Fenoterol and asthma mortality.
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Administration, Inhalation↗
Biomedical subjects
R Beasley
Publications and source records attributed to R Beasley.
Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case-control study.
A case-control study was conducted to examine the hypothesis that fenoterol by metered dose inhaler (MDI) increases the risk of death in patients with asthma. The case group comprised 117 patients aged 5-45 who died of asthma between August, 1981, and July, 1983. For each case, 4 controls, matched for age and ethnic group, were selected from asthma admissions to hospitals to which the cases themselves would have been admitted, had they survived. The relative risk of asthma death in patients prescribed fenoterol by MDI was 1.55 (95% CI 1.04-2.33, p = 0.03). The possibility of confounding or effect modification by severity was assessed by consideration of subgroups defined by markers of asthma severity. The fenoterol MDI relative risk was 2.21 (95% CI 1.26-3.88, p = 0.01) in patients prescribed three or more categories of asthma drugs, 2.16 (95% CI 1.14-4.11, p = 0.02) in patients with a hospital admission for asthma during the previous 12 months, and 6.45 (95% CI 2.72-15.3, p less than 0.01) in patients prescribed oral corticosteroids at time of death or admission. In the group of patients with the most severe asthma (defined by a hospital admission during the previous year and prescription of oral corticosteroids) the fenoterol MDI relative risk was 13.29 (95% CI 3.45-51.2, p less than 0.01). After adjustment for severity, no other asthma treatment commonly used in New Zealand seemed to be associated with an increased risk of asthma death. Not all sources of bias can be definitely excluded; however, when considered together with other epidemiological and experimental evidence, these findings are consistent with the hypothesis that use of fenoterol by MDI increases the risk of death in severe asthma.
Acute Disease↗
Subepithelial fibrosis in the bronchi of asthmatics.
The epithelial basement membrane and underlying collagen were examined by immunohistochemistry and electron microscopy in endobronchial biopsy specimens from 8 asthmatic and 3 control subjects. There was an excess of interstitial collagens beneath the basement membrane in the asthmatic subjects. There was no evidence of any epithelial contribution to this abnormality, nor was there any correlation with epithelial damage, disease duration, or severity. These findings contradict the long-held notion of basement membrane thickening in asthma and indicate that the subepithelial fibrosis is a result of fibroblast activation rather than bronchial epithelial cell dysfunction.
Adult↗
A comparison of the extent and duration of hypokalaemia following three nebulized beta 2-adrenoceptor agonists.
The hypokalaemic effects of equal doses (5 mg) of fenoterol, salbutamol, terbutaline and an equal volume of saline administered by nebulization were compared in eight healthy subjects. Plasma potassium was measured at 15-min intervals for 60 min and at 90 min, 2, 4 and 6 h following administration. Fenoterol, salbutamol and terbutaline all significantly decreased plasma potassium when compared to saline; however, the magnitude and duration of this effect differed between the active agents. Both fenoterol and terbutaline significantly reduced plasma potassium for 4 h whereas salbutamol was only different from 30 to 120 min. The maximum decrease occurred with fenoterol (-0.78 mmol/l), followed by terbutaline (-0.70 mmol/l) and salbutamol (-0.33 mmol/l). Both terbutaline and fenoterol had a significantly greater effect compared with salbutamol. When administered by nebulization fenoterol and terbutaline are likely to have a greater hypokalaemic effect than salbutamol and this effect is likely to be more long lasting.
Administration, Inhalation↗
Reduced selenium status of patients with asthma.
1. Selenium is an essential component of glutathione peroxidase (GSH-Px, EC 1.11.1.9), an enzyme which helps protects cells against damage caused by free radicals and hydroperoxides. 2. We report the plasma, whole blood and platelet concentrations of selenium, and whole blood and platelet activities of GSH-Px, in 49 patients with asthma, 23 of whom had coexisting eczema, and 76 healthy control subjects. 3. The asthmatic patients had significantly lower concentrations of selenium measured in plasma (P less than 0.001) and whole blood (P less than 0.001), but not in platelets. When the data were summarized as odds ratios there was a highly significant 3.54- and 5.08-fold increased probability of asthma observed for the lower range of plasma and whole blood selenium concentrations, respectively. 4. No overall decrease in platelet or whole blood GSH-Px activity was found when the asthmatic and control groups were compared. 5. Although patients with symptomatic asthma have a reduced selenium status, this does not appear to influence the antioxidant capacity of their circulating blood cells.
Adolescent↗
The effect of an increase in inhaled allergen dose after terfenadine on the occurrence and magnitude of the late asthmatic response.
