New Pharmacological Agents Which Antagonize Leukotriene D4 and Platelet Activating Factor

  • Ann F. Welton
  • Margaret O’Donnell
Conference paper
Part of the NATO ASI Series book series (NSSA, volume 177)


Leukotriene D4 (LTD4) and Platelet Activating Factor (PAF) are two important lipid mediators of allergy and inflammation which were defined structurally in the late 1970’s and early 1980’s, although these substances had been identified many years earlier based on their biological activities. The structure of LTD4 was elucidated from initial observations made during investigations ongoing in Samuelsson’s laboratory in 1979 (1). Subsequently it was demonstrated that LTD4 is one of a family of peptidoleukotriene metabolites of arachidonic acid formed by the sequential bioconversion of arachidonic acid via Δ5-lipoxygenase and LTC4 synthetase (a glutathione-S-transferase enzyme). Metabolism of arachidonic acid via this pathway leads to the formation of LTC4, LTD4, and LTE4 (the peptidoleukotrienes) (2). LTD4 was ultimately shown to be the major biologically active component of slow reacting substance of anaphylaxis (3), a substance originally described by Kellway and Trethewie in 1940 (4).


Platelet Activate Factor Platelet Activate Factor Receptor Platelet Activate Factor Antagonist Platelet Activate Factor Analog LTD4 Receptor Antagonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    R.C. Murphy, S. Hammarström, and B. Samuelsson, Leukotriene C: A slow reacting substance from murine mastocytoma cells, Proc. Natl. Acad. Sci. U.S.A., 76: 4275 (1979).PubMedCrossRefGoogle Scholar
  2. 2.
    B. Samuelsson, Leukotrienes: Mediators of immediate hypersensitivity reactions and inflammation, Science, 220: 568 (1983).PubMedCrossRefGoogle Scholar
  3. 3.
    H.R. Morris, G.W. Taylor, P.J. Piper, and J.R. Tippins, Slow reacting substance of anaphylaxis from guinea pig lung, Nature, 285: 104 (1980).PubMedCrossRefGoogle Scholar
  4. 4.
    C.H. Kellaway and E.R. Trethewie, The liberation of a slow reacting smooth muscle-stimulating substance in anaphylaxis, Q.J. Exp. Physiol. Cogn. Med. Sci., 30: 121 (1940).Google Scholar
  5. 5.
    J. Benveniste, P.M. Henson, and C.G. Cochrane, Leukocyte dependent histamine release from rabbit platelets. The role of IgE and a platelet activating factor, J. Exp. Med., 136: 1356 (1972).PubMedCrossRefGoogle Scholar
  6. 6.
    C.A. Demopoulos, R.N. Pinkard, and D.J. Hanahan, Platelet activating factor. Evidence for 1–0-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine as the active component (a new class of lipid chemical mediators), J. Biol. Chem., 254: 9355 (1979).PubMedGoogle Scholar
  7. 7.
    J. Benveniste, J.P. LeCouedic, J. Polonsky, and M. Tence, Structural analysis of purified platelet activating factor by lipases, Nature, 269: 170 (1977).PubMedCrossRefGoogle Scholar
  8. 8.
    C.L. Swendsen, J.M. Ellis, F.H. Chilton III, J.T. O’Flaherty, and R.L. Wykle, 1–0-alkyl-2-acyl-sn-glycero-3-phosphocholine: a novel source of arachidonic acid in neutrophils stimulated by calcium ionophore A23187, Biochem. Biophys. Res. Commun., 113: 72 (1983).CrossRefGoogle Scholar
  9. 9.
    J.H. Musser, A.F. Kreft, and A.J. Lewis, New developments concerning leukotriene antagonists: A review, Agents Actions, 18: 332 (1986).PubMedCrossRefGoogle Scholar
  10. 10.
    J.H. Fleisch, L.E. Rinkema, C.A. Whitesitt, and W.S. Marshall, Development of cysteinyl leukotriene receptor antagonists, Advances in Inflammation Research, 12: 173 (1988).Google Scholar
  11. 11.
    C.D. Perchonock, T.J. Torphy, and S. Mong, Peptidoleukotrienes: Pathophysiology, receptor biology and receptor antagonists, Drugs of the Future, 12: 871 (1987).Google Scholar
  12. 12.
