Rise and Fall of Asthma Mortality in England and Wales in Relation to Use of Pressurised Aerosols

Inman, W. H. W.; Adelstein, A. M.

doi:10.1016/s0140-6736(69)90051-8

Cited by 347 publications

(88 citation statements)

References 9 publications

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“…The possible adverse effects of ␤ 2 -AR agonist given by mouth and by inhalation have been discussed in earlier reports (4,5,14). Importantly, the major detrimental actions of ␤ 2 -AR agonists occur as a result of excessive activation of ␤ 2 -AR.…”

Section: Discussionmentioning

confidence: 90%

Renal Effects of β2-Adrenoceptor Agonist and the Clinical Analysis in Children

2007

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ABSTRACT:The objectives of the present study were to define the contribution of ␤ 2 -adrenoceptors(␤ 2 -ARs) agonists to renal physiology and to investigate whether over-expression of renal ␤ 2 -ARs might be implicated in the pathogenesis of renal dysfunction in children as an adverse effect of ␤ 2 -AR activation. The renal functional responses to the systemic injection of the ␤ 2 -AR agonist terbutaline in Wistar rats over-expressing renal ␤ 2 -AR were compared with those of nontreated rats. Furthermore, we evaluated intrarenal ␤ 2 -AR expression in 34 children (age 2-15 y) and the changes in serum creatinine levels of 99 children (age 1-15 y) who received ␤ 2 -AR agonists. The animal study showed that the suppression of glomerular function by terbutaline was associated with a reduction in systemic blood pressure and over-expression of renal ␤ 2 -ARs. Moreover, in rats over-expressing renal ␤ 2 -ARs, administration of terbutaline resulted in a high mortality rate after a lipopolysaccharide challenge. The clinical study showed that renal ␤ 2 -AR expression gradually increased with age and was up-regulated by steroid therapy. These findings indicate that the renal dysfunction caused by ␤ 2 -AR agonists can be explained, at least partly, by enhanced ␤ 2 -AR expression in the kidney. This may have important implications for the use of ␤ 2 -AR agonists in the treatment of sick children with, for example, steroid therapy or endotoxemia. ␤ 2 -adrenoceptor (␤ 2 -AR) agonists are used as standard agents in the treatment of bronchial asthma and chronic bronchitis. The majority of the ␤ 2 -AR agonists is eliminated via the kidneys in an unchanged form and it is likely that the compound will exert pharmacological effects during its passage along the nephron. However, these pharmacological effects have, to our knowledge, not been taken into consideration when using these compounds in clinical practice because the significance of ␤ 2 -ARs in the regulation of renal function remains unclear.Renal ␤ 2 -ARs in the rat are predominantly localized to the renal tubular epithelia and the membranes of smooth muscle cells in the renal vasculature (1). From this morphologic evidence, the possibility arises that ␤ 2 -AR activation may impact on glomerular function and thereby sodium and water handling at different nephron segments. We recently demonstrated that injection into the kidney of an adenoviral construct expressing the human ␤ 2 -AR gene induced a widespread increase in ␤ 2 -AR expression in the renal glomeruli and tubules, which was associated with enhanced glomerular filtration and sodium re-absorption as a consequence of overactivation of renal ␤ 2 -ARs (2). Since the level of ␤ 2 -AR expression will importantly determine the magnitude of ␤ 2 -AR-mediated responses following administration of a ␤ 2 -AR agonist (3), the density of intrarenal ␤ 2 -AR expression may determine the impact of ␤ 2 -AR agonists on renal function. However, there have been no studies evaluating the relationship between intrarenal ␤ 2 -AR expression a...

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Section: Discussionmentioning

confidence: 90%

Renal Effects of β2-Adrenoceptor Agonist and the Clinical Analysis in Children

2007

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“…No adequate studies were undertaken to identify a cause for this trend. However, the (over)use of β-agonists was circumstantially implicated by the temporal association between increasing sales and an increase in asthma-related death, followed by a reduction in mortality once warnings as to the potential role of these drugs were disseminated (1,3). A second epidemic of asthma deaths in New Zealand, commencing the year after the local launch of fenoterol and reaching an unprecedented peak of 4.1 asthma deaths per 100,000 per annum amongst those aged 5 to 34 years in 1979 (4), prompted a series of case-control studies which indicated that excessive use of fenoterol (5-7), and to a lesser extent salbutamol (8) (albuterol), increased the risk of asthma death.…”