We have attempted to use a potent and selective histamine H1-receptor antagonist terfenadine to allow a larger dose of allergen to be administered to previous single early responders to investigate if an increased dose of allergen could induce a late asthmatic response. Pre-treatment with 180 mg of terfenadine enabled a geometric mean increase in allergen dose of 4.12-fold to be inhaled by eight atopic subjects with mild asthma, who initially were classified as single early responders, with maximal fall in FEV1 3-8 hr after allergen challenge (Lmax) of less than 15% from baseline value. The magnitude of early asthmatic response was similar to that obtained on the control day when allergen challenge was performed in the absence of terfenadine. Two subjects were converted to dual responders with Lmax of 23.1 and 24.3%, which occurred with a 32- and 65-fold increase in allergen dose respectively, and a 6- and 4.9-fold decrease in non-specific airways responsiveness measured as the cumulative provocative concentration of methacholine that caused a 20% fall in FEV1 from baseline. The remaining six subjects failed to achieve an Lmax of greater than 10% even with a 1.29-2.66-fold increase in allergen dose. For the group as a whole an increase in allergen dose was associated with an increase in overall bronchoconstrictor response 3-8 hr after challenge. These results indicate that it is possible to induce a late asthmatic response in a subject who previously demonstrated only an early response by increasing the dose of allergen inhaled.
Administration, Inhalation↗
Bronchial gland duct ectasia in fatal bronchial asthma: association with interstitial emphysema.
To determine the incidence of bronchial gland duct ectasia in fatal asthma and its association with interstitial emphysema, the histological features of 72 patients in whom death was considered to be due to asthma, and 72 matched control subjects in whom sudden death was not attributed to asthma, were reviewed. In all cases and controls, sections of two or more blocks of lung tissue stained with haematoxylin and eosin were obtained at necropsy. Bronchial gland duct ectasia was diagnosed if there was more than one abnormally dilated epithelial lined protrusion from a bronchus, extending through the smooth muscle layer. A histological diagnosis of asthma was made if four of the five following criteria were present: mucus plugging, basement membrane thickening, epithelial shedding, submucosal eosinophil leucocyte infiltration and smooth muscle hypertrophy. A histological diagnosis of asthma was made in 53 of 72 clinical cases of fatal asthma and in five of 72 control subjects. Interstitial emphysema was present in 10 clinical cases of fatal asthma, all of whom had bronchial gland duct ectasia and a histological diagnosis of asthma. Interstitial emphysema was not observed in control subjects. It is concluded that bronchial gland duct ectasia is a common histological feature of severe asthma, and that interstitial emphysema may be consequent on rupture of these dilated gland ducts.
Asthma↗
Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline.
The cardiovascular and hypokalaemic effects of equal doses of inhaled fenoterol, isoprenaline and salbutamol were compared in eight healthy male volunteers, in a double blind, placebo controlled study. Increasing doses of 400, 600, and 800 micrograms were given from a metered dose inhaler at 15 minute intervals, followed by measurements of heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval, and plasma potassium concentration. After repeated inhalation, fenoterol resulted in significantly greater chronotropic, electrocardiographic, and hypokalaemic effects than either isoprenaline or salbutamol. The maximum inotropic effect of fenoterol was similar to that of isoprenaline.
Administration, Inhalation↗
A self management plan in the treatment of adult asthma.
To determine whether routine assessment of peak expiratory flow (PEF) in association with a self management plan based on inhaled corticosteroid use is effective in the management of chronic asthma, 36 consecutive adult patients with asthma attending an outpatient chest clinic were admitted to an open prospective study. Patients were treated with inhaled salbutamol and beclomethasone dipropionate in an attempt to achieve normal lung function. Each patient had a "potential normal value," which was either the predicted normal or the maximum PEF value achieved by the patient, whichever was the higher. Patients measured PEF at home and if it fell by more than 30% from the potential normal value the dose of beclomethasone was doubled until PEF returned to the potential normal value, then continued at 20 mg/day for the same number of days. If PEF fell to below 150-200 l/min patients were asked to obtain emergency medical assistance. In the 30 patients who completed the trial the six months before and the six months after intervention with the self management plan were compared. There was a substantial improvement in both subjective and objective measurements of asthma severity, with a significant reduction in nights woken, days lost from work, and requirement for oral corticosteroids and a significant increase in baseline lung function. Routine measurement of PEF in association with a self management plan appears to be effective in reducing symptoms of asthma and improving lung function.
Adolescent↗
Cellular events in the bronchi in mild asthma and after bronchial provocation.
