Antileukotrienes in the Treatment of Asthma

  1. Paul M. O'Byrne, MB;
  2. Elliot Israel, MD; and
  3. Jeffrey M. Drazen, MD
  1. 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.
     
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    Abstract

    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.

    Koch outlined a series of experiments that must be completed to provide adequate proof that an infectious agent is responsible for a given disease. With respect to asthma, a noninfectious inflammatory condition, a family of related postulates has to be met in order to establish a role for a mediator in pathogenesis. These include 1) the determination that cells involved in the pathogenesis of asthma have the capacity to produce the mediator, 2) the demonstration that exogenous administration of the mediator recapitulates critical aspects of asthma pathophysiology, 3) the recovery of the mediator or its metabolites during asthmatic episodes, and 4) the demonstration that inhibition of the synthesis or action of the mediator prevents or alleviates both laboratory-induced and spontaneously occurring asthma. Until recently, no asthma mediator has met this final postulate.

    This review examines the evidence to determine whether the antileukotrienes satisfy the fourth postulate: that is, to determine whether inhibition of the formation or action of the cysteinyl leukotrienes has beneficial effects in both laboratory-induced and spontaneously occurring asthma. These data clearly show that this family of mediators is important in the pathogenesis of asthma and that antileukotriene drugs will be beneficial in asthma treatment.

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    Historical Perspectives

    In 1938, Feldberg and Kellaway [1] examined the effects of cobra venom on guinea pig lungs and discovered an activity in the lung perfusate that caused slow-onset, sustained contraction of smooth muscle. In 1940, Kellaway and Trethewie [2] showed that the time course of this contraction was distinct from that produced by histamine, and they named the mediator slow-reacting substance of anaphylaxis (SRS-A). In 1960, Brocklehurst [3] reported that lung fragments obtained from a person with asthma released SRS-A when they were exposed to an allergen. This finding suggested that SRS-A was an important mediator in the development of symptoms in persons with allergic asthma after allergen inhalation because of its ability to contract airway smooth muscle with a much longer duration of action than other smooth-muscle constrictors, such as histamine. These studies and others that demonstrated the potency of SRS-A as a bronchoconstrictor agonist in animals [4] resulted in enormous interest in the structure of SRS-A because of its potential as a mediator involved in the pathogenesis of asthma. In the late 1970s, the component molecules of SRS-A were identified [5], and we now know that what was considered SRS-A consists of the cysteinyl leukotrienes C4, D4, and E4.

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    Biosynthetic Pathways of the Leukotrienes

    The leukotrienes are derived from the ubiquitous membrane constituent arachidonic acid and are members of a larger group of biomolecules known as eicosanoids [5, 6]. Arachidonic acid (5,8,11,14-cis-eicosatetraenoic acid) is found esterified, in the sn-2 position, to cell-membrane phospholipids in a wide variety of mammalian cells [7-11]. The synthesis of leukotrienes is initiated by the action of phospholipase A2, which selectively cleaves arachidonic acid from cell membranes. Arachidonic acid is converted sequentially to 5-hydroperoxyeicosatetraenoic acid and then to leukotriene A4 (5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid) by a catalytic complex consisting of 5-lipoxygenase [12-14] and the 5-lipoxygenase activating protein [15-18]. In the intracellular microenvironment and in the presence of leukotriene C4 synthase [19], glutathione is adducted at the C6 position of leukotriene A4 to yield the molecule known as leukotriene C4 (5[S]-hydroxy-6[R]-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid) [20]. Leukotriene C4 is exported from the cytosol to the extracellular microenvironment [21], where the glutamic acid moiety is cleaved by γ-glutamyltranspeptidase to form leukotriene D4 (5[S]-hydroxy-6[R]-cysteinyl-glycyl-7,9 trans-11,14-cis-eicosatetraenoic acid) [22, 23]. Cleavage of the glycine moiety from leukotriene D4 by a variety of dipeptidases results in the formation of leukotriene E4 (5[S]-hydroxy-6[R]-cysteinyl-7,9-trans-11,14-cis-eicosatetraenoic acid) [24]. Because they each contain cysteine, leukotriene C4, leukotriene D4, and leukotriene E4 are known as the cysteinyl leukotrienes; together, these molecules constitute the material formerly known as SRS-A. All three cysteinyl leukotrienes have the same range of biological effects, although leukotriene E4 is much less potent than its precursor molecules. Among the cells in the lung that possess the enzymatic activities necessary to produce the cysteinyl leukotrienes are mast cells [25], eosinophils [26], and alveolar macrophages [27, 28]; mast cells and eosinophils have been strongly implicated as critical effector cells in the pathobiology of asthma.

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    Inhibition of Leukotriene Production or Action

    It is theoretically possible to inhibit the production of the leukotrienes by inhibiting any of the enzymes in their biosynthetic pathway (Figure 1). However, the only enzyme that has been selectively inhibited to date is 5-lipoxygenase [29]. It has also been possible to interrupt leukotriene formation by preventing the binding of arachidonic acid to the 5-lipoxygenase activating protein [30].

    Figure 1. 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 1. 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 . 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

    The cysteinyl leukotrienes transduce airway obstruction in humans through stimulation at a specific receptor now called the cysteinyl leukotriene receptor type 1 (CysLT1) [31]. This receptor, previously known as the leukotriene D4 receptor or leukotriene Rd[32], is a 45-kd membrane protein [33-36]. Stimulation of this receptor results in smooth-muscle constriction with signal transduction occurring through the stimulation of phosphoinositide turnover [37-40]. Numerous chemically distinct, specific, selective antagonists have been identified [41-49] and used in studies in humans with asthma (Table 1).

