Bronchodilating and cardiovascular effects of intraduodenally and orally administered clenbuterol in dogs

The bronchodilating and cardiovascular effects of intraduodenally and orally administered 4-amino-alpha-[tert-butylamino)methyl]-3,5-dichlorobenzylalcohol hydrochloride (clenbuterol, NAB 365) in anesthetized and conscious dogs were investigated and compared with those of salbutamol, isoprenaline (isoproterenol) and (4-amino-3,5-dichlorophenyl) glycolic acid (M-7), a metabolite of clenbuterol. In pentobarbitalized dogs, clenbuterol, 3-100 micrograms/kg i.d., inhibited the increase in airway resistance induced by histamine in a dose-related manner; clenbuterol was approximately 2 and 100 times more potent than salbutamol and isoprenaline, respectively. The plasma level of clenbuterol increased within 15 min and reached the maximum level within 60 to 90 min, which lasted for over 4 h after administration. The inhibitory effect was abolished by pretreatment with propranolol. M-7 showed no significant effect. In anesthetized dogs, clenbuterol and salbutamol, 10 and 100 microgram/kg i.d., decreased arterial blood pressure and increased heart rate and maximum rate of rise of left ventricular pressure. Isoprenaline, 10 and 100 micrograms/kg i.d., caused no marked changes in these parameters. In conscious dogs, clenbuterol, 10 and 100 micrograms/kg p.o., and salbutamol, 100 micrograms/kg p.o., increased heart rate; the maximum responses were observed 1 to 2 h after administration and lasted for over 3 h. No marked effects were observed after salbutamol, 10 micrograms/kg p.o., isoprenaline, 10 and 100 micrograms/kg p.o., and M-7, 100 micrograms/kg p.o.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of the effect of salmeterol and salbutamol in normal subjects.

1. The effects of salmeterol hydroxynaphthoate (50 micrograms, 8.3 x 10(-8) M) and salbutamol (200 micrograms, 3.5 x 10(-7) M) on sGaw were compared in a double-blind, placebo-controlled, randomised study in 10 normal subjects. 2. SGaw increased by 29% (14-43) (mean (CI)), 5 min after salmeterol and by 35% (19-51) at 15 min compared with an increase of 32% (14-51) and 37% (10-63) after salbutamol and 4% (-3-11) and 8% (0-16) after placebo. 3. The mean area under the sGaw-time curve (AUC480) after salmeterol inhalation was 22,500 kPa-1 (10,100-39,500) compared with 14100 kPa-1 (8020-24,500) after salbutamol and 5300 kPa-1 (1500-10,400) after placebo. 4. Salmeterol produced a significantly prolonged bronchodilator effect compared with salbutamol in normals.     

Assessment of airways, tremor and chronotropic responses to inhaled salbutamol in the quantification of beta 2-adrenoceptor blockade.

1. The purpose of the study was to assess and compare the effects of inhaled salbutamol on heart rate (HR), finger tremor (Tr) and specific airways conductance (sGaw) in the measurement of beta 2-adrenoceptor blockade in normal subjects. 2. Five healthy volunteers were given oral doses of atenolol 50 mg, 100 mg, 200 mg (A50, A100, A200), propranolol 40 mg (P40) or identical placebo (P1) in a single-blind crossover design. 3. Three hours after drug ingestion, dose-response curves were constructed using cumulative doses of inhaled salbutamol: 200 micrograms, 700 micrograms, 1700 micrograms, 3200 micrograms, 6200 micrograms. HR, Tr and sGaw were measured at each dose increment, made every 20 min. 4. Increasing doses of atenolol were associated with progressive reduction in salbutamol induced beta-adrenoceptor responses. The greatest attenuation occurred with propranolol. These effects on beta-adrenoceptor responses were similar for HR, Tr and sGaw. Geometric mean dose ratios (compared with placebo) for A50, A100, A200 and P40 were as follows HR: 1.98, 2.75, 4.29; Tr: 1.60, 3.78, 6.34, 80.50; sGaw: 1.08, 4.35, 12.30, 66.0 (no dose ratio was obtained for HR with P40). 5. These results showed that atenolol and propranolol attenuated the effects of salbutamol on HR to a similar degree as Tr and sGaw. Furthermore, the variability was least in the measurement of chronotropic responses, suggesting that this may be used to quantify beta 2-adrenoceptor antagonism. The beta 1-adrenoceptor selectivity of atenolol was a dose-dependent phenomenon, although the beta 2-adrenoceptor blockade of A200 was much less than with P40.     

