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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°1   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 A patient preference study comparing Turbuhaler with Diskus, two multi-dose dry powder inhaler devices. Van Spiegel PI, Jenner F. Br J of Clin Research 1997;8:33-45 Ass. Professor Leif Rosenhall 2 Results of the first U.S. double-blind, placebo-controlled, multicenter clinical study in asthma with pranlukast, a novel leukotriene receptor antagonist Grossman J, Faiferman I, Dubb JW et al Journal of Asthma 1997;34:321-328 No. 4 Ass. Professor Leif Rosenhall 3 Nebulized salbutamol with and without ipratropium bromide in the treatment of acute asthma. Garrett JE, Town GI, Rodwell P et al. Allergy and Clin Immunol 1997;100:165-170 Ass. Professor Leif Rosenhall 4 A 1-year, placebo-controlled, double-blind house-dust-mite immunotherapy study in asthmatic adults Olsen OT et al Allergy 1997; 52:853-859 Professor Duncan Geddes 5 Effects of high dose intravenous immunoglobulin in two severe corticosteroid insensitive asthmatic patients Vrugt et al Thorax 1997;52:662 Professor Duncan Geddes 6 Results of the first U.S. double-blind, placebo-controlled, multicenter clinical study in asthma with Pranlukast, a novel leukotriene receptor antagonist Grossman J, Ffaiferman I, Dubb JW et al Journal of Asthma 1997;34:321-328 Professor Duncan Geddes 7 Is asthma treatment affordable in developing countries ? Watson JP, Lewis RA Thorax 52:605-607 Professor Philippe Godard 8 A national estimate of the economic costs of asthma Smith DH, Malone DC, Lawson KA et al Am J Respir Crit Care Med 1997;156:787-793 Professor Philippe Godard 9 Improvement of bronchial hyperresponsiveness in asthmatic children treated for concomitant sinusitis Oliveira CAA, Solé D, Naspitz CK et al Annals of Allergy, Asthma & Immunology 1997;79:70-74 Professor Philippe Godard 10 A 1-year, placebo-controlled, double-blind house-dust-mite immunotherapy study in asthmatic adults. Olsen OT, Larsen KR, Jacobsen L, Svendsen UG Allergy 1997;52:853-859 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. ...

Which is the best, Turbuhaler or Diskus?

In this study sponsored by Astra, the answer to the question which is the best inhaler is of course Turbuhaler. In a study sponsored by Glaxo Wellcome the answer will be Diskus. Why does sponsoring seem to influence the result? The explanation is that these inhalers are both excellent although they have interesting differences. Therefore, each company can put forward the advantages of their own inhaler.

In this study, asthmatics have been confronted with a Turbuhaler or a Diskus. It was found that most patients at the first contact prefer Turbuhaler. If Glaxo Wellcome would have done a similar study, they would have asked patients their preference after a period of regular use and they would have added questions indicating the importance of the dose-counter.

A study like this is more marketing than science, in about the same way that it is impossible to scientifically decide if a glass of Carlsberg is better than a Tuborg beer!

The introduction of anti-leukotrienes will be very interesting for everyone involved in asthma treatment.

This is a report from the first US-study with the Japanese drug pranlukast. The primary objective was to evaluate the side effects; none were found. However, the main problem with leukotriene antagonists has been the rise in eosinophils. Unfortunately, eosinophil levels were not reported.

Of course, also the clinical activity of pranlukast was studied and compared with placebo. All 65 patients were asthmatics with chronic obstruction (FEV₁< 80% of predicted) and without any other treatment than b ₂-agonists (p.r.n) and oral theophyllines. A treatment of this kind is remarkable because according to the international guidelines all patients should have been treated with inhaled steroids.

Patients were given pranlukast in one of two different doses, or placebo, in a double-blind manner. A small but significant rise in FEV₁ was recorded. However, two patients in the actively treated groups were taken out of the study because of an asthma attack. In contrast, none of the placebo treated patients experienced an asthma deterioration. Probably, if the patients had received inhaled steroids instead of pranlukast the number of asthma attacks would have been lower.

