The effect of benzalkonium chloride on the bronchodilator response to salbutamol nebuliser solution.
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Biomedical subjects
Publications and source records attributed to J Crane.
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In this double blind study, the cardiovascular and hypokalaemic effects of equal doses of inhaled pirbuterol and salbutamol were compared in eight healthy volunteers. Increasing doses of 200, 400, 600 and 800 micrograms (total dose 2000 micrograms) were given from a metered dose inhaler at 15 min intervals, followed by measurement of heart rate, blood pressure, total electromechanical systole (QS2I) (as a measure of inotropic response) and plasma potassium (K+) concentration 15 min after each inhalation. After inhalation of the highest concentration, salbutamol resulted in a greater increase in heart rate (10.5 bpm vs 4.4 bpm, p less than 0.0007), and reduction in QS2I (-25.4 ms vs -9.6 ms, p less than 0.0001) than pirbuterol. There were no significant differences in changes in systolic blood pressure (1.9 mmHg vs 6 mmHg, p = 0.27), diastolic blood pressure (-5.8 mmHg vs -3.9 mmHg, p = 0.64) or plasma K+ (-0.21 mmol/L vs -0.15 mmol/L, p = 0.57). We conclude that the new beta-2 adrenergic agonist pirbuterol is at least as beta-2 selective as salbutamol when administered by repeated inhalation in healthy volunteers.
Trends in mortality from asthma in non-Maori New Zealanders aged 5 to 34 years were examined for the period 1908-1986. Two previously documented epidemics of death from asthma occurred in the 1960s and the late 1970s. These epidemics are most likely to have been due to changes in the management of asthma: the introduction of isoprenaline forte by metered dose inhaler in the 1960s and inhaled fenoterol in the 1970s. A previously unreported rise in mortality, which was more gradual in onset and less severe, occurred in the 1940s and 1950s; a similar pattern occurred in England and Wales during the same period. It is unlikely that this increase in mortality was solely due to changes in diagnostic fashion or disease coding. Possible explanations include changes in the management or prevalence of asthma, or in environmental factors. It is notable that mortality was below 0.5 per 100,000 person-years prior to 1940, but has subsequently increased considerably. Thus, while modern methods for treating asthma have improved the quality of life of many asthmatics, mortality has increased during the period of their introduction and use.
Interviews were conducted with 101 consecutive adult patients admitted to Wellington Hospital with a diagnosis of asthma to assess the extent to which beta agonist drugs are self-administered by asthmatic patients during severe asthma. The 99 patients prescribed an inhaled beta agonist were subdivided into two groups: group A comprising 79 patients prescribed a beta agonist for inhalation via an inhaler (metered dose aerosol or dry powder device) alone; group B comprising 20 patients prescribed beta agonist for inhalation via both an inhaler and nebuliser. In group A, the attacks of asthma lasted greater than 24 hours in 64/79 patients, and 22% of these patients reported taking more than 60 doses of their inhaler, and 52% more than 30 doses during the 24 hr period prior to admission. In group B, the attacks of asthma lasted greater than 24 h in 17/20 patients, and 35% of these patients self-administered their nebuliser more than six times, and 76% more than four times during the 24 h period prior to admission. In addition to their nebuliser use, these patients also took a median 23 doses of their inhaler during this 24 h period. This use of inhaled beta agonist contrasts with the recommended practice in both the USA and Europe, where most physicians recommend no more than 15 doses of a beta agonist as the maximal dose per day. We conclude that asthmatic patients in New Zealand self-administer high doses of inhaled beta 2 agonist drugs during severe exacerbations of asthma.
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The cardiovascular, respiratory, and hypokalemic effects of repeated inhalation of fenoterol, albuterol, and isoproterenol were compared in 12 subjects with stable asthma according to a double-blind, crossover design. Ipratropium bromide served as a control providing bronchodilatation without extrapulmonary effects. Subjects inhaled the beta-agonists on an equal-weight basis (400 micrograms) at 0, 30, 40, and 45 minutes. Measurements of heart rate, blood pressure, total electromechanical systole (measure of inotropic activity), preejection period, QTc interval, plasma potassium levels, and forced expiratory volume in 1 second were made 5 minutes after each dose and again at 60 and 75 minutes. There were no differences in the bronchodilating effect between the beta-agonists. However, both fenoterol and isoproterenol resulted in greater positive inotropic stimulation than did albuterol, and fenoterol caused a greater fall in plasma potassium levels than did the other beta-agonists.
