Cromoglycate, reproterol, or both--what's best for exercise-induced asthma?

OBJECTIVE: International guidelines recommend short- (SABA) or long-acting b-agonists for the prevention of bronchoconstriction after exercise (EIB) in patients with exercise-induced asthma (EIA). However, other drugs are still in discussion for the prevention of EIB. We investigated the efficacy of a combination of inhaled sodium cromoglycate and the ß-mimetic drug reproterol versus inhaled reproterol alone and both versus inhaled placebo in subjects with exercise-induced asthma (EIA). METHODS: The study aimed to prove the preventive effect of a combination of 1-mg reproterol and 2-mg disodium cromoglycate (DSCG) and its single components vs. placebo, measuring the decrease of FEV1 after a standardized treadmill test in 11 patients with recorded EIA. The study medication was twice as high as those of drugs which are commercially available (e.g., Allergospasmin®, Aarane®). RESULTS: The results revealed that the combination of reproterol and DSCG was significantly effective against a decrease of FEV1 after a standardized exercise challenge test (ECT) compared to placebo. The short-acting b-agonist reproterol alone had almost the same effectiveness as the combination of reproterol and DNCG. The difference between the combination with DNCG and reproterol alone was less than 10% and insignificant (p 0.48). DNCG alone did not show a difference in the effectiveness compared to placebo. CONCLUSION: Prevention of EIA with the combination of reproterol and DSCG or with reproterol only is effective. An exclusive recommendation in favor of the combination cannot be given due to the low difference in the effectiveness versus reproterol alone. Due to the limited number of subjects and some probands showing protection under DSCG, it cannot be completely excluded that there is some preventive power of DSCG in individual cases.

Pharmacological Provocation of Outflow-Tract Tachycardia in a Patient With Brugada Syndrome.

We present a case of a symptomatic patient with Brugada syndrome, who had sustained right ventricular outflow tract tachycardia after pronounced exercise-induced ST segment elevation in V1 and V2. In electrophysiological study he developed right ventricular outflow tract tachycardia provoked by combined infusion of ajmaline and orciprenaline. After ablation no further arrhythmia was provoked by pharmacological stimulation.

Is electrical stimulation during administration of catecholamines required for the evaluation of success after ablation of atrioventricular node re-entrant tachycardias?

OBJECTIVES: The purpose of this study was to answer the question of whether stimulation after administration of catecholamines is mandatory for identifying unsuccessful ablations of atrioventricular node re-entrant tachycardia (AVNRT). BACKGROUND: The success of radiofrequency (RF) catheter ablation in AVNRT is confirmed in many centers by noninducibility of tachycardias during stimulation after the administration of catecholamines. METHODS: A total of 131 patients (81 women and 50 men; mean age 53.6 +/- 13.7 years [range 20 to 77]) were studied. Electrical stimulation was performed without and with the beta-adrenergic amine Orciprenaline (metaproterenol) before and after RF catheter ablation. RESULTS: In 100 patients (76.3%; confidence interval [CI] 68.1% to 83.3%) an AVNRT was inducible without administration of Orciprenaline. Thirty minutes after the initially successful ablation in 95 patients, tachycardia was inducible in none of these patients, not even after Orciprenaline administration. In the 31 patients (23.7%; CI 16.7% to 31.9%) in whom there was no tachycardia inducible before ablation, Orciprenaline was given, and the stimulation protocol was repeated. In only five patients (3.8%; CI 1.3% to 8.7%) was there still no tachycardia inducible. After an initially successful ablation in the 26 patients who had inducible tachycardias with Orciprenaline before ablation, no tachycardia could be re-induced. After Orciprenaline, the tachycardia was inducible again in only one patient. CONCLUSIONS: Only patients who require catecholamines for tachycardia induction before ablation need catecholamines for control of the success of the ablation of AVNRT.

An adrenergic drug in depression.

