This study of guanfacine in 27 patients suffering from moderate-to-severe hypertension showed a satisfactory blood pressure control in 26 patients. Twenty-one of the 27 patients completed a one-year clinical trial with good blood pressure response. The new drugs, acting through the stimulation of the central alpha-adrenoceptors, are useful in patients suffering from moderate-to-severe hypertension. They are a good alternative to adrenergic neuron-blocking drugs, methyldopa, or beta-blockers, and useful in patients with refractory hypertension where conventional therapy has failed.

The bronchodilator effect of ipratropium bromide (IB) (Atrovent-Sch 1000), 40 micrograms inhaled, and metaproterenol (Met), 1.25 mg in various combinations, was compared in ten allergic asthmatic patients, aged 23 to 63 years. Six combinations were used at random in a double blind study. The following ventilatory functions-FVC, TGV, SGAW, FEV1, FEF 25-75, VEmax, VE50, VE25, were measured at 30 min. intervals for the first two hours and at 60 minute intervals for the additional three hours. Inhalation of IB followed by Met resulted in additive bronchodilator effect that was significantly greater and longer than IB alone (p less than 0.05), Met alone (p less than 0.05), two consecutive inhalations of Met (p less than 0.05), or Met followed by IB (p less than 0.05). The bronchodilating effect of IB and Met after five hours was the same as IB after one hour.

CP-804-S is a substituted phenylbutylamine, known to lower arterial pressure in hypertensive animal models. In a double-blind, crossover study, 12 patients with essential hypertension receiving a constant sodium intake received placebo and CP-804-S, 150 mg daily. Standing (-5.5/-6.0 mm Hg) and supine (-8.5/-7.5 mm Hg) blood pressures and standing (-7.0 beats/min) and supine (-7.5 beats/min) pulse rates were significantly reduced by CP-804-S. Plasma renin activity (-0.41 ng/ml/hr) and plasma angiotensin I (-47 pg/ml) and angiotensin II (-3.0 pg/ml) levels decreased significantly. No significant changes were observed in plasma aldosterone or in the urinary excretion of aldosterone, kallikrein, and prostaglandin E2, F2 alpha, and F alpha metabolite.

To determine the amount of sympathetic outflow suppression due to the alpha 2-adrenergic receptor stimulating agent clonidine, its effect on heart rate, blood pressure, and on circulating plasma catecholamines was assessed in ten healthy subjects at rest and during submaximal ergometric exercise. Similar exercise studies were performed in eight healthy normotensive persons after beta-blockade using propanolol. In nine healthy subjects the effect of an acute intravenous (IV) intervention of clonidine on plasma catecholamines was compared with the results obtained after IV administration of the cardioselective beta-blocker metoprolol or of both drugs. Clonidine taken orally produced significantly reduced plasma levels of epinephrine and norepinephrine (p less than 0.01). During submaximal ergometric exercise, the sympatholytic effect of clonidine was relatively less marked than at rest (p less than 0.05). After beta-blockade, either orally with propanolol or IV with metoprolol, plasma catecholamines at rest did not change significantly; their plasma levels during exercise, however, exceeded those obtained after administration of placebo (p less than 0.05). Giving IV clonidine and metoprolol combined revealed no significant changes of plasma catecholamines at rest and during exercise; heart rate and blood pressure decreased significantly (p less than 0.001). Clonidine on the one hand and the beta-blocking agents on the other exhibit oppositely directed effects on plasma levels of catecholamines.

To evaluate the hemodynamic effects of nifedipine on anginal patients during exercise in the upright position, a placebo (P) and 20 mg of nifedipine were administered in a double-blind random sequence to ten patients presenting with exertional angina and a healed myocardial infarction. All patients had previously undergone coronary angiography. The effects of nifedipine in the upright position at rest, at the anginal threshold, and at the maximal level of exercise were studied. Nifedipine decreased systemic vascular resistances in upright position and increased the cardiac index. It reduced the severity of angina and allowed a higher physical work capacity without anginal symptoms. The most important beneficial effect of nifedipine appears to be the reduction in afterload, but an improvement of left ventricular function cannot be ruled out.

The effect of chewable isosorbide dinitrate on submaximal bicycle exercise capacity was evaluated in a double-blind randomized study involving 13 patients with chronic heart failure. All patients had impaired maximal exercise capacity (VO2 max = 12.0 +/- 2.6 ml/kg/min) due to fatigue and dyspnea but not angina. The administration of isosorbide dinitrate lowered the resting mean blood pressure (82 +/- 9. mm Hg to 78 +/- 10 mm Hg, (p less than 0.03)) and the resulting pulmonary wedge pressure (26 +/- 5 mm Hg to 12 +/- 6 mm Hg, (p less than 0.01)). Isosorbide dinitrate acutely improved exercise duration during upright bicycle exercise at a workload fixed at 50 percent of the maximal workload (placebo): 21.8 +/- 14.1 min vs isosorbide dinitrate: 31.4 +/- 13.6 min, (p less than 0.003)) due to reduced exertional dyspnea. Administration of chewable isosorbide dinitrate acutely improved submaximal exercise tolerance in patients with chronic heart failure.

The efficacy of guaifenesin in reducing cough frequency in young adults with acute respiratory disease was evaluated by both an objective cough counting system and a questionnaire. A guaifenesin cough preparation and the syrup vehicle were administered in a double-blind manner. Coughs were recorded on tape over a 24-hour baseline evaluation period and a 36-hour treatment period for 42 patients. A pronounced diurnal variation in cough frequency was observed. The evaluation of efficacy was based upon comparisons between equivalent six-hour time periods of successive days. No antitussive effect of guaifenesin was demonstrated. The questionnaire was administered to 65 patients, including the 42 whose coughs were recorded. Of 26 patients with productive cough receiving guaifenesin, 25 (96 percent) reported a decrease in sputum thickness compared to 13 (54 percent) of 24 patients receiving the vehicle (p = 0.01, Fisher exact test). Twenty-three of 26 (88 percent) patients receiving guaifenesin also reported reduction in sputum quantity compared to 15 of 24 (62.5 percent) receiving the vehicle (p = 0.07, Fisher exact test). The diurnal variation in cough frequency measured by the tape recording was not apparent from the subjective cough frequency estimates obtained by the questionnaire.

The ability of digoxin to increase exercise capacity and stroke volume (SV) during exercise was evaluated in ten patients with cystic fibrosis (CF) ages 12 to 20 years with moderate to severe degrees of airway obstruction but no history of heart failure. A double-blind crossover trial of digoxin versus placebo was carried out. An evaluation of exercise performance was undertaken upon entry into the study, and after each of the one-week periods in which digoxin 0.25 mg/day or placebo was taken. Exercise testing consisted of a progressive exercise test on a cycle ergometer to measure maximum work capacity (Wmax) and a steady state test at 2/3 of the baseline Wmax. During the steady state test, the oxygen consumption and carbon dioxide production were measured and cardiac output (Q) was calculated by the indirect Fick (CO2) method. From Q and heart rate (HR), SV was derived. After digoxin, Wmax was unchanged. On steady state exercise HR was unchanged, but there was a slight but significant fall in Q due to a fall in SV. The decrease in SV was associated with exercising hypoxemia. We conclude that digoxin did not increase exercise capacity or improve exercising cardiac function in patients with moderate to severe airway obstruction due to CF.

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.