ARLS 3 1997 Astra Respiratory Literature Service Experts comments

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AstraZeneca Respiratory Literature Service
N°3 1997 (see N° 1 1997 also N° 2 1997 and N° 4 1997)

For many years, AstraZeneca Draco laboratories have brought to the asthmolgist community an excellent "Respiratory Literature Service" (ARLS) with an alert to new references, selected summaries and comments by a group of experts. In 1997, AstraZeneca is extending this concrete service with Asmanet in order to take advantage of the Internet capabilities. The following comments have been edited ( HTML format) to smooth the reading with hypertext links to integrate the comment in the Asmanet server and the worldwide distributed library on asthma, such as : abstract of the commented paper, references as seen on Medline and others, author's e-mail ...

	Title	Authors	Journal	Reviewer
1	Effect on the lung bioavailability of salbutamol	Clark D. J., Lipworth B. J.	Thorax 1996	Professor Duncan Geddes
2	Bronchodilators and acute cardiac death.	Suissa S., Hemmelgarn B., Blais L., Ernst P.	Am J Respir Crit Care Med 1996	Professor Duncan Geddes
3	Adult asthma and gastro-oesophageal reflux	Teichtahl H., Kronborg I.J., Yeomans N. D., Robinson P.	Aust N Z J Med 1996	Professor Duncan Geddes
4	Dose-response of inhaled drugs in asthma	Clark D.J., Lipworth B.J.	Clin Pharmacokinet 1997	Professor Philippe Godard
5	Bronchoprotective effect of a long-acting inhaled b2-agonist	Yates D. H., Kharitonov S. A., Barnes P. J.	Am J Respir Crit Care Med 1996	Professor Philippe Godard
6	Children treated with inhaled glucocorticosteroids	Wolthers O.D., Hansen M., Juul A., et al	Pediatr Res 1997	Professor Philippe Godard
7	Oral prednisolone and fluticasone propionate in the treatment of adults	Levy M. L., Stevenson C. Maslen T.	Thorax 1996	Professor John H. Toogood
8	Changes in bone markers in children with asthma	Sorva R., Tähtelä R., Turpeinen M., et al	Acta Paediatr 1996	Professor John H. Toogood

AstraZeneca Draco laboratories is also supporting the European Federation of Asthma and Allergy Associations which can be seen at http://www.efanet.org/

Access for abstracts to Medline through Healthgate (http://www.healthgate.com/HealthGate/MEDLINE/search.shtml ) or through HealthWorld Medline Search (http://www.healthy.net/library/search/medline.htm ): direct access to the abstract whenever it's available is not possible. You have to perform a "search" using the search engine (and be exposed to the local advertiser banner which sort-of pays for the free access). You will then go through the following steps :

Select the names of the first two authors (or part of the title) and do a "copy" (ctrl C on a PC under Windows) so that you will have the search key at hand.
Click on the link in order to get the HealthGate/HealthWorld search home page.
Paste the search key (ctrl V) into the search window displayed on your screen and perform the search.

The search engine will send you back the list of papers with those two authors. HealthWorld search engine will give you related papers if you select it by the title. You will then select the link which you want if the paper is known and click on the link to get the abstract.

...

Spacers are a valuable way of improving inhaled drug delivery in asthma but must be used correctly. This simple, but well designed, study shows that salbutamol is delivered more effectively when the dose is given as a single rather than a multiple actuation. Similarly efficiency is reduced bye a 20-second delay between actuation of the pMDI and inhalation from the spacer. Finally, a wash-resistant antistatic coating intended to improve drug delivery was no more effective than simple washing with warm water.

The differences were likely to be clinically important in that multiple puffs and delayed inhalation reduced the biological effect by nearly half. Unfortunately, the study did not examine the importance of shorter than 20-second delays. This study is useful in two ways. First, it defines optimum conditions for spacer use and secondly, it emphasises that the way in which a spacer is used is likely to make much more difference than switching from one drug to another within a class or changing the dose of that drug.

Author Clark DJ; Lipworth BJ
Address: Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, UK.
Source: Thorax, 51(10):981-4 1996 Oct

Abstract
BACKGROUND: The aim of this study was to extend previous in vitro observations regarding the effects of multiple actuations of aerosols into spacer devices, delayed inhalation, and antistatic treatment of spacer devices on the amount of drug delivered for inhalation. An in vivo study of lung bioavailability of salbutamol from a large volume (Volumatic) spacer was conducted.

