Double-blind, crossover comparison of carbuterol and salbutamol.

The bronchodilator efficacy of oral carbuterol in the dose of 2 mg or 3 mg was compared with that of 4 mg salbutamol in a double-blind, crossover trial in 21 patients with bronchial asthma. Carbuterol 3 mg was found to be a more effective bronchodilator than salbutamol 4 mg. Both the drugs in these doses produced mild tachycardia but were otherwise well tolerated.     

The effect of metaproterenol in chronic asthmatic children receiving therapeutic doses of theophylline.

The effect of metaproterenol added to therapeutic doses of theophylline was compared with a combination of placebo and theophylline by measurement of the forced expiratory volume in 1 sec (FEV₁), forced vital capacity (FVC), and maximum midexpiratory flow rate (MMEFR) in 17 asthmatic children in a double-blind crossover study. Plasma theophylline levels were measured at 1.5 hr (peak) and 6 hr (trough) after drug administration on all test days. Children weighing less than 60 pounds received 10 mg of metaproterenol (1 tsp), while those weighing more than 60 pounds received 20 mg every 6 hr. The mean peak theophylline level for both metaproterenol and placebo treatment days was approximately 10 μg/ml, while the trough was 6 μg/ml. Metaproterenol caused a significantly greater increase in FEVI (p < 0.05) of 17% at 1.5 hr when given with theophylline than the placebo- theophylline combination. The metaproterenol effect on MMEFR was even greater with increases over placebo of more than 80% at 1.5 hr and 2 hr (p < 0.0025) and 30% at 3 hr and 4 hr (p < 0.05). No increase in adverse effects with the metaproterenol-theophylline combination compared with placebo-theophylline was observed. This study suggests that metaproterenol can improve pulmonary function of both large and small airways when added to moderate theophylline doses without risking increased side effects in asthmatic children.     

Comparison of subcutaneous terbutaline with epinephrine in the treatment of asthma in children.

Comparison of the bronchodilator and cardiovascular effects of subcutaneous terbutaline and epinephrine in the treatment of acute asthmatic attacks in children disclosed that bronchodilation occurred with 5 min after subcutaneous injection of either drug (0.01 mg/kg, maximum 0.25 mg). Bronchodilation was maintained for 4 hr after administration of either drug. Small increases in pulse rate followed administration of terbutaline but not epinephrine. No clinically significant side effects were noted with either drug.     

Acute bronchial and cardiovascular effects of oral pirbuterol and metaproterenol

The acute pulmonary and cardiovascular effects of pirbuterol dihydrochloride 10 mg and 15 mg, a new orally active beta 2-selective sympathomimetic agent, were compared with those of placebo and metaproterenol 20 mg over a period of seven hours in 24 stable asthmatics. Pirbuterol 15 mg and metaproterenol 20 mg had a comparable onset of action (30 min) and magnitude of peak bronchodilator effect (29 +/- 5 mean % increase in FEV1) but the bronchodilatation following pirbuterol was longer lasting (seven hours) than that following metaproterenol (three hours). Pirbuterol 15 mg also caused a greater magnitude and duration of bronchodilatation than pirbuterol 10 mg. No effect on heart rate or PEP/LVET ratio was noted with either drug. Side effects reported following each of the active agents were comparable in frequency and were almost always mild. These findings indicate that pirbuterol is an effective bronchodilator with a relatively long duration of action, definite beta 2-adrenergic specificity and insignificant toxicity when administered in a single dose.     

Bronchodilating effect of oral theophylline-ephedrine combination.

Ten adults with mild but continuously symptomatic asthma were compared with 10 nonsmoking normal persons. In Phase I after 2 wk without oral bronchodilators and 8 hr without aerosols, each subject received on five different days and in a randomized sequence either placebo, ephedrine 24 mg, theophylline 130 mg, theophylline + ephedrine, or theophylline + ephedrine +phenobarbital 8 mg. During Phase II, the 20 subjects took the theophylline-ephedrine-phenobarbital compound 4 times a day for 2 wk and continued this schedule for an additional 10 to 14 days while the five drug administrations of Phase I were repeated. The drug effects were evaluated by spirometry and flow volume loops and correlated and blood levels of theophylline. A single dose of the combination produced therapeutically useful bronchodilation of central and peripheral airways without producing much more frequent or severe side effects than either drug alone. The greater improvement that occurred by combining a low dose of theophylline with a low dose of ephedrine does not preclude a conclusion that similar improvement could have been achieved with a larger dose of theophylline. Addition of phenobarbital did not reduce symptoms of nervousness, tremor, or nausea. After 2 wk or longer of repeated doses, the combination produced about as much bronchodilation as after a single dose. Before the second set of measurements, theophylline levels had reached steady state after regular administration of 130 mg four times a day. Eight hours after the single dose, the mean serum level was 2.3 μg/ml; after 2 wk of repeated doses, 8 hr after a dose the mean was 5.3 μg/ml. Each drug, and the combination more than either, had a bronchodilating effect on small airways of normal subjects.     

