Clinical and Experimental Allergy. 1992, Volume 22, pages 980-983

REVIEW

Current status of PAF antagonists H. O. HEUER Department of Pharmacology, Boehringer Ingelheim KG, Ingelheim'Rhein. Germany Introduction The evidence that PAF may be involved in the pathophysiology of asthma was initially derived from its ability to induce bronchoconstriction [ 1 ] at very low doses as well as its properties as an inflammatory mediator [2]. The bronchoconstrictive action [1] as well as the inflammatory action [2] of PAF is shared by other putative mediators of inflammation like histamine, thromboxane and leukotrienes; but in contrast PAF is so far unique as PAF concomitantly and in addition increases mucus secretion [3] and recruits platelets and eosinophils [4] from the extravascular space into the lungs. Since an important role is attributed to eosinophils in the pathogenesis of asthma [5], it is of particular interest, that PAF is one of the most potent chemotactic factors so far discovered for eosinophils [6]. Furthermore PAF seems to be involved in the late-phase response [7,8] of asthma and may induce bronchial hyperreactivity [9,10] in different species including man (Fig. I). In addition there is support that PAF may be involved in down-regulation of betareceptors in human lung tissue [11]. With respect to increased level of PAF in asthma and allergies the short half-life of PAF has to be taken into account. The limitations from available methods for determination of PAF in tissue and the compartmentation of PAF-mediated processes in disease may explain the paucity of reports on measurements of PAF in lung disease. In relation to asthma both increased levels of PAF-like activity in the bronchoalveolar lavage fluid and in saliva [12] as well as increased levels of lyso-PAF after allergen provocation in plasma in patients with late phase response [13], have been reported. The antigen-induced release of PAF from sensitized lung tissue has been described [14]. Effect of PAF-antagonists in preclinical models Current antagonists of platelet activating factor can be classified into three types: (a) PAF-analogties, e.g. CV 6209 and TCV 309; (b) natural products or their derivatives, e.g, ginkgolide B and L 680.573; and (c) synthetic compounds, e.g. RP 52770 and the hetrazepines (WEB Correspondence: Dr H. O. Hcucr, Department or Pharmacology. Boehringer Ingelheim KG. W-6507. Ingelheim/Rhein, Germany,

980

2086. INN: apafant; WEB 21 70, INN: bepafant [15]; Y 24 180. E 6123 etc.) and others (for review see [16]). The most potent and long acting PAE-antagonists are among the hetrazepines. Some representative PAF-antagonists are shown in Fig. 2. The status of development of some candidates of PAF-antagonists which have entered or may enter clinical trials (not complete) is listed in Table I. The results obtained with structurally and even the same antagonists of PAF in models of antigen-induced bronchoconstriction and in vivo anaphylax is arc divergent, although most authors do report at least some protective action during passive anaphylaxis in the guinea pig [17,18]. The divergent results may be due to differing protocols (e.g. testing in the absence of a small dose of an antihistamine, route and dose of antigen during challenge, booster sensitization etc) and the different potency, bioavailability and route of administration of PAF antagonists/>U77Y>. PAF seems to be more important in passive anaphylaxis and during challenge with the antigen by the inhaled tracheal route [19], In active anaphylaxis PAF-antagonists seem to be more effective when animals are once sensitized compared to a booster sensitization regimen [20,21] but can still block anaphylaxis in boosted animals [21]. The contribution of PAF to airway inflammation and recruitmenl of inflammatory cells (particularly eosinophils) and associated late phase reaction and bronchial hyperreactivity is assumed to be more prominent than its putative contribution to acute bronchoconstriction. With respeet to airway microvascular leakage there are contradictory results as to whether PAF-antagonists block antigen-induced microvascular leakage. In one set of experiments a PAF-antagonist failed to block leakage at a dose which blocked PAF-induced leakage [22]. Other results are in favour of blocking antigen-induced microvascular leakage [23], Concerning injillralion of eosinophils into the lungs in several studies selective PAF-antagonists prevented eosinophil infiltration in the bronchial walls or appearance of the ceils in bronchoalveolar fluid of sensitized guinea pigs, rabbits or monkeys [4,8.9]. A few studies have, however, failed to show this effect. Therefore further work is needed to specify the conditions under which PAFantagonists block atitigen-induced eosinophil-infiltration.

