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previous  next Provided by/avec le support de :     S-221 87     Lund Sweden ARLS information : Myrna Mansson Get the paper version from your local Marketing representative. Find the address ont the net at http://www.astrazeneca.com/Marketing-worldwide AstraZeneca Respiratory Literature Service N°3   1998 (see other Expert comments on Asmanet) 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 Prevalence of asthma symptoms, diagnosis and treatment in 12-14 year old children across Great Britain (International study of asthma and allergies in childhood, ISAAC UK) Kaur B, Anderson HR, Austin J, et al. Brit Med J 1998;316:118-124 Professor Philippe Godard 2 Perinatal factors and atopic disease in childhood Fergusson DM, Crane J, Beasley R, et al. Clin & Exp Allergy 1997;27:1394-1401 Professor Philippe Godard 3 Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval Bronsky EA, Kemp JP, Zhang J, et al. Clin Pharm & Therapeutics 1997;62:556-561 Professor Philippe Godard 4 A comparison of beclomethasone, salmeterol and placebo in children with asthma Simons FER N Engl J Med 1997;337:1659-1665 Professor Duncan Geddes 5 Exercise-induced asthma Tan RA, Spector SL. Sports Medicine 1998;25:1-6 Professor Duncan Geddes 6 Nebulized wet aerosol treatment in emergency department - is it essential? Comparison with large spacer device for metered-dose inhaler Mandelberg A, Chen E, Noviski N, et al Chest 1997;112:1501-1505 Professor Duncan Geddes 7 Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval Bronsky EA, Kemp JP, Zhang J, et al Clin Pharm & Therapeutics 1997;62:556-561 Ass. Professor Leif Rosenhall 8 Nebulized wet aerosol treatment in emergency department -is it essential? Comparison with large spacer device for metered-dose inhaler. Mandelberg A, Chen E, Noviski N, et al Chest 1997;112:1501-1505 Ass. Professor Leif Rosenhall 9 The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma Lazarus SC, Wong HH, Watts MJ, et al. Am J Respir Crit Care Med 1997;156:1725-1730 Ass. Professor Leif Rosenhall 10 A comparison of beclomethasone, salmeterol, and placebo in children with asthma Simons FER N Engl J Med 1997;337:1659-1665 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. ...

Two international surveys in asthma have been performed recently: ECRHS and ISAAC. The second survey is still ongoing. They were and they are very fruitful because they provide numerous papers and interesting results. These results are important to improve daily clinical practice and to increase knowledge of asthma.

This study confirms, once again, that prevalence of asthma is very high in Great Britain. The prevalence of wheeze symptoms seems to be higher in Scotland than in England. However, it is still not possible to explain variations in prevalence, both in the UK and worldwide.

Moreover, this study underlines the lack of asthma treatment in relation to need. The authors state that "A substantial proportion (30 to 40%) of adolescents with asthma symptoms that interfered with their daily lives were not treated for the disease". This observation is very important and is in accordance with other data. ¹

Several guidelines on asthma management have been published but their impact on public health is unknown. Therefore, global evaluation of the ISAAC results will be very exciting and will provide insight into how the global differences in asthma management affect public health.

Reference:

Bousquet J, Knani J, Henry C, Liard R, Richard A, Michel FB, Neukirch F TI: Undertreatment in a nonselected population of adult patients with asthma. J Allergy Clin Immunol 1996; 98: 514-21