Dose-response characteristics of nebulized isoproterenol in asthmatic children.

The optimal dose of nebulized isoproterenol for nontoxic bronchodilation in asthmatic children is not established. In this study the response of 23 asthmatic children to four doses of nebulized isoproterenol hydrochloride, 1:200, a metered dose form of isoproterenol, and placebo were compared for onset, duration, and degree of bronchodilatation as well as cardiovascular responses and side effects. Data, including forced expiratory volume in 1 sec (FEV₁), maximum mid-expiratory flow (MMEF), heart rate, and blood pressure obtained before and at 5, 15, 30 and 60 min after each test nebulization, were analyzed. The results show that all doses of isoproterenol produced significant bronchodilatation at all times. The lowest dose of nebulized isoproterenol produced bronchodilatation which was initially equal to the higher doses but was significantly less effective at 60 min. There was no significant difference in the bronchodilator response to doses 2, 3, and 4. There was, however, a progressive increase in heart rate with increasing doses of isoproterenol, but significant effects were observed on blood pressure only with doses 3 and 4. We conclude that a dose of 0.005 ml/kg (0.025 mg/kg) of inhaled isoproterenol by the nebulization technique described and using the same equipment (air compressor, T tube apparatus, and nebulizer) is optimal for bronchodilatation in asthmatic children with minimal cardiovascular side effects.     

Protection by ipratropium bromide and metaproterenol against methacholine and histamine bronchoconstriction

To establish relative protection against methacholine and histamine, 40 μg of ipratropium bromide, an anticholinergic compound, 1.3 mg of metaproterenol or placebo aerosols were administered by metered-dose inhaler prior lo inhalation challenge with methacholine or histamine in nine asthmatic subjects. Double-blind, randomized challenges were performed. Subjects required a mean methacholine dose of l.72 ± 0.73 and 2.46 ± 0.72 (Ln inhalation units), and mean histamine dose of 2.l6 ± 0.65 and 2.68 ± 0.49, to cause a drop of 20% and 35% respectively in the FEV₁ following the placebo. In the methacholine challenges, both ipratropium bromide and metaproterenol had significant protection as compared to placebo (P<0.001). There was no statistical difference in the degree of protection against methacholine between ipratropium bromide and metaproterenol. In histamine challenges, metaproterenol had significant protection as compared to the placebo, while ipratropium bromide did not protect against histamine.     

Effect of bronchodilator therapy administered by canister versus jet nebulizer

Bronchodilator efficacy of metaproterenol sulfate aerosol therapy delivered either by canister or jet nebulizer was compared in 25 patients, 13 with severe asthma and 12 with COPD. Treatment was carried out in double-blind crossover fashion on 2 days and consisted of either metaproterenol sulfate solution 15 mg in 2.3 ml administered from a jet nebulizer or three puffs of metered-dose metaproterenol sulfate (total 1.95 mg) inhaled sequentially. FVC and FEV1 were monitored before and after therapy for 2 hr. In 13 asthmatic patients, FEV1 increased from a baseline mean of 0.83 L to 1.57 L at 2 hr after jet nebulizer therapy and increased from 0.84 L to 1.52 L after canister therapy. In 12 patients with COPD, FEV1 increased from 0.58 L to 0.78 L after jet nebulizer therapy and from 0.57 L to 0.76 L after canister therapy. FVC also increased similarly after each form of therapy. The two types of aerosol therapy were equally effective and were without side effects. Canister therapy has the advantage over jet nebulizer therapy by being convenient and cheaper.     

