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màj : 08/11/99Asmanet : Eicosanoids, Aspirin and Asthma workshop Cracow April 1998
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Symposium on Eicosanoids, Aspirin and Asthma.
chaired by Richard Dworski and Andrew Szczeklik
American LungAssociation/American Thoracic Society Conference.
Epidemiology
Hedman and coll.(ref-01) estimated the
prevalance of asthma, aspirin intolerance, and nasal polyposis
among adult inhabitants of a southern district in Finland. In the
study, based on a postal questionnaire survoy of a random sample
population the prevalance of physician-diagnosed asthma was 4.4%.
In the group of asthmatics, the prevalance of aspirin intolerance
was 5.7%, and nasal polyposis 4.3%. There was a strong
relationship between aspirin sensitivity and allergic rhinitis in
the studied population.
Mechanism
of aspirin- induced asthma
Sanak and Szczeklik (ref-02) described a
diallelic polymorphism in the promoter region of LTC4 synthase,
the final enzyme in the synthesis cascade of cysteinyl
leukotrienes. The new allelic variant in characterized by the
transversion of adenosine to cysteine in 444 position (A 444C).
Genotyping scrcening included 51 patients with aspirin-induced
asthma (AIA), 66 aspirin-tolerant asthmatics (ATA), and 42 normal
subjects (NS). The frequency of the A444C transversion in AIA was
0.441. It was doubled compared to ATA (0.227), and NS (0.226).
The homozygosity of A444C was found in seven AIA patients, one
ATA, and one healthy subject. The investigators suggest that the
A 444C allele is "the first genetic marker of AIA", and
speculate that patients who carry the allelic variant of LTC4
synthase promoter may specially benefit from anti-leukotriene
drugs. Certainly, the surmise will require further studies and
confirmation.
Kowalski and coll.(ref-03) assessed eicosanoid formation by cultured nasal polyp epithelial cells (NPEC) obtained from 8 patients with "aspirin triad" and 11 subjects with rhinitis who tolerated aspirin well. The spontaneous production of PGE2 by NPEC from aspirin- sensitive patients was significantly lower compared to aspirin tolerant subjects, but the difference vanished when the cells were stimulated with ionophore A23187. Pretreatment with aspirin in vitro blocked prostanoid synthesis in cells from both groups. 15- HETE production at baseline and after stimulation with ionophor A23187 was similar in aspirin sensitive and tolerant subjects; however after aspirin in vitrO7 the release of 15-HETE increased only in NPEC from patients with "aspirin triad". Experiments with normal nasal epithelial cells have not been performed in the study.
Langmack and coll.(ref-04) measured 15HETE in bronchoalveolar lavage fluid (BALF) at baseline and 15 min after endobronchial challenge with indomethacin in 4 aspirin-sensitive, 7 aspirin-tolerant, and 5 healthy subjects. 15-HETE was analysed by enzyme immunoassay employing a polyclonal 15-HETE antibody. The mean baseline levels of 15HETE were comparable for all groups. After indomethacin, the concentrations of 15-HETE became elevated in asthmatic patients but not in normal individuals. The magnitude of the increase in aspirin-sensitive and aspirin-tolerant asthmatics was similar. This study clearly demonstrates that the defect in arachidonic acid metabolism causing an increased synthesis of 15- HETE in BALF following COX inhibition in vivo is not a characteristic feature of aspirin sensitivity.
Dworski and coll.(ref-05) measured endothelin (ET) in urine from 9 asthmatics with AIA at baseline, and then at 2 hr intervals for 8 hrs after inhalation challenge with Iysine- aspirin (L-ASA). ET was anlyzed by immunoassay based on a double- antibody "sandwich" technique. The mean urinary levels of the immunoreactive ET were significantly elevated after L-ASA inhalation at each of the measured time points. The maximal response in individual subjects occured either at 0-2 hrs or 2-4 hrs after provocation. The authors speculate that ET may have a pathophysiological role in both the respiratory symptoms, as well as in vascular responses provoked by aspirin in some patients with AIA. Clinical trial with endothelin receptor antagonist will be necessery to address this hypothesis.
