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RESPIRATORY MEDICINE (1998) 92, 795-809

Leukotriene antagonism in asthma and rhinitis

S. J. LANE

Department of Allergy and Respiratory Medicine, United Medical and Dental Schools, Guys Hospital, London, U.K.

Introduction 1998. All agents are administered orally. This review will outline the background to the development of these drugs Bronchial asthma and rhinosinusitis are inflammatory con- from the ‘molecule to the bedside’ and suggest their poten- ditions which affect the lower and upper airways, respect- tial role in the management of asthma and rhinosinusitis. ively, and frequently co-exist. Indeed, evidence shows that 80% of asthmatics also have rhinosinusitis, and 50% of patients with rhinosinusitis have asthma (1). Moreover, in 45% of cases, the development of rhinosinusitis occurs Biosynthesis before that of asthma and adequate control of rhinosinus- itis can improve asthma control in patients with concomi- Leukotrienes (LTs) were discovered during the elucidation tant disease (2). Both conditions are underpinned by similar of a mixture of compounds referred to as the slow reacting pathological changes characterized by an intense inflamma- substance of anaphylaxis or SRS-A. In 1940, Kellaway and tory infiltrate of activated mononuclear cells and granulo- Trethewie found that a product of an in vitro anaphylactic cytes of which the eosinophil is prominent (3-8). In reaction in guinea-pig lung caused smooth muscle tissue addition, it is now firmly established that both conditions to constrict more slowly than did histamine (12). The are mediated in part by the cysteinyl-leukotrienes. In both discovery of antihistamines in the 1950s allowed the of these conditions, site-specific leukotrienes can be discovery of a non-histamine component which was subse- detected in increased quantities as compared to normal quently identified as SRS-A. In view of the lack of efficacy control subjects; their levels change in response to specific of antihistamines in the management of patients with challenge procedures and disease exacerbations; exogenous asthma, it seemed likely that SRS-A was involved in the administration can mimic components of the disease pro- reversible airway problems of humans with this disease. In cesses; and specific antagonists have been demonstrated to 1980, the composition of SRS-A was finally elucidated by reverse components of these diseases in vitro, in vivo and in Morris et al., Lewis, Austen and Samuelsson et al., as the real clinical setting. As compared to glucocorticoids comprising leukotriene C4 (LTC,) and its biologically (GCS), which are currently the most effective treatment active metabolites, LTD, and LTE, (13-l 5). In addition to available for asthma and rhinosinusitis, leukotriene antag- asthma and rhinosinusitus, LTs have been implicated onists are specific in their mechanism of action and are in the pathogenesis of psoriasis, ischaemic heart disease, thereby relatively free from serious side-effects (9,lO). At rheumatoid arthritis, inflammatory bowel disease, and present, two such agents have been approved for the malignancy. treatment of asthma by the Food and Drug Administration LTs are generated de lzovo upon cellular activation when (FDA) in the U.S.A. Zileuton (Zyflo@), an inhibitor of arachidonic acid (AA), a 20-carbon polyunsaturated fatty 5-lipoxygenase, and zafirlukast (Accolate@), an inhibitor of acid, is released from nuclear membrane phospholipids by the action of LTD, at its receptor, are now available the action of the cytosolic enzyme phospholipase A, by prescription in the U.S.A., Ireland, and Norway. (PLA,), and is converted to the unstable intermediate LTA, Pranlukast and montelukast (Singulaira) (ll), both of by the enzyme 5-lipoxygenase (5-LO) in the first dedicated which are also inhibitors of LTD,, will likely receive steps of leukotriene generation (16) (Fig. 1). Cytosolic approval before the end of 1998. Montelukast has been PLA, is upregulated by inflammatory cytokines and inhib- licensed in the U.K. since February 1998 as add-on therapy ited by glucocorticoids. LTA, is then converted to either in mild to moderate persistent asthma that is inadequately LTB, or LTC, depending upon the cellular availability of controlled by inhaled glucocorticoids and &-agonists, and LTA, hydrolase or LTC, synthase, respectively. Multiple also for the prophylaxis of exercise-induced broncho- lipoxygenases exist that catalyse molecular oxygen insertion constriction. Accolate is expected to be available later in into arachidonic acid at either the 5-, 12-, or 15-carbon position. In the resting cell, 5-LO is closely bound to Received 6 April 1997 and accepted 24 March 1998 nuclear euchromatin. Upon cellular activation, 5-LO trans- Correspondence to be sent to: S. J. Lane, Department of Allergy locates to the nuclear membrane in a Ca”- and ATP- and Respiratory Medicine, United Medical and Dental Schools, dependent mechanism where it binds to the 5-LO activating 5th Floor, Thomas Guy House, Guy’s Hospital, London SE1 9RT, protein (FLAP). FLAP is an essential co-factor for eventual U.K. LT generation (17). U937 cells express FLAP but not 5-LO

0954.6111/98/060795 + 15 $12.00/O 0 1998 W. B. SAUNDERS COMPANY LTD 796 S. J. LANE

Membrane phospholipids LTA, hydrolase or LTD, synthase, respectively. Phagocytic cells (monocytes, tissue, macrophages, and neutrophils) Cytosolic phospholipase A2 preferentially generate LTB,, whereas eosinophils, mast I cells, and basophils preferentially generate cysteinyl leuko- Arachidonic acid triene products (19,20) (Table 1). Unlike 5-LO, LTC, synthase and LTAb hydrolase are widely distributed in 15.lipoxygenase &lip”+ 1 l~-lipovgenase mammalian cells. Thus LTA, released by a cell capable of / \ generating 5-LO products may be utilized for further 15-HPETE SHPETE FLAP 12-HPETE metabolism by other cells without the enzyme 5-LO. Such transcellular metabolism can lead to the generation of 5.lipoxygenase 12.lipoxygenase 16lipoxygenase ’ J LTC, by cells such as endothelium, which would not I I normally generate it (21). After formation, LTB, is 15-HETE LTA4 12-HETE exported from the cell to exert its biological effects. If LTB, undergoes reuptake or is retained intracellularly, its LTC4 sptA LTA4 hydrolase catabolism/inactivation varies with cell type. Neutrophils inactivate LTB, by a series of three sequential oxidations of LTC4 LTB4 the C-20 carbon, while monocytes/macrophages and kidney Gamma glutamyl mesangial cells inactivate LTB, via oxidation of the C-12 transpeptidase I carbon. The biological activity of each of the intermediates LTD4 decreases and the final product is inactive when metabo- dipeptidase lized in this fashion. LTC, is metabolized to the other I biologically active cysteinyl leukotrienes after transport LTE4 from the cell. This occurs by enzymes that sequentially FIG. 1. Schematic representation of leukotriene synthetic cleave amino acid residues to form leukotriene D4 (LTD,), pathways and the enzymes catalysing specific reactions. which is then converted to the final bioactive cysteinyl FLAP, 5-lipoxygenase activating protein; HETE, leukotriene, leukotriene E, (LTE,). LTE, is then excreted hydroxy-eicosatetraenoic acid; HPETE, hydroperoxy- directly or after N-acetylation. The cysteinyl leuko- eicosatetraenoic acid; LT, leukotriene. trienes may also be inactivated in the local extracellular environment via oxidation. and therefore cannot synthesize LTs. The ability to synthe- size LTs can be restored by transfection with a retroviral Biological Activity vector encoding the 5-LO mRNA (18). As the cellular synthesis of leukotrienes is limited by the requirement to For a molecule to be implicated in any disease process such express both 5-LO and FLAP, cells of myeloid lineage as asthma or rhinosinusitis, it must satisfy certain criteria. provide the major source of leukotriene production. Cells The mediator should mimic a component of the disease can be divided by their ability to preferentially synthesize both in vitro and in vivo. The mediator, or its metabolite, LTB, or the cysteinyl leukotrienes, LTC,, LTD, and LTD,, should be identified in the blood, urine, or other relevant depending on the intracellular predominance of either biological fluid, and be shown to increase temporally in

TABLE 1. Cellular source of human leukotriene generation

Approximate Predominant amount leukotriene Activating generated/lo6 Cell product stimulus cells

Neutrophils LTB, A23 187 50 ng LTC, A23187 10 11g Eosinophils LTB, A23187 long LTC, A23187 40 ng Peripheral blood LTB, A23 187 70 ng Monocytes LTC, 30 ng Alveolar macrophages LTB, A23187 30 ng Mast cells LTC, A23187 or anti-IgE 20 ng Basophils LTC, A23187 long

LTB,, leukotriene B,; LTC,, leukotriene C,; A23187, divalent calcium ionophere; AA, arachidonic acid (18-21). LEUKOTRIENE ANTAGONISM 797

TABLE 2. Biological activity of cysteinyl leukotrienes

Activity Reference

Augment post-capillary dermal vascular permeability (23) in guinea-pigs (14) Increased microvascular permeability (23) Increase leukocyte adhesion to endothelial cells (26) Increase mucous secretion (144) Potent contractile agonists for bronchial smooth muscle (28) Vasoconstriction (145) (146) Coronary vasoconstriction in sheep (147) Systemic vasoconstriction in rats (148) Renal vasoconstriction in rats (149) Recruit granulocytes into the lamina propria of asthmatic airways (LTE,) (150)