Status of PAF-antagonists

981

Allergic Non-ailergic

Bronchospasm

Epithelial damage

Fig. 1. Working hypothesis for involvement of platelet-activating factor (PAF) in the pathophysiology of bronchial asthma.

Laie phase reociion and bronchial hyperresponsiveness

Table 1. Present status of some PAF-antagonists which have entered OT may cnlcT clinical (rials Compound Apafant (WFB 2086) Bepafant (WFB 2170) Y 24180 E6123 MK2H7 = L680.573 RP 59227 UK 74505 BN 52021

Company Boehringer Ingelheim Boehringer Ingelheim Yoshitomi Esai MSD

Status

Remark

Phase II

Asthma

Phase I Phase U Asthma Phase I? Phase I/il Asthma

Asthma RhonL'-PouIenc Phase I Pfizer Phase I Asthma Ipsen-Beaufour Phase 11? Stroke

The late phase response to antigen and its inhibition by selective PAF-antagonists has recently been shown in models for investigating the late phase reaction produced by antigen mhalation in allergic guinea pigs, rabbits, sheep and monkeys [7,8,24,25]. Inhibition of antigenincreased bronchial responsiveness by selective PAFantagonists has been reported by several authors in guinea pigs [9], rabbits [25] and other species [26]. In summary, with respect to different aspects of the pathophysiology of asthma, there is increasing evidence that several selective but structurally unrelated PAFantagonists inhibit antigen-induced bronchoconstriction, oedema fonnation, disturbed mucus secretion, eosinophil inflltration, late phase response and bronchial hyperreactivity.

982

H. O. Heuer

(b)

H,C CI

WEB 2086 Boehringer Ingelheim

WEB 2170 Boehringer Ingelheim

MK 287 Merck, Sharp 8 Dohme

H,C

Y24I80 Yoshiiomi

E6I23 Eisai

UK74505 Pfizer

Fig. 2. Structures of some PAF-antagonists. which are candidates for clinical development.

Effect of PAF-antagonists in clinical trials

So far several PAF-antagonists have been demonstrated to be potent blockers of exogenous PAF (ex vivo platelet aggregation, weal and flare reaction in the skin, inhaled PAF) in man [27,28]. In regard to effects in human asthma and allergies few results from antigen provocation studies have been reported. Oral Ginkolide B decreased bronchial responsiveness 6 hours after antigen challenge [29] in atopic patients. In another study inhaled Gingkolide B wiped out the antigen response in three out of seven asthmatic patients and shifted the antigen-response to the right in the remainder [30]. This is in contrast to results using even more potent PAF-antagonists (WEB 2086 = Apafant and L680.573 - MK 287) which failed to inhibit early or late phase response or bronchial hyperreactivity after oral or inhaled administration [31-33]. Although these results are not in favour of a major role for PAF in antigen-induced asthmatic reactions in man the question remains open whether dosing and bioavailability of the tested compounds have been adequate (as in early trials with peptido-leukotriene antagonists). Also antigen-challenge studies in atopic patients are not necessarily predictive for human asthma and the real

contribution of PAF to human bronchial asthma and allergies may be answered by ongoing phase II clinical trials in these diseases.