Anzai and coll.(ref-06) studied the distribution of Th-1 and Th-2 like cells in peripheral blood from 5 non-atopic aspirin-sensitive asthmatics; 5 non- atopic, aspirin-tolerant asthmatics; and 5 atopic aspirin-tolerant asthmatics. White blood cells were stimulated ex viPo, and analysed by flow cytometry. The percentage of interferon-y (Th-1) and IL- 4 (Th-2) producing cells was similar in aspirinsensitive and aspirin-tolerant non-atopic asthmatics. Allergic asthmatics had a higher number of Th-2 like cells than nonatopic asthmatics.
Hattori and coll.(ref-07) analyzed the profiles of peripheral blood Iymphocytes from 8 aspirin-sensitive asthmatics at baseline, and after intravenous challenge with Iysine- aspirin at 30 min and 24 hrs. There was a small but significant increase in CD4+, CD4xCD25, and CD4xHLA-DR Iymphocytes, and a decrease in CD8+ cells, at 24 hrs after aspirin challenge. The specificity of the response is unknown, since neither aspirin-tolerant asthmatics nor normal control subjects have been studied.
Clinical
issues
A comprehensive description of the natural history of AIA
syndrome was presented by the investigators from 14 academic
centers located in 8 different European countries collaborating
within the European Network on Aspirin-Induced Asthma (AIANE).(ref-08) The database consisted of 365 patients
with confirmed aspirin intolerance. The average age of the
patients was 46 + 12 year. Two-thirds of them were female. In
most of the adult subjects "aspirin triad" developed
gradually between the age of 30 and 35 years. Typically, rhinitis
preceded asthma which was followed by nasal polyposis. The first
asthma attack was usually associated with respiratory infection
or an ingestion of cyclooxygenase inhibitor. Most patients had
moderate or severe asthma, and half of them required maintenance
therapy with systemic corticosteroids in addition to topical
steroids for satisfactory control of asthma symptoms.
Interestingly, approximately 5% of the patients had a positive
family history of aspirin sensitivity. These individuals suffered
from particularly severe asthma.
Could nasal provocation test (NPT) with Iysine-aspirin be a useful alternative to either oral or inhaled aspirin challenge? Milowski and coll.(ref-09) performed NPTwith aspirin in 51 patients with AIA confirmed by oral aspirin test, 13 ATA, and 10 healthy subjects. After application of 16 mg of aspirin to each nostril, 35 patients with AIA and control subject developed rhinorrhea and nasal congestion. All ATA remained symptoms free. The intensity of the reaction was evaluated by a clinical judgment and an anterior rhinomanometry. Importantly, none of the subjects developed asthma attack after intranasal administration of aspirin. In conclusion, NPT with aspirin is a relatively simple, specific, sensitive and safe procedure that could be used for diagnostic and investigational purposes. However, the test can be performed only in patients with preserved nasal flow. No results on the reproducibility of the test in this study have been provided.
Vaghi and coll. (ref-10) tested the hypothesis that COX-2 inhibition would not trigger aspirin reactions in sensitive individuals. They performed oral challenges with meloxicam, a relatively specific COX-2 inhibitor in AIA patients. In the first study, 19 subjects with docomented AIA received three doses of meloxicam (1.87 mg, 1.87 mg, and 3.74 mg) or placebo every hour on two separate days. Two patients developed mild bronchoconstriction (maximal decrease in FEV, 14% and 15%), and thrce developed rhinorrhea. Twelve patients continued the second study with 7.5 mg, 7.5 mg, and 15 mg of meloxicam. Two of them had bronchospasm and one rhinorrhea. In one "meloxicam-sensitive" patient who participated in both parts of the study, the higher dose of the drug provoked greater asthmatic reaction (25% fall in FEV,). This study suggests that COX-2 inhibition is not involved in the mechanism of AIA. However, all currently available COX-2 inhibitors are not free of anti-COX-1 activity. Therefore, serious adverse reactions to these compounds can be expected in patients who are extremely sensitive to aspirin. In conclusion, presently accessible selective COX-2 inhibitors should be avoided in patients with AIA.