association with an occurrence of the disease process in an smaller responses when compared with a reference agonist animal and human model of the disease. Finally, and most such as histamine or methacholine. The results of these importantly, a selective mediator antagonist should be able studies indicate that, compared with normal airways, to reverse the disease component in vitro and eventually in asthmatic airways are relatively less responsive to LTC, the real clinical setting. LTs exert their biological effects via and LTD, but have a disproportionate hyperresponsiveness specific cell membrane receptors. The leukotriene B recep- to the bronchoconstricting effects of LTE, (31-33). This tors are characterized in terms of their activation by LTB, indicates an important role for LTE, in bronchial asthma as well as their antagonism by potent and selective antag- which may be due to its greater stability compared with onists. Although the structure of these receptors has not other cysteinyl leukotrienes, and because it persists for the been fully elucidated, two forms have been identified in longest time at the site of release. neutrophils. These two receptor forms each have different LTs also enhance BHR in normal, asthmatic and rhinitic affinity states: the one with high affinity transduces chemo- patients. Kern et al. have shown that LTD, enhanced BHR tactic and adhesion responses, and the low affinity receptor to methacholine by 280-590% in normal subjects (34). is responsible for granule content release and superoxide These studies were extended by Smith et al. who demon- generation. The cysteinyl leukotriene receptors can be strated that LTD, enhanced methacholine BHR in rhinitics divided into two categories. Cys-LTR, responds primarily (without asthma) and in asthmatics by three to five-fold to LTCJLTD, and is responsive to antagonists. Cys-LTR, and 250~850-fold., respectively when compared to normal interacts with LTC, and is relatively resistant to antagonists control subjects (35). O’Hickey et al. have demonstrated (22-23). that LTC,, LTD, and LTE, enhanced airway responsive- The main biological activities of LTB, relate to the ness to histamine by 3.9-, 2.8 and 3.1-fold, respectively, in augmentation of phagocytic and non-specific immune asthmatic airways (36). The effect of LTE, was partially responses, whereas the activities of the cysteinyl-LTs abrogated by indomethacin indicating that LTE,- are more directly pertinent to asthma and rhinosinusitis induced BHR is mediated in part by cyclooxygenase (Table 2). The latter are vastly more potent contractile pathway-derived products (37). agonists of smooth muscle than histamine, they greatly increase microvascular permeability, and are chemotactic for granulocytes, particularly eosinophils (24-27). LTC, Leukotriene Release and LTD, are lOOO-fold more potent than histamine in contracting human bronchial smooth muscle strips in vitro Leukotrienes have been detected in a variety of biological (28). fluids by employing sensitive assay systems to detect pico- The inhalation of leukotrienes by human subjects has gram quantities such as high-performance liquid chroma- shown potent contraction of the airways in both normal tography (HPLC), radioimmunoassay and fast-atom and asthmatic subjects and leads to airway obstruction. bombardment mass spectrometry (Table 3). Bronchalveolar When data from different sources are combined, inhaled lavage (BAL) has been used as a tool to obtain fluid in LTC, and LTD, in normal subjects are 2000 times more pulmonary disease states. Because the ratio of the volume potent than histamine or methacholine in causing airway of lavage fluid instilled to that recovered is not always obstruction (29). LTE, is, however, only 40- to 60-fold constant, BAL suffers from the drawback that it is not more potent than histamine but produces a longer lasting easy to interpret the absolute values given and the results bronchoconstruction in normal subjects (30). Asthmatic are usually expressed in terms of amounts per volume airways also respond by bronchoconstruction to inhaled recovered. Urine is a more reliable biological fluid and leukotrienes but, in contrast to normal airways, exhibit amounts of mediator are easily standardized by expressing 798 S. J. LANE

TABLE 3. Release of leukotrienes into biological fluids

Biological Disease fluid Leukotriene release

Asthma Clinical disease BAL LTE, detected in mild asthma/severe Symptomatic BAL LTB,/LTC, Acute Urine LTE, - highest levels in patients responding to &agonist treatment Allergen challenge Early allergen response BAL LTC, increases nine-fold Urine LTE, increases 24 h after allergen challenge Aspirin-sensitive Urine LTE, six-fold higher at baseline and increases a further four-fold after aspirin challenge Exercise-induced BAL LTB, rises 12-fold and LTC, rises five-fold after isocapnic hyperventilation Urine LTE, found to increase 1.7-fold in a study of children with severe asthma Nasal lavage LTC, levels increase after lysine-aspirin challenge Cryptogenic-fibrosing alveolitis BAL LTB, detected Persistent pulmonary hypertension BAL LTC, and LTD, detected in newborn infants Adult respiratory distress syndrome Pulmonary oedema fluid LTD, increased four-fold Rheumatoid arthritis Synovial fluid LTB, detected in active disease Gouty arthritis Joint fluid LTB, levels significantly increased Psoriasis Skin chamber fluid LTB,, LTC, and LTD, levels detected in increased quantities Inflammatory bowel colitis disease Intestinal mucosal fluid LTB, detected in both ulcerative and Crohn’s disease Acute myocardial infarction Urine LTE, levels raised and return to normal by day 3 Hepatorenal syndrome Urine LTE, levels elevated three-fold