Section: Main Textmentioning

confidence: 99%

Safety of β2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice

Dissanayake

2015

AAPS J

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Abstract. An epidemic of asthma fatalities in the 1970s prompted a series of case-control studies which indicated that short acting β-agonists increased the risk of death. Subsequent mechanistic and pharmacodynamic studies have suggested that β-agonist monotherapy facilitates airway inflammation, although when co-administered with inhaled corticosteroids (ICSs), similar evidence is lacking. The Salmeterol Multicenter Asthma Research Trial, which revealed a fourfold increase in asthma-related deaths in salmeterol-treated patients, prompted a paradigm shift in the evidential assessment of β-agonist safety. The FDA's meta-analysis of over 60,000 patients ultimately concluded that long-acting β-agonist (LABA) therapy increased the risk of serious asthma-related events. However, this meta-analysis itself raised questions given a large body of omitted data and a limited emphasis on the risk of ICS-LABA coadministration. Subsequently, the FDA mandated the conduct of five large studies to definitively ascertain whether ICS-LABAs increase asthma-related risk. Whether this ambitious programme will provide certainty remains to be seen given issues of multiplicity, the very low frequency of fatal and nearfatal asthma, and the administration of a free combination of ICS and LABA in one trial. The FDA's de facto use of FEV1 as a safety parameter, based on findings from the Foradil NDA, is a further topical issue: subsequent clinical study data, considerations relating to regional pulmonary drug deposition and pharmacological differences between different β-agonists suggest that FEV1 may be a suboptimal safety metric. Models evaluating airway inflammation and bronchial reactivity may be more appropriate to assess the relative risk of asthma-related events.

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“…It was related to the use of pressurized aerosols containing sympathomimetic bronchodilators which had become popular in the treatment of asthma since 1960 Speizer, Doll, Heaf & Strang, 1968). Since 1968 further reports have been published which show a positive correlation between the use of pressurized aerosols containing sympathomimetic bronchodilators and an increase in the asthma mortality rate (Inman & Adelstein, 1969;Fraser, Speizer, Waters, Doll & Mann, 1971;Stolley, 1972).…”

Section: Introductionmentioning

confidence: 99%

TOLERANCE TO SYMPATHOMIMETIC BRONCHODILATORS IN GUINEA‐PIG ISOLATED LUNGS FOLLOWING CHRONIC ADMINISTRATION in vivo

Benoy

Elfellah

Schneider

et al. 1975

British J Pharmacology

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Pretreatment of the guinea‐pig subcutaneously three times daily with either 5 μg/kg isoprenaline or adrenaline reduced the response of the isolated perfused histamine‐constricted lung when challenged with either the same or a different sympathomimetic bronchodilator. The longer the animals were pretreated and the higher the dose of bronchodilator the greater was the degree of tolerance developed. Tolerance was developed to aminophylline in the same preparation when the guinea‐pig had been pretreated with aminophylline or isoprenaline. Cross‐tolerance also developed to adrenaline when the guinea‐pig had been pretreated with aminophylline. Tolerance was still persistent in guinea‐pigs one and two weeks after pretreatment three times daily with either isoprenaline or adrenaline (5 μg/kg s.c.) for seven days in the same preparation. Only after three weeks was the tolerance diminished. These results suggest that asthmatic patients who use bronchodilators excessively may become refractory to the bronchodilator effect of these drugs. They also support the hypothesis that induced cross‐resistance to endogenous sympathetic stimulation could lead to a deterioration of the asthmatic state in patients using the sympathomimetic bronchodilators and that this may explain the increase in asthma mortality rate. A mechanism of tolerance to sympathomimetic bronchodilators is postulated.

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Rise and Fall of Asthma Mortality in England and Wales in Relation to Use of Pressurised Aerosols

Cited by 347 publications

References 9 publications

Renal Effects of β2-Adrenoceptor Agonist and the Clinical Analysis in Children

Renal Effects of β2-Adrenoceptor Agonist and the Clinical Analysis in Children

Safety of β2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice

TOLERANCE TO SYMPATHOMIMETIC BRONCHODILATORS IN GUINEA‐PIG ISOLATED LUNGS FOLLOWING CHRONIC ADMINISTRATION in vivo

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