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.

In a double-blind crossover controlled study, intravenous (IV) or nebulized terbutaline was given to eight patients with moderately severe asthma on two separate days. Four incremental doses of terbutaline were given by each route to establish a maximal effect. Both routes of administration produced significant increases increases in FEV1, FVC, PEFR, MEF50% single-breath TLC, and effective pulmonary blood flow. A decrease in slope of alveolar argon plateau was observed with both routes, but helium responsiveness showed variable changes with no significant or consistent effect seen. There was no significant difference between responses to incremental doses and maximal response apart from pulse rate, which rose during IV treatment. These results showed that the IV route had no advantage in terms of effectiveness or site of action over the inhaled route. Since IV treatment can produce systemic side effects, inhaled bronchodilator therapy should be used as the route of choice.

The effects of oral doses of theophylline and a beta-adrenergic agonist, fenoterol, were examined in 18 asthmatic young adults. Significant bronchodilation was seen with high-dose theophylline (FEV1 increased 14 percent) and with full 10-mg doses of fenoterol (FEV1 increased 10 percent). Low-dose theophylline alone (130 mg) increased FEV1 by 5 percent, but when combined with 5 mg of fenoterol, a 14 percent improvement was seen, demonstrating significant (P = .003) additive effects. The ability of the two drugs to prevent the asthmatic response to exercise was not additive. The mean fall in FEV1 was not statistically different when subjects exercised after receiving a placebo (32 percent) 130 mg of theophylline (27 percent), or 130 mg of theophylline with 5 mg of fenoterol (18 percent). Furthermore, side effects associated with the two drugs, such as tachycardia, tremor, or CNS stimulation, were significantly increased when the two drugs were given simultaneously. Thus, little therapeutic benefit was gained from simultaneous therapy. Both bronchodilation and toxicity were equivalent to that seen with larger therapeutic doses of either drug given alone, and protection from the effects of a frequently encountered stress was not significantly enhanced.

The effect of nifedipine on exercise tolerance was studied in 30 patients with stable angina and positive graded exercise testing. Treadmill exercise testing was performed on each of five consecutive days. Placebo or nifedipine, 10 mg sublingually, was given 30 minutes before exercise on the third day. The following day the intervention was reversed in a double-blind manner. Angina was abolished by nifedipine but not by placebo in 12 patients (40 percent). The time to onset of angina in the remaining patients increased from 4.1 +/- 0.4 (SEM) to 6.7 +/- 0.6 min (p less than .001). Time to ST depression greater than or equal to 2 mm increased from 4.0 +/- 0.3 to 5.4 +/- 0.5 min, while duration of exercise increased from 6.3 +/- 0.3 to 8.2 +/- 0.4 min (p less than .001). The maximum heart rate was 145 +/- 3.3 with nifedipine and 122 +/- 3.8 min-1 with placebo (p less than .01). Resting systolic blood pressure decreased 30 min after nifedipine administration from 131 +/- 3.4 to 106 +/- 2.9 mm Hg (p less than .01). Maximal systolic blood pressure during exercise was lower with nifedipine (127 +/- 4.8 mm Hg) than with placebo (155 +/- 5.6 mm Hg, p less than .01). We conclude that nifedipine significantly improves the exercise tolerance of patients with stable angina pectoris by decreasing peripheral vascular resistance and myocardial oxygen demand.

A rapid, simple method for predicting the arterial oxygen tension (PaO2) at any fractional concentration of inspired oxygen (FIO2) is presented. The method is based on a nomogram interrelating PaO2, arterial carbon dioxide tension (PaCO2) and FIO2, allowing rapid determination of the arterial to alveolar oxygen tension ratio a/A PO2. The applicability of the nomogram and its reliability for predicting the PaO2 at any FIO2 were studied prospectively in nine consecutive patients requiring mechanical ventilation (16 trials). On each occasion, a desired PaO2 was chosen and from the nomogram an FIO2 expected to yield this PaO2 was administered. The PaO2 was then measured. Actual PaO2 differed from desired PaO2 by a mean of 2.6 mm Hg (range 0 to 10 mm Hg, standard deviation (SD) 4.8). Retrospectively, we analyzed the nomogram's ability to predict the PaO2 +/- 9.6 mm Hg (2 SD) at varying FIO2. The overall sensitivity of this method was 85 percent (126 predictions out of 149 trials). We conclude that appropriate levels of supplemental oxygen can be rapidly and reliably chosen using the nomogram in selected patients.

With the objectives of improving response rate, duration of response, and survival in small-cell carcinoma of the lung, 39 patients were randomized to remission-induction with either one of two potentially non-cross-resistant drug combinations: APE (consisting of adriamycin, 35 mg/m2 IV, D1 Q 3 weeks; procarbazine, 60 mg/m2 PO, D1-10 Q 3 weeks; and the epipodophyllotoxin (VP16-213), 130 mg/m2 IV, D8, 15 Q 3 weeks) or MOCC (composed of methotrexate, 15 mg/m2 IV (with [vincristine] Oncovin) or PO twice weekly D8-21 Q 3 weeks; Oncovin, 1.5 mg/m2 IV, D8, 15 Q 3 weeks; cyclophosphamide, 600 mg/m2 IV, D1 Q 3 weeks, and CCNU, 60 mg/m2 PO Q 6 weeks). A fixed crossover to the alternate regimen occurred at three months. Radiotherapy was delivered to the primary tumor (locoregional disease only) by a split course technique (1,750 rads for five days with a three-week split, followed by 3,400 rads over 17 days). The median survival including both arms was 11 months for regional and nine months for extensive disease. The chemotherapeutic activity of both regimens was comparable, with 15/17 (88 percent) of the patients responding to APE (including six complete) and 14/17 (82 percent) responding to MOCC (including five complete). The median survival for the complete responders was 11.7 months, while the partial responders survived for a median of 9.7 months. There were 2/9 (22 percent) responders to the alternate regimen at progressive disease. The overall incidence of CNS progression was 17 percent. The toxicity of the regimens was moderate, except for one instance of granulocytopenic death. This study establishes two equipotent drug combinations for the treatment of small-cell carcinoma of the lung.