Title (1): . Prevalence of asthma symptoms, diagnosis and treatment in 12-14 year old children across Great Britain (International study of asthma and allergies in childhood, ISAAC UK) (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Kaur B; Anderson HR; Austin J; Burr M; Harkins LS; Strachan DP; Warner JO
Address / Department of Public Health Sciences, St George's Hospital Medical School, London.
Source : BMJ, 316(7125):118-24 1998 Jan 10
Abstract :
OBJECTIVE: To investigate variations in the prevalence of self reported symptoms, diagnosis, and treatment of asthma in 12-14 year old children. DESIGN: Self completion questionnaire. SETTING: Great Britain. SUBJECTS: All pupils aged 12-14 years in a stratified cluster sample of 93 large mixed secondary schools in 1995. MAIN OUTCOME MEASURES: Self reported prevalence of symptoms, diagnosis, and treatment of asthma at four geographical levels. RESULTS: 27,507 questionnaires were completed (85.9% response rate). The national 12 month prevalence of any wheezing, speech limiting wheeze, four or more attacks of wheeze, and frequent night waking with wheeze was 33.3% (n = 9155), 8.8% (2427), 9.6% (2634), and 3.7% (1023) respectively. The prevalence of ever having had a diagnosis of asthma was 20.9% (5736). In total, 19.8% (5438/27,507) of pupils reported treatment with anti-asthma drugs in the past year, but, of pupils reporting frequent nocturnal wheeze in the past year, 33.8% (342/1012) had no diagnosis of asthma and 38.6% (395/1023) denied receiving inhaler therapy. The 12 month prevalence of wheeze was highest in Scotland (36.7%, 1633/4444), but in England and Wales there was no discernible north-south or east-west gradient. Wheeze prevalence was slightly higher in non-metropolitan areas (35.0%, 6155/17,605) than in metropolitan areas (30.3%, 3000/9902). The prevalence of self reported asthma diagnosis and inhaler use showed no discernible national, regional, north-south, or east-west geographical pattern but was higher in non-metropolitan areas. CONCLUSION: Prevalence of self reported symptoms, diagnosis, and treatment of asthma was high among 12-14 year olds throughout Great Britain with little geographical or urban-rural variation. Underdiagnosis and undertreatment were substantial.

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Who could have been able to predict that head circumference at birth could be a risk factor for the development of asthma?!

The paper by Fergusson et al demonstrates it. They conclude that large head circumference at birth may be associated with increased risks for the development of asthma.

As a clinician it is hard to comment upon the study, other professions need to be involved:

• - Epidemiologists have to confirm the observation.
• - Statisticians need to check whether or not the study is biased.
• - Pediatricians must be involved in finding an explanation for the observation.
• - Embryologists must join studies investigating the link between perinatal factors and risks of asthma.

Title (2) : Perinatal factors and atopic disease in childhood (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Fergusson DM; Crane J; Beasley R; Horwood LJ
Address : Department of Psychological Medicine, Christchurch School of Medicine, New Zealand.
Source : Clin Exp Allergy, 27(12):1394-401 1997 Dec
Abstract :
BACKGROUND: Recent work has suggested possible linkages between perinatal factors and notably,head circumference and risks of subsequent atopic illness. OBJECTIVE: To examine the linkages between perinatal factors and risks of atopic conditions in a birth cohort of New Zealand children studied to the age of 16.
METHODS: Measures of atopic illness including asthma, eczema, and other allergies were assessed prospectively during the course of a 16 year longitudinal study of a birth cohort of 1265 New Zealand children. In the initial stage of this research, measures of perinatal variables including birthweight, gestational age, head circumference and length at birth were obtained from hospital record data.
RESULTS: Children with head circumference at birth of 37 cm or greater had (unadjusted) odds of asthma that were 1.8 (P < 0.01) to 3.0 (P < 0.0001) times higher than the odds for children of lesser head circumference. However, risks of asthma were not related to other perinatal measures including birthweight, gestational age or length or ratios of these measures. There were no consistent associations between perinatal measures and other measures of childhood atopy including eczema, allergic rhinitis and other allergies. The associations between head circumference and asthma risks persisted when due allowance was made for potentially confounding social and perinatal factors.
CONCLUSIONS: It is concluded that large head circumference at birth may be associated with increased risks for the development of asthma. Possible explanations for the linkages between head circumference and asthma risks are considered.

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Montelukast is now being launched in numerous countries. To use this new compund correctly in the management of asthma, all its properties need to be investigated. Although not all properties of montelukast are fully evaluated yet, its effect in exercise-induced bronchoconstriction is now well established.

The study of Bronsky et al. compared the effects of 4 doses of montelukast with placebo (0 mg, 0.4 mg, 2.0 mg, 10 mg and 50 mg). It appeared that a dose of 10 mg and 50 mg were effective and equivalent. This is important from a marketing and - secondly - from a clinical point of view: the study shows that a dose of 10 mg per day should be prescribed.

This paper on montelukast is very interesting because a significant linear dose-response relationship was detected. This is in contrast to inhaled corticosteroids for which many studies could not show a dose-response relationship.