quantities per mg of creatinine which is excreted in rela- There was only a slight rise in BAL LTC, levels after tively constant fashion throughout a 24-h period (38). allergen in the atopic non-asthmatic group and no change Maltby et al. found that by infusing three subjects with in the non-atopic samples (42). In a further study by Wenzel three doses of radiolabelled LTC, it was possible to recover et al. the levels of PGD,, TXB,, LTC, and histamine were a constant 4.1%6.3%, regardless of the amount infused, in measured in BAL fluid before, and 5 min after, endo- the form of LTE,, the most stable of the cysteinyl leuko- bronchial allergen challenge in three groups of atopic trienes (39). Radiolabelled LTC, instilled into the airways subjects: seven non-asthmatic; six asthmatic subjects with- of asthmatics, non-asthmatics and asthmatics challenged out a late asthmatic response; and six asthmatic subjects with allergen was found to be excreted in a constant fashion with a late asthmatic response. LTC, was detected in in all three groups with LTE, as the major metabolite (40). nine out of the 12 asthmatic subjects but in only one out of Christie et al. found a significant correlation between the seven subjects without asthma. Significant increases in all dose of inhaled LTC, and the amounts excreted as urinary mediator levels were observed in both groups with asthma LTE, (41). These studies provide strong evidence for the post-allergen challenge compared to the non-asthmatic utility of urinary LTE, as a marker of pulmonary cysteinyl group. Interestingly, the asthmatic group without a late leukotriene release. asthmatic response recorded significantly higher levels of all four mediators post-challenge than the groups with a late response and the non-asthmatic controls (43). In a study of ALLERGEN-INDUCED ASTHMA 17 allergic asthmatic subjects undergoing allergen provoca- Leukotriene release has been measured in studies employ- tion, there was a fall in FEV, within the first 2 h of between ing various bronchial challenge procedures. Wenzel et al. 25% and 59% and this was accompanied by a rise in urinary reported that, using HPLC, the predominant leukotriene in LTE, levels from 46 ng to 92 ng over a 12 h collection BAL fluid in atopic asthmatic subjects after endobronchial period. Methacholine challenge alone, which led to similar bronchial allergen challenge is LTC,, and there was an falls in FEV,, did not significantly change urinary LTE, approximate nine-fold rise in levels compared to baseline. excretion. There was a significant correlation between the Measurable levels of LTC, at baseline were found in nine of decrease in FEV, during the early asthmatic response 11 atopic asthmatic subjects but in only one of seven atopic (EAR), the excretion of urinary LTE, and the airways non-asthmatic subjects and one of six non-atopic subjects. reactivity. No correlation was found between urinary LTE, LEUKOTRIENE ANTAGONISM 799 excretion and the severity of the late response to allergen aspirin sensitive asthmatics. Christie and colleagues found but there was a significant prolonged elevated urinary six-fold higher urinary LTE, levels in aspirin-sensitive LTE, excretion in those patients with the most severe subjects compared to non-aspirin sensitive asthmatic con- late asthmatic responses (40). Manning et al. studied 18 trols (50). Furthermore, oral aspirin challenge which led to asthmatic subjects who were divided into three groups: a mean 21% fall in FEV, in six ASA subjects resulted in a those with an isolated EAR; those with an isolated late four-fold increase in urinary LTE, values over baseline asthmatic response (LAR); and a third group with a dual values. There was no such increase in urinary LTE, levels asthmatic response (DAR) (44). Urinary LTE, rose signifi- in the control subjects and no fall in FEV, on aspirin cantly from baseline values only in the two groups with an ingestion. Smith and colleagues reported that baseline EAR, with a rise from 150 to 1816 pg rng- ’ creatinine in urinary LTE, levels in ten ASA subjects were 101 pg mg - ’ the group with an isolated EAR and a rise from 66 to creatinine compared to 43 pg mg - i creatinine in 31 174pgmgg’ creatinine in the group with an EAR preced- non-aspirin sensitive asthmatic subjects, and 34 pg mg - i ing a LAR. No increase in urinary LTE, was found in the creatinine in 17 normals (38). There was substantial overlap group with an isolated LAR. Furthermore, the degree of between the groups and no correlation was found between maximum bronchoconstriction during the EAR correlated urinary LTE, and histamine PD20 or baseline FEV, and so with urinary LTE, release suggesting that the cysteinyl measurement of LTE, in a single sample of urine does not leukotrienes are only released during the EAR and that predict the degree of resting airflow obstruction or the they contribute significantly to the bronchoconstriction degree of bronchial hyperresponsiveness, or diagnose found during this phase of the asthmatic response. Several aspirin sensitivity. Recent studies have also confirmed subsequent studies have also documented urinary LTE, increased urinary LTE, levels in ASA subjects following release 2-4 h following specific bronchial allergen challenge iysine-aspirin bronchial challenge (5 1,52). Nasal lavage (45,46). mediator levels have been studied in aspirin-sensitive rhinosinusitis. Following lysine-aspirin challenge, increased levels of both histamine and LTC, were detected in nasal EXERCISE-INDUCED ASTHMA lavage samples in three out of four ASA subjects with Pliss et al. found increases in BAL fluid levels of LTB, from both naso-ocular symptoms and a bronchospastic reaction. No increases in these mediators was found in normals or 10 to 121 pg ml ~ ’ and immunoreactive cysteinyl leuko- trienes from 46 to 251 pg ml- i following isocapnic hyper- non aspirin-sensitive subjects or aspirin-sensitive subjects in whom lysine-aspirin did not provoke naso-ocular ventilation as a model for exercise-induced asthma (47). symptoms (53). There were also increases in eosinophil and epithelial cell numbers but no changes in prostaglandin or histamine levels were detected. Urinary levels of LTE, were not found CHRONIC ASTHMA to increase in a study of six asthmatic subjects after On bronchoalveolar lavage, 15 out of 17 asthmatic sub- treadmill leading to a mean 22% fall in FEV, (48). How- jects with mild to severe disease were found to have ever, small increases in urinary LTE, (14.3 before and 24.3ngmgg’ creatinine after exercise) were found in eight detectable LTE, in BAL fluid but there was no corre- lation between LTE, levels and pulmonary function. out of ten children with severe asthma following exercise which produced a 60% fall in FEV,, but no increases in None of the group of nine control subjects had detectable urinary LTE, in seven children with moderate asthma who LTE, (54). In a study by Wardlaw et al., eight sympto- matic asthmatic subjects had significantly higher levels of experienced only a 24% fall in FEV, (49). Despite the BAL LTB, and LTC, than a control group of 14 without conflicting evidence, pharmacological studies have indi- cated an important role for cysteinyl leukotrienes in asthma (55). In a study using urinary LTE, as a marker for pulmonary cysteinyl leukotriene release, Smith and exercise-induced bronchospasm. It is likely that our inabil- ity to detect these mediators consistently in biological fluids colleagues found no difference in baseline urinary levels of may be because whole body cysteinyl leukotriene release LTE, between 17 normal and 31 asthmatic subjects. In addition, there was no correlation between urinary LTE, does not change significantly after exercise which may be further modified by changes in bronchial or pulmonary levels as measured in pg mg ~ ’ of creatinine, and baseline airways responsiveness to histamine or FEV, as a per cent blood flow in response to airway cooling and local changes in pH and osmolarity. Furthermore, the modest local of predicted values (38). Drazen et al. examined 72 sub- jects presenting to accident and emergency and classified increases in cysteinyl leukotriene release in exercise-induced asthma are likely to be difficult to detect with currently 22 patients with a doubling of peak expiratory flow rate (PEFR) following nebulized salbutamol as responders, employed assays. and 19 patients with a less than 25% increase in PEFR as non-responders (56). Urinary LTE, levels were assayed ASPIRIN-SENSITIVE ASTHMA by pre-column extraction, HPLC and radioimmuno- assay in these two groups and compared to 13 normal The cysteinyl leukotrienes have considerable importance in controls. Urinary LTE, levels were significantly higher in the pathogenesis of aspirin-sensitive asthma (ASA). Mean responders compared to non-responders or normal sub- resting urinary LTE, levels in aspirin-sensitive asthmatic jects. The authors concluded that the highest levels subjects are significantly higher than in normals or non- of LTE, found in those with acute reversible airflow 800 S. J. LANE obstruction was consistent with a bronchospastic role for enzymatic properties, or by secondary inhibition of its cysteinyl leukotrienes in spontaneous acute asthma. interaction with FLAP. A large number of clinical trials have been completed with these agents, establishing their efficacy in the treatment of spontaneous or induced asthma. RHINOSINUSITIS All drugs have been shown to provide a superior effect, Evidence for the role of LTs in the pathogenesis of rhino- when compared to placebo, in the treatment of patients sinusitis comes from studies of the nasal lavage fluid with mild-to-moderate asthma. For example, in trials of obtained during the early- and late-phase reactions after 4-6 weeks duration, individuals with moderate asthma nasal allergen challenge; in spontaneous rhinitis during (average FEV, values of about 65% of predicted) treated seasonal allergen exposure; after topical leukotriene only with P-agonists were randomized in a double-blind challenge; and from clinical studies demonstrating the fashion to either active agent or placebo. Patients receiving clinical efficacy of leukotriene antagonists (57). Although either zileuton, zafirlukast, or montelukast had a lo-15% the majority of the signs and symptoms of allergic rhino- improvement in FEV,; this benefit was statistically signifi- sinusitis are believed to be mediated by histamine (and cant when compared to the placebo group. Active therapy effectively relieved by antihistamines), nasal allergen was also associated with both a significant decrease in the challenge results in increased cysteinyl LTs in nasal lavage need for rescue P-agonist therapy and improved asthma fluid, and in tear fluid during both early- and late-phase symptoms, especially at night (70,71). These results are inflammation and during natural exposure. Various studies similar in magnitude to those achieved with inhaled steroids have demonstrated a dose- and time-dependent release of given at recommended doses. predominantly LTC, into the nasal lavage fluid, which peaks at 10 min after nasal challenge with allergen but not with methacholine (5859). Levels of LTC, are also elevated LEUKOTRIENE RECEPTOR ANTAGONISTS during the late-phase response although the absolute quan- The first antagonist to be evaluated was the hydroxy- tity is much lower. In addition, if patients with ragweed acetophenone FPL 55712 which had demonstrated selective sensitive allergic rhinosinusitis are challenged with specific activity as an inhibitor of SRS-A even before the chemical allergen there is an early inflammatory cellular infiltrate structure of SRS-A was elucidated (72). However, it proved associated with LTC, generation in the nasal lavage fluid disappointing in clinical trials of asthma because of low (60,61). Moreover, increased levels of LTC, have been potency, a short half-life and bioavailability only by in- found to peak at weeks 3 and 10 during natural grass pollen halation (73). Other first generation LTD, antagonists to be and ragweed exposure during the hay-fever season (62,63). evaluated in humans include L-648,051, L-649,923, Furthermore, increased levels of eosinophils LTC, and LY-171,883, LY-170,680, and SK&F 104,353 (74-78). LTD, have been found in increased amounts in the nasal These compounds were of modest potency with a rightward lavage fluid from patients with chronic perennial rhino- shift in the LTD, dose-response curve of three- to ten-fold sinusitis (64). Allergic rhinosinusitis is characterized by with poor to moderate clinical efficacy in early trials. epithelial infiltration of activated mast cells, basophils and More recently, highly selective, second-generation LTD, eosinophils and a submucosal infiltration of eosinophils antagonists have been developed with up to loo-fold and activated Th,-type CD4+ve T lymphocytes (65-67). greater potency than FPL 55712. The most potent of these Mast cells and eosinophils are abundant cellular sources of compounds include: zafirlukast (Accolate@, ICI 204,219) the increased levels of LTC,, as described above. Bisgaard with potency up to lOOO-fold greater than FPL 55712 in et al. demonstrated that nasal challenge with LTD, inhibiting contraction of guinea-pig tracheal and parenchy- increased nasal blood flow and resistance but did not ma1 strips (79); ON0 1078 (Pranlukast) which causes a increase nasal secretions or induce itching and sneezing loo-fold rightward shift of the LTD, dose-response curve; (68). Okuda et al. found similar results and showed that the MK-571, a member of a family of quinolone-derived LTD, duration of the LTD,-induced increase in nasal resistance antagonists that show a 44- to 84-fold rightward shift in the exceeded that of histamine and was similar to that observed LTD, dose-response curve in asthmatic subjects (80). In after allergen challenge (69). In addition, LTD, was found addition, MK-0476 (montelukast) has recently been shown to be 5000 times more potent than histamine on a weight to be a highly potent and long-lasting antagonist of LTD,- basis. Thus, LTs would appear to be responsible predomi- induced bronchoconstriction in patients with asthma (8 1). nantly for the vascular congestion and nasal blockage associated with rhinitis. Allergen-induced asthma Anti-leukotriene Therapy In early studies, LY-171,883, which has a similar structure to FPL 55712 and L-649,923, showed a slight reduction of LT action may be pharmacologically modulated by the EAR, but had no effect on baseline lung function or the antagonism at the receptor site or by biosynthesis LAR (82,83). In a study of ten asthmatics, a single oral dose inhibition. LTB, receptor antagonists have not yet been of 40 mg zafirlukast, a highly selective and potent LTD, evaluated in humans, but LTD, receptor antagonists have antagonist, attenuated the EAR by 80% and the LAR by been developed for use in human trials. Inhibition of 5-LO 50%, and reduced the allergen-induced rise in non-specific biosynthesis is effected either by direct interference with its BHR at 6 h post-challenge (84). An inhaled formulation of LEUKOTRIENEANTAGONISM 801 zafirlukast was less effective but still significantly inhibited such as mast cell derived histamine or prostaglandins are the EAR but not the LAR (85). A further study using a involved in the pathogenesis of exercise-induced asthma. single inhaled dose of 40 mg zafirlukast displaced the Strek has recently reported that pranlukast can significantly allergen dose-response curve to inhaled cat-allergen inhibit cold air-induced bronchoconstriction in patients ten-fold compared with placebo; the same inhaled formu- with asthma (98). lation was shown to shorten the recovery time of the EAR from 60 to 40 min (8687). In a study of asthmatic subjects, the quinolone derivative MK 571 substantially inhibited the Bronchodilation EAR by 88% and the LAR by 63% (88). Ellis and Undem found that isolated human bronchi of 3-12 mm in diameter had a high degree of intrinsic bron- chomotor tone which was on average more than 50% of the Aspirin-sensitive asthma available maximal constrictor response to 30 mm 1 - ’ Current evidence suggests that aspirin-sensitive asthma is BaCI,. In the presence of the LTD, agonists zafirlukast or the most leukotriene dependent model presently available SKF 104,353, there was relaxation of the bronchi; this effect for the evaluation of anti-leukotriene therapy in asthma. was additive with a histamine H, antagonist leading to the The weak LTD, antagonist SK&F 104,353, administered conclusion that intrinsic bronchomotor tone is caused by by the inhaled route, demonstrated inhibition of the bron- the continual production of cysteinyl leukotrienes and choconstrictor response to ingested aspirin by a mean of histamine (99). 47% in five out of six subjects (89). In a study of eight Further clinical studies have now been carried out to subjects with ASA, MK-0679 improved baseline pulmonary support a role for cysteinyl leukotrienes in the maintenance function and significantly attenuated the airways obstruc- of intrinsic bronchial muscle tone. An intravenous infusion tion produced by inhaled lysine-aspirin with a median of the LTD, antagonist MK-0679 in nine asthmatic 4.4-fold rightward shift in the dose-response curve (90). patients with baseline FEV, ranging from 40% to 80% of predicted values, produced an increase in FEV, of 15.8% and 7.8% with 500 mg and 125 mg, respectively, and a fall Exercise challenge and isocapnic hyperventilation of 2.6% 15 min after placebo infusion (100). In a separate study, an oral dose of 40 mg zafirlukast Provided respiratory heat exchange is matched in a time- produced a significant resting increase in FEV, compared dependent manner, the degree of bronchospasm achieved with placebo, and the effect persisted after inhalation by exercise can be mimicked by controlled isocapnic hyper- salbutamol (101). In a study of 12 male asthmatic patients, ventilation. Exercise and isocapnic hyperventilation are there was further confirmation of the additive effect of considered to stimulate similar if not identical pathological inhaled /&-agonist administration. The maximum broncho- effector mechanisms for the initiation of bronchoconstric- dilation achieved from the start of a 6 h intravenous tion. In a study of 20 asthmatic subjects treated for 2 weeks infusion of MK-571 was 22% compared with 1.3% after with LY-171,883, the geometric mean respiratory heat loss placebo. Administration of salbutamol 5-6 h from the start required to reduce FEV, was increased by 20%, and there of the infusion produced additional bronchodilatation. The was also a marginal reduction of bronchoconstriction overall degree of bronchodilatation correlated inversely induced by isocapnic hyperventilation of cold air. In this with baseline FEV,, suggesting a major contribution from study the most reactive subjects showed greatest protection cysteinyl leukotrienes in resting airway tone (102). A study (91). with aspirin sensitive asthmatics examined the magnitude of Inhaled SK&F 104,353, a weak LTD, antagonist, cysteinyl leukotriene effect on intrinsic airway tone using a reduced the exercise-induced bronchoconstrictor response single dose of 825 mg MK-0679 in eight subjects. A mean from 29% to 20% with similar efficacy to disodium cromo- peak increase in FEV, of 18% was observed with a range of glycate (92). During a treadmill exercise challenge involving 5-34% and correlated strongly with the severity of asthma eight asthmatic subjects breathing cold dry air, a 20 mg oral (103). A recent study by Reiss et al. has demonstrated that dose of zafirlukast reduced the fall in FEV, from 36% to montelukast at 100 mg or 250 mg orally induces a signifi- 21.6% (86). cant increase in FEV, in patients with mild to moderate In a study of nine subjects undergoing exercise challenge, asthma, irrespective of whether the patient is taking con- inhaled zafirlukast reduced the exercise-induced fall in comitant inhaled GCS (11). In addition, a recent report by FEV, (93). MK-571 produced similar results with a 70% Smith et al. has demonstrated that pranlukast can inhibit attenuation of the exercise-induced decrease in FEV, in 12 LTD,-induced bronchoconstriction in patients with asthma asthmatic subjects, and a marked reduction in recovery (104). time from 33 to 8 min (94). Pre-dosing with a once daily dose of montelukast was able to attenuate exercise-induced bronchoconstriction in a dose-related fashion in adults as Chronic asthma well as in 6- to 14-year-old children (95,96). In addition, it attenuated the exercise-induced increase in urinary LTD, The leukotriene receptor antagonists have shown consider- (97). Despite their potency, these LTD, antagonists were able efficacy in models of experimental asthma and there unable to completely inhibit the bronchoconstrictor are now many studies demonstrating efficacy in clinical response to exercise. This suggests that other mediators asthma. In a multicentre, placebo-controlled study, 138 802 S. J. LANE patients with asthma received LY-171,883 1200 mg day-’ and larger scale studies are required to predict accurately for 6 weeks (105). In the treatment group, mean FEV, rose the future role of leukotriene antagonists in asthma significantly from 73.8% to 83.3% of predicted values, therapy, and determine whether their major role is as compared with placebo. There were also significant bronchodilators, anti-inflammatory agents, or whether improvements in the severity of day-time and nocturnal they can replace existing treatments such as inhaled corti- wheeze and breathlessness, with a significant reduction in costeroids or theophyllines. These smaller studies of rela- P,-agonist use, although there was no change in symptoms tively short duration would suggest that these drugs can of cough or chest tightness. In a separate study, treatment bronchodilate, are as effective as theophylline and can act with 225 mg t.d.s. MK-571 for 2 weeks followed by 4 weeks as steroid sparing agents. of treatment with 150 mg t.i.d. produced a mean S-14% improvement in FEV, and a 30% reduction in morning and Rhinitis evening symptom scores, accompanied by a 30% reduction in salbutamol usage (102). A recent study of montelukast In contrast to asthma there are relatively few trials available has shown similar efficacy irrespective of the presence of on the effectiveness of LT receptor antagonists in rhinitis. inhaled GCS (106). One week’s treatment with ONO-1078 Flowers found that L-649,923 was ineffective at blocking in a crossover study of 11 asthmatic subjects produced a the early response to nasal challenge in 12 patients with significant decrease in methacholine bronchial responsive- grass pollen-sensitive rhinitis in a cross-over study (116). ness as compared with placebo; there was no change in Donnelly et al. has tested the efficacy and safety of single either resting FEV, or forced vital capacity (FVC) during oral doses of zafirlukast in 162 subjects with acute seasonal that period (107). allergic rhinitis and found that 20 mg and 40 mg effectively In a placebo-controlled, dose-ranging study of 266 sub- attenuated the rhinitic symptoms after 2 h post-dose with jects with moderate asthma, treatment with 40 mg b.d. no serious adverse events reported (117). Zafirlukast was zafirlukast over 6 weeks was more effective than 20 mg b.d. able to reduce both sneezing and rhinorrhoea in this study or 10 mg b.d. without any increase in adverse effects. and is contrary to the results obtained with intranasal Compared with placebo there was a significant reduction in LTD, provocation (68). This discrepancy may be due to the nocturnal awakenings (by 46%), first morning asthma release of LTD, in conjunction with other mediators of symptoms, day-time asthma scores (by 26X), salbutamol inflammation in the clinical setting. Grossman et al. have use (by 30%) and an increase in FEV, (11%) and evening recently reported that pranlukast (Ultair@‘) significantly peak expiratory flow rates (71). The largest study reported relieves symptoms in patients with seasonal allergic rhinitis to date is that of Fish and colleagues who demonstrated (118). that zafirlukast 20 mg b.d. was more effective than inhaled &agonists alone in 762 patients with moderate asthma LEUKOTRIENE BIOSYNTHESIS INHIBITORS over a 13-week study period (108). This effect was also seen by Suissa in a smaller study (109). These studies highlight Inhibitors of leukotriene biosynthesis were thought to be the need for a direct comparison of zafirlukast with inhaled more effective than LTD, receptor antagonists in prevent- glucocorticoids in these patients. Although the toxicity ing the pathophysiological consequences of leukotriene profile of this drug is excellent, a recent report has linked its release within the airways because of the dual inhibition of usage to the development of a rare Churg-Strauss-type both LTD, and cysteinyl leukotriene generation. Current syndrome in eight patients (seven women, one man) using evidence suggests that 5-LO contains a non-haem iron that this drug (110). The clinical syndrome developed in gluco- is normally in the dormant ferrous state (Fe”) and, upon corticoid dependent patients when receiving zafirlukast activation by hydroperoxides, adenosine triphosphate from 3 days to 4 months following attempted glucocorti- (ATP) and calcium, is converted to the active ferric form coid withdrawal. It is unclear whether these patients had a (Fe3+). Some 5-LO inhibitors have more than one mode of primary steroid dependent pulmonary infiltrative disorder action. At low concentrations of racaemic WY-50,295, that had been clinically recognized as asthma which was inhibition of 5-LO binding to FLAP predominates but at eventually unmasked by steroid withdrawal or whether this higher concentrations its activity as an arachidonic acid effect is a rare side-effect of this drug. analogue becomes more significant (119). Hydroxamic One study has reported that adding an LTD, receptor acides and hydroxyureas act primarily by chelating the antagonist (10 days treatment with RG 12 525) to existing essential iron at the active site of the enzyme but are also therapy with inhaled steroids significantly improved FEV, likely to have additional antioxidant activity (120). Clinical in stable asthmatic subjects (111). A recent study by trials involving 5-LO inhibitors have followed the pattern Tamaoki et al. has shown that pranlukast can allow set by the cysteinyl leukotriene receptor antagonists with halving of high dose inhaled steroids over a 6-week period earlier studies using compounds, such as piriprost, with without a deterioration in asthma control (112). This weak inhibitory activity, which demonstrated little clinical effect was not seen in patients who required oral pred- use. nisolone (113). In addition, Barnes et al. has recently demonstrated that pranlukast improved symptom scores Allergen-induced asthma and rescue bronchodilator use in a 4 week study (114). The drug was well tolerated, improved FEV, within 1 h of In a single-dose, placebo-controlled crossover study, nine oral dosing which was maintained for 8 h (115). Further asthmatic subjects received the iron chelator zileuton LEUKOTRIENE ANTAGONISM 803

