The Experts below are selected from a list of 243 Experts worldwide ranked by ideXlab platform
F. A. Fitzpatrick - One of the best experts on this subject based on the ideXlab platform.
-
Inhibition of Leukotriene A4 hydrolase/aminopeptidase by captopril.
Journal of Biological Chemistry, 1991Co-Authors: Lars Örning, Gwen G. Krivi, G.s. Bild, James K. Gierse, Serdar Aykent, F. A. FitzpatrickAbstract:Abstract Captopril ((2S)-1-(3-mercapto-2-methyl-propionyl)-L-proline) inhibited the bifunctional, Zn(2+)-containing enzyme Leukotriene A4 hydrolase/aminopeptidase reversibly and competitively with Ki = 6.0 microM for Leukotriene B4 formation and Ki = 60 nM for L-lysine-p-nitroanilide hydrolysis at pH 8. Inhibition was independent of pH between pH 7 and 8, the optimum range for each catalytic activity. Half-maximal inhibition of Leukotriene B4 formation by intact erythrocytes and neutrophils required 50 and 88 microM captopril, respectively. In neutrophils and platelets neither 5(S)-hydroxyeicosatetraenoic acid, 12(S)-hydroxyeicosatetraenoic acid, nor Leukotriene C4 formation were reduced, indicating selective inhibition of Leukotriene A4 hydrolase/aminopeptidase, not 5-lipoxygenase, 12-lipoxygenase, or Leukotriene C4 synthase. In whole blood, captopril inhibited Leukotriene B4 formation with an accompanying redistribution of substrate toward formation of cysteinyl Leukotrienes. The decrease in Leukotriene B4 was more substantial than the corresponding increase in cysteinyl Leukotrienes suggesting that nonenzymatic hydration predominates over transcellular metabolism of Leukotriene A4 by platelets during selective inhibition of Leukotriene A4 hydrolase. Enalapril dicarboxylic acid and Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro which inhibit angiotensin-converting enzyme: angiotensin I, bradykinin, and N-[3-(2-furyl)acryloyl]Phe-Gly-Gly which are substrates; and chloride ions which activate angiotensin-converting enzyme did not modulate Leukotriene A4 hydrolase/aminopeptidase activity. The results indicate that: (i) the sulfhydryl group of captopril is an important determinant for inhibition of Leukotriene A4 hydrolase/aminopeptidase, probably by binding to an active site Zn2+; (ii) aminopeptidase and Leukotriene A4 hydrolase display differential susceptibility to inhibition; (iii) there is minimal functional similarity between angiotensin-converting enzyme (peptidyl dipeptidase) and Leukotriene A4 hydrolase/aminopeptidase; (iv) captopril may be a useful prototype to identify more potent and selective Leukotriene A4 hydrolase inhibitors.
-
inhibition of Leukotriene a4 hydrolase aminopeptidase by captopril
Journal of Biological Chemistry, 1991Co-Authors: Lars Örning, Gwen G. Krivi, G.s. Bild, James K. Gierse, Serdar Aykent, F. A. FitzpatrickAbstract:Abstract Captopril ((2S)-1-(3-mercapto-2-methyl-propionyl)-L-proline) inhibited the bifunctional, Zn(2+)-containing enzyme Leukotriene A4 hydrolase/aminopeptidase reversibly and competitively with Ki = 6.0 microM for Leukotriene B4 formation and Ki = 60 nM for L-lysine-p-nitroanilide hydrolysis at pH 8. Inhibition was independent of pH between pH 7 and 8, the optimum range for each catalytic activity. Half-maximal inhibition of Leukotriene B4 formation by intact erythrocytes and neutrophils required 50 and 88 microM captopril, respectively. In neutrophils and platelets neither 5(S)-hydroxyeicosatetraenoic acid, 12(S)-hydroxyeicosatetraenoic acid, nor Leukotriene C4 formation were reduced, indicating selective inhibition of Leukotriene A4 hydrolase/aminopeptidase, not 5-lipoxygenase, 12-lipoxygenase, or Leukotriene C4 synthase. In whole blood, captopril inhibited Leukotriene B4 formation with an accompanying redistribution of substrate toward formation of cysteinyl Leukotrienes. The decrease in Leukotriene B4 was more substantial than the corresponding increase in cysteinyl Leukotrienes suggesting that nonenzymatic hydration predominates over transcellular metabolism of Leukotriene A4 by platelets during selective inhibition of Leukotriene A4 hydrolase. Enalapril dicarboxylic acid and Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro which inhibit angiotensin-converting enzyme: angiotensin I, bradykinin, and N-[3-(2-furyl)acryloyl]Phe-Gly-Gly which are substrates; and chloride ions which activate angiotensin-converting enzyme did not modulate Leukotriene A4 hydrolase/aminopeptidase activity. The results indicate that: (i) the sulfhydryl group of captopril is an important determinant for inhibition of Leukotriene A4 hydrolase/aminopeptidase, probably by binding to an active site Zn2+; (ii) aminopeptidase and Leukotriene A4 hydrolase display differential susceptibility to inhibition; (iii) there is minimal functional similarity between angiotensin-converting enzyme (peptidyl dipeptidase) and Leukotriene A4 hydrolase/aminopeptidase; (iv) captopril may be a useful prototype to identify more potent and selective Leukotriene A4 hydrolase inhibitors.
