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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   1999 (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 Low-dose formoterol Turbuhaler® (Oxis®) b.i.d., a 3-month placebo-controlled comparison with terbutaline (q.i.d.) Ekstrom T et al Respir Med 1998 Aug;92(8):1040-5 Dr. Lars Larsson 2 Salmeterol prevents aspirin-induced attacks of asthma and interferes with eicosanoid metabolism. Szczeklik A et al Am J Respir Crit Care Med 1998 Oct;158(4):1168-72 Prof. Philippe Godard 3 Tolerability to high doses of formoterol and terbutaline via Turbuhaler® for 3 days in stable asthmatic patients Totterman KJ Eur Respir J 1998 Sep;12(3):573-9 Ass. Prof. Leif Rosenhall Dr. Lars Larsson 4 Fluticasone propionate 750 µg/day versus beclomethasone dipropionate 1500 µg/day: comparison of efficacy and adrenal function in paediatric asthma Fitzgerald D et al. Thorax 1998 Aug;53(8):656-61 Dr. Lars Larsson 5 Association of inhaled corticosteroid use with cataract extraction in elderly patients Garbe E et al JAMA 1998 Aug 12;280(6):539-43 Prof. Philippe Godard Ass Prof. Leif Rosenhall 6 Effect of theophylline withdrawal on airway inflammation in asthma Minoguchi K et al Clin Exp Allergy 1998 Aug;28 Suppl 3:57-63 Ass. Professor Leif Rosenhall 7 Neuropharmacologic treatment of bronchial asthma with the antidepressant tianeptine: a double-blind, crossover placebo-controlled study. Lechin F et al Clin Pharmacol Ther 1998 Aug;64(2):223-32 Prof Duncan Geddes Prof Philippe Godard 8 Clinical benefits and cost reduction associated with a comprehensive asthma management programme at a managed care organisation Groban MD et al Dis Manage Health Outcomes 1998, Aug:4 (2) 93-100 Ass. Professor Leif Rosenhall 9 Long term trends in quality of life from the FACET study. Juniper EF et al Am J Respir Crit Care Med 1998, 157, A400. Poster presented at the ATS 98, Chicago Professor Duncan Geddes 10 A 15-year follow-up study of ventilatory function in adults with asthma Lange P et al N Engl J Med 1998 Oct 22;339(17):1194-200 Professor Duncan Geddes Prof. Philippe Godard 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 ) or through http://www.ncbi.nlm.nih.gov/ ...

Some years ago, it was intensively debated whether regular use of b ₂-agonist places asthma patients at risk by decreasing asthma control and reducing the effect of rescue treatment in acute situations.

This study adds to the evidence that such is not the case - at least not with regular use of formoterol. Even a low dose of formoterol was in this study shown to increase morning PEF, demonstrating clinically relevant effects even at the lower end of the dosing interval. This effect was maintained throughout the 12 weeks treatment, indicating that no clinically relevant tolerance developed.

Moreover, the FEV1 in response to a high dose of terbutaline was similar both before and after 12 weeks regular treatment with formoterol. This may appear to contradict the findings of a number of studies which claim that tolerance or tachyphylaxis to the bronchodilating effects of b ₂-agonists occurs. In my opinion there is, however, no contradiction. There may very well be a rightward shift of the dose response curve to terbutaline after 12 weeks treatment, and the ?FEV1 is in fact somewhat smaller due to a higher baseline, both findings indicating a tolerance. What this study shows is, that if this is the case, it is of no clinical relevance as it is overcome by a slightly larger dose of inhaled terbutaline and has no effect on the resulting lung function.

Title (1): . Low-dose formoterol Turbuhaler® (Oxis®) b.i.d., a 3-month placebo-controlled comparison with terbutaline (q.i.d.)(partial abstract from http://www.healthy.net/library/search/medline.htm )

Respir Med 1998 Aug;92(8):1040-5
Ekstrom T, Ringdal N, Sobradillo V, Runnerstrom E, Soliman S
Department of Respiratory Disease, University Hospital, Linkoping, Sweden.