A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension

It has been suggested that the metabolic side effects of antihypertensive drugs are responsible for their failure to reduce cardiovascular morbidity in patients with hypertension. Therefore, in 50 patients with essential hypertension, we performed a randomized, double-blind, crossover study comparing the effects of carbohydrate and lipid metabolism of captopril (mean [+/- SD] dose, 81 +/- 24 mg per day) and hydrochlorothiazide (40 +/- 12 mg per day) over two four-month treatment periods. Captopril increased the insulin-mediated disposal of glucose, as compared with placebo, from 5.7 +/- 2.4 to 6.3 +/- 2.5 mg per kilogram of body weight per minute (P less than 0.05), whereas hydrochlorothiazide caused a decrease from 6.4 +/- 2.0 to 5.7 +/- 1.9 (P less than 0.01). Captopril had no effect on the basal insulin concentration, but it decreased the late (30- to 90-minute) insulin response to glucose and increased the early (2- to 6-minute) insulin peak. Hydrochlorothiazide increased the basal insulin concentration and the late insulin response to glucose. These findings may be explained by an increase in insulin sensitivity with captopril and a decrease with hydrochlorothiazide. Little or no change was seen in serum lipid or lipoprotein levels during treatment with captopril, whereas hydrochlorothiazide caused significant increases in serum total (5 percent) and low-density lipoprotein (6 percent) cholesterol levels and total (15 percent) and very-low-density lipoprotein (25 percent) triglyceride levels, as compared with placebo (P less than 0.01 for all comparisons). We conclude that hydrochlorothiazide for the treatment of essential hypertension has adverse effects on glucose and lipid metabolism. It is possible, but not proved in this study, that these changes may contribute to the risk for diabetes mellitus and coronary heart disease. In contrast, captopril appears to have beneficial or no effects on glucose and lipid metabolism.     

Double-blind, dose-response study of metaproterenol inhalant solution in children with acute asthma

One hundred children, aged 6 to 12 years, with acute asthma received nebulized therapy with saline, 5, 10, or 15 mg of metaproterenol aerosol solution according to a prerandomized, double-blind protocol. Pulmonary function and cardiac function were assessed for 60 minutes. All patients then received 5 mg of metaproterenol aerosol solution, and observation continued for another 30 minutes. The best response to therapy in terms of rise in FEV1, forced expiratory flow rate between 25% and 75% of FVC, and area under the curve (change in lung function with time) occurred with 5 and 10 mg of metaproterenol. The highest dose, 15 mg, produced significantly less bronchodilation. Although there were no electrocardiographic abnormalities, pulse rate was significantly higher with 10 and 15 mg of metaproterenol than with 5 mg. Five milligrams of metaproterenol aerosol solution is the optimal bronchodilating dose for treating acute asthma in children. Repeating this dose provides some additional bronchodilation and is well tolerated.     

Effect of tiagabine on sleep in elderly subjects with primary insomnia: a randomized, double-blind, placebo-controlled study

SUBJECT OBJECTIVE: This study further evaluated the effects of tiagabine on sleep in elderly subjects with primary insomnia. METHODS: Elderly subjects (aged 65-85 years) meeting DSM-IV-TR criteria for primary insomnia were randomly assigned to receive tiagabine 2, 4, 6, or 8 mg or placebo on 2 consecutive nights. Efficacy was assessed using standard polysomnography and a postsleep questionnaire. Additional assessments included the Assessment of Daily Functioning, Digit Symbol Substitution Test (for residual effects), and visual analog scale (for sleepiness/alertness). RESULTS: A total of 207 subjects were randomly assigned to study medication (tiagabine: 2 mg, n = 43; 4 mg, n = 38; 6 mg, n = 45; 8 mg, n = 43; placebo, n = 38). Tiagabine did not significantly effect wake after sleep onset, latency to persistent sleep, or total sleep time compared with placebo (P > .05). Significant increases in Stage 3+4 sleep (i.e., slow-wave sleep) were found for tiagabine 4, 6, and 8 mg versus placebo, with a corresponding significant decrease in Stage 1 sleep (P < .05). At 6 and 8 mg, tiagabine also significantly reduced the number of awakenings and increased the ratio of Stage 3+4/(Stage 1 +wake after sleep onset). In general, there were no significant effects on subjects' ratings of sleep or daily functioning with tiagabine 2, 4, and 6 mg versus placebo. These 3 doses had tolerability profiles comparable with that of placebo and were not associated with significant residual effects or reduced alertness. The 8-mg dose, however, significantly decreased subjective total sleep time and refreshing quality of sleep, as well as daily functioning. This dose was associated with troublesome adverse events, significant residual effects, and reduced alertness. CONCLUSIONS: In elderly subjects with primary insomnia, tiagabine did not have a significant effect on wake after sleep onset, latency to persistent sleep, total sleep time, or the subjective rating of sleep. Tiagabine 4, 6, and 8 mg significantly increased slow-wave sleep, with a corresponding significant decrease in Stage 1 sleep. Tiagabine was generally well tolerated, with doses of less than 6 mg having tolerability profiles generally similar to that of placebo. The 8-mg dose, however, was associated with troublesome adverse events, residual effects, and reduced alertness.     