We have undertaken detailed cellular and ultrastructural examination of bronchial biopsies and bronchial lavage fluid from allergic asthmatic patients in order to determine the nature and degree of the inflammatory processes in mild allergic asthma. Eight atopic asthmatic patients (mean PC20 histamine, 0.90 mg/ml) and four nonasthmatic control subjects underwent fiberoptic bronchoscopy. All asthmatic subjects were clinically stable for 2 wk prior to bronchoscopy and required either no treatment or inhaled albuterol alone. A single 50-ml bronchial wash was undertaken, followed by endobronchial biopsy of subcarinae. These procedures were repeated in the asthmatic subjects 18 h after bronchial provocation with allergen or methacholine. Subsequently, all subjects underwent bronchial reactivity testing with inhaled histamine. The clinical and physiologic data were not revealed to the pathologist interpreting the specimens. The asthmatic subjects shed a significantly greater number of epithelial cells into the lavage fluid than did the nonasthmatic subjects (7.23 versus 1.48 x 10(4)/ml, p = 0.048). There was a statistically significant inverse correlation between the lavage epithelial cell count and bronchial reactivity (rho = -0.64, p = 0.03). In the asthmatic subjects, but not in the control subjects, there was extensive deposition of collagen beneath the epithelial basement membrane, mast cell degranulation, and mucosal infiltration by eosinophils, which exhibited morphologic evidence of activation. Eosinophils, monocytes, and platelets were found in contact with the vascular endothelium, with emigration of eosinophils and monocytes in the asthmatic subjects. These changes were found irrespective of bronchial challenge with allergen. We conclude that allergic asthma is accompanied by extensive inflammatory changes in the airways, even in mild clinical and subclinical disease.
Asthma↗
Unsuitability of the human erythrocyte as a model for in vivo sodium transport activation by beta 2 adrenergic agonists.
Administration of the beta 2 adrenergic agonists fenoterol, salbutamol and terbutaline to volunteers significantly reduced plasma potassium concentration in a double-blind crossover study. There was no consistent effect of the three active compounds on erythrocyte sodium concentration. Storage of whole blood at 4 degrees C increased erythrocyte sodium concentration by 33% after 2 h; this could explain the differences between this and another study of the effects of beta 2 adrenergic agonists on erythrocyte sodium concentration. We conclude that the human erythrocyte is unsuitable as an indirect in vivo model to demonstrate stimulation of cellular sodium potassium transport mediated by beta 2 adrenergic agonists.
Adrenergic beta-Agonists↗
The cardiovascular effects of inhaled fenoterol alone and during treatment with oral theophylline.
We have investigated whether oral theophylline potentiated the cardiovascular effects of fenoterol administered by metered-dose inhaler. Eight healthy subjects were investigated on four occasions. On successive days (1 and 2), the subjects were given doses of 400 micrograms, 600 micrograms, and 800 micrograms of fenoterol at 15-minute intervals (total dose, 1.8 mg) or matched placebo. Systolic time intervals, blood pressure, and the ECG were recorded at baseline and five minutes after each inhalation. Thereafter, the subjects were treated with slow-release theophylline for eight days. On days 9 and 10, the procedures on days 1 and 2 were repeated. The order of treatment was applied according to a crossover Latin-square design. The effects after theophylline alone were no different from placebo. Theophylline potentiated those hemodynamic effects of fenoterol due to enhanced cardiac sympathetic tone (mean +/- SE) as measured by a decrease in Q-S2I (-41.6 +/- 7.6 ms vs -27.3 +/- 5.9 ms; p = 0.0004), an increase in systolic BP (23.5 +/- 2.8 mm Hg vs 9.0 +/- 5.3 mm Hg; p = 0.00001), and an increase in heart rate (15.8 +/- 1.6 bpm vs 9.1 +/- 3.7 bpm; p = 0.0013). The responses mediated by beta 2-adrenergic receptor stimulation, namely, a decrease in PEP and diastolic BP, were not potentiated. Although fenoterol prolonged the Q-Tc interval and decreased T-wave amplitude, these effects were not potentiated by theophylline. Oral theophylline potentiates the positively inotropic and chronotropic effects of fenoterol.
Administration, Inhalation↗
Inflammatory processes in bronchial asthma.
Bronchial asthma is an inflammatory disease. The characteristic pathological features of epithelial cell loss, goblet cell hyperplasia, increased deposition of collagen beneath the basement membrane, mast cell degranulation, and inflammatory cell infiltration of the mucosa are not limited to fatal asthma. Similar inflammatory events have been observed in subjects who would be considered to have clinically stable asthma. These observations would suggest that pharmacological treatment directed against the underlying inflammatory processes in asthma should not be limited to those patients with severe forms of the disease.