This study compared the efficacy of a low dose of formoterol Turbuhaler 6 micrograms b.i.d. (F) with that of terbutaline 0.5 mg q.i.d. (T), and placebo (P) from Turbuhaler. After a 2-week run-in, 397 adults with mild to moderate asthma were randomly allocated to one of the treatments for 12 weeks. During run-in, the mean morning peak expiratory flow (PEF) was 360 (F), 368 (T) and 367 1 min-1 (P). F was better than T (P = 0.014) and P (P = 0.0001) in improving morning PEF [mean changes from run-in: 20 (F), 9 (T), and 21 min-1 (P)]. F was statistically significantly more effective than either T or P in reducing asthma symptoms. F gave also statistically significantly higher evening PEF and less use of rescue medication than P. Bronchodilator response to study drugs and additional 1.25 mg terbutaline was similar before and after the 12-week treatment period. There were no adverse effects of clinical relevance. In conclusion, formoterol Turbuhaler, 6 micrograms b.i.d. was more effective in improving PEF and offered better asthma control than either terbutaline Turbuhaler, 0.5 mg q.i.d. or placebo. Regular use of formoterol did not reduce the bronchodilator response to additional terbutaline. There were no clinically relevant adverse effects.

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/...formoterol-turbuhaler+terbutaline

Andrzej Szczeklik is well known for his extensive work on aspirin-induced asthma. This paper describes an interesting new study from his group.

The study, conducted in aspirin-sensitive patients, convincingly shows that salmeterol effectively attenuates aspirin-precipitated bronchoconstriction. However, the effect of salmeterol on urinary LTE4 and blood eosinophils is not clear. Statistical differences between the salmeterol and the placebo groups were observed for these parameters but a relationship between bronchoprotective effect was not shown.

Based on these findings, the authors suggest that salmeterol might posses some anti-inflammatory effects in aspirin-induced asthma, although they admit that this needs further investigation.

The action of salmeterol on smooth muscles cells is well documented; its possible influence on inflammation is not. Further investigation is certainly required, especially in light of a recent publication suggesting that salmeterol masks inflammation in the bronchi1.

Reference:

• 1 McIvor et al., Am J Respir Crit Care Med 1998, 158:924-30

Title (2) : Salmeterol prevents aspirin-induced attacks of asthma and interferes with eicosanoid metabolism.(partial abstract from http://www.healthy.net/library/search/medline.htm )

Am J Respir Crit Care Med 1998 Oct;158(4):1168-72
Szczeklik A, Dworski R, Mastalerz L, Prokop A, Sheller JR, Nizankowska E, Cmiel A, Oates JA
Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland.

We determined the effect of a long acting beta2-agonist, salmeterol, on aspirin-induced asthma (AIA) attacks and urinary release of eicosanoids in a double-blind, placebo-controlled, crossover study in 10 asthmatics sensitive to aspirin. The patients inhaled 50 microgram of salmeterol or placebo 15 min prior to a cumulative challenge with increasing doses of lysine-aspirin (L-ASA) (Part I), and before a single, predetermined dose of L-ASA that caused a 20% fall in FEV1 (PD20) (Part II). Salmeterol significantly attenuated aspirin-precipitated bronchoconstriction and the increase in urinary LTE4. Salmeterol also prevented the decrease in blood eosinophils, and abolished the correlation between the urinary levels of LTE4 and provocative doses of aspirin. In addition, PGD-M, the major urinary metabolite of PGD2, increased after L-ASA inhalation in six of nine subjects; this increase was blocked in all six by salmeterol. The protective effect of salmeterol on aspirin-induced attacks and mediator release suggests that it may be efficacious in aspirin-sensitive asthma.

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/...salmeterol-prevents-aspirin-induced-attacks

Comment by Ass. Prof. Leif Rosenhall

It is of course favourable if the effect of a rapid bronchodilator is long lasting. The rather new inhaled bronchodilator formoterol combines a rapid onset of action, similar to salbutamol and terbutaline, with a long duration of action, similar to salmeterol. However, if patients who are used to the short action of salbutamol take formoterol in the same manner, the doses will be much too high. This study was undertaken to evaluate the effect of several doses of formoterol.

Two groups of Finnish asthmatics received either 12 or 20 doses/day of formoterol alternating with terbutaline in a conventional pharmacological study. No serious systemic effect on heart functions was found, even if the effect was considerably greater with terbutaline than with formoterol. Even headache and tremor were slightly more common with terbutaline, while muscular cramps occured about in the same frequency for both drugs.

Comment by Dr. Lars Larsson:

I myself was surprised how well the patients tolerated these rather extremely high doses of the two drugs. It is of course very convenient for the patient to use only one bronchodilator, formoterol, which can be taken prophylactically in the morning and night but also as a rescue medicine when neeeded.

