Allergology International (1996) 45: 163-169

Review Article

The role of cysteinyl in : From the molecule to the bedside

BEA Lams and TH Lee Department of Allergy and Respiratory Medicine, Guy's Hospital, London, UK

ABSTRACT via LTC4synthase, to the cysteinyl LTC4which is sub- sequently converted by y-glutamyltranspeptidase to LTD4and by There is increasing interest in the role played by the cysteinyl a dipeptidase to LTE4. leukotrienes in the pathogenesis of bronchial asthma. They have been demonstrated to have a bronchoconstrictor effect both in vitro and in vivo and have been isolated from bron- BRONCHOCONSTRICTOR EFFECT OF THE choalveolar lavage fluid and urine from stable asthmatics LEUKOTRIENES and from asthmatics during exacerbations and after endo- In vitro studies with LTC4have demonstrated a contractile action bronchial challenge. Pharmacological intervention has been on isolated human bronchus2 and tracheal smooth muscle3 with studied through antagonism of leukotriene receptors and a potency of 1000 times that of histamine. Isolated human inhibition of leukotriene synthesis. Both have been shown to bronchi of diameter 3-12mm have a high degree of baseline have an effect on the asthmatic response after challenge with bronchomotor tone equivalent to 50% of maximal broncho- allergen, exercise and inhalation of cold air and to have an constriction induced by. BaCI2. This resting tone is reduced by effect on aspirin sensitive asthmatics and on the symptoms preincubation with the LTD4antagonists ICI 204,219 and SKF and markers of severity of chronic asthma. The differences 104,353 and this reduction is additive to that induced by the between antagonism and synthesis inhibition are addition of histamine Hl antagonists suggesting thatthis resting discussed. tone is mediated by the continuous production of histamine and leukotrienes.4 Key words: asthma, leukotriene, leukotriene antagonist, 5- In vivo studies have revealed a bronchoconstrictor effect of inhaled nebulized solutions of leukotrienes in both normal and asthmatic individuals. In normal subjects, LTC4is 600-9500 INTRODUCTION times as potent as histamine in causing a 30% fall in expiratory flow at a lung volume of 30% of baseline vital capacity above There is increasing evidence for the role played by the cysteinyl residual volume.5 LTD4was found to be 6000 times more potent leukotrienes LTC4, LTD4 and LTE4 in the pathogenesis of than histamine.b LTE4appears to be only 40-60 times as potent bronchial asthma. Evidence is also accumulating that pharma- as histamine but has a longer duration of action when com- cological manipulation through antagonism or inhibition of pared to the other cysteinyl leukotrienes.7,8 their synthesis might be clinically useful in the treatment of In asthmatic individuals the leukotrienes also have a bron- asthma. choconstrictor effect. However, in asthmatics LTC4is only 40 The cysteinyl leukotrienes are generated by the 5- times as potent as histamine in inducing bronchoconstriction9 lipoxygenase (5LO; Fig. 1) which acts on in and LTD4only 140 times as potent.10 Further studies have conjunction with 5LO associated protein (FLAP)to generate the confirmed that the relative (to histamine) potencies of LTC4and unstable epoxide LTA4.This is then either converted to LTB4or, LTD4 are reduced in asthmatics when compared to non- asthmatics.11 A further study has shown that when compared to normal individuals, asthmatics have a 14-fold greater response to his- Correspondence: Professor TH Lee, Department of Allergy and Respira- tamine, a 15-fold greater response to methacholine, a 6-fold tory Medicine, 4th Floor, Hunt's House, Guy's Hospital, London SE1 9RT, UK. greater response to LTC4,a 9-fold greater response to LTD4,and Received 10 August 1996. a 219 times greater response to LTE4.Furthermore, as airways 164 BEA LAMS AND TH LEE