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    Table 1. Antileukotrienes Studied in Humans*
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    Roles of Leukotrienes in Asthma

    Asthmatic Airway Obstruction

    Spontaneous bronchoconstriction has been used as a model for examination of the role of leukotrienes in airway narrowing in asthma. The capacity of a CysLT1 receptor antagonist to reverse asthmatic bronchoconstriction was first shown by Hui and Barnes [50] in a group of patients with moderately severe asthma, most of whom were using inhaled steroids. Hui and Barnes showed that the administration of zafirlukast (ICI204219) resulted in a 5% to 10% improvement in the FEV1. In the same patients, inhalation of a β2-agonist increased the FEV1 by 20% to 30%. However, the effects of the β2-agonist were additive with the effects of the CysLT1 receptor antagonist; this observation suggests that distinct contractile mechanisms are involved in each response. In a trial of similar design in which MK-571 (a chemically distinct CysLT1 receptor antagonist) was given intravenously, similar results occurred [51, 52]. In addition, when the 5-lipoxygenase inhibitor zileuton was given to persons with asthmatic bronchoconstriction [53], a 10% to 15% increase in FEV1 was seen. These data indicate that a significant component of asthmatic bronchoconstriction is directly due to the action of leukotrienes at their receptors and that the stimuli resulting in leukotriene synthesis are continuously activated. The latter point is evidenced by the fact that zileuton was as effective as leukotriene-receptor antagonists in reversing asthmatic bronchoconstriction.

    Airway Hyperresponsiveness

    The term airway responsiveness describes the ease with which airways narrow after exposure to constrictor agonists. Patients with asthma have airway hyperresponsiveness compared with persons who do not have asthma: that is, it takes less stimulus to achieve the same bronchoconstrictor response [54]. In general, the more responsive the airways, the more severe the asthma [55]. In addition, the severity of airway hyperresponsiveness is related, in populations of persons with asthma, to the amount of treatment needed to optimally control symptoms [56]. Finally, the degree of bronchoconstriction caused by exercise [57] or hyperventilation of cold, dry air in persons with asthma is related to the level of airway hyperresponsiveness [58].

    The capacity of leukotrienes to cause airway hyperresponsiveness in persons with stable asthma has not been well studied. In one study [59] but not in another [60], exogenously administered inhaled leukotriene D4 was shown to increase airway responsiveness. However, one recently published study from Fischer and colleagues [61] demonstrated that regular treatment with zileuton for 13 weeks improved airway responsiveness to cold air for as many as 10 days after completion of treatment, much longer than the expected duration of zileuton's pharmacologic action. This study suggests that the inhibition of leukotriene generation can improve airway hyperresponsiveness, possibly by alleviating airway inflammation. The only other class of antiasthma drug consistently shown to have an effect beyond the duration of its direct pharmacologic action is the glucocorticosteroids [62].

    Airway Inflammation

    Airway inflammation is central to the pathogenesis of symptoms, bronchoconstriction, and airway hyperresponsiveness in patients with asthma. Many studies have shown the presence of mast cells and activated eosinophils in the airway lumen and airway wall of patients with asthma, even those with mild disease [63-65]. Activated eosinophils and mast cells have the ability to release the cysteinyl leukotrienes, and measurements of urinary leukotrienes in asthmatic children suggest that the persistent generation of leukotrienes is a consequence of persisting airway inflammation [66]. In addition, inhaled leukotriene D4 has been shown to increase numbers of eosinophils in induced sputum specimens from asthmatic patients [67], and inhaled leukotriene E4 has been shown to markedly increased numbers of eosinophils in biopsy specimens from the airways of asthmatic patients [68]. These studies confirm the results of in vitro studies showing that the cysteinyl leukotrienes can cause eosinophil chemotaxis [69], and they suggest that the cysteinyl leukotrienes may be involved in the airway eosinophilia of asthma. This concept is supported by a study demonstrating that in patients with nocturnal asthma who were receiving zileuton, a reduction in airway eosinophil and leukotriene E4 levels was associated with an improvement in lung function when measurements were made at night [70]. These interesting results, taken together with the results of a study that indicate an improvement in airway hyperresponsiveness after zileuton treatment [61], suggest that the inhibition of leukotriene biosynthesis improves not only airway inflammation but also its physiologic effect on airway hyperresponsiveness. However, further studies are needed to show that the improvements in airway inflammation and airway hyperresponsiveness occur in the same patients.

    Laboratory-Induced Models of Asthma

    Exercise and Cold Air Hyperventilation

    Exercise-induced bronchoconstriction occurs in 70% to 80% of patients with symptomatic asthma [71]. The cysteinyl leukotrienes play a central role in causing exercise-induced and cold air-induced bronchoconstriction, as is shown by the effects of a variety of different CysLT1 receptor antagonists and leukotriene synthesis inhibitors. Administration of these agents markedly attenuates the bronchoconstrictor responses after exercise and cold air hyperventilation. The receptor antagonists, such as MK-571 [72] or zafirlukast (Accolate, Zeneca, Inc., United Kingdom), given orally [73] or by inhalation [74], inhibit the maximal bronchoconstrictor response after exercise by 50% to 70%, greatly shorten the time to recovery of normal lung function, and thus markedly reduce the time-response curve (Figure 2). In 30% to 50% of asthmatic patients studied, these agents completely inhibited response. Administration of the potent and long-lasting receptor antagonist cinalukast resulted in a reduction in exercise-induced bronchoconstriction (measured as the area under the time-response curve) after exercise by more than 80% in asthmatic patients, and this effect lasted more than 8 hours after dosing [75].

    Figure 2. Pretreatment with MK-571 markedly attenuated the decrease in FEV after exercise. Reproduced from Impens and colleagues with permission.
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    Figure 2. Pretreatment with MK-571 markedly attenuated the decrease in FEV after exercise. Reproduced from Impens and colleagues with permission. 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]

    Similar effects were shown when cold air hyperventilation was used to provoke bronchoconstriction. Israel and colleagues [76] have shown that treatment with zileuton attenuates this bronchoconstrictor response. Taken together, these studies indicate that cooling and drying the airways results in the generation of leukotrienes (presumably from resident airway cells, such as mast cells), which in turn results in bronchoconstriction. Multiple groups of investigators have observed heterogeneity among patients; they have observed that interruption of the leukotriene cascade results in complete inhibition of the bronchospastic response to exercise in some patients but has no effect in others. This indicates that the pathways leading to bronchoconstriction after exercise vary in different patients with asthma and that in some, mediators other than the leukotrienes may be more important bronchoconstrictor agonists.