In general, it has been suggested that some patients might be non-responders to the so-called anti-leukotrienes. This study was not designed to evaluate that. However, in future studies, the relationship between heterogeneity of leukotriene receptors and non-responders needs to be determined.

Title (3): Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Bronsky EA; Kemp JP; Zhang J; Guerreiro D; Reiss TF
Address : AAAA Medical Research Group, Salt Lake City, USA.
Source : Clin Pharmacol Ther, 62(5):556-61 1997 Nov
Abstract :
The dose-related protective effects of montelukast, a potent and selective cysteinyl leukotriene-receptor antagonist, against exercise-induced bronchoconstriction were investigated in a five-period, randomized, incomplete-block, crossover study with montelukast (0.4, 2, 10, 50 mg) and placebo. The study subjects were 27 nonsmoking, healthy stable patients with asthma (mean forced expiratory volume in 1 second [FEV1], 82.0% predicted) who demonstrated a > or = 20% decrease in FEV1 while beta-agonist was withheld for 6 hours before treadmill exercise. The standard exercise challenge was performed 20 to 24 hours, and again 32 to 36 hours, after the second of two once-daily doses. The effect of oral montelukast on exercise was measured by the area above the postexercise percentage decrease in FEV1 versus time curve from 0 to 60 minutes [AUC(0-60)], the maximal percentage decrease in FEV1 after exercise, and time after maximal decrease to recovery of FEV1 to within 5% of the preexercise baseline. Twenty to 24 hours after administration, montelukast caused dose-related protection, while providing similar protection against exercise-induced bronchoconstriction at the two highest doses. The AUC(0-60) values (mean +/- SD) were 637 +/- 898, 715 +/- 870, 988 +/- 1147, and 927 +/- 968 min. % for 50, 10, 2, and 0.4 mg montelukast, respectively, and 1193 +/- 1097 min. % for placebo (p = 0.003). No important clinical effect was present 36 hours after dosing. Montelukast was generally well tolerated at all dose levels. In conclusion, montelukast caused dose-related protection against exercise-induced bronchoconstriction at the end of a once-daily dosing interval. Protection against exercise-induced bronchoconstriction can be used to determine appropriate dose selection.

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The study by Simons is another large study providing good evidence that current asthma guidelines are correct.

A total of 241 children with stable asthma were randomised into three groups to receive beclomethasone dipropionate 200 m g twice daily or salmeterol 50 m g twice daily or placebo. Measurements were made over a twelve month period. Beclomethasone was best in terms of airway hyper-responsiveness, peak flow variability, exacerbations and rescue therapy. Salmeterol was as good as beclomethasone in control of asthma symptoms but worse than beclomethasone for the other measures. Linear growth was less in the beclomethasone as compared with the salmeterol or the placebo groups.

The finding that beclomethasone is the best treatment but that systemic effects are measureable in terms of both growth and eosinophil count is in line with previous data and adds further fuel to the debate about the importance of inhaled corticosteroid side effects.

A surprising associated editorial seized on the growth differences as a way of promoting the use of other, less effective, anti-inflammatory drugs.

Sadly, both this study and the editorial fail to draw attention to the inhaled cortico-steroid dose. When beclomethasone was first introduced on the market the top dose for adults was 400 m g daily and worked very well. This dose is almost certainly unnecessarily high for the treatment of children. It is likely that a lower dose of 100 m g twice daily would have provided similar benefits without appreciable systemic effects.