Treatment
Szczeklik and coll. (ref-11) determined the
effect of a long acting,b2-agonist, salmeterol, on AIA attacks
and urinary release of eicosanoids in a double- blind,
placebo-controlled, cross-over study in 10 asthmatics sensitive
to aspirin. The patients inhaled 50,ug of salmeterol or placebo
15 min prior to a cumulative challenge with increasing doses of
Iysineaspirin (L-ASA), and before a single, predetermined dose of
L- ASA that caused a 20% fall in FEV~ (PD20).
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 6 of 9 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.
* * *
Several investigators further evaluated the importance of PGE2 as an inhibitory mediator in human asthmatic airways.
Gauvreau and coll. (ref-12) performed a randomized, placebo controlled, crossover study on the effect of inhaled PGE2 on allergen-induced bronchoconstriction and airway inflammation in 8 atopic asthmatics with documented dual reaction to allergen. 100,ug of PGE2 or placebo was inhaled immediately before allergen provocation. FEV' was measured for 7 hrs thereafter. Provocation test with methacholine was performed the day before, and 24 hrs following challenge. Sputum for differential counts of eosinophils, metachromatic cells and neutrophils was induced the day before and after allergen challenge at 7 and 24 hrs. Inhalation of PGE2 significantly inhibited the early and late fall in FEV, caused by allergen, attenuated airway hyperresponsiveness to methacholin at 24 hrs after allergen, and reduced allergen-induced increase in sputum eosinophils at 7 and 24 hrs.
The mechanism of the protective action of PGE2 on early allergen- induced asthmatic respons was investigated by Harter and coII.. (ref-13) In a randomized double-blind placebo controlled cross-over study, 10 atopic asthmatics underwent fiberoptic bronchoscopy immediately after inhalation of 100,ug of PGE2 or placebo. BALwas performed at baseline, and in a separate segment 5 min after allergen deposition. Allergen- stimulated release of PGD2 was significantly reduced. The release of LTC4/D4/E4 was attenuated, but the difference was not statistically significant.
Pavord and coll. (ref-14) measured induced sputum supernatant eicosanoid concentrations in 6 normal and 16 asthmatic subjects. The investigators observed a negative correlation between the percentage of sputum eosinophil count and sputum PGE2 concentration in subjects with asthma.
Department of Medicine, Vanderbilt University School of
Medicine,
Nashville, TN, USA
Workshops'
report by Dr Ewa Nizankowska,
Department of Medicine,
Jagiellonian University School of Medicine,
Cracow, Poland
The morning session started with the presentation of Klaus Rabe, Germany, on the role of leukotrienes in human airway smooth muscle tone. The cysteinyl leukotrienes (cys-LTs), LTC4 and LTD4, are potent constrictors of human airways in vitro and in viro, their potency boing at least 1000-fold greater than that of histamine. Since the studies of Ellis and Undem (1994), we know that the inherent tone in human airways is primarily the result of 5-lipoxygenase metabolites, but it is unclear what stimulates the production of these metabolites. According to several studies the leukotriene-dependent component amounts to more than 60- 70% of the detectable inherent tone, the remaining being due to histamine and bronchodilating prostaglandins such as PGE2. The source of the prostanoids in humans is believed to be epithelial cell, however, histamine and leukotrienes are likely to be continuously produced by resident inflammatory cells such as mast cells and possibly eosinophils in the airway wall, even in the individuals without asthma or allergic sensitisation. The physiological relevance of cys-LTs to airway tone in viro is underlined by many clinical studies, demonstrating that both 5- lipoxygenase inhibitors and cys-LTs receptor antagonists, affect airway caliber after acute and chronic administration.