became more hyperresponsive as judged by their response to only one out of seven of the non-asthmatics. An increase in all histamine and methacholine, so the relative potency of LTE4 four mediators after challenge was found in the asthmatics only. increases when compared to LTC4and LTD4.12 In addition, the asthmatic group without a LAR had a greater increase in mediator levels when compared with asthmatics with Aspirin-sensitive asthma a LAR. In a study of allergen provocation sufficient to cause 25-59% fall in FEV,(forced expiratory volume in one second) in Studies in asthmatics whose asthma is precipitated by aspirin 17 allergic asthmatics, urinary LTE4 levels were found to have shown that these individuals are exquisitely sensitive to increase from 46 to 92ng/24h. No increase in urinary LTE4was LTE4. In aspirin-sensitive asthmatics LTE4 is 1870 times more detected after methacholine challenge caused a similar fall in potent than histamine in inducing bronchospasm whereas in FEV,. Whereas a correlation existed between urinary LTE4and non-aspirin-sensitive asthmatics, LTE4 is only 145 times as the decrease in FEY,in the early asthmatic response (EAR),there potent as histamine.13 Furthermore, desensitization of these was no correlation with the fall in FEV1,in the LAR.20 patients to aspirin leads to a fall in the relative potency of LTE4 Manning et al. looked at 18 asthmatics and found an by 20-fold, suggesting that LTE4plays a part in the induction of increase in urinary LTE4 in those with an early asthmatic bronchospasm in this group. This hyperresponsiveness is spe- response and that the degree of bronchoconstriction correlated cific to LTE4and is not seen with LTC4.14 with the level of urinary LTE4.21Those with a dual asthmatic These studies suggest that LTC4and LTD4appear to have less response had a lesser but still significant increase in urinary LTE4 relative potency in asthmatics when compared to normal indi- and those with an isolated LAR had no increase. Cysteinyl viduals but that asthmatic airways, and especially those of leukotrienes, therefore, appear to be important in the EARand aspirin-sensitive asthmatics, have a disproportionate respon- contribute significantly to the degree of bronchoconstriction. siveness to LTE4.This implies that LTE4 may play an important role in bronchial asthma, perhaps because of its stability and Aspirin-sensitive asthma the fact that it persists for the longest time at its site of release.15 Christie et al. have demonstrated a 6-fold increase in urinary LTE4in aspirin-sensitive asthmatics when compared to normal ISOLATION OF LEUKOTRIENESFROM ASTHMATICS individuals and non-aspirin-sensitive asthmatics.22 Six aspirin- Various investigators have looked at the concentrations of sensitive asthmatics had a 4-fold increase in urinary LTE4after leukotrienes in the bronchoalveolar lavage fluid (BALF)and oral aspirin challenge which led to a 21% fall in FEV1,whereas urine of asthmatics. A study of 17 subjects with mild to severe a control group had no fall in FEV1and no increase in urinary asthma revealed that 15 had detectable levels of LTE4in BALF LTE4levels after aspirin ingestion. whereas no LTE4was detected in nine controls.14 Similarly, Wardlaw et al. found increased levels of LTB4and LTC4in the LEUKOTRIENEANTAGONISTS BALFof eight symptomatic asthmatics when compared to 14 The evidence for the role of the cysteinyl leukotrienes in asthma controls.16 Drazen et al. looked at 72 patients attending acci- has been supported by studies involving both leukotriene antag- dent and emergency departments with asthma and found that onists and agents which inhibit their synthesis. Several studies urinary LTE4levels were higher in those who responded to a nebulized bronchodilator when compared to those who did not, suggest that a number of LTD4antagonists developed for use in human trials have a blunting effect on the fall in FEV1seen in suggesting that cysteinyl leukotrienes may have a broncho- asthmatics when experimentally challenged with allergen, exer- spastic role in acute asthma.17 cise, inhalation of cold dry air and aspirin. The first generation antagonists LY 171,883 and LY649,923 ENDOBRONCHIAL CHALLENGE produce a slight fall in the EARafter allergen challenge but have Wenzel et al. investigated a group of atopic asthmatics with no effect on baseline FEV,or the LAR.23,24Ten asthmatics pre- endobronchial allergen challenge and found that LTC4was the treated with the selective and potent second generation oral predominant leukotriene and increased 9-fold after chal- agent ICI 204,219 showed a reduction of 80% in their EARand lenge.18 In addition, whereas LTC4was detected in 9 of 11 of 50% in their LAR (Fig. 2).25 Treatment also suppressed an atopic asthmatics at baseline, it was detected in only one out of increase in bronchial reactivity 6h post challenge. Inhaled ICI seven atopic non-asthmatics and one out of six non-atopics. A 204,219 was not as effective and although it reduced the EAR, further study by the same group19 measured levels of the mast it had no effect on the LAR.26In addition, a single dose of inhaled cell derived products PGD2, TXB2,LTC4 and histamine before ICI 204,219 produced a 10-fold rightward shift in the dose and 5 min after endobronchial allergen challenge in seven non- response curve to inhaled cat allergen.27 Inhaled ICI 204,219 asthmatics, six asthmatics and six asthmatics with a late asth- also led to a shortening of the recovery time of the EARfrom 60 matic response (LAR),all of whom were atopic.19 Detectable to 40 min.28 The quinolone derivative MK571 has also been levels of LTC4were found in 9 out of 12 of the asthmatics and in shown to inhibit the EARby 88% and the LARby 63%.29 CYSTEINYL LEUKOTRIENES IN ASTHMA 165