A placebo-controlled trial of procaterol: A new long-acting oral beta2-agonist in bronchial asthma

Procaterol hydrochloride, a potent beta 2-adrenergic bronchodilator developed in Japan, was evaluated in a double-blind, placebo-controlled study for efficacy and safety in 45 patients (ages 18 to 55 yr) with chronic documented reversible airway disease. After a 1-week placebo washout period, patients were administered either 0.05 mg or 0.10 mg of procaterol or placebo twice daily for 2 wk. Spirometric determinations, vital signs, and ECGs were obtained at 1/2, 1, 2, 4, 6, and 8 hr after the first dose and at the same time intervals after 1 and 2 wk of treatment. Patients recorded on a daily basis peak flow rates, asthma symptoms, need for supplemental aerosol, concurrent medications, and side effects. Spirometry results indicated significant improvement in pulmonary function with both doses of procaterol compared with placebo (P less than 0.05). The larger dose was generally more effective. Bronchodilatation was evident 1/2 hr after dosing and peaked at 2 hr. At 8 hr after 0.10 mg of procaterol, FEV1 was still above predose values. Daily peak flow rates were significantly higher with 0.10 mg than with 0.05 mg (P less than 0.05) and placebo (P less than 0.001). Tremor and nervousness were the most frequent side effects. They occurred in a dose-related frequency, were mild and transient, and occurred early in treatment. No significant drug-related changes were noted in ECGs, heart rate, blood pressure, or clinical laboratory data. Procaterol was found to be an effective, well-tolerated oral bronchodilator with a long duration of action, especially at 0.10 mg twice daily.     

Alteration in both insulin release and its hypoglycemic effects in atopic bronchial asthma

In 31 patients with atopic bronchial asthma in clinical remission and in 21 healthy sex- and age-matched subjects, the responses to intravenous tolbutamide (1.0 gm) and insulin (0.1 U/kg) were studied over a period of 2 hr. In response to tolbutamide, asthmatics released significantly less insulin, but their blood glucose levels did not differ from those of controls. Asthmatics also reacted to tolbutamide-induced hypoglycemia with significantly greater output of growth hormone to blood. Following intravenous injection of insulin, the recovery of the blood glucose concentrations was significantly reduced in asthmatic patients. More economical use of insulin and increased responsiveness to its hypoglycemic action, together with the well-known reduction in hypoglycemic effects of catecholamines in bronchial asthma, might explain why asthmatics rarely develop diabetes mellitus.     

Histologic responses in human skin test reactions to ragweed. IV. Effects of a single intravenous injection of steroids.

A controlled study has been carried out dealing with the early effects of a single intravenous dose of either methylprednisolone or placebo or newly developed and ongoing cellular inflammatory responses in immediate hypersensitivity skin test reactions. There was no significant difference in the tissue eosinophil responses to ragweed injected 2 hr before and 2 hr after placebo; there was a significant rise (101% +/- 39) from the second to fourth hour after antigen injection. By contrast, there was a marked decrease in the tissue eosinophil response to antigen injected 2 hr after steroids as compared to the pattern seen in the presteroid reaction. In addition, the eosinophil numbers not only did not increase from the second to fourth hour when steroids were injected at the second hour but decreased markedly. These findings suggest early suppressive effects on tissue eosinophil responses within 2 hr after steroid were administered intravenously. Also, there may be trafficking of eosinophils both into and out of these inflammatory sites during the first hours after intradermal antigen injection.     

Quantitative effects of cetirizine and diphenhydramine on mental performance measured using an automobile driving simulator

The purpose of this study was to assess the effects of cetirizine on objective measures of mental performance. Fifteen subjects were given single doses of cetirizine (20 mg, 10 mg, and 5 mg) diphenhydramine, 50 mg (positive control), and placebo (negative control) in this randomized, double-blinded, crossover study. An automobile driving simulator, digit symbol substitution, Trails B maze tracking and subjective feelings of drowsiness were measured at 0, 2, 4, 6, 8, and 24 hours after the dose. No differences between placebo and any of the three doses of cetirizine could be detected, however, diphenhydramine produced impaired mental performance and drowsiness. These data indicate that these doses of cetirizine produce little or no effect on cognitive function or mental performance.     

Endocrine and cardiovascular responses during phobic anxiety

In vivo exposure therapy for phobias is uniquely suited for controlled studies of endocrine and physiologic responses during psychologic stress. In this study, exposure therapy induced significant increases in subjective anxiety, pulse, blood pressure, plasma norepinephrine, epinephrine, insulin, cortisol, and growth hormone, but did not change plasma glucagon or pancreatic polypeptide. Although the subjective and behavioral manifestations of anxiety were consistent and intense, the magnitude, consistency, timing, and concordance of endocrine and cardiovascular responses showed considerable variation.     