(A64077). Despite almost complete inhibition of ex viva for 2 days with zileuton 2.4 g day- ’ showed a 40% inhibi- whole blood LTB, generation and 50% reduction of the rise tion of exercise-induced bronchospasm. The study also of urinary LTE,, there was no significant attenuation of the showed a significant protection against the fall in FVC early or late asthmatic response, and no decrease of the compared with placebo (70,127). airway responsiveness to methacholine (121). The potent and selective non-redox 5-LO inhibitor ZD2138 was evalu- Chronic asthma ated in a study of eight asthmatic subjects and although there was an 82% reduction of ex viva LTB, generation in As part of a multicentre study, 139 asthmatic patients, not whole blood and an overall 72% inhibition of the rise in taking oral or inhaled corticosteroids and with baseline urinary LTE, excretion, again there was no inhibition of FEV, values of 40-75%, were placed on placebo or zileuton the allergen-induced early or late asthmatic response (46). 2.4 g or 1.6 g day - ’ for 4 weeks (70). Patients treated with In a separate placebo-controlled study of eight atopic zileuton had a statistically significant 13.6% improvement men, the FLAP inhibitor MK-886 was given 1 h before in FEV, after 4 weeks therapy. There was also a significant (500 mg) and 2 h after (250 mg) allergen inhalation. improvement in asthmatic symptom scores and a reduction MK-886 inhibited the early asthmatic response by 58% and in &agonist use in subjects on the higher dose of zileuton. the late asthmatic response by 44%. This was accompanied In an extension of this study, 398 asthmatic patients with by a 54.2% inhibition of A23187 stimulated whole blood moderately severe asthma (baseline FEV, 61%) and who LTB, generation and a 51.5% inhibition of the rise in had been previously stabilized on salbutamol were treated urinary LTE, during the early, and 80% during the late, for 13 weeks with either 2.4 g or 1.6 g day- r zileuton or asthmatic response. However, compared with placebo, no placebo. In the subjects taking 2.4 g day- ’ zileuton there significant change in airways responsiveness to histamine was a sustained increase in FEV, of 0.25 1 compared with a was observed at 30 h after allergen challenge (122). In 0.08 1 increase in the patients receiving placebo. another study, the FLAP inhibitor MK-0591 (250 mg) was In a separate study, 109 asthmatic subjects taking administered at 24, 12, and 1.5 h before allergen inhalation. 400-1600 mg of either beclomethasone or budesonide with Over the 24 h period following allergen inhalation, LTB, baseline FEV, 50-75% were placed on placebo or 125 mg generation was inhibited by 96% and urinary LTE, excre- MK-0591 twice daily (128). After 4 weeks’ treatment, FEV, tion by 84%. The early asthmatic response to allergen was increased by 6.8% in the MK-0591-treated group compared inhibited by 79% and the late asthmatic response delayed with an increase of 0.6% in the placebo-treated group. In by 3 h. No effect was observed on airway responsiveness to addition, there was an increase in morning and evening histamine 24 h post-allergen challenge (123). PEFR of 19% and 13%, respectively, in the MK-0591 treated group, compared with a fall in morning and evening PEFR of 5% and 6%, respectively, in the placebo group. Aspirin-induced asthma Furthermore, subjects on active treatment reported a reduction in &agonist use. A recent study by Liu The effect of aspirin ingestion was examined in eight et al. assessed the effects of two doses of Zileuton in 122 subjects with ASA and hyperexcretion of urinary LTE, patients with mild to moderate asthma (129). Zileuton who were premeditated with zileuton or placebo. Zileuton produced an acute bronchodilatory response, 2-5 hours reduced baseline urinary LTE, excretion by 70% and after initial dosing. In addition, zileuton improved FEV, prevented the fall in FEV, in response to aspirin challenge. morning peak flows and reduced f12 agonist use and eosino- In addition, there was protection against the development phi1 count. In a recently published, longer-term trial of of nasal, gastrointestinal, and dermal symptoms in response zileuton, 401 patients were randomized in a double-blind to aspirin ingestion (124). fashion to 3 months of therapy with placebo or with one of In a separate study, seven subjects with aspirin-induced two doses of zileuton, 400 mg or 600 mg four times a day asthma and hyperexcretion of urinary LTE, were premedi- (131). There was a significant increase in FEV, with zileu- cated with a single dose of 350 mg ZD2138 which provided substantial inhibition of both LTB, generation and urinary ton compared with placebo (16% in the 600 mg group vs 8% in the placebo group) and a significantly lower percentage LTE, excretion. In response to oral aspirin challenge, the of patients who required treatment with corticosteroids (6 mean maximum fall in FEV, was 20.3% after placebo and vs 16%). The main adverse effect was an approximately 2% 4.9% following ZD2138 premeditation associated with a reduction in systemic symptoms (125). incidence of elevated plasma transaminase levels, which reversed with drug withdrawal. In long-term safety studies, approximately 5% of patients treated with zileuton had Exercise-induced asthma clinically significant increases in transaminases, while the usual care group had an increase in 2% of patients. Patients A single 800 mg dose of zileuton administered to 13 treated with zileuton will require monitoring of liver func- asthmatic subjects inhibited ex vivo whole blood LTB, tion tests at the onset of treatment and periodically there- generation by 74% without affecting TXB, levels. This after. This complication, occurring within the first months produced a 47% increase in the amount of cold dry air of therapy, has not been observed with zafirlukast; public required to reduce FEV, by 10% with an increase in minute data have not been made available for pranlukast or ventilation from 27.5 1 min- ’ to 39.8 1 min- ’ (126). A montelukast. A recent study has suggested that patients further study of 24 subjects with mild asthma, premeditated who demonstrate improved asthma control on zileuton 804 S. J. LANE