It has been suggested that depression is a disease of cholinergic dominance and since the beta-adrenergic blocking drug propranolol hydrochloride can cause depression, there arises the possibility that a beta-adrenergic stimulant could benefit the condition. For ethical reasons, the adrenergic drug metaproterenol sulfate was combined with chlordiazepoxide hydrochloride and compared to placebo and chlordiazepoxide in a formal double-blind trial. However, the results did not show any advantage for the addition of metaproterenol either in respect of enhanced antidepressant effect or a reduced incidence, nature, or severity of side-effects.

Metaproterenol in children with chronic asthma.

Metaproterenol sulfate was given to 25 children with asthma in the form of a syrup in a continuous treatment course of 180 days. Dosage amounted to 10 to 20 mg metaproterenol four times daily, depending on the patient's age and weight. Double-blind crossover tests of pulmonary function were run against placebo at the beginning and after 3 and 6 mo of treatment. The peak expiratory flow rate responses to metaproterenol consistently exceeded the responses to placebo, the differences proving statistically significant at several intervals after administration. Adverse reactions were limited to instances of hyperactivity in one child and of mild tremors in another; laboratory values remained normal throughout the 6-mo period except for low normal fasting blood sugar values recorded in 2 patients at the end of the study. Pulse rate increases occurring after metaproterenol were not considered clinically important.

Comparison of oral aminophylline and aerosol metaproterenol in asthma.

The bronchodilator efficacy of oral aminophylline and aerosol metaproterenol was compared in 18 asthmatic patients in a stable clinical condition. Treatment consisted of four regimens in a double-blind random sequence on four different days after withholding bronchodilators: (1) the administration of aminophylline tablets, 0.4 to 0.6 g, orally, (2) 3 puffs of aerosol metaproterenol administered in a sequential manner, (3) a combination of both, (4) placebos. Both oral aminophylline and aerosol metaproterenol produced significant bronchodilatation measured by forced expiratory volume in 1 second (FEV1). After the administration of aerosol metaproterenol, there was a more prompt and larger improvement in FEV1 than after the administration of aminophylline (p less than 0.01). The combined therapy produced a response which was larger, but not significantly, than the effect of metaproterenol. Side effects were frequent after the administration of aminophylline but absent after aerosol metaproterenol. The advantages of the aerosol adrenergic agonists are the prompt onset of action and efficacy, small dosage preferentially delivered to the bronchial tree and lack of side effects.

Use of ipratropium bromide in asthma. Results of a multi-clinic study.

A multi-center, double-blind, 90-day study compared an ipratropium bromide metered-dose inhaler (40 microgram four times a day) with a metaproterenol metered-dose inhaler (1,500 micrograms four times a day) in 164 patients with asthma; of the 144 patients who completed the study, 71 received ipratropium and 73 received metaproterenol. Our results suggest that both drugs were equally effective bronchodilators. Although the shape of the pulmonary function response curves suggested that ipratropium has different bronchodilator kinetics than metaproterenol (in that it has a slower onset of action and a more prolonged duration), comparison of the areas under the curves for the two drugs showed that there was no statistical difference between ipratropium or metaproterenol. The only significant side effects noted with ipratropium were cough and exacerbation of symptoms; no anticholinergic side effects were noted.

Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A 90-day multi-center study.

The short- and long-term efficacy and safety of an inhaled quaternary ammonium anticholinergic agent, ipratropium bromide, and a beta agonist aerosol, metaproterenol, were compared in 261 nonatopic patients with chronic obstructive pulmonary disease (COPD). The study was a randomized, double-blind, 90-day, parallel-group trial. On three test days-one, 45, and 90-mean peak responses for forced expiratory volume in one second and forced vital capacity and mean area under the time-response curve were higher for ipratropium than for metaproterenol. Clinical improvement was noted in both treatment groups, especially during the first treatment month, with persistence of improvement throughout the remainder of the study. Side effects were relatively infrequent and generally mild; tremor, a complication of beta agonists, was not reported by any subject receiving ipratropium. These results support the effectiveness and safety of long-term treatment with inhaled ipratropium in COPD.

Dose-response relationship of inhaled metaproterenol sulfate in preschool children with mild asthma.