    The clinical importance of these observations is that the currently available treatment for exercise-induced bronchoconstriction is not optimal for all patients. The usual treatment for such patients is two puffs of a medium-acting inhaled β2-agonist (such as albuterol) 5 to 10 minutes before exercise or two puffs of inhaled cromoglycate 15 to 20 minutes before exercise [77]. The effects of these interventions, however, are of limited duration. Long-acting inhaled β2-agonists (such as salmeterol) have been shown to provide more prolonged protection against exercise-induced bronchoconstriction. However, the regular use of both short-acting inhaled β2-agonists [78] and long-acting inhaled β2-agonists [79], rather than their use as prophylaxis, results in reduced protection against exercise-induced bronchoconstriction.

    Other types of antiasthma treatment are not very effective in protecting against exercise-induced bronchoconstriction. For example, oral β2-agonists and methylxanthines are marginally effective or ineffective in almost all patients [80, 81]. Thus, for the patients in whom leukotriene inhibition has a salutary effect, having an orally available treatment that provides prolonged protection against exercise-induced bronchoconstriction will be a therapeutic advance. In the only direct comparison published to date, the leukotriene antagonist SK&F 104353 was as effective as cromoglycate in preventing exercise-induced bronchoconstriction [82].

    Aspirin-Induced Asthma

    The cysteinyl leukotrienes are the primary mediators of the physiologic changes that occur in patients with aspirin-sensitive asthma after exposure to aspirin. When such patients inhale lysine aspirin, only a bronchoconstrictor response is observed. In clinical trials in which patients with aspirin-sensitive asthma were pretreated with the inhaled leukotriene-receptor antagonist SK&F 104353 [83] or the leukotriene-receptor antagonist MK-0679 [84], many patients tolerated-without developing clinically significant bronchoconstriction-all doses of inhaled lysine aspirin that had previously caused a bronchoconstrictor reaction. When aspirin is given systemically to patients with aspirin-sensitive asthma, naso-ocular, dermal, gastrointestinal, and bronchospastic responses occur. However, pretreatment of these persons with zileuton [85] or ZD2138 [86] completely ablated all physiologic responses seen after aspirin challenge. These data clearly implicate products of the 5-lipoxygenase pathway as the primary effector molecules in aspirin-induced asthma. Dahlen and coworkers [87] obtained additional evidence for this hypothesis by showing that the systemic administration of a CysLT1 receptor antagonist is associated with improved lung function in persons with aspirin-induced asthma in the absence of specific aspirin provocation. These observations suggest that inhibition of the leukotriene pathway will be the treatment of choice for patients with aspirin-induced asthma.

    Allergen-Induced Asthma

    Epidemiologic studies have suggested that the inhalation of environmental allergens is, overall, the most important cause of asthma [88]. Inhalation of specific allergens by sensitized patients results in acute bronchoconstriction, which usually resolves within 2 hours; this is known as the early asthmatic response. In as many as 50% of adult patients, the early asthmatic response is followed by a second period of bronchoconstriction beginning 3 to 4 hours after inhalation and lasting as long as 24 hours; this is known as the late asthmatic response [89]. The late asthmatic response is associated with increases in airway hyperresponsiveness, which can last several days to weeks [90].

    Cysteinyl leukotrienes are generated during the early asthmatic response [91, 92], and the magnitude of leukotriene generation, as indicated by increases in urinary excretion of the metabolite leukotriene E (4), directly correlates with the magnitude of the early asthmatic response [91]. Despite the increased availability of leukotrienes during the early asthmatic response, some of the early studies that used antileukotriene drugs did not show attenuation of this response [93-95]. However, this lack of a salutatory effect was probably due either to a lack of potency of the test compound or to inadequate bioavailability in the airways at the time of allergen inhalation. Since these equivocal results were found, many studies using antileukotriene drugs have shown that most of the bronchoconstriction seen during the early asthmatic response is attenuated and that the late asthmatic response is partially attenuated by such treatment. These studies have included a variety of antileukotriene agents, including such receptor antagonists as zafirlukast [96] and MK-571 [97], and other biosynthesis inhibitors, such as MK-886 [98], MK-0591 [99], and BAYx1005 [100]. The magnitude of the protection afforded by these drugs during the early asthmatic response has varied from 58% [98] to 84% [100]; taken together, these results show that the cysteinyl leukotrienes are the mediators responsible for most of the bronchoconstriction that occurs during the early asthmatic response. Similarly, treatment with antileukotriene agents has shown varied effectiveness in the magnitude of the protection afforded during the late asthmatic response; this effectiveness has ranged from 49% [97] to 60% [100]. This suggests that (because inhaled leukotriene D4 does not itself cause the development of late responses [101]), newly generated cysteinyl leukotrienes (possibly from inflammatory cells, such as eosinophils recruited into the airways during the late asthmatic response [102]), are only partially responsible for the bronchoconstriction seen during this response.

    Efficacy of Antileukotriene Drugs in Chronic Asthma

    Four different antileukotrienes have been used in trials of 1.5 to 26 weeks' duration, the results of which are published in the archival literature. The primary goal of these studies was to assess the capacity of these agents to control chronic stable asthma (Table 1). In the first, LY171883, an antagonist at the CysLT1 receptor that shifts the leukotriene D4 dose-response curve about fivefold to the right in nonasthmatic patients, was given to patients with mild asthma in a 6-week, parallel-group, placebo-controlled trial [103]. Patients receiving the leukotriene D4 receptor antagonist had a small but statistically significant increase in FEV1 (approximately 300 mL) during the trial. Moreover, in patients who were using inhaled β2-agonists more frequently before randomized treatment was begun, use of β2-agonists decreased while the FEV1 increased. In two other trials of 4 to 6 weeks' duration, zileuton [53] or zafirlukast [104] was compared with placebo. Each study used a randomized, double-blind, parallel-group design with a run-in period (during which patients received placebo [single blind]), followed by 4 [53] or 6 [104] weeks of double-blind randomized treatment. Patients receiving higher doses of either antileukotriene had a significantly greater increase in FEV1 than did patients receiving placebo, whereas patients receiving the lower doses had an increase of intermediate magnitude. Long-term treatment with either antileukotriene was also associated with significant decrements in use of asthma medication and asthma symptoms and with an increase in morning peak flow. The final shorter-term study compared the CysLT1 antagonist montelukast with placebo in a crossover study for 1.5 weeks and demonstrated a mean 16% improvement in FEV1[105]. Taken together, these data indicate that the leukotrienes mediate a clinically significant component of airway obstruction in patients with mild chronic stable asthma.

