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previous  next Provided by/avec le support de :     Box 34        S-221 00 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°5   1997 (see N° 3 1997 N° 4 1997 also ) 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 Inhibition of allergen-induced airway obstruction and leukotriene generation in atopic asthmatic subjects by the leukotriene biosynthesis inhibitor BAYx1005   Dahlén B, Kumlin M, Ihre E, et al Thorax 1997 Professor Philippe Godard 2 Effect of long term treatment with salmeterol on asthma control: a double blind, randomised crossover study. Wilding P, Clark M, Coon J.T, et al Br Med J 1997 Professor Philippe Godard 3 The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. Rosenstreich D.L., Eggleston P., Kattan M.,et al. N Engl J Med 1997 Professor Philippe Godard 4 Adult patients may outgrow their asthma. A 25 year follow-up study Panhuysen C.I.M., Vonk J.M., Koëter G.H. et al. Am J Respir Crit Care Med 1997 Professor Duncan Geddes 5 The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. Rosenstreich D.L., Eggleston P., Kattan M.,et al. N Engl J Med 1997 Professor Duncan Geddes 6 Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid   Tamaoki J., Kondo M., Sakai N. et al. Am J Respir Crit Care Med 1997 Professor Duncan Geddes 7 Suppression of the immune system by oral glucocorticoid therapy in bronchial asthma Oehling AG, Akdis CA, Schapowal A et al. Allergy 1997 Professor John H. Toogood 8 Adult patients may outgrow their asthma. A 25 year follow-up study Panhuysen C., Vonk J., Koëter G., Schouten J. et al. Am J Respir Crit Care Med 1997 Professor John H. Toogood 9 Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid Tamaoki J., Kondo M., Sakai N., Nakata J. et al. Am J Respir Crit Care Med 1997 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. ...

The so-called leukotriene modifiers comprise three different types of drugs: receptor antagonists, inhibitors of synthesis at the level of 5-lipoxygenase and inhibitors of synthesis at the level of 5-lipoxygenase activating protein (FLAP). This protein was discovered in 1990, and the drugs which act as antagonists at this protein appear to be promising.

This paper reports the results of a pharmacological study demonstrating a protective effect of BAYx1005 in allergen induced airway obstruction.

I have the following comments on the paper:

It would have been interesting to know if the asthmatic patients experienced shortness of breath and wheezing during placebo treatment and if these symptoms were absent after BAYx1005. The observed 70% inhibition of the fall in FEV1 with BAYX1005 is obviously interesing but clinical correlations are always useful.

A dose effect or a time dependent effect has not been evaluated. This should be done and will provide additional valuable information.

Late asthmatic response has not been studied. The authors underline the fact that the main point was the effect of BAYx1005 on urine LTE4. The net increase in urinary LTE4 inhibited by 76% which is identical to the inhibition of the airway response. This is very interesting.

In conclusion, this new compound appears very promising; but additional data are required. Hopefully, there will be a succesful drug at the end of the experimental process.

Title (1): Inhibition of allergen-induced airway obstruction and leukotriene generation in atopic asthmatic subjects by the leukotriene biosynthesis inhibitor BAYx1005 (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Dahlén B; Kumlin M; Ihre E; Zetterström O; Dahlén SE
Address : Department of Internal Medicine at Karolinska Hospital, Stockholm, Sweden.
Source : Thorax, 52(4):342-7 1997 Apr

Abstract
BACKGROUND: Leukotriene receptor antagonists significantly blunt allergen-induced bronchoconstriction in asthmatic subjects. Inhibitors of leukotriene synthesis should theoretically provide similar protection, but conflicting results have been obtained when synthesis inhibitors have been tested in allergen challenge. BAYx 1005, a new inhibitor of leukotriene synthesis, was therefore evaluated in an allergen bronchoprovocation study. METHODS: Ten men with mild allergic asthma and bronchial hyperresponsiveness to histamine were recruited. On two different occasions each subject inhaled a single dose of allergen, previously determined to cause at least a 20% fall in forced expiratory volume in one second (FEV1) four hours after ingestion of 750 mg BAYx 1005 or placebo in a double blind crossover design. Urinary excretion of leukotriene E4 was measured before and during the challenges.