Studies in exercise-induced asthma have shown that SK& F Bronchodilator effect 104,353, a weak LTD4antagonist, led to a reduction from 29 to Several studies have shown that leukotriene antagonists have a 20% in the exercise-induced bronchoconstrictor response, this bronchodilator effect on asthmatics. Intravenous treatment with being of a similar degree to that seen with sodium cromogly- MK679 led to an increase in baseline FEV1of up to 15.8% in a cate.30 In a model for exercise-induced asthma, oral treatment with ICI 204,219 resulted in a reduction in the fall in FEV1after group of nine asthmatics with resting FEV1of between 40 and 80% of that predicted by age and height.36 Oral administration inhalation of cold dry air from 36 to 21% in eight asthmatics.33 of ICI 204,219 led to an increase in resting FEV1 compared to A further study on the same compound revealed a halving of the fall in FEV1after exercise in nine asthmatics.32 MK571 also led placebo with the effect of salbutamol being additive.37 This additive effect was confirmed in a study of 12 asthmatics treated to a decrease in the fall in FEV1and a shortening in the recovery with intravenous MK571, with the degree of bronchodilation time from 33 to 8 min in 12 asthmatics after exercise (Fig. 3) 33 However, despite their potency, LTD4antagonists were unable to abolish the bronchospastic response to exercise completely, suggesting that other mediators such as histamine and are important in this reaction. Aspirin-sensitive asthma is probably the most leukotriene- dependent model for the investigation of anti-leukotriene ther- apy. The weak LTD4 antagonist SK& F 104,353 reduced the response to ingested aspirin by a mean of 47% in five out of six subjects.34 The quinolone derivative MK679 was found to improve baseline function in eight aspirin-sensitive asthmatics and to block the airways obstruction caused by inhaled lysine aspirin, producing a 4.4-fold rightward shift in the dose response curve.35

Fig.2 Effect of (○) ICI 204,219 and (●) placebo on early and late responses to allergen challenge. Reproduced with permission from The Lancet Ltd. (Ref. 25).

Fig. 1 Leukotriene biosynthesis. LT, leukotriene; 5-HETE, 5-hydroxy- Fig. 3 Mean percentage change in FEV, after exercise following treat- eicosatetraenoic acid; 5-H PETE, 5-hydroperoxyeicosatetraenoic. ment with 166 BEA LAMS AND TH LEE being inversely proportional to the baseline FEV1and additive to that produced by albuterol (Fig. 4).38 MK679 also led to an 18% increase in FEV1in eight aspirin-sensitive asthmatics with the degree of bronchodilation again strongly correlating with the severity of asthma39 suggesting that cysteinyl leukotrienes play a major role in determining resting tone. Treatment with MK476 led to a 12% increase in FEY,in a group of moderate asthmatics.40 Addition of the LTD4antagonist RG 12525 to existing steroid treatment led to an increase in FEV1in stable asthmatic subjects.41