METHODS: Ten healthy volunteers of mean age 20.5 years with a mean forced expiratory volume in one second of 112.1% predicted were studied in a randomised single blind (investigator blind) crossover study. 1200 micrograms of salbutamol was given with mouth rinsing (100 micrograms/puff) on four study days: single puffs via spacer, multiple puffs via spacer (3 x 4 puffs), single puffs with 20 second delay before inhalation via spacer, and single puffs via an antistatic treated spacer. All spacers, including those treated with antistatic, were prewashed prior to each study day.

This paper is a further analysis of the Saskatchewan asthma epidemiological project much of which has been previously reported. The population-based cohort of over 12,000 subjects who were precribed anti-asthma medications was examined and 30 deaths from cardiovascular causes were analysed in more detail to investigate the possibility that anti- asthma drugs were in part responsible. The risk ratio of cardiovascular death was increased by 2.7 in users of theophylline and by 2.4 in users of b-agonists taken either orally or by nebuliser (chiefly salbutamol and fenoterol). There was no increased risk in users of b-agonists administered by pMDI. The deaths occurred in people who already had significant cardiovascular pathology; the asthma drugs were only contributing to a pre-existing cause.

The overall frequency of these events was very low, confirming that anti-asthma drugs are in general very safe but care must be taken in prescribing theopylline or systemic beta-agonists to people with pre-existing risk factors for cardiovascular disease. The recent resurgence of interest in theophylline as an anti-asthma drug needs to be balanced against the considerable experience of serious toxicity.

Author : Suissa S; Hemmelgarn B; Blais L; Ernst P
Address : McGill Pharmacoepidemiology Research Unit, Department of Medicine, Royal Victoria Hospital, MontrÍeal, QuÍebec, Canada.
Source : Am J Respir Crit Care Med, 154(6 Pt 1):1598-602 1996 Dec

Abstract
Bronchodilators used in the treatment of airway disease have been shown to have a variety of cardiac effects that may contribute to the occurrence of life-threatening events such as cardiac arrhythmias and cardiac arrest. We investigated whether theophylline and beta-agonists were associated with cardiovascular mortality among a cohort of subjects prescribed antiasthma medications. We used a population-based cohort of 12,301 subjects aged 5 to 54 yr, formed from health-insurance data bases from Saskatchewan, Canada, and spanning the period 1978 to 1987. Within this cohort, we identified all 30 deaths from cardiovascular causes in which acute asthma did not appear to be a contributing factor. We identified all asthma and cardiovascular drugs dispensed to these subjects shortly before their deaths and compared this therapy to that dispensed to a random sample of 4,080 person-time controls. ...

The relationship between gastro-oesophageal reflux and asthma has been the subject of much speculation but relatively few good data. This study examines the effect of omeprazole on asthma control in 28 patients selected for the presence of both asthma and gastro-oesophageal reflux. Omeprazole improved the symtoms of reflux but had no clinically significant effect on asthma.

This study adds further support to the hypothesis that gastro-oesophageal reflux is not an important mechanism in asthma in spite of the fact that the two conditions often occur together. Symptoms should be treated appropriately for both conditions, but there is little reason to suppose that treatment of one will affect symptoms of the other.

Author : Teichtahl H; Kronborg IJ; Yeomans ND; Robinson P
Address : Department of Respiratory Medicine, Western Hospital, Melbourne, Vic.
Source :Aust N Z J Med, 26(5):671-6 1996 Oct

Abstract
BACKGROUND: Approximately 40-60% of patients with asthma have gastro-oesophageal reflux (GOR) and it has been postulated that this may worsen asthma severity. AIMS: To investigate the effect of the potent gastric acid inhibitor omeprazole 40 mg orally daily on peak expiratory flow rate (PEFR), asthma symptoms and histamine bronchial responsiveness in adult patients with both asthma and GOR.

METHODS: This was a double blind, randomised, placebo controlled, crossover study. Upper gastrointestinal endoscopy, 24 hour oesophageal pH measurements, spirometry and histamine bronchoprovocation test (HIT) were performed prior to entry. Phase 1:2 week placebo run-in period, with baseline recording of PEFR, asthma and GOR symptoms, and use of inhaled beta 2-agonist. Phase 2: patients randomised to receive either placebo or omeprazole 40 mg/d for four weeks. Phase 3: placebo for two weeks. Phase 4: patients crossed over to opposite treatment from that of phase 2. Spirometry, and diary cards were assessed at beginning and end of phases 2 and 4. HIT was performed at the end of phase 2 and at the beginning and end of phase 4.

