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15 September 1997 | Volume 127 Issue 6 | Pages 472-480
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 ß2-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 ß2-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.
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. REVIEW
Antileukotrienes in the Treatment of Asthma
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.
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.
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 
-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.
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].
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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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Roles of Leukotrienes in Asthma
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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 ß2-agonist increased the FEV1 by 20% to 30%. However, the effects of the ß2-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].
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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 ß2-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 ß2-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 ß2-agonists [78] and long-acting inhaled ß2-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 ß2-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 ß2-agonists more frequently before randomized treatment was begun, use of ß2-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 ß2-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 ß2-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.
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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 ß2-agonists who have exercise-induced bronchoconstriction. In these patients, the regular use of inhaled ß2-agonists will reduce the ability of inhaled ß2-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 ß2-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 ß2-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.
Conclusions
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Drs. Drazen and Israel: Respiratory Division, Harvard Medical School, Brigham and Woman's Hospital, 75 Francis Street, Boston, MA 02115.
Author and Article Information
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References
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