Formoterol is a long-acting b ₂-agonist with a rapid onset of action. It may consequently provide asthmatics with the desired rescue effect usually achieved with salbutamol or terbutaline, as well as the long lasting bronchodilatation usually achieved by salmeterol or bambuterol. Thus, formoterol is in a group of its own; it is not adequate nor accurate to categorize this drug as a short- or long-acting b ₂-agonist.

In order to take advantage of the dual actions of formoterol, it is important that the safety of the drug is carefully considered. The results of this study are very re- assuring; 4.5 µg formoterol delivered via Turbuhaler® is shown to have less of a systemic effect than 0.5 mg of terbutaline. Even more interesting is that the systemic effects of formoterol showed the same duration as those of terbutaline. In other words, formoterol seems to be long-acting in the lung, but short-acting systemically, properties that are potentially very beneficial to the patient. However, as the study does not include any efficacy parameters, it remains to be shown that the effect of 4.5µg formoterol is as good as that of 0.5 mg terbutaline.

Title (3): Tolerability to high doses of formoterol and terbutaline via Turbuhaler® for 3 days in stable asthmatic patients(partial abstract from http://www.healthy.net/library/search/medline.htm )

Eur Respir J 1998 Sep;12(3):573-9
Totterman KJ, Huhti L, Sutinen E, Backman R, Pietinalho A, Falck M, Larsson P, Selroos O Mjobolsta Hospital, Karis, Finland.

This randomized, double-blind, crossover study in two parts compared tolerability to high doses of formoterol (Oxis Turbuhaler) with that of high doses of terbutaline (Bricanyl Turbuhaler). After Holter monitoring at home, 12 patients were treated with 4+4+4 doses of formoterol Turbuhaler, 6 microg x dose(-1), (total daily metered dose 72 microg) or 4+4+4 doses of terbutaline Turbuhaler, 0.5 mg x dose(-1) (daily dose 6 mg) given in the morning, after lunch and in the evening, for 3 consecutive days. After a one week washout period at home, patients received the alternative treatment. Thereafter, 15 other patients received 8+6+6 doses of formoterol Turbuhaler (total daily metered dose 120 microg) or 8+6+6 doses of terbutaline Turbuhaler (daily dose 10 mg). Pulse, cardiac frequency, blood pressure, serum potassium, electrocardiogram and forced expiratory volume in one second (FEV1) were registered at regular intervals and Holter monitoring was applied during all 4 treatment days. Terbutaline 6 mg showed significantly greater systemic effects than formoterol 72 microg on pulse, blood pressure, cardiac frequency and QTc (QT interval corrected for heart rate). Terbutaline 10 mg had significantly greater effects than formoterol 120 microg on serum potassium levels, pulse, cardiac frequency and QTc. No differences in FEV1 levels were found. Both drugs were safe and generally well tolerated on both dose levels. In conclusion, high doses of formoterol Turbuhaler over 3 days were generally safe and well tolerated. Daily doses of 6 mg and 10 mg terbutaline Turbuhaler were systemically more potent than 72 microg and 120 microg formoterol, respectively. The safety margin thus appears to be wide if patients happen to use extra doses of formoterol in addition to those prescribed for regular use.

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/...tolerability-of-high-doses+asthmatic

In this study the authors conclude that 750 µg of FP is as effective as 1500 µg of BDP in children with persistent asthma.

It has to be remembered that this finding does not allow the conclusion that FP is twice as potent as BDP.

The reason is that it is as probable that both treatments have reached the flat, upper part of the dose-response curve. In fact, this study, as other trials comparing one drug with half the dose of another and finding no difference, does not provide any information on their relative potency.

This criticism is acknowledged by the authors in the discussion, but not reflected in the abstract.

Title (4): Fluticasone propionate 750 µg/day versus beclomethasone dipropionate 1500 µg/day: comparison of efficacy and adrenal function in paediatric asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

Thorax 1998 Aug;53(8):656-61
Fitzgerald D, Van Asperen P, Mellis C, Honner M, Smith L, Ambler G
Royal Alexandra Hospital for Children, Sydney, New South Wales, Australia.