The dose-response relationship of single doses of nebulized metaproterenol sulfate 5% inhalant solution was evaluated by placebo-controlled, parallel-group study of 30 children, aged 3 to 6 years old, with stable asthma. Total respiratory resistance, the primary variable used to assess response, was measured by the forced oscillation method for a period of 6 hours from the start of inhalation. When comparisons were made between metaproterenol sulfate and saline, only 0.01 and 0.02 mL/kg showed significant bronchodilation (P less than .05) in percent change from baseline and area under the curve. However, no significant differences were seen between these doses. Moreover, the effect was sustained for 3 hours with both higher doses. Minimal side effects were observed. Metaproterenol sulfate 5% inhalant solution at a dose of 0.01 mL/kg seems to be optimal to elicit significant and sustained bronchodilatory response in preschool children with mild asthma.

Long-term efficacy and safety of nebulized metaproterenol solution in bronchial asthma.

A 5-percent solution of the sympathomimetic bronchodilator, metaproterenol sulfate (Alupent) was evaluated by comparison with an 0.5-percent solution of isoproterenol in a double-blind crossover study before and after 60 days of inhalation of metaproterenol administered at least four times daily via a hand-bulb nebulizer. Data from tests of pulmonary function obtained in 27 asthmatic patients indicated that metaproterenol sulfate in this dose form surpassed isoproterenol in the duration of effect after seven weeks of continuous administration. Side effects did not necessitate the interruption of metaproterenol therapy. No evidence of the development of tolerance to the drug was shown by any of the patients at the end of the study.

Hypokalemia induced by inhaled bronchodilators.

Since parenteral beta 2-adrenergic stimulation can induce hypokalemia, we postulated that administration of beta 2 adrenoreceptor agonists by inhalation could induce the same. We administered the usual clinical doses of three commonly used bronchodilators to each of six subjects receiving assisted mechanical ventilation in line with the ventilator: two beta 2-adrenoreceptor agonists, metaproterenol, 5 percent solution, and isoetharine, 1 percent solution; and the anticholinergic agent atropine as a control. Each bronchodilator was nebulized over 10 to 15 minutes in random order, four hours apart, and given to every subject. Plasma potassium was measured at five-minute intervals and arterial blood gases at 15-minute intervals, for a total of 50 minutes after administration of each bronchodilator. Following administration of each drug, plasma potassium showed an average decline. The mean decline in plasma potassium from baseline was statistically significant for metaproterenol (p = 0.04) and atropine (p = 0.001) but not for isoetharine (p = 0.09). Although there were no statistically significant differences among the declines in plasma potassium induced by the three drugs, metaproterenol caused the greatest decline (-0.6 mEq/L).

Metaproterenol solution in the treatment of asthmatic patients by intermittent positive pressure breathing.

The effects of five different doses of a 5% inhalant solution of metaproterenol on pulmonary function were compared in a placebo-controlled double-blind cross-over study in 40 asthmatic patients who received the drug via intermittent positive pressure breathing (IPPB). The response to metaproterenol in terms of FVC, FEV1, RA, and FEF25-75% was significantly superior to the placebo response. The effect of metaproterenol set in within 5 minutes of adminstration, and clinically significant improvement in pulmonary function was sustained for 6 hours even at the lowest dose level. Global response evaluations reflected a progressive increase in effectiveness with each successive dose increment. Typical sympathomimetic side effects such as nervousness and shakiness slightly increased in frequency with higher doses. At none of the metaproterenol doses were any clinically significant changes observed in the mean blood pressure and pulse rate values.

Bronchodilator and side effects of different modes of administration of metaproterenol: inhaled, oral, and in combination.

Twenty subjects with clinically stable asthma were treated in double-blind crossover manner with inhaled and oral metaproterenol, alone and in combination. The combination of inhaled and oral metaproterenol resulted in a greater degree of bronchodilation than either inhaled or oral alone. Inhaled metaproterenol was not associated with any significant side effects. Oral metaproterenol was associated with a small but significant increase in pulse rate and systolic blood pressure, and a small incidence of unpleasant sensations such as tremor and palpitation. Older subjects were more likely to experience the unpleasant sensations, whereas younger subjects were more likely to experience the increase in pulse rate.