    These findings have been confirmed and extended in a 13-week and a 26-week study in patients with mild-to-moderate chronic stable asthma in which zileuton (400 mg or 600 mg four times daily) was compared with placebo [106, 107]. All patients were receiving treatment only with inhaled β2-agonists and had prebronchodilator FEV1 values that were approximately 60% of predicted normal values. Zileuton treatment was associated with an approximate 15% improvement in FEV1, decreased asthma symptoms, and decreased β2-agonist use. In both trials, more than 2.5-fold more patients receiving placebo required steroid “rescue” treatment than did patients receiving high-dose zileuton (Figure 3). The improvement in FEV1 did not significantly deteriorate during either study; thus, these studies extend previous findings that patients do not become “tolerant” of the effects of 5-lipoxygenase inhibition.

    Figure 3. 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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    Figure 3. 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. 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]

    Safety

    Because this entire class of drugs is new, total patient exposure to these agents is limited. Nevertheless, several issues have emerged. Zafirlukast has no clinically significant side effects and does not induce any laboratory abnormalities. In contrast, in a recent safety study done in more than 3000 patients, about 4.5% of the patients receiving zileuton and 1.1% of the patients receiving placebo had reversible elevations in hepatic aminotransferase levels to more than three times the upper limit of the reference range. These elevations occurred in the first 2 to 3 months after the initiation of treatment; after this time, the increased hepatic aminotransferase levels decreased to the levels seen in the placebo group [106].

    Antileukotriene Drugs in Asthma Treatment

    The studies described above were designed to evaluate the efficacy of antileukotrienes in asthma treatment, and they used study designs that would allow the investigators to obtain registration of the drugs in order to allow the drugs to be available for prescription. These studies have shown that antileukotrienes improve control of asthma, but they have not yet clearly shown how these drugs will fit into asthma management schemes. This is because no reports have yet been published on the comparative efficacy of these drugs in relation to already well-established antiasthma drugs, particularly inhaled corticosteroids.

    The published studies already, however, support two indications for the use of antileukotrienes. One is in patients with aspirin-sensitive asthma; these drugs are completely effective in blocking aspirin-induced asthmatic responses [85, 86], which can be life-threatening and are not prevented by any other currently available antiasthma treatment. Thus, antileukotrienes should be used in all patients with aspirin-induced asthma, together with other antiasthma treatments needed to control other manifestations of asthma. The second indication is in patients using regular inhaled β2-agonists who have exercise-induced bronchoconstriction. In these patients, the regular use of inhaled β2-agonists will reduce the ability of inhaled β2-agonists to protect against exercise-induced bronchoconstriction [78, 79]. Although no direct evaluation has been done, it is likely that antileukotrienes will be effective in this setting.

    No indication is apparent for the use of antileukotrienes in patients with very mild, intermittent asthma, in whom infrequent use of inhaled β2-agonists is adequate to control symptoms. In patients with more persistent symptoms, in whom another treatment is needed, the currently available consensus guidelines on asthma management suggest that inhaled corticosteroids or cromoglycate should be considered [108]. The available studies suggest that the antileukotrienes will be effective in some, perhaps as many as 50%, of these patients. If an antileukotriene is chosen as the next line of treatment, a 6- to 8-week therapeutic trial will allow a decision to be made about the efficacy of the treatment. If the treatment is not effective, no currently available evidence shows that it should be continued beyond 8 weeks. Obviously, studies directly comparing the antileukotrienes with more established antiasthma therapy are eagerly awaited.

    Some preliminary evidence suggests that the antileukotrienes may be even more effective in patients with more severe asthma. The fact that their effect is additive to the bronchodilation achieved even with high doses of inhaled β2-agonists [50-52] suggests that they may have a place in the treatment of the severe bronchoconstriction associated with acute severe asthma. In addition, clinical benefit has been shown with the addition of antileukotrienes to the treatment of patients with poor asthma control who are already using high doses of inhaled corticosteroids [109]. However, no evidence indicates that antileukotrienes can reduce the doses of inhaled or ingested corticosteroids required for asthma control.

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    Conclusions

    Antileukotrienes are an important novel therapy for asthma. Currently available data indicate that the inhibition of leukotriene synthesis or action has a salutary effect in the treatment of both induced and spontaneously occurring asthma. These results provide strong biological proof that leukotrienes are important mediators of the asthmatic response. Although encouraging results have been obtained in clinical trials of the antileukotrienes, the results do not yet provide guidelines for the optimal clinical use of antileukotrienes in asthma treatment; such recommendations await the results of further studies.

    Drs. Drazen and Israel: Respiratory Division, Harvard Medical School, Brigham and Woman's Hospital, 75 Francis Street, Boston, MA 02115.