Title (2) : Results of the first U.S. double-blind, placebo-controlled, multicenter clinical study in asthma with pranlukast, a novel leukotriene receptor antagonist(partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Grossman J; Faiferman I; Dubb JW; Tompson DJ; Busse W; Bronsky E; Montanaro A; Southern L; Tinkelman D
Address : University of Arizona, Tucson 85719, USA.
Source : J Asthma, 34(4):321-8 1997

Abstract : Pranlukast (SB 205312; ONO-1078), a potent, orally active selective cysteinyl-leukotriene receptor antagonist (LTRA), was developed in Japan for the treatment of asthma. This article reports results of the initial U.S. clinical evaluation of pranlukast. The primary objective of this multicenter study was to evaluate the safety and tolerability of pranlukast administered at doses of 337.5 mg b.i.d. and 450 mg b.i.d. in 65 patients with mild to moderate asthma. Pranlukast, a novel LTRA, is safe and well tolerated at doses of 337.5 mg b.i.d. and 450 mg b.i.d. Pranlukast has demonstrated clinical activity in patients with asthma.

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

This study shows that addition of 0.5 mg ipratropium to 2.5 mg of salbutamol in acute asthma provides an additional bronchodilatory effect.

The additional effect by adding ipratropium to salbutamol is not very surprising because adding more bronchodilator would usually produce more effect. In fact less effect is never expected. Probably, a better bronchodilation would have been obtained by giving more salbutamol instead of adding ipratropium.

Patients who experienced the least bronchodilatory effect were also those who had had most salbutamol before coming to the emergency department and entering the study. This indicates that ipratropium does not have an effect on its own i.e., it does not further relax bronchial smooth muscle which is already maximally relaxed by salbutamol.

This study does not convince me that a fixed combination of salbutamol and ipratropium is really necessary.

Title (3): Nebulized salbutamol with and without ipratropium bromide in the treatment of acute asthma.. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Garrett JE; Town GI; Rodwell P; Kelly AM
Address : Department of Respiratory Services, Green Lane Hospital, Auckland, New Zealand.
Source : J Allergy Clin Immunol, 100(2):165-70 1997 Aug

Abstract :
BACKGROUND: Routine addition of ipratropium bromide to beta-agonist therapy in acute asthma is of uncertain benefit. OBJECTIVE: This study was carried out to evaluate: (1) whether nebulized ipratropium (0.5 mg) plus salbutamol (2.5 mg) (Combivent) confers additional bronchodilation over nebulized salbutamol (2.5 mg) alone in patients with acute asthma and (2) whether adjustment for prognostic indicators of outcome influences any benefit seen with ipratropium.
METHODS: A double-blind, two-center, randomized, single-dose study was performed in 338 patients with asthma, aged 18 to 55 years, who attended the emergency department for treatment of acute asthma. The primary end point was FEV1 at 90 minutes.
RESULTS: The mean absolute difference in FEV1 at 90 minutes for Combivent compared with salbutamol was 113 ml (SEM +/- 48 ml, p < 0.05). Independent of the study drug received, a poor response to treatment was predicted by frequent use of inhaled beta-agonist before presentation (p < 0.0001), severity of the attack (p < 0.05), and longer duration of attack (p < 0.05). Subjects who had taken more than 10 puffs of inhaled beta-agonist through a metered-dose inhaler or who had serum salbutamol levels of greater than 2 mmol/L on presentation demonstrated no benefit from the addition of ipratropium....

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

This study shows that immunotherapy can produce changes in immune reactivity and clinical parameters in selected patients within the setting of a well-supervised controlled trial.

The trial was a well designed and diligently executed study of immunotherapy in 31 asthmatic adults. There was a three-way randomization to placebo, D. pteronyssinus or D. farinae injections. After 1 year the code was revealed with regard to whether the patient received an active or placebo treatment (but not to which active treatment). Of the 23 patients completing the study there was a reduction in asthma medicine consumption and symptom score in the actively treated group, in association with decrease in skin and bronchial sensitivity to house dust mite. There were minimal improvements in FEV₁ in the actively treated group but no changes in home peak flow measurements.

There are three difficulties in extending the results of the study to routine practice. First, there was a high drop out in the placebo group (40%) which raises questions about the validity of the statistical comparisons. Second, patients were selected for mild asthma (normal lung function) together with house dust mite sensitivity but those with continued exposure to other allergens to which they were sensitive were excluded. In routine practice patients are usually continuously exposed to these allergens. Third, the study protocol required a reduction in maintenance treatment during the trial.

Highly selected patients may benefit from immunotherapy. However, it is far from clear what proportion of asthmatic patients may benefit and whether this approach has advantages over conventional inhaled anti-inflammatory treatment.