600 mg q.d.s. may be able to reduce their daily dose and/or (143). In the U.K. this would entail introducing montelu- frequency of administration while still maintaining the kast as add-on therapy at step 3 of the British Thoracic same level of symptom control, which has obvious implica- Society asthma guidelines. There is reason to believe that tions for toxicity (132). In addition, a recent study by these drugs will be partially effective preventative therapy Schwartz has shown that zileuton appears to be as effective for patients with exercise-induced asthma. They will play an and as safe as theophylline in patients with chronic asthma important role as single therapy in patients with co-existing over the 14-week study period (133). asthma and rhinitis and are likely to have a unique place in In clinical studies, leukotriene receptor antagonists have the management of the aspirin-sensitive syndrome. The proven as effective as biosynthesis inhibitors in suppressing leukotriene inhibitors will not supplant B-agonists since cysteinyl leukotriene mediated disease processes. Specula- their acute bronchodilator effects are not as marked as tion suggests that the ideal compound to modulate the those of b-agonists. Their use in more severe asthma is effects of leukotrienes in asthma would possess both leuko- currently under study. triene receptor antagonism and 5-LO synthesis inhibitory activity because these activities may be functionally addi- tive. Over the next few years, the place of anti-leukotriene therapy in the treatment of asthma is likely to be estab- Conclusion lished; first, however, more clinical studies are required to define whether they possess glucocorticoid-sparing activity, LTs have been shown to be central to the pathogenesis of bronchial asthma and to contribute to the inflammation of lead to long-term symptomatic improvement, or affect the allergic rhinitis. Inhibition of their activity has been shown underlying disease processes. to be associated with an improvement of control in these disease states. However, their exact role in the management Rhinitis of these diseases remains to be established and, in particu- lar, comparative studies with topical glucocorticoids are During the immediate response to nasal allergen in patients eagerly awaited. with allergic rhinosinusitis, the 5-LO inhibitor zileuton reduced nasal congestion but did not alter histamine secre- tion or sneezing (134). The 5-LO inhibitor, A78773, signifi- References cantly inhibited the increase in nasal lavage fluid protein and histamine levels following allergen challenge in patients 1. Creticos P. Allergic rhinitis. In: Busse WW, Holgate with allergic rhinosinusitis (135). Knapp examined the effect ST, eds. Asthma and Rhinitis. Oxford, U.K.: Blackwell of a single dose of zileuton on symptoms and mediator Scientific, 1995; 1394-1414. release into the nasal lavage fluid after nasal allergen 2. Watson WTA, Becker AB, Simons FER. Treatment challenge in eight allergic subjects in a double-blind ran- of allergic rhinitis with intranasal corticosteroids in domized trial. Zileuton significantly reduced nasal conges- patients with mild asthma: effect on lower airways tion and the release of LTB, and 5-HETE into the nasal responsiveness. J Allergy Clin Immunol 1993; 91: fluid (130). There was no effect on sneezing or on histamine 97-101. release. Spaeth et al. has demonstrated that azelastine 3. Enarson DA, Vedal S, Schulzer M, Chan-Yeung M. (Astelin) nasal spray was superior to place0 in attenuating Asthma, asthma-like symptoms, chronic bronchitis nasal obstruction after provocation with both histamine and the degree of bronchial hyperresponsiveness in and allergen (136). Fischer et al. investigated the effects of epidemiological surveys. Am Rev Respir Dis 1987; 136: zileuton on the nasal response in patients with confirmed 613-617. aspirin sensitivity (137). One week of zileuton 600 mg q.i.d. 4. Hogg JC, James AL, Pare PD. Evidence for inflam- followed by aspirin challenge greatly reduced the aspirin- mation in asthma. Am Rev Respir Dis 1991; 143 induced increase in nasal symptoms and the level of (Suppl.): s39-s42. leukotrienes found in nasal lavage fluids when compared to 5. Djukanovic R, Roche WR, Wilson JW et al. Mucosa an aspirin challenge prior to taking zileuton. inflammation in asthma. Am Rev Respir Dis 1990; 142: 434457. 6. Jeffery PK, Nelson FC, Wardlaw A, Kay AB, Collins Future role of LT antagonists in the treatment of asthma JV. Ultrastructural analysis of bronchial-mucosa in and rhinitis asthma. J Pathol 1987; 151A: 58. Agents active on the 5-LO pathway such as zileuton, Howarth PH, Bradding P, Feather I. Wilson S, zafirlukast, montelukast and pranlukast are likely to be an Church MK, Holgate ST. Mucosal cytokine expres- alternative to inhaled steroids for patients who are using sion in allergic rhinitis. Int Arch Allergy Immunol P-agonists as their primary asthma treatment, as the efficacy 1995; 107: 390-391. of these drugs is clearly established in this setting (138-142). Djukvanovic R, Wilson SJ, Howarth PH. Pathology It also seems likely that they will be effective adjunctive of rhinitis and bronchial asthma. Clin Exp Allergy therapy in patients whose asthma is poorly controlled 1996; 91 (Suppl.): s44-~51. despite use of inhaled steroids at a low dose or at a high Barnes PJ. Drug therapy - inhaled glucocorticoids for dose, in order to prevent long-term oral steroid exposure asthma. N Engl J Med 1995; 332: 868-875 LEUKOTRIENE ANTAGONISM 805