    P. Braquet, P.E. Chabrier, and J.M. Mencia-Huerta, The promise of PAF-acether antagonists, Advances in Inflammation Research, 12: 135 (1988).Google Scholar
  13. 13.
    P.J. Barnes, K.F. Chung, and C.P. Page, Platelet-activating factor as a mediator of allergic disease, J. Allergy Clin. Immunol., 81: 919 (1988).PubMedCrossRefGoogle Scholar
  14. 14.
    K.F. Chung and P.J. Barnes, PAF Antagonists: Their potential therapeutic role in asthma, Drugs, 35: 93 (1988).PubMedCrossRefGoogle Scholar
  15. 15.
    J. Augstein, J.B. Farmer, T.B. Lee, P. Sheard, and M.L. Tattersall, Selective inhibitor of slow reacting substance of anaphylaxis, Nature New Biol., 245: 215 (1973).PubMedCrossRefGoogle Scholar
  16. 16.
    R.A. Appleton, J.K. Bantick, T.R. Chamberlain, D.N. Hardern, T.B. Lee, and A.D. Pratt, Antagonists of slow reacting substance of anaphylaxis. Synthesis of a series of chrome-2-carboxylic acids, J. Med. Chem., 20: 371 (1977).PubMedCrossRefGoogle Scholar
  17. 17.
    P. Sheard, M.C. Holroyde, A.M. Ghelani, J.R. Bantick, and T.B. Lee, Antagonists of SRS-A and leukotrienes, in “Leukotrienes and Other Lipoxygenase Products”, B. Samuelsson and R. Paoletti (eds.): Raven Press, New York (1982), pp. 229–235.Google Scholar
  18. 18.
    R.D. Krell, R. Osborn, L. Vickery, K. Falcone, M. O’Donnell, J. Gleason, C. Kinzig, and D. Bryan, Contraction of isolated airway smooth muscle by synthetic leukotrienes C4 and D4, Prostaglandins 22: 387 (1981).PubMedCrossRefGoogle Scholar
  19. 19.
    J.H. Fleisch, L.E. Rinkema, K.D. Haisch, D. Swanson-Bean, T. Goodson, P.P.K. Ho, and W.S. Marshall, LY171883, 1-<2-hydroxy-3propyl-4-<4-(1-H-tetrazol-5-yl) butoxy >phenyl>ethanone, an orally active leukotriene D4 antagonist, J. Pharmacol. Exp. Ther., 233: 148 (1985).PubMedGoogle Scholar
  20. 20.
    G.W. Carnathan, J.H. Sanner, J.M. Thompson, C.M. Prusa, and M. Miyano, Antagonism of the in vivo and in vitro effects of leukotriene D4 by SC-39070 in guinea pigs, Agents Actions, 20: 124 (1987).PubMedCrossRefGoogle Scholar
  21. 21.
    M. O’Donnell, A.F. Welton, H. Crowley, D. Brown, R. Garippa, N. Cohen, G. Weber, B. Banner, and R.J. Lopresti, Pharmacological profile of Ro 23–3544, a new aerosol active leukotriene receptor antagonists, Advances in Prostaglandin, Thromboxane and Leukotriene Research, 17: 519 (1987).Google Scholar
  22. 22.
    T.R. Jones, Y. Guindon, E. Champion, L. Charette, R.N. Dehaven, D. Denis, D. Ethier, A.W. Ford-Hutchinson, R. Fortin, R. Frenette, J.Y. Gauthier, R. Hamel, P. Masson, A. Maycock, C. McFarlane, H. Piechuta, S.S. Pong, J. Rokach, C. Yoakim, and R.N. Young, L-648,051: An aerosol active leukotriene D4 receptor antagonist, Advances in Prostaglandin, Thromboxane and Leukotriene Research, 17: 1012 (1987).Google Scholar
  23. 23.
    R.N. Young, T.R. Jones, J.G. Atkinson, P. Bélanger, E. Champion, D. Denis, R.N. Dehaven, A.W. Ford-Hutchinson, R. Fortin, R. Frenette, J.Y. Gauthier, J. Gillard, Y. Guindon, M. Kakushima, P. Masson, A. Maycock, C.S. McFarlane, H. Piechuta, S.S. Pong, J. Rokach, H. Williams, C. Yoakim, and R. Zamboli, Novel arylthio-and arylsulfonylpropyl oxyacetophenones: Design and synthesis of L-648,051 and L-649,923, potent antagonists of leukotriene D4, Advances in Prosta-glandin, Thromboxane and Leukotriene Research, 17: 544 (1987).Google Scholar
  24. 24.