Two patients whose asthma was poorly controlled in spite of maximum systemic and inhaled corticosteroids, were treated with intravenous immunoglobulin. Both patients improved. The improvements were documented in terms of lung function, peak flow variability and reduction in prednisolone dose. In one patient there was bronchoscopic biopsy data available obtained before and after treatment, showing a decrease in T lymphocytes associated with a reduction in peripheral blood T cell activation.

The positive effects of immunoglobulin treatment in these two cases add further interesting data to the previous open-label study of high dose intravenous immunoglobulin in severe childhood asthma¹. Also in this study immunoglobulin treatment was found to be beneficial.

However, while there is no doubt that both patients in the case report improved during the course of treatment there is no way of judging whether the treatment was responsible. A number of other patients have been treated by immunoglobulin without success. Inevitably, such events are not reported and so biased evidence in favour of an effect accumulates in the literature.

Before advocating intravenous immunoglobulin treatment (or not) a properly conducted clinical trial should be carried out.

Reference:

¹Mazer BD, Gelfand EW. An open-label study of high-dose intravenous immunoglobulin in severe childhood asthma. J Allergy Clin Immunol 1991;87:967-983.

Title (5): Effects of high dose intravenous immunoglobulin in two severe corticosteroid insensitive asthmatic patients. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Vrugt B; Wilson S; van Velzen E; Bron A; Shute JK; Holgate ST; Djukanovic R; Aalbers R
Address : Pathology Department, University Hospital, Utrecht, The Netherlands.
Source : Thorax, 52(7):662-4 1997 Jul

Abstract : Preliminary observations of the clinical efficacy of intravenous immunoglobulin in two patients with severe corticosteroid insensitive asthma are reported. In both patients treatment with intravenous immunoglobulin resulted in clinical improvement and enabled a significant reduction in the dose of prednisolone. In one of the patients fibreoptic bronchoscopy with endobronchial biopsies was performed and peripheral blood was analysed by flow cytometry before and after treatment. Immunohistological analysis of the biopsy samples after treatment showed a decrease in the number of all cell types, especially CD3+ T cells, CD4+ T cells, and activated CD25+ T lymphocytes, which was associated with a reduction in peripheral blood T cell activation. Intravenous immunoglobulin may be a valid option for the treatment of corticosteroid insensitive asthma. To elucidate the role and mode of action of intravenous immunoglobulin further studies in larger groups of patients are needed.

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

This is a small study involving 65 patients with mild to moderate asthma who received two doses of pranlukast or placebo. Although the primary objective was to evaluate safety and tolerability, clinical activity is also claimed.

Patients randomised to 337.5 mgs b.i.d. or 450 mgs b.i.d. showed no greater frequency of adverse effects than those randomised to placebo. At these doses the drug appears to be safe and well tolerated over the study period of four weeks.

Although efficacy was not the main aim of the study, adequate assessments were performed which are claimed to show an improvement in FEV₁ in both active groups as compared with placebo, with no difference between the two dose levels. Symptom scores and bronchodilator usage showed no difference between placebo and the low dose but there were suggestions of improvement with the higher dose.

Interestingly, the paper did not mention statistical significance on any occasion. This does not reflect well on the peer review process and should not allow in the abstract the conclusion of clinical activity/efficacy.

The authors Watson and Lewis conducted a survey in developing countries asking how asthma was treated. Although the response rate was only 25% the replies represent 14,000 asthmatic patients.

Key issues in the paper are: the frequent use of oral administration, the minor use of inhaled steroids and lack of money for drugs. This could have been expected beforehand, but the results are nevertheless interesting. Moreover, the results suggest that treatments have not changed much in the last 20 years.

The question is: how to improve the current inappropriate asthma treatment in developing countries? The authors ask the pharmaceutical industry to provide effective inhaled medication at prices which are realistically affordable. This is a valid request but out with our control. Moreover, even if this could be possible (as an hypothesis), the main subsequent problem will be compliance and education.

Administration of drugs by inhalation is an important advance. However, it is not clear if this is really practical in developing countries. Therefore, other strategies should be validated, for example theophylline treatment or low dosing of oral steroids.