A comparison of the ventilatory, cardiovascular and metabolic effects of salbutamol, aminophylline and vasoactive intestinal peptide in normal subjects.

Intravenous infusion of placebo for 30 min followed by either salbutamol 10 micrograms min-1, aminophylline 0.2 mg kg-1 min-1 or vasoactive intestinal peptide (VIP) 6 pmol kg-1 min-1 for 30 min was performed in a single blind fashion in six normal volunteers. Both salbutamol and aminophylline increased minute ventilation, (P less than 0.05) the mean increase being 26% and 19% respectively. Aminophylline also increased the ventilatory response to carbon dioxide by 47% (P less than 0.05) when measured by hyperoxic rebreathing, whereas salbutamol and VIP were without significant effect. All three drugs caused a tachycardia, mean increase in the pulse being 16, 8 and 2 beats min-1 for salbutamol, aminophylline and VIP respectively, and aminophylline also increased both systolic and diastolic blood pressure, mean arterial pressure increasing by 14 mmHg. VIP caused haemoconcentration and salbutamol the expected changes in plasma biochemistry. Plasma catecholamines increased slightly during drug infusion, although this effect is unlikely to be important.     

Salmeterol protects against hyperventilation-induced bronchoconstriction over 12 hours

To study the dose-response relationship of salmeterol for protection against a naturally occurring stimulus, isocapnic hyperventilation tests of cold air were done in 16 asthmatic patients. The subjects inhaled either 50 micrograms salmeterol, salbutamol 200 micrograms, or placebo in a double-blind, randomised, cross-over study. The FEV1 was measured prior to medication and the provocative ventilation (PV20) required to induce a 20% fall in FEV1 was calculated by linear interpolation from ventilation-response curves obtained 0.5, 4, 8, and 12 h after medication. Following salbutamol, the mean FEV1 were 4.11, 3.89, 3.58, and 3.55 l, with a significant difference from placebo up to 4 h. Following salmeterol, mean FEV1 values were 3.95, 4.10, 3.93, and 3.88 l, with a significant difference from placebo up to 12 h. The mean PV20FEV1 after salbutamol was 78.8, 58.5, 52.7, and 48.4 l.min-1, the 0.5 h value being significantly different from placebo. After salmeterol, the mean PV20FEV1 values were 84.6, 82.5, 67.8, and 65.8 l.min-1, with a significant difference from placebo up to 12 h. We conclude that, besides its long-lasting bronchodilating effect, salmeterol protects against hyperventilation-induced bronchoconstriction for at least 12 h.     

A comparison of the bronchodilatory effect of 50 and 100 μg salbutamol via Turbuhaler® and 100 μg salbutamol via pressurized metered dose inhaler in children with stable asthma

Aim: The aim of the study was to compare the efficacy of single doses of salbutamol Turbuhaler® (50 and 100 μg), salbutamol pressurized metered dose inhaler (pMDI) (100 μg) and placebo in children with stable chronic reversible airway obstruction. Primary efficacy variable (FEV₁-av) was calculated as the area under the curve of forced expiratory volume in one second (FEV₁) (AUC, 0–4 h) and divided by the observed time. Design: The study was of a randomized, single-dose, crossover and double-blind design. Seven centres participated. FEV₁ was measured pre-dose and at 15 min, 0.5, 1, 1.5, 2, 3 and 4 h post study dose. Patients: Forty asthmatic children (9 girls) with a mean age of 9 years (range: 6–12), mean FEV₁ of 1.6 l (range: 0.9–2.4) and a mean FEV₁ in percentage of predicted normal value of 80% (range: 61–109) were randomized into the study. The mean reversibility 30 min after inhaling 2×100 μg salbutamol from pMDI was 20% (range: 9–45) or 15% (range: 8–27) in percentage of predicted normal value. Results: The mean FEV₁-av was 1.63 l for placebo, 1.71 l for 50 μg salbutamol Turbuhaler, 1.76 l for 100 μg salbutamol Turbuhaler and 1.76 for 100 μg salbutamol pMDI. Corresponding values for maximum FEV₁ were 1.76, 1.85, 1.87 and 1.87 l, respectively. There were no statistically significant differences between the active treatments in FEV₁-av or maximum FEV₁. All active treatments were significantly better than placebo. Conclusion: No significant differences in bronchodilating effect between 50, 100 μg salbutamol Turbuhaler and 100 μg salbutamol pMDI in children, aged 6–12 years, with stable asthma could be demonstrated. All active treatments were significantly better than placebo.     

