In the course of a double-blind controlled study of intravenous indomethacin therapy in premature infants with patent ducts arteriosus (PDA), dynamic lung compliance (CL) was determined in 11 infants (six control, five indomethacin) who were not on assisted ventilation during the study period. The clinical, biochemical and laboratory data before the study were comparable between the groups. Following therapy with indomethacin there was a significant decrease in left atrial/aortic root ratio (LA/Ao), left ventricular end-diastolic dimension (LVEDD) on echocardiogram, and an increase in tidal volume (VT) and CL. In the control group, these variables did not change significantly. The improved lung compliance following early indomethacin closure of PDA may alter the clinical course and outcome of these premature infants.

A double-blind study with placebo control was carried out in 20 patients with chronic bronchitis to analyze the effect of oral terbutaline on mucociliary transport and sputum properties. Terbutaline (2.5 mg tablets) was given 3 times a day for 1 week. The clinical score, forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) significantly improved after treatment with terbutaline and confirmed the bronchodilating action of this drug. The mucociliary clearance measured with a radioactive aerosol tracer did not significantly differ after treatment with terbutaline and placebo although the initial site of aerosol deposition was similar in the two groups before and after treatment. The viscoelastic properties of sputum and their in vitro transport rate on the frog palate were not modified by terbutaline. The decrease in sputum volume and serum albumin concentration suggests a bronchial anti-inflammatory effect of this medication.

The effect of clenbuterol, a beta adrenergic drug, and ambroxol, a secretolytic agent, on regional mucociliary clearance and pulmonary radioaerosol distribution was investigated in two groups of 15 patients with COLD in a double-blind cross-over trial with placebo. Clearance rates of inhaled 99mTc-labelled human serum albumin minimicrospheres (HAMM) were determined over upper, middle, lower, central, and peripheral anterior lung regions. Additionally, an index was employed for quantitative analysis of initial pulmonary aerosol distribution in order to detect changes in the site of particle deposition caused by the drugs. Regional measurement of tracheobronchial particle clearance showed clenbuterol to have a significant (P less than 0.05) stimulating effect in 4 of 5 tested pulmonary zones resulting in significantly accelerated whole lung clearance. Ambroxol was effective in only 1 of 5 tested lung areas and did not prove to enhance whole lung clearance significantly. The secretolytic agent was associated with significant (P less than 0.05) improvement of lung aerosol distribution in obstructive emphysematous patients, whereas no significant change in lung deposition of the inhaled particles was encountered in the patients with chronic obstructive bronchitis after either drug regimen.

We investigated, in a double blind fashion, the acute effect of an inhaled beta 2-agonist drug (salbutamol) on mucociliary clearance in 20 patients with chronic bronchitis: ten treated with the drug and the remaining ten with placebo. Following inhalation of pre-sized human albumin microspheres with a mass median diameter of 1.5 micrometers, radioactivity was recorded for one hour (control period) with the patient in the supine posture with a large field computerized gamma camera collimated over the chest. At the end of the first hour, without moving the patient, either salbutamol (500 micrograms) or placebo was nebulized from a commercial canister and recording carried out for another two hours. At the end of the recording period areas of interest were selected and time activity curves generated, from which the percentage activity cleared in the first, second and third hour was calculated. Whereas no significant differences in clearance between the two groups were found in the control period, inhaled salbutamol significantly increased mucociliary clearance rate; particle removal in the second hour (test period) was 36.42 +/- 5.61 (SD) percent for the group treated with salbutamol, and 10.87 +/- 2.47 (SD) percent for the group receiving placebo.

The purpose of this study was to compare the effectiveness of flunisolide aerosol prescribed as .5 mg (two inhalations) twice daily and placebo in terms of oral steroid sparing ability in a population of 32 known steroid-dependent children and adolescents. Patients were stabilized on the lowest tolerated dose of daily AM or alternate AM oral corticosteroid for at least one month before entering the study. They were randomly assigned to either flunisolide or placebo treatment for the 12-week, double-blind trial. Patients were seen every two weeks for symptom assessment, physical examination, and pulmonary function testing. Tests of adrenal function were done initially and at the study's conclusion. The flunisolide group had improved asthma control compared with the placebo group. The daily oral steroid requirement decreased in 100 percent of the flunisolide group compared with 53 percent of the placebo group (P less than .01). Pulmonary function and endocrine function remained stable for both groups. There were no adverse effects. Flunisolide aerosol in doses of .5 mg twice daily appears to be topically active and to have oral steroid potential without apparent adverse effects.