The next lecture was devoted to the leukotriene pathway enzyme expression in asthmatic lung. Diverse responses to allergen, viral infection and NSAIDs were presented by Anthony P. Sampson from Southampton, United Kingdom. Cys-LTs, present an ultimate inflammatory mediators, released after allergen exposure or NSAIDS challenge in sensitive patients, as well as after viral infections. In a search for the regulatory mechanisms of cys-LTs synthesis, the main precursors of their synthesis, and its modulators were compared in the bronchial biopsies of aspirin-tolerant (ATA), aspirin- sensitive patients (AIA) and normal subjects. No differences were found in immunohistochemistry results of 5- lipoxygenase (5-LO), FLAP, COX-1 and COX-2 staining. The most important difference, which correlated with aspirin- sensitivity in the examined subjects, was LTC4 synthase overexpression in bronchial biopsies. This finding was in agreement with the observed marked eosinophilic infiltration of the submucosa and may explain cys-LTs surges in BAL fluid after aspirin provocation. Increased numbers of IL-5 positive cells in AIA biopsies offers a plausible explanation of a self-sustained inflammatory process. Thus, increased production of cys-LTs scems to be due to overexpression of the specific synthase, a phenomenon not observed in ATA and normal subjects. Aspirin-induced asthma would be a disorder of the inflammatory regulation rather than of the effectors cells excitability, attributed to common asthma. Dr Sampson presented also the possible mechanisms leading to exacerbations of asthma, which frequently follow viral infections. In vivo model of rhinovirus type 16 infection was examined for inflammatory markers in the bronchial biopsies. The induction of 5-LO and COX-2 (but not COX-1) was found, as might be expected from direct interaction of the pathogen with the nuclear transcription factor NF-kB in macrophages. In contrast, in a study with allergic asthmatics, bronchial biopsy expression of only 5-LO, FLAP and LTC4 synthase increased following a seasonal allergen exposure. The immunochemistry data on human bronchial biopsies point to the eicosanoids pathway upregulation as the most important pathomechanism of asthma.
Marek Sanak and Andrew Szczeklik presented the new data on leukotriene C4 synthase promoter polymorphism in bronchial asthma. Familiar aggregation of asthma and atopy is extensively investigated since many years. Very little is known about the genetic predisposition in AIA. In aspirin-induced asthma incidence of the disease among the relatives of the patients is lower than in other forms of the discase, however it exceeds distinctly the general population disease frequency. The multifactorial inheritance model is proposed currently for those diseases, which does not conform with simple mendelian inheritance patterns. The concept of genetic predisposition relies on genetic polymorphism of human population, in which frequent allelic variants may cause different expression, facilitating the onset of the disease. Leukotriene C4 synthase, the rate limiting enzyme for cys-LTs synthesis was screened for genetic variation using molecular genetics methods.
The promoter region of the gene was analysed by polymerase chain reaction amplification and single strand conformation polymorphism, followed by sequencing.
A single nucleotide transversion (A 444C) was found that may interact with a common transcription factor AP,. Population studies of the LTC4 synthase revealed association of 444C allele with AIA. In vitro experiments, in which two promoter variants were compared in transiently transfected COS-7 cells indicatod enhanced transcriptional activity of the 444C allele, as measured by a reporter,B- galactosidase gene activity.
Dietrich Keppler from Heidelberg, Germany, presented data on molecular basis of LTC4 transport during its biosynthesis and excretion. The co-authors of the study were I. Leier and J. Konig.