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    References

    1. 1.↵
      Feldberg W, Kellaway CH. Liberation of histamine and formation of lysocithin-like substances by cobra venom. J Physiol. 1938; 94:187-91.
    2. 2.↵
      Kellaway CH, Trethewie ER. The liberation of a slow-reacting smooth muscle-stimulating substance in anaphylaxis. Q J Exp Physiol. 1940; 30:121-45.
    3. 3.↵
      Brocklehurst W. The release of histamine and formation of a slow reacting substance (SRS-A) during anaphylactic shock. J Physiol. 1960; 151:416-35.
    4. 4.↵
      Drazen JM, Austen KF. Effects of intravenous administration of slowreacting substance of anaphylaxis, histamine, bradykinin, and prostaglandin F2α on pulmonary mechanics in the guinea pig. J Clin Invest. 1974; 53:1679-85.
    5. 5.↵
      Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science. 1983; 220:568-75.
    6. 6.↵
      Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987; 237:1171-6.
    7. 7.↵
      Davidson FF, Dennis EA. Biological relevance of lipocortins and related proteins as inhibitors of phospholipase A2. Biochem Pharmacol. 1989; 38:3645-51.
    8. 8.↵
      Dennis EA. Modification of the arachidonic acid cascade through phospholipase A2 dependent mechanisms. Adv Prostaglandin Thromboxane Leukot Res. 1990; 20:217-23.
    9. 9.↵
      Kaiser E, Chiba P, Zaky K. Phospholipases in biology and medicine. Clin Biochem. 1990; 23:340-70.
    10. 10.↵
      Ferguson JE, Hanley MR. The role of phospholipases and phospholipidderived signals in cell activation. Curr Opin Cell Biol. 1991; 3:206-12.
    11. 11.↵
      Waite M. Phospholipases, enzymes that share a substrate class. Adv Exp Med Biol. 1990; 279:430-7.
    12. 12.↵
      Matsumoto T, Funk CD, Radmark O, Hoog JO, Jornvall H, Samuelsson B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci U S A. 1988; 85:26-30.
    13. 13.↵
      Rouzer CA, Rands E, Kargman S, Jones RE, Register RB, Dixon RA. Characterization of cloned human leukocyte 5-lipoxygenase expressed in mammalian cells. J Biol Chem. 1988; 263:10135-40.
    14. 14.↵
      Balcarek JM, Theisen TW, Cook MN, Varrichio A, Hwang SM, Strohsacker MW, et al. Isolation and characterization of a cDNA clone encoding rat 5-lipoxygenase. J Biol Chem. 1988; 263:13937-41.
    15. 15.↵
      Miller DK, Gillard JW, Vickers PJ, Sadowski S, Leveille C, Mancini JA, et al. Identification and isolation of a membrane protein necessary for leukotriene production. Nature. 1990; 343:278-81.
    16. 16.↵
      Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, et al. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature. 1990; 343:282-4.
    17. 17.↵
      Reid GK, Kargman S, Vickers PJ, Mancini JA, Leveille C, Ethier D, et al. Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis. J Biol Chem. 1990; 265:19818-23.
    18. 18.↵
      Woods JW, Evans JF, Ethier D, Scott S, Vickers PJ, Hearn L, et al. 5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes. J Exp Med. 1993; 178:1935-46.
    19. 19.↵
      Lam BK, Penrose JF, Freeman GJ, Austen KF. Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. Proc Natl Acad Sci U S A. 1994; 91:7663-7.
    20. 20.↵
      Lewis RA, Drazen JM, Austen KF, Clark DA, Corey EJ. Identification of the C(6)-S-conjugate of leukotriene A with cysteine as a naturally occurring slow reacting substance of anaphylaxis (SRS-A). Importance of the 11-cisgeometry for biological activity. Biochem Biophys Res Commun. 1980; 96:271-7.
    21. 21.↵
      Lam BK, Owen WF Jr, Austen KF, Soberman RJ. The identification of a distinct export step following the biosynthesis of leukotriene C4 by human eosinophils. J Biol Chem. 1989; 264:12885-9.
    22. 22.↵
      Lewis RA, Austen KF, Drazen JM, Clark DA, Marfat A, Corey EJ. Slow reacting substances of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources. Proc Natl Acad Sci U S A. 1980; 77:3710-4.
    23. 23.↵
      Parker CW, Huber MM, Hoffman MK, Falkenhein SF. Characterization of the two major species of slow reacting substance from rat basophilic leukemic cells as glutathionyl thioesters of eicosatetraenoic acids oxygenated at the 5 position. Evidence that peroxy groups are present and important for spasmogenic activity. Prostaglandins. 1979; 18:673-86.
    24. 24.↵
      Parker CW, Koch D, Huber MM, Falkenhein SF. Formation of the cysteinyl form of slow reacting substance (leukotriene E4) in human plasma. Biochem Biophys Res Commun. 1980; 97:1038-46.
    25. 25.↵
      Schleimer RP, MacGlashan DW Jr, Peters SP, Pinckard RN, Adkinson NF Jr, Lichtenstein LM. Characterization of inflammatory mediator release from purified human lung mast cells. Am Rev Respir Dis. 1986; 133:614-7.
    26. 26.↵
      Weller PF, Lee CW, Foster DW, Corey EJ, Austen KF, Lewis RA. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4. Proc Natl Acad Sci U S A. 1983; 80:7626-30.
    27. 27.↵
      Rankin JA, Hitchcock M, Merrill W, Bach MK, Brashler JR, Askenase PW. IgE-dependent release of leukotriene C4 from alveolar macrophages. Nature. 1982; 297:329-31.
    28. 28.↵
      Schonfeld W, Schluter B, Hilger R, Konig W. Leukotriene generation and metabolism in isolated human lung macrophages. Immunology. 1988; 65:529-36.
    29. 29.↵
      Carter GW, Young PR, Albert DH, Bouska J, Dyer R, Bell RL, et al. 5-lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther. 1991; 256:929-37.
    30. 30.↵
