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Antileukotrienes in the Treatment of Asthma

Paul M. O'Byrne, MB; Elliot Israel, MD; and Jeffrey M. Drazen, MD
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From McMaster University, Hamilton, Ontario, Canada; and Harvard Medical School, Boston, Massachusetts. Requests for Reprints: Paul M. O'Byrne, MB, Asthma Research Group, Department of Medicine, Division of Respirology, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada. Current Author Addresses: Dr. O'Byrne: Asthma Research Group, Department of Medicine, Division of Respirology, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1997;127(6):472-480. doi:10.7326/0003-4819-127-6-199709150-00009
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Purpose: To review the activity in clinical models, the efficacy, and the safety of antileukotrienes as a new class of antiasthma treatment.

Data Sources: English-language trials identified from the archival literature, including the MEDLINE database, through 1996; bibliographic references; and textbooks.

Study Selection: Reports from placebo-controlled, double-blind, randomized trials were selected.

Data Extraction: Study designs and results were extracted from the clinical trial reports. Statistical evaluation of combined results was not attempted.

Data Synthesis: The various classes of antileukotrienes have shown activity in clinical models of asthma, including exercise-induced, cold air hyperventilation-induced, allergen-induced, and aspirin-induced bronchoconstriction. In addition, the antileukotrienes partially reverse spontaneous bronchoconstriction in asthmatic persons, an effect additive to that of inhaled β2-agonists. Clinical trials of the antileukotrienes have shown clinical benefit, as measured by reductions in asthma symptom scores, improvements in air flow obstruction, and reductions in the rescue use of inhaled β2-agonists. Some, but not all, of the antileukotrienes have been shown to cause liver microsomal activation with increases in hepatic aminotransferase levels.

Conclusions: Antileukotrienes are an important new therapy for asthma. Inhibition of leukotriene synthesis or action has a beneficial effect in the treatment of both induced and spontaneous asthma. These results show that leukotrienes are important mediators of the asthmatic response. In addition, encouraging results have been obtained from clinical trials of antileukotrienes; however, these results do not yet provide guidelines for the optimal clinical use of antileukotrienes in asthma treatment. Such recommendations await the results of further studies.


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Figure 1.
The 5-lipoxygenase (5-LO) pathway of arachidonic acid (AA) metabolism, showing the other enzymes (5-lipoxygenase activating protein [FLAP] and leukotriene C4 [LTC4] synthetase) necessary for the production of the cysteinyl leukotrienes.1444444

In addition, 5-LO activating protein antagonists, such as BAYx1005 and MK-886; 5-LO inhibitors, such as zileuton; and cysteinyl leukotriene receptor type 1 (CysL T ) receptor antagonists, such as zafirlukast, inhibit the production or action of the cysteinylleukotrienes. 5-HPETE = 5-hydroperoxyeicosatetraenoic acid; LTA ( ) = leukotriene A ; LTD = leukotriene D ; LTE = leukotriene E .

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Figure 2.
The effect of a selective cysteinyl leukotriene receptor type 1 (CysLT1) receptor antagonist, MK-571, on the percentage decrease from baseline in the FEV1 after exercise in asthmatic patients.1[52]

Pretreatment with MK-571 markedly attenuated the decrease in FEV after exercise. Reproduced from Impens and colleagues with permission.

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Figure 3.
Percentage of patients who required corticosteroid treatment for exacerbations of asthma after receiving zileuton, 400 mg or 600 mg four times daily, or placebo.1111P[106]

Groups are stratified by FEV as a percentage of predicted value at study entry. A total of 111 patients had an FEV greater than 70%, 187 had an FEV of 50% to 70%, and 103 had an FEV ( ) less than 50%. *  < 0.05 for comparison with placebo. Reproduced from Israel and colleagues with permission.

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