Leukotriene C4 is a cell membrane impermeable compound; its release from the cell into the extracellular space needs an active transport mechanism. This biosynthetic release of LTC4 is mediated by a primary active ATP- dependent export pump termed multidrug resistance protein 1 (MRP- 1),which is a member of ATP-binding casette transporter family. This multifunction transporter pump is affected by some new leukotriene modifying drugs, resulting in additional inhibition of the cys-LTs biosynthesis and excretion. The clearance of cys-LTs from the blood is effectuated, however, by another enzyme with the significant homology with MPR-1, namely MRP- 2, which localises to the hepatocytes. The existence of these, at least, two transporting systems for cys-LTs, and the possibility of its cellular uptake by another, prostaglandin transporting system, challenges our knowledge on the transcellular effects of those potent mediators. A high polarity of some cells, which restricts the transporter proteins either to basal or to apical surface of the cell suggests such a possibility.
Sebastiano Bianco from Milano, Italy, in his lecture reviewed extensively almost all the drugs, and different substances which were studied in vivo in aspirin-precipitated adverse reactions. He reminded us of the influence of antihistaminics, furosemide, PGE2 and the new specific COX-2 inhibitors on aspirin- induced bronchospasm.
The second part of the workshop started with the lecture of Alan J. Knox from Nottingham, UK, who discussed the regulatory role of proinflammatory cytokines and mediators on COX isoforms in human airway smooth muscle cells. Airway smooth muscles are a rich sources of prostaglandins such as PGE2, which have a potent in vitro and in viro effects on the airways.
A.J. Knox studied the isoforms of COX present in human airway smooth muscle cells under resting conditions and following stimulation with proinflammatory cytokines and mediators. At rest only COX-1 was expressed by Western blotting in smooth muscle cells. Following IL-1 beta or bradykinin, COX-2 was induced, while TNF- alfa or interferon-gamma had no effect. The main COX products were PGE2 and PGI2. Dr Knox underlined that the fact that proinflammatory cytokines or mediators can induce COX-2 in human airway smooth muscle suggest an important role of COX-2 in asthma pathophysiology.
Marek Kowalski from Lodz, Poland, discussed the role of airway epithelial cells as a source of eicosanoids in aspirin-sensitive asthma/rhinosinusitis syndrome. From the recent studies it is obvious that the airway epithelial cells are not only a protective barrier in the respiratory tract, but importantly contribute to the pathophysiology of the airways inflammation by the generation of both proinflammatory and antiinflammatory cytokines and mediators. Both COX metabolites (e.g. PGE2, PGF2c`, PGD2) and lipoxygenase metabolites (e.g. 15- HETE) are released from bronchial and nasal epithelial cells. Kowalski studied the local production of eicosanoids produced by cultured respiratory epithelium from nasal polyps in patients with AIA and the asthmatics who tolerate aspirin well. The cultured epithelial cells from AIA patients produced higher levels of 15- HETE as compared to aspirin tolerant patients. These results, as well as the suggestion, that ASA-sensitivity may be a local phenomenon confined to the respiratory airway epithelium, need confirmation.
Barbro Dahlen from Karolinska Institutet, Stockholm, Sweden spoke on: The pivotal role of leukotrienes in aspirin-induced asthma. She reviewed recent evidence, supporting the hypothesis that leukotrienes have a central role in this syndrome. There is an overproduction of cys-LTs in AIA patients, expressed as increased urinary excretion of LTC4 at baseline; following aspirin challenge there is a further increase in urinary LTC4. Pretreatment with the drugs which inhibit the formation or action of leukotrienes prevents aspirin-induced bronchoconstriction. Studies in aspirinintolerant asthmatics have documented that antileukotrienes such as zileuton (5- LO inhibitor) or montelucast (cys-LTs receptor antagonist) produce acute and chronic improvement in asthma symptoms and pulmonary function tests. This improved control of asthma occurred in add-on studies, where both above cited drugs were administered on the top of the conventional asthma treatment with inhaled and oral corticosteroids. As corticosteroids scem not to inhibit in viro formation of leukotrienes, it may explain, why addition of the antileukotrienes have an anti-asthmatic effects over those exerted by corticosteroids.