Chronic asthma

The LTD4antagonists also appear to provide symptomatic ben- Fig. 4 Mean change in FEVJ in asthmatic patients with existing airways efit in chronic asthma. Treatment with oral LY 171,883 for 6 obstruction after infusion of weeks in a group of 138 asthmatics led to an increase in FEV1 from 73.8 to 83.3% of that predicted by age and height, an improvement in symptoms of wheeze and dyspnea and a

decrease in the use of β-2 agonists, but no change in cough or chest tightness.42Oral MK571 treatment for 6 weeks led to an 8-14% increase in FEV, and a 30% reduction in salbutamol usage.43 Six weeks of oral ICI 204,219 in mild to moderate asthma led to an improvement in their daytime asthma score, nocturnal awakenings and morning peak flow recordings.39 A study of varying doses of the antagonist ICI 204,219 in 266 moderate asthmatics found a reduction in nocturnal awakening (by 46%), a decrease in first morning asthma symptoms, day- time asthma scores (by 26%) and salbutamol use (by 30%), and an increase in FEV1(by 11%) and evening peak expiratory flow rates (PEFR).44

5-LIPOXYGENASE(5LO) INHIBITORS

There are a number of theoretical arguments to suggest that an inhibition of 5LO would be more effective than antagonism of a specific . First, inhibition of 5LO leads to a Fig. 5 Mean percentage change in FEV1 after aspirin challenge after reduction in not only the cysteinyl leukotrienes LTC4, LTD4and premedication with the LTE4,but also LTB4.45In addition, there is evidence that leukotriene receptor antagonism alone may prolong the half lives of some of the leukotrienes by interfering with their elimination, thereby pos- inhibitor MK886 revealed a fall in the EAR of 58% and a fall in sibly potentiating their action.36 Studies on the 5LO inhibitors the LAR of 44%. This was accompanied by a 54% fall in the have addressed their effect on the asthmatic response to chal- A23187 stimulated whole blood LTB4generation and a 51.5% lenge with allergen, cold air, exercise and aspirin. inhibition in the rise of urinary LTE4in the EAR and an 80% inhi- In a study of nine asthmatics, the 5LO inhibitor, , led bition during the LAR.49 to complete inhibition of ex vivo whole blood LTB4generation Administration of the FLAP inhibitor MK0591 prior to aller- and a reduction of 50% in the rise of urinary LTE4post-allergen gen challenge led to a 96% inhibition of LTB4and an 84% inhi- challenge. However, there was no reduction in the EAR or LAR bition of urinary LTE4production 24 h post-allergen challenge. and no reduction in airway responsiveness post-challenge.47 In addition, there was a fall of 79% in the EAR and the LARwas The potent and selective inhibitor ZD2138 led to an 82% fall in delayed by 3 h.50 BAYx1005, a FLAP inhibitor of similar potency ex vivo whole blood LTB4generation and a 72% decrease in the to MK0591, was administered to atopic asthmatics and led to a rise in urinary LTE4but again had no effect on the EAR or the reduction of 68% in the EAR to inhaled allergen and an 87% LAR.48 A study of eight atopic men wtih the translocation reduction in urinary LTE4.51 CYSTEINYL LEUKOTRIENES IN ASTHMA 167

Thirteen asthmatics premedicated with a single dose of zileu- cyclooxygenase pathway with the generation of proinflamma- ton had a reduction in ex vivo LTB4generation of 74% and an tory products. increase of 47% in the amount of cold air required to cause a Further details are needed to investigate whether these com- fall in FEV, of 10%.52Twenty-four asthmatics treated wtih a 2 pounds have steroid sparing effects and their effect on long- day course of zileuton had a 40% fall in the amount of exercise term symptoms. Similarly, biopsy studies to investigate the induced bronchospasm.53 effects on airways of these compounds are Treatment with zileuton in eight aspirin-sensitive asthmatics needed. Finally, although there is evidence that leukotrienes are led to a fall in urinary LTE4of 70% and prevented a drop in FEV1 implicated in the pathogenesis of asthma and that pharmaco- after aspirin challenge.54 Similarly, ZD2138 protects against logical modification of their action has been shown to be effec- aspirin-induced asthma with a 20.3% fall after challenge tive in both models of acute asthma and on chronic asthma, it and treatment with placebo, and a fall of 4.9% after treatment should be noted that leukotrienes are just one of many proin- with ZD2138 was associated with a reduction in whole blood flammatory compounds active in asthma. LTB4generation of 72% and of urinary LTE4of 74% at 6 h (Fig. 5) 55 REFERENCES