Title (4): A comparison of beclomethasone, salmeterol and placebo in children with asthma Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Simons FE
Address : Children's Hospital of Winnipeg, MB, Canada.
Source : N Engl J Med, 337(23):1659-65 1997 Dec 4
Abstract :
BACKGROUND: An inhaled glucocorticoid is currently the medication of choice for long-term control of persistent asthma in children. The role of long-acting beta2-adrenergic-receptor agonists, such as salmeterol, needs to be defined. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group, one-year study of 241 children (mean [+/-SD] age, 9.3+/-2.4 years) with clinically stable asthma and less than one month of prior glucocorticoid use. We compared inhaled beclomethasone dipropionate (200 microg twice daily) with salmeterol xinafoate (50 microg twice daily) and placebo (lactose). The primary outcome measure, airway responsiveness (as assessed with a methacholine challenge) was evaluated before treatment; after 3, 6, 9, and 12 months of treatment (12 and 36 hours after study medications had been withheld); and 2 weeks after the end of treatment. Spirometry, symptoms, use of rescue medication (200 microg of albuterol inhaled as needed), and adverse effects were also assessed.
RESULTS: During months 1 through 12 overall, beclomethasone was associated with significantly less airway hyperresponsiveness than salmeterol (P= 0.003) or placebo (P<0.001). This effect was lost two weeks after treatment had been stopped. As compared with placebo, beclomethasone was associated with less variability between morning and evening in the peak expiratory flow (P=0.002), as was salmeterol (P=0.02). Beclomethasone was also associated with a reduced need for albuterol as rescue therapy (P<0.001) and fewer withdrawals because of asthma exacerbations (P=0.03), but salmeterol was not (P=0.09 and 0.55, respectively). During months 1 through 12, linear growth was 3.96 cm in the children receiving beclomethasone, as compared with 5.40 cm in the salmeterol group (P=0.004) and 5.04 cm in the placebo group (P=0.018). Height was not measured after treatment ended.
CONCLUSIONS: Beclomethasone was effective in reducing airway hyperresponsiveness and in controlling symptoms of asthma ...

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The paper by Tan and Spector is a useful review of exercise-induced asthma and is notable for appearing in a journal on sports medicine rather than respiratory disease. This is in line with current thinking that asthma should be a condition compatible with all normal activities rather than an illness.

The article is slanted somewhat towards laboratory studies and is therefore particularly strong on mechanisms and experimental forms of treatment which help understand these mechanisms. Thus, treatments such as inhaled heparin and frusemide which are not clinical realities are mentioned along side conventional measures.

The article provides a great deal of good common sense advice on the ways in which athletes can avoid exercise-induced asthma by modifying their training by warming up and warming down, exploiting the refractory period following exercise-induced asthma, and being aware of the importance of environmental conditions.

The basic message is that for almost everyone with exercise-induced asthma, simple practical advice combined with b -agonists can solve the problem. There remains, however, a small group of athletes whose exercise asthma prevents them achieving their full potential.

Title (5): Exercise-induced asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Tan RA; Spector SL
Address : Allergy Research Foundation, Los Angeles, California, USA.
Source : Sports Med, 25(1):1-6 1998 Jan
Abstract :
Exercise-induced asthma (EIA) is characterised by transient airway obstruction occurring after strenuous exertion. A fall of 10% or more in the FEV1 after exercise is diagnostic. Inhalation of large volumes of dry, cold air during exercise leads to loss of heat and water from the bronchial mucosa and airway cooling and drying. Proposed mechanisms for bronchoconstriction include: (i) mucosal drying and increased osmolarity stimulating mast cell degranulation; and (ii) rapid airway rewarming after exercise causing vascular congestion, increased permeability and oedema leading to obstruction. EIA symptoms start after exercise, peak 8 to 15 minutes after exercise and spontaneously resolve in about 60 minutes. A refractory period of up to 3 hours after recovery, during which repeat exercise causes less bronchospasm, has been observed. The amount of ventilation and the temperature of inspired air are important factors in determining the severity of EIA. Greater ventilation and cold, dry air increase the risk for EIA. Education regarding the nature and management of EIA is important not only for asthmatics but also for their families and coaches. With the proper precautions and workout techniques, there is no limit to what individuals with asthma can achieve in sports. Prevention is the main objective in managing EIA. Nonpharmacological measures include warming up before vigorous exertion, covering the mouth and nose in cold weather, exercising in warm, humidified environments if possible and warming down after exercise...

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The study by Mandelberg et al compared 2500 m g of nebulised salbutamol with 200 m g salbutamol delivered by MDI plus spacer in patients attending an emergency department with acute exacerbations of breathlessness. Treatments were delivered at 15 minute intervals unless limited by side effects. Similar improvements in symptoms and lung function were observed for both treatments.

The main strength of this study is that it was performed in a real life emergency room setting and so confirms previous studies showing that MDI plus spacer is an efficient delivery system and that the doses normally given by nebuliser are unnecessarily high.

This is welcome news for those treating acute airflow obstruction due to either asthma or COPD under difficult circumstances where a nebuliser is not available.

The study results do not however provide any reason to stop using nebulised salbutamol in an emergency room. This form of treatment continues to have a number of advantages, notably drug delivery is reliable, oxygen is delivered at the same time, an adequate dose will be given for all patients (different patients have different dose response curves), patients and staff alike find nebulisers reassuring in a stressful situation.

