Concepts of the mode of action and toxicity of anti-inflammatory drugs. A basis for safer and more selective therapy, and for future drug developments

  • K. D. Rainsford
Part of the Inflammation and Drug Therapy Series book series (IDTH, volume 3)

Abstract

The enormous range of drugs which have recently become available for the treatment of the 100 or so different arthritic conditions present the physician with a challenge to determine if there are some of these which are more suitable than others. Inspection of Table 1 indicates that of over 100 or so nonsteroidal anti-inflammatory drugs (NSAIDs) these can be graded in terms of overall potency to be roughly equivalent to one of the four ‘traditional’ or well-established drugs, i.e. aspirin, ibuprofen, indomethacin and phenylbutazone. It could therefore, be argued that it is pointless having many of the new NSAIDs since these may be no better than those which are well established? This challenging question receives further provocate support from several well-established tenets frequently uttered by clinicians and even experts alike that (a) NSAIDs act by inhibiting the synthesis of inflammatory prostaglandins (PGs) (b) the anti-inflammatory and analgesic efficacy of these drugs is directly related to their inhibitory effects as PG synthesis inhibitors, and (c) with some few exceptions their potency as anti-inflammatory agents is correlated with their propensity to produce side-effects especially in the gastrointestinal tract1–3. Even the term ‘Aspirin-like’2 as frequently and, probably inappropriately, misapplied to all NSAIDs, conjures up in the mind the notion that all NSAIDs are the same, but possibly differ in potency only. If these features constitute the basis for the actions of the NSAIDs overall then it can be logically argued why do we really need all the drugs that we have, except for the few cases they have proven unacceptably toxic.

Keywords

Mefenamic Acid Tiaprofenic Acid Gastric Mucosal Injury Niflumic Acid Gastric Mucosal Damage 
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. 1.
    Buchanan, WW and Kean, WF (1987). Current non-steroidal anti-inflammatory drug therapy in rheumatoid arthritis, with emphasis on use in the elderly. In Lewis, AJ and Furst, DE (eds) Nonsteroidal Anti-inflammatory Drugs. Mechanisms and Clinical Use, pp. 9–29. (Marcel Dekker: New York and Basel)Google Scholar
  2. 2.
    Vane, JR (1971). Inhibition of prostaglandin biosynthesis as a mechanism of action of aspirin-like drugs. Nature New Biol,231, 232–235PubMedGoogle Scholar
  3. 3.
    Rainsford, KD and Velo, GP (eds)(1984). Side Effects of Anti-inflammatory/Analgesic Drugs. (Raven Press: New York)Google Scholar
  4. 4.
    Rainsford, KD and Velo, GP (eds) (1987). Side Effects of Anti-inflammatory Drugs, Vols. I and II. (MTP Press: Lancaster)Google Scholar
  5. 5.
    Rainsford, KD (1984). Aspirin and the Salicylates. (Butterworth: London)Google Scholar
  6. 6.
    Rainsford, KD (1985). Anti-inflammatory and Anti-rheumatic Drugs, 3 Vols. (CRC Press: Boca Raton, FI)Google Scholar
  7. 7.
    Pemberton, RE and Strand, LJ (1979). A review of upper gastro-intestinal effects of newer non-steroidal anti-inflammatory drugs. Dig Dis Sci, 24, 53–62PubMedGoogle Scholar
  8. 8.
    Rainsford, KD (1982). An analysis of the gastro-intestinal side-effects of non-steroid anti-inflammatory drugs, with particular reference to comparative studies in man and laboratory species. Rheumatol Internat, 2, 1–11Google Scholar
  9. 9.
    Rainsford, KD (1981). Comparison of the gastric ulcerogenic activity of new non-steroid anti-inflammatory drugs in stressed rats. Br J Pharmacol,73, 79c–80cGoogle Scholar
  10. 10.
    Rainsford, KD (1982). A comparison of the gastric ulcerogenic activity of benoxaprofen with other non-steroid anti-inflammatory drugs in rats and pigs. Europ J Rheumatol Inflamm,5, 148–164Google Scholar
  11. 11.
    Dearden, JC and Nicholson, RM (1984). Correlation between gastric irritancy and anti-inflammatory activity of non-steroidal anti-inflammatory drugs. J Pharm Pharmacol, 36, 713–715PubMedGoogle Scholar
  12. 12.
    Greenberg, BP and Bernstein, J (1985). Fenbufen. In Rainsford, KD (ed) Anti-Inflammatory and Anti-rheumatic Drugs, Vol. II, pp. 87–103. (CRC Press: Boca Raton, FL)Google Scholar
  13. 13.
    Rainsford, KD (1985). Anti-inflammatory drugs and the gastro-intestinal mucosa. Gastroenterol Clin Biol, 9, 98–101PubMedGoogle Scholar
  14. 14.
    Mangan, FR (1987). Nabumetone. In Lewis, AJ and Furst, DE Nonsteroidal Anti-inflammatory Drugs, pp439–472. (Marcel Dekker: New York and Basel)Google Scholar
  15. 15.
    Rainsford, KD (1987). Gastric ulcerogenicity of non-steroidal anti-inflammatory drugs in mice with mucosa sensitized by cholinomimetic treatment. J Pharm Pharmacol, 39, 669–672PubMedGoogle Scholar
  16. 16.
    Bunning, RD and Barth, WF (1982). Sulindac: A potentially renal-sparing nonsteroidal anti-inflammatory drug. J Am Med Assoc,248, 2864–2867Google Scholar
  17. 17.
    Ciabattoni, G, Cinotti, GA and Pierucci, A (1984). Effects of sulindac and ibuprofen in patients with chronic glomerular disease. Evidence for the dependence of renal function on prostacyclin. N Engl J Med, 310, 279–283PubMedGoogle Scholar
  18. 18.
    Arroyo, V, Gines, P, Rimola, A and Gaya, J (1986). Renal function abnormalities, prostaglandins and effects of nonsteroidal anti-inflammatory drugs in cirrhosis with ascites. Am J Med, 81(Suppl. 2B), 104–122PubMedGoogle Scholar
  19. 19.
    Clive, DM and Stoff, JS (1984). Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med, 563–572Google Scholar
  20. 20.
    Ishioka, T (1987). Is tiaprofenic acid different from other NSAIDs with regard to renal function in the elderly? In Huskinsson, EC and Shiokawa, Y (eds) Focus on Tiaprofenic Acid. Proceedings of the International Symposium on Rheumatology, Tokyo 1987, pp. 159–168. (Excerpta Medica: Amsterdam)Google Scholar
  21. 21.
    Palmoski, MJ and Brandt, KD (1980). Effects of some nonsteroidal anti-inflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arth Rheum,23, 1010–1020Google Scholar
  22. 22.
    Palmoski, MJ and Brandt, KD (1983). Benoxaprofen stimulates proteoglycan synthesis in normal canine knee cartilage in vitro. Arth Rheum,26, 771–774Google Scholar
  23. 23.
    Brandt, KD and Palmoski, MJ (1984). Effects of salicylates and other non-steroidal anti-inflammatory drugs on articular cartilage. Am J Med, 11, 65–69Google Scholar
  24. 24.
    Herman, JH and Hess, EV (1984). Nonsteroidal anti-inflammatory drugs and modulation of cartilagenous changes in osteoarthritis and rheumatoid arthritis. Clinical implications. Am J Med,77, 16–25PubMedGoogle Scholar
  25. 25.
    Cooke, TDV (1985). Mechanisms of cartilage degradation: relation to choice of therapeutic agent. Sem Arth Rheum, 15, 16–23Google Scholar
  26. 26.
    Palmoski, MJ and Brandt, KD (1985). Proteoglycan depletion, rather than fibrilation, determines the effects of salicylate and indomethacin on osteoarthritis cartilage. Arth Rheum, 28, 548–553Google Scholar
  27. 27.
    Kirkpatrick, KJ, Mohr, W, Wildfeyer, A and Hafercamp, O (1983). Influence of nonsteroidal anti-inflammatory agents on lapine articular chondrocyte growth in vitro. Z Rheumatol, 42, 58–65PubMedGoogle Scholar
  28. 28.