Platelets may contribute to the pathogenesis of atherosclerotic coronary artery disease (CAD), and platelet reactivity may be activated by exercise. Fourteen men with CAD participated in a double-blind, crossover study of aspirin (ASA), dipyridamole (DPY), ASA-DPY, and placebo. The ASA therapy increased platelet survival time (autologous labelling with 51Cr), but had no effect on either the duration of angina-limited treadmill exercise or the heart rate-systolic blood pressure product (x 10(-2)) at peak exercise. The combination DPY-ASA had a greater effect on platelet survival, but did not substantially increase the duration of exercise. Administration of DPY alone at a higher dosage increased the exercise duration and had a similar effect on platelet survival. At the time that control exercise was completed with the higher dosage of DPY, the rate-pressure product was decreased. The results suggest that DPY and ASA favorably alter the platelet survival in men with CAD, and that DPY, but not ASA, favorably alters exercise performance. Although ASA and ASA-DPY may alter platelet response to exercise, the effect is not shown in hemodynamic measurements during exercise. In higher dosages, DPY may be an effective coronary vasodilator for men with CAD.

Beta-adrenergic blockade may be hazardous in asthma and chronic obstructive lung disease. The beta-adrenergic antagonist pindolol (LB-46) has been suggested to be more tolerable in such patients. We gave intravenously both 0.4 mg pindolol and placebo to 24 mild to moderate asthmatic subjects in remission. In 23 subjects who completed the study, there was no significant difference in pulmonary function between the pindolol and placebo trials either after drug administration or following exhausting exercise after drug administration, although a trend toward reduced pulmonary function after pindolol was seen. Significant differences (P less than 0.05) were found after inhaled isoproterenol when FEV1 and peak expiratory flow rates were compared. We conclude that in this group of mild to moderate asthmatic subjects, there was no adverse effect from pindolol even during exercise-induced bronchospasm. The response to isoproterenol may have been slightly impaired, but the clinical meaning of this is unclear.

Verapamil or placebo was administered as a bolus infusion in a double-blind fashion to 24 patients with either atrial fibrillation or flutter and to ten patients with paroxysmal supraventricular tachycardia. Patients whose heart rate did not decrease below 100 beats/min were given a second dose. Of the 24 patients with atrial fibrillation or flutter, 11 received placebo first. Control heart rate and blood pressure were not modified by placebo; however, verapamil significantly reduced heart rate and systolic blood pressure in the 24 patients. Of the ten patients with paroxysmal supraventricular tachycardia, one reverted to sinus rhythm after administration of placebo. For the remaining nine, the heart rate was not modified by placebo but was significantly reduced by verapamil administration. Blood pressure was not modified by verapamil or placebo in these ten patients. Long-term oral verapamil treatment was maintained without interruption in 18 patients for a mean of 16 +/- 7.5 months, and 15 patients required concomitant therapy with other antiarrhythmic drugs for rhythm control. All patients reported symptomatic improvement, and the number of hospitalizations required for arrhythmia control decreased significantly. Verapamil is safe and effective for acute control of supraventricular arrhythmias. Long-term oral administration, alone or with other antiarrhythmic drugs, is an important contribution to the management of recurrent supraventricular arrhythmias.

Exercise intolerance is common in cystic fibrosis (CF). We examined the effects of a supervised three-month running program on exercise tolerance, pulmonary function, cardiorespiratory fitness (peak oxygen consumption), and respiratory muscle endurance in CF patients. We studied 31 patients, 21 exercise and ten control, aged 10 to 30 years, with pulmonary involvement ranging from mild to severe. The exercise and control groups were not significantly different with respect to age, sex, pulmonary function, exercise tolerance, or cardiorespiratory fitness. After three months of physical conditioning, the exercise group had significantly increased exercise tolerance and peak oxygen consumption and significantly lower heart rates for submaximal work loads, while the nonexercising (control) group was unchanged in all these variables. The FEV1 decreased significantly in the control group. There were no other significant changes in pulmonary function in either the control or exercise group. Respiratory muscle endurance increased significantly in the exercise patients, and did not change in the control patients. There were no adverse effects of the program. The data suggest that a supervised running program can increase CF patients' exercise tolerance and cardiorespiratory fitness, perhaps in part by increasing respiratory muscle tolerance. The effects of a much longer program deserve study.

