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.

The purpose of this investigation was to determine whether long-term oral administration of commonly prescribed doses of quinidine sulfate and procainamide hydrochloride to patients with ischemic heart disease affects myocardial contractility. Segmental contractility, assessed by the systolic shortening fraction, the relative change in interclip distance from diastole to systole, was measured by cineradiography of metal clips that had been sutured to the epicardium at the time of coronary artery bypass surgery. Global contractility was assessed by gated blood-pool scintigraphy. Systolic shortening fraction determinations and scintigraphy were obtained following five to seven days' administration of procainamide (500 mg every four hours), quinidine (200 mg every six hours), or neither drug in a random sequence. Serum drug levels (milligrams per liter) were 1.8 +/- 0.8 (mean +/- 1 SD) for quinidine and 3.7 +/- 1.1 for procainamide, when measured one hour before the next dose. During quinidine administration, mean segment shortening fraction decreased only slightly, but significantly (P less than 0.02), from 12.4 percent to 10.6 percent. The clinical importance of so small a change is questionable. During procainamide administration, there was a very small, insignificant (P greater than 0.9), decrease in segmental shortening. Global left ventricular function was not significantly changed by either drug. It appears that both drugs can be used over long periods in commonly prescribed doses in patients with ischemic heart disease without a major overall deleterious effect on cardiac performance.

The bronchodilator and cardiovascular effects of orally administered tablets containing 2.5 mg of terbutaline and 25 mg of ephedrine were compared in a double-blind parallel manner in children (ages, 7 to 14 years) weighing 25 to 50 kg (44 to 110 lb). Both drugs produced bronchodilation within one-half hour, and this effect was maintained up to six hours, with a peak between two and three hours. Small increases in the pulse rate were measured within an hour following administration of both drugs. No significant variation was noted in blood pressure. No adverse effects (including tachyphylaxis and tremor) were observed for either drug during a three-month period. Both bronchodilator agents were shown to be equally effective in the dosages used. Terbutaline is a safe bronchodilator drug when administered orally in 2.5-mg doses for children with chronic asthma in this range of ages and weights, with minimal cardiovascular side effects and effective bronchodilation.

Because atelectasis of the left lower lobe is a frequent complication of open heart surgery, we evaluated the efficacy of routine therapy with positive end-expiratory pressure (PEEP) to prevent this complication. Twenty-four patients were randomly assigned to either a group receiving therapy with PEEP (ten patients) or to a group with no PEEP (14 patients). The two groups could not be distinguished by age, weight, the forced expiratory volume in one second (FEV1), the ratio of FEV1 over the forced vital capacity, the time on the pump, the units of blood transfused, the tidal volume, or the hours of mechanical ventilation. There was no significant roentgenographic difference between the two groups in either the degree or frequency of left lower lobe atelectasis. While the arterial-alveolar ratios tended to improve over time in those patients receiving therapy with PEEP, this improvement was not clinically significant. No complications were encountered with the use of PEEP. We conclude that the routine use of PEEP following open heart surgery is safe but offers no advantage over standard ventilatory techniques.

Glucocorticosteroid, methylprednisolone sodium succinate (MPSS), 30 mg/kg of body weight, or dexamethasone sodium phosphate (DSP), 6 mg/kg of body weight, were given intravenously to 60 patients, divided into two groups of 30 45 minutes prior to cardiopulmonary bypass for coronary artery bypass. These two groups were compared with 30 patients in a control group receiving a placebo and undergoing the same surgery. The study was carried out in a double-lind fashion. Patients receiving MPSS had a significantly higher cardiac index in both the preoperative and postoperative periods. This was accompanied by a decreased peripheral resistance. Patients receiving either MPSS or DSP also showed some evidence for the "washout" phenomenon indicating the possibility of better microcirculatory flow. Gluconeogenesis may have been enhanced in both groups receiving MPSS or DSP, but the evidence was greater in thos patients receiving MPSS. There were no hospital deaths in any of the three groups totaling 90 patients.

Fifteen noninfected patients received three consecutive doses of tobramycin (1.7 mg/kg intramuscularly). Serum and bronchial secretions were obtained during bronchoscopy. Microbiologic assay demonstrated that bronchial secretions containing tobramycin produced inappropriately small zone sizes when compared with serum. Also, it was shown that bronchial secretions frequently do achieve therapeutic concentrations of tobramycin at this dosage level and route of administration.

Sisomicin or a placebo was administered endotracheally to two groups of 18 and 20 unconscious patients, respectively, who had tracheostomies or endotracheal tubes in place and developed a severe gram-negative broncho-pneumonia. In addition, the patients received systemically a combination of sisomicin and carbenicillin. A favorable clinical response was obtained in 14 (77 percent) of the 18 patients who were treated with sisomicin and in nine (45 percent) of the 20 patients who received the placebo (P less than 0.05). Endotracheal therapy with sisomicin was well tolerated and resulted in high levels of sisomicin and in elevated bactericidal activity within the bronchial secretions. Endotracheally administered amino-glycosides might be an important adjunct to systemically administered antibiotics in the management of severe gram-negative bronchopneumonia.

The effects of smoking and inhalation of carbon monoxide on the systolic time intervals and blood pressure were examined in ten healthy smokers with a mean age of 24.3 years. Each subject smoked a low-nicotine cigarette with a ventilated filter (0.1 mg nicotine, 1.1 vol percent CO), and a high-nicotine plain cigarette (2.6 mg nicotine, 4.5 vol percent CO), as well as a cigar in random sequence and in a standardized way. Cigar smoke was not inhaled. The product heart rate x blood pressure was increased and the left ventricular ejection time index (LVETc) prolonged following smoking the high-nicotine cigarette, whereas changes after smoking the low-nicotine cigarette and the cigar were not as pronounced. These changes are presumably caused by nicotine-induced catecholamine release. Inhalation of CO did not affect cardiac performance acutely as shown by unchanged systolic time intervals. When a high-nicotine cigarette was smoked after the subject received a beta blocker, a significant prolongation of the pre-ejection period index (PEPc) occurred as a result of the increased afterload. Thus, the effects of catecholamines on parameters of myocardial contractility (PEPc, PEP/LVET) were presumably offset by the increased afterload. We conclude that the acute hemodynamic changes of smoking in healthy subjects depend upon the amount of nicotine absorbed.