RESULTS: The mean (SE) maximal fall in FEV1 was 7.1 (1.7)% after BAYx 1005 and 21.0 (3.0)% afterplacebo (p < 0.001). The mean difference between treatments was 13.9 (95% CI 7.0 to 20.8) for the maximalfall in FEV1. ....

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

This paper can be read from at least two points of view: pharmacology and clinical practice. In addition to showing that salmeterol is an effective long acting ß2 -agonist, the study design allows the authors to demonstrate several interesting aspects.

- efficacy on a long term basis.
- with no tachyphylaxis.
- and no desensitisation of ß2 receptors.

However the 17% reduction of inhaled corticosteroid (ICS) use appears to be small. The authors explain that this result should not be interpreted as a steroid sparing effect of salmeterol. Indeed the study design does not allow this conclusion to be drawn.

In their conclusion, the authors state "the design of this study is relevant to how salmeterol is likely to be used in clinical practice" However I don´t understand the relevance of reducing low doses of ICS ( the authors indicate that higher doses are reduced by a lesser extent) in the long term treatment of asthmatics.

If we recommended such a strategy, several patients could be treated - ultimately with only a - long acting ß2 -agonist without ICS. On the other hand if salmeterol were to be reduced, step by step ( instead of ICS) in relation to the control of asthma, asthmatics could be treated only by one drug; this is better for them.

This paper is really very interesting. From a pharmacological point of view, it is well designed and the description of the various end points is excellent. The results indicate clearly that salmeterol is an exellent treatment. From a clinical point of view, management of exacerbation at home was excellent and this is the main message for the use of the drug in clinical practice.

However - in cauda venenum! - I don´t agree with the suggested strategy of progressively reducing low dose ICS, whilst keeping the long acting ß2-agonist constant.

Title (2) : Effect of long term treatment with salmeterol on asthma control: a double blind, randomised crossover study. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Wilding P; Clark M; Coon JT; Lewis S; Rushton L; Bennett J; Oborne J; Cooper S; Tattersfield AE
Address : Division of Respiratory Medicine, City Hospital, Nottingham.
Source : BMJ, 314(7092):1441-6 1997 May 17

Abstract
OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months tocurrent treatment in subjects with asthma who control their inhaled corticosteroid dose according to amanagement plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham.

SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily ofbeclomethasone dipropionate or budesonide.

INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids.

RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a .......

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This paper is really excellent and very exiting. The authors have to be congratulated on this prospective study conducted over a one year period of time. The results are interesting from several point of views.

• - The prospective assessment of true exacerbations. In fact a gradation of the exacerbations has been used (from instability, unscheduled visit, unexpected treatment to hospitalisation) and de facto validated. This step-wise approach of categorising exacerbation should be used in clinical practice in order to assess correctly the control of asthma.
• - Prospective evalution of PEFR was not useful. This is an unexpected result but which should be emphazised. Consider how many studies are based only on PEFR variablility or improvement!
• - The diagnosis of allergy in asthma is very difficult. We proposed a stepwise approach for tackling this problem (see reference): first of all, atopy is diagnosed by the skin prick tests (at least one or two positives are required); secondly, according the positive skin prick test, the patient has to be questionned to evaluate the relationship between exposure to allergen and symptoms; in fact - in daily clinical practice - the best method is to observe an improvement of asthma symptoms in conjunction with avoidance of allergens (but this is very difficult to obtain). This study demonstrates that evaluation of allergen at home is absolutely necessary.
• - The diagnosis of mite induced asthma is not as easy to make as one might expect. It can be hypothetized that if these children had been desensitized the results should have been negative.
• - Cat allergen appears to be less frequent, in this, as compared to other studies. Once again, the home has to be inspected carefully by a professional person in order to check indoor pollution.

