Theophylline is commonly prescribed for patients with nonasthmatic chronic airflow obstruction (CAO) even though clinical efficacy is not well established. We studied objective and subjective responses to theophylline in 14 men with CAO. Subjects randomly received week-long treatments of placebo or theophylline at two dosages: one that produced low (8.7-13.0 micrograms/ml) and the other high (16.0-23.6 micrograms/ml plasma concentrations. During the final three days of each treatment, we measured spirometric and hemodynamic function. Exercise tolerance was assessed with the 12 minute walk and progressive cycle ergometry. The patients' perception of breathlessness during the usual activities of daily living was evaluated with the oxygen cost diagram and the breathlessness rating. For low and high dose theophylline there were significant (p less than .05) increases in forced vital capacity (7.1 +/- 2.1 percent; 12.0 +/- 1.7 percent), forced expiratory volume at one second (14.6 +/- 4.9 percent; 12.1 +/- 3.3 percent) and in pulse rate (8.3 +/- 1.2 percent; 19.1 +/- 3.1 percent), but no changes in blood pressure. There were also no significant differences among the three treatments for any of the tests which assessed exercise tolerance or breathlessness. These results suggest that most patients with CAO experience little symptomatic benefit from taking theophylline.

Patients with culture-positive pulmonary tuberculosis were allocated at random into two groups for a three-phase regimen in original course chemotherapy. The first group was given rifampicin (RMP) plus isoniazid (INH) plus ethambutol until sensitivity tests were completed, then RMP plus INH until culture conversion, thereafter INH alone for four months. The second group received the same drugs until obtaining culture conversion, thereafter IHN alone for a period lasting two years after onset of chemotherapy. One hundred sixty-eight patients were available for the final assessment after a five-year follow-up after culture conversion. Two bacteriologic relapses occurred among the two-year scheme patients, none in the short-course patients.

In two groups of patients, 15 with asthma and 15 with chronic bronchitis, the bronchodilator effects of ipratropium bromide, of fenoterol plus theophylline, and of the combination of the three drugs, were compared using a double-blind, single-dose, placebo-controlled format. Ipratropium bromide caused rapid bronchodilatation which was not significantly different in asthmatic patients and patients with bronchitis (delta FEV1 = .29 L in one hour in asthmatic patients, .18 L in patients with bronchitis). In contrast, fenoterol plus theophylline induced a considerably greater effect in asthmatic patients (delta FEV1 = .41 L in one hour) than in those with bronchitis (delta FEV1 = .07 in one hour). The use of the three drugs in combination compared with ipratropium bromide alone, or fenoterol plus theophylline alone, resulted in a significant additional bronchodilatation in asthmatic patients. In the patients with bronchitis, the triple combination was clearly superior to fenoterol plus theophylline. A similar trend was present in comparing the triple combination to ipratropium bromide, but the difference did not reach statistical significance. There was no evidence of synergism when ipratropium bromide was combined with fenoterol plus theophylline in that the total bronchodilator effect was approximately additive. Asthmatic patients and the physician were able to distinguish the triple combination from placebo. No such ability was demonstrated with respect to those with bronchitis. All three drugs were well tolerated. Side effects were mostly mild, and none was related to the use of ipratropium.

We compared the effects of two histamine receptor blocking agents, chlorpheniramine (H1) and cimetidine (H2) on the airways of healthy and asthmatic subjects. Eleven healthy subjects and ten asthmatic patients underwent histamine aerosol challenge. A threshold dose (T) for response to histamine was determined for each subject using maximal expiratory flow rates on partial expiratory flow rates on partial expiratory flow volume curves (MEF40 %[P]). On subsequent study days, the subjects were pre-treated with 8 mg of chlorpheniramine, 300 mg of cimetidine or a lactose placebo. Histamine challenge was performed two hours later with the individual's own T dose and doses one dilution below (T-1) and one dilution above (T+1) that dose. In both asthmatic and healthy subjects chlorpheniramine significantly reduced the bronchoconstrictor responses to histamine (p less than 0.02 and 0.05, respectively) as measured by MEF40 percent (P) at the T dose. When treated with cimetidine asthmatic patients displayed significantly more bronchospasm at T than with placebo (p less than 0.035). By contrast, pretreatment with cimetidine did not alter airway responses to histamine in healthy subjects when compared to placebo. We conclude that H2 receptors mediating bronchodilatation can be demonstrated in asthmatic patients but not in healthy subjects.

Fifteen years ago we began a prospective study using alternate case treatment with prednisone in patients with pulmonary function abnormalities due to sarcoidosis. Twenty-five patients were divided into treatment and control groups that were similar in sex, age, race, degree of pulmonary dysfunction, and duration of disease. Evaluation included complete spirometric studies, single-breath carbon monoxide diffusion capacity, and arterial blood gases. Follow-up studies at six months, one to two years, and ten to 15 years show no difference between the treated and untreated groups. Improvement or deterioration in pulmonary function of individual patients in the treated group was reflected in the control group, even in those patients with a diffusing capacity and forced vital capacity less than 65 percent of predicted. Data from this long-term study fail to show any benefit of short-term use of steroids in therapy for pulmonary sarcoidosis.