Chronic asthma 1 Snyder DW, Fleisch JH. Leukotriene receptor antagonists as poten- tial therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 1989; 29; Studies have been conducted to assess the effect of the 5LO 123-43. inhibitors on baseline FEV1 and symptoms in chronic asthma. 2 Dahlen S-E, Hedqvist P, Hammarstrom S, Samuelsson B. Treatment with zileuton led to an increase in baseline FEV1 of Leukotrienes are potent constrictors of human bronchi. Nature 1980; 288: 484-6. 15% after 1 h in a group of chronic asthmatics treated with 3 Jones TR, Davis C, Daniel EE. Pharmacological study of the con- salbutamol only.56 Treatment of a group of aspirin-sensitive tractile activity of leukotriene C4 and D4 on isolated human airway asthmatics with ZD2138 led to a 10% increase in baseline smooth muscle. Can. J. Physiol. Pharmacol. 1982; 60: 638-43. FEV1.55In a study of 139 asthmatics with a baseline FEV1 of 4 Ellis JL, Undem BJ. Role of cysteinyl-leukotrienes and histamine in between 40 and 75% of that predicted by age and height and mediating intrinsic tone in isolated human bronchi. Am. J. Respir. Crit. Care Med. 1994; 149: 118-22. not taking steroids, zileuton led to a 13.6% increase in FEV,, a 5 Weiss JW, Drazen JM, Coles N, McFadden ER Jr et al. Broncho- decrease in asthma symptom score, a decrease in β-2 agonist constrictor effects of leukotriene C in humans. Science 1982; use and a decrease in excreted urinary LTE4.56In a group of 398 216: 196-8. asthmatics treated with salbutamol only and with a mean base- 6 Weiss JW, Drazen JM, McFadden ER Jr et al. Airway constriction in line FEV1of 61%, treatment with zileuton for 13 weeks led to an normal humans produced by inhalation of Leukotriene D. Potency, time course, and effect of aspirin therapy. JAMA 1983; 249: increase in FEV1of 0.251 compared with 0.081 with placebo.56 2814-17. For 4 weeks, 109 asthmatics with baseline FEV1 ranging from 7 Davidson AB, Lee TH, Scanlon PD et al. Bronchoconstrictor effects 50 to 75% of predicted were treated with inhaled steroids with of leukotriene E4 in normal and asthmatic subjects. Am. Rev. MK0591 or placebo. The group treated with MK0591 had an Respir. Dis. 1987; 135: 333-7. increase in their FEV1of 6.8% whereas placebo had an increase 8 O'Hickey SP, Arm JP, Rees PJ, Spur BW, Lee TH. The relative responsiveness to inhaled leukotriene E4,methacholine and hista- of 0.6%. Increases in morning and evening PEFR of 19 and mine in normal and asthmatic subjects. Eur. Respir. J. 1988; 1: 135% respectively, were also noted as was a decrease in 13-2 913-17. agonist use.57 9 Smith U, Greenberger PA, Patterson R, Krell RD, Bernstein PR. The effect of inhaled leukotriene D4 in humans. Am. Rev. Respir. Dis. 1985; 131: 368-72. CONCLUSION 10 GriffinM, Weiss JW, LeitchAG et al. Effects of leukotriene D on the airways in asthma. N. Engl. J. Med. 1983; 308: 436-9. It appears that despite theoretical advantages over the 11 Barnes NC, Piper PJ, Costello JF Actions of inhaled leukotrienes leukotriene antagonists the 5-lipoxygenase (5LO) antagonists and their interactions with other allergic mediators. Prostaglandins do not suppress leukotriene mediated processes any more than 1984; 28: 629-30. the leukotriene antagonists. This may be because, although 12 Arm JP,O'Hickey SP,Hawksworth RJ.Asthmatic airways have a dis- 5LO inhibitors are effective in reducing ex vivo LTB4generation proportionate hyperresponsiveness to LTE4as compared with nor- mal airways, but not to LTC4,LTD4, methacholine, and histamine. and urinary LTE4excretion, they are not potent enough to inhibit Am. Rev. Respir. Dis. 1990; 142: 1112-18. intra-airways Leukotriene generation and that even small 13 Arm JP, O'Hickey SP Spur BW, Lee TH. Airway responsiveness amounts of leukotrienes in this area may be able to exert patho- to histamine and leukotriene E4 in subjects with aspirin-induced logical effects. In addition, 5LO inhibition may decrease the asthma. Am. Rev. Respir. Dis. 1989; 140: 148-53. 14 Christie PE, Schmitz-Schumann M, Spur BW, Lee TH. Airway amount of A4 generated which may itself have a moder- responsiveness to leukotriene C4 (LTC4),leukotriene E4 (LTE4) and ating effect on leukotriene action.' Similarly, inhibition of 5LO histamine in aspirin-sensitive asthmatic subjects. Fur. Respir. J. may lead to shunting of arachidonic acid derivatives down the 1993; 6: 1468-73. 168 BEA LAMS AND TH LEE