BACKGROUND: Previous studies have suggested a 2:1 efficacy advantage of fluticasone propionate (FP) over beclomethasone dipropionate (BDP) in adults on high dose inhaled steroids and children on low dose inhaled steroids. The lower doses of FP required to provide equivalent efficacy to BDP also appear to have fewer systemic effects as measured by adrenal function. METHODS: The efficacy and safety of FP 750 micrograms/day and BDP 1500 micrograms/day were compared in 30 children with persistent asthma (requiring 1000-2000 micrograms/day of inhaled corticosteroids) in a 12 week randomised double blind crossover study. Medication was delivered by a spacer device in two divided doses. Primary efficacy variables were peak expiratory flows (PEF). Adrenal function was assessed by 24 hour urinary free cortisol levels at eight and 12 weeks and ACTH and low dose synacthen tests (LDST) at 12 weeks. The results were adjusted for sequence and period differences. RESULTS: There was no difference in the primary efficacy variables over the two 12 week treatment periods (difference in adjusted means for morning PEF 1.3 l/min (95% CI -6.1 to 8.8), p = 0.112) and symptom scores (cough, tachypnoea, wheeze, shortness of breath; difference in adjusted means of night time scores: -0.06 (95% CI -0.14 to 0.03); p = 0.136). Similar degrees of mild adrenal dysfunction were found during BDP and FP treatment phases. Identical height gain velocities were shown during the corresponding periods. CONCLUSIONS: FP 750 micrograms/day is as effective as BDP 1500 micrograms/day in children with persistent asthma. At these very high doses we were unable to demonstrate a safety advantage of FP over BDP as assessed by adrenal function. However, measures of adrenal function may have been influenced by concurrent and previous systemic steroid usage, and possibly by effects of disease activity.

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/...fluticasone-propionate+asthma

Comment by Prof. Philippe Godard:

Long-term use of any medication can be potentialy deleterious. Therefore, adverse effects must be balanced by positive effects. Quality of life questionnaires are new tools which can determine whether a good balance has been reached.

To determine the risk for cataract among asthmatics, Garbe et al. performed a case-control study using data from a Canadian provincial health insurance plan database. The authors found a correlation between the use of high doses inhaled steroids and an increased likelihood of undergoing cataract extraction in elderly patients. These results are in line with results from a previously published survey.1

Based on this results, asthmatics who are on high dose of inhaled steroids should be checked by an ophthalmologist at least every two years.

Reference:

• Cumming et al., N Eng J Med 1997; 337: 8-14.

Comment by Ass Prof. Leif Rosenhall:

By using a huge data base in Quebec, a very confirming case-control study in elderly people was performed. Among 3677 patients who had undergone a cataract extraction and whose prescribed drugs for the last 5 years were known, the treatment with inhaled steroids for more than 3 years was a significant risk factor. The odds ratio was also increased if the patients had been on high doses (more than 1 mg) for more than 2 years.

This is a very convincing report and de- monstrates that the systemic effects of inha- led steroids never should be neglected. The dose should always be kept as low as possible.

It should be noted that the increased risk for cataract extraction shown in this paper is by no way particularly alarming. In 10 000 patients treated for more than 3 years, 361 additional cataract extractions will occur per year, according to the calculations of this study.

The increased risk, however, was probably caused by the subgroup who had had high doses. The number of individuals who had had inhaled steroids for more than three years was too small to allow an analysis of the different doses.

These types of studies are very interesting and important. However large databases are needed to be able to detect cataracts as a possible consequence of inhaled steroids since the incidence is relatively low.

Title (5): Association of inhaled corticosteroid use with cataract extraction in elderly patients (partial abstract from http://www.healthy.net/library/search/medline.htm )

JAMA 1998 Aug 12;280(6):539-43 Published erratum appears in JAMA 1998 Dec 2;280(21):1830
Garbe E, Suissa S, LeLorier J
Potsdam Institute of Pharmacoepidemiology and Technology Assessment, Germany. 106700.3205 (at) compuserve.com