References 1 Vargaftig BB. Lefort J. Chignard M, Benvenisie J. Plateletactivating iactor induces a platelet-dependent bronchoconstriction unrelated to the formation of prostaglandin derivatives. Eur J Pharmacol 1980: 65:185-92. 2 Camussi G. Pawlowski J, Tetta C et al. Acute lung inflammation induced in the rabbit by local instillation of I0-octadecyl-2-aeetyl-sn-g]yceryl-3-phosphorylcho]ine or of native platelet activating factor. Am J Pathol 1983: 112:7888. 3 Hahn H-L, Pumama I, Lang M, Sonnwald U. Effects of platelet activating factor on tracheal mucus secretion, on airway mechanics and on circulating blood cells in live ferrets, Eur J Resp Dis 69, Suppl, 1986; 146:277-84. 4 Leilouch-Tubiana A, Lefort J, Simon MT, Ptister A. Vargaftig BB. Fosinophil recruitment into guinea-pig lungs after PAF-acetherand allergen administration: modulation by prostacyclin, platelet depletion and selective antagonists. Am Rev Resp Dis 1988. 137:948.

Status of PA F-aniagonists

5 Frigas E, Gleich GJ, The eosinophil and the patbophysiology of asthma. J Allergy Clin Immunol 1986; 77:527-37. 6 Wardlaw AJ, Moqbel R, Cromwell O, Kay AB, Platelet activating factor, A potent chemotactic and chemokinetic factor for human eosinophils. J Clin Invest 1986; 78:1701-6. 7 Stevenson JS, Tallent M, Blinder L. Abraham WM. Modification of antigen-induced late response with an antagonist of platelet activating factor (WEB 2086), Fed Proc 1987; 46:1461. 8 Gundel RH, Letts LG. Wegner C D . The role of platelet activating factor in airway inflammation, airway hyperresponsiveness, and pulmonary funetion in monkeys. Ann NY Acad Sci 1991; 629:205-15. 9 Coyle AJ. Urwin SC. Page CP. Touvay C. Villain B. Braqucl P. The effect of the selective PAF-antagonist BN 52021 on PAF and antigen induced bronchial hyperreaetivity and eosinophil accumulation, Eur J Pharmacol 1988: 148:51-8, 10 Cuss FM, Dixon CMS, Barnes PS. Effects of inhaled platelet activating factor on pulmonary function and bronchial responsiveness in man. Lancet I9S6; 2:189-92. 11 Agrawal DK, Townlcy RG. Effect of platelet-activating factor on beta-adrenoceptors in human lung. Biochem Biophys Res Commun 1987; 143:1 6, 12 Court EN, Goadby P, Hendrick DJ, Platelet activating factor in bronchoalveoiar lavage fluid from asthmatic subjects. Br J Clin Pharmacol 1987; 24:258P-9P, 13 Nakamura T. Morita Y. Kuriyama M, Ishihara K, Uo K. Miyamoto T. Platelet-activating factor in late asthmatic response. Int Arch Allergy Appl Immunol 1987; 82:57-61. 14 Chignard M, Le Couedic JP, Andersson P, Brange C, Use of steroidal antiinfiammatory drug provides further evidence for a potential role of paf-acether in bronchial anaphylaxis. Int Archs Allergy Appl Immunol 1986; 81:184-5. 15 Hcuer HO, Pharmacology of hetrazepines as PAF-aniagonists. In: Braquet P, ed. Handbook of Pafand Paf Antagonists. Boca Raton: CRC Press. 1991; 17N202, 16 Braquet P. Handbook of Paf and Paf antagonists, Boca Raton: CRC Press, 1991. I 7 Casals-Stenzel J. Effects of WEB 2086, a novel antagonist of platelet activating factor, in active and passive anaphylaxis. Immunopharmacology 1987; 13:117 24. 18 Pretolani M. Lefort J, Malanchere E, Vargaftig BtJ, Interference by the novel PAF-acether antagonist WEB 2086 with the bronchopulmonary responses to PAF-acether and to active and to passive anaphylactic shock in guinea pigs. Eur J Pharmacol 1987; 140:311-21. 19 Heuer H. Casals-Stenzel J, Effect of the PAF-antagonist WEB 2086 on anaphylactic lung reaction: comparison of inhalative and intravenous challenge. Agents and Actions 1988; Suppl, 23:207-15, 20 Dcsquand S. Lefort J. Dumarey C, Vargaftig BB, The booster injection of antigen during active sensitization of guinea pigs modifies the anti-anaphylactic activity of the paf-anlagonist WEB 2086, Br J Pharmacol 1990; 100:21722, 21 Heuer HO. WEB 2347: pharmacology of a novel very potent