      Ford-Hutchinson AW. FLAP: a novel drug target for inhibiting the synthesis of leukotrienes. Trends Pharmacol Sci. 1991; 12:68-70.
    31. 31.↵
      Coleman RA, Eglen RM, Jones RL, Narumiya S, Shimizu T, Smith WL, et al. Prostanoid and leukotriene receptors: a progress report from the IUPHAR working parties on classification and nomenclature. Adv Prostaglandin Thromboxane Leukot Res. 1995; 23:283-5.
    32. 32.↵
      Wetmore LA, Gerard NP, Herron DK, Bollinger NG, Baker SR, Feldman HA, et al. Leukotriene receptor on U-937 cells: discriminatory responses to leukotrienes C4 and D4. Am J Physiol. 1991; 261(2 Pt 1):L164-71.
    33. 33.↵
      Mong S, Wu HL, Scott MO, Lewis MA, Clark MA, Weichman BM, et al. Molecular heterogeneity of leukotriene receptors: correlation of smooth muscle contraction and radioligand binding in guinea-pig lung. J Pharmacol Exp Ther. 1985; 234:316-25.
    34. 34.↵
      Mong S, Wu HL, Stadel JM, Clark MA, Crooke ST. Solubilization of [3H]leukotriene D4 receptor complex from guinea pig lung membranes. Mol Pharmacol. 1986; 29:235-43.
    35. 35.↵
      Mong S, Chi-Rosso G, Hay DW, Crooke ST. Subcellular localization of leukotriene D4 receptors in sheep tracheal smooth muscle. Mol Pharmacol. 1988; 34:590-6.
    36. 36.↵
      Thorpe JE, Murlas CG. Effects of leukotriene D4 and antagonists of arachidonic acid metabolism and calcium entry on guinea pig tracheal muscle responsiveness. Prostaglandins Leukot Med. 1986; 24:269-77.
    37. 37.↵
      Crooke ST, Mattern M, Sarau HM, Winkler JD, Balcarek J, Wong A, et al. The signal transduction system of the leukotriene D4 receptor. Trends Pharmacol Sci. 1989; 10:103-7.
    38. 38.↵
      Crooke ST, Sarau H, Saussy D, Winkler J, Foley J. Signal transduction processes for the LTD4 receptor. Adv Prostaglandin Thromboxane Leukot Res. 1990; 20:127-37.
    39. 39.↵
      Mong S, Hoffman K, Wu HL, Crooke ST. Leukotriene-induced hydrolysis of inositol lipids in guinea pig lung: mechanism of signal transduction for leukotriene-D4 receptors. Mol Pharmacol. 1987; 31:35-41.
    40. 40.↵
      Mong S, Wu HL, Miller J, Hall RF, Gleason JG, Crooke ST. SKF 104353, a high affinity antagonist for human and guinea pig lung leukotriene D4 receptor, blocked phosphatidylinositol metabolism and thromboxane synthesis induced by leukotriene D4. Mol Pharmacol. 1987; 32:223-9.
    41. 41.↵
      Dillard RD, Hahn RA, McCullough D, Carr FP, Rinkema LE, Roman CR, et al. (Phenylmethoxy)phenyl derivatives of omega-oxo- and omega-tetrazolylalkanoic acids and related tetrazoles. Synthesis and evaluation as leukotriene D4 receptor antagonists. J Med Chem. 1991; 34:2768-78.
    42. 42.↵
      Fleisch JH, Rinkema LE, Haisch KD, Swanson-Bean D, Goodson T, Ho PP, et al. LY171883, 1 < 2-hydroxy-3-propyl-4-< 4-(1H-tetrazol-5-yl) butoxy > phenyl > ethanone, an orally active leukotriene D4 antagonist. J Pharmacol Exp Ther. 1985;233:148-57.
    43. 43.↵
      Hay DW, Muccitelli RM, Tucker SS, Vickery-Clark LM, Wilson KA, Gleason JG, et al. Pharmacologic profile of SK&F 104353: a novel, potent and selective peptidoleukotriene receptor antagonist in guinea pig and human airways. J Pharmacol Exp Ther. 1987;243:474-81.
    44. 44.↵
      Jones TR, Young R, Champion E, Charette L, Denis D, Ford-Hutchinson AW, et al. L-649,923 sodium (β S, γ R)-4-(3-[4-acetyl-3-hydroxy-2-propylphenoxy]-propylthio)-γ-hydroxy-β-methylbenzenebutanoate, a selective, orally active leukotriene receptor antagonist. Can J Physiol Pharmacol. 1986; 64:1068-75.
    45. 45.↵
      Jones TR, Zamboni R, Belley M, Champion E, Charette L, Ford-Hutchinson AW, et al. Pharmacology of L-660,711 (MK-571): a novel, potent and selective leukotriene D4 receptor antagonist. Can J Physiol Pharmacol. 1989; 67:17-27.
    46. 46.↵
      O'Donnell M, Crowley HJ, Yaremko B, O'Neill N, Welton AF. Pharmacologic actions of RO 24-5913, a novel antagonist of leukotriene D (4). J Pharmacol Exp Ther. 1991; 259:751-9.
    47. 47.↵
      Snyder DW, Giles RE, Keith RA, Yee YK, Krell RD. In vitro pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist. J Pharmacol Exp Ther. 1987; 243:548-56.
    48. 48.↵
      Torphy TJ, Newton JF, Wasserman MA, Vickery-Clark L, Osborn RR, Bailey LS, et al. The bronchopulmonary pharmacology of SK&F 104353 in anaesthetized guinea pigs: demonstration of potent and selective antagonism of responses to peptidoleukotrienes. J Pharmacol Exp Ther. 1989;249:430-7.
    49. 49.↵
      Weichman BM, Wasserman MA, Gleason JG. SK&F 88046: a unique pharmacologic antagonist of bronchoconstriction induced by leukotriene D (4), thromboxane and prostaglandins F2α and D2 in vitro. J Pharmacol Exp Ther. 1984;228:128-32.
    50. 50.↵
      Hui KP, Barnes NC. Lung function improvement in asthma with a cysteinylleukotriene receptor antagonist. Lancet. 1991; 337:1062-3.
    51. 51.↵
      Gaddy JN, Margolskee DJ, Bush RK, Williams VC, Busse WW. Bronchodilation with a potent and selective leukotriene D4 (LTD4) antagonist (MK-571) in patients with asthma. Am Rev Respir Dis. 1992; 146:358-63.
    52. 52.↵
      Impens N, Reiss TF, Teahan JA, Desmet M, Rossing TH, Shingo S, et al. Acute bronchodilation with an intravenously administered leukotriene D4 antagonist, MK-679. Am Rev Respir Dis. 1993; 147(6 Pt 1):1442-6.
    53. 53.↵
      Israel E, Rubin P, Kemp JP, Grossman J, Pierson W, Siegel SC, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med. 1993; 119:1059-66.