CONTEXT: The use of systemic corticosteroids is a known risk factor for the development of cataracts. OBJECTIVE: To determine whether treatment with inhaled corticosteroids is associated with cataract extraction in the elderly. DESIGN: Case-control study. SETTING: Quebec universal health insurance program for all elderly (provincial health insurance plan database [RAMQ database]). PATIENTS: RAMQ enrollees 70 years and older. The 3677 cases were patients with a cataract extraction between 1992 and 1994. The 21868 controls were randomly selected from patients who did not have a diagnosis of cataract and matched to cases on the index date of the case. MAIN OUTCOME MEASURES: Odds ratio of cataract extraction in patients with prolonged cumulative exposure to inhaled corticosteroids compared with nonusers. RESULTS: Excluding patients with systemic steroid treatment and after adjusting for age, sex, diabetes, systemic hypertension, glaucoma, ophthalmic steroids, and the number of physician claims for services, use of inhaled corticosteroids for more than 3 years was associated with undergoing cataract extraction (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.53-6.13). For high average daily doses of beclomethasone or budesonide (>1 mg), the OR was elevated after more than 2 years of treatment (OR, 3.40; 95% CI, 1.49-7.76), whereas for low to medium doses (< or =1 mg) of these drugs, the OR was 1.63 (95% CI, 0.85-3.13) after 2 years. CONCLUSION: Prolonged administration of high doses of inhaled corticosteroids increases the likelihood of undergoing cataract extraction in elderly patients. Further studies are needed to investigate the risk of developing cataracts for low to medium doses over longer periods.

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/...corticosteroid+cataract-extraction+Garbe

Theophylline was given to almost all asthmatics before inhaled steroids became available. It certainly didn’t have the same good effect as inhaled steroids and for this reason most patients nowadays aren’t prescribed the drug. This study and many others shows that theophylline may not only exhibit some bronchodilator effects but also some antiinflammatory efffects. It could thus be used as a steroid sparing agent in patients where the doses of inhaled steroids otherwise would be considered too high. The drug, correctly used, is safe and it is inexpensive; thus, it still deserves a place in the antiasthma arsenal.

Title (6): Effect of theophylline withdrawal on airway inflammation in asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

Clin Exp Allergy 1998 Aug;28 Suppl 3:57-63
Minoguchi K, Kohno Y, Oda N, Wada K, Miyamoto M, Yokoe T, Hashimoto T, Akabane T, Kobayashi H, Mita S, Kihara N, Adachi M
First Department of Internal Medicine, Showa University, Tokyo, Japan.

Theophylline has been used as a bronchodilator in acute and chronic asthma management, although there is accumulating evidence that it may have anti-inflammatory effects. We have investigated the effect of theophylline withdrawal for 6 weeks in asthmatic subjects whose peak expiratory flow (PEF) readings were more than 80% of the predicted value and its variability was less than 20% (Green Zone) by treatment with both a moderate dose of inhaled corticosteroids (BDP), 400-800 microg/day) and low dose theophylline (400 mg/day) for more than 3 months. In 38 asthmatic subjects, changes in clinical symptoms, respiratory function and airway inflammation detected with hypertonic saline induced sputum, and airway reactivity to histamine were investigated. One half of the patients were randomly withdrawn from theophylline, while the other half continued to take the same dose of theophylline for a period of 6 weeks. Mean steady state plasma theophylline concentrations when receiving treatment with theophylline were 8.08 microg/mL in the theophylline withdrawal group and 7.64 microg/mL in the control theophylline group, respectively. Although a significant increase in asthma symptoms emerged in the theophylline group, there were no significant changes in the theophylline administration group. In the theophylline withdrawal group, there were small but significant falls in PEF in the morning, FEV1 and V50 at the end of the study period. Analysis of induced sputum showed that there was also a significant increase in the percentage of total and activated (EG2+) eosinophils only in those patients who withdrew from theophylline. These results indicate that chronic treatment with low dose theophylline exerts an anti-inflammatory effect and that the additional use of theophylline with inhaled corticosteroids provides an effective treatment for moderate asthma. Taken together, we conclude that theophylline has long-term beneficial effects on the chronic asthma management.

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/...theophylline+airway-inflammation+asthma+Minoguchi

Comment by Prof Duncan Geddes:

Plasma serotonin levels are increased in asthma and correlate with the severity of disease. This has led to the suggestion that a reduction in circulating serotonin level might result in improvement in asthma control and so tianeptine has been suggested as a possible treatment. In this cross-over trial lasting 52 weeks there was substantial improvement in FEV1 from around 55% predicted to 80% predicted with associated improvement in clinic symptom score and reduction in serotonin levels.

Since tianeptine is primarily an antidepressant this study raises questions about whether the benefit was due to an alteration in asthma pharmacology or a change in mood. Somewhat surprisingly all 69 patients were children who had previously responded poorly to conventional therapy but details are not provided. This lack of response suggests that they were either a very severe or very unusual group of asthmatics and raises questions about the applicability of this study to other populations. Nevertheless, the study is interesting in suggesting a new approach to asthma treatment and clearly needs to be confirmed by further work.