Title (6): Nebulized wet aerosol treatment in emergency department - is it essential? Comparison with large spacer device for metered-dose inhaler (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Mandelberg A; Chen E; Noviski N; Priel IE
Address : Department of Pulmonary Medicine, The Edith Wolfson Medical Center, Holon, Israel.
Source : Chest, 112(6):1501-5 1997 Dec
Abstract :
OBJECTIVE: To determine the efficacy of a metered-dose inhaler (MDI) with a large spacer device as compared to nebulized wet aerosols in the treatment of an unselected population with severe airflow limitation. DESIGN: Randomized, double blind, placebo-controlled trial. SETTING: University Hospital Department of Emergency Medicine (DEM). PATIENTS: Fifty patients, referred to the DEM between October 1, 1994 and March 31, 1995 with a severe, acute obstructive pulmonary event. Thirteen patients were diagnosed as having COPD; 37 patients were diagnosed as having asthma. INTERVENTION AND RESULTS: Patients received either placebo MDI through a 750-mL cone-shaped spacer (Glaxo) [2 puffs] and nebulized salbutamol aerosol 0.5 mL in 1.5 mL saline solution (group 1, n=25) or salbutamol MDI and 0.5 mL saline solution in 1.5 mL saline solution administered in the same manner as above (group 2, n=25). The above treatment was repeated three times every 15 min, unless side effects appeared. Upon enrollment into the study, the FEV1 in group 1 was 0.78+/-0.7 L (mean+/-SD), 32% of predicted, and in group 2, 0.74+/-0.51 L, 29% of predicted (p=0.83). The FEV1 values after the first, second, and third interventions were as follows: in group 1, 1.18+/-0.99 L, 1.40+/-0.8, and 1.47+/-0.79, respectively, and in group 2, 1.17+/-0.99 L, 1.46+/-1.01, and 1.54+/-0.79 (p=0.83, 0.36, and 0.48, respectively). We observed no difference in spirometric measurements between the two groups at any time. CONCLUSION: Even in the setting of the unselected group of patient referrals to the DEM for episodes of severe airflow limitation, ...

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Montelukast has recently been introduced in Sweden and many other countries. One of its main indications is protection against exercise-induced asthma.

The study by Bronsky et al. is one of the studies where the effect is clearly demonstrated compared to placebo. It also shows a dose-dependent protective effect 20-24 hours after oral intake when comparing 0.4, 2, 10 and 50 mg of montelukast.

It is surprising that the authors conclude in the discussion that the effects of 10 mg and 50 mg once daily were similar and probably maximal. This does not appear from figure 1 in the paper. For example, the mean time required for FEV₁ to return to normal after the exercise was much shorter with 50 mg than 10 mg.

Obviously, protection against exercise-induced asthma is one of the main indications for the new antileukotrienes. In future studies the effects of these new drugs should be compared with cromones and, particularly, with long-acting b ₂-agonists.

Title (7): Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval (partial abstract below from http://www.healthy.net/library/search/medline.htm )

see abstract #3

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

In an unselected population of patients attending an emergency department, 50 patients with acute obstruction were treated either with 2500 m g salbutamol given by Aeromistâ nebulizer or with 200 m g of salbutamol given by MDI plus a spacer. The study was double-blind and double-dummy. The inhalations were repeated three times as needed. No difference in effect was found between the two groups although the MDI plus a spacer provided a much lower dose of salbutamol.

The authors conclude that the spacer device is a very attractive alternative for ordinary patients who require treatment for acute obstruction. It is safer and obviously much cheaper than giving the treatment with a nebulizer.

Regarding the population of patients in the study, it should be noted that only 26% of the patients were classified as having COPD. The other patients had asthma, some in combination with COPD.

The only objection to the study is that the wet nebulization may have beneficial effect in itself. However, the use of spacer devices, even in adult patients with acute exacerbations, should be tried as a first line treatment.

Title (8): Nebulized wet aerosol treatment in emergency department -is it essential? Comparison with large spacer device for metered-dose inhaler. (partial abstract from http://www.healthy.net/library/search/medline.htm )

see absctract #6

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

It is well known that several chemical agents induce bronchoconstriction in asthmatics. Among these, SO₂ is important as it explains some of the problems asthmatics may have due to air pollution. It is known that the bronchoconstrictor effect of SO₂ may be inhibited by cromones and that it is not really affected by inhaled steroids.