Lars Örning - One of the best experts on this subject based on the ideXlab platform.
-
Inhibition of Leukotriene A4 hydrolase/aminopeptidase by captopril.
Journal of Biological Chemistry, 1991Co-Authors: Lars Örning, Gwen G. Krivi, G.s. Bild, James K. Gierse, Serdar Aykent, F. A. FitzpatrickAbstract:Abstract Captopril ((2S)-1-(3-mercapto-2-methyl-propionyl)-L-proline) inhibited the bifunctional, Zn(2+)-containing enzyme Leukotriene A4 hydrolase/aminopeptidase reversibly and competitively with Ki = 6.0 microM for Leukotriene B4 formation and Ki = 60 nM for L-lysine-p-nitroanilide hydrolysis at pH 8. Inhibition was independent of pH between pH 7 and 8, the optimum range for each catalytic activity. Half-maximal inhibition of Leukotriene B4 formation by intact erythrocytes and neutrophils required 50 and 88 microM captopril, respectively. In neutrophils and platelets neither 5(S)-hydroxyeicosatetraenoic acid, 12(S)-hydroxyeicosatetraenoic acid, nor Leukotriene C4 formation were reduced, indicating selective inhibition of Leukotriene A4 hydrolase/aminopeptidase, not 5-lipoxygenase, 12-lipoxygenase, or Leukotriene C4 synthase. In whole blood, captopril inhibited Leukotriene B4 formation with an accompanying redistribution of substrate toward formation of cysteinyl Leukotrienes. The decrease in Leukotriene B4 was more substantial than the corresponding increase in cysteinyl Leukotrienes suggesting that nonenzymatic hydration predominates over transcellular metabolism of Leukotriene A4 by platelets during selective inhibition of Leukotriene A4 hydrolase. Enalapril dicarboxylic acid and Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro which inhibit angiotensin-converting enzyme: angiotensin I, bradykinin, and N-[3-(2-furyl)acryloyl]Phe-Gly-Gly which are substrates; and chloride ions which activate angiotensin-converting enzyme did not modulate Leukotriene A4 hydrolase/aminopeptidase activity. The results indicate that: (i) the sulfhydryl group of captopril is an important determinant for inhibition of Leukotriene A4 hydrolase/aminopeptidase, probably by binding to an active site Zn2+; (ii) aminopeptidase and Leukotriene A4 hydrolase display differential susceptibility to inhibition; (iii) there is minimal functional similarity between angiotensin-converting enzyme (peptidyl dipeptidase) and Leukotriene A4 hydrolase/aminopeptidase; (iv) captopril may be a useful prototype to identify more potent and selective Leukotriene A4 hydrolase inhibitors.