Determination of beta2-agonists by ion chromatography with direct conductivity detection

A simple method for the simultaneous detection of four beta2-agonists (salbutamol, fenoterol, clorprenaline, and clenbuterol) using ion chromatography (IC) with direct conductivity detection (CD) based on their ionization in acidic medium without chemical suppression is presented. The mixture of 1.8 mM HNO3 and 2% (v/v) acetonitrile was used as eluent. The method could be applied to the determination of the beta2-agonists in pharmaceutical preparations. The recovery of salbutamol and clenbuterol in tablets was more than 97% (n=3) and the relative standard deviation (n=11) less than 2.8%. With the proposed method, salbutamol could also be successfully detected in human plasma. In a single chromatographic run, the four beta2-agonists can be separated and determined in less than 8 min. The linear ranges were of 7.0-1.4 x 10(3)ng/ml for salbutamol, 34-7.8 x 10(3)ng/ml for fenoterol, 8.0-1.6 x 10(3)ng/ml for clorprenaline, and 25-7.5 x 10(3)ng/ml for clenbuterol. The detection limits were 2.0 ng/ml for salbutamol, 10 ng/ml for fenoterol, 3.0 ng/ml for clorprenaline, and 10 ng/ml for clenbuterol.     

Double-blind cross-over comparison of clenbuterol and salbutamol tablets in asthmatic out-patients

Summary A double-blind cross-over comparison of a new ₂-sympathomimetic bronchodilator, clenbuterol, with salbutamol and placebo has been made during a 24 day period of out-patient treatment of 19 adults with moderately severe asthma. Oral clenbuterol (10 µg 3 times a day) and salbutamol (4 mg 3 times a day) were equally and significantly (p<0.001) more effective than placebo, when daily records of peak expiratory flow or use of isoprenaline inhalations were the criteria of activity. Daily records of symptoms according to a questionnaire also suggested relief of the subjective effects of asthma during treatment with both active drugs (p<0.01).     

Salbutamol inhibits metabisulphite-induced bronchoconstriction.

The effect of salbutamol on bronchoconstriction induced by inhaled sodium metabisulphite has been studied in 12 atopic subjects. Salbutamol (200 micrograms, 3.5 x 10(-7) M) and matched placebo were administered by identical metered dose inhaler 15 min before a dose-response to sodium metabisulphite (1.25-100 mg ml-1) was performed. Geometric mean provocative dose of metabisulphite causing a 35% fall in sGaw after placebo pretreatment was 12.8 [5.75-28.1, 95% Cl] mumol, and after salbutamol was 75.9 [46.5-126] mumol. Mean maximum fall in sGaw after placebo pre-treatment was 47.4 [41-53.9]%. At the same metabisulphite concentration mean maximum fall in sGaw after salbutamol was 2.9 [-8.2-14.1]%.     

Does a single priming injection of clenbuterol alter behavioral response to beta-adrenoceptor agonists and antagonists in mice through a time-dependent process?

The present study investigated the extent to which a single priming injection of clenbuterol, a beta-adrenoceptor agonist, could alter the behavioral response (locomotor activity recorded for 30 min with photocell counters) of mice to the subsequent administration of beta-adrenoceptor agonists or antagonists. In mice pretreated with clenbuterol (0.25 mg/kg), the dose-response curve of clenbuterol (0.06 to 2 mg/kg) for reducing locomotor activity was shifted to the right with minimal alteration of the maximal response. The magnitude of the shift was dependent on both the priming dose of clenbuterol and the time interval between the priming and the test injections (maximum between 15 to 24 h, disappearance for intervals exceeding 72 h). The coadministration of propranolol (0.5; 2; 8 mg/kg) dose dependently antagonized the effects of the priming injection of clenbuterol. A previous injection of clenbuterol was also found to reduce the ability of another beta-adrenoceptor stimulant, salbutamol (8 mg/kg), but not apomorphine, to reduce locomotor activity. Finally, previous beta-adrenoceptor stimulation resulted in an enhanced ability of two beta-adrenoceptor antagonists, propranolol (0.125 to 8 mg/kg) and penbutolol (0.5 to 32 mg/kg), to reduce locomotor activity in mice. All these data add to the evidence concerning the remarkable plasticity of central beta-adrenoceptors and indicate that initial stimulation of a class of beta-adrenoceptors may trigger a relatively important, time-dependent alteration in the behavioral reactivity to beta-adrenoceptor agonists and antagonists.     

