Use Of Salmeterol Research Articles

Drug use and pulmonary death rates in increasingly symptomatic asthma patients in the UK.

BACKGROUND: There is concern about an increase in deaths from respiratory causes in asthma patients using long acting beta agonists. According to the guidelines of the British Thoracic Society, long...

The effects of salmeterol on power output in nonasthmatic athletes

Background: Salmeterol xinafoate is a new aerosol inhalant that is used in the treatment of asthma. It is currently banned by the International Olympic Committee because of the concern that it may lend an unfair competitive advantage to the user. Objective: The purpose of this study was to determine whether salmeterol improves short-term anaerobic performance in elite nonasthmatic track cyclists. Methods: Eleven elite track cyclists volunteered to perform a 30-second all-out cycle ergometer test 3 hours after receiving either 42 μg of salmeterol xinafoate or placebo applied in a double-blind crossover procedure. During the ergometer test, peak power output, total work, time to peak power, and percent fatigue (decline in power output) were measured. Pulmonary measurements were also taken before and at various time points after inhalation and the ergometer test. A methacholine challenge was administered to each subject before participation in the study to ensure that none of the subjects had any reactive airway diseases. Results: There were no significant differences ( p > 0.05) between the placebo and salmeterol trials for peak power output, total work performed during the 30-second test, percent fatigue, and time to peak power. No differences between trials were observed for the pulmonary function test variables at any of the time points. Blood lactate concentrations before and after administration of drug or placebo were also not significantly different between trials. Additionally, salmeterol did not affect the maximal heart rate achieved during the test as compared with the placebo. Conclusion: Short-term salmeterol use within the prescribed dosage was not shown to increase short-term power output in nonasthmatic cyclists. (J Allergy Clin Immunol 1997;99:443-9.)

Safety and appropriate use of salmeterol in the treatment of asthma

Safety and appropriate use of salmeterol in the treatment of asthma

Inhaled Corticosteroids Do Not Prevent the Development of Tolerance to the Bronchoprotective Effect of Salmeterol

Twice-daily inhaled salmeterol produces rapid reduction in its acute bronchoprotective effect against methacholine in patients with mild asthma. This investigation examined this effect in patients with moderate asthma who were using inhaled corticosteroids. Eight asthmatic volunteers who required inhaled corticosteroids for control of their symptoms and who were able to withhold treatment with beta 2-agonists for 4 weeks before and during the study participated in a double-blind, crossover, placebo-controlled study with two random-order treatment periods: inhaled salmeterol, 50 microg twice a day for seven doses, and placebo in similar fashion, with a 7-day or greater washout between these periods. Methacholine inhalation tests were done 1 h after doses 1, 3, 5, and 7, and then 24 h after the last dose of the study inhaler, 10 min post-200 microg salbutamol. Baseline FEV1 measurements before doses 3, 5, and 7 of salmeterol, ie, 12 h after salmeterol, were significantly higher than all other baseline values. Twenty-four hours after the last dose of salmeterol, the FEV1 was no different from that during the placebo period. The geometric mean methacholine concentration causing a 20% fall in FEV1 (PC20) following the third dose of salmeterol (6.8 mg/mL) was significantly lower than after the first dose of salmeterol (12.0 mg/mL; p=0.031), and this reduction of bronchoprotection persisted following doses 5 and 7. The methacholine PC20 10 min postsalbutamol measured after the salmeterol period was significantly lower than after placebo (5.6 vs 13.3 mg/mL; p<0.001). Tolerance to the acute bronchoprotective effect of salmeterol was significant after the first two doses and persisted after the seventh dose. Tolerance to the acute bronchoprotective effect of salbutamol was also significant after regular use of salmeterol for seven doses. These effects, in subjects using inhaled corticosteroids regularly, were similar to the those previously seen in patients with mild asthma using as-required beta 2-agonists only, indicating that tolerance is not prevented by use of inhaled corticosteroids.