    R.G. Van Inwegen, A. Khandwala, R. Gordon, P. Sonnino, S. Coutts, and S. Jolly, REV 5901: An orally effective peptidoleukotriene antagonist, detailed biochemical/pharmacological profile, J. Pharmacol. Exp.Ther., 241: 117 (1987).PubMedGoogle Scholar
  25. 25.
    J.M. Hand, J.H. Musser, A.F. Kreft, S. Schwalm, I. Englebach, M. Auen, M. Skowronek, and J.Y. Chang, Wy-48,252 (1,1,1-trifluoro-N[3-(2-quinolinylmethoxy) phenyl] methanesulfonamide): A selective orally active leukotriene antagonist, The Pharmacologist, 29: 174 (1987).Google Scholar
  26. 26.
    L. Charette, T.R. Jones, E. Champion, P. Masson, A.W. Ford-Hutchinson, R. Dehaven, S.S. Pong, M. Belley, R. Frenette, J.Y. Gauthier, S. Leger, J. Rokach, H. Williams, R.N. Young, and R. Zamboni, In vitro pharmacology of L-660,711, a new LTD4 receptor antagonist, Fed. Proc., 2:Al264 (1988).Google Scholar
  27. 27.
    T.R. Jones, M. Belley, E. Champion, L. Charette, R. Dehaven, A.W. Ford-Hutchinson, R. Frenette, J.Y. Gauthier, S. Leger, C.S. McFarlane, P. Masson, H. Piechuta, S.S. Pong, J. Rokach, H. Williams, R.N. Young, and R. Zamboni, Pharmacology of L-660,711, a potent selective, orally active LTD4 receptor antagonist, Am. Rev.Respir. Dis., 137: A427 (1988).Google Scholar
  28. 28.
    P. Masson, T.R. Jones, L. Charette, E. Champion, C.S. McFarlane, H. Piechuta, A.W. Ford-Hutchinson, M. Belley, R. Dehaven, R. Frenette, J.Y. Gauthier, S. Leger, S.S. Pong, J. Rokach, H. Williams, R.N. Young, and R. Zamboni, In vivo pharmacology of L-66O,711, a potent and selective leukotriene antagonist, Fed. Proc., 2:Al265 (1988).Google Scholar
  29. 29.
    G.W. Carnathan, D. Sweeney, J. Travis, and R.G. Van Inwegen, The effect of RG 12525 on leukotriene D4-mediated pulmonary responses in guinea pigs, Inflammation Research Association, Fourth International Conference: A67 (1988).Google Scholar
  30. 30.
    J.G. Gleason, R.F. Hall, C.D. Perchonock, K.F. Erhard, J.S. Frazee, T.W. Ku, K. Kondrad, M.E. McCarthy, S. Mong, S.T. Crooke, G. Chi-Russo, M.A. Wasserman, T.J. Torphy, R.M. Muccitelli, D.W. Hay, S.S. Tucker, and L. Vickery-Clark, High-affinity leukotriene receptor antagonists. Synthesis and pharmacological characterization of 2-Hydroxy-3-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl) phenyl] propanoic acid, J. Med. Chem., 30: 959 (1987).PubMedCrossRefGoogle Scholar
  31. 31.
    D.W.P. Hay, R.M. Muccitelli, S.S. Tucker, L.M. Vickery-Clark, K.A. Wilson, J.G. Gleason, R.F. Hall, M.A. Wasserman, and T.J. Torphy, Pharmacologic profile of SKamp;F 104353: A novel, potent and selective peptidoleukotriene receptor antagonist in guinea pig and human airways, J. Pharmacol. Exp. Ther., 243: 474 (1987).PubMedGoogle Scholar
  32. 32.
    D.W. Snyder, R.E. Giles, R.A. Keith, Y.K. Yee, and R.D. Krell, In vitro pharmacology of ICI 198,615: A novel, potent and selective peptide leukotriene antagonist, J. Pharmacol. Exp. Ther., 243:548 (1987).Google Scholar
  33. 33.