Lessons learned from the struggle against tuberculosis should be remembered. Help should be sought from organizations with experience of implementing health strategies in developing countries such as International Union Against Tuberculosis and Lung Disease (IUATLD http://iuatld.vjf.inserm.fr/ ). This will be done during the World Asthma Meeting in Barcelona , December 1998 ( http://www.asmanet.com/congress.html#Barcelone98 ).

In Ethiopia, the prevalence of asthma appears to be low in the country side and higher in towns. This suggests a role for pollution. Consequently, an effort should be made at the level of prevention rather than treatment. Moreover, education is an important issue which should begin at the government

Title (7): Is asthma treatment affordable in developing countries ?. (partial abstract below from http://www.healthy.net/library/search/medline.htm )

Author : Watson JP; Lewis RA
Address : Department of Thoracic Medicine, Killingbeck Hospital, Leeds, UK.
Source : Thorax, 52(7):605-7 1997 Jul

Abstract :
BACKGROUND: A study was undertaken to assess whether the therapeutic aspects of published international asthma management guidelines are practically applicable in developing countries. METHODS: Questionnaires were sent to expatriate doctors working in developing countries.
RESULTS: Forty one replies were received from 24 countries in Africa and Asia. Oral salbutamol was prescribed "usually" or "often" by 35 of the 41 respondents, theophyllines by 30, inhaled bronchodilators by 12, inhaled steroids by two, and cromoglycate by two. Theophyllines were locally available in all 41 cases, oral salbutamol in 40, inhaled bronchodilators in 34, and inhaled steroids (usually beclomethasone 50 micrograms) in only 15. Where they were available, the median (range) coat of a beclomethasone 50 micrograms inhaler was 20% (6.8-100%) of average local monthly income, salbutamol inhaler 13% (3.3-250%), 90 salbutamol 4 mg tablets 3.8% (0.8-75%), and 90 aminophylline 100 mg tablets 4.5% (0.5-70%). If they were available locally at a cheaper price, 34 (83%) respondents would prescribe more inhaled steroids and 37 (90%) would prescribe more inhaled bronchodilators...

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

The economic burden of asthma has been the subject of many papers. This paper describes a cost of illness analysis using a single data source, the 1987 National Medical Expenditure Survey (NMES), consisting of approximately 35 000 subjects representative of the noninstitutionalised, civilian U.S. population.

From the data it could be calculated that for the whole U.S. population in 1987:

• an estimate of 4.7 million people sought care or incurred indirect costs for asthma
• approximately 30.5 million prescriptions were filled for asthma (average: 6.5 prescription/person/year)
• only 6.2% of all prescriptions accounted for inhaled steroids

Although all separate results are interesting, the two main results which the authors point out are that hospitalizations for asthma cost a lot and that 20% of the asthmatics account for 80% of the expenditure ("high-cost patients").

Also the discussion section of the paper is interesting. The authors compared their results with a similar study reported by Weiss¹. This study was based on multiple data sources, charges instead of costs and it simplified assumptions regarding medication use. It appeared that the direct costs (the sum of the costs of ambulatory visits, hospitalization and prescribed medicines) estimated in the two studies were similar. However, there was an important difference regarding indirect costs (the sum of the costs due to loss of housekeeping, work, or school, restricted activity, bed days (age 0-4) and mortality). From the NMES the total indirect costs were estimated to be $ 674 million versus more than $ 2.9 billion in the study by Weiss et al.. The authors conclude that the indirect costs of asthma may be substantially lower than previously thought.

Costs of asthma analyses similar to this study by Smith et al. should be done in other countries, for example those in Europe.

In other countries treatments will be different, especially treatment with inhaled steroids. It will be interesting to compare the results of different countries. This may provide understanding of how steroids are able to save money and at the same time improve quality of life.

Reference:

Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. N Eng J Med 1992;326:862-866.

This paper from São Paulo, Brazil, shows that it is difficult to clearly understand the nose and sinuses.

The authors conclude that treatment of sinusitis improves bronchial hyperresponsiveness among children with severe asthma and sinusitis. Their conclusions are based on the results of an open study of 20 non-atopic normal children, and 46 atopic children with rhinitis. Of the atopic children, 18 had allergic rhinitis (12 without sinusitis, 6 with sinusitis) while 28 had both rhinitis and asthma (13 without sinusitis, 15 with sinusitis). The group of atopic children with sinusitis (complete opacification of maxillary sinus by CT) received intranasal saline, prednisone (5 days), antibiotics (21 days) and antihistamine/decongestant (21 days) during a study period of 30 days. Of the 15 children with rhinitis and asthma and a complete opacification of maxillary sinus, 7 children still had opacification at the end of treatment while 8 children returned to normal at the end of treatment. These 8 children who experienced resolution of their sinusitis after treatment, also showed significant increases in PC₂₀.

