Dose-related protection against histamine-induced bronchoconstriction by inhaled salmeterol.

A double-blind crossover study was carried out in 8 subjects to compare the effect of inhaled salmeterol 12.5, 50 and 100 micrograms with inhaled salbutamol 200 micrograms on resting lung function and on bronchoconstriction in response to inhaled histamine up to 12 hours following each treatment. Changes in resting lung function were measured using forced expiratory volume in one second (FEV1) and flow at 70% of vital capacity taken from partial expiratory flow volume curves (pEFR70). The concentrations of histamine which produced a 15% fall in FEV1 (PC15) and a 40% fall in pEFR70 (PC40) were also measured. The peak bronchodilator effect after salmeterol 50 and 100 micrograms was similar in magnitude to salbutamol 200 micrograms. Salmeterol produced dose-related changes in lung function and protection against histamine-induced bronchoconstriction. The duration of the effect of salmeterol (50 and 100 micrograms) was longer than that for salbutamol (200 micrograms). Although pEFR70 is a more sensitive measure of lung function there was no greater separation between different doses of salmeterol than with FEV1. Both salmeterol and salbutamol were well tolerated.

Does tachyphylaxis occur to the non-pulmonary effects of salmeterol?

1. The potential for tachyphylaxis to the non-pulmonary effects of salmeterol, a long-acting selective beta 2-adrenoceptor agonist was investigated in 12 healthy male subjects in a double-blind two period crossover study design. 2. Subjects received cumulative doses of up to 400 micrograms (50 + 50 + 100 + 100 + 100 micrograms at 45 min intervals) inhaled salmeterol prior to a 13 day dosing schedule of twice-daily inhaled salmeterol 100 micrograms or placebo. Twelve hours after the last dose of salmeterol or placebo, subjects again received cumulative doses of up to 400 micrograms inhaled salmeterol. 3. Pulse rate, blood pressure, 12-lead ECG, physiological tremor and peak expiratory flow rate (PEFR) were measured before administration of cumulative doses of salmeterol, at 10, 20, 30 and 40 min after each incremental dose of salmeterol and at 4, 6 and 8 h after the first dose. Blood samples were taken for plasma potassium, magnesium, non-esterified fatty acids (NEFA) and blood glucose concentrations at 20 and 40 min after each dose and at 4, 6 and 8 h after the first dose. 4. Eleven subjects completed the study. One subject withdrew due to beta 2-adrenoceptor related adverse events. All other adverse events reported were mild in nature. 5. Dose-related changes to the effects of salmeterol on pulse rate, QTc interval, tremor, PEFR, blood glucose and plasma potassium were seen, but there was no dose-related effect of salmeterol on blood pressure, plasma magnesium and NEFA. 6. Tachyphylaxis occurred to the effects of salmeterol on tremor, QTc and blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of salmeterol xinafoate in laboratory animals and humans.

The disposition of [14C]salmeterol xinafoate, a new inhaled beta 2-adrenoceptor agonist with both bronchodilator and antiinflammatory activity, has been studied in laboratory animals and humans following intravenous and oral administration. [14C]Salmeterol was rapidly absorbed in animal species and humans with Cmax observed within 2 hr. Cmax was similar for normalized oral dose level in mice, rats, and rabbits. In dogs, Cmax was higher and reflected the greater oral bioavailability in this species. The plasma t1/2, after intravenous administration, was 5 hr in rats and 2 hr in dogs. The volume of distribution of salmeterol was significantly greater than total body water in both rats (40 liters/kg) and dogs (6 liters/kg) and indicated high tissue uptake of the compound. Plasma clearance was high in rats (95 ml/min/kg) and dogs (30 ml/min/kg). Radioactive drug-related material was widely distributed throughout body tissues in rats. The highest concentrations were present in kidney, liver, gastrointestinal tract, pituitary, lung, heart, and bone marrow. Transfer of radioactive drug-related material across the placental barrier or into milk, studied in rats, was low. In all species the majority of an oral or intravenous dose (55-75%) was excreted in feces. Biliary excretion in rats and dogs accounted for 53% (0-27 hr) and 40% (0-8 hr) of an oral dose, respectively, indicating good absorption across the gastrointestinal tract. Enterohepatic circulation was significant in rats. Salmeterol was cleared predominantly by metabolism in animals and humans.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Plasma concentrations of salbutamol after an oral slow-release preparation.

Studies were carried out to investigate the plasma concentrations of salbutamol after administration of a slow-release formulation (8 mg) compared with those after 1 and after 2 standard 4 mg tablets. In the first study, 9 subjects received, at random, either the slow-release tablet or a single standard tablet. Blood samples were taken and histamine challenge tests were carried out before and at fixed time intervals after drug administration. The procedures were repeated after an interval of at least 5 days with the alternative treatment. In the second study, plasma concentrations were measured in 5 of the subjects before and after taking 2 standard 4 mg tablets. The results showed that there was slower attainment of peak plasma concentrations after the slow-release formulation compared to those after one 4 mg and two 4 mg standard tablets. In addition, the 8 mg slow-release formulation produced lower peak plasma concentrations than did two 4 mg standard tablets. Protection against a bronchoconstricting histamine challenge lasted at least twice as long after the slow-release compared with after a single 4 mg standard tablet.

