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.

We studied the effects of a combined treatment with beta 2-stimulating and beta-blocking drugs in 35 patients suffering from chronic obstructive lung disease (COLD) and ischemic heart disease, and/or arterial hypertension. The drugs used were equipotent repeated oral doses of metoprolol (100 mg twice daily [bid]), propranolol (80 mg bid), and a matching placebo for beta-adrenoceptor blockade given in a double-blind and crossover fashion. The intake period of each beta-blocker was two days with consecutive two-day-washout period; 2.5 mg terbutaline and beta-stimulator placebo, respectively, were given throughout the whole trial three times daily (tid). Propranolol alone caused severe deterioration of lung function. After 18 patients had been studied, this drug had to be excluded from the trial. When compared with placebo, metoprolol provoked increasing obstruction, too, but to a significantly lesser degree than propranolol. These negative effects on FEV1 and FRC were completely equalized by terbutaline. Predictive factors for the tolerability of beta-blockers in patients with COLD could not be found. Therefore, careful observations in the initial phase of the treatment with beta-selective blockers are necessary.

Bitolterol mesylate (WIN 37284) is alpha-[tert-butylaminomethyl]-3,4-dihydroxybenzyl alcohol 3,4-di(p-toluate) methanesulfonate, a diester sympathomimetic amine bronchodilator. Bitolterol mesylate represents a new concept in sympathomimetic amine therapy. It is "prodrug" which is inactive until altered in the body. The intact 3,4-diester molecule is metabolized by esterase hydrolysis to release the active catecholamine, N-t-butylarterenol. Because the level of esterase is greater in the pulmonary tissue than in the heart, bitolterol mesylate aerosol was shown to be an effective bronchodilator drug, without any significant cardic side effects. The onset of action was rapid and lasted more than six hours. The improvement over baseline values in the forced expiratory volume in the first second and the mean forced expiratory flow during the middle half of the forced vital capacity was greater than 15 percent and 30 percent, respectively.

The hemodynamic and clinical effects of verapamil administration were examined in patients with hypertrophic cardiomyopathy. Infusion of 0.021 mg/kg/min of verapamil decreased the basal left ventricular outflow tract gradient from 94 +/- 14 to 49 +/- 14 mm Hg, while cardiac index increased from 2.5 +/- 0.2 to 2.8 +/- 0.2 L/min/sq m. Orally administered, 80 or 120 mg four times daily (QID), increased exercise capacity relative to placebo by 26% (1.6 +/- 0.5 minute; p less than 0.005) and propranolol, 40 or 80 mg QID, increased it by 21 +/- 8% (1.3 +/- 0.5 minute, p less than 0.025). Nine patients considered their symptomatic status "best" while receiving verapamil, seven while receiving placebo, and only three while receiving propranolol. Seventy-three patients have been discharged from the hospital receiving long-term verapamil therapy, and 49 have reported continuing symptomatic benefit with many showing improved exercise capacity up to two years later. Thus, verapamil can improve exercise capacity and symptomatic status in certain patients with hypertrophic cardiomyopathy, thereby providing physicians with a new therapeutic agent for the treatment of this disorder.

Although diltiazem has been shown to alleviate vasospastic angina pectoris, its effect on exercise-inducible chronic stable angina has not been objectively studied. Accordingly, the effect of diltiazem was studied in this condition with a placebo controlled double-blind randomized cross-over protocol at three dose levels (120, 180 and 240 mg/day) during graded treadmill exercise. Three end-points were evaluated: 1) time to onset of angina or fatigue if angina were eliminated; 2) time to 1 mm ST segment depression or fatigue if ST depression were eliminated; and 3) time to termination of exercise (2+ angina or fatigue). All end-points were prolonged at all dose levels. At the highest dose of 240 mg/day, time to onset angina or termination was prolonged from a placebo time of 8.0 +/ 0.9 to 9.8 +/- 0.9 minutes (p = < .001); time to ST depression or termination was prolonged from 7.8 +/- 0.9 to 9.1 +/- 0.8 minutes (p = .007); and time to termination was prolonged from 9.9 +/- 0.9 to 10.8 +/- 0.8 minutes (p = .02).

Medical therapy for Prinzmetal's variant angina has been treatment of the acute attack with sublingual nitroglycerin. Prophylactic therapy has been more difficult, utilizing long-acting vasodilators that are limited because of their short half-life and side effects when therapeutic doses are used. Alpha-adrenergic blockade has been effective in some patients but is frequently associated with intolerable side effects or apparent development of tolerance to the drug. Preliminary experience from a randomized double-blind trial of diltiazem, a new calcium antagonist, has demonstrated a 90% reduction in pain episodes, with many patients becoming pain-free on the 240-mg daily dose. These data and the lack of adverse side effects demonstrate a dramatically effective therapy for patients with coronary artery spasm.

The antiarrhythmic efficacy and pharmacokinetics of tocainide, an oral analog of lidocaine, was evaluated in 18 hospitalized convalescing myocardial infarction patients. Holter ECG tapes were recorded daily during two-day placebo therapy preceding and succeeding two days of tocainide treatment. Left ventricular function was characterized from prior or subsequent arteriographic studies (ten cases) or from radionuclide scanning (eight cases). Tocainide dosage was 17.7 +/- 4.9 SD mg/kg/day. Plasma half-time of elimination was 19.1 +/- 6.8 hours (r = 0.9). Tocainide had no significant effect on heart rate, pulse rate, or QTC intervals and did not worsen chronic heart failure, even in patients with ejection fraction < 30%. In seven of 18 patients, tocainide significantly reduced ventricular premature beat (VPB) frequency as compared to predrug and postdrug placebo periods. Drug responders averaged a 200 to 545% reduction in VPB frequency at tocainide blood levels of > 3.5 microgram/ml.

A study was undertaken to compare the use of three types of deep-breathing devices in patients undergoing upper-abdominal operations. Seventy-nine patients were divided into three groups, each receiving preoperative bedside testing of pulmonary function and instruction in the use of one of three randomly assigned deep-breathing devices thought to be representative of those currently available (Triflo II, Bartlett-Edwards Incentive Spirometer, or Spirocare). Repeat testing and instruction were provided daily during each of the first five postoperative days. There were few statistically significant differences in pulmonary function, vital signs and white blood cell count, and no difference in length of postoperative stay. No device was uniformly acceptable to patients, and none was used as frequently as recommended. When left at the bedside and only one daily reinforcement of instructions, the three devices showed no clinically important differences.

Change in the magnitude of density dependence of the maximal expiratory flow (D/MEF) following inhalation of isoproterenol was used as a test for predicting the long term response to isoproterenol vs atropine in 24 adult patients with longstanding asthma. Eleven subjects showed a decrease in D/MEF manifested by increase in volume of isoflow (VisoV) and/or decrease in Vmax50 Helox/air following isoproterenol inhalation (group 1). Thirteen subjects manifested an opposite response (group 2). Atropine sulphate (0.08 mg/kg) and isoproterenol hydrochloride (2.5 mg) were then administered by inhalation, each four times a day for seven days in a randomized double-blind cross over fashion to all subjects. One of group 1 but ten of group 2 subjects had a greater subjective and objective improvement with atropine than with isoproterenol (P less than .005). An increase in D/MEF following isoproterenol can be used as a test to predict a better response to atropine than to isoproterenol over a one week period. Such a response occurs in almost half of the adult chronic asthmatic patients. The results are consistent with a preferential dilatation of the large airways by atropine.