Reference:

Godard Ph. et coll. Abrégé d´asthmologie. Masson ed Paris 1996.

Title (3): The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Rosenstreich DL; Eggleston P; Kattan M; Baker D; Slavin RG; Gergen P; Mitchell H; McNiff-Mortimer K; Lynn H; Ownby D; Malveaux F
Address : Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Source : N Engl J Med, 336(19):1356-63 1997 May 8

Abstract
BACKGROUND: It has been hypothesized that asthma-related health problems are most severe among children in inner-city areas who are allergic to a specific allergen and also exposed to high levels of that allergen in bedroom dust. METHODS: From November 1992 through October 1993, we recruited 476 children with asthma (age, four to nine years) from eight inner-city areas in the United States. Immediate hypersensitivity to cockroach, house-dust-mite, and cat allergens was measured by skin testing. We then measured major allergens of cockroach (Bla g 1), dust mites (Der p 1 and Der f 1), and cat dander (Fel d 1) in household dust using monoclonal-antibody-based enzyme-linked immunosorbent assays. High levels of exposure were defined according to proposed thresholds for causing disease. Data on morbidity due to asthma were collected at base line and over a one-year period.

RESULTS: Of the children, 36.8 percent were allergic to cockroach allergen, 34.9 percent to dust-mite allergen, and 22.7 percent to cat allergen. Among the children's bedrooms, ...

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

There are relatively few good longitudinal studies of asthma and so it is difficult to give good advice about long term prognosis. Up to 50% of children may "grow out of" their asthma but the evidence is incomplete and follow-up has never been sustained for very long. This study provides reliable data after 25 years of follow-up in a well characterised group of adults (median age 24 years) with asthma. The main findings were that nearly half the subjects had no persistent pulmonary symptoms and about a quarter had no evidence of asthma whatsoever (normal FEV1, normal bronchial hyperresponsiveness). Three factors were associated with disapperance of asthma: young age, good lung function, and early treatment.

This study supports the use of early treatment and suggests a good prognosis for many young asthmatics with mild disease. Interestingly, even among those with peristent asthma and bronchial hyperresponsiveness, the FEV1 was better after 25 years than it had been at the beginning, suggesting that progressive airflow obstruction is only seldom a problem.

Title (4): Adult patients may outgrow their asthma A 25 year follow-up study. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Panhuysen CI; Vonk JM; Koëter GH; Schouten JP; van Altena R; Bleecker ER; Postma DS
Address : University of Maryland, Baltimore, USA.
Source : Am J Respir Crit Care Med, 155(4):1267-72 1997 Apr

Abstract
The present study investigated the outcome of asthma in a population of 181 adult patients 13 to 44 yr of age (median, 24 yr) who were extensively tested between 1962 and 1970 and in whom asthma was diagnosed. When retested 25 yr later, 38 subjects (21%) did not show bronchial hyperresponsiveness (BHR)(PC20 > 16 mg/ml), 45 subjects (25%) showed a FEV1 > 90% predicted, and 72 subjects (40%) did not report pulmonary symptoms. When absence of asthma was defined as no BHR, FEV1 > 90% predicted, and the absence of pulmonary symptoms reported by the patient, 20 subjects (11%) were no longer considered asthmatic when retested. Absence of asthma after 25 yr was associated with a younger age and less severe airway obstruction at first testing, odds ratios (OR) being 0.36 for age/10 yr, and 1.42 for FEV1/height2 (dl/m2). ...

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This study examined immediate hypersensitivity reaction and allergen exposure to cockroach, dust mite and cat in 476 children with asthma. The children came from eight different inner-city areas in the USA. Positive skin tests were found to cockroach in 37%, house dust mite in 35 % and cat in 23%. Surprisingly half the bedrooms had high levels of cockroach allergen while only approximately 10% had high levels of dust mite or cat allergen. Asthma morbidity was predominantly linked to the combination of allergy and exposure to cockroach.

This study is surprising in showing cockroach to be the dominant allergen for inner-city children and finding dust mite to be relatively unimportant. While this finding clearly cannot be generalised to all communities, the study is valuable in drawing attention to another major allergen and suggests strategies for environmental control of asthma in inner-cities.