    C. Buckner, J. Fedyna, R. Krell, J. Robertson, R. Keith, V. Matassa, F. Brown, P. Bernstein, Y. Yee, J. Will, R. Fishleder, R. Saban, B. Hesp, and R. Giles, Antagonism by ICI 204,219 of leukotriene receptors in guinea pig and human airways, Fed. Proc., 2:Al264 (1988).Google Scholar
  34. 34.
    T. Obata, F. Nambu, T. Kitagawa, H. Terashima, M. Toda, T. Okegawa, and A. Kawasaki, ONO-1078: An antagonist of leukotrienes, “Advances in Prostaglandin, Thromboxane and Leukotriene Research ”, 17: 540 (1987).Google Scholar
  35. 35.
    N. Barnes, P.J. Piper, and J. Costello, The effect of an oral leukotriene antagonist L-649,923 on histamine and leukotriene D4-induced bronchoconstriction in normal man, J. Allergy Clin. Immunol., 79: 816 (1987).PubMedCrossRefGoogle Scholar
  36. 36.
    J. Biollaz, E. Stahl, J.Y. Hsieh, L. Distlerath, A. Jaeger, P. Leuenberger, and J.L. Schelling, Tolerability and pharmacokinetics of L-648,051, a leukotriene antagonist, in healthy volunteers, Eur. J. Clin. Pharmacol., 33: 603 (1988).CrossRefGoogle Scholar
  37. 37.
    G.D. Phillips, P. Raggerty, C. Robinson, and S.T. Holgate, Doserelated antagonism of leukotriene D4-induced bronchoconstriction by p.o. administration of LY-171883 in nonasthmatic subjects, J. Pharmacol. Exp. Ther., 246: 732 (1988).PubMedGoogle Scholar
  38. 38.
    N. Barnes, J. Evans, J. Zakrzewski, P. Piper, and J. Costello, Pharmacology and physiology of leukotriene and their antagonists, Ann. N. Y. Acad. Sci., 524: 369 (1988).PubMedCrossRefGoogle Scholar
  39. 39.
    J.M. Evans, N.C. Barnes, J.T. Zabrzewski, H.P. Glenny, P.J. Piper, and J.F. Costello, The activity of an inhaled leukotriene (LT) antagonist (SKF 104,353-Z2) on LTD4-induced bronchoconstriction in normal man, Br. J. Clin. Pharmacol., 26: P61 (1988).Google Scholar
  40. 40.
    J.R. Britton, S.P. Hanley, and A.E. Tattersfield, The effect of an oral leukotriene D4 antagonist L-649,923 on the response to inhaled antigen in asthma, J. Allergy Clin. Immunol., 79: 811 (1987).PubMedCrossRefGoogle Scholar
  41. 41.
    E. Israel, E.F. Juniper, M.M. Morris, A.R. Dowell, F.E. Hargreave, and J.M. Drazen, A leukotriene D4 (LTD4) receptor antagonist, LY171883, reduces the bronchoconstriction induced by cold air challenge in asthmatics: a randomized, double-blind, placebo controlled trial, Am. Rev. Respir. Dis., 137: A27 (1988).Google Scholar
  42. 42.
    J.H. Fleisch, M.L. Cloud, and W.S. Marshall, A brief reveiw of preclinical and clinical studies with LY171883 and some comments on newer cysteinyl leukotriene receptor antagonists, Ann. N. Y. Acad. Sci., 524: 356 (1988).PubMedCrossRefGoogle Scholar
  43. 43.
    P.N. Mathur, J.T. Callaghan, N.A. Farid, and A.J. Sylvester, The prevention of allergen induced late asthmatic response by LY171883 a leukotriene antagonist, Clin. Res., 34: 580A (1986).Google Scholar
  44. 44.
    Z.-I. Tereshita, S. Tsushima, Y. Yoshioka, H. Nomura, Y. Inada, and K. Nishikawa, CV-3988 - a specific antagonist of platelet activating factor (PAF), Life Sci., 32: 1975 (1983).CrossRefGoogle Scholar
  45. 45.
    Z.-I. Terashita, Y. Imura, and K. Nishikawa, Inhibition by CV-3988 of the binding of [3H]-platelet activating factor (PAF) to the platelet, Biochem. Pharmacol., 34: 1491 (1985).PubMedCrossRefGoogle Scholar
  46. 46.