Hemodynamic and metabolic effects of methylprednisolone were investigated in a double-blind study of 28 patients with acute myocardial infarction (AMI), confirmed by unequivocal electrocardiographic and enzyme changes. Measurements were performed prior to and at 1.5, 3, 4, 4.5, 12 and 24 hours following infusion of methylprednisolone (13 patients) or placebo (15 patients). Although systemic vascular resistance decreased from 1,750 to 1,420 dynes . sec . cm-5 (p less than .001) and cardiac index increased from 2.77 to 3.10 L/min/m2 (p less than .02) between 0 and 4.5 hours, an abnormal increase in blood lactate was observed in 10 of the 13 patients following administration of methylprednisolone (3.0 vs 1.2 mM/L, p less than .001). Lactate elevation appeared one hour after infusion of methylprednisolone, was maximal at 12 hours, and persisted for more than 24 hours. There was no significant change in blood lactate in placebo treated patients. A transient but significant decrease in plasma volume was also observed following infusions of methylprednisolone. The elevation of blood lactate could not be explained by the reduction in plasma volume since the most striking increases in lactate were observed 12 hours following the initial infusion of methylprednisolone when the plasma volume was returning to the control value. No significant differences in other hemodynamic or metabolic parameters, infarct size or patient survival were observed between the two groups. We conclude that the hemodynamic benefits of glucocorticoids characterized by increased cardiac output and lowered systemic vascular resistance are counterbalanced by the potentially unfavorable conditions of lactate elevation and volume depletion.

The bronchodilator response to aerosolized terbutaline and optimal doses of theophylline, given singly and in combination, was studied in ten patients with perennial asthma. Optimal doses of theophylline were determined (mean peak theophylline level of 20.9 micrograms/ml). Patients then received this theophylline dose plus 500 micrograms aerosolized terbutaline by metered-dose nebulizer qid for one week. Placebo was then substituted for one of the active agents for two weeks, followed by both active agents again for one week, and finally, placebo substituted for the second agent for a two-week period. The therapeutic response was determined by measurement of peak expiratory flow rate four times daily at different intervals following medication and the patient's subjective assessment of each period. The combination was found to be superior to either theophylline or terbutaline alone (P < .05). Theophylline alone and aerosolized terbutaline alone were equally effective. No side effects were encountered with any of the treatment regimens.

The hemodynamic effects of intravenous labetalol (a combined alpha- and beta-blocking agent) were studied in 11 patients during early post-open heart surgery hypertension. With a mean dosage of 15 mg, labetalol reduced both systemic arterial pressures and the heart rate by an average of 21 percent (p < .001). The patients failed to compensate for the decline in pressure and pulse rate by elevation of their stroke volume, and even the cardiac index (CI) was severely depressed (from 2.30 to 1.67 L/min/m2, ie, 27 percent; p < .001). Neither left ventricular filling pressure nor vascular resistance was affected by labetalol early after open heart surgery. In four patients, 3 mg of glucagon after administration of labetalol elevated pulmonary arterial pressures and increased the CI by 16 percent. Two patients were observed on the preoperative day, and their response to labetalol was similar to that described in earlier studies: during blood pressure decline, CI was slightly augmented, and the systemic vascular resistance was greatly reduced (26 percent). The results indicate that after open heart surgery, patients are highly sensitive to the beta-blocking effects of labetalol, and although labetalol can greatly reduce myocardial oxygen consumption, it cannot be recommended for the treatment of post-open heart surgery hypertension.

A 5 percent solution of metaproterenol sulfate (Alupent) and a fixed-combination solution of isoetharine and phenylephrine were compared in a single-dose double-blind study in a total of 27 patients with reversible bronchospastic disease. The patients were assigned to parallel groups for treatment and received the usual dose of 0.3 ml of metaproterenol and 0.5 ml of the isoetharine-phenylephrine solution via equipment for intermittent positive-pressure breathing. Tests of pulmonary function, blood pressure, and pulse rate were performed before the treatment and at intervals of 30 minutes to six hours after administration. The duration of effect (defined as an increase over baseline in the forced expiratory volume in one second [FEV1] of at least 15 percent) of metaproterenol averaged four hours, as compared with one hour for the reference solution. The overall response of FEV1 to metaproterenol was significantly (P = 0.01) superior to the response to the isoetharine-phenylephrine solution. Metaproterenol also surpassed the reference drug in terms of increases in the mean forced expiratory flow during the middle half of the forced vital capacity (FEF-25-75%) to a degree approaching statistical significance. Changes in blood pressure and pulse rate were clinically insignificant with both drugs, and the total number of adverse experiences was substantially the same with both solutions.