A survey of asthma symptoms and spirometry in 435 adolescent schoolchildren was undertaken in 1989 in a rural, largely Maori population. The survey questionnaires were identical to those used in a 1975 survey at the same school. The prevalence of reported asthma or wheeze significantly increased from 26.2% to 34.0%. This increase occurred in groups reporting asthma, and also those reporting wheeze unassociated with colds, but without a previous diagnosis of asthma. There was a tendency for a rise in reported wheeze in Europeans (24.3% to 27.4%) and a significant rise in Maoris (27.1% to 36.2%). The reclassification of other respiratory problems did not account for the increase. Data from this study provides evidence that there has been a rise in the prevalence of asthma in this New Zealand population over a time period of 14 years.
The cardiovascular effects of equal doses (5 mg) of nebulised fenoterol, salbutamol and terbutaline were compared in 12 healthy individuals in a double-blind, placebo-controlled study. Measurements of heart rate, blood pressure, systolic time intervals, QTc interval and T-wave amplitude were made at baseline and at 15, 30, 45, 60 and 90 minutes after nebulisation. Fenoterol caused significantly greater chronotropic electrocardiographic and inotropic effects than either salbutamol or terbutaline. The peak effects after terbutaline occurred later than those after fenoterol or salbutamol.
A previous New Zealand case-control study of asthma deaths in the 5-45 year age group during 1981-3 found that prescription of fenoterol (by metered dose inhaler) was associated with an increased risk of death in patients with severe asthma. One major criticism of this study was that drug data for the cases and controls came from different sources. A new case-control design has been used to evaluate the same hypothesis, with a different set of asthma deaths, the same source for drug information being used for both cases and controls. This depended on identifying deaths from asthma during 1977-81 from national mortality records, and ascertaining which patients from those who died had been admitted to a major hospital for asthma during the 12 months before death. The study was confined to this subgroup, which accounted for about 20% of all asthma deaths in the areas served by a major hospital. For each of the eligible patients who died four age matched controls were selected from patients admitted to hospital for asthma during the year that the death occurred who had also had an admission for asthma in the previous 12 months. For the 58 cases and 227 control subjects information on prescribed drugs was collected from the hospital records relating to the previous admission. The odds ratio of asthma death in patients prescribed inhaled fenoterol was 1.99 (95% confidence interval 1.12-3.55, p = 0.02). As in the previous study, subgroups defined by markers of chronic asthma severity were also considered. The inhaled fenoterol odds ratio was 2.98 (95% CI 1.15-7.70, p = 0.02) in patients prescribed three or more categories of asthma drugs, 3.91 (95% CI 1.79-8.54, p less than 0.01) in patients with a previous admission for asthma in the past 12 months, and 5.83 (95% CI 1.62-21.0, p = 0.01) in patients prescribed oral corticosteroids at the time of admission. In patients with the most severe asthma (defined by a previous admission for asthma during the past 12 months and prescribed oral corticosteroids at time of admission) the inhaled fenoterol odds ratio was 9.82 (95% CI 2.23-43.4, p less than 0.01). These findings add further support to the hypothesis that inhaled fenoterol increases the risk of death in patients with severe asthma.
The mean blood alcohol concentration (BAC) in 175 fatal cases of acute alcohol intoxication was found to be 355 mg/100 ml. This figure is less than that quoted in many standard textbooks on forensic medicine. The BAC in fatal cases of acute alcohol intoxication complicated by aspiration was lower than in those cases where there was no evidence of aspiration at autopsy. In those individuals with a previous history of alcohol abuse the BAC causing death was found to be significantly higher than in those without a history of prolonged heavy alcohol consumption suggesting that a degree of tolerance to the effects of alcohol may be induced.
Chlorbutol is an antibacterial and antifungal agent incorporated in terbutaline (Bricanyl) nebulizer solution. Ten stable atopic asthmatic subjects undertook bronchial challenge testing, according to a double-blind protocol. Patients inhaled doubling concentrations of either methacholine (0.13-4.0 mg.ml-1) or chlorbutol (0.16-5.0 mg.ml-1) for 2 min until the forced expiratory volume in one second (FEV1) had fallen by 20% from baseline. If this had not occurred following the administration of the final concentration, then this highest concentration was repeated for 4 min. The nine subjects completing the study had a geometric mean provocation concentration producing a 20% fall from baseline FEV1 (PC20) methacholine of 0.16 mg.ml-1 (range less than 0.125-0.475 mg.ml-1). After inhalation of 2.5 mg.ml-1 chlorbutol one subject experienced a fall in FEV1 greater than 20%. In the remaining eight subjects, inhalation of chlorbutol did not affect airway calibre. We conclude that chlorbutol, in the concentration present in Bricanyl nebulizer solution, has no clinically significant effect on airway calibre.
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