This paper on the clinical pharmacology of inhaled drugs in asthma should be read by everybody who is interested in asthma. The review is well done and with many references. Professor Toogood has previously produced interesting data which demonstrated an anti-asthmatic dose effect of inhaled steroids. However, these works have not been fully accepted.

In fact, our clinical tools appear to be too insensitive. Moreover, bronchial asthma, which is a variable airway condition, has to be considered from three different points of view:

Rather than to think in terms of one drug, we will have to think in terms of strategy. Pharmacologists have to consider this concept.

However, instead of waiting for a possible decline of FEV1 or a similar parameter, the clinicians have to take into account the exacerbations. This could be the good endpoint to demonstrate that there exists a dose effect of inhaled steroids in bronchial asthma.

Author : Clark DJ; Lipworth BJ
Address : Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Scotland. dclark (at) clinpharm.dundee.ac.uk
Source : Clin Pharmacokinet, 32(1):58-74 1997 Jan

Abstract
The demographic characteristics of patients used in clinical trials (such as the severity of airway obstruction) can significantly influence the results of dose-response studies, emphasising the need to evaluate effects on the steep part of the dose-response curve. Differences in inhaler devices can also influence study outcomes, as for inhaled drugs both airway efficacy and adverse effect profiles are primarily determined by lung deposition and hence bioavailability. Dose-response studies with short- and long-acting beta 2-agonists show an excellent therapeutic ratio at conventional doses used in everyday clinical practice (i.e. 2 to 4 puffs). Dose-related systemic effects of beta 2-agonist occur at higher doses, for salbutamol (albuterol) > 500 micrograms. Fenoterol is a beta 2-agonists with higher intrinsic activity than salbutamol and produces greater systemic effects at higher than conventional doses on a microgram equivalent basis, although even at 4000 micrograms such differences are unlikely to be clinically relevant. No differences between fenoterol and salbutamol have been shown in terms of bronchodilator potency on a microgram equivalent basis.

Professor Barnes is a fine and clever pharmacologist. From bench to bed he has developed many, very exciting studies. This is one of them. The study design appears really excellent and should be used as a model for teachers and students. The discussion explaining the results must also be read and memorized.

The main aim of the study was to analyse the effect of an inhaled steroid (budesonide) against the loss of protective effect induced by a long-acting b2-agonist (salmeterol).

However, there appears to exist a great gap between bench and bed. In vitro, glucocorticosteroids have a facilitating effect on beta-2 function, that is the reverse of the clinical results. Explanations for this paradox are lacking.

The authors do not discuss the role of salmeterol vs formoterol, or budesonide vs other inhaled steroids.

Finally, the clinical relevance of this observation on tolerance to bronchoprotective effects should be addressed. The difference was statistically significicant, but small. Daily clinical practice favors the opinion that this tolerance development has no clinical relevance. However, the definitive answer is not known; specific designs must be set up. In the future, prospective evaluations of exacerbations, managed either at home or at hospital, must take into account this hypothesis.

Author : Yates DH; Kharitonov SA; Barnes PJ
Address : Department of Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom.
Source :Am J Respir Crit Care Med, 154(6 Pt 1):1603-7 1996 Dec

Abstract
There is increasing evidence for the development of tolerance to the protective effects of inhaled beta 2-agonists against bronchoconstrictor stimuli. Animal studies have suggested that glucocorticoids protect against the down-regulation of beta 2-receptors after chronic exposure to beta 2-agonists. In a double-blind placebo-controlled crossover study in 12 patients with mild asthma, we investigated the effect of inhaled budesonide or identical placebo on the protection conferred by albuterol (200 micrograms) against methacholine-induced bronchoconstriction before and after treatment with the long-acting beta 2-agonist salmeterol. Patients were randomized to be treated for 3 wk with inhaled budesonide (800 micrograms twice a day) or placebo; salmeterol (50 micrograms twice a day) was added during the third week. Airway responsiveness to methacholine was measured 15 min after albuterol, both before and exactly 23 h after the last salmeterol dose.

A group of Danish pediatricians with Professor S. Pedersen, continue to assess adverse effects and safety of inhaled steroids in asthmatic children. In this paper the authors try to validate serum markers in order to monitor systemic activity of inhaled steroids.