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24

25

26

27

28

29

30

31

32

33

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and long acting hetrazepinoic paf-antagonist and its action in repeatedly sensitized guinea pigs. J Lipid Mediators, 1991; 4; 39-44. Evans TW. Dent G. Rogers DF. Aursudkij B. Chung KF. Barnes PJ, Effect of a PAF antagonist, WEB 2086, on microvascuiar leakage in the guinea-pig and platelet aggregation in man. Br J Pharmacol 1988; 94:164-8. Christy LJ. Stewart AG, Dusting GJ, Platelet-activating factor and leukotnenes in rat pulmonary anaphylaxis, Proc Australian Physiol Pharmacol Society 1988; 19:94. Hutson PA, Holgate ST. Church MK, Effect of WEB 2086 on early and tate airway responses to ovalbumin challenge in conscious guinea-pigs, Br J Pharmaeol 1988; 95 (Proc, Suppl ). 77nP. Metzger WJ. Sjoerdsma K. Brown L, Coyle T. Page C, Touvay C. The late phase asthmatic response in the allergic rabbit: a role for platelet-activating factor (PAF) and modification by paf antagonist, ginkgoiide BN 52021, In: Braquet P, ed, Ginkgoiides—chemistry, biology, pharmacology and clinical perspectives, vol. I. Barcelona: J,R. Prous Science Publishers. 1988:313-31. Soler M, Sielezak MW, Abraham WM. Platelet/acti\atmg factor (PAF) contributes to antigen-induced airway hyperresponsiveness and inflammation in allergic sheep: modulation by a selective PAF-antagonist. J Appl Physiol W89; 67:406. Adamus WS. Heuer H. Meade CJ. Brecht HM. Safety. tolerability and pharmacologic activity in man of multiple doses ofthe new PAF-aeether antagonist. WEB 2086- Clin Pharmacol Ther 1988; 45:270-6, Guinot P. Braquet P. Duchier J. Cournot A, Inhibition of PAF-acether weal and flare reaction in man by a specific PAF antagonist, Prostaglandins 1986; 32:160- 3, Guinot P, Brambilla C, Dvichier J. Braquet P. Bonvoism B, Cournot A, Effect of BN52063. a specific PAF-acether antagonist, on bronchial provocation test to allergens in asthmatic patients. A preliminary study, Prostagiandins 1987; 34: 723-31, Hsieh K-H, Effects of PAF antagonist, BN 52021. on the PAF-, Methaeholme-. and allergen-induced bronchoconstrietion in asthmatic children. Chest 1991; 99:877-82. Freilag A. Watson RM. Hatsos G, Eastwood C, O'Byrne. PM, The effect ol" treatment with an oral platelet activating factor antagonist (WEB 2086) on allergen induced asthmatic responses in human subjects. An:i Rev Resp Dis U^)l; 143 (part 2): I99I; A 157, Bel EH. De Smet M, Rossing TH, Timmers MC, Dijkman JH, Sterk PJ, The effect of a specific oral PAF-antagonist, MK-287, on antigcn-indueed early and late asthmatic reactions in man. Am Rev Resp Dis 1991; 143. Suppl, (part 2) 1991; A 811. Wilkens H. Wilkcns JH, Bosse S. Kempe F. Fril7 S. Froelich JC, Fabel H, Eflccts of inhaled PAF-antagonist (WEB 2086) on allevgcn-mduced early and late asthmatic responses and increased bronchial responsiveness to methaeholine. Am Rev Resp Dis 1991; 143 (part 2). A 812.

Current status of PAF antagonists.

Clinical and Experimental Allergy. 1992, Volume 22, pages 980-983 REVIEW Current status of PAF antagonists H. O. HEUER Department of Pharmacology, B...
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