Comments by Prof Philippe Godard:

Lechin et al. presents exciting data demonstrating a dramatic improvement in FEV1 by tianeptine. The increase of FEV1 was nearly 15% (standard deviation was not mentioned).

Unfortunately, the study is not clearly presented. For example, the different steps of the study design are not fully explained in relation to the study outcomes. The design of the study is complex but nevertheless scientifically correct (double blind, placebo controlled, crossover, randomized).

The main treatment period with tianeptine or placebo was 16 weeks. In total, the duration of the trial was 52 weeks which is enough to evaluate efficacy and tolerance. The authors interpret efficacy and tolerance in terms of changes in (daily) severity score, and FEV1. Unfortunately, PEFR was not taken into account. Moreover, exacerbation rates were badly analysed. In general, the analysis of the data was not described in full detail.

A remarkable new finding was the observed correlation between free seretonin levels and severity scores, and FEV1. It would be interesting to investigate further whether seretonin levels could be used as a marker of asthma severity.

In conclusion, this study is complex and correctly designed but the methodology and results are, unfortunately, unclear. The results suggest exciting areas for further study.

Title (7): Neuropharmacologic treatment of bronchial asthma with the antidepressant tianeptine: a double-blind, crossover placebo-controlled study.(partial abstract below from http://www.healthy.net/library/search/medline.htm )

Clin Pharmacol Ther 1998 Aug;64(2):223-32
Lechin F, van der Dijs B, Orozco B, Jara H, Rada I, Lechin ME, Lechin AE
Section of Psychopharmacology, Institute of Experimental Medicine, Central University of Venezuela, Caracas. flechin (at) telcel.net.ve

Studies have shown the levels of free serotonin in plasma are increased in symptomatic patients with asthma. In addition, the concentration of free serotonin in symptomatic children with asthma correlates positively with clinical status and negatively with pulmonary function (forced expiratory volume in 1 second [FEV1]). Thus, reducing the concentration of free serotonin in plasma may be useful in treating children with asthma. We studied the effectiveness of tianeptine in treating these patients. Tianeptine is the only drug known to be able to reduce the level of free serotonin in plasma and to enhance the uptake by platelets. Sixty-nine of the 82 children with asthma initially enrolled participated in this study. Children were randomized to receive tianeptine or placebo or both in a double-blind crossover trial. The trial lasted 52 weeks. Tianeptine provoked a dramatic and sudden decrease of both clinical rating and free serotonin plasma levels and an increase in pulmonary function.

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/...neuropharmacologic-treatment+bronchial-asthma

This paper should be studied by all interested in modern asthma therapy and particularly those who are worried by high costs of drugs. It shows very convincingly that while inhaled steroids and other new treatments are expensive, total medical costs are significantly reduced with these therapies. For every dollar spent on pharmacy, 1.31 dollars of nonpharmacy medical costs were saved.

The study is particularly important because it deals only with medical costs. Usually health economic studies also include a calculation of savings for society caused by fewers days away from work, reduced sick pay, etc. These costs are difficult to calculate and they are not helpful to the medical community. Therefore, it is important to document that expensive drugs, used correctly, may mean substantial savings in other medical costs.

Title (8): Clinical benefits and cost reduction associated with a comprehensive asthma management programme at a managed care organisation (partial abstract from http://www.healthy.net/library/search/medline.htm )

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/...cost-reduction+asthma-management+Groban

This is the best study to date relating quality of life to conventional clinical measures in the treatment of asthma.

852 patients were divided into four groups who took 200 or 800 µgs of budesonide daily, with or without formoterol. The results of this study are already well known1 but the quality of life measurements have only recently been communicated.

The basic message is that quality of life measures parallel clinical indices as a whole but the correlations between one single clinical index and quality of life is relatively weak. Furthermore, individual patient changes in quality of life cannot be predicted from changes in clinical measurements. Some patients seem very sensitive to small changes, others hardly notice large variations in lung function.

These data are particularly useful to emphasise the need to do more than simply make measurements in assessing a patient’s response to treatment.

Reference:

• Pauwels et al., Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med. 1997 Nov 13;337(20):1405-11.

Title (9): Long term trends in quality of life from the FACET study.(partial abstract from http://www.healthy.net/library/search/medline.htm )

...