The effects of fluticasone and BDP on many parameters were investigeted. The aim of the study was not to rule out any adverse effects of the recently introduced fluticasone. The study design has not been made for that. It's important to read carefully this paper to make the reasoning clear and eliminate false conclusions.

The serum markers of collagen turnover could be influenced by airway inflammation. As the symptoms were not modified during the study, the authors conclude that the decrease of these serum markers in blood was the consequence of the systemic activity of the inhaled steroids. This is possible, but should be confirmed by a more in depth evaluation of airway inflammation. In medicine, the explanation of a phenomenon is - as a rule - multifactorial. The coefficients of correlation are low and even if the statistics are significant, other explanations have to be considered.

In conclusion, the assessment of systemic activity of inhaled steroids is not so easy to do. Several methods are available; sensitivity and specificity of each one has to be described.

In clinical practice, minimal dose of an inhaled steroid has to be given,statural growth of the children has to be checked carefully; to date, there is no serum marker which could be recommended to be used on a routine basis.

Title (6): Knemometry, urine cortisol excretion, and measures of the insulin-like growth factor axis and collagen turnover in children treated with inhaled glucocorticosteroids. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Wolthers OD; Hansen M; Juul A; Nielsen HK; Pedersen S
Address : Department of Paediatrics, Kolding Hospital, Denmark.
Source : Pediatr Res, 41(1):44-50 1997 Jan

Abstract
Correlations between knemometric (lower leg length) growth rates and urine free cortisol excretion,respectively, and serum concentrations of IGF-I, IGF binding protein-3, osteocalcin, carboxy terminal propeptide of type I collagen (PICP), carboxy terminal pryridinoline cross-linked telopeptide of type I procollagen (ICTP), and amino terminal propeptide of type III procollagen (PIIINP) were investigated in 17 asthmatic children aged 7-14 y during treatment with fluticasone propionate, 200 micrograms, and beclomethasone dipropionate, 400 and 800 micrograms/d, taken from dry powder inhalers. The study was a double blind, crossover trial with three active treatment periods and two wash-out periods. All periods were 15 d long. Overnight urine free cortisol/ creatinine x 10(6) did not correlate with knemometric growth rates or any of the serum markers. Significant correlations (Pearson's correlation coefficient, P) between knemometric growth rates and IGF-I (0.41; 0.006), IGFBP-3 (0.35; 0.02), PICP (0.44; 0.003), ICTP (0.35; 0.001), and PIIINP (0.46; 0.002) were found.

This randomized, placebo-controlled, double-blind study examined the question: Is a short course of high dose fluticasone more efficacious than high dose prednisolone for aborting periodic acute exacerbations of asthma?

No difference was found. Thus the choice between these therapeutic approaches may reasonably be based on cost, convenience and patient preference - modified by clinical judgement.

The first two considerations would favour prednisolone/prednisone over inhaled corticosteroid. Additionally, as the authors point out, clinical judgement, based on factors not measurable in terms of ventilatory impairmant, often favour the oral steroid. On the other hand, high dose inhaled corticosteroid has a clear advantage for patients known to be intolerant of high dose prednisone in the past - provided the treatment can be started relatively early in the exacerbation and reliable patient-physician communications are in place.

Title (7): Comparison of short courses of oral prednisolone and fluticasone propionate in the treatment of adults with acute exacerbations of asthma in primary care. (partial abstract below from http://www.healthy.net/library/search/medline.htm )

Author : Levy ML; Stevenson C; Maslen T
Address : Prestwood Avenue Surgery, Kenton, Harrow, UK.
Source : Thorax, 51(11):1087-92 1996 Nov

Abstract
BACKGROUND: Oral corticosteroids used in short courses for acute asthma are regarded as safe, although the frequent use of these drugs may result in patients suffering from systemic side effects. It has become common practice for patients to increase their own inhaled corticosteroid intake when their asthma goes out of control, but it has never been established whether a high dose of inhaled corticosteroid can be as effective as a short course of oral corticosteroid in the treatment of acute exacerbations.

METHODS: A multicentre, randomised, double blind, double dummy, parallel group study was undertaken to determine whether the introduction of a high dose of inhaled fluticasone propionate (2 mg daily) is as effective as a short reducing course of oral prednisolone (starting at 40 mg/day and reducing by 5 mg every other day) in the treatment of acute exacerbations of asthma not considered severe enough for admission to hospital but requiring treatment with oral corticosteroid.

