟鲁司特钠治疗轻、中度支气管哮喘(简称哮喘)并发运动诱发支气管收缩(EIB)或运动性哮喘(EIA)的治疗及预防作用。方法　采用前瞻性开放、自身治疗前、后对照的方法。选择轻、中度哮喘并运动激发试验阳性患者30例,给予孟鲁司特钠每晚10mg治疗1个月。分别于治疗前1d、治疗后3d及4周进行运动激发试验。主要观察运动后的前60min一秒钟用力呼气容积(FEV1)自基线下降的百分比时间曲线下面积(AUC0~60min),运动后FEV1最大下降程度(FEV1最低值)及自最低FEV1恢复至运动前基值5%以内所需的时间(FEV1最低值恢复时间)。结果　孟鲁司特钠治疗前1d、治疗后3d和治疗后4周,运动激发试验后AUC0~60min分别为(39±21)、(13±14)、(12±14)%·min,治疗前、后比较差异有统计学意义(P<001);FEV1最低值分别为(18±06)、(21±06)、(23±08)L,治疗前、后比较差异有统计学意义(P<001);FEV1最低值恢复时间分别为(51±36)、(26±28)、(25±33)min,治疗前、后比较恢复时间显著缩短(P<001),并持续1个月。EIB/EIA患者孟鲁司特钠治疗前、后肺功能[FEV1、峰流速(PEFR)]均可维持接近正常且无明显变化。吸入糖皮质激素不能预防EIB/EIA。结论　孟鲁司特钠对轻度哮喘患者并发EIB/EIA疗效和预防作用显著,而且安全、快捷。     

Bepridil--electrophysiologic properties of a new calcium antagonist with an anti-arrhythmia effect

In 12 patients with recurrent pre-syncope or syncope and suspected sick sinus syndrome, the electrophysiologic properties of bepridil were tested using 1-2 extrastimuli during four basic pacing rates. Bepridil was given in a dose of 5 mg/kg body weight over 10 min. It caused no significant changes in sinus cycle length (+5%) and corrected sinus node recovery time during pacing of 100/min (-6%), 120/min (+8%) and 140/min (+4%). The conduction times PQ- (+10%) and QRS-interval (+6%) increased significantly, AH- (+8%) and HV-interval (+5%) were slightly prolonged. Antegrade Wenckebach point increased from 460 to 508 ms (p less than 0.05). The effective refractory period was prolonged in the atrium (+11%, p less than 0.05), the AV-node (+14%, p less than 0.05) and the right ventricle (6-11% at pacing rates 100-140/min, p less than 0.05 for each cycle length). In relation to the pacing rate, QTc-interval increased highly significantly (p less than 0.01) by 16% (sinus rhythm), 12% (100/min), 20% (120/min) and 19% (140/min). After a mean of 5 min after the start of infusion a doubled T-wave was observed in 11/12 patients, persisting during Holter monitoring for several hours without evidence of increased incidence of spontaneous ventricular arrhythmias. During programmed electrical stimulation with 1-2 extrastimuli, no increase in vulnerability of the right ventricle was obvious in any patient.     

Comparative efficacy of nicardipine, a new calcium antagonist, versus nifedipine in effort stable angina

The relative efficacy of nicardipine and nifedipine was examined in a double-blind randomized trial. We studied 12 patients with chronic effort angina who had reproducible chest pain and greater than or equal to 1.5 mm of ST-segment depression on treadmill exercise testing performed before and after 1-week control period of single-blind placebo administration. Subsequently over a 9-week period, nicardipine 20 mg or nifedipine 10 mg or an identical placebo four times a day, was administered in a randomized double-blind crossover fashion. Treadmill exercise testing was performed at the end of each 3-week period. Both nicardipine and nifedipine reduced the frequency of anginal attacks and trinitrate consumption. Compared with placebo both drugs caused a comparable increase of the total duration of exercise (p less than 0.05 placebo versus nicardipine; p less than 0.01 placebo versus nifedipine) and of the time to the onset of angina (p less than 0.05 placebo versus nicardipine; p less than 0.01 placebo versus nifedipine) and to the appearance of 1.5 mm ST depression (p less than 0.05 placebo versus nicardipine; p less than 0.01 placebo versus nifedipine). Moreover 4 patients no longer had angina with either drug and only 1 patient with placebo. Both drugs increased resting heart rate and reduced systolic blood pressure at resting (p less than 0.01) and submaximal exercise (p less than 0.01). Peak heart rate, systolic blood pressure and rate-pressure product were similar with placebo, nicardipine and nifedipine. No important side effects were observed with either drug. We conclude that nicardipine and nifedipine produce similar haemodynamic and clinical effects in patients with stable angina.     

Comparative efficacy of nicardipine, a new calcium antagonist, versus nifedipine in stable effort angina

The relative efficacy of nicardipine and nifedipine was examined in a double-blind placebo-controlled randomized crossover trial. We studied 12 patients with chronic effort angina involving reproducible angina and greater than or equal to 1.5 mm of ST-segment depression on exercise treadmill test performed before and after a 1-week control period of single-blind placebo administration. Subsequently, indistinguishably prepared nicardipine 20 mg, nifedipine 10 mg, or placebo, four times a day, was administered in a randomized double-blind crossover fashion for 3 weeks (total study period 9 weeks). Exercise treadmill test was performed at the end of each 3-week period. Both nicardipine and nifedipine significantly reduced the frequency of anginal attacks and nitroglycerin consumption. Compared with placebo both drugs caused a comparable increase of the duration of exercise, of the time to angina and to the appearance of 1.5 mm ST-segment depression (P less than 0.05 placebo versus nicardipine; P less than 0.01 placebo versus nifedipine respectively). No significant side effects were observed with either drug. We conclude that nicardipine and nifedipine produce similar hemodynamic and clinical effects in patients with stable effort angina.     

ECG changes in exercise-induced asthma

Changes in ECG during and after exercise were analyzed in 17 patients with exercise-induced asthma (EIA) and in 12 control patients (asthmatic patients without exercise-induced bronchial obstruction). The changes in ECG were compared with those in peak expiratory flow (PEF) rate and in arterial PCO2, PO2 and pH. It was found that in EIA the amplitude of the P wave increased in the inferior leads and decreased in the aVL lead during and after exercise. In addition, the amplitude of the R wave diminished and the amplitude of the S wave increased in the anterior precordial leads during bronchoconstriction. The changes in the ECG of the control patients were small and were already beginning to return to normal 4 min after exercise, whereas the changes in EIA patients persisted for 4-10 min after exercise. In EIA, a significant negative correlation was found between the PEF rate and the amplitude of the P wave in leads II, III and aVF. In addition, the PEF rate and the amplitude of the S wave in the V3 lead showed significant negative correlation. Almost no changes were observed in PO2 or PCO2 in the EIA or in the control patients. The pH decreased significantly in both groups during exercise. The PEF rate did not correlate with arterial PO2, PCO2 or pH after exercise in EIA.     

Sympathoadrenal reactivity in exercise-induced asthma

The possibility that sympathoadrenal activity is altered in asthma was examined in eight patients with a history of exercise-induced asthma (EIA), eight matched patients with nonexercise induced asthma (NEIA), and eight matched healthy control subjects. No medication was allowed for at least one week before examination. In a pretrial exercise test diagnosis of EIA was confirmed and each individual's work capacity (Vo2 max) was determined. The trial consisted of an orthostatic test and a standardized exercise test at 80 to 90 percent of VO2 max on a treadmill. The trial exercise test caused a decrease in FEV1 in EIA patients only, whereas measurements of Sgaw revealed a significant but less pronounced postexercise bronchoconstriction in NEIA-patients as well. Basal plasma catecholamine levels were similar in all groups. Noradrenaline and adrenaline levels were approximately doubled by the orthostatic test and increased approximately ten-fold following exercise, with no differences between the groups. Plasma cAMP levels were approximately doubled by the exercise test. In the EIA patients there was an inverse correlation between increases in plasma cAMP and decreases in Sgaw. Our study does not support earlier claims that exaggerated catecholamine response to exercise causes postexercise bronchoconstriction by alpha-adrenoceptor stimulation in EIA. Differences in study results appear to have methodologic explanations.     

The effect of the calcium antagonist nifedipine on stress-induced bronchial asthma

Studies of the efficiency of the calcium antagonist nifedepine on the exercise-induced asthma bronchiale (EIA) were carried out in 15 cases of asthmatics (11 men, 5 women; average age 28.5 years; average time of illness 6.4 years). Duration of exercise was 6 minutes at 80-85% of the maximal age related heart frequency, either on the bicycle ergometer or free running. Rtot, TGV, MEF50, MEF25 and arterial pO2 were measured, Rtot and TGV with air breathing as well as with He/O2 (80% He, 20% O2). Nifedepine reduces significantly the exercise-induced obstruction of the large and the peripheral airways. Possible mechanisms are discussed. Prophylactic treatment with nifedepine is possible. The development of a selective calcium antagonist is desirable.