15 LamS, Chan H, LeRicheJC, Chan-YeungM, Salari H. Releaseof 204,219 a potent leukotriene D4 receptor antagonist. Am. Rev. leukotrienesin patients with bronchial asthma. J. AllergyClin. Respir. Dis. 1992;145: 746-9. Immunol.1988; 81: 711-17. 32 Makker HK, Lau LC, Thomson HW, Binks SM, Holgate ST. The 16 WardlawAJ, Hay H, Cromwell O,Collins JV, Kay AB. Leukotrienes, protective effect of inhaled leukotriene D4 receptor antagonist ICI LTC4and LTB4in bronchoalveolarlavage in bronchialasthma and 204,219 against exercise-induced asthma. Am. Rev. Respir. Dis. other respiratorydisease. J. AllergyClin. Immunol. 1989; 84: 1993; 147: 1413-18. 19-26. 33 Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz 17 DrazenJM, O'BrienJ, SparrowD, WeissST, Martins MA, Israel E. JI. Inhibition of exercise-induced bronchoconstriction by MK-571, Recoveryof leukotrieneE4 from the urine of patients with airway a potent leukotriene D4-receptor antagonist (comments) N. Engl. J. obstruction.Am. Rev.Respir. Dis. 1992; 146: 104-8. Med. 1990; 323: 1736-9. 18 Wenzel SE, Larsen GL, Johnston K, VoelkelNF, Westcott JY. 34 Christie PE, Hawksworth R, Spur BW, Lee TH. Effect of indo- Elevatedlevels of leukotrieneC4 in bronchoalveolarlavage fluid methacin on leukotriene E4-induced histamine hyperresponsive- from atopic asthmatics after endobronchialallergen challenge. ness in asthmatic subjects. Am. Rev. Respir. Dis. 1992; 146: Am. Rev.Respir. Dis. 1990;142: 112-19. 1506-10. 19 WenzelSE, WestcottJY, Larsen GL. Bronchoalveolarlavage fluid 35 KumlinM, Johansson H, Larsson C et al. The leukotriene antago- mediator levels 5 minutesafter allergen challengein atopic sub- nist MK-0679 improves baseline pulmonary function and blocks jects with asthma: relationshipto the developmentof late asth- aspirin-induced airways obstruction in aspirin-sensitive asthmatics matic responses.J. AllergyClin. Immunol.1991; 87: 540-8. (abstract). Am. Rev. Respir. Dis. 1992; 145: Al 5. 20 WestcottJY, Smith HR, Wenzel SE, LarsenGL, Thomas RB,Felsien 36 Impens N, ReissTF, Teahan JA et al. Acute Bronchodilation with an D. Urinaryleukotriene E4 in patientswith asthma. Effectof airways intravenously administered leukotriene D4 antagonist, MK-679. reactivityand sodium cromoglycate.Am. Rev.Respir. Dis. 1991; Am. Rev. Respir. Dis. 1993; 147: 1442-6. 143: 1322-8. 37 Hui KP,Barnes NC. Lung function improvement in asthma with a 21 ManningPJ, RokachJ, Malo JL et al. Urinaryleukotriene E4 levels cysteinyl-leukotriene receptor antagonist. Lancet 1991; 337: during early and late asthmatic responses. J. Allergy Clin. 1062-3. Immunol.1990; 86: 211-20. 38 Gaddy JN, Margolskee DJ, Bush RK, Williams VC, Busse WW. 22 Christie PE, Tagari P, Ford-HutchinsonAW et al. Urinary Bronchodilation with a potent and selective leukotriene D4 (LTD4) leukotrieneE4 concentrationsincrease after aspirin challenge in receptor antagonist (MK-571) in patients with asthma. Am. Rev. aspirin-sensitiveasthmatic subjects. Am. Rev.Respir. Dis. 1991; Respir. Dis. 1992; 146: 358-63. ' 143: 1025-9. 39 Spector SL, Glass M, MinkwitzMC. ICI Asthma Trial Group. The 23 FullerRW, Black PN, DolleryCT. Effectof the oral leukotrieneD4 effect of six weeks of therapy with oral doses of ICI 204,219 in antagonist LY171883on inhaled and intradermalchallenge with asthmatics (abstract). Am. Rev. Respir. Dis. 1992; 145: A16. antigen and leukotriene D4 in atopic subjects. J. AllergyClin. 