-
inhibition of Leukotriene a4 hydrolase aminopeptidase by captopril
Journal of Biological Chemistry, 1991Co-Authors: Lars Örning, Gwen G. Krivi, G.s. Bild, James K. Gierse, Serdar Aykent, F. A. FitzpatrickAbstract:Abstract Captopril ((2S)-1-(3-mercapto-2-methyl-propionyl)-L-proline) inhibited the bifunctional, Zn(2+)-containing enzyme Leukotriene A4 hydrolase/aminopeptidase reversibly and competitively with Ki = 6.0 microM for Leukotriene B4 formation and Ki = 60 nM for L-lysine-p-nitroanilide hydrolysis at pH 8. Inhibition was independent of pH between pH 7 and 8, the optimum range for each catalytic activity. Half-maximal inhibition of Leukotriene B4 formation by intact erythrocytes and neutrophils required 50 and 88 microM captopril, respectively. In neutrophils and platelets neither 5(S)-hydroxyeicosatetraenoic acid, 12(S)-hydroxyeicosatetraenoic acid, nor Leukotriene C4 formation were reduced, indicating selective inhibition of Leukotriene A4 hydrolase/aminopeptidase, not 5-lipoxygenase, 12-lipoxygenase, or Leukotriene C4 synthase. In whole blood, captopril inhibited Leukotriene B4 formation with an accompanying redistribution of substrate toward formation of cysteinyl Leukotrienes. The decrease in Leukotriene B4 was more substantial than the corresponding increase in cysteinyl Leukotrienes suggesting that nonenzymatic hydration predominates over transcellular metabolism of Leukotriene A4 by platelets during selective inhibition of Leukotriene A4 hydrolase. Enalapril dicarboxylic acid and Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro which inhibit angiotensin-converting enzyme: angiotensin I, bradykinin, and N-[3-(2-furyl)acryloyl]Phe-Gly-Gly which are substrates; and chloride ions which activate angiotensin-converting enzyme did not modulate Leukotriene A4 hydrolase/aminopeptidase activity. The results indicate that: (i) the sulfhydryl group of captopril is an important determinant for inhibition of Leukotriene A4 hydrolase/aminopeptidase, probably by binding to an active site Zn2+; (ii) aminopeptidase and Leukotriene A4 hydrolase display differential susceptibility to inhibition; (iii) there is minimal functional similarity between angiotensin-converting enzyme (peptidyl dipeptidase) and Leukotriene A4 hydrolase/aminopeptidase; (iv) captopril may be a useful prototype to identify more potent and selective Leukotriene A4 hydrolase inhibitors.
Jesper Z. Haeggström - One of the best experts on this subject based on the ideXlab platform.
-
Leukotriene A4 Hydrolase and Leukotriene C4 Synthase
Lipoxygenases in Inflammation, 2016Co-Authors: Agnes Rinaldo-matthis, Jesper Z. HaeggströmAbstract:Leukotrienes are potent proinflammatory and immune modulating lipid mediators synthesized along the 5-lipoxygenase pathway of arachidonic acid metabolism. Leukotriene B4 is one of the most potent chemotactic agents known while Leukotriene C4, D4, and E4 are a powerful smooth muscle contracting agents, particularly in the respiratory tract and microcirculation. The committed steps in the biosynthesis of Leukotriene B4 and C4 are catalyzed by the key enzymes Leukotriene A 4 hydrolase and Leukotriene C 4 synthase, respectively. In this chapter we discuss the most recent advances in the understanding of these two enzymes at a structural, functional, and biological level.
-
Leukotriene A4 Hydrolase and Leukotriene C4 Synthase
Lipoxygenases in Inflammation, 2016Co-Authors: Agnes Rinaldo-matthis, Jesper Z. HaeggströmAbstract:Leukotrienes are potent proinflammatory and immune modulating lipid mediators synthesized along the 5-lipoxygenase pathway of arachidonic acid metabolism. Leukotriene B4 is one of the most potent chemotactic agents known while Leukotriene C4, D4, and E4 are a powerful smooth muscle contracting agents, particularly in the respiratory tract and microcirculation. The committed steps in the biosynthesis of Leukotriene B4 and C4 are catalyzed by the key enzymes Leukotriene A 4 hydrolase and Leukotriene C 4 synthase, respectively. In this chapter we discuss the most recent advances in the understanding of these two enzymes at a structural, functional, and biological level.
-
pre steady state kinetic characterization of thiolate anion formation in human Leukotriene c synthase
Biochemistry, 2012Co-Authors: Agnes Rinaldomatthis, Ralf Morgenstern, Shabbir Ahmad, Anders Wetterholm, P J Lachmann, Jesper Z. HaeggströmAbstract:Human Leukotriene C4 synthase (hLTC4S) is an integral membrane protein that catalyzes the committed step in the biosynthesis of cysteinyl-Leukotrienes, i.e., formation of Leukotriene C4 (LTC4). Thi...