    Newman, NM, Ling, RSM (1985). Acetubular bone destruction related to non-steroidal anti-inflammatory drugs. Lancet,2, 11–14PubMedGoogle Scholar
  29. 29.
    Annenfield, M, Raiss, R and Cleres, C (1984). Einfluss steroidaler und nichtsteroidaler Antiphlogistika auf die Ultrastruktur von Chondrozyten der Ratte. Arzneim Forsch,34, 1763–1765Google Scholar
  30. 30.
    Lewis, AJ and Furst, DE (eds)(1987). Nonsteroidal Anti-inflammatory Drugs. Mechanisms and Clinical Use. (Marcel Dekker: New York and Basel)Google Scholar
  31. 31.
    Rainsford, KD (1985). Preliminary investigations on the pharmacological control of catabolin-induced cartilage destruction in vitro. Agents and Actions, 16, 55–57PubMedGoogle Scholar
  32. 32.
    Rainsford, KD (1986). Effects of anti-malarial drugs on interleukin 1-induced cartilage proteoglycan degradation in vitro. J Pharm Pharmacol,38, 829–833PubMedGoogle Scholar
  33. 33.
    Kagiwara, T, Mitsui, K, Fuju, K and Murota, K (1987). Effects of NSAIDs and synovial fluid on proteoglycan metabolism. In Huskisson, EC and Shiokawa, Y (eds) Focus on Tiaprofenic Acid. Proceedings of the International Symposium on Rheumatology, Tokyo, Japan, pp. 14–23. (Excerpta Medica: Amsterdam)Google Scholar
  34. 34.
    Carney, SL (1987). A study of the effects of NSAIDs on proteoglycan metabolism in cartilage expiant cultures. In Huskisson, EC and Shiokawa, Y (eds) Focus on Tiaprofenic Acid. Proceedings of the International Symposium on Rheumatology, Tokyo, Japan, pp. 24–34. (Excerpta Medica: Amsterdam)Google Scholar
  35. 35.
    Iwata, H (1987). Effect of anti-arthritic drugs for articular cartilage and synovial fluid. In Huskisson, EC and Shiokawa, Y (eds) Focus on Tiaprofenic Acid. Proceedings of the International Symposium on RJteumatology, Tokyo, Japan, pp. 35–46. (Excerpta Medica: Amsterdam)Google Scholar
  36. 36.
    Shinmei, M, Kikuchi, T, Masuda, K and Shimomura, Y (1987). Effects of interleukin 1 and anti-inflammatory drugs on the degradation of human articular cartilage. In Huskisson, EC and Shiokawa, Y (eds) Focus on Tiaprofenic Acid. Proceedings of the International Symposium on Rheumatology, Tokyo, Japan, pp. 33, 47–59. (Excerpta Medica: Amsterdam)Google Scholar
  37. 37.
    Rainsford, KD (1987). Effects of anti-inflammatory drugs on the release from porcine synovial tissue in vitro of interleukin-1 like cartilage degrading activity. Agents and Actions, 21, 328–340Google Scholar
  38. 38.
    Rainsford, KD (1988). Inhibition by cartilage and bone marrow fractions of cartilage resorption induced by interleukin 1 and tumour necrosis factor. Agents and Actions, 23, 67–68PubMedGoogle Scholar
  39. 39.
    Rainsford, KD (1987). Introduction and historical aspects of the side effects of anti-inflammatory analgesic drugs. In Rainsford, KD and Velo, GP (eds) Side Effects of Anti-inflammatory Drugs, Part 1, pp. 3–26. (MTP Press: Lancaster)Google Scholar
  40. 40.
    Rainsford, KD (1987). Toxicity of currently used anti-inflammatory and anti-rheumatic drugs. In Lewis, AJ and Furst, DE (eds) Non-steroidal Anti-inflammatory Drugs. Mechanisms and Clinical Use, pp. 215–244. (Marcel Dekker: New York)Google Scholar
  41. 41.
    Anonymous (1986). Pfizer on NSAI ADRs. Scrip, 1079, 22Google Scholar
  42. 42.
    Anonymous (1986). FDAs NSAI GI warning. Scrip, 1163, 11Google Scholar
  43. 43.
    Anonymous (1986). Feldene hearing evidence. Scrip, 1084, 18–20Google Scholar
  44. 44.
    Wolfe, SM (1986). Safety of Piroxicam. Lancet, 2, 808–809PubMedGoogle Scholar
  45. 45.
    Anonymous (1987). CSM on ADRs in the Elderly. Scrip, 1084, 25Google Scholar
  46. 46.
    Orme, M (1985). Pharmacokinetics of non-steroidal anti-inflammatory drugs in the elderly. In Brooks, P and Day R (eds) Non-steroidal Anti-inflammatory Drugs. Basis for Variability in Response. Agents and Actions, (Suppl. 17), pp. 135–140. (Birkhauser: Basel)Google Scholar
  47. 47.
    Lamy, PP (1987). Non-steroidal anti-inflammatories in the elderly. In Rainsford, KD and Velo, GP Side Effects of Anti-inflammatory Drugs, pp. 151–172. (MTP Press: Lancaster)Google Scholar
  48. 48.
    O’Brien, WM and Bagby, GF (1985). Rare adverse reactions to nonsteroidal anti-inflammatory drugs. Pt. I. J Rheumatol, 12, 13–20PubMedGoogle Scholar
  49. 49.
    O’Brien, WM and Bagby, GF (1985). Rare adverse reactions to non-steroidal anti-inflammatory drugs. Pt. II. j Rheumatol, 12, 347–353PubMedGoogle Scholar
  50. 50.
    O’Brien, WM and Bagby, GG(1985). Rare adverse reactions to non-steroidal anti-inflammatory drugs. Pt. III. J Rheumatol, 12, 562–567PubMedGoogle Scholar
  51. 51.
    O’Brien, WM and Bagby, GG (1985). Rare adverse reactions to non-steroidal anti-inflammatory drugs. Pt. IV. J Rheumatol, 12, 785–790PubMedGoogle Scholar
  52. 52.
    Pullar, T and Cappell, HA (1986). Can treatment really influence the radiological progression of rheumatoid arthritis? Br J Rheumatol,25, 2–4PubMedGoogle Scholar
  53. 53.
    Day, RO (1985). Variability in response to NSAID. In Brooks, P and Day, R (eds), Non-Steroidal Anti-inflammatory Drugs. Basis for Variability in Response, pp. 15–19. (Birkhauser: Basel)Google Scholar
  54. 54.
    Famaey, J-P (1987). Synovial anti-inflammatory and anti-rheumatic drug levels: importance in therapeutic efficacy. In Lewis, AJ and Furst, DE (eds), Nonsteroidal Anti-inflammatory Drugs, Mechanisms and Clinical Use, Chapter 13, pp. 201–214. (Marcel Dekker: New York and Basel)Google Scholar
  55. 55.
    Rainsford, KD, Schweitzer, A and Brune, K (1981). Autoradiographic and biochemical observations on the distribution of non-steroidal anti-inflammatory drugs. Arch Int Pharmacodyn, 250, 180–194PubMedGoogle Scholar
  56. 56.
    Fowler, PD, Shadforth, MF, Crook, PR and John, VA (1983). Plasma and synovial fluid concentrations of diclofenac sodium and its major hydroxylated metabolites during long-term treatment of rheumatoid arthritis. Europ J Clin Pharmacol,25, 389–394Google Scholar
  57. 57.
    Liauw, L, Moscaritola, JD and Burcher, J (1987). Diclofenac. In Lewis, AJ and Furst, DE (eds), Nonsteroidal Anti-inflammatory Drugs, Mechanisms and Clinical Use, Chapter 19, pp. 329–347. (Marcel Dekker: New York and Basel)Google Scholar
  58. 58.
    Wanwimolruk, S, Brooks, PM and Birkett, DJ (1983). Protein building of non-steroidal anti-inflammatory drugs in plasma and synovial fluid of arthritic patients. Br J Clin Pharmacol, 15, 91–94PubMedGoogle Scholar
  59. 59.
    Wallis, WJ and Simpkin, PA (1983). Anti-rheumatic drug concentrations in human synovial fluid and synovial tissue. Observations on extravascular pharmacokinetics. Clin Pharmacokinet, 8, 496–522PubMedGoogle Scholar
  60. 60.
    Lin, JH, Cocchetto, DM and Duggan, DE (1987). Protein building as a primary determinant of the clinical pharmacokinetic properties of non-steroidal anti-inflammatory drugs. Clin Pharmacokinet, 12, 402–432PubMedGoogle Scholar
  61. 61.
    Hutt, AJ and Caldwell, AJ (1983). The metabolic conversion of 2-aryl propionic acids — a novel route with pharmacological consequences. J Pharm Pharmacol, 35, 693–704PubMedGoogle Scholar
  62. 62.
    Hutt, AJ and Caldwell, AJ (1984). The importance of stereochemistry in the clinical pharmacokinetics of the 2-aryl propionic acid non-steroidal anti-inflammatory drugs. Clin Pharmacokinet, 9, 371–373PubMedGoogle Scholar
  63. 63.
    Jamali, F (1988). Research methodology in NSAID monitoring: plasma concentrations of chiral drugs. J Rheumatol, 15 (suppl. 17) 71–78Google Scholar
  64. 64.
    Hayball, PJ and Meffin, PJ (1987). Enantioselective disposition of 2-aryl propionic acid nonsteroidal anti-inflammatory drugs. III. Fenoprofen distribution. J Pharmacol Exp Therap, 240, 631–636Google Scholar
  65. 65.
    Abas, A and Meffin, PJ (1987). Enantioselective disposition of 2-aryl propionic acid nonsteroidal anti-inflammatory drugs. IV. Ketoprofen distribution. J Pharmacol Exp Therap, 240, 637–641Google Scholar
  66. 66.
    Jones, ME, Sallustio, BC, Purdie, YJ and Meffin, PJ (1986). Enantioselective disposition of 2-aryl propionic acid nonsteroidal anti-inflammatory drugs. II. 2-phenyl-propionic acid protein binding. J Pharmacol Exp Therap, 238, 288–294Google Scholar
  67. 67.
    Meffin, PJ, Sallustio, BC, Purdie, YJ and Jones, ME. Enantioselective disposition of 2-aryl propionic acid nonsteroidal anti-inflammatory drugs. I. 2-phenyl propionic acid disposition. J Pharmacol Exp Therap, 238, 280–287Google Scholar
  68. 68.
    Lee, EJD, Williams, K, Day, R, Graham, G and Champion, D (1985). Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol, 19, 669–674PubMedGoogle Scholar
  69. 69.
    Cox, JW, Cox, SR, Van biessen, G and Ruivart, MJ (1985). Ibuprofen stereoisomer hepatic clearance and distribution in normal and fatty in situ perfused rat liver. J Pharmacol Exp Therap, 232, 636–643Google Scholar
  70. 70.
    Williams, K, Day, R, Knihinicki, R and Duffield, A (1986). The stereoselective uptake of ibuprofen enantiomers into adipose tissue. Biochem Pharmacol, 35, 3403–3405PubMedGoogle Scholar
  71. 71.
    McMahan, FG, Vargas, R, Ryan, JR and Fitts, DA (1987). Nabumetone kinetics in the young and elderly. Am J Med, 83,(Suppl. 4B), 92–95Google Scholar
  72. 72.
    Thomson, CM (1987). Recent developments in the formulation of anti-inflammatory drugs. In Williamson, WRN (ed), Anti-inflammatory Compounds, pp. 303–322. (Marcel-Dekker: New York and Basel)Google Scholar
  73. 73.
    Day, RO (1985). Variability in response to NSAID. In Brooks, P and Day, R (eds), Non-Steroidal Anti-inflammatory Drugs. Basis for Variability in Response, pp. 15–19. (Birkhauser: Basel)Google Scholar
  74. 74.
    Cox, NL and Doherty, SM (1987). Non-steroidal anti-inflammatories: outpatient audit of patient preferences and side-effects in different diseases. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory Drugs, pp137–153. (MTP Press: Lancaster)Google Scholar
  75. 75.
    Sebaldt, R-J (1986). A shorter plasma half life does not predict less drug accumulation. J Rheumatol, 13, 1185–1186PubMedGoogle Scholar
  76. 76.
    Brune, K (1974). How aspirin might work: a pharmacokinetic approach. Agents and Actions, 4, 230–232PubMedGoogle Scholar
  77. 77.
    Brune, K, Rainsford, KD and Schweitzer, A (1980). Biodistribution of mild analgesics. Br J Clin Pharmacol,10, 279S–284SPubMedGoogle Scholar
  78. 78.
    Brune, K and Lanz, R (1985). In Bonta, IL, Bray, MA and Parnham, MJ (eds), Handbook of Inflammation, Vol.5: The Pharmacology of Inflammation, pp. 413–449. (Elsevier: Amsterdam)Google Scholar
  79. 79.
    McCormack, K and Brune, K (1987). Classical absorption theory and the development of gastric mucosal damage associated with non-steroidal anti-inflammatory drugs. Archiv Toxicol,60, 261–269Google Scholar
  80. 80.
    Rainsford, KD (1984b). Side-effects of anti-inflammatory/analgesic drugs: epidemiology and gastrointestinal tract. Trends Pharmacol Sci,5, 156–159Google Scholar
  81. 81.
    Rainsford, KD (1988). Animal models for the assay of gastrointestinal toxicity of anti-inflammatory drugs. In Greenwald, RA and Diamond, HS (eds), CRC Handbook of Animal Models for Arthritis Research, in press. (CRC Press: Boca Raton, FI)Google Scholar
  82. 82.
    Collier, D St J and Pain, JA (1985). Anti-inflammatory drugs and upper gastrointestinal ulcer perforation. Clin Rheumatol, 4, 389–391PubMedGoogle Scholar
  83. 83.
    Duggan, JM, Dobson, AJ, Johnson, H and Fahey, P (1986). Peptic ulcer and nonsteroidal anti-inflammatory agents. Gut,27, 929–933PubMedGoogle Scholar
  84. 84.
    Collins, AJ and DuToit, JA (1987). Upper gastrointestinal findings and faecal occult blood in patients with rheumatic diseases taking nonsteroidal anti-inflammatory drugs. Brit J Rheumatol,26, 527–532Google Scholar
  85. 85.
    Armstrong, CP and Blower, AL (1987). Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut, 28, 527–532PubMedGoogle Scholar
  86. 86.
    Collier, D St J and Pain, JA (1987). Anti-inflammatory drugs and upper gastrointestinal perforation. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory Drugs, pp. 285–293. (Lancaster: MTP Press)Google Scholar
  87. 87.
    Beard, K (1987). Nonsteroidal anti-inflammatory drugs and hospitalization for gastroesophageal bleeding in the elderly. Arch Intern Med,147, 1621–1623PubMedGoogle Scholar
  88. 88.
    Sladen, G (1986). Peptic ulcer, nonsteroid anti-inflammatory drugs and the rheumatic diseases. Brit J Rheumatol, 25, 330–332Google Scholar
  89. 89.
    Caruso, I and Bianchi Porro, G (1980). Gastroscopio evaluation of anti-inflammatory agents. Brit Med J, 180, 75–77Google Scholar
  90. 90.
    Collins, AJ, Davies, JF and Dixon, A St J (1986). Contrasting presentations and findings between patients with rheumatic complaints, taking non-steroidal anti-inflammatory drugs and a general population referred for endoscopy. Br J Rheumatol,25, 50–53PubMedGoogle Scholar
  91. 91.
    Malone, DE, McCormick, PA, Daly, L, Jones, B, Long, A, Breshirihan, B, Malony, J and O’Donogue, DP (1986). Peptic ulcer in rheumatoid arthritis — intrinsic or related to drug therapy?. Br J Rheumatol, 25, 342–344PubMedGoogle Scholar
  92. 92.
    CSM Update (1986). Non-steroidal anti-inflammatory drugs and serious gastrointestinal adverse reactions, Parts 1 and 2. Br Med J,292, 614 and 1190-1Google Scholar
  93. 93.
    Weber, JCP (1986). Epidemiology in the United Kingdom of adverse drug reactions from non-steroidal anti-inflammatory drugs. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory drugs, Part 1, pp. 27–34. (MTP Press; Lancaster)Google Scholar
  94. 94.
    Inman, WHW and Rawson, NSB (1987). Prescription-event monitoring of five nonsteroidal anti-inflammatory drugs. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory drugs, Part 1, pp. 111–123. (MTP Press; Lancaster)Google Scholar
  95. 95.
    Jick, H (1987). Incidence of serious side effects from non-steroidal anti-inflammatory drugs (NSAIDs) in the USA. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory drugs, Part 1, pp. 47–52. (MTP Press; Lancaster)Google Scholar
  96. 96.
    Wiholm, BE, Myrhed, M and Eckman, E (1987). Trends and patterns in adverse drug reactions to non-steroidal anti-inflammatory drugs reported in Sweden. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory drugs, Part 1, pp. 55–70. (MTP Press; Lancaster)Google Scholar
  97. 97.
    Langman, MJS (1987). Anti-inflammatory drugs and gastrointestinal disease. Reasons for the failure of adverse reaction reporting and surveillance systems to detect a significant association. In Rainsford, KD and Velo, GP (eds), Side Effects of Antiinflammatory drugs, Part 1, pp. 303–306. (MTP Press; Lancaster)Google Scholar
  98. 98.
    Haglund, U, Frost, L and Wiholm, BE (1987). An evaluation of the frequency of anti-inflammatory drug intake among patients with acute gastrointestinal bleeding. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory drugs, Part 1, pp. 309–314. (MTP Press; Lancaster)Google Scholar
  99. 99.
    Henry, DA, Johnston, A, Dobson, A and Duggan, J (1987). Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs, aspirin and corticosteroids. Br Med J, 295, 1227–1229Google Scholar
  100. 100.
    Carson, JL, Strom, BL, Soper, KA, West, SL and Morse, ML (1987). The association of non-steroidal anti-inflammatory drugs with upper gastrointestinal bleeding. Arch Intern Med, 147,85–88PubMedGoogle Scholar
  101. 101.
    Walt, R, Katshinsky, B, Logan, R, Ashley, J and Langman, M (1986). Rising frequency of ulcer perforation in elderly people in the United Kingdom. Lancet, 1, 489–492PubMedGoogle Scholar
  102. 102.
    Rainsford, KD (1987). Mechanisms of gastric contrasted with intestinal damage by non-steroidal anti-inflammatory drugs. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory Analgesic Drugs, Part 2, pp. 3–26. (MTP Press; Lancaster)Google Scholar
  103. 103.
    Brune, K, Dietzel, K, Nürnberg, B and Schneider, Th (1988). New insights into the mechanism of gastrointestinal tract ulcertations. In Lewis, A, Ackerman, N and Otterness, I (eds), New Perspectives in Anti-inflammatory Therapies. Advances in Inflammation Research, Vol. 12, pp. 239–245. (Raven Press: New York)Google Scholar
  104. 104.
    Bjarnason, I, Zanelli, G, Prouse, P, Williams, P, Gumpel, MJ and Levi, AJ (1986). Effect of non-steroidal anti-inflammatory drugs on the human small intestine. Drugs, 32,(Suppl. 1), 35–41PubMedGoogle Scholar
  105. 105.
    Jenkins, RT, Rooney, PJ, Jones, DB, Bienenstock, J and Goodacre, RL (1987). Increased intestinal permeability in patients with rheumatoid arthritis: a side-effect of oral non-steroidal anti-inflammatory drug therapy? Br J Rheumatol, 26, 103–107PubMedGoogle Scholar
  106. 106.
    Terhaag, B and Hermann, U (1986). Biliary elimination of indomethacin in man. Eur J Clin Pharmacol, 29, 691–695PubMedGoogle Scholar
  107. 107.
    Rainsford, KD (1987). Drug induced mucosal damage. In Rees, WDW (ed), Peptic Ulcer Disease. Proc. 7th BSG. SK and F International Workshop 1986, pp. 7–12. (Smith Kleine & French Labs: Welwyn Garden City)Google Scholar
  108. 108.
    Rainsford, KD (1988). Interplay between anti-inflammatory drugs and eicosanoids in gastrointestinal damage. In Hillier, K (ed), Eicosanoids and the Gastrointestinal Tract, pp111–128. (MTP Press: Lancaster)Google Scholar
  109. 109.
    Ligumsky, M, Golanska, EM, Hansen, DG and Kaufmann, GL (1985). Aspirin can inhibit mucosal cyclo-oxygenase without causing lesions in the rat. Gastroenterology, 84, 756–761Google Scholar
  110. 110.
    Whittle, BJR (1981). Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology, 80, 94–98PubMedGoogle Scholar
  111. 111.
    Rainsford, KD and Willis, C (1982). Relationship of gastric mucosal damage induced in pigs by anti-inflammatory drugs. Dig Dis Sci, 27, 624–635PubMedGoogle Scholar
  112. 112.
    Rainsford, KD, Fox, SA and Osborne, DJ (1984). Comparative effects of some non-steroidal anti-inflammatory drugs on the ultrastructural integrity and prostaglandin levels in the rat gastric mucosa: relationship to drug uptake. Scand J Gastroenterol, 19,(Suppl. 101), 55–68Google Scholar
  113. 113.
    Rainsford, KD, Fox, SA and Osborne, DJ (1985). Relationship between drug absorption, inhibition of cyclo-oxygenase and lipoxygenase pathways and the development of gastric mucosal damage by non-steroidal anti-inflammatory drugs in rats and pigs. In Bailey, MJ (ED), Advances in Prostaglandins, Leukotrienes and Lipoxins, pp. 639–653. (Plenum Press: New York)Google Scholar
  114. 114.
    Rainsford, KD. Comparative irritancy of oxaprozin on the gastrointestinal tract of rats and mice: relationship to drug uptake and effects in vivo on eicosanoid metabolism. Aliment Pharmacol Therap,2, 439–450Google Scholar
  115. 115.
    Rainsford, KD (1983). Microvascular injury during gastric mucosal damage by anti-inflammatory drugs in pigs and vats. Agents and Actions, 13, 457–460PubMedGoogle Scholar
  116. 116.
    Szabo, S, Spill, WF and Rainsford, KD (1988). Non-steroidal anti-inflammatory drug-induced gastropathy: mechanisms and management. Medical Toxicology, in pressGoogle Scholar
  117. 117.
    Pihan, G and Szabo, S (1988). Effect of eicosanoids on gastrointestinal blood flow and microcirculation. In Hiller, K (ed), Eicosanoids and the Gastrointestinal Tract, pp. 163–194. (MTP Press: Lancaster)Google Scholar
  118. 118.
    Shriver, DA, Dove, PA, White, CB, Sandor, A and Rosenthale, ME (1977). A profile of the gastrointestinal toxicity of aspirin, indomethacin, Oxaprozin, phenylbutazone and fentiazic in arthritic and normal Lewis rats. Toxicol App Pharmacol,42, 75–83Google Scholar
  119. 119.
    Rainsford, KD (1978). The role of aspirin in gastric ulceration. Some factors involved in the development of gastric mucosal damage induced by aspirin in rats exposed to various stress conditions. Am J Dig Dis, 23, 521–530PubMedGoogle Scholar
  120. 120.
    Rainsford, KD (1978). The effects of aspirin and other non-steroid anti-inflammatory /analgesic drugs on the gastrointestinal mucos glycoprotein biosynthesis in vivo: relationship to ulcerogenic actions. Biochem Pharmacol, 27, 877–885PubMedGoogle Scholar
  121. 121.
    Rainsford, KD (1982). Effects of anti-inflammatory drugs on mucus production: relationship to ulcerogenesis. In Pfeiffer, CJ (ed), CRC Handbook “Drugs and Peptic Ulcer Disease”, Vol. 2, pp. 227–236. (CRC Press Inc)Google Scholar
  122. 122.
    Berrisford, RG, Wells, M and Dixon, MF (1985). Gastric epithelial mucus — a densetometric histochemical study of aspirin-induced damage in the rat. Br J Exp Path, 66, 27–33Google Scholar
  123. 123.
    Allen, A, Garner, A, Hunter, AC and Keogh, JP (1988). The gastrointestinal mucus barrier and the place of eicosanoids. In Hillier, K (ed), Eicosanoids and the Gastrointestinal Tract, pp. 195–213. (MTP Press: Lancaster)Google Scholar
  124. 124.
    Ezer, E and Szporny, L (1970). Prevention of experimental gastric ulcer in rats by a substance which increases biosynthesis of acid mucopolysaccharides. J Pharm Pharmacol, 22, 143–144PubMedGoogle Scholar
  125. 125.
    Corinaldesi, R, Casadio, R, Sovera, A, Girotti, A, Practico, A, Paparo, GF and Barbara, L (1980). Zolimidine: protection against aspirin damage in man. Drugs Exptl Clin Res,2, 55–60Google Scholar
  126. 126.
    Murakami, M, Oketani, K, Fujisaki, H, Wakabayashi, T and Ohgo, T (1982). Effects of the anti-ulcer drug geranyl-geranylacetone on aspirin-induced gastric ulcers in rats. Jap J Pharmacol,32, 299–306PubMedGoogle Scholar
  127. 127.
    Muramatsu, M, Arai, I, Isobe, Y, Hirose, H, Usaki, C and Aihara, H (1986). Effect of sofalcone on acute gastric mucosal lesions induced by aspirin and ethanol in reference to the biosynthesis of gastric mucosal glycoprotein. Res Commun Chem Path Pharmacol,54, 321–337Google Scholar
  128. 128.
    Hills, BA, Butler, BD and Lichtenberger, LM (1983). Gastric mucosal barrier: hydrophobic lining to the lumen of the stomach. Am J Physiol, 244, G561–G568PubMedGoogle Scholar
  129. 129.
    Lichtenberger, LM, Grazian, LA, Dial, EJ, Butler, BD and Hills, BA (1983). Role of surface-active phospholipids in gastric cytoprotection. Science, 219, 1227–1229Google Scholar
  130. 130.
    Lichtenberger, LM, Richards, JE and Hills, BA (1985). Effect of 16, 16-dimethyl prostaglandin E2 on the surface hydrophobicity of aspirin-treated canine gastric mucosa. Gastroenteroly, 88, 308–314Google Scholar
  131. 131.
    Rainsford, KD (1979). Prostaglandins and the development of gastric mucosal damage by anti-inflammatory drugs. In Rainsford, KD and Ford-Hutchinson, AW (eds), Prostaglandins and Inflammation, pp. 193–210. (Birkhauser: Basel)Google Scholar
  132. 132.
    Rainsford, KD (1989). The biochemical protective mechanisms against anti-inflammatory drug-induced GI mucosal damage. Acta Physiologica Hungarica, in pressGoogle Scholar
  133. 133.
    Rainsford, KD (1987). Effect of 5-lipoxygenase inhibitors and leukotriene antagonists pathway on the development of gastric mucosal lesions induced by anti-inflammatory drugs in cholinomimetic treated mice. Agents and Actions, 21, 316–319PubMedGoogle Scholar
  134. 134.
    Young, JM and Tomdonis, AJ (1987). Diphenylsulfide inhibits indomethacin-induced ulcerogenesis in rats. Agents and Actions, 21, 314–315PubMedGoogle Scholar
  135. 135.
    Whittle, BJR, Higgs, GA, Eakins, KE, Moncado, S and Vane, JR (1980). Selective inhibition of prostaglandin production in inflammatory acidates and gastric mucosa. Nature, 284, 271–273PubMedGoogle Scholar
  136. 136.
    Rainsford, KD (1978). Comparative studies of gastric ulcerogenesis by non-steroid anti-inflammatory drugs: effects of fenclofenac. Proc Roy Soc Med, 70(Suppl. 6), 4–10Google Scholar
  137. 137.
    Rainsford, KD (1978). Structure-activity relationship of non-steroid anti-inflammatory drugs. I. Gastric ulcerogenic activity. Agents and Actions, 8, 587–605PubMedGoogle Scholar
  138. 138.
    Hawkey, CJ and Rampton, DS (1985). Prostaglandins and the gastro-intestinal mucosa: are they important in its function, disease or treatment? Gastroenterology, 89, 1162–1188PubMedGoogle Scholar
  139. 139.
    Hawkey, CJ and Walt, RP (1986). Prostaglandins for peptic ulcer: a promise unfulfilled. Lancet, II, 1084–1086Google Scholar
  140. 140.
    Londong, W (1986). Anti-ulcer drugs in anti-secretory doses for ‘cytoprotection’ in arthritic patients? Klin Wochenschr, 64(Suppl. VII), 32–34PubMedGoogle Scholar
  141. 141.
    McLean, AJ, Harcourt, DM, McCarthy, PG, Dudley, GJ and McNeil, JJ (1987). Relative effectiveness and costs of anti-ulcer medications as a basis for rational prescribing. Med J Aust,146, 431–438PubMedGoogle Scholar
  142. 142.
    Malchow-Moller, A (1987). Treatment of peptic ulcer induced by non-steroidal anti-inflammatory drugs. Scand J Gastroenterol,22(Suppl. 127), 87–91Google Scholar
  143. 143.
    Konturek, SJ (1988). Clinical uses of prostaglandins in peptic ulcer disease. In Hillier, K (ed), Eicosanoids and the Gastrointestinal Tract, pp. 46–74. (MTP Press: Lancaster)Google Scholar
  144. 144.
    Boyd, EJS and Wormsley, KG (1987). Gastrointestinal side-effects of prostaglandins. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory Drugs, Vol.2, pp. 143–149. (MTP Press: Lancaster)Google Scholar
  145. 145.
    Robert, A, Lancaster, C, Davis, JP, Field, SO and Nezamis, JC (1984). Distinction between anti-ulcer effect and cytoprotection. Scand J Gastroenterol, 19(Suppl. 101), 69–72Google Scholar
  146. 146.
    Miller, TA (1983). Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol, 245, G601–G623PubMedGoogle Scholar
  147. 147.
    Robert, A (1984). Mechanisms of cytoprotection. In Paton, W, Mitchell, J and Turner, P (eds), Proceedings of the 9th International Congress of Pharmacology, IUPHAR, London, Vol 3, pp. 355–359. (Macmillan: London)Google Scholar
  148. 148.
    Wilson, DE (1986). Therapeutic aspects of prostaglandins in the treatment of peptic ulcer disease. Dig Dis Scie, 31 (Suppl), 42S–46SGoogle Scholar
  149. 149.
    Szabo, S and Szelenyi, I (1987). ‘Cytoprotection’ in gastrointestinal pharmacology. Trends Pharmacol Sci,8, 149–155Google Scholar
  150. 150.
    Young, RN, Zamboni, R and Leger, S (1987). Preparation and formulation of 2-substituted quinolines as antagonists of leukotrienes and inhibitors of leukotriene biosynthesis. Europ Patent Appl EP219,307, 22 Apr 1987. US Patent Appl 788, 180, 16 Oct 1985. Chem Abstr,107, 39645SGoogle Scholar
  151. 151.
    Young, RN and Zamboni, R (1987). Preparation and formulation of 2-(phenoxymethyl)-quinolines as anti-allergic, anti-asthmatic, anti-inflammatory and cytoprotective agents. US Patent 4, 661, 499, 28 Apr 1987. Chem Abstr, 107 Google Scholar
  152. 152.
    Okabe, S, Takeuchi, K, Nakamura, K and Takagi, K (1974). Inhibitory effects of L-Glutamine on the aspirin-induced lesions in the rat. J Pharm Pharmacol, 26, 605–611PubMedGoogle Scholar
  153. 153.
    Okabe, S, Takeuchi, K, Nakamura, K and Takagi, K (1976). Effects of various amino-acids on gastric lesions induced by acetylsalicylic acid (ASA) and gastric secretion in pylorus-ligalidrates. Arzneim-Forsch, 26, 534–537Google Scholar
  154. 154.
    Rainsford, KD and Whitehouse, MW (1980). Biochemical gastro-protection from acute ulceration induced by aspirin and related drugs. Biochem Pharmacol, 29, 1281–1289PubMedGoogle Scholar
  155. 155.
    Rainsford, KD and Whitehouse, MW (1980). Are all aspirins alike? A comparison of gastric ulcerogenicity and bioefficacy in rats. Pharmacol Res Commun, 12, 85–95PubMedGoogle Scholar
  156. 156.
    Mersereau, WA and Hinchey, EJ (1982). Prevention of phenylbutazone ulcer in the rat by glucose: role of a glycoprivic receptor system. Am J Physiol, 242, G429–G432PubMedGoogle Scholar
  157. 157.
    Whitehouse, MW, Rainsford-Koechli, V and Rainsford, KD (1984). Aspirin gastrotoxicity: protection by various strategies. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-Inflammatory /Analgesic Drugs, pp. 77–87. (Raven Press: New York)Google Scholar
  158. 158.
    Rainsford, KD (1987). Prevention of indomethacin-induced gastrointestinal ulceration in rats by glucose-citrate formulations: role of ATP in mucosal defences. Br J Rheumatol, 26 (Abstr. Suppl. 2), Abstr. 144, 81Google Scholar
  159. 159.
    Walker, FS, Pritchard, MH, Jones, JM, Owen, GM and Rainsford, KD (1987). Inhibition of indomethacin-induced gastrointestinal bleeding, both immediate and persistent, in man by citrate-glucose formulations. Br J Rheumatol, 26 (Abstr. Suppl. 2), Abstr 20, 12Google Scholar
  160. 160.
    Swarm, RA, Ashley, SW, Soybel, DI, Ordway, FS and Cheung, LY (1987). Protective effect of exogenous phospholipid on aspirin-induced gastric mucosal injury. Am J Surg, 153, 48–52PubMedGoogle Scholar
  161. 161.
    Leyck, S, Huther, AM and Parnham, MJ (1987). Polyene phosphatidylcholine: an inhibitor of NSAID gastric toxicity which increases impaired mucosal PGE2 synthesis. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-Inflammatory Drugs, Pt. II, pp. 163–164. (MTP Press: Lancaster)Google Scholar
  162. 162.
    Huang, YS, Drummond, R and Harrobin, DF (1987). Protective effect of gamma linolenic acid on aspirin-induced gastric haemorrhage in rats. Digestion, 36, 36–41PubMedGoogle Scholar
  163. 163.
    Ghanayem, BI, Mathews, HB and Maronpot, RR (1987). Calcium channel blockers protect against ethanol-and indomethacin-induced gastric lesions in rats. Gastroenterology, 92, 106–111PubMedGoogle Scholar
  164. 164.
    Von Kolfschoten, AA, Hagelin, F and van Noordwijk, J (1984). Butyl hydroxy toluene antagonizes the gastric toxicity but not the pharmacological activity of acetylsalicylic acid in rats. Naunyn Schmiedeberg’s Arch Pharmacol, 325, 283–285Google Scholar
  165. 165.
    Goldenberg, MI and Keller, DL (1984). Anti-inflammatory/analgesic combination of cyclo-(N-methyl-ala-tyr-D-trp-lys-val-phe) and a selected non-steroidal anti-inflammatory drug (NSAID). US Patent No. 4,474,766, 2Oct 1984Google Scholar
  166. 166.
    Rainsford, KD and Whitehouse, MW (1980). Anti-inflammatory/anti-pyretic salicylic acid esters with low gastric ulcerogenic activity. Agents and Actions, 10, 451–456PubMedGoogle Scholar
  167. 167.
    Whitehouse, MW and Rainsford, KD (1980). Esterification of acidic anti-inflammatory drugs suppresses their gastrotoxicity without adversely affecting their anti-inflammatory activity in rats. J Pharm Pharmacol, 32, 795–796PubMedGoogle Scholar
  168. 168.
    Donowitz, M, Wicks, J, Cusolito, S and Sharp, GWG (1984). Pharmacotherapy of diarrheal diseases: an approach based on physiologic principles. In Mechanisms of Intestinal Electrolyte Transport and Regulations by Calcium, pp. 329–359. (Alan R Liss)Google Scholar
  169. 169.
    Taggard, H McA and Alderdice, JM (1982). Fatal cholestatic jaundice in elderly patients taking benoxaprofen. Br Med J, 284, 1372Google Scholar
  170. 170.
    Del Favero, A (1983). Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout. In Dukes, MNG and Elis, J (eds), Side Effects of Drugs Annual 7, Chapter 10, pp. 104–125. (Excerpta Medical: Amsterdam)Google Scholar
  171. 171.
    Prescott, LF and Leslie, PJ (1982). Side effects of benoxaprofen. Br Med J, 284, 1783Google Scholar
  172. 172.
    Stewart, IC (1982). Gastrointestinal haemorrhage and benoxaprofen. Br Med J, 284, 163–164Google Scholar
  173. 173.
    Halsey, JP and Cardoe, N (1982). Benoxaprofen: side-effect profile in 300 patients. Br Med J, 284, 1365–1368Google Scholar
  174. 174.
    Babany, G and Pessayre, D (1984). Heptatites dues aux nouveaux anti-inflammatoires non-steroidiens. Gastroenterol Clin Biol, 8, 523–429PubMedGoogle Scholar
  175. 175.
    Hamdan, JA, Manasra, K and Ahmed, M (1985). Salicylate-induced hepatitis in rheumatic fever. Am J Dis Child, 139, 453–455PubMedGoogle Scholar
  176. 176.
    Bernstein, BH, Singsen, BH, King, KK and Hanson, V (1977). Aspirin-induced hepatotoxicity and its effect on juvenile rheumatoid arthritis. Am J Dis Child, 131, 659–663PubMedGoogle Scholar
  177. 177.
    Scaman, WE, Ishak, KG and Plotz, PH (1974). Aspirin-induced hepatotoxicity in patients with systemic lupus erythematosus. Ann Intern Med, 80, 1–8Google Scholar
  178. 178.
    Saltzman, DA, Gall, EP and Robinson, SF (1976). Aspirin-induced hepatic dysfunction in a patient with adult rheumatoid arthritis. Am J Dig Dis, 21, 815–820PubMedGoogle Scholar
  179. 179.
    Rossi, F, Filipelli, W, Guarino, V, Russo, S, Magliulo, R and Marmo, E (1985). Organ tolerance of non-steroidal anti-inflammatory drugs: effect on Ever cells. Drugs Exptl Clin Res, 11, 511–516Google Scholar
  180. 180.
    Bullock, GR, Delaney, VB, Sawyer, BC and Slater, TF (1970). Biochemical and structural changes in rat liver resulting from the parenteral administration of a large dose of sodium salicylate. Biochem Pharmacol, 19, 245–253PubMedGoogle Scholar
  181. 181.
    Whitehouse, MW (1977). Some biochemical complexities of inflammatory disease affecting drug action. In Bouta, IL (ed), Recent Developments in the Pharmacology of Inflammatory Mediators, Agents and Actions, Suppl. 2, pp. 135–147. (Birkhauser: Basel)Google Scholar
  182. 182.
    Parke, AL and Parke, DV (1987). Genetic and environmental aspects of drug metabolism relevant to side-effects in arthritic disease. In Rainsford, KD and Velo, GP (eds), Side-Effects of Anti-Inflammatory Drugs, Pt. I, pp. 241–255. (MTP Press: Lancaster)Google Scholar
  183. 183.
    Whitehouse, MW (1987). Drug disease interactions: utility of the conditional concept for experimental pharmacology and toxicology in the context of inflammation. In Rainsford, KD and Velo, GP (eds), Side-Effects of Anti-Inflammatory Drugs, Pt. I, pp. 259–271. (MTP Press: Lancaster)Google Scholar
  184. 184.
    Zimmerman, HJ (1981). Effects of aspirin and acetaminophen on the liver. Arch Intern Med, 141, 333–342PubMedGoogle Scholar
  185. 185.
    Douidar, SM, Boor, PJ and Ahmed, AE (1985). Potentiation of the hepatotoxic effect of acetaminophen by prior administration of salicylate. J Pharmacol Expt Therap, 233, 242–248Google Scholar
  186. 186.
    Sorensen, EMB and Acosta, D (1985). Relative toxicities of several non-steroidal anti-inflammatory compounds in primary cultures of rat hepatocytes. J Toxicol Environ Health, 16, 425–440PubMedGoogle Scholar
  187. 187.
    Burke, MD, Falzon, M and Milton, AS (1983). Decreased hepatic microsomal cytochrome P450 due to indomethacin: protective roles of 16, 16-dimethyl prostaglandin F and inducing agents. Biochem Pharmacol, 32, 389–397PubMedGoogle Scholar
  188. 188.
    Dunn, MJ (1984). Non-steroidal anti-inflammatory drugs and renal function. Ann Rev Med, 35, 411–428PubMedGoogle Scholar
  189. 189.
    Unsworth, J, Sturman, S, Lunec, J and Blake, DR (1987). Renal impairment associated with non-steroidal anti-inflammatory drugs. Ann Rheum Dis, 46, 233–236PubMedGoogle Scholar
  190. 190.
    Anon (1988). Voltaren “approvable” in the US: FDA caution on NSAI labelling. Scrip, 1311, 25 May, 22Google Scholar
  191. 191.
    Cox, NL and Doherty, SM (1987). Non-steroidal anti-inflammatories: outpatient audit of patient preferences and side effects on different diseases. In Rainsford, KD and Velo, GP (eds), Side-Effects of Anti-Inflammatory Drugs, Pt. I, pp. 137–148. (MTP Press: Lancaster)Google Scholar
  192. 192.
    The Merck Manual of Diagnosis and Therapy, 15th Edn (1987), pp. 2287–2288 and 2024-5. (Merck, Sharp & Dohme Res Labs: Rahway, NJ)Google Scholar
  193. 193.
    Bork, K (1988). Cutaneous side effects of drugs. (WB Saunders: Philadelphia)Google Scholar
  194. 194.
    Reszka, K and Chignell, CG (1983). Spectroscopic studies of cutaneous photosensitizing agents — IV. The photolysis of benoxaprofen, an anti-inflammatory drug with phototoxic properties. Photochem Photohiol, 38, 281–291Google Scholar
  195. 195.
    Anon (1987). Isoxicam — a scientific ‘whodunnit’. Rheumatol Pract, Sept 1987, 21Google Scholar
  196. 196.
    Sik, RH, Pasehall, CS and Chignell, CF (1983). The phototoxic effect of benoxaprofen and its analogs on human erythrocytes and rat peritoneal mast cells. Photochem Photohiol, 38, 411–415Google Scholar
  197. 197.
    Kochevar, IE, Morison, WC, Lamm, JL, McAuliffe, DJ, Western, A and Hood, AG (1986). Possible mechanisms of piroxicam-induced photosensitivity. Archiv Dermatol, 122, 1283–1287Google Scholar
  198. 198.
    Jones, RA, Navaratnam, S, Parsons, RJ and Philips, GO (1987). Photosensitivity due to anti-inflammatory analgesic drugs: a laser flash photolysis study of azapropazone. In Rainsford, KD and Velo, GP (eds), Side-Effects of Anti-Inflammatory Drugs, Pt II, pp. 345–354. (MTP Press: Lancaster)Google Scholar
  199. 199.
    Hort, JF (1975). Adverse reactions to alclofenac. Curr Med Res Opin, 3, 333–337PubMedGoogle Scholar
  200. 200.
    Ford-Hutchinson, AW (1980). Personal communicationGoogle Scholar
  201. 201.
    Aked, D, Foster, SJ, Howarth, A, McCormick, ME and Potts, HC (1986). The inflammatory responses of rabbit skin to tropical arachidonic acid and its pharmacological modulation. Br J Pharmacol, 89, 431–438PubMedGoogle Scholar
  202. 202.
    Chang, J, Carlson, RP, O’Niell-Davis, L, Lamb, B, Sharma, RN and Lewis, AJ (1986). Correlation between mouse skin inflammation induced by arachidonic acid and eicosanoid synthesis. Inflammation, 10, 205–214PubMedGoogle Scholar
  203. 203.
    Aked, DM and Foster, SJ (1987). Leukotriene and prostaglandin E2 mediate the inflammatory responses of rabbit skin to intradermal arachidonic acid. Br J Pharmacol, 92, 545–552PubMedGoogle Scholar
  204. 204.
    Ring, J, Przybilla, B and Ruzicka, T (1987). Nonsteroidal anti-inflammatory drugs induce UV-dependent histamine and leukotriene release from peripheral human leukocytes. Int Arch Allergy Appl Immunol, 82, 344–346PubMedGoogle Scholar
  205. 205.
    Jaudl, RC, George, JL, Dinarello, CA and Schur, PH (1987). The effect of interleukin 1 on IgG synthesis in systemic lupus erythematosus. Clin Immunol Immunopathol, 45, 384–394Google Scholar
  206. 206.
    Sandborg, CI, Berman, MA, Andrews, BS and Friou, GJ (1985). Interleukin-1 production by mononuclear cells from patients with scleroderma. Clin Exp Immunol,60, 294–302PubMedGoogle Scholar
  207. 207.
    Hunneyball, I (1988). Pharmacological regulation of interleukin 1. In Glauert, AM (ed), Control of Connective Tissue Degradation, in press. (Elsevier: Amsterdam)Google Scholar
  208. 208.
    Gahring, LC, Buckley, A and Daynes, RA (1985). Presence of epidermal-derived thymocyte activating factor/interleukin 1 in normal human stratum corneum. J Clin Invest, 76, 1585–1591PubMedGoogle Scholar
  209. 209.
    Hsu, S-M and Zhao, X (1987). Localization of interleukin-1 in normal or reactive lymphoid tissues and skin: abundance of IL-1 in interdigitating reticulum cells. Lymphokine Res, 6, 13–18PubMedGoogle Scholar
  210. 210.
    Lange-Wantzin, G, Rotheim, R, Kahn, J and Faanes, RB (1987). Effect of UV irradiation on expression of membrane IL-1 by rat macrophages. J Immunol, 38, 383–3807Google Scholar
  211. 211.
    Faure, M, Dezutter-Dambuyant, C, Schmitt, D, Gaucherand, M and Thivolet, J (1985). Langerhans cell induced cytotoxic T-cell responses against normal epidermal cell targets: in vitro studies. Br J Dermatol, 113(Suppl. 28), 114–117PubMedGoogle Scholar
  212. 212.
    Morley, J, Sanjar, S, Page, CP and Bretz, U (1985). The role of circulating cells in skin reactions. Br J Dermatol, 113(Suppl. 28), 86–90PubMedGoogle Scholar
  213. 213.
    Yancey, KB, Hammer, CH, Harvath, L, Kenfer, L, Frank, MM and Lawley, TS (1985). Studies on human C5a as a mediator of inflammation in normal skin. J Clin Invest, 75, 486–495PubMedGoogle Scholar
  214. 214.
    Emerit, I and Michelson, AM (1981). Mechanisms of photosensitivity in systemic lupus erythematosus patients. Proc Natl Acad Sci, 78, 2537–2540PubMedGoogle Scholar
  215. 215.
    Cox, H (1967). Long term indomethacin therapy of coxarthrosis. Ann Rheum Dis, 26, 346–357Google Scholar
  216. 216.
    Walker, SR, Schuetz, E, Schuppan, D and Gelzer, J (1984). A comparative retrospective analysis of data from short-and long-term toxicity studies on 40 pharmaceutical compounds. Arch Toxicol, Suppl 7, 485–487Google Scholar
  217. 217.
    Lyle, H (1986). Penicillamine. In Rainsford, KD (ed), Anti-inflammatory and Antirheumatic Drugs, Vol III, pp. 3–30. (CRC Press: Boca Raton, FI)Google Scholar
  218. 218.
    Walters, MT, Smith, JL, Moore, K, Evans, PR and Midcawley. An investigation of the action of disease modifying antirheumatic drugs on the rheumatoid synovial membrane: reduction in T lymphocyte subpopulations and HLA-DR and DQ antigen expression after gold or penicillamine therapy. Ann Rheum Dis, 46, 7–16Google Scholar
  219. 219.
    Arrigoni-Martelli, E, Binderup, L and Bramm, E (1977). Role of macrophages in D-penicillamine-induced stimulation of DNA synthesis in lymph node cells. In Willoughby, DA, Giroud, JP and Velo, GP (eds), Future Trends in Inflammation, pp. 295–301. (MTP Press: Lancaster)Google Scholar
  220. 220.
    Binderup, L, Bramm, E and Arrigoni-Martelli, E (1978). D-Penicillamine and macrophages modulation of lymphocyte transformation by concanavalin A. Scand J Immunol, 7, 259–264PubMedGoogle Scholar
  221. 221.
    Lyle, H (1987). Side effects of penicillamine. In Rainsford, KD and Velo, GP (eds), Side Effects of Anti-inflammatory Drugs, Pt. 2 pp. 171–181. (MTP Press: Lancaster)Google Scholar
  222. 222.
    Paulus, HE (1985). Slowly acting anti-rheumatic drugs (SARDS) rarely improve the outcome of rheumatoid arthritis patients. XVIth International Congress of Rheumatology, Sydney, Australia, 19–25 May 1985, Abstract R35.Google Scholar
  223. 223.
    Davies, PT, Fowler, PD, Clarke, S et al (1986). Rheumatoid arthritis: treatment which controls the C-reactive protein and ESR reduces the radiological progression. Br J Rheumatol, 25, 44–49Google Scholar
  224. 224.
    Cooperating Clinics Committee of American Rheumatism Association (1970). A controlled trial of cyclophorphamide in rheumatoid arthritis. New Engl J Med, 283, 883–889Google Scholar
  225. 225.
    Gordon, AJ and Koj, A (eds)(1985). The Acute Phase Response to Infection and Immunity. (Elsevier: Amsterdam)Google Scholar
  226. 226.
    Merryman, PF, Nowakowski, J and Jaffe, LA (1978). Alteration of lymphocyte response by sulfydral and disulfide compounds. Biochem Pharmacol, 28, 2297–2302Google Scholar
  227. 227.
    Sedgwick, AD, Moore, AR, Sin, YM, Al-Daub, AY, Lansdon, B and Willoughby, DA (1984). The effect of therapeutic agents on cartilage degradation in vivo. J Pharm Pharmacol, 36, 709–710PubMedGoogle Scholar
  228. 228.
    Pickup, ME, Dixon, JS and Bird, HA (1980). On the effects of antirheumatic drugs on protein sulphydryl reactivity in human serum. J Pharm Pharmacol, 32, 301–302PubMedGoogle Scholar
  229. 229.
    Castell, M, Moreno, JJ, Oliva, JC, Queralt, J and Castellote, MC (1987). Serum sulfhydryl group levels in experimental chronic inflammation. Rev Esp Fisiosy, 43, 19–24Google Scholar
  230. 230.
    Olivia, JC, Castell, M, Queralt, J and Castellote, C (1987). Effect of chronic inflammation on copper and zinc metabolism. Rev Esp Fisiol, 43, 25–32Google Scholar
  231. 231.
    Butt, TR, Sternberg, EJ, Mirabelli, CK and Crooke, ST (1986). Regulation of metallothionein gene expression in mammalian cells by gold compounds. Molec Pharmacol, 29, 204–210Google Scholar
  232. 232.
    Glennas, A and Rugstad, HE (1985). Acquired resistance to auranofin in cultured human cells. Scand J Rheumatol, 14, 230–238PubMedGoogle Scholar
  233. 233.
    Glennas, A and Rugstad, HE (1986). Cultured human cells acquire resistance to the antiproliferative effect of sodium aurothiomalate. Ann Rheum Dis, 45, 389–395PubMedGoogle Scholar
  234. 234.
    Glennas, A, Hunziker, PE, Garvey, JS, Kagi, JHR and Rugstad, HE (1986). Metallothionein in cultured human epithelial cells and synovial rheumatoid fibroblasts after in vitro treatment with auranofin. Biochem Pharmacol, 35, 2033–2040PubMedGoogle Scholar
  235. 235.
    Broome, JD and Jeng, MW (1973). Promotion of replication in lymphoid cells by specific thiols and disulfides in vitro. J Exp Med, 138, 574–592PubMedGoogle Scholar
  236. 236.
    Thorne, KJ, Free, J and Franks, D (1982). Role of sulphydryl groups in T lymphocyte-mediated cytotoxicity. Clin Exp Immunol, 50, 644–650PubMedGoogle Scholar
  237. 237.
    Oilman, SC and Lewis, AJ (1985). Immunology drugs in the treatment of rheumatoid arthritis. In Rainsford, KD (ed), Anti-inflammatory and Anti-rheumatic Drugs, Vol. III, pp. 127–154. (CRC Press: Boca Raton, FI)Google Scholar
  238. 238.
    Various authors (1987). Proceedings of a symposium, osteoarthritis: the clinical picture, pathogenesis, and management with studies on a new therapeutic agent. Sadenosyl-methionine Am J Med, 83Suppl, 5AGoogle Scholar
  239. 239.
    Gualano, M, Stramentimoli, G and Berti, F (1983). Anti-inflammatory activity of Sadenosyl-L-methionine: interference with the eicosanoid system. Pharmacol Res Commun, 15, 683–696PubMedGoogle Scholar
  240. 240.
    Harmand, M-F, Vilamitjana, J, Maloche, E, Duphil, R and Ducasson, D (1987). Effects of S-adenosylmethionine on human articular chrondrocyte differentiation. Am J Med, 83,(Suppl. 5A), 48–54PubMedGoogle Scholar
  241. 241.
    Hamilton, JA and Williams, N (1985). In vitro inhibition of myelopoiesis by gold salts and D-penicillamine. J Rheumatol, 12, 892–896PubMedGoogle Scholar
  242. 242.
    Rainsford, KD (1989). Doxorubicin (Adriamycin{R}) is a potent inhibitor of interleukin-1 induced cartilage resorption in vitro. Agents and Actions, 21, 337–340Google Scholar
  243. 243.
    Connolly, KH, Stecher, VJ, Davis, E, Pruden, DJ and La Brie, T. (1988). Alteration of interleukin-1 activity and the acute phase response in adjurant arthritic rats treated with disease — modifying antirheumatic drugs. Agents and Actions, 25, 94–105PubMedGoogle Scholar
  244. 244.
    Rainsford, KD (1988). Effects of anti-inflammatory drugs and pharmacological agents which modify intracellular events in inflammation on interleukin-1 induced cartilage proteoglycan resorption in vitro. Submitted for publicationGoogle Scholar
  245. 245.
    Rainsford, KD (1989). Effects of anti-inflammatory drugs on interleukin-1 induced cartilage proteoglycan resorption in vitro: inhibition by aurothiophosphines but no influence from perturbed eicosanoid metabolism. J Pharm Pharmacol. In pressGoogle Scholar
  246. 246.
    Rainsford, KD (1988). Actions of auinoline antimalarials in control of cartilage resorption by interleukin-1 and E. coli lipopolysaccharide. Abstracts 4th Int. Conference of the Inflammation Research Association, White Haven, PA, Oct 23–27 (1988)Google Scholar
  247. 247.
    Rainsford, KD (1985). Preliminary investigations on the pharmacological control of catabolin-induced cartilage destruction in vitro. Agents and Actions, 16, 55–57PubMedGoogle Scholar
  248. 248.
    Chang, J, Gilman, SC and Lewis, AJ (1986). Interleukin 1 activates phospholipase A2 in rabbit chondrocytes: a possible signal for IL-1 action. J Immunol, 136, 1283–1287PubMedGoogle Scholar
  249. 249.
    Carroll, GJ (1986). A study of the effects of catabolin on cyclic adenosine monophosphate biosynthesis and prostaglandin E2 secretion in pig articular chondrocytes. Br J Rheumatol, 25, 359–365PubMedGoogle Scholar
  250. 250.
    Zeevi, A, Duquesnoy, R, Eiras, G, Rabinowich, H, Todo, S, Makowka, L and Starzi, TE (1987). Immunosuppressive effect of FK-506 on in vitro lymphocyte alloactivation: synergism with cyclosporine A. Transp Proc, 19, 40–41Google Scholar
  251. 251.
    Wolf, RE and Hall, VC (1988). Inhibition of in vitro proliferative response of cultured T lymphocytes to interleukin-2 by gold sodium thiomalate. Arth & Rheum, 31, 176–181Google Scholar
  252. 252.
    Lee, JC, Rebar, L, