Advertisement

The Therapeutic and Toxic Effects of Anti-Inflammatory Drugs Which Interfere with Arachidonic Acid Metabolism

  • G. A. Higgs
  • B. J. R. Whittle

Abstract

Inflammation is a complex process which presents several targets for drug action and a large number of chemically unrelated drugs have been used in the treatment of inflammatory diseases. There are, however, signs and symptoms which are common to inflammatory responses induced by different trauma. Furthermore, it is evident that many anti-inflammatory drugs share the same therapeutic and toxic effects. Vane (1971) has suggested that the anti-inflammatory effects and the gastrointestinal irritancy of aspirin-like drugs is due to the inhibition of prostaglandin synthesis. Evidence is now accumulating which links the inhibition of arachidonic acid metabolism to the mechanism of action of the two major groups of anti-inflammatory drugs, the corticosteroids and the non-steroid aspirin-like drugs. In this paper these theories will be reviewed and their implications for future drug development will be discussed.

Keywords

Arachidonic Acid Gastric Mucosa Arachidonic Acid Metabolism Inflammatory Exudate Lipoxygenase Product 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Adcock, J. J., Garland, L. G., Moncada, S. & Salmon, J. A. (1978). The mechanism of enhancement by fatty acid hydroperoxides of anaphylactic mediator release. Prostaglandins, 16, 179–187.CrossRefPubMedGoogle Scholar
  2. Austen, K. (1978). Homeostasis of effector systems which can also be recruited for immunologic reactions. J. Immunol., 121, 793–805.PubMedGoogle Scholar
  3. Bitensky, L., Cashman, B., Chayen, J., Henderson, B., Higgs, G. A., Salmon, J. A. & Vane, J. R. (1980). Synthesis of arachidonate cyclo-oxygenase products by rheumatoid and non-rheumatoid synovial tissue. Brit. J. Pharmac., in press.Google Scholar
  4. Borgeat, P. & Samuelsson, B. (1979). Arachidonic acid metabolism in polymorphonuclear leukocytes. Effects of ionophore A23187. Proc. Nat. Acad. Sci., USA, 76, 2148–2152.CrossRefGoogle Scholar
  5. Bragt, P. C. & Bonta, I. L. (1979). In vivo metabolism of [1-14C] arachidonic acid during different phases of granuloma development in the rat. Biochem. Pharmac., 28, 1581–1586.CrossRefGoogle Scholar
  6. Bragt, P. C. & Bonta, I. L. (1980). Indomethacin inhibits the formation of the lipoxygenase product HETE (12-hydroxy-5,8,10,14-eicosatetraenoic acid) during granulomatous inflammation in the rat. J. Pharm. Pharmac., 32, 143–144.CrossRefGoogle Scholar
  7. Bray, M. A., Gordon, D. & Morley, J. (1975). Macrophages on intrauterine contraceptive devices produce prostaglandins. Nature, 257, 227–228.CrossRefPubMedGoogle Scholar
  8. Brocklehurst, W. E. (1967). Properties which distinguish SRS-A from bradykinin. In The Third International Symposium on Vaso-active Polypeptides: Bradykinin and related polypeptides, ed. Rocha e Silva, M. & Rothschild, H. A. pp. 189–191. Oxford: Pergamon.Google Scholar
  9. Brune, K., Glatt, M., Kalin, H. & Peskar, B. A. (1978). Pharmacological control of prostaglandin and thromboxane release from macrophages. Nature, 274, 261–263.CrossRefPubMedGoogle Scholar
  10. Chang, W. C., Murota, S-I., Matsuo, M. & Tsurufuji, S. (1976). A new prostaglandin transformed from arachidonic acid in carrageenin-induced granuloma. Biochem. Biophys. Res. Commun., 72, 1259–1264.CrossRefPubMedGoogle Scholar
  11. Chang, W. C., Murota, S-I. & Tsurufuji, S. (1977). Thromboxane B2 transformed from arachidonic acid in carrageenin-induced granuloma. Prostaglandins, 13, 17–24.CrossRefPubMedGoogle Scholar
  12. Davenport, H. W. (1964). Gastric mucosal injury by fatty acid acetylsalicylic acids. Gastroenterol. 46, 245–253.Google Scholar
  13. Eakins, K. E., Higgs, G. A., Moncada, S., Salmon, J. A. & Spayne, J. A. (1980). The effects of arachidonate lipoxygenase products on plasma exudation in rabbit skin. J. Physiol., in press.Google Scholar
  14. Ferreira, S. H. (1972). Prostaglandins, aspirin-like drugs and analgesia. Nature, 240, 200–203.CrossRefGoogle Scholar
  15. Ferreira, S. H., Nakamura, M. & Abreu Castro, M. S. (1978). The hyperalgesic effects of prostacyclin and PGE2. Prostaglandins, 16, 31–37.CrossRefPubMedGoogle Scholar
  16. Ferreira, S. H. & Vane, J. R. (1979). Mode of action of anti-inflammatory agents which are prostaglandin synthetase inhibitors. In Anti-inflammatory drugs ed. Vane, J. R. & Ferreira, S. H. pp. 348–398. Handbook of Experimental Pharmacology, 50/II. Springer Verlag.CrossRefGoogle Scholar
  17. Flower, R. J. & Blackwell, G. J. (1979). Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation. Nature, 278, 456–459.CrossRefPubMedGoogle Scholar
  18. Flower, R. J., Gryglewski, R., Herbaczynska-Cedro, K. & Vane, J. R. (1972). Effects of antiinflammatory drugs on prostaglandin biosynthesis. Nature, 238, 104–106.Google Scholar
  19. Ford-Hutchinson, A. W., Bray, M. A. Shipley, M. E., Doig, M. V. & Smith, M. J. H. (1980). Leukotriene B: a biologically active release product of polymorphonuclear leukocytes. In Inflammation: Mechanisms and Treatment. Proceedings of Future Trends in Inflammation vol. 4, ed. Willoughby, D. A., Giroud, J. P & Schwarz, N. Lancaster: MTP Press, in press.Google Scholar
  20. Goetzl, E. J. & Sun, F. F. (1979). Generation of unique mono-hydroxy eicosatetraenoic acids from arachidonic acid by human neutrophils. J. exp. Med., 150, 406–411.CrossRefPubMedGoogle Scholar
  21. Greaves, M. W. & McDonald-Gibson, W. J. (1972). Inhibition of prostaglandin biosynthesis by cortico-steroids. Brit. med. J., 2, 83–84.PubMedCentralCrossRefPubMedGoogle Scholar
  22. Grossman, M. I., Matsumoto, K. K. & Lichter, R. J. (1961). Fecal blood loss by oral and intravenous administration of various salicylates. Gastroenterol, 40, 383–388.Google Scholar
  23. Gryglewski, R. J., Panczenko, B., Korbut, R., Grodzinska, L. & Ocetkiewicz, A. (1975). Corticosteroids inhibit prostaglandin release from perfused lungs of sensitized guinea-pigs. Prostaglandins, 10, 343–355.CrossRefPubMedGoogle Scholar
  24. Hamberg, M. & Samuelsson, B. (1974). Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc. Nat. Acad. Sci. USA, 71, 3400–3404.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Hamberg, M., Svensson, J. & Samuelsson, B. (1975). Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc. Nat. Acad. Sci. USA, 72, 2994–2998.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Hammarstrom, S., Hamberg, M., Samuelsson, B., Duell, E. A., Stawiski, M. & Voorhees, J. J. (1975). Increased concentrations of free arachidonic acid, prostaglandins E2 and F2 α and of 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE) in epidermis of psoriasis: Evidence for perturbed regulation of arachidonic acid levels in psoriasis. Proc. Nat. Acad. Sci. USA, 72, 5130–5134.PubMedCentralCrossRefPubMedGoogle Scholar
  27. Higgs, E. A., Moncada, S. & Vane, J. R. (1978). Inflammatory effects of prostacyclin (PGI2) and 6-oxo-PGF in the rat paw. Prostaglandins, 16, 153–161.CrossRefPubMedGoogle Scholar
  28. Higgs, G. A., Bunting, S., Moncada, S. & Vane, J. R. (1976). Polymorphonuclear leukocytes produce thromboxane A2-like activity during phagocytosis. Prostaglandins, 12, 749–757.CrossRefPubMedGoogle Scholar
  29. Higgs, G. A., Eakins, K. E., Mugridge, K. G., Moncada, S. & Vane, J. R. (1980). The effects of non-steroid anti-inflammatory drugs on leukocyte migration in carrageenin-induced inflammation. Eur. J. Pharmac, 66, 81–86CrossRefGoogle Scholar
  30. Higgs, G. A., Flower, R. J. & Vane, J. R. (1979). A new approach to anti-inflammatory drugs. Biochem. Pharmac, 28, 1959–1961.CrossRefGoogle Scholar
  31. Higgs, G. A., Harvey, E. A., Ferreira, S. H. & Vane, J. R. (1976). The effects of antiinflammatory drugs on the production of prostaglandins in vivo. In Advances in Prostaglandin and Thromboxane Research Vol. 1, ed. Samuelsson, B. & Paoletti, R., pp. 105–110. New York: Raven Press.Google Scholar
  32. Higgs, G. A., McCall, M. E. & Youlten, L. J. F. (1975). A chemotactic role for prostaglandins released from polymorphonuclear leukocytes during phagocytosis. Brit. J. Pharmac, 53, 539–546.CrossRefGoogle Scholar
  33. Higgs, G. A., Moncada, S. & Vane, J. R. (1978). Prostacyclin reduces the number of ‘slow moving’ leukocytes in hamster cheek pouch venules. J. Physiol., 280, 55–56P.CrossRefGoogle Scholar
  34. Higgs, G. A. & Salmon, J. A. (1979). Cyclo-oxygenase products in carrageenin-induced inflammation. Prostaglandins, 17, 737–746.CrossRefGoogle Scholar
  35. Hong, S. L. & Levine, L. (1976). Inhibition of arachidonic acid release from cells as the biochemical action of anti-inflammatory corticosteroids. Proc Nat. Acad. Sci. USA, 73, 1730–1734.PubMedCentralCrossRefPubMedGoogle Scholar
  36. Humes, J. L., Bonney, R. J., Peius, L., Dahlgren, M. E., Sadowski, S. J., Kuehl, F. A. & Davies, P. (1977). Macrophages synthesise and release prostaglandins in response to inflammatory stimuli. Nature, 269, 149–151.CrossRefPubMedGoogle Scholar
  37. Lewis, G. P. & Piper, P. J. (1975). Inhibition of release of prostaglandins as an explanation of some of the actions of anti-inflammatory cortico-steroids. Nature, 254, 308–311.CrossRefPubMedGoogle Scholar
  38. McCarty, J. & Goetzl, E. J. (1979). Stimulation of human T-lymphocyte chemokinesis by arachidonic acid. Cell Immunol., 43, 103–112.CrossRefPubMedGoogle Scholar
  39. Meacock, S. C. R. & Kitchen, E. A. (1979). Effects of the non-steroid anti-inflammatory drug benoxaprofen on leukocyte migration. J. Pharm. Pharmac., 31, 366–370.CrossRefGoogle Scholar
  40. Moncada, S., Ferreira, S. H. & Vane, J. R. (1978). Pain and inflammatory mediators. In Inflammation ed. Vane, J. R. & Ferreira, S. H., pp. 588–616, Handbook of Experimental Pharmacology, 50/1. Springer Verlag.CrossRefGoogle Scholar
  41. Moncada, S., Gryglewski, R. J., Bunting, S. & Vane, J. R. (1976). An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature, 263, 663–665.CrossRefPubMedGoogle Scholar
  42. Moncada, S. & Vane, J. R. (1979). Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmac Rev., 30, 293–331.Google Scholar
  43. Morris, H. R., Taylor, G. W., Piper, P. J. & Tippins, J. R. (1980). Structure of slow-reacting substance of anaphylaxis from guinea-pig lung. Nature, 285, 104–106.CrossRefPubMedGoogle Scholar
  44. Murota, S-I., Kawamura, M. & Morita, I. (1978). Transformation of arachidonic acid into thromboxane B2 by the homogenates of activated macrophages. Biochim. Biophys. Acta, 528, 507–511.CrossRefPubMedGoogle Scholar
  45. Murphy, R. C., Hammarstrom, S. & Samuelsson, B. (1979). Leukotriene C: A slow-reacting substance from murine mastocytoma cells. Proc. Nat. Acad. Sci. USA, 76, 4275–4279.PubMedCentralCrossRefPubMedGoogle Scholar
  46. Nugteren, D. A. (1975). Arachidonate lipoxygenase in blood platelets. Biochim. Biophys. Acta, 380, 299–307.CrossRefPubMedGoogle Scholar
