Andrew Szczeklik

Asthma and Anti-inflammatory Drugs Mechanisms and Clinical Patterns

Non-steroidal anti-inflammatory drugs (NSAIDs) are inhibitors of prostaglandin formation in tissues (Vane, 1971). Therefore, before discussing the effects of NSAIDs on bronchial asthma, it seems appropriate to examine the influence of prostaglandins and other arachidonic acid metabolites on lung function. Numerous reviews on the products formed from arachidonic acid and their influence on the airways have appeared in the literature (Gryglewski, 1980; Sirois and Borgeat, 1980; Spannhake et aI., 1981; Szczeklik, 1980b). Here we present only a brief outline of this subject.

Bronchial Reactivity to Prostaglandins F2α, E2, and Histamine in Different Types of Asthma

Bronchial reactivity to prostaglandins F2alpha (PGF2alpha), E2 (PGE2) and histamine has been studied in 27 patients with aspirin-sensitive asthma and in 28 asthmatics without this sensitivity. Of the latter group, 13 patients had atopic, 9 infectious, and 6 mixed type of asthma. Atopic patients were characterized by vivid reactivity to low doses of both PGF2alpha and histamine. In patients with infectious asthma significantly higher doses of both PGF2alpha and histamine were necessary to induce bronchoconstriction as compared to atopics. Aspirin-sensitive patients responded quickly with bronchial spasm to similar doses of histamine as atopics, but tolerated significantly higher doses of PGF2alpha. There was no difference in reactivity to PGF2alpha between patients with aspirin sensitivity and those with infectious asthma. 5 and 10 min after administration of 60 microgram PGE2 significantly better improvement in ventilation occurred in aspirin-sensitive patients than in those of either atopic or infectious groups. The results obtained point to differences in bronchial reactivity to prostaglandins and histamine depending on type of asthma and severity of its symptoms.

Asthma improved by aspirin-like drugs

In six adult patients with bronchial asthma aspirin in a single dose of 0.3-1.2 g produced bronchodilatation with a marked improvement in both clinical symptoms and pulmonary function tests. In these patients asthma was characterized by the following traits: onset after a flu-like infection, perennial course, lack of relation to specific allergenic exposures, negative skin tests with common aeroallergens, and history of rhinorrhoea or sinusitis. Oral challenge with 12 nonsteroidal anti-inflammatory drugs performed in two patients showed that bronchodilatation could be induced not only by aspirin but also by other drugs which inhibit cyclo-oxygenase. This response to aspirin is rare and proper diagnosis is of vital importance, since the same aspirin-like drugs which proved effective in these patients may provoke dangerous bronchoconstriction in other clinically indistinguishable patients with asthma.

Aspirin-Induced Asthma: New Insights into Pathogenesis and Clinical Presentation of Drug Intolerance

Aspirin-induced asthma (AIA) is a distinct clinical syndrome, present in about 10% of adult asthmatics. Precipitation of the asthmatic attacks by aspirin and other nonsteroidal anti-inflammatory drugs is the hallmark of the syndrome. The idea that the attacks might result from the specific inhibition of a single enzyme in the respiratory tract, namely cyclooxygenase, has found support in experimental and clinical studies, and has generated a number of new hypotheses on the mechanism of bronchoconstriction. These hypotheses, operating within the frame of cyclooxygenase theory, point to the involvement of leukotrienes, platelets or chronic viral infection. Progress in studies on AIA has improved our knowledge on the drugs - safe and contraindicated - in this relatively common and fascinating clinical syndrome. Studies on mechanisms operating in AIA might eventually lead to new insights in pathogenesis of bronchial asthma.

Anti-cyclo-oxygenase agents and asthma.

Aspirin inhibits cyclo-oxygenase by an irreversible time-dependent process of inactivation; this mechanism appears to be responsible for precipitation of asthmatic attacks in about 5%-10% of adult asthmatic patients. Besides aspirin, all other cyclo-oxygenase inhibitors induce bronchoconstriction in sensitive patients, while nonsteroidal anti-inflammatory drugs without anti-cyclo-oxygenase activity can be taken by the same patients with impunity. While aspirin-sensitive patients should avoid the potential for adverse reactions, there are rare reports of bronchodilation following ingestion of aspirin and aspirinlike drugs.

Bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E1

We evaluated in a double-blind study the bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E1 (PGE1-carbinol), described recently as a nonirritant bronchodilator in animals. Fifteen asthmatic patients received by inhalation single doses of 1, 10, and 30 micrograms PGE1-carbinol, 55 micrograms PGE2, and placebo (10% ethanol in normal saline, which was also used as diluent for the PGs). Such pulmonary function tests as forced expiratory volume in 1 second, forced vital capacity, and maximal expiratory flow were monitored during 2 hours following inhalation of each compound. 10 and 30 micrograms PGE1-carbinol produced significant but short-acting bronchodilation, similar to that caused by 55 micrograms PGE2. One-third of the patients reported mild cough and throat irritation during and shortly after inhalation of 30 micrograms PGE1-carbinol or 55 micrograms PGE2. Placebo and 1 microgram PGE1-carbinol produced minimal side effects, but neither agent caused bronchodilation. In an adjunctive, unblinded trial, the same patients received 400 micrograms fenoterol. Fenoterol caused greater bronchodilation 15 and 30 minutes after inhalation than did the PGs in the double-blind study.