Nadolol, a new nonselective beta 1 and beta 2 adrenergic blocking agent, has a plasma half-life of 17 to 23 hours. We studied 37 volunteers with stable angina pectoris who had five or more episodes of pain per week and who also had a 1 mm or greater ST segment depression 80 msec past the J point during a Bruce protocol treadmill test. An eight-week placebo controlled run-in period preceded double-blind randomization to nadolol administered once per day (17 patients) or identical appearing placebo for four weeks (20 patients), after which an exercise test was done. Diaries for pain episodes and nitroglycerin consumption were kept. Exercise tests were performed 24 hours after the last nadolol or placebo dose. Episodes of pain per week were reduced 59.8 percent after nadolol and 28.2 percent after placebo (P less than .01). Nitroglycerin consumption after nadolol was reduced 66.8 percent while after placebo it was reduced 36.2 percent (P less than .05). Resting and peak heart rates and peak rate-pressure products showed typical reductions due to beta-blockade 24 hours after nadolol compared with stability of these during placebo, all P less than .001. Exercise time after nadolol increased 42.2 percent, which was more than the 14.5 percent increase after placebo (P less than .05). Exercise work after nadolol increased 64.7 percent, greater than the 22 percent increase after placebo (P less than .05). Mean ST segment depression at end of exercise was little changed before and after treatment in both groups, reflecting consistency of effort. Improvement in symptoms and work capacity associated with nadolol significantly exceeded the placebo group responses. Unlike other available agents of this class, a single daily dose of nadolol produced therapeutically effective 24-hour beta-blockade in patients with disabling angina pectoris.

In an attempt to find the optimal single therapeutic dose of fenoterol inhalant solution administered by compressor-powered nebulization, bronchodilator and side effects of five different doses of fenoterol (0.5, 1.0, 1.5, 2.0, and 2.5 mg) and of placebo were compared with those of the recommended therapeutic dose delivered from a metered dose canister in 16 patients with reversible airway obstruction. The fenoterol (except for the metered dose) and the placebo were given in a double-blind, cross-over manner. In comparison with placebo, all doses of fenoterol produced a significant increase in average values of FEV1, FEF25-75%, FVC, and SGaw and decrease in FRC for five to eight hours. There was a trend for the bronchodilator action to become greater and more prolonged with increasing doses of fenoterol. Compared with 0.4 mg given from a metered dose canister, 0.5 mg of fenoterol delivered by compressor powered nebulization was equally effective in bronchodilator potency. Dose-by-dose comparison with isoproterenol indicates that fenoterol is a more potent and longer lasting bronchodilator and has no significant effect on heart rate and blood pressures. The most common side effects were shakiness or tremor of hands which appeared to be dose-related in terms of incidence and intensity. The results of the present study suggest that 0.5 to 1.0 mg of fenoterol is a suitable single therapeutic dose when administered by compressor-powered nebulization.

To examine the additive properties and the sites of action of inhaled atropine sulfate (0.05 mg/kg of body weight) and terbutaline sulfate (0.005 mg/kg) in patients with chronic airflow obstruction, we tested these aerosols separately and together in a double-blind random sequence. Twelve patients with chronic bronchitis and perennial obstruction of airflow were studied by measuring three indices of efficacy (specific airway conductance [Gaw/VL], the forced expiratory volume in one second [FEV1] and the forced vital capacity [FVC]) and three indices of the site of action within the airway (delta [(Gaw/VL)/FEV1], the difference between the change in forced expiratory flow at 75 percent of vital capacity and the change in forced expiratory flow at 25 percent of vital capacity, and the change in density dependence of maximal airflow at 50 percent of vital capacity). Both atropine and the combination of atropine and terbutaline improved all indices of efficacy significantly more than did terbutaline. With individual exceptions, the addition of terbutaline to atropine improved Gaw/VL but not forced airflow. All measures of site of action suggested an advantage for atropine in relatively proximal airways. These results indicate that combined therapy with beta-adrenergic and anticholinergic bronchodilator drugs is marginally more effective than therapy with atropine alone in these patients and suggest that anticholinergic aerosols dilate larger airways more effectively than the beta-agonists.