Title (5): The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. (partial abstract from http://www.healthy.net/library/search/medline.htm )

see above (Title (3))

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

This study compared the effect of pranlukast with placebo in 79 patients with asthma whose inhaled corticosteroid dose was halved from 1.5 mg/day over a period of six weeks. The pranlukast group tolerated the reduction with no change in subjective or objective measures of asthma. In contrast the placebo group showed a reduction in peak flow and FEV1 with an increase in asthma symptoms and beta agonist use together with an increase in eosinophil cationic protein and exhaled nitric oxide.

If these results are true and can be confirmed in other studies they show a striking steroid-sparing benefit from pranlukast which would be clinically valuable. Perhaps the most surprising finding however was the way in which the placebo group promptly deteriorated when the inhaled steroid dose was reduced when most large studies have shown little change under these circumstanses.

Title (6): Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Tamaoki J; Kondo M; Sakai N; Nakata J; Takemura H; Nagai A; Takizawa T; Konno K
Address : First Department of Medicine, Tokyo Women's Medical College, Japan.
Source : Am J Respir Crit Care Med, 155(4):1235-40 1997 Apr

Abstract
To test whether the leukotriene antagonist ONO-1078 (pranlukast) prevents asthma exacerbations during reduction of high-dose inhaled corticosteroid, we conducted a randomized, double-blind, placebo-controlled study in 79 asthma patients requiring high doses (1,500 microg/d or more) of inhaled beclomethasone dipropionate (BDI) for clinical control (duration of asthma, 11.0 +/- 3.1 yr; duration of BDI treatment, 0.5 +/- 0.3 yr; FEV1 percentage of predicted, 80.7 +/- 2.0%). After a 2-wk run-in period, the doses of BDI were halved, while the patients were assigned to receive orally ONO-1078, 450 mg twice daily, or placebo. In the placebo group FEV1 decreased by 0.33 +/- 0.20 L after 6 wk (p < 0.001). Likewise, morning and evening PEF decreased by 46 +/- 7 L/min and 18 +/- 6 L/min, respectively. .....

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In contrast to the humoral immunosuppressive effects of oral or systemic steroid therapy demonstrated in these, and other 1,2 asthmatic patients, and in healthy test subjects 3 short-term treatment with doses of inhaled budesonide as high as 2.4 mg/day does not suppress humoral immunity4,5.

Nor is there evidence of any increase in the incidence, severity or duration of seasonally prevalent viral or bacterial respiratory infections in patients receiving beclomethasone 6,7,8.

However, local suppression of cell-mediated immunity may trigger locally invasive fungal infection in asthmatic patients who have epithelialized cavities, cysts or bronchiectatic segments that may harbour a mycetoma9.

References:

1. Posey WC, Nelson HS, Branch B, Pearlman DS. The effects of acute corticosteroid therapy for asthma on serum immunoglobulin levels. J. Allergy Clin Immunol 1978; 62: 340-8

2. Settipane GA, Pudupakkam PK, McGowan JH. Corticosteroid effect on immunoglobulins. J. Allergy Clin Immunol 1978; 62: 162-6.

3. Butler WT, Rossen PD. Effects of corticosteroids on immunity in man. I. Decreased serum IgG concentration caused by 3 or 5 days of high doses of methylprednisolone. J Clin Invest 1973; 52: 2629-40

4. Van Schoor J, Toogood JH, Pauwels RA. Short courses of high-dose inhaled budesonide and serum lgG subclass levels in healthy volunteers. Clin Exp Allergy 1997; 27: 113-118.

5.Van Schoor J, Toogood JH, Pauwels RA. Differential effects of inhaled budesonide and oral prednisolone on serum immunoglobulin G and its subclasses in healthy adult volunteers. Clin Exp Allergy 1997; 27: 113-118.

6. Tarlo S, Broder I, Spence L. A prospective study of respiratory infection in adult asthmatics and their normal spouses. Clin Allergy 1979; 9: 293-301.