-
Enzymes and receptors in the Leukotriene cascade
Cellular and molecular life sciences : CMLS, 2002Co-Authors: Jesper Z. Haeggström, Anders WetterholmAbstract:Leukotrienes are a family of paracrine hormones derived from the oxidative metabolism of arachidonic acid. These lipid mediators are recognized as important signal molecules in a variety of inflammatory and allergic conditions affecting the skin, joints, gastrointestinal and respiratory systems, in particular asthma. Such conditions are typified by local pain, tissue edema, hyperemia and functional losses. In the tissues, immunocompetent cells accumulate at the site of injury which contribute to tissue damage and perpetuation of the disease process. Leukotrienes can elicit most, if not all, of these signs and symptoms. Thus, Leukotriene B4 is one of the most powerful chemotactic agents known to date and participates in the recruitment of leukocytes. The cysteinyl Leukotrienes, on the other hand, contract smooth muscles, particularly in the peripheral airways and microcirculation. Recently, drugs which block the formation and action of Leukotrienes have been introduced as novel antiasthmatic medications. This chapter reviews the biochemistry, molecular biology and cell biology of the key enzymes and cognate receptors in the Leukotriene cascade.
Magnus Back - One of the best experts on this subject based on the ideXlab platform.
-
Leukotrienes as Biomarkers of Cardiovascular Disease
2016Co-Authors: Magnus Back, C. Labat, Françoise Stanke-labesque, Athanase BenetosAbstract:Myocardial infarction and stroke are major causes of morbidity and mortality and result from an underlying atherosclerosis of the coronary and cerebrovascular vasculature. Atherosclerotic plaques are a site of lipid accumulation and chronic inflammation. There is a need for novel biomarkers to predict an individual’s cardiovascular risk, and several inflammatory biomarkers have been explored for their prognostic value. Leukotrienes are lipid mediators of inflammation, which are formed in atherosclerotic lesions and participate in the atherosclerosis process. The local production of Leukotrienes leads to high levels in atherosclerotic plaques, whereas circulating levels are negligible and difficult to measure. Ex vivo stimulation of leukocytes reflects the Leukotriene synthesizing capacity and the Leukotriene B4 levels released from granulocytes in response to calcium inophore are associated with echographic measures of carotid artery vascular remodeling. Urinary Leukotriene E4 is a validated biomarker of asthma, and is increased in coronary artery disease. Salivary levels of Leukotriene B4 were recently associated with vascular stiffness and subclinical atherosclerosis. Leukotriene measures have in addition been associated with several cardiovascular risk factors, such as smoking, diabetes, obesity, and obstructive sleep apnea. The present chapter reviews the available literature using these different approaches for evaluating Leukotrienes as biomarkers for cardiovascular disease.
-
international union of basic and clinical pharmacology lxxxiv Leukotriene receptor nomenclature distribution and pathophysiological functions
Pharmacological Reviews, 2011Co-Authors: Magnus Back, Takehiko Yokomizo, Jilly F. Evans, Sven-erik Dahlén, Jeffrey M. Drazen, Charles N Serhan, Takao Shimizu, Enrico G RovatiAbstract:The seven-transmembrane G protein-coupled receptors activated by Leukotrienes are divided into two subclasses based on their ligand specificity for either Leukotriene B4 or the cysteinyl Leukotrienes (LTC4, LTD4, and LTE4). These receptors have been designated BLT and CysLT receptors, respectively, and a subdivision into BLT1 and BLT2 receptors and CysLT1 and CysLT2 receptors has been established. However, recent findings have also indicated the existence of putative additional Leukotriene receptor subtypes. Furthermore, other ligands interact with the Leukotriene receptors. Finally, Leukotrienes may also activate other receptor classes, such as purinergic receptors. The aim of this review is to provide an update on the pharmacology, expression patterns, and pathophysiological roles of the Leukotriene receptors as well as the therapeutic developments in this area of research.
-
Leukotriene signaling in atherosclerosis and ischemia.
Cardiovascular Drugs and Therapy, 2009Co-Authors: Magnus BackAbstract:INTRODUCTION: The inflammatory process of atherosclerosis is associated with several pathophysiological reactions within the vascular wall. The arachidonic acid released by phospholipase A(2) serves as substrate for the production of a group of lipid mediators known as the Leukotrienes, which induce pro-inflammatory signaling through activation of specific BLT and CysLT receptors. DISCUSSION: Leukotriene signaling has been implicated in early lipid retention and foam cell accumulation, as well as in the development of intimal hyperplasia and advanced atherosclerotic lesions. Furthermore, the association of Leukotrienes with degradation of extracellular matrix has suggested a role in atherosclerotic plaque rupture. Finally, studies of either myocardial or cerebral ischemia and reperfusion indicate that Leukotriene signaling in addition may be involved in the development of ischemic injury. CONCLUSION: Both Leukotriene synthesis inhibitors and Leukotriene receptor antagonists have been suggested to induce beneficial effects at different stages of the atherosclerosis process.
-
Inflammatory signaling through Leukotriene receptors in atherosclerosis
Current Atherosclerosis Reports, 2008Co-Authors: Magnus BackAbstract:The atherosclerotic lesion is a site of local production of the lipid-derived inflammatory mediators known as Leukotrienes. This production leads to autocrine and paracrine activation of Leukotriene receptors of the BLT and CysLT receptor subtypes expressed on leukocytes and structural cells within the vascular wall. Studies in mice, rats, and rabbits have revealed a key role for Leukotriene signaling in atherosclerosis, abdominal aneurysms, and intimal hyperplasia. In addition, a major atherosclerotic immune activation may be Leukotriene-dependent through mediation of leukocyte cross-talk within the atherosclerotic lesion. Furthermore, Leukotrienes induce endothelium-dependent and independent vascular responses. Finally, recent findings indicate that Leukotriene-dependent degradation of the extracellular matrix may link this pathway to atherosclerotic plaque instability. Taken together, the Leukotriene pathway may represent a putative therapeutic target in the treatment of atherosclerotic vessel disease.
-
Functional characteristics of cysteinyl-Leukotriene receptor subtypes.
Life Sciences, 2002Co-Authors: Magnus BackAbstract:Abstract Cysteinyl-Leukotrienes, i.e. Leukotriene (LT) C 4 , D 4 and E 4 , are inflammatory mediators and potent airway- and vasoconstrictors. Two different cysteinyl-Leukotriene receptors, CysLT 1 and CysLT 2 , have been cloned and functionally characterised using potent CysLT 1 receptor antagonists and the dual CysLT 1 /CysLT 2 receptor antagonist BAY u9773. However, the rank order of potency of the cysteinyl-Leukotrienes at the CysLT receptors differs between tissues and studies, and a CysLT receptor classification based on agonist selectivity has not been established. In addition, the existence of more than two receptor subtypes for cysteinyl-Leukotrienes has been suggested.
Sven-erik Dahlén - One of the best experts on this subject based on the ideXlab platform.
-
international union of basic and clinical pharmacology lxxxiv Leukotriene receptor nomenclature distribution and pathophysiological functions
Pharmacological Reviews, 2011Co-Authors: Magnus Back, Takehiko Yokomizo, Jilly F. Evans, Sven-erik Dahlén, Jeffrey M. Drazen, Charles N Serhan, Takao Shimizu, Enrico G RovatiAbstract:The seven-transmembrane G protein-coupled receptors activated by Leukotrienes are divided into two subclasses based on their ligand specificity for either Leukotriene B4 or the cysteinyl Leukotrienes (LTC4, LTD4, and LTE4). These receptors have been designated BLT and CysLT receptors, respectively, and a subdivision into BLT1 and BLT2 receptors and CysLT1 and CysLT2 receptors has been established. However, recent findings have also indicated the existence of putative additional Leukotriene receptor subtypes. Furthermore, other ligands interact with the Leukotriene receptors. Finally, Leukotrienes may also activate other receptor classes, such as purinergic receptors. The aim of this review is to provide an update on the pharmacology, expression patterns, and pathophysiological roles of the Leukotriene receptors as well as the therapeutic developments in this area of research.
-
Pharmacological characterization of Leukotriene receptors.
American Journal of Respiratory and Critical Care Medicine, 2000Co-Authors: Sven-erik DahlénAbstract:Whereas inhibition of 5-lipoxygenase will result in global inhibition of the production of Leukotrienes, antagonism of Leukotrienes at their tissue receptors provides selective inhibition of actions mediated by distinct classes of receptors (Table 1). The different profiles of biological activities for Leukotriene B 4 (LTB 4 ) and the cysteinyl-Leukotrienes suggested that the two main classes of Leukotrienes possessed different classes of receptors, and pharmacological investigations have indeed confirmed this. The receptors for LTB 4 are called BLT receptors whereas the receptors for cysteinyl-Leukotrienes are designated CysLT receptors (1). With regard to antagonism of the CysLT receptors, studies support some heterogeneity and at least two main subgroups of receptors have therefore been proposed, CysLT 1 and CysLT 2 . It is likely that there are more subdivisions to consider, but as the CysLT receptors remain to be cloned, this classification so far remains the framework for our understanding. Although there are experimental compounds that may block several of the known Leukotriene receptors (Table 1), clinically useful drugs have so far been developed only against the main receptor for cysteinyl-Leukotrienes in the human lung. This receptor is now called the CysLT 1 receptor but was previously known as the LTD 4 receptor. This article serves to give an overview of the Leukotriene receptors, with particular attention to the virgin state of knowledge in this area.