10. International Rhinitis Working Group. International postcapillary venules: in vivo effects with relevance to report on the diagnosis and management of rhinitis. the acute inflammatory response. Proc Nat1 Acad Sci Allergy 1994; 49 (Suppl.): slls34. U.S.A. 1981; 78: 388773891. 11. Reiss TF, Sorkness CA, Stricker W et al. Effects of 26. McIntyre TM, Zimmerman GA, Prescott SM. Leuko- montelukast (MK-0476), a potent cysteinyl leuko- trienes C4 and D4 stimulate human endothelial triene receptor antagonist, on bronchodilation in cells to synthesize platelet-activating factor and bind asthmatic subjects treated with and without inhaled neutrophils. Proc Nat1 Acad Sci U.S.A. 1986; 83: corticosteroids. Thorax 1997; 52: 45-48. 2204-2208. 12. Kelleway CH, Trethewie WR. The liberation of a 27. Laitinen LA, Laitinen A, Haahtela T, Vikka V, Spur slow reacting smooth muscle stimulating substance BW, Lee TH. Leukotriene-E4 and granulocytic infil- of anaphylaxis. Quart J Exp Physiol 1940; 30: tration into asthmatic airways. Lancet 1993; 341: 124145. 989-990. 13. Morris HR, Taylor GW, Piper PJ. Structure of slow 28. Dahlen SE, Hedqvist P, Hammaarstrom SBS. Leuko- reacting substance of anaphylaxis from guinea pig trienes are potent constrictors of human bronchi. lung. Nature 1980; 285: 104-106. Nature 1980; 288: 484-486. 14. Lewis RA. Austen KF, Drazen JM. Slow reacting 29. Adelroth E, Morris MM, Hargreave FE, M OBP. substance of anaphylaxis: identification of leukotriene Airway responsiveness to leukotrienes C4 and D4 and C-l and D from human and rat sources. Proc Nat1 to methacholine in patients with asthma and normal Acad Sci U.S.A. 1980; 77: 3712-3714. controls. N Engl J Med 1986; 315: 480484. 15. Samuelsson B, Hammarstrom S, Murphy RC. Leuko- 30. Davidson AB, Lee TH, Scanlon PD et al. Broncho- trienes and slow reacting substance of anaphylaxis constrictor effects of leukotriene-E4 in normal and (SRS-A). Allergy 1980; 35: 375-381. asthmatic subjects. Am Rev Respir Dis 1987; 135: 16. Nasser SN, Lee TH. Lipid mediators ~ Leukotrienes, 333-337. Prostanoids and platelet activating factor. In: Kay 31. Barnes NC, Piper PJ, Costello JF. Comparative effects AB, ed. Allergy and Allergic Diseases. Oxford: of inhaled leukotriene C4, leukotriene D4, and hista- Blackwell Science, 1996: 380-418. mine in normal human subjects. Thorax 1984; 39: 17. Dixon RAF, Diehl RE, Opas E. Requirement of a 500-504. 5-lipoxygenase-activating protein for leukotriene 32. O’Hickey SP, Arm JP, Rees PJ, Spur BW, Lee TH. synthesis. Nature 1990; 343: 2822284. The relative responsiveness to inhaled leukotriene-E4, 18. Kargman S, Rousseau P, Reid GK. Leukotriene methacholine and histamine in normal and asthmatic synthesis in U937 cells expressing recombinant subjects. Eur Resp J 1988; 1: 913-917. 5-lipoxygenase. J Lipid Mediators 1993; 7: 31-35. 33. Arm JP, O’Hickey SP, Hawksworth RJ, et al. 19. Williams JD, Czop JK, Austen KF. Release of leuko- Asthmatic airways have a disproportionate hyper- trienes by human monocytes on stimulation of their responsiveness to LTE,, as compared with normal phagocytic receptor for particulate activators. J airways, but not to LTC,, LTD,, methacholine and Immunol 1984; 132: 3034-3040. histamine. Am Rev Respir Dis 1990; 142: 1112-1118. 20. Weller PF, Lee CW, Foster DW, Corey EJ, Austen KF, Lewis RA. Generation and metabolism of 34. Kern R, Smith LJ, Patterson R. Characterization 5-lipoxygenase pathway leukotrienes by human of the airway response to inhaled leukotriene D4 eosinophils: predominant production of leukotriene in normal subjects. Am Rev Respir Dis 1986; 131: 1127-l 132. C4. Proc Nat1 Acad Sci U.S.A. 1983; 80: 7626-7630. 21. Feinmark SJ, Cannon PJ. Endothelial cell leukotriene 35. Smith LJ, Greenberger PA, Patterson R. The effect of C4 synthesis results from intercellular transfer of inhaled leukotriene D4 in humans. Am Rev Respir Dis leukotriene A4 synthesized by polymorphonuclear 1985; 131: 368-372. leukocytes. J Biol Chem 1986; 261: 16 466-16 472. 36. O’Hickey SP, Hawksworth RJ, Fong CY, Arm JP, 22. Coleman RA, Eglen RM, Jones RL et al. Prostanoid Spur BW, Lee TH. Leuoktriene-C4, Leukotriene-D4, and leukotriene receptors - a progress report from the and leukotriene-E4 enhance histamine responsiveness IUPHAR Working Parties on Classification and in asthmatic airways. Am Rev Respir Dis 1991; 144: Nomenclature. Adv Prostaglandin Thromboxane 105331057. Leukotriene Res 1995; 23: 283-285. 37. Christie PE, Hawksworth R, Spur BW, Lee TH. 23. Drazen JM, Austen KF, Lewis RA. Comparative Effect of indomethacin on leukotriene E4-induced airway and vascular activities of leukotrienes C-l and histamine hyperresponsiveness in asthmatic subjects. D in vivo and in vitro. Proc Nat1 Acad Sci U.S. A. 1980; Am Rev Respir Dis 1992; 146: 150661510. 77: 43544358. 38. Smith CM, Hawksworth RJ, Thien FCK, Christie PE, 24. Goldman DW, Goetzl EJ. Selective transduction of Lee TH. Urinary leukotriene-E4 in bronchial-asthma. human polymorphonuclear leukocyte functions by Eur Respir J 1992; 5: 693-699. subsets of receptors for leukotriene B4. J Allergy Clin 39. Maltby NH, Taylor GW, Ritter JM. Moore K, Fuller Immunol 1984; 74: 373-377. RW, Dollery CT. Leukotriene C4 elimination and 25. DahlCn S-E, Bjijrk J, Hedqvist P et al. Leukotrienes metabolism in man. J Allergy Clin Immunol 1990; 85: promote plasma leakage and leukocyte adhesion in 3-9. 806 S.J. LANE

40. Westcott JY, Smith HR, Wenzel SE, Larsen GL, 54. Lam S, Chan H, Leriche JC, Chanyeung M, Salari H. Thomas RB, Felsien D. Urinary leukotriene E4 in Release of leukotrienes in patients with bronchial patients with asthma. Effect of airways reactivity and asthma. J Allergy Clin Immunol 1988; 81: 711-717. sodium cromoglycate. Am Rev Respir Dis 1991; 143: 55. Wardlaw AJ, Hay H, Cromwell 0, Collins JV, Kay 1322-1328. AB. Leukotrienes, LTC, and LTB, in brochoalveolar 41. Christie PE, Tagari P, Ford-Hutchinson AW et al. lavage in bronchial-asthma and other respiratory Increased urinary LTE(4) excretion following inhala- diseases. J Allergy Clin Immunol 1989; 84: 19-26. tion of LTC(4) and LTE(4) in asthmatic subjects. Eur 56. Drazen JM, O’Brien J, Sparrow D et al Recovery of Resp J 1994; 7: 9077913. leukotriene-E4 from the urine of patients with airway 42. Wenzel SE, Larsen GL, Johnston K, Voelkel NF, obstruction. Am Rev Respir Dis 1992; 146: 104-108. Westcott JY. Elevated levels of leukotriene C4 in 57. Naclerio RM, Baroody FM, Togias AC. The role of bronchoalveolar lavage fluid from atopic asthmatics leukotrienes in allergic rhinitis - a review. Am Rev after endobronchial allergen challenge. Am Rev Respir Respir Dis 1991; 143 (Suppl.): S91-S95. Dis 1990: 142: 112-l 19. 58. Miadonna A, Tedeschi A, Leggieri E. Behaviour and 43. Wenzel SE, Westcott JY, Larsen GL. Bronchoalveo- clinical relevance of histamine and leukotrienes lar lavage fluid mediator levels 5 minutes after allergen C4 and B4 in grass pollen-induced rhinitis. Am Rev challenge in atopic subjects with asthma: relationship Respir Dis 1987; 136: 357-62. to the development of late asthmatic responses. J 59. Creticos PS, Peters SP, Adkinson NF et al. Peptide Allergy Clin Immunol 1991; 87: 540-548. leukotriene release after antigen challenge in patients 44. Manning PJ, Rokach J, Malo JL et al. Urinary sensitive to ragweed. N Eng J Med 1984; 310: leukotriene E4 levels during early and late asthmatic 162661630. responses. J Allergy Clin Immunol 1990; 86: 211-220. 60. Georgitis JW, Stone BD, Gottschlich G. Nasal 45. Kumlin M, Dahlen B, Bjorck T, Zetterstrom 0, inflammatory mediator release in ragweed allergic Granstrom E, Dahlen SE. Urinary excretion of rhinitis - correlation with cellular influx into nasal leukotriene-E4 and 1 I-dehydro-thromboxane-B2 in secretions. Int Arch Allergy Appl Immunol 1991; 96: response to bronchial provocations with allergen, 231-237. aspirin, leukotriene-D4, and histamine in asthmatics. 61. Wilson SJ, Lau LCK, Howarth PH. Mediator and Am Rev Respir Dis 1992; 146: 96-103. cellular events in naturally ocurring seasonal allergic 46. Nasser SMS, Bell GS, Hawksworth RJ et al Effect of rhinitis. Clin Exp Allergy 1994; 24: 997A. the 5-lipoxygenase inhibitor ZD2 138 on allergen- 62. Skoner DP, Lee L Doyle WJ. Nasal physiology induced early and late asthmatic responses. Thorax and inflammatory mediators during natural pollen 1994; 49: 743-748. exposure. Ann Allergy 1990; 65: 206-210. 47. Pliss LB, Ingenito EP, Ingram RH Jr, Pichurko B. 63. Volovitz B, Osur SL, Ogra PL. Leukotriene-C4 Assessment of bronchoalveolar cell and mediator (LTC,) release in respiratory mucosa during natural response to isocapnic hyperpnea in asthma. Am Rev exposure to ragweed in ragweed sensitive children. Respir Dis 1990; 142: 73378. Ped Research 1987; 21: A506-A506. 48. Smith CM, Christie PE, Hawksworth RJ, Thien F, Lee TH. Leukotriene-E4 levels after allergen and 64. Knani J, Campbell A, Enander I. Indirect evidence of exercise challenge in bronchial asthma. Am Rev Respir nasal inflammation assessed by titration of inflamma- Dis 1991; 144: 1411-1413. tory mediators and enumeration of cells in nasal 49. Kikawa Y, Miyanomae T, Inoue T et al. Urinary secretions of patients with chronic rhinitis. J Allergy leukotriene E4 after exercise challenge in children with Clin Immunol 1992; 90: 880. asthma. J Allergy Clin Immunol 1992; 89: 1111-1119. 65. Bentley AM, Jacobson MR, Cumberworth V et al. 50. Christie PE, Tagari P, Ford-Hutchinson AW, et al. Immunohistology of the nasal mucosa in seasonal Urinary leukotriene-E4 concentrations increase after allergic rhinitis - increases in activated eosinophils aspirin challenge in aspirin-sensitive asthmatic sub- and epithelial mast-cells. J Allergy Clin Immunol 1992; jects. Am Rev Respir Dis 1991; 143: 1025-1029. 89: 877-883. 51. Christie PE, Tagari P, Ford-Hutchinson AW, Black 66. Durham SR, Ying S, Varney VA. Cytokine mRNA C, Markendorf A, Lee TH. Urinary leukotriene E4 expression of IL-2, IL-4, IL-5 and GM-CSF in the after lysine-aspirin inhalation in asthmatic subjects. nasal mucosa after local allergen provocation: Am Rev Respir Dis 1992; 146: 1531-1534. relationship to tissue eosinophilia. J Immunol 1992; 52. Sladek K, Dworski R, Soja J, Sheller JR, 148: 2390-2394. Nizankowska E, Oates JA. Eicosanoids in broncho- 67. Naclerio RM, Baroody FM, Kagey-Sobottka A, alveolar lavage fluid of aspirin-tolerant patients with Lichtenstein LM. Basophils and Eosinophils in asthma after aspirin challenge. Am J Respir Crit Care allergic rhinitis. J Allergy Clin Immunol 1994; 94: Med 1994; 149: 940-946. 130331309. 53. Picado C, Ramis I, Rose110 J et al. Release of peptide 68. Bisgaard H, Olsson, Bende M. Effect of leukotriene leukotriene into nasal secretions after local instillation D4 on nasal mucosal blood-flow, nasal airway- of aspirin in aspirin-sensitive asthmatic patients. Am resistance and nasal secretions in humans. Clin Allergy Rev Respir Dis 1992; 145: 65-69. 1986; 16: 289-297. LEUKOTRIENEANTAGONISM 807