In attempting to apply these results to clinical practice, two difficulties will often be encountered: diagnosing sinusitis and determining bacterial infection.

The diagnosis of sinusitis is difficult because no golden standard exists. Although 4 coronal computed tomography might be useful, this method is not easily performed even in developed countries. Moreover, the safety of this method in children, especially if performed on a regular basis as a means of follow-up, has not been properly documented.

Bacterial infection is not easy to assess either. It is especially difficult to determine if antibiotics are really necessary. Air fluid level seems to be a good indicator of bacterial infection, and the presence of purulent nasal secretion may also be useful.

Long-term follow-up of asthmatic patients with data from the nose, sinuses and bronchi is an exciting prospect for the future. Such information may reveal the real interrelationship between these three organs and provide a better understanding of how to treat these related conditions.

Title (9): Improvement of bronchial hyperresponsiveness in asthmatic children treated for concomitant sinusitis. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Oliveira CA; Solé D; Naspitz CK; Rachelefsky GS
Address : Department of Pediatrics, Federal University of São Paulo Escola Paulista de Medicina, Brazil.
Source : Ann Allergy Asthma Immunol, 79(1):70-4 1997 Jul

Abstract :
BACKGROUND: There appears to be an association between sinusitis and asthma. The effect on bronchial hyperresponsiveness of clinical therapy for sinusitis in children may help to decipher whether sinusitis and asthma are independent manifestations of the same disease. OBJECTIVE: To evaluate the effect of clinical treatment for sinusitis in patients with rhinitis and/or asthma on symptoms and on bronchial hyperresponsiveness to methacholine.
METHODS: Open label, randomized, non-treatment control in a teaching hospital in São Paulo, Brazil. Forty-six atopic and 20 normal children were studied. The atopic children consisted of 18 with allergic rhinitis (12 without sinusitis and 6 with sinusitis), and 28 children with rhinitis with asthma (13 with normal sinus radiographs and 15 with complete opacification of the maxillary sinuses). Methacholine PC20 was determined before and 30 days after treatment with nasal saline, sulfamethoxazole-trimethoprim, antihistamine/decongestant, and five days of prednisone. Sinus radiographs were also repeated.
RESULTS: The only patients with increase in methacholine PC20 were patients with rhinitis and asthma with opacified maxillary sinuses at entry and who at 30 days had normal sinus radiographs (P < .05)....

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

This careful study of house dust-mite immunotherapy for asthma documented a statistically significant antiasthmatic response which included a reduction in patient requirements for inhaled corticosteroid (ICS) averaging about 300 m g/day.

Previous trials of allergen immunotherapy observed significant reductions in asthma medication requirements but did not quantify the changes in steroidal and non-steroidal drugs separately^1,2.

The magnitude of the observed ICS-sparing effect in this trial was similar to that attained in some trials of nedocromil^3,4 , and it appears substantially less than that potentially attainable with adjunct theophylline therapy⁵ .

The investigators applied immunotherapy to carefully selected patients with mild to moderate asthma. In general, cost/benefit, convenience, and disease severity considerations limit the applicability of allergen immunotherapy.

References:

1. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials. Am J Respir Crit Care Med 1995;151:969-974.
2. Creticos PS, Reed CE, Norman PS, et al. Ragweed immunotherapy in adult asthma. N Engl J Med 1996;334:501-506.
3. Bone MF, Kubik MM, Keaney NP, Summers GD, Connolly CK, Burge PS, Dent RG, Allan GW. Nedocromil sodium in adults with asthma dependent on inhaled corticosteroids; a double-blind, placebo-controlled study. Thorax 1989;44:654-659.
4. Brogden RN, Sorkin EM. Nedocromil sodium: an uppdated review of the pharmacological properties and therapeutic efficacy in asthma. Drugs 1993;45:693- 715.
5. Evans DJ, Taylor DA, Zetterström O, Chung F, O’Connor BJ, Barnes PJ. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma.

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Date de création: 1er Mars 1998 -Dernière mise à jour: 17/06/99
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