Drugs interfering with sympathetic tone may result in depression of the function of the sinus node, especially in patients with disease of the sinus node. In 11 patients presenting with palpitations, vertigo, or syncope, the heart rate, the recovery time of the sinus node, the carotid sinus pressure slowing, and the atrioventricular conduction capacity were assessed before and every five minutes up to 30 minutes after intravenous administration of 0.15 mg of clonidine. The following significant maximal mean effects were noted at about 15 minutes after the administration of clonidine: the heart rate decreased 12 percent (59 vs 52 beats per minute); and the atrioventricular conduction capacity (ie, paced heart rate at second-degree atrioventricular block) decreased by 9 percent (132 vs 121 beats per minute), while the maximal recovery time of the sinus node increased by a factor of two (1,704 vs 3,562 msec) when atrial overdrives of 120, 150, and 200 beats per minute were used for each five minute period. In analyzing maximal carotid sinus pressure slowing after administration of clonidine, three of 11 patients developed hypersensitive carotid sinus reflex de novo, and two patients showed a decrease and three patients an increase of carotid sinus pressure slowing, while three patients had no carotid sinus pressure slowing both before and after administration of clonidine. We conclude that caution should be taken in administering clonidine to patients with signs indicative of dysfunction of the sinus node.

We studied the effect of a single oral dose of 40 mg of pentaerythritol tetranitrate (PETN) on the exercise capacity of ten patients with angina pectoris. The study design was a randomized double-blind crossover comparing the effects of 40 mg of oral PETN with placebo on exercise tolerance. Patients were exercised to moderate angina pectoris before and 2 1/2 and 4 1/2 hours after receiving the placebo or PETN at seven-day intervals during the double-blind crossover period. Exercise tolerance time was measured using a multistage, progressive treadmill test. Exercise times were greater 2 1/2 hours and 4 1/2 hours following PETN compared with placebo (P less than 0.05). Heart rate, systolic and diastolic blood pressure, and double product at rest (supine and standing) and at point of angina pectoris did not change significantly.

Six asthmatic children were studied to determine whether supplemental, parenteral atropine would increase the effects of bronchodilation and protection against exercise-induced bronchoconstriction after maximal effects had been achieved by inhalation. First, we determined the amount of inhaled atropine sulfate that would give maximal bronchodilation for each patient at rest. This quantity of atropine was designated as "A." Then all subjects exercised for five sessions with the following pre-exercise treatments in a random order: (a) inhaled distilled water plus intramuscular (IM) saline solution; (b) inhaled A dose of atropine plus IM saline solution; (c) inhaled distilled water plus 0.35 mg IM atropine; (d) inhaled A dose of atropine plus 0.35 mg IM atropine; and (e) inhaled double the A dose plus IM saline solution. The results showed that the combination of inhaled and IM atropine had the greatest bronchodilation effect and the greatest protection against exercise-induced bronchoconstriction. Atropine inhalation alone (A dose) or IM injection (0.35 mg) was not as effective in bronchodilation or in alleviation of exercise-induced bronchoconstriction. Doubling the dose of inhalation (2A) did not increase the effects of the A dose. These results support the hypothesis that inhaled atropine does not reach all the airways where cholinergic receptors are present.

Bronchomotor tone is, in part, under beta-adrenergic control, and beta-adrenergic agonists are commonly used in the therapy for chronic obstructive pulmonary disease (COPD). Beta-adrenergic blockade with propranolol is contraindicated in asthmatic patients, yet little is known of its effect in patients with COPD. We studied 13 patients with COPD in a random-entry, double-blind crossover comparison of oral propranolol, 40 mg, and oral placebo on separate day. Pulmonary function worsened after administration of propranolol. Significant differences were present between the drugs' effect on heart rate, airway resistance, specific resistance, and flow rates at one hour, and persisting through four hours (p less than 0.01). Propranolol may have a deleterious effect on pulmonary function in nonasthmatic COPD. We conclude that when propranolol is to be used in patients with COPD, the short- and long-term effects on airway should be measured sequentially.