Tiaramide--a new oral drug for the treatment of asthma.

1 TIaramide, an anti-inflammatory drug, inhibits the action of mediators released from mast cells and has direct smooth muscle relaxant properties. It may therefore have a beneficial effect in asthma. 2 A double-blind crossover trial comparing the bronchodilator activity of tiaramide and placebo over 16 days was undertaken in 13 patients with asthma. 3 Peak expiratory flow rate (PEFR) was recorded on three separate occasions every day and frequency of salbutamol aerosol usage was noted on a diary card. 4 During treatment with tiaramide the mean mid-morning PEFR (362 1/min) was higher than mean PEFR on placebo (328) (P less than 0.001) as was the evening PEFR (378) compared with placebo (388) (P less than 0.001). 5 There was a significant reduction in daily use of the salbutamol inhaler whilst on tiaramide (1.8) compared with placebo (2.3) (P less than 0.05). 6. Tiaramide may be a useful addition to existing prophylactic treatment for asthma.     

Hemodynamic effects on hepatic blood flow of a selective beta 2-adrenoceptor agonist, clenbuterol, in rat.

Acute clenbuterol administration (50 micrograms/kg, i.v.) to anesthetized normotensive rats, produce a marked reduction in the mean blood pressure, (MBP), about 58 mm Hg. Indocyanine Green clearance analysis (control, 1.83 +/- 0.15: clenbuterol, 1.10 +/- 0.20 ml/min/100 g, P < 0.05) showed that the action in the hepatic vascular bed is opposite to its systemic vasodilator effects. The hepatic blood flow (HBF) appears significantly reduced (control, 8.24 +/- 0.35: clenbuterol, 3.83 +/- 0.71 ml/min/100 g, P < 0.05) whereas the hepatic uptake and excretion proceedings were apparently not affected (control hepatic extraction coefficient, 0.225 +/- 0.024: clenbuterol, 0.300 +/- 0.04, NS). These findings show that a marked reduction in HBF follows systemic vasodilator effects produced by clenbuterol.     

Stimulation of beta-adrenergic receptors and spontaneous motor activity in mice

The effects of 3 beta-adrenergic agonists (clenbuterol, isoproterenol and salbutamol) on the spontaneous motor activity of mice were studied. The present research indicated that motor activity was significantly decreased 30 minutes after IP injection of either clenbuterol (0.06 mg/kg), isoproterenol (0.5 mg/kg) or salbutamol (2 mg/kg). Hypomotility induced by clenbuterol was also significantly antagonized by propranolol in doses ranging from 1 to 8 mg/kg and by penbutolol in doses from 0.03 to 0.5 mg/kg. However, practolol, which does not cross the blood brain barrier, did not antagonize the effect of clenbuterol. Therefore, it may be hypothesized that beta adrenergic agonists decrease motor activity by a central mechanism. It was also found that tachyphylaxis or resistance to treatment, observed in cardiovascular and bronchopulmonary systems with beta-adrenergic agonists, developed after 7 injections of clenbuterol (0.25 mg/kg IP, twice daily) in the behavioral model of spontaneous motor activity in mice.     

Accumulation of β-agonists clenbuterol and salbutamol in black and white mouse hair

Hair has been shown to be an excellent site for the accumulation of different drugs including β-agonists, and therefore, it would be an appropriate matrix for surveillance for the presence of drug residues. The aim of this study was to determine concentrations and to compare accumulation of two different β-agonists in black and white mice hair by use of ELISA as a screening quantitative method. The study included 200 8-week-old white and black mice. One group of black mice and one group of white mice were treated with clenbuterol in a dose of 2.5 mg/kg body mass per os for 28 days. Other animals were treated in the same way with salbutamol. The highest (±SD) clenbuterol concentration of 631.4 ± 23.5 ng/g in black hair and 228.5 ± 156.2 ng/g in white hair was determined on day 1 of treatment withdrawal. Study results revealed the black-to-white hair ratio of clenbuterol accumulation to be 1:2-1:4 and of salbutamol accumulation 1:1.4. The mean (±SD) salbutamol concentrations determined on day 1 of treatment withdrawal was 23.9 ± 0.9 ng/g and 16.4 ± 1.1 ng/g in black and white hair samples, respectively. The study demonstrated that residues could be determined in hair samples even after a 30-day withdrawal period.     