Sorva and co-workers found high and intermediate doses of budesonide inhibited bone formation in asthmatic children but did not perturb the normal "coupling" between bone formation and resorption. This would imply no corollary increase in the risk of fracture - at least in the short term. However, the impact of the treatment on the peak bone density attained in adulthood remains to be determined.

In an earlier graded-dose study, Jennings and co-workers demonstrated in healthy adult test subjects that the dose level at which bone formation and resorption lose their normal "coupling" differs, depending on which inhaled corticosteroid is administered: budesonide conserved normal coupling at high dosage (2.5 mg/day), whereas beclomethasone dipropionate did not (1).

1. Jennings B.H., Larsson B., Andersson K.E., Johansson S.A. A comparison of budesonide and beclomethasone dipropionate in healthy volunteers. In: The assessment of systemic effects of inhaled glucocorticoids.Department of Clinical Pharmacology Lund, Sweden, 1990: VII:1 - VII:14

Author : Sorva R; TÍahtelÍa R; Turpeinen M; Juntunen-Backman K; Haahtela T; Risteli L; Risteli J; Sorva A
Address :Department of Allergic Diseases, Helsinki University Central Hospital, Finland.
Source : Acta Paediatr, 85(10):1176-80 1996 Oct

Abstract
We evaluated serum and urinary markers of bone turnover in 14 children with asthma during inhaled budesonide and nedocromil treatments. Both the markers of formation (serum carboxy- and amino-terminal propeptides of type I procollagen and serum osteocalcin) and the markers of degradation (serum carboxy-terminal telopeptide of type I collagen and urinary pyridinium cross-links) decreased (p < 0.05) during budesonide treatment for 6 months. During inhaled nedocromil treatment (for the following 6 months), the markers returned to the normal levels. These transient decreases in the markers of both formation and degradation of bone suggest that inhaled budesonide may slightly decrease the bone turnover rate.

Asmanet

Congrès Conçue et réalisée par: Michel Godard (at)

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Date de création: 1997 - Dernière mise à jour: 17/06/99
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Toute personne citée dispose d'un droit d'accès, de modification, de rectification et de suppression des données le concernant (art. 34 de la loi "Informatique et Libertés" n° 78-17 du 6 janvier 1978). Pour l'éxercer adressez-vous à Michel Godard (at)

Title (1) :	Effect of multiple actuations, delayed inhalation and antistatic treatment on the lung bioavailability of salbutamol via a spacer device
Authors:	Clark D. J., Lipworth B. J. Thorax 1996; 51: 981-984
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (2) :	Bronchodilators and acute cardiac death.
Authors:	Suissa S., Hemmelgarn B., Blais L., Ernst P. Am J Respir Crit Care Med 1996; 154: 1598-1602
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (3) :	Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma
Authors:	Teichtahl H., Kronborg I.J., Yeomans N. D., Robinson P. Aust N Z J Med 1996; 26: 671-676
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (4) :	Dose-response of inhaled drugs in asthma: an update
Authors:	Clark D.J., Lipworth B.J. Clin Pharmacokinet 1997; 32: 58-74
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (5) :	An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled b2-agonist
Authors:	Yates D. H., Kharitonov S. A., Barnes P. J. Am J Respir Crit Care Med 1996; 154: 1603-1607
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (6 ) :	Knemometry, urine cortisol excretion, and measures of the insulin-like growth factor axis and collagen turnover in children treated with inhaled glucocorticosteroids
Authors:	Wolthers O.D., Hansen M., Juul A., et al Pediatr Res 1997; 41: 44-50
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (7) :	Comparison of short courses of oral prednisolone and fluticasone propionate in the treatment of adults with acute exacerbations of asthma in primary care
Authors:	Levy M. L., Stevenson C., Maslen T. Thorax 1996;51: 1087-1092
Comments by:	Professor John H. Toogood Victoria Hospital LONDON, Ontario N6A 4G5, Canada

Title (8) :	Changes in bone markers in children with asthma during inhaled budesonide and nedocromil treatments
Authors:	Sorva R., Tähtelä R., Turpeinen M., et al Acta Paediatr 1996; 85: 1176-80
Comments by:	Professor John H. Toogood Victoria Hospital LONDON, Ontario N6A 4G5, Canada