Salmeterol: A study by Prescription Event Monitoring in a UK cohort of 15,407 patients

Objective. To examine the safety of the long acting β 2-agonist, salmeterol, in general medical practice in the U.K. Design. In Prescription-Event Monitoring (PEM) the exposure data are derived from prescriptions confidentially provided by the Prescription Pricing Authority. Outcome data are obtained by questionnaires (green forms) on which prescribing medical practitioners recorded event (safety) data. Additional information is obtained from the patients' lifetime clinical records, from follow-up of all pregnancies, and from death certificates. Setting. PEM provides an observational cohort study in which there is no interference with the medical decision on which drug is prescribed for individual patients. Subjects. A total of 15,407 patients were given salmeterol and observed for a minimum of 1 year. Results. Headache, tremor, and palpitations were associated with the use of salmeterol. No unexpected major adverse events were noted, although in this study there was a total of 1022 deaths. Of these, 73 were due to asthma, but only 39 of these patients were taking salmeterol in the last month of life. All of these deaths appear on careful examination of the clinical records to have been due to natural causes, although in a minority (four, 10%) of the group of 39 subjects, a temporal relationship between death and the use of salmeterol makes it difficult to exclude a possible association. The study suggests that advanced age and severity of disease were the most likely factors contributing to asthma mortality in the population studied. Conclusion. Headache, tremor, and palpitations occur as adverse effects of salmeterol and lead to withdrawal of the drug in some subjects. No unexpected adverse reaction has been noted and paradoxical bronchospasm was reported in only three subjects. The study has produced no evidence that salmeterol contributed to death in any of the patients examined.

Asthma Mortality and β-Agonists

Dr. Devoy and colleagues have performed a valuable service by reviewing the clinical studies of inhaled long-acting β2-agonists in asthma (CHEST 1995; 107:1116-24). Of the studies reviewed, only one was large enough to begin to examine the effect of these drugs on the prevalence of asthma death. 1 Castle W. Fuller R. Hall J. et al. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodialator treatment. BMJ. 1993; 306: 1034-1037 Crossref PubMed Scopus (425) Google Scholar In this study, Castle and colleagues 1 Castle W. Fuller R. Hall J. et al. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodialator treatment. BMJ. 1993; 306: 1034-1037 Crossref PubMed Scopus (425) Google Scholar found that regular use of salmeterol resulted in an asthma death rate three times that associated with regular use of albuterol. They indicated that there was an 89.5% probability that this was a result of the difference in therapy and a 10.5% probability that this occurred by chance alone.1, footnote to Tabe 3 Thus, it is not proven that salmeterol does not adversely affect asthma mortality, although Devoy and colleagues make this assertion (Table 1).

Rapid Onset of Tolerance to the Bronchoprotective Effect of Salmeterol

Twice-daily inhaled salmeterol for 4 weeks produces marked reduction in its acute bronchoprotective effect against methacholine. This investigation examined the onset of this effect over 5 days, and also assessed cross-tolerance with salbutamol. Ten asthmatic volunteers who were able to withhold beta 2-agonist therapy for 4 weeks before and during the study participated in a double-blind, crossover, placebo-controlled study with two random-order treatment periods: inhaled salmeterol, 50 micrograms twice a day for seven doses, and placebo in similar fashion. Methacholine inhalation tests were done 1 h after doses 1, 3, 5, and 7, and then 24 h after the last dose of the study inhaler 10 minutes after 200 micrograms of salbutamol. Baseline FEV1 value before doses 3, 5, and 7 of salmeterol (ie, 12 h after salmeterol) was significantly higher than all other (n = 7) values. Twenty-four hours after the last dose of salmeterol, the FEV1 was no different from that during the placebo period. The geometric mean methacholine concentration causing a 20% fall in FEV1 (PC20) after the first dose of salmeterol (6.1 mg/mL) was statistically similar to the value achieved 10 min after salbutamol after the placebo period (8.3 mg/mL), and these were significantly (analysis of variance, p < 0.00005) larger than the second, third, and fourth salmeterol days (3.4 mg/mL, 2.6 mg/mL, 1.9 mg/mL, respectively). The methacholine PC20 10 min after salbutamol measured after the salmeterol period was significantly lower than after placebo (2.3 mg/mL vs 8.3 mg/mL; p < 0.001). Tolerance to the acute bronchoprotective effect of salmeterol was significant after the first two doses and progressively increased to the seventh dose. Tolerance to the acute bronchoprotective effect of salbutamol was significant after regular use of salmeterol for seven doses.