    Z.-I. Terashita, Y. Imura, M. Takatani, S. Tsushima, and K. Nishikawa, CV-6209, a highly potent antagonist of platelet activating factor in vitro and in vivo, J. Pharmacol. Exp. Ther., 242: 263 (1987).PubMedGoogle Scholar
  47. 47.
    V. Lagente, S. Desquand, P. Hadvary, M. Cirino, A. Lellouch-Tubiana, J. Lefort and B.B. Vargaftig, Interference of the PAF antagonist Ro 19–3704 with PAF and antigen-induced bronchoconstriction in the guinea-pig, Br. J. Pharmacol., 94: 27 (1988).PubMedGoogle Scholar
  48. 48.
    D.A. Handley, R.C. Anderson, and R.N. Saunders, Inhibition by SRI 63–072 and SRI 63–119 of PAF-acether and immune complex effects in the guinea pig, Eur. J. Pharmacol., 141: 409 (1987).PubMedCrossRefGoogle Scholar
  49. 49.
    V. Lamant, G. Mauco, P. Braquet, H. Chap, and L. Douste-Blazy, Inhibition of the metabolism of platelet activating factor (PAFacether) by three specific antagonists from Ginkgo biloba, Biochem. Pharmacol., 36: 2749 (1987).PubMedCrossRefGoogle Scholar
  50. 50.
    B.F. Omini, G. Rossoni, and P. Braquet, Protection by two ginkgolides, BN-52020 and BN-52021, against guinea-pig lung anaphylaxis, Pharmacol. Res. Commun., 18: 775 (1986).Google Scholar
  51. 51.
    T.Y. Shen, S.B. Hwang, M.N. Chang, T.W. Doebber, M.H. Lam, M.S. Wu, and X. Wang, The isolation and characterization of kadsurenone from haifenteng (Piper futokadsura) as an orally active specific receptor antagonist of platelet-activating factor, Int. J. Tissue React., 7: 339 (1985).PubMedGoogle Scholar
  52. 52.
    S.-B. Hwang, M.-H. Lam, T. Biftu, T.R. Beattie, and T.-Y. Shen, Trans-2,5-Bis-(3,4,5-trimethoxyphenyl) tetrahydrofuran. An orally active specific and competitive receptor antagonist of platelet activating factor, J. Biol. Chem., 260: 15639 (1985).PubMedGoogle Scholar
  53. 53.
    S.-B. Hwang, M.-H. Lam, A.W. Alberts, R.L. Bugianesi, J.C. Chabala, and M.M. Ponpipom, Biochemical and pharmacological characterization of L-659,989: an extremely potent, selective and competitive receptor antagonist of platelet-activating factor, J. Pharmacol. Exp. Ther., 246: 534 (1988).PubMedGoogle Scholar
  54. 54.
    R.N. Saunders, R.G. Van Valen, M.K. Melden, W.J. Houlihan, and D.A. Handley, Pharmacology of the PAF antagonist SDZ 64–142, Fed. Proc., 2: A412 (1988).Google Scholar
  55. 55.
    J. Casals-Stenzel, Triazolodiazepines are potent antagonists of platelet activating factor (PAF) in vitro and in vivo, Naunyn Schmiedebergs Arch. Pharmacol., 335: 351 (1987).PubMedCrossRefGoogle Scholar
  56. 56.
    H. Mikashima, S. Takehara, Y. Muramoto, T. Khomaru, M. Terasawa, T. Tahara, and Y. Maruyama, An antagonistic activity of etizolam on platelet-activating factor (PAF). In vitro effects on platelet aggregation and PAF receptor binding, Jpn. J. Pharmacol., 44:387 (1987).Google Scholar
  57. 57.
    J. Casals-Stenzel, G. Muacevic, and K.-H. Weber, Pharmacological actions of WEB 2086, a new specific antagonist of platelet activating factor, J. Pharmacol. Exp. Ther., 241: 974 (1987).PubMedGoogle Scholar
  58. 58.