69. Okuda M, Watase T, Mezawa A, Liu CM. The role of 83. Britton JR, Hanley SP, Tattersfield AE. The effect of leukotriene-D4 in allergic rhinitis. Ann Allergy 1988; an oral leukotriene D4 antagonist L-649 923 on the 60: 537-540. response to inhaled antigen in asthma. J Allergy Clin 70. Israel E, Rubin P, Kemp JP et al. The effect of Immunol 1987; 79: 811-816. inhibition of 5-lipoxygenase by zileuton in mild- 84. Taylor IK, O’Shaughnessy KM, Fuller RW, Dollery to-moderate asthma. Ann Intern Medic 1993; 119: CT. Effect of cysteinyl-leukotriene receptor antagonist 1059-1066. ICI 204 219 on allergen-induced bronchoconstriction 71. Spector SL, Smith LJ, Glass M and Accolate Asthma and airway hyperreactivity in atopic subjects. Lancet Trialists Group. Effects of 6 weeks therapy with oral 1991; 337: 690-694. doses of ICI 204 219, a leukotriene D4 receptor antag- 85. O’Shaughnessy KM, Taylor IK, O’Connor B, onist in subjects with bronchial asthma. Am J Respir O’Connell F, Thomson H. Potent leukotriene D4 Crit Care Med 1994; 150: 618-623. receptor antagonist ICI 204 219 given by the inhaled 72. Augstein J, Farmer JB, Lee TB. Selective inhibitor of route inhibits the early but not the late phase of slow reacting substance of anaphylaxis. Nature 1973; allergen-induced bronchoconstriction. Am Rev Respir 254: 215-217. Dis 1993; 147: 1431-1435. 73. Lee TH, Walport MJ, Wilkinson AH, Turner- 86. Findlay SR, Barden JM, Easley CB, Glass M. Effect Warwick M, Kay AB. Slow reacting substance if of the oral leukotriene antagonist, ICI 204 219, on anaphylaxis antagonist FPL 55712 in chronic asthma. antigen-induced bronchoconstriction in subjects with Lancet 1981; ii: 304305. asthma. J Allergy Clin Immunol 1992; 89: 1040-1045. 74. Jones TR, Young R, Champion E et al. L-649 923, 87. Dahlen B, Zetterstrom 0, Bjorck T, Dahlen SE. The sodium (beta S*, gamma R*)-4-(3-(4-acetyl- leukotriene-antagonist ICI-204 219 inhibits the early 3-hydroxy-2-propylphenoxy)-propylthio)-gamma- airway reaction to cumulative bronchial challenge hydroxy-beta-methylbenzenebutanoate, a selective, with allergen in atopic asthmatics. Eur Resp J 1994; 7: orally active leukotriene receptor antagonist. Can J 324331. Physiol Pharmacol 1986; 64: 10681075. 88. Rasmussen JB, Eriksson LO, Margolskee DJ, Tagari 75. Barnes N, Piper PJ, Costello J. The effect of an oral P, Williams VC, Andersson KE. Leukotriene-D(4) leukotriene antagonist L-649 923 on histamine and receptor blockade inhibits the immediate and late leukotriene D4-induced bronchoconstriction in bronchoconstrictor responses to inhaled antigen in normal man. J Allergy Clin Immunol 1987; 79: patients with asthma. J Allergy Clin Immunoll992; 90: 816-821. 193-201. 76. Phillips GD, Rafferty P, Robinson C, Holgate ST. 89. Christie PE, Smith CM, Lee TH. The potent and Dose-related antagonism of leukotriene-D4-induced selective sulfidopeptide leukotriene antagonist, SK- bronchoconstriction by po administration of and-F-104 353, inhibits aspirin-induced asthma. Am Ly-171883 in nonasthmatic subjects. J Pharmacol Exp Rev Respir Dis 1991; 144: 9577958. Therap 1988; 246: 732-738. 90. Kumlin M, Johansson H, Larsson C et al. The leuko- 77. Wood-Baker R, Phillips GD, Lucas RA, Turner GA, triene antagonist MK-0679 improves baseline pul- Holgate ST. The effect of inhaled Ly-170680 on monary function and blocks aspirin-induced airways leukotriene-D4-induced bronchoconstriction in obstruction in aspirin-sensitive asthmatics. Am Rev healthy volunteers. Drug Invest 1991; 3: 239-247. Respir Dis 1992; 145: A15. 78. Joos GF, Kips JC, Pauwels RA, Van Der Straeten 91. Israel E, Juniper EF, Callaghan JT et al. Effect of a ME. The effect of aerosolized SK&F 104353-22 on leukotriene antagonist, LY 171883, on cold air- the bronchoconstrictor effect of leukotriene D4 in induced bronchoconstriction in asthmatics. Am Rev asthmatics. Pulmon Pharmacol 1991; 4: 3742. Respir Dis 1989; 140: 134881353. 79. Krell RD, Aharony D, Buckner CK et al. The 92. Robuschi M, Riva E, Fuccella LM et al. Prevention of preclinical pharmacology of ICI 204 219. A peptide exercise-induced bronchoconstriction by a new leuko- leukotriene antagonist. Am Rev Respir Dis 1990; 141: triene antagonist (SK&F-104353) - a double-blind- 978-987. study versus disodium-cromoglycate and placebo_ Am 80. Kips JC, Joos GF, DeLepeleire I et al. MK-571, a Rev Respir Dis 1992; 145: 1285-1288. potent antagonist of leukotriene D4-induced bron- 93. Makker HK, Lau LC, Thomson HW, Binks SM, choconstriction in the human. Am Rev Respir Dis Holgate ST. The protective effect of inhaled 1991; 144: 617-621. leukotriene-D(4) receptor antagonist ICI-204 219 81. DeLepeleire I, Reiss TF, Rochette F et al. Monte- against exercise-induced asthma. Am Rev Respir Dis lukast causes prolonged, potent leukotriene D-4- 1993; 147: 141331418. receptor antagonism in the airways of patients with 94. Manning PJ, Watson RM, Margolskee DJ, Williams asthma. Clin Pharmacol Therap 1997; 61: 83-92. VC, Schwartz JI, O’Byrne PM. Inhibition of exercise- 82. Fuller RW, Black PN, Dollery CT. Effect of the oral induced bronchoconstriction by MK-571, a potent leukotriene D4 antagonist LY171883 on inhaled and leukotriene D4 antagonist. N Engl J Med 1990; 323: intradermal challenge with antigen and leukotriene 1736-1739. D4 in atopic subjects. J Allergy Clin mmunol 1989; 83: 95. Bronsky EA, Kemp JP, Zhang J, Guerreiro D, 939-944. Reiss TF. Dose-related protection of exercise 808 S. J. LANE