Acebutolol, a relatively cardioselective beta-adrenergic blocking drug, was administered to 20 men with coronary artery disease and angina. A three month double-blind cross-over (placebo and acebutolol) design was used following a 12-week placebo phase and a six-week dose-titration phase. During the cross-over phase, acebutolol (400 mg in 19 men and 300 mg in one, orally three times per day) increased the duration of treadmill exercise (placebo, 6.8 +/- 0.5) min [average +/- SEM]; acebutolol, 8.1 +/- 0.6 min; P less than 0.05) and decreased the frequency of ST segment depression during exercise (placebo, 12 or 20 men; acebutolol, 6 of 20 men). The heart rate x systolic blood pressure product (x 10(-2)) was decreased both at rest (placebo, 105.0 +/- 4.0; acebutolol, 84.0 +/- 3.0; P less than 0.01) and during exercise (placebo, 199.0 +/- 10.0; acebutolol, 144.0 +/- 8.0; P less than 0.01). Acebutolol treatment decreased the frequency of angina (diary cards) (placebo, 9.0 +/- 2.4 episodes per week; acebutolol, 6.4 +/- 2.2 episodes per week; P less than 0.05) and decreased the consumption of nitroglycerin (placebo, 9.0 +/- 4.4 tablets per week; acebutolol, 7.4 +/- 4.0 tablets per week; P less than 0.05). Results suggest that acebutolol increases exercise performance and decreases the occurrence of angina in men with coronary disease.

We compared steady-state theophylline pharmacokinetics in 13 healthy adults before and immediately after erythromycin therapy. All subjects received a five-day course of oral aminophylline 3 mg/kg every six hours prior to and during a five-day course of oral erythromycin stearate (1 g daily). Each subject acted as his own control. Multiple serum samples were collected over ten hours following the last dose of aminophylline during both the control and experimental phases of the study. Erythromycin did not significantly affect theophylline clearance (P greater than 0.70), elimination (P greater than 0.75), or volume of distribution (P greater than 0.30). We found no evidence of a pharmacokinetic interaction between theophylline and erythromycin at steady state. Worsening pulmonary function may be responsible for altered theophylline pharmacokinetics in patients coincidentally receiving erythromycin.

The purpose of this study was to evaluate ECG recording by telephone as a research tool for documenting the cardiac rhythm during symptoms of paroxysmal atrial tachycardia. Eleven patients were enrolled in the study during the first year. They transmitted 34 rhythm strips during symptoms, 17 of which showed paroxysmal atrial tachycardia; only one of the 34 was uninterpretable. Three patients thought they were having paroxysmal atrial tachycardia when their rhythm strips showed that they were having sinus tachycardia. Patient compliance and satisfaction with our follow-up system were high. Our study supports the use of ECG recording by telephone as an excellent tool to document arrhythmias in patients enrolled in clinical trials.

We evaluated the effectiveness of oral verapamil therapy for control of ventricular rate in digitalized patients with atrial fibrillation (AF) with three clinical problems: chronic AF with rapid rate at rest (four patients), chronic AF with accelerated rate during modest exercise (five patients), and rapid rates during paroxysmal AF (four patients). Patients in the first two categories were evaluated both by open-label dosage titration and by a randomized, double-blind, cross-over protocol. In chronic AF with rapid rate of rest, there was a significant reduction in resting heart rate (from 125 +/- 7 to 87 +/- 14, P less than 0.01) and in peak exercise heart rate (from 162 +/- 33 to 126 +/- 25, P less than 0.01). In chronic AF with rapid rate during exercise, there was also a significant decrease in resting heart rate (from 90 +/- 7 to 66 +/- 4, P less than 0.01) and in peak exercise heart rate (from 126 +/- 19 to 101 +/- 15, P less than 0.01). These effects continued during longterm follow-up of one to 12 months (mean seven months). In patients with paroxysmal AF, verapamil slowed the ventricular response from 16- +/- 24 to 72 +/- 4 P less than 0.01) with only some amelioration of symptoms. Therapy was well tolerated despite a high prevalence (seven of 13 patients) of radiographic cardiomegaly (cardiothoracic ratio greater than 0.55). We conclude that verapamil is a safe and useful drug for control of ventricular rate in digitalized patients with chronic and paroxysmal AF.

Triamcinolone acetonide aerosol (TAA) and a placebo aerosol were compared in a six-week, double-blind multicenter study. Ninety-six steroid-independent asthmatic patients were randomized into two parallel groups. Each patient was evaluated weekly. After four weeks of treatment, those patients treated with TAA showed highly significant (P less than 0.001) improvement from baseline in pulmonary function tests (FEV1, FVC, and FEF25-75%) and in asthmatic symptoms, whereas no significant improvement was observed in those patients who received placebo aerosol. In the TAA-treated patients, 78 percent were rated wtih an excellent or good response, compared with 24 percent in the placebo patients. During the subsequent one-week washout period, mean pulmonary function test values of the TAA-treated group were significantly reduced (P less than 0.0001). Eighty-eight patients continued into the one-year, open-label phase of the study. Highly significant (P less than 0.001) improvement from baseline was observed in pulmonary function tests and in asthmatic symptoms at each bimonthly evaluation during the 12-month segment. Mean plasma-cortisol level changes were not statistically significant. At the end of the long-term study, the performance of TAA was subjectively rated by the investigators (excellent or good in 92 percent of the patients) and by the patients (excellent or good in 89 percent). Mild-to-moderate adverse reactions (sore throat, hoarseness) were reported by six patients during the six-week phase and by ten patients during the 12-month phase. Thus, TAA was a safe and effective treatment in this series of bronchial asthma patients.

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.