-
The cysteinyl-Leukotriene receptor antagonist BAY u9773 is a competitive antagonist of Leukotriene C4 in the guinea-pig ileum.
European journal of pharmacology, 1996Co-Authors: Magnus Back, Eva Wikström Jonsson, Sven-erik DahlénAbstract:Two main classes of receptors exist for Leukotrienes C4, D4 and E4, collectively named cysteinyl-Leukotrienes (CysLTs). The CysLT1 receptor is blocked by currently available Leukotriene antagonists, and the CysLT2 receptor is defined by the absence of selective antagonists. The contractile response to Leukotriene C4 in guinea-pig ileum longitudinal muscle is resistant to CysLT1 receptor antagonists. However, the Leukotriene E4 analogue BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11(Z), 14(Z)-eicosatetraenoic acid) has recently been reported to inhibit CysLT2 responses. Therefore BAY u9773 was evaluated for antagonism of the effect of Leukotriene C4 in the guinea-pig ileum longitudinal muscle. We found that BAY u9773 (0.3-10 microM) did not contract the preparation, but produced a concentration-dependent rightward shift in the concentration-response relation for Leukotriene C4. Schild plot analysis yielded a slope which was not significantly different from unity and a pA2 value of 6.1. The inhibition of Leukotriene C4 by BAY u9773 was not altered by antagonism of CysLT1 receptors by ICI 198,615 {[1-[[2-methoxy-4-[[(phenylsulfonyl)amino]carbonyl]-phenyl] methyl]-1H-indazol-6-yl]carbamic acid cyclopentyl ester}(100 nM). The CysLT1 receptor agonist, Leukotriene E4 (1 microM), contracted the preparation but did not inhibit the contraction induced by Leukotriene C4. Taken together, the antagonism exerted by BAY u9773 appeared unrelated to actions on CysLT1 receptors. In conclusion, BAY u9773 was a useful selective competitive antagonist of Leukotriene C4, and the findings support the classification of the receptors for Leukotriene C4 in the guinea-pig ileum as CysLT2.
-
effect of the Leukotriene receptor antagonist mk 0679 on baseline pulmonary function in aspirin sensitive asthmatic subjects
Thorax, 1993Co-Authors: Barbro Dahlén, D J Margolskee, O Zetterstrom, Sven-erik DahlénAbstract:BACKGROUND--The cysteinyl Leukotrienes (LTC4, LTD4, and LTE4) have been shown to mediate airway obstruction evoked by several factors which trigger asthmatic reactions--for example, allergen and exercise. Accordingly, drugs which block the action or formation of these Leukotrienes are being evaluated as a new treatment of asthma. Elevated production of Leukotrienes has been reported in asthmatic subjects who are intolerant to aspirin and related nonsteroidal anti-inflammatory drugs. In this study the influence of the specific Leukotriene receptor antagonist MK-0679 was tested on basal airway function in asthmatic patients with documented aspirin intolerance. METHODS--The eight subjects in the study had a mean baseline FEV1 of 78% predicted (range 58-99%) and six required treatment with inhaled glucocorticosteroids (400-1200 micrograms budesonide/beclomethasone daily). On two separate days the subjects received either 825 mg MK-0679 or placebo, orally in a double blind, randomised, crossover design. RESULTS--The Leukotriene antagonist MK-0679 caused bronchodilation which lasted for at least nine hours. The average peak improvement in FEV1 was 18% above the predrug baseline, but the bronchodilator response varied between 34% and 5% and was found to correlate strongly with the severity of asthma and aspirin sensitivity. CONCLUSIONS--The findings indicate that ongoing Leukotriene production may be one cause of persistent airway obstruction in aspirin sensitive asthmatic subjects and that they may benefit from treatment with a Leukotriene receptor antagonist.
