October 28, 2002
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Z.KLEIN AWARD for Human Ethology
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including Psychoneuroimmunology, Neuro
Reproductive Medicine, Chronobiology
and Human Ethology
ISSN 0172–780X

NEL Vol.23 No.4, August 2002


Aspirin-sensitive asthma due to diffuse neuroendocrine system pathology

2002; 23:281285
pii: NEL230402R02
PMID: 12195225

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Aspirin-sensitive asthma due to diffuse neuroendocrine system pathology
Helen V. Evsyukova

Department of Hospital Therapy, The I.P. Pavlov Medical University, St.Petersburg, Russia.

Key words:
aspirin-sensitive asthma; melatonin; platelets; nitric oxide; APUD-system

Submitted: May 17, 2002
Accepted: May 22, 2002


Available clinical data on aspirin-sensitive asthma (ASA) indicate that ASA patients have certain disturbances in the nervous, endocrine, immune and other body systems. It has been found that such patients have a lower melatonin (MT) production in daytime, a pathology of the platelet membrane-receptor complex, and a pathological response to exogenic MT and acetylsalicylic acid. A hypothesis has been suggested in which ASA is considered as apudopathy caused by dysfunction of MT-producing cells. The decreased MT production and the disturbed cell sensitivity to MT lead to pathological changes in individual organs and functional systems. As a result, there is an enhanced lipid peroxidation, an excessive production of reactive oxygen radicals, and a reduced inhibitory action of MT on the 5-lipoxygenase and NO-synthase activities. The lower MT content also results in an intense aggregation of platelets, activating these cells and increasing the production of leukotrienes and nitric oxide. These changes disturb the pulmonary microcirculation, causing the bronchial obturation syndrome even in patient who do not take aspirin or other nonsteroidal anti-inflammatory drugs. The lower basic production of MT is also responsible for a lower content of its metabolite – endogenic acetylsalicylic acid, thereby increasing the sensitivity of melatonin-producing cells, in particular of platelets, to this acid. So, even minimal aspirin doses inhibit the activity of COX-1, which shunts the already abnormal metabolism of arachidonic acid. This, in turn, leads to a greater production of leukotrienes and, hence, to a severe course of the disease.
This hypothesis has become the basis for a new pathogenetic approach to the treatment of ASA patients by correcting the melatonin content with peptide bioregulators – the epiphysis extracts – Epithalamin and Epiphamin.


ASA   aspirin-sensitive asthma
NSAIDS   nonsteroidal antiinflammatory drugs
ATA   aspirin-tolerant asthma
APUD   diffuse neuroendocrine system
MT   melatonin
aMT6S   6-sulphatoxymelatonin
SNAS   5-sulphatoxy-N-acetylserotonin
NO   nitric oxide
COX-1   cyclooxygenase 1

Aspirin-sensitive asthma (ASA) occurs in 20% of patients with bronchial asthma and is tending to increase its rate [1, 2]. Its characteristic symptom is intolerance to aspirin and other nonsteroidal antiinflammatory drugs (NSAIDS), which is manifested as acute asthma attack, often with recurrent polypose rhinosinusopathy, the latter known as the "asthmatic triad".
Recently, the European Coordination Committee has been set up to coordinate the research on aspirin-sensitive asthma, with special emphasis on its pathogenesis and effective therapy [3]. Since the attempts to prove an allergic nature of this type of asthma have failed [4,5,6], a hypothesis has been put forth that ASA is due to an enhanced production of leukotrienes, which cause a persistent and intense contraction of the bronchial smooth muscles, to edema, eosinophils infiltration of the bronchial tree, and mucous hypersecretion [7,8]. The high production of leukotrienes is attributed by some researchers to LTC4 synthase hyperexpression [9] and by others to the inhibition of endogenic PGE2 synthesis, which controls the leukotriene synthesis in the absence of NSAIDS [10]. However, this hypothesis explains only the mechanism of aspirin-induced bronchoconstriction but fails to account for the disease gravity, its rapid progress, and the addiction to glucocorticoid hormones of even those patients who do not take aspirin or other NSAIDS.
Our clinical and laboratory studies of 133 ASA patients and 143 aspirin-tolerant (ATA) patients indicate that the former exhibit nervous, endocrine, immune and other functional disturbances prior to the asthmatic syndrome [11,12]. The ASA patients show early indications of psychological disorders, manifesting themselves as alarm-depressive or asthenoneurotic syndromes. The disease origin in 18,3% of the patients was found to be associated with a psychological stress, which provoked an acute recurrent asthmatic syndrome in 78,6% of ASA patients.
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