Animals↗
The contribution of histamine release to bronchoconstriction provoked by inhaled benzalkonium chloride in asthma.
1. To investigate the possibility that benzalkonium chloride-induced bronchoconstriction results from the endogenous release of histamine, we examined the effect of the selective histamine antagonists terfenadine and astemizole, on the airways response to inhaled benzalkonium chloride and histamine in 12 asthmatic subjects. 2. Double-blind concentration- and time-course studies were undertaken, 3 h after treatment with terfenadine or matched placebo. 3. Benzalkonium chloride and histamine caused concentration-related falls in FEV1 in all subjects with benzalkonium chloride being 7.4 times less potent as a bronchoconstrictor agonist than histamine. Terfenadine displaced to the right the benzalkonium chloride and histamine concentration-response curves by 3.7 and 111 fold respectively. Terfenadine attenuated the initial (5 min) bronchoconstrictor response to benzalkonium chloride by 40%. However, over the whole 45 min period, the response was reduced by only 13% compared with 86% inhibition of the response to histamine. 4. In an open study, eight of the 12 subjects undertook a time course study with inhaled benzalkonium chloride after pretreatment with the chemically unrelated histamine antagonist astemizole. Astemizole inhibited benzalkonium chloride-induced bronchoconstriction to an almost identical degree as that achieved with terfenadine. 5. We conclude that the initial bronchoconstrictor effect of benzalkonium chloride is due, in part, to histamine release. However, the majority of the adverse effect relates to other, as yet unrecognised effects of this bacteriocidal substance.
Adult↗
Adverse reactions to the non-drug constituents of nebuliser solutions.
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Drug Contamination↗
The influence of ipratropium bromide and sodium cromoglycate on benzalkonium chloride-induced bronchoconstriction in asthma.
1. Benzalkonium chloride, an antibacterial preservative that is added to nebuliser solutions, has been shown to cause bronchoconstriction when inhaled by asthmatic subjects. 2. To investigate the potential role of reflex and mast cell-dependent mechanisms in the pathogenesis of bronchoconstriction produced by benzalkonium chloride we examined the effects of ipratropium bromide and sodium cromoglycate on this response in both concentration-response and time-course studies in nine asthmatic subjects. 3. Pretreatment with inhaled ipratropium bromide (1 mg) and sodium cromoglycate (40 mg) displaced the benzalkonium chloride concentration-response curves to the right by a mean 2.2 fold and 3.1 fold respectively. 4. Ipratropium bromide and sodium cromoglycate markedly attenuated the airway response to benzalkonium chloride throughout the 45 min time course period, inhibiting the overall response by 56% and 78% respectively. 5. We conclude that benzalkonium chloride provokes bronchoconstriction in asthmatic subjects through a combination of mast cell activation and stimulation of peripheral and central neural pathways.
Adult↗
Comparative vascular effects of histamine, prostaglandin (PG) D2 and its metabolite 9 alpha,11 beta-PGF2 in human skin.
In this double-blind study we have investigated the vascular effects of prostaglandin, (PG) D2, in normal skin and compared these effects with histamine and the initial PGD2 metabolite 9 alpha, 11 beta-PGF2. In eight healthy subjects the vascular response to intradermal injections of histamine, PGD2, a combination of histamine and PGD2, and 9 alpha,11 beta-PGF2, was assessed by measurement of the weal and flare area. Histamine caused dose-related increases in weal area (P less than 0.01). The weal response due to PGD2 was greater than saline control only at a dose of 71.0 and 710 nmol (P less than 0.05). Because of the small size of the weal produced by PGD2 when compared with histamine, it was not possible to determine their relative potencies. Histamine and PGD2 caused dose-related increases in flare area (P less than 0.05), and when compared at a response level of 10 cm2 and 15 cm2, histamine was 45 and 251 (P less than 0.01) times more potent than PGD2 in molar terms. Weal and flare responses due to 9 alpha,11 beta-PGF2 were similar to those observed with the equimolar concentration of PGD2. The weal and flare responses when PGD2 and histamine when combined were not significantly different from that predicted by a purely additive effect. We conclude that histamine is likely to be an important mediator contributing towards increased vascular permeability and vasodilatation following immunological activation of skin mast cells in vivo, while PGD2 and its metabolite 9 alpha, 11 beta-PGF2 play only a minor role.
Dinoprost↗
The mediator and cellular basis of the allergic response.
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Animals↗