    G. Muacevic, W. Stransky, and K.H. Weber, Antagonism of PAF-induced bronchoconstriction and intrathoracic accumulation of platelets in the guinea pig by the hetrazepines WEB 2170 and STY 2108, Naunyn Schmiedeberqs Arch. Pharmacol., 337 [Suppl.]: R88 (1988).Google Scholar
  59. 59.
    H. Heuer, Activity of the hetrazepines WEB 2170 and STY 2108, two new and potent PAF-antagonists on PAF-induced changes in vitro and endotoxin or PAF-induced hypotension in the rat, Naunyn Schmiedebergs. Arch. Pharmacol., 337 [Suppl.]: R70 (1988).Google Scholar
  60. 60.
    M. O’Donnell, H. Crowley, B. Yaremko and A. Welton, Pharmacological Profile of Ro 24–0238, a novel compound with dual actions: PAF receptor antagonism and thromboxane A2 synthase inhibition, Am. Rev. Respir. Dis. in press (1989).Google Scholar
  61. 61.
    J. Lefort, P. Sedivy, S. Desquand, J. Randon, E. Coëffier, I. Maridonneau-Parini, A. Floch, J. Benveniste and B.B. Vargaftig, Pharmacological profile of 48740 R.P., a PAF-acether antagonist, Eur. J. Pharmacol., 150: 257 (1988).PubMedCrossRefGoogle Scholar
  62. 62.
    J. Arnout, A. van Hecken, I. deLepeleire, Y. Miyamoto, I. Holmes, P. deSchepper, and J. Vermylen, Effectiveness and tolerability of CV-3988, a selective PAF antagonist, after intravenous administration to man, Br. J. Clin. Pharmacol., 25: 445–451 (1988).PubMedGoogle Scholar
  63. 63.
    W.S. Adamus, H. Heuer, C.J. Meade, E.R. Kempe, and H.M. Brecht, Effect of intravenous or inhalative WEB 2086 on ex vivo platelet activating factor induced platelet aggregation in man, Prostaglandins, 35: 797 (1988).CrossRefGoogle Scholar
  64. 64.
    W.S. Adamus, H. Heuer, C.J. Meade, and H.M. Brecht, Effect of peroral WEB 2086 on ex vivo platelet activating factor induced platelet aggregation in man, Prostaglandins, 35: 836 (1988).CrossRefGoogle Scholar
  65. 65.
    J.L. Pinquier, P. Sedivy, R. Bruno, F. Gaisne, A. Opriou, F. Bompart, D. deLauture, G. Strauch, and J. Grégoire, Tolerance study, pharmacokinetics and ex vivo PAF-induced platelet aggregation after repeated oral doses of 48740 RP in normal volunteers, Prostaglandins, 35: 837 (1988).CrossRefGoogle Scholar
  66. 66.
    P. Guinot, P. Braquet, J. Duchier, and A. Cournot, Inhibition of PAF-acether induced weal and flare reaction in man by a specific PAF antagonist, Prostaglandins, 32: 160 (1986).PubMedCrossRefGoogle Scholar
  67. 67.
    K.F. Chung, M. McCusker, C.P. Page, G. Dent, Ph. Guinot, and P.J. Barnes, Effect of a ginkgolide mixture (BN 52063) in antagonising skin and platelet responses to platelet activating factor in man, Lancet, 1: 248 (1987).PubMedCrossRefGoogle Scholar
  68. 68.
    P. Guinot, C. Brambilla, J. Duchier, P. Braquet, B. Bonvoisin, and A. Cournot, Effect of BN 52063, a specific PAF-acether antagonist, on bronchial provocation test to allergens in asthmatic patients. A preliminary study, Prostaglandins, 34: 723 (1987).CrossRefGoogle Scholar
  69. 69.
    D.W.P. Hay, R.M. Muccitelli, L.M. Vickery-Clark, K.A. Wilson, L. Bailey, S.S. Tucker, L.P. Yodis, R.D. Eckardt, J.F. Newton, J.M. Smallheer, M.E. McCarthy, J.G. Gleason, M.A. Wasserman, and T.J. Torphy, Pharmacological profile of SKF S-106203, a novel leukotriene (LT) receptor antagonist, in guinea-pig airways, The Pharmacologist, 30: A96 (1988).Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Ann F. Welton
    • 1
  • Margaret O’Donnell
    • 1
  1. 1.Hoffmann-La Roche Inc.NutleyUSA

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