Inhibition of Leukotriene D₄-induced Bronchoconstriction in Normal Subjects by the Oral LTD₄Receptor Antagonist ICI 204,219

Abstract

The sulfidopeptide leukotrienes may play a role in the pathogenesis of asthma. Previous clinical trials with leukotriene antagonists have shown only minimal protection from subsequent challenge with inhaled LTD4. Using a double-blind, placebo-controlled crossover design, we tested the hypothesis that the LTD4 receptor antagonist, ICI 204,219, could inhibit LTD4-induced bronchoconstriction in normal subjects. On separate days, 3 to 7 days apart, a single oral 40-mg dose of ICI 204,219 or placebo was ingested. At 2 h (Group I), 12 h (Group II), or 24 h (Group III) after the dose, six subjects in each group underwent bronchoprovocation testing with aerosolized LTD4. The airway response was assessed by measuring specific airway conductance (SGaw) and the FEV1. ICI 204,219 had no effect on baseline pulmonary function. When given 2 h before the LTD4 challenge, ICI 204,219 increased by 117-fold the concentration of LTD4 required to reduce SGaw 35%: 34 +/- 10 versus 3,965 +/- 894 micrograms/ml (placebo versus ICI 204,219; p less than 0.05). When given 12 h before the LTD4 challenge, ICI 204,219 increased by ninefold the concentration of LTD4 required to reduce SGaw 35%: 33 +/- 11 versus 304 +/- 125 micrograms/ml (p less than 0.05). When given 24 h before the LTD4 challenge, a smaller effect was found: 12 +/- 3 versus 60 +/- 24 micrograms/ml (p less than 0.05). Plasma levels of ICI 204,219 correlated with efficacy across groups (r = 0.83, p less than 0.001), but imperfectly within groups. No adverse effects (symptoms or abnormal laboratory test results) were noted after ingesting the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

“…As of 1998, montelukast, pranlukast and zafirlukast have been registered for the treatment of asthma in many parts of the world. The compounds are administered orally, and have been found to cause significant shifts (25-to 1000-fold) in the dose-response relation for inhaled LTD 4 in normals or asthmatics [167][168][169][170].…”

“…When antileukotrienes were first studied in normal subjects or mild asthmatics subjected to bronchoprovocations with allergen [197,198,203] or LTD 4 [167,168,233], there were no significant effects on baseline pumonary function. However, when antileukotrienes were administered to asthmatics with baseline asthma symptoms and compromised baseline pulmonary function, an acute bronchodilator response was consistently observed [234,235].…”

The leukotriene-antagonist ICI-204,219 inhibits the early airway reaction to cumulative bronchial challenge with allergen in atopic asthmatics

“…There was a tendency that the subjects with the greatest antagonism of the skin response to LTD 4 were also those where ICI-204,219 caused the largest displacement of the dose-response relation for allergen in the airways. Nevertheless, the degree of antagonism by ICI-204,219 of the skin response to LTD 4 was not impressive, and was much less than has been reported for its effect on the bronchoprovocationresponse to LTD 4 [29,35]. In fact, a much less potent leukotriene-antagonist, LY-171,883, has been reported to cause a similar inhibition of the skin response to LTD 4 [20].…”

“…The purpose of this study was to confirm earlier indications [23,24] that the orally active and selective receptor antagonist of cysteinyl-leukotrienes, ICI-204,219 (Accolate) [28,29], could inhibit allergen-induced airway obstruction in atopic asthmatics. We focused on the early airway reaction (EAR) and tested the effect of ICI-204,219 on the provocative dose (units) required to produce a decrease of forced expiratory volume in one second (FEV 1 ) by 20% (PD 20 FEV 1 ), determined by cumulative challenge with increasing doses of allergen.…”

Drugs for the Treatment of Allergic Diseases

“…Pranlukast is one of the most efficacious antiallergic drugs for the treatment of bronchial asthma at present and is expected to reduce the dose of glucocorticoid necessary to control airway inflammation. Similar LT1 cysteinyl leukotriene-receptor antagonists, zafirlukast (18) and montelukast (19), have also been developed after pranlukast and applied clinically in Europe and America. They will be available in Japan in the near future.…”