7. Toogood JH, Jennings B, Greenway RW, Chuang L. Candidasis and dysphonia complicating beclomethasone treatment of asthma. J Allergy Clin Immunol 1980; 65: 145-53.

8.Frank A, Dash CH. Inhaled beclomethasone dipropionate in acute infections of the respiratory tract. Respiration 1985; 48: 122-6

9. Toogood JH. Complications of topical steroid theraphy for asthma. Am Rev Respir Dis 1990; 141: 89-96.

Title (7): Suppression of the immune system by oral glucocorticoid therapy in bronchial asthma. (partial abstract below from http://www.healthy.net/library/search/medline.htm )

Author : Oehling AG; Akdis CA; Schapowal A; Blaser K; Schmitz M; Simon HU
Address : Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
Source : Allergy, 52(2):144-54 1997 Feb

Abstract
The effect of systemic glucocorticoid therapy on immune parameters was studied in patients with bronchial asthma. Patients were divided into two groups: 1) those receiving oral glucocorticoid; 2) control patients who did not receive systemic glucocorticoid treatment. The glucocorticoid dose varied between 5 and 70 mg per day. Patients had been taking oral therapy for at least 1 year. Glucocorticoid treatment was associated with an increased frequency of respiratory tract infections. Therefore, we need to define immune parameters which may predict an increased risk of infections. In this study, we analyzed several surface markers on lymphocytes and monocytes by flow cytometry. A significant reduction of the ratio of peripheral blood CD4+ to CD8+ T cells was associated with the administration of oral glucocorticoids. Furthermore, the expression of the HLA-DR molecule on monocytes was reduced in patients with systemic glucocorticoid therapy compared to control patients. Moreover, the capacity to elaborate cytokines by peripheral blood mononuclear cells upon stimulation was greatly reduced after exposure to glucocorticoids in vivo and in vitro. In addition, the humoral immune response was affected, because reduced IgG, IgM, and IgA levels were observed in patients receiving oral glucocorticoids.....

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

There are relatively few good longitudinal studies in asthma and so it is difficult to give good advice about long term prognosis. Up to 50% of children may "grow out of" their asthma but the evidence is incomplete and follow-up has never been sustained for very long. This study provides reliable data after 25 years of follow-up in a well characterised group of adults (median age 24 years) with asthma. The main findings were that nearly half the subjects had no persistent pulmonary symptoms and about a quarter had no evidence of asthma what-so-ever (normal FEV? normal bronchial hyperresponsiveness). Three factors were associated with disapperance of asthma: young age, good lung function, and early treatment.

This study supports the use of early treatment and suggests a good prognosis for many young asthmatics with mild disease. Interestingly, even among those with persistent asthma and bronchial hyperresponsiveness the FEV? was better after 25 years than it had been at the beginning suggesting that progressive airflow obstruction is only seldom a problem.

Title (8): Adult patients may outgrow their asthma. A 25 year follow-up study. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Panhuysen CI; Vonk JM; Koëter GH; Schouten JP; van Altena R; Bleecker ER; Postma DS

same as above Title 4

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

This study compared the effect of pranlukast with placebo in 79 patients with asthma whose inhaled corticosteroid dose was halved from 1.5 mg/day over a period of six weeks. The pranlukast group tolerated the reduction with no change in subjective or objective measures of asthma. In contrast the placebo group showed reduction in peak flow and FEV? with increase in asthma symptoms and beta agonist use, together with an increase in eosinophil cationic protein and exhaled nitric oxide.

If these results are true and can be confirmed in other studies they show a striking steroid-sparing benefit from pranlukast which would be clinically valuable. Perhaps the most surprising finding however was the way in which the placebo group promptly deteriorated when the inhaled steroids were reduced when most large studies have shown little change under these circumstances.

Title (9): Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Tamaoki J; Kondo M; Sakai N; Nakata J; Takemura H; Nagai A; Takizawa T; Konno K

same as above Title 6

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

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