SALMETEROL XINAFOATE AS MAINTENANCE THERAPY COMPARED WITH ALBUTEROL IN PATIENTS WITH ASTHMA

The use of salmeterol inhaled twice daily compared with either placebo or albuterol gave significant increases in morning and evening peak flow as well as sustained increases in FEV1, and reduced asthma symptoms throughout the day and night. Responses were similar at day 1 and week 12 and no deterioration of asthma control was observed within the study period.

Pilgrim's progress: the effect of salmeterol in older children with chronic severe asthma

Twenty-four children aged 12–17 years entered a randomized, double-blind placebo-controlled study investigating the use of salmeterol in chronic severe asthma. In addition to their usual medication, the children were given either placebo or 100 μg salmeterol b.d. by dry powder inhalation. Treatment was continued throughout one term at a residential school for asthma. Symptom scores, peak expiratory flow rates, spirometry and quality-of-life scores were compared between the two treatment groups. One child withdrew during the run-in period. Twelve pupils received placebo and 11 pupils received salmeterol. There were consistent improvements in favour of salmeterol, reaching statistical significance for morning and evening peak flow rates and spirometry when measured on four occasions during the study period. There were no medication-related adverse events recorded and no pulse rate changes. Salmeterol (100 μg b.d.) is well tolerated and efficacious in older children with chronic severe asthma.

Another Word of Caution Regarding a New Long-Acting Bronchodilator

In a<i>JAMA</i>Editorial published on May 11,1994, I first warned of the dangers from misuse of salmeterol xinafoate.¹Newspaper reports assert that since the introduction of salmeterol in the United States, perhaps as many as 20 asthma patients have died because of the possible misuse of this bronchodilator.^2,3The newspaper articles were in reaction to a letter in the November 10,1994, issue of<i>The New England Journal of Medicine</i>in which Dr Frank N. Finkelstein⁴of Plymouth, Mass, noted the respiratory deaths of two elderly women who were both found holding salmeterol inhalers. The women had been warned about the delayed reaction of salmeterol, and both had albuterol for emergencies. It has been hypothesized that these and other deaths may be related to the inappropriate use of salmeterol for an acute attack of asthma. In a January 16,1995, "Dear Doctor" letter from Allen &amp; Hanburys, the

Salmeterol Xinafoate as Maintenance Therapy Compared With Albuterol in Patients With Asthma

To compare the efficacy and safety of inhaled salmeterol xinafoate, a long-acting beta 2-adrenoceptor agonist, with that of albuterol, a short-acting inhaled beta 2-agonist, in the treatment of asthma. Randomized, double-blind, placebo-controlled, parallel-group study. Eleven outpatient clinical centers. A total of 322 male and female patients at least 12 years of age with chronic symptomatic asthma requiring daily therapy. Patients were treated with salmeterol xinafoate (42 micrograms inhaled twice daily), albuterol (180 micrograms inhaled four times daily), or placebo (four times a day) for 12 weeks; patients in all three groups could use inhaled albuterol as backup medication for breakthrough symptoms. Serial 12-hour forced expiratory flow in 1 second (FEV1), peak expiratory flow (PEF), asthma symptoms, nocturnal awakenings due to asthma, episodes of asthma exacerbations, and electrocardiography. The mean area under the curve for FEV1 throughout each 12-hour period was consistently greater after a single dose of salmeterol than after two doses of albuterol administered 6 hours apart (P < .001), with the difference ranging from 3.1 to 4.3 L.h. Salmeterol produced an average increase in morning and evening PEF of 26 and 29 L/min, respectively, over pretreatment values compared with decreases of -13 and -3 L/min, respectively, in the albuterol group and -2 L/min both in the morning and evening in the placebo group (P < .001). Patients in the salmeterol group had significantly fewer days and nights with symptoms than did either the albuterol or placebo group (P < .001). Responses to salmeterol were similar at day 1 and at week 12. Adverse events in all treatment groups were equally infrequent, and no clinically significant change in cardiac rhythm was observed with salmeterol treatment. Salmeterol inhaled twice daily is more effective than albuterol inhaled four times a day (or as needed) in patients with asthma requiring maintenance therapy. No deterioration of asthma control was observed with the use of salmeterol over a 3-month period.