The metabolic actions of intravenous salbutamol and aminophylline singly and in combination.

1 The following four treatments were administered by constant intravenous infusion of four healthy volunteers in a balanced randomized study: 1) saline (30 min), salbutamol (0.15 micrograms kg-1 min-1 for 30 min) (sS), 2) saline, aminophylline (0.2 mg kg-1 min-1 for 30 min) (sA), 3) salbutamol, salbutamol (SS) and 4) aminophylline, salbutamol (AS). 2 Heart rate was recorded and venous blood taken for estimation of insulin, glucose, potassium and theophylline before and during the infusions (10, 20, 30, 40, 50 and 60 min). 3 The mean, peak heart rate increases from control, baseline values were 23.0 (sS), 3.5 (sA), 28.5 (SS) and 28.0 (AS) beats/min, the mean, peak insulin increases, 34.0 (sS), 0.5 (sA), 39.0 (SS) and 57.5 (AS) microU ml-1, the mean, peak glucose increases, 1.4 (sS), 0.1 (sA), 2.6 (SS) and 2.0 (AS) mmol 1(-1) and the mean, peak potassium changes, -0.45 (sS), 0.58 (sA), -0.78 (SS) and -0.68 (AS) mmol 1(-1). 4 The mean, peak serum theophylline levels were 48.1 mumol 1(-1) at 60 min in sA and 52.6 mumol 1(-1) at 50 min in AS (39.1 mumol 1(-1) at 30 min). 5 Salbutamol stimulated significant insulin release and produced hypokalaemia and glycogenolysis, whereas aminophylline induced no metabolic effect. 6 A comparison of sS and AS indicated a trend for aminophylline to potentiate the metabolic effects of salbutamol.     

Effects of beta 2-adrenoceptor stimulation on cardiac metabolism in the conscious dog.

1 The effects of the beta 2-adrenoceptor stimulant, salbutamol, on cardiac metabolism have been studied in conscious mongrel dogs. The potential effects of anaesthesia on the study of cardiac metabolism have been avoided by prior implantation of arterial (A) and coronary sinus (CS) catheters for blood sampling and a central venous catheter for infusion. Extraction of substrates for myocardial energy metabolism (CA-CS) was assessed 3 to 24 days post-operatively. A 100 micrograms bolus of salbutamol was given followed by an infusion of 3 micrograms/min for 1 h. 2 Although heart rate increased significantly from 106 to 165 beats/min, fractional extraction of oxygen tended to fall from 84% to 77%. Thus an increase in coronary blood flow rather than in oxygen extraction must have maintained an oxygen supply commensurate with the salbutamol-induced tachycardia. 3 Neither CA-CS glucose nor fractional glucose extraction altered significantly during salbutamol infusion despite increases in arterial concentration (CA) of glucose and arterial insulin immunoreactivity and a decrease in CA of free fatty acids (FFA). This suggests that an insulin-antagonistic action accompanies the infusion of salbutamol. 4 The fractional extraction of lactate increased during salbutamol infusion. In part, this may have been a reflection of a decreased myocardial extraction of FFA with salbutamol in this model.     

Salbutamol disposition and dynamics in conscious rabbits: influence of the route of administration and of the dose.

This study assessed the influence of dose and route of administration on salbutamol kinetics and hypokaliemic effect. Salbutamol plasma kinetics were studied in a first group of 6 rabbits who received 60, 800, and 60 micrograms/kg by the intravenous (iv), oral (po), and intratracheal (it) routes, respectively, at 1-week intervals. A second group of 6 rabbits received 120, 2400, and 120 micrograms/kg of salbutamol by the same three routes. Multiple blood samples were withdrawn to assay salbutamol and potassium. Following iv salbutamol (60 micrograms/kg), total plasma clearance was 82 +/- 5 ml/min per kg, apparent volume of distribution was 5.0 +/- 0.5 l/kg, and terminal half-life was 41 +/- 2 min. Similar values were estimated when 120 micrograms/kg of salbutamol was administered iv or was given po or it. The bioavailability of po and it salbutamol was approximately 1 and 20%, respectively. For the first group, the maximal decrease in plasma potassium elicited by salbutamol was 0.80 +/- 0.19, 0.48 +/- 0.22, and 0.78 +/- 0.46 mmol/l, and for the second group, maximal decrement was 1.31 +/- 0.37, 0.70 +/- 0.24, and 0.84 +/- 0.17 mmol/l for the iv, po, and it routes, respectively. Compared to salbutamol peak plasma concentrations, maximal decrease in plasma potassium appeared between 60 and 108 min later for the iv route, 90 and 25 min later for po and it routes, and for this reason, the hypokaliemic effect was not associated to salbutamol plasma concentrations. The hypokaliemic effect was dependent upon the route, e.g., po > it > iv.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiopulmonary interactions of salbutamol and hypoxaemia in healthy young volunteers.