In the study by Lazarus et al, the leukotriene receptor antagonist zafirlukast shows a protective effect against SO₂ induced bronchoconstriction which is significantly better than placebo two hours after oral intake. Ten hours after the drug intake, the protective effect was still seen in most of the twelve asthmatics but was completely lacking in one. However, statistically, the difference between placebo and zafirlukast treatment was no longer significant.

The study is well performed and its results can be used for discussing the role of the antileukotrienes in the future. For example, antileukotrienes may be applied as an alternative to cromones.

Title (9): The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Lazarus SC; Wong HH; Watts MJ; Boushey HA; Lavins BJ; Minkwitz MC
Address : Cardiovascular Research Institute, University of California, San Francisco, California 94143-0111, USA.
Source : Am J Respir Crit Care Med, 156(6):1725-30 1997 Dec
Abstract : Inhalation of sulfur dioxide (SO2) causes bronchoconstriction in most people with asthma. To examine the role of leukotrienes in this response, the antagonism of SO2-induced bronchoconstriction by a single oral dose of the leukotriene receptor antagonist zafirlukast was assessed in a double-blind, placebo-controlled, two-period crossover trial in 12 subjects with mild-to-moderate asthma. Subjects had bronchial hyperresponsiveness, an FEV1 < or = 70% of predicted, and a positive response to inhaled SO2 (an 8-unit increase in specific airway resistance on inhaling an SO2 concentration of < or = 4 ppm (PC8SRaw). Subjects were treated with zafirlukast (20 mg) or placebo on two treatment days 5 to 14 d apart. Two and 10 hours after treatment, subjects inhaled SO2 (0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 ppm) during eucapnic hyperventilation at 20 L/min. PC8SRaw was determined after each challenge. Blood samples were collected to assess zafirlukast plasma concentrations versus effect. PC8SRaw was significantly higher 2 h after zafirlukast compared with placebo (3.1 versus 1.5 ppm; p = 0.02) and remained higher 10 h after treatment with zafirlukast (2.7 versus 1.9 ppm; p = 0.09). An association was found between zafirlukast plasma concentrations and increases in PC8SRaw 10 h after treatment (p = 0.001). The safety profile of zafirlukast was not clinically different from placebo. A single 20-mg dose of zafirlukast attenuated SO2-induced bronchoconstriction. We conclude that S02-induced bronchoconstriction involves release of leukotrienes and that treatment with zafirlukast attenuates the bronchoconstrictor response.

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This 12 month comparison of low dose beclomethasone (BDP) versus salmeterol in children with mild to moderate asthma, found BDP to be significantly more effective than salmeterol. However the BDP reduced growth velocity by about 1 cm per year, on average.

The long-term consequences of this are not known. The only study published to date that followed BDP-treated children through to adulthood found they ultimately attained their predicted normal height¹. More such studies are needed.

Growth inhibition may be minimized by titrating the dose to the lowest level sufficient to eliminate symptoms, and by utilizing an alternative such as budesonide, which appears to have less growth inhibiting potential^2,3.

Since children vary in their susceptibility to glucocorticoid-induced growth inhibition^4,5, growth should be monitored and documented routinely, even in those children treated with low dosage.

References:

1. Balfour-Lynn L. Growth and childhood asthma. Arch Dis Child 1986;61:1039-1055.
2. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994;88:373-381.
3. Wolthers OD, Pedersen S. Growth of asthmatic children during treatment with budesonide: a double-blind trial. Br Med J 1991;303:163-165.
4. Redfearn A, O’Connor M, Holland FJ, et al. Correlates of reduced linear growth in asthmatics treated with inhaled corticosteroids. J Allergy Clin Immunol 1993;91:168. Toogood 1998:3:6
5. Thomas BC, Stanhope R, Grant DB. Impaired growth in children with asthma during treatment with conventional doses of inhaled corticosteroids. Acta Paediatr 1994;83:196-199.

Title (10): A comparison of beclomethasone, salmeterol, and placebo in children with asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

see abstract #4

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Date de création: 1er Mars 1996 -Dernière mise à jour: 17/06/99
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