A Word of Caution Regarding a New Long-Acting Bronchodilator

Physicians in the United States will soon be provided with a new, selective, long-acting β 2 -adrenergic aerosol, salmeterol xinafoate, 1,2 for the treatment of asthma. In this issue ofTHE JOURNAL, D'Alonzo et al 3 show that salmeterol inhaled twice daily compared with albuterol inhaled four times daily provides more effective bronchodilation in patients requiring maintenance therapy. Additionally, there was no deterioration in asthma control with the use of salmeterol throughout a 3-month period. Other studies have reported similar results. 4

Effect on Airway Responsiveness of Six Weeks Treatment with Salmeterol

Summary: It has been suggested that the new long-acting β2-agonist, salmeterol, has anti-inflammatory properties—properties which should improve airway responsiveness (AR). Conversely, several recent studies have suggested that regular β2-agonist treatment may worsen asthma and AR. Furthermore, a short-lived rebound increase in AR has been described following cessation of regular treatment with these agents. We have consequently assessed the effects on AR of regular treatment with either salmeterol or salbutamol at conventional doses over 6 weeks. FEV1 and AR were measured five times in 20 asthmatic subjects randomly allocated to one or other treatment regimen; twice during a 2-week run-in period; and 24 h, 72 h, and 2 weeks after the last dose of the study medication. Peak expiratory flow rate (PEFR) was also recorded throughout the study period. There were no statistically significant changes in FEV1 or AR between the run-in period and any of the post treatment measurements for either of the treatments used. Mean PEFR was significantly higher during the treatment period than the run-in period for the salmeterol group, but not the salbutamol group, confirming that therapeutically adequate doses of salmeterol had been given. We conclude that if the regular use of salmeterol is associated with beneficial or adverse effects on AR, this is not apparent after a treatment period of 6 weeks.

Inhibition by salmeterol of increased vascular permeability and granulocyte accumulation in guinea-pig lung and skin.

1. The long-acting beta 2-adrenoceptor agonist, salmeterol has been evaluated for its anti-inflammatory effects in the guinea-pig lung and skin. 2. Salmeterol, administered in bronchodilator doses to conscious guinea-pigs by both oral (0.01-1.0 mg kg-1) and inhaled (nebulizer concentration, 0.001-1.0 mg ml-1) routes, inhibited histamine-induced plasma protein extravasation (PPE) into the airway lumen. 3. Inhibition of PPE by salmeterol was long-lasting (greater than 6 h) and was inhibited by prior administration of propranolol (1 mg kg-1, s.c.), indicating an effect mediated by beta-adrenoceptors. 4. Inhaled salbutamol (nebulizer concentration, 0.001-1.0 mg ml-1) also inhibited PPE in guinea-pig lung but, in contrast to salmeterol, this effect was short-lived with substantial loss of activity 2 h after administration. 5. Inhaled salmeterol (0.1 mg ml-1) and salbutamol (1.0 mg ml-1) inhibited the accumulation of neutrophils in guinea-pig lung in response to lipopolysaccharide (100 micrograms ml-1). Salmeterol, but not salbutamol, inhibited the infiltration of eosinophils into the airway lumen in response to platelet activating factor (100 micrograms ml-1). These effects of salmeterol were blocked by prior administration of propranolol (5 mg kg-1, s.c.), indicating that they were also beta-adrenoceptor-mediated. 6. Oral salmeterol (10 mg kg-1, p.o.), but not salbutamol (10 and 100 mg kg-1, p.o.), inhibited zymosan-induced granulocyte accumulation and PPE in guinea-pig skin. Lower doses of salmeterol (0.1 and 1 mg kg-1) inhibited PPE, but not granulocyte accumulation.The effects of salmeterol were blocked by prior administration of propranolol (1mgkg-', s.c.). Both salmeterol and salbutamol inhibited histamine-induced PPE in guinea-pig skin.7. Intradermal salmeterol (10-'mol per site), but not salbutamol, was also effective in inhibiting zymosan-induced granulocyte accumulation and PPE in guinea-pig skin.8. It is concluded that salmeterol, at bronchodilator doses in the guinea-pig, inhibits granulocyte accumulation and PPE, possibly by an action on the vasculature. As this profile of activity is not shared by the shorter-acting compound, salbutamol, it would seem that anti-inflammatory activity is associated with beta-adrenoceptor agonism of long duration. The implications of these findings for the use of salmeterol in the treatment of bronchial asthma are discussed.