The effect of an inhaled leukotriene antagonist, L-648,051, on early and late asthmatic reactions and subsequent increase in airway responsiveness in man

doi:10.1016/0091-6749(90)90052-6

Journal of Allergy and Clinical Immunology

Volume 85, Issue 6, June 1990, Pages 1067-1075

https://doi.org/10.1016/0091-6749(90)90052-6 Get rights and content

Abstract

We have investigated the protective effects of the inhaled cysteinyl leukotriene antagonist, L-648,051, on allergen-induced early asthmatic response (EAR) and late asthmatic response (LAR) and the subsequent changes in bronchial responsiveness to methacholine. Ten atopic men with asthma participated in a double-blind, crossover, placebo-controlled trial. All subjects had documented EAR and LAR to house dust-mite extract. Responsiveness to methacholine was measured the day before and the day after a standardized allergen-challenge test. L-648,051 was inhaled in two doses of 12 mg 20 minutes before and 3 hours after the allergen challenge. The response was obtained from FEV, and flows from maximal (V_40m) and partial (V_40p) expiratory flow-volume curves. All subjects had an EAR and LAR during placebo therapy, but only a minority demonstrated an increase in methacholine responsiveness of more than one doubling dose. The ratio of V_40m to V_40p during methacholine challenge was higher than during both EAR and LAR (p < 0.05). There was no difference between drug- and placebo-therapy periods in baseline function, EAR, LAR, ratio of V_40m to V_40p, and the allergen-induced hyperresponsiveness (p > 0.1). These results indicate that an effective aerosolized leukotriene antagonist in man does not protect against allergen-induced airflow obstruction, despite the evidence of an inflammatory response to allergen challenge. This suggests that either the potency or duration of activity of L-648,051 is limited or that leukotrienes C₄ and D₄ do not play a causative role in human allergic asthma.

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During spontaneous exacerbations of asthma, DI are unable to reverse the bronchoconstriction and in some circumstances may induce further bronchoconstriction [20]; however, after resolution of the exacerbation, the ability for DI to reverse pharmacologically-induced bronchoconstriction is restored. Following allergen inhalation, the ability of DI to reverse bronchoconstriction induced by methacholine is reduced [21], particularly following the late phase asthmatic response [22] which is usually associated with an increase in airway inflammation and AHR. This suggests that airway inflammation and the mediator release associated with allergen exposure or spontaneous asthma can reduce the effectiveness of deep breaths.
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This chapter review that slow reacting substance (SRS) plays an important role in the pathophysiology of human asthma, but the very limited availability of biologically derived material and its instability severely hampered its study. A number of pharmaceutical companies were nonetheless stimulated to investigate SRS-A as a target for a novel asthma therapy. The chapter discusses the structure leukotriene C (2) as a peptido-lipid conjugate derived from the addition of cysteine or a cysteine-containing peptide to a tetraene epoxide , which itself was derived from oxidation of arachidonic acid. The complete structure assignment of SRS-A was determined via total synthesis and comparison of synthetic material with naturally derived SRS-A. It reviews that as the result of a significant body of work in several laboratories around the world, SRS-A was shown to be a variable mixture of three substances designated as leukotriene C₄, leukotriene D_4, and leukotriene E₄ (LTC₄, LTD₄ and LTE₄), differing by the nature of the cysteine-containing peptide attached at C-6 of the molecule.
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^☆: Supported by The Netherlands Asthma Foundation Grant 84.36 and a grant of Merck Sharp & Dohme Research Laboratories, Rahway, N.J.

¹: From the Department of Pulmonology, University Medical Center, Leiden, The Netherlands.

^∗: From the Department of Merck Sharp & Dohme Research Laboratories, Rahway, N.J.

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Original articleThe effect of an inhaled leukotriene antagonist, L-648,051, on early and late asthmatic reactions and subsequent increase in airway responsiveness in man☆

Abstract

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Blood leukotriene levels during the acute asthma attack in children: prostaglandins, leukotrienes, and medicine

Chest

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

Pulm Pharmacol

FEBS

J Allergy Clin Immunol

Late asthmatic responses

Am Rev Respir Dis

Allergen-induced increase in nonallergic bronchial reactivity

Clin Allergy

Leukotrienes and related eicosanoids

Am Rev Respir Dis

Leukotrienes and airway responses

Am Rev Respir Dis

Leukotrienes and the pulmonary microcirculation

Am Rev Respir Dis

Slow-reacting substances, leukotrienes C4 and D4 increase the release of mucus from human airways in vitro

Am Rev Respir Dis

Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4, and E4

Quantitation of leukotrienes in asthmatic sputum

Br J Clin Pharmacol

The importance of lipoxygenase products of arachidonic acid in allergen-induced late responses

Am Rev Respir Dis

Effect of an oral leukotriene antagonist (YM-16638) on antigen-induced early and late airway responses in allergic sheep

Am Rev Respir Dis

Original article
The effect of an inhaled leukotriene antagonist, L-648,051, on early and late asthmatic reactions and subsequent increase in airway responsiveness in man☆

Slow-reacting substances, leukotrienes C₄ and D₄ increase the release of mucus from human airways in vitro

Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C₄, D₄, and E₄