Insulin and C-peptide secretory responses to glucagon in man: studies on the dose-response relationships

The present study investigated the insulin and C-peptide secretory responses to glucagon in non-diabetic humans. Glucagon induced a transient increase in plasma insulin and C-peptide concentrations. At the dose level of 0.5 mg, glucagon elicited more efficient responses than at the dose level of 0.25 mg (p less than 0.05). However, the responses were not further potentiated by glucagon at 1.0 mg. Plasma glucose levels did not change during the first 2 min after glucagon injection, when already a marked increase in plasma insulin and C-peptide levels were observed. Thereafter, however, plasma glucose levels increased, to be maximal at 20 min after glucagon injection. Calculations of the minute-to-minute increase of plasma insulin and C-peptide levels revealed that plasma insulin levels increased by 32 +/- 7% of the increase in plasma C-peptide levels during the first 2 min, and by 36 +/- 6% of the increase in plasma C-peptide levels during the 3rd and 4th min after injection; the difference being the liver extraction of insulin. We conclude from this study in man that glucagon stimulates insulin secretion through both direct and indirect effects, that following glucagon injection, approximately 65% of the secreted insulin is extracted by the liver, and that the dose level of 0.5 mg glucagon is the optimal dose level for the stimulation of insulin secretion.     

Effect of inhaled lodoxamide tromethamine in prevention of antigen-induced bronchospasm

Lodoxamide tromethamine, a new cromolyn-like drug, was studied to determine its effectiveness and duration of action in preventing antigen-induced bronchospasm in 15 subjects with clinically stable extrinsic asthma. All subjects underwent antigen inhalation challenge 15 min after inhalation of an aerosolized solution of 0.1 mg of lodoxamide in saline or of saline solution alone (placebo) administered on separate days according to a double-blind, random-allocation protocol. Those subjects demonstrating a protective effect of lodoxamide subsequently underwent antigen inhalation challenges at various time intervals (2 to 8 hr) after lodoxamide treatment. Thirteen of 15 subjects (87%) showed a protective effect of lodoxamide administered 15 min prior to antigen challenge. Six of the 13 subjects who were protected initially remained protected 4 hr after lodoxamide treatment and one of these six subjects was also protected at 6 to 8 hr. One additional subject not protected at 4 hr was protected at 3 hr. Lodoxamide exhibited no bronchodilator activity and was not associated with any significant side effects. Further studies are warranted to compare the effectiveness of lodoxamide with that of cromolyn sodium in protection against antigen-induced bronchospasm and to evaluate the relative efficacy and safety of lodoxamide in long-term clinical trials.     

Comparison of oral and inhaled metaproterenol for prevention of exercise-induced asthma

The effectiveness of inhaled versus oral metaproterenol in preventing exercise-induced asthma (EIA) was studied. Inhaled metaproterenol given 10 min before the exercise significantly reduced the degree of EIA in a group of twenty-four patients, and in 75% of them completely prevented it. The mean percentage decrease in FEV₁ was 6-5% with the inhaler and 30.1%, with placebo. When inhaled 1 hr before the exercise, metaproterenol was still better than placebo but its effectiveness was considerably lower. Metaproterenol tablets had a slight protective effect given I hr before, and none when administered 2 hr before exercise. There was no correlation between the protective effect against EIA and the bronchodilating effect obtained before exercise. Metaproterenol administered by metered-dose inhaler is a very effective prophylactic medication against clinically troublesome EIA, while metaproterenol tablets should not be recommended for this purpose.     

Effect of hepatic vagotomy and/or coeliac ganglionectomy on the delayed eating response to insulin and 2DG injection in rats

The eating response that occurs following recovery from the effects of insulin or 2-deoxy-D-glucose (2DG) injection was examined in rats with hepatic vagotomy and/or coeliac ganglionectomy. Rats were deprived of food and injected with either saline (1 ml/kg), regular insulin (3 U/kg) or 2DG (200 mg/kg). Plasma glucose was measured periodically over the next 6 hr and then food was returned and intakes were measured over the next 2 hr. Rats increased food intake 6–8 hr after insulin or 2DG injection compared to the saline (control) condition. Nerve section did not affect the plasma glucose or food intake responses to insulin or 2DG injection. The results indicate that the innervation of the liver via the vagus nerve or coeliac ganglion is not involved in the delayed eating response to insulin and 2DG injection.