Oxygen desaturation in adults following inhaled metaproterenol therapy.

Following bronchodilator therapy in asthmatic patients, a fall in arterial oxygen tension (PaO2) has been attributed to increased perfusion of persistently underventilated alveoli. We used continuous noninvasive pulse oximetry to evaluate the extent and timing of oxygen saturation (SaO2) decrease in adults following metaproterenol inhalation for acute bronchospasm. We also examined the effect of supplemental oxygen upon these factors. Baseline and peak drop in SaO2 after completion of the first bronchodilator therapy were measured and the percent change in SaO2 was calculated. A total of 47 patient visits were studied; 10 patients received supplemental oxygen. Mean age was 38 +/- 17.9 years. Baseline was SaO2 = 94.6 +/- 2.9%, peak drop SaO2 = 91.4 +/- 3.4%, and percent change in SaO2 = -3.4 +/- 2.5%. The mean time to peak drop was 24.4 +/- 15.4 minutes in the 40 patients, with an observed drop after initial treatment. The absolute change in SaO2 from baseline was significant both with and without oxygen (P less than .05 and less than .01, respectively). The group receiving oxygen had a significantly smaller percent drop and a larger proportion of patients showing no drop in SaO2 (P less than 0.01 and less than 0.03, respectively). Clinically significant oxygen desaturation can occur within 30 minutes of inhaled bronchodilator therapy. Supplemental oxygen (2-3 L/min) helps blunt the metaproterenol-induced drop in SaO2.

A comparison of controlled-release aminophylline (Phyllocontin Continus tablets) and sympathomimetic bronchodilators.

In a crossover trial on twenty-four patients with reversible airways obstruction the rise in FEV1 on Phyllocontin Continus tablets (15%) was comparable to that achieved with Alupent tablets (14%). The usage of inhaled salbutamol and frequency of attacks of wheeziness were both greater when the patients were taking Alupent tablets. In a second study the effect of Phyllocontin tablets and Ventolin tablets both in combination with inhaled Ventolin and alone were examined. It was found that on Phyllocontin tablets alone patients showed a similar improvement (22%) in FEV1 to Ventolin tablets alone (19%). When inhaled Ventolin was added to Phyllocontin tablets a further rise in FEV1 was seen but not when inhaled Ventolin was added to Ventolin tablets.

Comparison of fenoterol and orciprenaline with regard to broncho-dilating action and beta 2-selectivity.

A double-blind crossover trial was performed comparing orciprenaline (10 mg) and fenoterol (5 mg) by oral administration in forty-four patients with bronchial asthma. Measurement of VC, FEV1, respiratory impedance (ZR), blood pressure and pulse rate, and observation of subjective symptoms, râles, and side-effects, were made over the 4 hours following oral administration of the drugs. FEV1 increased through the 4 hours reaching a peak at 3 hours with both drugs. The per cent increase of FEV1 was statistically significant at each measuring time for both drugs (p less than 0.01), and was significantly larger in fenoterol than in orciprenaline at 2 and 3 hours (p less than 0.05). ZR with fenoterol decreased from 2 hours to 4 hours with a significant difference from ZR with orciprenaline (p less than 0.05). Side-effects such as palpitation, finger tremor or headache were seen in 36.4% cases with fenoterol and 30.5% with orciprenaline, but the degree of the side-effects was minimal. Finger tremor was observed in one case with orciprenaline and ten cases with fenoterol. Palpitation was observed in five cases with each of the drugs. Because finger tremor seems to be due to beta 2-stimulation and palpitation seems to be due to beta 1-stimulation, fenoterol was supposed to be more beta 2-selective than orciprenaline. In conclusion fenoterol had a high beta 2-selectivity and a powerful and long-lasting broncho-dilating effect compared with orciprenaline.