40 Sorkness CA, Reiss TF,Zhang J et al. Bronchodilation with a selec- Immunol.1989; 83: 939-44. tive and potent leukotriene D4 (LTD4)antagonist (MK-0476) in 24 BrittonJR, Hanley SP TattersfieldAE. The effect of an oral patients with asthma (abstract). Am. J. Respir. Crit. Care Med. leukotrieneD4 antagonist L-649,923 on the response to inhaled 1994; 149: A216. antigenin asthma. J. AllergyClin. Immunol. 1987; 79: 811-16. 41 Wahedna I, Wisniewski AFZ, Wong CS, Tattersfield AE. Effect of 25 TaylorIK, O'Shaughnessy KM, Fuller RW, Dollery CT. Effect of cys- multiple doses of RG 12525, an oral leukotriene D4 antagonist, in teinyl-leukotrienereceptor antagonist ICI 204,219 on allergen- chronic asthma (abstract). Am. Rev. Respir. Dis. 1992; 145: A16. induced bronchoconstrictionand airwayhyperreactivity in atopic 42 Cloud ML, Enas GG, Kemp J et al. A specific LTD4/LTE4-receptor subjects.Lancet 1991; 337: 690-4. antagonist improves pulmonary function in patients with mild, 26 O'Shaughnessy KM, Taylor IK, O'Connor B, O'Connell F, chronic asthma. Am. Rev. Respir. Dis. 1989; 140: 1336-9. Thomson H. Potent leukotriene D4 receptor antagonist ICI 43 Gaddy J, McCreedy W, Margolskee D, Williams V, Busse W. A 204,219 given by the inhaled route inhibitsthe early but not the potent leukotriene D4 antagonist (MK-571) significantly reduces late phase of allergen-inducedbronchoconstriction. Am. Rev. airway obstruction in mild to moderate asthma (abstract). J. Respir.Dis. 1993; 147: 1431-5. Allergy Clin. Immunol. 1991; 87: A306. 27 FindlaySR, Barden JM, Easley CB, Glass M. Effectof the oral 44 Spector SL, Smith U, Glass M, Accolate Asthma Trialists Group. leukotrieneantagonist, ICI 204,219, on antigen-inducedbron- Effects of 6 weeks therapy with oral doses of ICI 204,219, a choconstrictionin subjectswith asthma. J. AllergyClin. Immunol. leukotriene D4 receptor antagonist in subjects with bronchial 1992; 89: 1040-5. asthma. Am. J. Resp. Crit. Care Med. 1994; 150: 618-23. 28 Dahlen B, Zetterstrom O, BjorckT, Dahlen SE. The leukotriene- 45 Anderson GP, Fennessy MR. Lipoxygenase metabolites as media- antagonistICI-204,219 inhibits the earlyairway reaction to cumu- tors of activating factor-induced increased airways lative bronchialchallenge with allergen in atopic asthmatics.Eur. responsiveness to histamine in the guinea-pig. Agents Actions Respir.J. 1994; 7: 324-31. Suppl. 1988; 23: 195-200. 29 RasmussenJB, ErikssonLO, Margolskee DJ, Tagari P, Williams VC. 46 Christie PE, Spur BW, Lee TH. The effects of lipoxin A4 on airway LeukotrieneD4 receptor blockade inhibitsthe immediateand late responses in asthmatic subjects. Am. Rev. Respir. Dis. 1992; 145: bronchoconstrictorresponses to inhaled antigen in patients with 1281-4. asthma. J. AllergyClin. Immunol. 1992; 90: 193-201. 47 Hui KP Taylor IK, Taylor GW, Rubin P, Kesterson J, Barnes NC. 30 RobuschiM, Riva E, FuccellaLM et al. Preventionof exercise- Effectof a 5-lipoxygenase inhibitor on leukotriene generation and induced bronchoconstrictionby a new leukotriene antagonist airway responses after allergen challenge in asthmatic patients. (SK& F 104353). A double-blindstudy versus disodium cromogly- Thorax 1991; 46: 184-9. cate and placebo.Am. Rev.Respir. Dis. 1992; 145: 1285-8. 48 Nasser SM, BellGS, Hawksworth RJ et al. Effectof the 5-lipoxyge- 31 FinnertyJP, Wood-BakerR, Thomson H, Holgate ST. Role of nase inhibitor ZD2138 on allergen-induced early and late asth- leukotrienesin exercise-inducedasthma. Inhibitoryeffect of ICI matic responses. Thorax 1994; 49: 743-8. CYSTEINYL LEUKOTRIENES IN ASTHMA 169