    54. 54.↵
      Woolcock AJ, Salome CM, Yan K. The shape of the dose-response curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis. 1984; 130:71-5.
    55. 55.↵
      Ryan G, Latimer KM, Dolovich J, Hargreave FE. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway calibre. Thorax. 1982; 37:423-9.
    56. 56.↵
      Juniper EF, Frith PA, Hargreave FE. Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma. Thorax. 1982; 37:288-91.
    57. 57.↵
      Anderton RC, Cuff MT, Frith PA, Cockcroft DW, Morse JL, Jones NL, et al. Bronchial responsiveness to inhaled histamine and exercise. J Allergy Clin Immunol. 1979; 63:315-20.
    58. 58.↵
      O'Byrne PM, Ryan G, Morris M, McCormack D, Jones NL, Morse JL, et al. Asthma induced by cold air and its relation to nonspecific bronchial responsiveness to methacholine. Am Rev Respir Dis. 1982; 125:281-5.
    59. 59.↵
      Smith LJ, Greenberger PA, Patterson R, Krell RD, Bernstein PR. The effect of inhaled leukotriene D4 in humans. Am Rev Respir Dis. 1985; 131:368-72.
    60. 60.↵
      Manning PJ, O'Byrne PM. The effects of inhaled leukotriene D4 on histamine airway responsiveness in asthmatic subjects [Abstract]. Am Rev Respir Dis. 1992; 145:287A.
    61. 61.↵
      Fischer AR, McFadden CA, Frantz R, Awni WM, Cohn J, Drazen JM, et al. Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness, in asthmatic subjects. Am J Respir Crit Care Med. 1995; 152(4 Pt 1):1203-7.
    62. 62.↵
      Juniper EF, Kline PA, Vanzieleghem MA, Hargreave FE. Reduction of budesonide after a year of increased use: a randomized, controlled trial to evaluate whether improvements in airway responsiveness and clinical asthma are maintained. J Allergy Clin Immunol. 1991; 87:483-9.
    63. 63.↵
      Kirby JG, Hargreave FE, Gleich GJ, O'Byrne PM. Bronchoalveolar cell profiles of asthmatic and nonasthmatic subjects. Am Rev Respir Dis. 1987; 136:379-83.
    64. 64.↵
      Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis. 1989; 139:806-17.
    65. 65.↵
      Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, et al. Predominant TH-2 like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992; 326:298-304.
    66. 66.↵
      Sampson AP, Castling DP, Green CP, Price JF. Persistent increase in plasma and urinary leukotrienes after acute asthma. Arch Dis Child. 1995; 73:221-5.
    67. 67.↵
      Diamant Z, Rensen EL, Callenbach PM, Veselic-Charvat MA, van der Veen H, Sterk PJ. Cell differentials in induced sputum after inhaled leukotriene D4 in subjects with mild asthma [Abstract]. Am J Respir Crit Care Med. 1996; 153:A290.
    68. 68.↵
      Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur BW, Lee TH. Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet. 1993; 341:989-90.
    69. 69.↵
      Spada CS, Nieves AL, Krauss AH, Woodward DF. Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro. J Leukoc Biol. 1994; 55:183-91.
    70. 70.↵
      Wenzel SE, Trudeau JB, Kaminsky DA, Cohn J, Martin RJ, Westcott JY. Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma. Am J Respir Crit Care Med. 1995; 152:897-905.
    71. 71.↵
      Anderson SD. Exercise-induced asthma. The state of the art. Am Rev Respir Dis. 1985; 875:191-5.
    72. 72.↵
      Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O'Byrne PM. Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med. 1990; 323:1736-9.
    73. 73.↵
      Finnerty JP, Wood-Baker R, Thomson H, Holgate ST. Role of leukotrienes in exercise-induced asthma. Inhibitory effect of ICI 204,219, a potent leukotriene D4 receptor antagonist. Am Rev Respir Dis. 1992; 145:746-9.
    74. 74.↵
      Makker HK, Lau LC, Thomson HW, Binks SM, Holgate ST. The protective effect of inhaled leukotriene D4 receptor antagonist ICI 204,219 against exercise-induced asthma. Am Rev Respir Dis. 1993; 147:1413-8.
    75. 75.↵
      Adelroth E, Inman MD, Summers E, Pace D, Modi M, O'Byrne PM. Prolonged protection against exercise-induced bronchoconstriction by the leukotriene D4-receptor antagonist cinalukast. J Allergy Clin Immunol. 1997; 99:210-5.
    76. 76.↵
      Israel E, Dermarkarian R, Rosenberg M, Sperling R, Taylor G, Rubin P, et al. The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med. 1990; 323:1740-4.
    77. 77.↵
      Anderson S, Seale JP, Ferris L, Schoeffel R, Lindsay DA. An evaluation of pharmacotherapy for exercise-induced asthma. J Allergy Clin Immunol. 1979; 64:612-24.
    78. 78.↵
      Inman M, O'Byrne PM. The effect of regular inhaled albuterol on exercise-induced bronchoconstriction. Am J Respir Crit Care Med. 1996; 153:65-9.
    79. 79.↵
      Ramage L, Lipworth BJ, Ingram CG, Cree IA, Dhillon DP. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med. 1994; 88:363-8.
    80. 80.↵
      Ellis EF. Inhibition of exercise-induced asthma by theophylline. J Allergy Clin Immunol. 1984; 73:690-2.
    81. 81.↵
      Fuglsang G, Hertz B, Holm EB. No protection by oral terbutaline against exercise-induced asthma in children: a dose-response study. Eur Respir J. 1993; 6:527-30.
    82. 82.↵
      Robuschi M, Riva E, Fuccella LM, Vida E, Barnabe R, Rossi M, et al. Prevention of exercise-induced bronchoconstriction by a new leukotriene antagonist (SK&F 104353). A double-blind study versus disodium cromoglycate and placebo. Am Rev Respir Dis. 1992;145:1285-8.
    83. 83.↵
      Christie PE, Smith CM, Lee TH. The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353, inhibits aspirin-induced asthma. Am Rev Respir Dis. 1991;144:957-8.