bronchoconstriction by montelukast, a cysteinyl antagonist zafirlukast for mild-to-moderate asthma - leukotriene-receptor antagonist, at the end of a once- a randomized, double-blind, placebo-controlled trial. daily dosing interval. Clin Pharmacol Therap 1997; 62: Ann Intern Med 1997; 126: 177. 556-561. 110. Wechsler ME, Garpestad E, Flier SR et al. Pulmonary 96. Kemp JP, Dockhorn RJ, Shapiro GG et al. Monte- infiltrates, eosinophilia and cardiomyopathy following lukast, a leukotriene receptor antagonist, inhibits corticosteroid withdrawal in patients with asthma exercise-induced bronchoconstriction in 6- to 14-year- receiving receiving zafirlukast. J Am Med Assoc 1998; old children. J Allergy Clin Immunol 1997; 99: 279:455-457. 13141314. 111. Wahedna I, Wisniewski AFZ, Wong CS, Tattersfield 97. Reiss TF, Hill JB, Harman B et al. Increased urinary AE. Effect of multiple doses of RG 12525, an oral excretion of LTE, after exercise and attenuation of leukotriene D4 antagonist, in chronic asthma. Am Rev exercise-induced bronchospasm by montelukast, a Respir Dis 1992; 145: A16. cysteinyl leukotriene receptor antagonist. Thorax 112. Tamaoki J, Kondo M, Sakai N et al. Leukotriene 1997;52: 1030-1035. antagonist prevents exacerbation of asthma during 98. Strek ME, Sedy J, Solway J, Jorkasky DK, Jones B, reduction of high-dose inhaled corticosteroid. Am J Boike SC. Pranlukast (lIltair@) inhibits cold air- Respir Crit Care Med 1997; 155: 1235-1240. induced bronchoconstriction in patients with asthma. 113. Oosaki R, Mizushima Y, Kashii T, Kawasaki A, J Allergy Clin Immunol 1997; 99: 1342. Kobayashi M. Therapeutic effect of pranlukast, a 99. Ellis JL, Undem BJ. Role of cysteinyl-leukotrienes selective cysteinyl leukotriene receptor antagonist, on and histamine in mediating intrinsic tone in isolated bronchial asthma. Int Arch Allergy Immunol 1997; human bronchi. Am J Respir Crit Care Med 1994; 149: 114: 97-100. 118-122. 114. Barnes NC, Pujet JC. Pranlukast, a novel leukotriene 100. Impens N, Reiss TF, Teahan JA et al. Acute receptor antagonist: Results of the first European, bronchodilation with an intravenously administered placebo controlled, multicentre clinical study in leukotriene- D(4) antagonist, MK-679. Am Rev Respir asthma. Thorax 1997; 52: 523-527. Dis 1993;147: 1442-1446. 115. Grossman J, Faiferman I, Dubb JW et al. Results of 101. Hui KP, Barnes NC. Lung-function improvement the first US double-blind, placebo-controlled, multi- in asthma with a cysteinyl-leukotriene receptor center clinical study in asthma with pranlukast, a antagonist. Lancet 1991; 337: 1062-1063. novel leukotriene receptor antagonist. J Asthma 1997; 102. Gaddy JN, Margolskee DJ, Bush RK, Williams VC, 34:321-328. Busse WW. Bronchodilation with a potent and 116. Flowers BK, Proud D, Kagey-Sobotka A, selective leukotriene-D4 (LTD,) receptor antagonist Lichtenstein LM. The effect of leukotriene antagonist (MK-571) in patients with asthma. Am Rev Respir Dis on the early response to antigen. Otolaryngol Head 1992; 146: 358-363. Neck Surg 1990; 102:219-224. 103. Dahlen B, Margolskee DJ, Zetterstrom 0, Dahlen SE. 117. Donnelly AL, Glass M, Minkwitz MC, Casale TB. Effect of the leukotriene receptor antagonist MK-0679 The leukotriene’ D4 receptor antagonist, on base-line pulmonary-function in aspirin-sensitive ICI 2 204,219, relieves symptoms of acute seasonals asthmatic subjects. Thorax 1993; 48: 1205-1210. rhinitis. Am J Respir Crit Care Med 1995; 151: 1734- 104. Smith LJ, Jorkasky DK, Carr S, Boike SC. Intra- 1739. venous pranlukast (Ultair@) inhibits LTD(4)-induced 118. Grossman J, Ratner PH, Nathan R, Adelglass J, bronchoconstriction in patients with asthma. J Allergy deJong B. Pranlukast (Ultair@, SB 205312, ONO- Clin Immunoll997; 99: 1341-1341. 1078) an oral leukotriene receptor antagonist, relieves 105. Cloud ML, Enas GG, Kemp J et al. A specific symptoms in patients with seasonal allergic rhinitis LTD,/LTE,-receptor antagonist improves pulmonary (SAR). J Allergy Clin Immunol 1997; 99: 1799. function in patients with mild, chronic asthma. Am 119. Evans JF, Leville C, Mancini JA et al. 5-lipoxygenase- Rev Respir Dis 1989; 140: 133661339. activating protein is the target of a quinolone class of 106. Reiss TF, Altman LC, Chervinsky P et al. Effects of leukotriene biosynthesis inhibitors. Mole Pharmacol montelukast (MK-0476) a new potent cysteinyl 1991;40:22-27. leukotriene (LTD(4)) receptor antagonist, in patients 120. Garland LG, Salmon JA. Hydroxamic acids and with chronic asthma. J Allergy Clin Immunoll996; 98: hydroxureas as inhibitors of arachidonate 528-534. 5-lipoxygenase. Drugs Future 1991; 16: 547-558. 107. Fujimura M, Sakamo S, Kamio Y, Matsuda T. Effect 121. Hui KP, Taylor IK, Taylor GW et al. Effect of a of a leukotriene antagonist, ONO-1078, on bronchial 5-lipoxygenase inhibitor on leukotriene generation hyperresponsiveness in patients with asthma. Respir and airway responses after allergen challenge in Med 1993; 87: 133-138. asthmatic patients. Thorax 1991; 46: 184189. 108. Fish JE, Kemp JP, Lackey RF et al. Zafirlukast for 122. Friedman BS, Be1 EH, Buntinx A et al. Oral leuko- symptomatic mild-to-moderate asthma: A 13-week triene inhibitor (MK-886) blocks allergen-induced air- multicenter study. Clin Therap 1997; 19: 675-690. way responses. Am Rev Respir Dis 1993; 147: 839-844. 109. Suissa S, Dennis R, Ernst P, Sheehy 0, Wood- 123. Diamant Z, Timmers MC, Vanderveen H et al. The Dauphinee S. Effectiveness of the leukotriene receptor effect of MK-0591, a novel 5-lipoxygenase activating LELIKOTRIENEANTAGONISM 809

protein inhibitor, on leukotriene biosynthesis and 137. Fischer AR, Rosenberg MA, Lilly CM et al. Direct allergen-induced airway responses in asthmatic sub- evidence for a role of the mast-cell in the nasal jects in-vivo. J Allergy Clin Immunol 1995; 95: 42-51. response to aspirin in aspirin-sensitive asthma. J 124. Israel E, Fischer AR, Rosenberg MA et al. The Allergy Clin Immunol 1994; 94: 1046-1056. pivotal role of 5-lipoxygenase products in the reaction 138. Owens CA, Grundy GW. Focus on zileuton: the first of aspirin-sensitive asthmatics to aspirin. Am Rev FDA-approved agent of a new class of drugs for the Respir Dis 1993; 148: 1447-1451. management of asthma. Formulary 1997; 32: 455. 125. Nasser SMS, Bell GS, Foster S et al. Effect of the 139. Spector SL. Management of asthma with zafirlukast- 5-lipoxygenase inhibitor ZD2138 on aspirin-induced clinical experience and tolerability profile. Drugs 1996; asthma. Thorax 1994; 49: 749-756. 52: 36-46. 126. Israel E, Dermarkarian R, Rosenberg M, Sperling R, 140. Barnes NC, deJong B, Miyamato T. Worldwide clini- Taylor G, Rubin P. The effects of a 5-lipoxygenase cal experience with the first marketed leukotriene inhibitor on asthma induced by cold, dry air. N Engl J receptor antagonist. Chest 1997; 111: (Suppl.) Med 1990; 323: 1740-1744. S52-S60. 127. Meltzer SS, Hasday JD, Cohn J, Bleecker ER. Inhibi- 141. Sorkness CA. The use of 5-lipoxygenase inhibitors tion of exercise-induced bronchospasm by zileuton ~ a and leukotriene receptor antagonists in the treatment 5-lipoxygenase inhibitor. Am J Respir Crit Care Med of chronic asthma. Pharmacotherapy 1997; 17 1996; 153: 931-935. (Suppl.): s50-s54. 128. Chapman KR, Friedman BS, Shingo S, Heyse J, Reiss 142. Kelloway JS, Zafirlukast: the first leukotriene- T, Spector R. The efficacy of an oral inhibitor of receptor antagonist approved for the treatment of leukotriene synthesis (MK-0591) in asthmatics treated asthma. Ann Pharmacotherapy 1997; 31: 1012-1021. with inhaled steroids. Am J Respir Crit Care Med 143. Bethesda Guidelines for the Diagnosis and Manage- 1994; 149: A215. ment of Asthma. National Heart, Lung and Blood 129. Liu MC, Dube LM, Lancaster J. Acute and chronic Institute, National Institutes of Health, 1997. effects of a 5-lipoxygenase inhibitor in asthma- a 144. Marom Z, Shelhamer JH, Bach MK, Morton, DR, 6-month randomized multicenter trial. J Allergy Clin Kaliner, M. Slow-reacting substances, leukotrienes C4 Immunol 1996; 98: 859-871. and D4, increase the release of mucus from human 130. Knapp HR. Reduced allergen-induced nasal conges- airways in vitro. Am Rev,.Respir Dis 1982; 126: 449- tion and leukotriene synthesis with an orally active 451. 5-LO inhibitor. N Engl J Med 1990; 323: 1740-1748. 145. Camp RDR, Coutts AA, Greaves MW, Kay AB, 131. Israel E, Cohn J, Dube L, Drazen JM. Effect of Walport MK. Response of human skin to intra- treatment with zileuton, a 5-lipoxygenase inhibitor, in dermal injection of leukotrienes C4, D4 and B4. B J patients with asthma - a randomized controlled trial. Pharmacol 1983; 80: 4977502. J Am Med Assoc 1996; 275: 931-936. 146. Soter NA, Lewis RA, Corey EJ, Austen KF. Local 132. DuBuske LM, Grossman J, Dube LM et al. effects of synthetic leukotrienes (LTC,, LTD,, LTE,, Randomized trial of zileuton in patients with moder- and LTB,) in human skin. J Invest Dermatol 1983; 80: ate asthma: effect of reduced dosing frequency and 115-119. amounts on pulmonary function and asthma 147. Michelassi F, Landa L, Hill RD, Lowenstein E, symptoms. Am J Managed Care 1997; 3: 6333640. Watkins WD, Petkau AJ. Leukotriene D4: a potent 133. Schwartz HJ, Petty T, Dube LM, Swanson LJ, coronary artery vasoconstrictor associated with Lancaster JF. A randomised controlled trial compar- impaired ventricular contraction. Science 1982; 217: ing zileuton with theophylline in moderate asthma. 841-843. Arch Intern Med 1998; 158: 141-148. 148. Pfeffer MA, Pfeffer JM, Lewis RA, Braunwald E, 134. Howarth PH, Harrison K, Lau L. The influence of Corey EJ, Austen KF. Systemic hemodynamic effects 5-lipoxygenase inhibition in allergic rhinitis. Int Arch of leukotrienes C4 and D4 in the rat. Am J Physiol Allergy Immunol 1995; 107: 423424. 1983; 244: H6288H633. 135. Ancill RJ, Takahashi Y, Kibune Y, Campbell R, 149. Badr KF, Baylis C, Pfeffer JM et al. Renal and Smith JR. Randomized double-blind, placebo- systemic hemodynamic responses to intravenous controlled clinical trial of a selective 5-lipoxygenase infusion of leukotriene C4 in the rate. Circ Res 1984; inhibitor (AA-861) for the prevention of seasonal 54: 492499. allergic rhinitis. J Int Med Res 1990; 18: 75-88. 150. Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur 136. Spaeth J, Schultze V, Klimek L, Lengersdorf A, BW, Lee TH. Leukotriene E4 and granulocytic infil- Mosges R. Azelastine reduces histamine-induced tration into asthmatic airways. Lancet 1993; 341: swelling of nasal-mucosa. O&J- Oto-Rhino-Laryngol 989-990. Related Specialities 1996; 58: 157-163.