49 Friedman BS, Bel EH, Buntinx A et al. Oral leukotriene inhibitor nase inhibitor (abstract). Am. J. Respir. Crit. Care Med. 1994; (MK-886) blocks allergen-induced airway responses. Am. Rev. 149: A215. Respir. Dis. 1993; 147: 839-44. 54 Israel E, Fischer AR, Rosenberg MA et al. The pivotal role of 5- 50 Diamant Z, Timmers MC, van der Veen H et al. The effect of MK- lipoxygenase products in the reaction of aspirin-sensitive asthmat- 0591, a potent oral leukotriene biosynthesis inhibitor, on allergen- ics to aspirin. Am. Rev. Respir. Dis. 1993; 148: 1447-51. induced airway responses in asthmatic subjects (abstract). Am. 55 Nasser SM, Bell GS, Foster S et al. Effect of the 5-lipoxygenase Rev. Respir. Dis. 1993; 147: A446. inhibitor ZD2138 on aspirin-induced asthma. Thorax 1994; 49: 51 Dahlen S-E, Dahlen B, Ihre E et al. The leukotriene biosynthesis 749-56. inhibitor BAYx1005 is a potent inhibitor of allergen-induced air- 56 Israel E, Rubin P,Kemp JP et al. The effect of inhibition of 5-lipoxy- way obstruction and leukotriene formation in man. Pulm. genase by zileuton in mild-to-moderate asthma. Ann. Intern. Med. Pharmacol. 1993; 6: 87-96. 1993; 119: 1059-66. 52 Israel E, Dermarkarian R, Rosenberg M, Sperling R, Taylor G, 57 Chapman KR, Friedman BS, Shingo S, Heyse J, Reiss T, Spector R. Rubin P The effects of a 5-lipoxygenase inhibitor on asthma The efficacy of an oral inhibitor of leukotriene synthesis (MK-0591) induced by cold, dry air. N. Engl. J. Med. 1990; 323: 1740-4. in asthmatics treated with inhaled steroids (abstract). Am. J. Respir. 53 Meltzer SS, Rechsteiner EA, Johns MA, Cohn J, Bleecker ER. Crit. Care Med. 1994; 149: A215. Inhibition of exercise-induced asthma by zileuton, a 5-lipoxyge-