1. Nebulised salbutamol is frequently used in the treatment of asthma and chronic obstructive pulmonary disease. Its effects on the cardiovascular system have been extensively investigated although as yet little is known concerning its effects on the pulmonary circulation, particularly during hypoxaemia. We have therefore examined the effects of nebulised salbutamol on pulmonary haemodynamics to see if it modifies hypoxic pulmonary vasoconstriction. 2. Eight healthy normal volunteers were studied on two separate occasions. After resting to achieve baseline haemodynamics patients were randomised to receive 5 mg salbutamol or placebo via a nebuliser. They were restudied after 30 min and then rendered hypoxaemic by breathing an N2/O2 mixture to achieve an SaO2 of 75-80%. Doppler echocardiography was used to measure mean pulmonary artery pressure (MPAP), cardiac output (CO) and hence pulmonary vascular resistance (PVR). 3. Treatment with salbutamol significantly increased MPAP during normoxaemia and hypoxaemia compared with placebo at 12.0 +/- 1.2 vs 8.0 +/- 0.7 mm Hg and 28.6 +/- 0.9 vs 25.2 +/- 1.0 mm Hg, respectively (P < 0.05). Salbutamol caused a significant increase in heart rate compared with placebo and effects were additive to those of hypoxia at 74 +/- 2 vs 67 +/- 3 beats min-1 during normoxaemia and 84 +/- 3 vs 77 +/- 4 beats min-1 during hypoxaemia, respectively (P < 0.05). Whilst systemic vascular resistance fell in response to salbutamol, PVR was unchanged by salbutamol during either normoxaemia or hypoxaemia. Cardiac output was increased by salbutamol and by hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

A new bronchodilating agent, procaterol, in preventing exercise-induced asthma

The aim of the present study was to verify the effectiveness of procaterol, a recent and specific beta-2-adrenoceptor stimulant, in preventing exercise-induced asthma (EIA). Twelve asthmatic patients were selected aged 18.6 +/- 5.6 years with a positive response to EIA and a basal forced expiratory volume of the first second (FEV1) better than 80% of predicted. The patients underwent four bronchoprovocation challenges on four consecutive days. On the first day they performed an inclusion test, and, on the three subsequent days, they were submitted, to three identical standardized challenges according to a randomized design. Fifteen minutes before, procaterol (20 mcg), salbutamol (200 mcg) and a placebo were administered as metered aerosol. No pharmacological treatment was given for 24 h (48 h for antihistamines) before each challenge. The test was carried out running on treadmill (10% grade) for 7 min. Room temperature (20-25 degrees C) and relative humidity (40-55%) were maintained constant. At baseline, 15 min before, 5, 10, 15, 30 and 60 min after the exercise, lung function was assessed. Basal mean values of FEV1 were 94.7, 94.9, 90.7 and 91.5% of predicted for the inclusion and the three protected tests, respectively, without significant differences. The FEV1 mean values showed a mild bronchodilation 15 min after salbutamol (+13.2%, p less than 0.006) and procaterol (+8%, NS). At every considered time all indices showed a significant gap (p less than 0.01) between drugs and the placebo with no appreciable differences between procaterol and salbutamol.     

Dose-response study with high-dose inhaled salmeterol in healthy subjects.

A double-blind, placebo-controlled, cross-over study in 10 healthy male subjects has been carried out to investigate the non-pulmonary effects of single inhaled doses of salmeterol 100 micrograms, 200 micrograms and 400 micrograms and salbutamol 400 micrograms from a metered-dose inhaler. At all doses tested, salmeterol produced statistically significant changes in pulse rate, tremor, blood glucose and plasma potassium concentrations, compared with placebo. All changes were dosed related. A number of dose-related adverse events including tremor, awareness of heart beat and headache were reported after salmeterol administration.