    84. 84.↵
      Dahlen B, Kumlin M, Margolskee DJ, Larsson C, Blomqvist H, Williams VC, et al. The leukotriene-receptor antagonist MK-0679 blocks airway obstruction induced by inhaled lysine-aspirin in aspirin-sensitive asthmatics. Eur Respir J. 1993; 48:1018-26.
    85. 85.↵
      Israel E, Fischer AR, Rosenberg MA, Lilly CM, Callery JC, Shapiro J, et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis. 1993; 148:1447-51.
    86. 86.↵
      Nasser SM, Bell GS, Foster S, Spruce KE, MacMillan R, Williams AJ, et al. Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax. 1994; 49:749-56.
    87. 87.↵
      Dahlen B, Margolskee DJ, Zetterstrom O, Dahlen SE. Effect of the leukotriene receptor antagonist MK-0679 on baseline pulmonary function in aspirin sensitive asthmatic subjects. Thorax. 1993; 48:1205-10.
    88. 88.↵
      Peat JK, Tovey E, Toelle BG, Haby MM, Gray EJ, Mahmic A, et al. House dust mite allergens. A major risk factor for childhood asthma in Australia. Am J Respir Crit Care Med. 1994; 153:141-6.
    89. 89.↵
      O'Byrne PM, Dolovich J, Hargreave FE. Late asthmatic responses. Am Rev Respir Dis. 1987; 136:740-51.
    90. 90.↵
      Cartier A, Thomson NC, Frith PA, Roberts R, Hargreave FE. Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber. J Allergy Clin Immunol. 1982; 70:170-7.
    91. 91.↵
      Taylor GW, Taylor I, Black P, Maltby NH, Turner N, Fuller RW, et al. Urinary leukotriene E4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet. 1989; 1:584-8.
    92. 92.↵
      Manning PJ, Rokach J, Malo JL, Ethier D, Cartier A, Girard Y, et al. Urinary leukotriene E4 levels during early and late asthmatic responses. J Allergy Clin Immunol. 1990; 86:211-20.
    93. 93.↵
      Mann JS, Robinson C, Sheridan AQ, Clement P, Bach MK, Holgate ST. Effect of inhaled piriprost (U-60, 257) a novel leukotriene inhibitor, on allergen and exercise induced bronchoconstriction in asthma. Thorax. 1986; 41:746-52.
    94. 94.↵
      Bel EH, Timmers MC, Dijkman JH, Stahl EG, Sterk PJ. The effect of an inhaled leukotriene antagonist, L-648,051, on early and late asthmatic reactions and subsequent increase in airway responsiveness in man. J Allergy Clin Immunol. 1990; 85:1067-75.
    95. 95.↵
      Hui KP, Taylor IK, Taylor GW, Rubin P, Kesterson J, Barnes NC, et al. Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax. 1991; 46:184-9.
    96. 96.↵
      Taylor IK, O'Shaughnessy KM, Fuller RW, Dollery CT. Effect of cysteinyl-leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet. 1991; 337:690-4.
    97. 97.↵
      Rasmussen JB, Eriksson LO, Margolskee DJ, Tagari P, Williams VC, Andersson KE. Leukotriene D4 receptor blockade inhibits the immediate and late bronchoconstrictor responses to inhaled antigen in patients with asthma. J Allergy Clin Immunol. 1992; 90:193-201.
    98. 98.↵
      Friedman BS, Bel EH, Buntinx A, Tanaka W, Han YH, Shingo S, et al. Oral leukotriene inhibitor (MK-886) blocks allergen-induced airway responses. Am Rev Respir Dis. 1993; 147:839-44.
    99. 99.↵
      Diamant Z, Timmers MC, van der Veen H, Friedman BS, De Smet M, Depre M, et al. The effect of MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on leukotriene biosynthesis and allergen-induced airway responses in asthmatic subjects in vivo. J Allergy Clin Immunol. 1995; 95:42-51.
    100. 100.↵
      Hamilton AL, Watson R, Strong HA, Wylie G, O'Byrne PM. A 5-lipoxygenase activating protein antagonist, Bayx1005, attenuates both early and late phase allergen-induced bronchoconstriction in asthmatic subjects. Thorax. 1997; 52:348-54.
    101. 101.↵
      Higgins DA, O'Byrne PM. Inhaled leukotriene D4 does not cause a late response in atopic subjects. Allergy Clin Immunol. 1987; 79:141.
    102. 102.↵
      De Monchy JG, Kauffman HF, Venge P, Koeter GH, Jansen HM, Sluiter HJ, et al. Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am Rev Respir Dis. 1985; 131:373-6.
    103. 103.↵
      Cloud ML, Enas GC, Kemp J, Platts-Mills T, Altman LC, Townley R, et al. A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma. Am Rev Respir Dis. 1989; 140:1336-9.
    104. 104.↵
      Spector SL, Smith LJ, Glass M. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. ACCOLATE Asthma Trialists Group. Am J Respir Crit Care Med. 1994; 150:618-23.
    105. 105.↵
      Reiss TF, Altman LC, Chervinsky P, Bewtra A, Stricker WE, Noonan GP, et al. Effects of montelukast (MK-0476), a new potent cysteinyl leukotriene (LTD4) receptor antagonist, in patients with chronic asthma. J Allergy Clin Immunol. 1996; 98:528-34.
    106. 106.↵
      Israel E, Cohn J, Dube L, Drazen JM. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized, controlled trial. Zileuton Clinical Trial Group. JAMA. 1996; 275:931-6.
    107. 107.↵
      Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J Allergy Clin Immunol. 1996; 98:859-71.
    108. 108.↵
      Sheffer AL, Bartal M, Bousquet J, Carrasco E, et al. Global Strategy for Asthma Management and Prevention. Bethesda, MD: National Institutes of Health; 1995; 70-114.
    109. 109.↵
      Chapman KR, Friedman BS, Shingo S, Heyse J, Reiss T, Spector R. The efficacy of an oral inhibitor of leukotriene synthesis (MK-0591) in asthmatics treated with inhaled steroids [Abstract]. Am J Respir Crit Care Med. 1994; 149:A215.
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