Effects of H1- and H2-receptor blocking agents on histamine-induced bronchoconstriction in non-asthmatic subjects.

1 Two studies have been carried out to investigate the effect of H1- and H2-receptor blocking agents on histamine-induced bronchoconstriction in non-asthmatic subjects. 2 The H2-receptor blocker cimetidine administered orally had no effect on histamine-induced bronchoconstriction on any of the subjects tested. In three of four subjects, the H1-receptor blocker, chlorpheniramine given orally, inhibited the effect of the histamine in the lung. 3 The effects of intravenous chlorpheniramine and cimetidine, both alone and in combination, upon histamine-induced bronchoconstriction, were also studied. Chlorpheniramine inhibited the effect of the histamine and this was significantly dose related. This was not so with cimetidine and there was no evidence that the dose response curve to chlorpheniramine was affected by the additional administration of cimetidine. 4 The results show that histamine-induced bronchoconstriction in non-asthmatic subjects is not mediated by H2-receptors, but it is likely that H1-receptors are involved.

Effects of labetalol and propranolol on histamine-induced bronchoconstriction in normal subjects.

1 The effects of oral propranolol (80 mg), labetalol (400 mg) and placebo on blood pressure, pulse rate and FEV1 at rest and after inhaled histamine, have been compared in six healthy male volunteers. 2 At 90 and 120 min after ingestion propranolol reduced the pulse rate and labetalol reduced the blood pressure, thus confirming absorption of each drug. 3 At 120 min propranolol reduced resting FEV1 and enhanced the fall in FEV1 after histamine, whereas the alterations in FEV1 after labetalol did not differ from placebo. 4 These findings suggest that labetalol is less likely than propranolol to cause bronchoconstriction in asthmatic patients.

Comparison of the effects of labetalol and propranolol in healthy men at rest and during exercise.

1. Oral labeltalol and propranolol have been compared in healthy men with regard to the effects on heart rate, blood pressure and peak expiratory flow rate (PEFR) at rest and the changes induced by exercise. 2. Labetalol caused a dose-related reduction in standing diastolic pressure at rest whereas propranolol did not but neither drug altered standing systolic pressure at rest. 3. In the doses compared, propranolol was consistently more potent than labetalol in influencing blood pressure changes induced by exercise, in lowering heart rate at rest and reducing PEFR at rest. 4. Labetalol and propranolol are both beta-adrenoreceptor antagonists and the observed differences in the profiles of the two drugs are probably directly related to the additional alpha-adrenoreceptor blocking property of labetalol not possessed by propranolol. Because of these differences labetalol may be expected to have advantages in the treatment of hypertension.

Relationship between plasma concentrations and pharmacological effects of labetalol.

In healthy normal subjects following the administration of labetalol the pharmacological effects were measured and compared with the plasma concentrations achieved. The inhibition of exercise induced tachycardia and inhibition of exercise induced increases in systolic pressure were significantly related to the administered dose of labetalol. Labetalol was rapidly absorbed from the gastrointestinal tract and peak plasma concentrations occurred two hours after oral administration. There was a linear correlation (r = 0.84) between the logarithm of the plasma concentration and the maximum inhibition of exercise tachycardia at two hours. After intravenous administration there was an immediate reduction in systolic and diastolic blood pressure with a concomitant small increase in heart rate. There was a rapid decline in the associated plasma concentration but the pharmacological effects were maintained in excess of two hours. Our findings are consistent with those of others who have studied the relationship between pharmacological events and plasma concentrations after single doses of other adrenoceptor blocking drugs.

The effects of oral AH 5158, a combined α and ß-adrenoceptor antagonist, in healthy volunteers.

1 In healthy male volunteers after single oral doses, AH 5158 produced inhibition of exercise induced tachycardia, falls in systolic and diastolic pressure at rest and in response to exercise, which are probably related to combined ß- and α-adrenoceptor antagonism. 2 At increasing doses from 100 mg to 400 mg there exists a dose related antagonistic effect, though the dominant effect of ß-adrenoceptor antagonism is more easily demonstrable than is α antagonism. 3 As indicated by the pattern of pharmacological effects, absorption of the oral drug is good and the duration of action of a 400 mg dose is approximately 8 hours. 4 Despite being administered in ß-adrenoceptor blocking doses, AH 5158 had no adverse effects upon peak expiratory flow at rest or in response to exercise. 5 It is concluded that the pharmacological profile of this combined α- and ß-adrenoceptor antagonism suggests a potential therapeutic role as an antihypertensive drug.