Michacl Schmitz-Schumann with co-workers from Swiss Institute for Asthma and Allergy Research Davos, Switzerland, discussed the similarity between some symptoms and laboratory findings observed in aspirin-induced asthma and Churg-Strauss syndrome (CSS). CSS is a small vessel vasculitis with an eosinophil rich and granulomatous infiltration involving the respiratory tract, and necrotising vasculitis affecting small- to mediumsized vessels associated with asthma and eosinophilia. In AIA, especially in patients with high doses systemic corticotherapy, the diagnosis of CSS may be very difficult to establish. The typical cases of CSS and the formes frustes in AIA patients were presentod. An interesting case of corticosteroid- resistant aspirin-induced asthma with many features suggesting also the diagnosis of CSS was described; the patient responded favourably to interferonalpha therapy. The drug controlled the extremely augmented eosinophil production in bone marrow and reduced other tissue infiltration by activated eosinophils.
Pal Magyar and Andreas Wollak from Budapest, Hungary, studied the cross-inhibition of exercise and inhaled KCl-induced bronchospasm. They confirmed the cross-refractoriness between these two stimuli and found that indomethacin abolished the refractory period. They concluded that the factors responsible for the refractoriness after exercise are associated with the exercise stimulus itself, rather than the bronchoconstriction induced by exercise and that the protective effect of indomethacin against refractoriness to KCl-induced bronchoconstriction suggests an increased production of the bronchoprotective prostaglandins after exercise.
Giampiero Patriarca with his team from Rome, Italy, discussed the clinical effectiveness of intranasal therapy with Iysine- acetylsalicylate (L- ASA) in patients with nasal polyposis, both ASAsensitive and ASA-tolerant. As treatment of nasal polyposis is mainly surgical, relapses are frequent despite long term local nasal corticosteroids. The authors studied the effect of prolonged treatment with intranasal L- ASA on polyps relapse in 76 patients who underwent sinus surgery. In the follow-up at 12 and 60 months, relapses occurred in 6.9% and 57.5% of treated patients respectively, versus 49.2 and 88% in the control group. In another group of patients with nasal polyposis the authors studied the effect of similar treatment, however the patients were not subjected to sinus surgery, but instead received 3 doses of intramuscular depot triamcinolone. After 1 year in half of the subjects studied the symptoms improved and the partial regression of the polyps were observed. At the end of his presentation, Dr Patriarca presented their recent studies of the antiproliferative effect of L-ASA on fibroblasts derived from nasal polyps from both ASA-sensitive and ASA- intolerant patients and also from fibroblasts from the normal skin of a healthy donor. L-ASA had a growth- inhibitory effect on cells, independently of their derivation and at concentrations which correspond to those used in the local treatment of nasal polyposis.
I suppose, this international symposium must have been a rare opportunity to meet very outstanding scientists from different fields of medicine and for many participants from different countries it was a unique possibility to walk where Copernicus used to walk during his life.