  47. Orange, R. P. (1974). The formation of slow reacting substance of anaphylaxis in human lung tissue. In Progress in Immunology, II, Vol. 4, ed. Brent, L. & Holborow, T., pp. 29–39. North Holland: Amsterdam.Google Scholar
  48. Palmer, R. J., Stepney, R., Higgs, G. A. & Eakins, K. E. (1980). Chemokinetic activity of arachidonic acid lipoxygenase products on leukocytes from different species. Prostaglandins, 20, 411–418.CrossRefPubMedGoogle Scholar
  49. Ryan, G. B. & Majno, G. (1977). Acute Inflammation. Am. J. Path., 86, 184–276.Google Scholar
  50. Samuelsson, B., Goldyne, M., Granstrom, E., Hamberg, M., Hammarstrom, S. & Malmsten, C. (1978). Prostaglandins and thromboxanes. Ann. Rev. Biochem., 47, 997–1029.CrossRefPubMedGoogle Scholar
  51. Schiffman, E., Corcoran, B. A. & Wahl, S. M. (1975). N-formylmethionyl peptides as chemoattractants for leukocytes. Proc. Nat. Acad. Sci. U.S.A., 72, 1059–1062.CrossRefGoogle Scholar
  52. Tateson, J. E., Moncada, S. & Vane, J. R. (1977). Effects of prostacyclin (PGX) on cyclic AMP concentrations in human platelets. Prostaglandins, 13, 389–399.CrossRefPubMedGoogle Scholar
  53. Trang, L. E., Granstrom, E. & Lovgren, O. (1977). Levels of prostaglandin F2 α E2 and thromboxane B2 in joint fluid in rheumatoid arthritis. Scand. J. Rheumat., 6, 151–154.CrossRefGoogle Scholar
  54. Turner, S. R., Tainer, J. A. & Lynn, W. S. (1975). Biogenesis of chemotactic molecules by the arachidonate lipoxygenase system of platelets. Nature, 257, 680–681.CrossRefPubMedGoogle Scholar
  55. Vane, J. R. (1971). Inhibition of prostaglandin synthesis as a mechanism of action for the aspirinlike drugs. Nature, 231, 232–235.Google Scholar
  56. Walker, J. R. & Dawson, W. (1980). Inhibitory effect of benoxaprofen and BW755C on rabbit PMN leukocyte lipoxygenase. In Inflammation: Mechanisms and Treatments. Proceedings of Future Trends in Inflammation Vol. 4, ed. Willoughby, D. A., Giroud, J. P. & Schwarz, N. Lancaster: MTP Press, in press.Google Scholar
  57. Walker, J. R., Smith, M. J. H. & Ford-Hutchinson, A. W. (1976). Anti-inflammatory drugs, prostaglandins and leukocyte migration. Agents & Actions, 6, 602–606.CrossRefGoogle Scholar
  58. Weksler, B. B., Knapp, J. M. & Jaffe, E. A. (1977). Prostacyclin (PGI2) synthesised by cultured endothelial cells modulates polymorphonuclear leukocyte function. Blood, 50, Suppl. 1, 287.Google Scholar
  59. Whittle, B. J. R. (1977). Mechanisms underlying gastric mucosal damage induced by indomethacin and bile salts, and the actions of prostaglandins. Brit. J. Pharmac., 60, 455–460.CrossRefGoogle Scholar
  60. Whittle, B. J. R., Boughton-Smith, N. K., Moncada, S. & Vane, J. R. (1978). Actions of prostacyclin (PGh) and its product, 6-oxo-PGF on the rat gastric mucosa in vivo and in vitro. Prostaglandins, 15, 955–967.CrossRefPubMedGoogle Scholar
  61. Whittle, B. J. R., Higgs, G. A., Eakins, K. E., Moncada, S. & Vane, J. R. (1980). Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa. Nature, 284, 271–273.CrossRefPubMedGoogle Scholar
  62. Williams, T. J. & Peck, M. J. (1977). Role of prostaglandin-mediated vasodilatation in inflammation. Nature, 270, 530–532.CrossRefPubMedGoogle Scholar
  63. Williams, T. J. & Piper, P. J. (1980). The actions of chemically pure SRS-A on the microcirculation in vivo. Prostaglandins, 19, 779–789PubMedGoogle Scholar

Copyright information

© The contributors 1980

Authors and Affiliations

  • G. A. Higgs
    • 1
  • B. J. R. Whittle
    • 1
  1. 1.Department of Prostaglandin ResearchWellcome Research LaboratoriesBeckenhamEngland

Personalised recommendations