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/htbin-post/...long-term-trends+quality-of-life+Juniper

Comment by Prof. Duncan Geddes:

Lung function is known to decline with age and the rate of decline has been shown in many studies to be more rapid among smokers. This study is valuable as one of the few that have looked at long term changes in lung function with self-reported asthma and includes both smokers and non-smokers. This study covered a 15-year period and included 17,506 subjects of whom 1,095 had asthma.

The FEV1 declined by 38 mls per year among asthmatics as compared with 22 mls per year in those without asthma. This change is in line with a number (but not all) similar studies and suggests that chronic airways inflammation leads to progressive damage with resulting loss of lung function. The findings were true for both smokers and non-smokers although the importance of this finding is difficult to assess since ex-smokers were classified as non-smokers and so may have distorted the results. Nevertheless, the study provides further good evidence that treatment of asthma should be aimed at long term maintenance of lung function as well as short term results. Naturally a study going back this far does not cover a period during which patients were treated with inhaled steroids and so the key questions of the role of inhaled steroids in preventing long term lung function decline remains unanswered.

Comment by Prof. Philippe Godard:

"You’re as old as your arteries say". This is an old french dictum which could be changed into "You’re as old as your bronchi say".

The study by Lange et al. is very interesting because it is a longitudinal epidemio- logical study covering a period of 15 years. Moreover, the results of the paper are in line with conclusions from previous studies. It has convincingly been shown that the natural age-related decline in FEV1 is greater in asthmatics.

Another interesting result is the finding that mucus hypersecretion is a significant marker of an accelerated decline in FEV1. This suggests the possibility of using induced sputum analysis for tracking the disease process in clinical practice.

This epidemiological study also has some draw-backs. First, the effect of asthma treatment (especially of inhaled steroids) was not assessed. Although a study of early and continuous treatment of mild asthma with inhaled steroids for up to 3 years found beneficials effects, there is at the moment no evidence indicating that asthma treatment prevents decline in lung function. However, experience from daily clinical practice suggests that inhaled steroids do prevent decline in FEV1. A longitudinal study including the evaluation of asthma treatment would therefore be very welcome.

Another draw-back of the study is that airway reversibility was not measured. In the past, the medical literature suggested that the greater the b2-induced reversibility, the greater the FEV1 decline. However, my personal feeling is that the absence of any reversibility is a marker of accelerated FEV1 decline.

In a epidemiological study, it also would have been interesting to analyse the influence of indoor and outdoor pollution. Unfortunately, this was not a part of the study.

Overall, this 15-year follow-up study of ventilatory function provides us with interesting information and might be important in the development of new views on asthma treatment.

Title (10): A 15-year follow-up study of ventilatory function in adults with asthma(partial abstract from http://www.healthy.net/library/search/medline.htm )

N Engl J Med 1998 Oct 22;339(17):1194-200
Lange P, Parner J, Vestbo J, Schnohr P, Jensen G
Copenhagen City Heart Study, Epidemiologic Research Unit, Bispebjerg University Hospital, Denmark.

BACKGROUND: Although the prevalence of asthma and morbidity related to asthma are increasing, little is known about the natural history of lung function in adults with this disease. METHODS: We used data from a longitudinal epidemiologic study of the general population in a Danish city, the Copenhagen City Heart Study, to analyze changes over time in the forced expiratory volume in one second (FEV1) in adults with self-reported asthma and adults without asthma. The study was conducted between 1976 and 1994; for each patient, three measurements of lung function were obtained over a 15-year period. The final data set consisted of measurements from 17,506 subjects (8136 men and 9370 women), of whom 1095 had asthma. RESULTS: Among subjects who participated in all three evaluations, the unadjusted decline in FEV1 among subjects with asthma was 38 ml per year, as compared with 22 ml per year in those without asthma. The decline in FEV1 normalized for height (FEV1 divided by the square of the height in meters) was greater among the subjects with asthma than among those without the disease (P<0.001). Among both men and women, and among both smokers and nonsmokers, subjects with asthma had greater declines in FEV1 over time than those without asthma (P<0.001). At the age of 60 years, a 175-cm-tall nonsmoking man without asthma had an average FEV1 of 3.05 liters, as compared with 1.99 liters for a man of similar age and height who smoked and had asthma. CONCLUSIONS: In a sample of the general population, people who identified themselves as having asthma had substantially greater declines in FEV1 over time than those who did not.

... for the complete abstract, please enquire http://www.ncbi.nlm.nih.gov/...study-of-ventilatory-function

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