Dr
Ewa Nizankowska
Department of Medicine, Jagiellonian University School of
Medicine,
Cracow, Poland
1. Hedman J.V.J., Poussa T., Nieminen M.: Prevalence of asthma, ASA-intolerance, nasal polyposis and COPD in a population based study. Am. J. Respir. Crit. Care Med., 1998;157: A162
2. Sanak M., Szczeklik A.: Aspirin-induced asthma is associated with an allelic variant of the leukotriene C4 synthase promoter. Am. J. Respir. Crit. Care Med., 1998;157: A716
3. Kowalski M., Pawliczak R., Wozniak J., Siuda K, Poniatowska M., Iwaszkiewicz J., Kornatowski T, Kaliner M.A.: Differential metabolism of arachidonic acid in nasal polyp epithelial cells cultured from aspirinsensitive and aspirin-tolerant patients. Am. J. Respir. Crit. Care Med., 1998;157: A197
4. Langmack E.L., Warren M.S., Westcott J.Y., Wenzel S.E.: Endobronchiall indomethacin increases 15-HETE in bronchoalveolar lavage fluid of both aspirin- tolerant and aspirin-intolerant asthmatics. Am. J. Respir. Crit. Care Med., 1998; 157: A716
5. Dworski R., Szczeklik A., Prokop A. Mastalerz L., Nizankowska E., ShellŽr J.R.: Urinaly levels of endothelin-1 increase in patients with aspirin-induced asthma atter inhaled challenge with asthma. Am. J. Respir. Crit. Care Med., 1998;157: A718
6. Anzai K., Taniguchi M., Hatton Y., Isogai S., Nakagawa C., Matsui K., Mizuno H., Sakakibara H., Suetsugu S.: Thl and Th2 cells in peripheral blood in patients with aspirin-induced asthma. Am. J. Respir. Crit. Care Med., 1998;157: A718
7. Hattori Y., l~niguchi M., Anzai K., Nakagawa C., Matsui K., Tanaka 1., Koko K., Satou M., Okazawa M., Sakakibara H. Suetsugu S.: T cell response in peripheral blood during aspirin-induced attack in patients with aspirin- induced asthma. Am. J. Respir. Crit. Care Med., 1998;157: A718
8. Szczeklik A., Niiankowska E., Duplaga M., Bochenek G., Bianco S., Bousquet J., Godard P., Jager L., Joseph M., Kowalski M., Kuna P., Kunkel G., Lee TH., Patriarca G., Picado C., Popov T, Rodrigues J., Roiniecki J., Vaz Azavedo M., Vervloct D.: New insights into course of aspirin-induced asthma: results of the AIANE project. Am. J. Respir. Crit. Care Med., 1998;157: A716
9. Milewski M., Mastalerz L., Niiankowska E., Szczeklik A.: Standardization of nasal provocation test with Iysine-aspirin for diagnosis of aspirin-sensitive asthma. Am. J. Respir. Crit. Care Med., 1998;157: A716
10. Vaghi A., DeBernardi G., Grassi N., Refini R.M., Sestini R, Robuschi P.M., Bianco S.: Tolerance of melox~cam in aspirin-sensitive asthmatics. Am. J. Respir. Cnt. Care Med. 1998; 157: A715
11. Szczeklik A., Dworski R., Mastalerz L., Prokop A., Sheller J.R., Niiankowska E. Miel A., Oates J.A.: Salmeterol prevents aspirin-precipitated asthma and interferes with eicosanoid metabolism. Am. Rev. Respir. Crit. Care Med., 1998;157: A717
12. Gauvreau G.M., Watson R.M., Rerecich TJ., O'Byrne RM.: Effects of inhaled P GE2 o n all ergen - in du ce d airw ay inflammation. Am. Rev. Respir. Crit. Care Med., 1998;157: A717
13. Hartert TV., Dworski R., Oates J.A., Murray J.J., Sheller J.R.: Prostaglandin E2 decreases allergen stimulated release of prostaglandin D2 in patients with asthma. Am. J. Respir. Crit. Care Med., 1998;157: A717
14. Pavord l.D., Ward R., Woltmann G., Sheller J.R., Dworski R.: Induced sputum eicosanoid concentrations in asthma. Arn. Rev. Respir. Crit. Care Med., 1998;157: A717
1999
International Symposium November 12-13,1999, Rome/Italy Organised by: Universitat Cattolica del S. Cuore - Rome European Netwerk on Aspirin Induced Asthma (AIANE) Organisers: Prof. G. Patriarca (Rome), President of
the Organising Committee Venue: Centro Congressi Europa, at Cattolica del Sacro
Cuore Organising Secretariat: Additional information: Further information regarding the scientific programme, registration, hotel accommodation, etc. will be included in the Preliminary Programme to be issued at the beginning of 1999. Main Topics:
The scientific programme will encompass oral and poster presentations. The call for abstracts will be included in the Preliminary Programme which will be circulated at the beginning of 1999. Official language will be English. Simultaneous translation English/Italian will be provided. |
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Date de création: 14 Septembre1998-Dernière mise à jour: 08/11/99
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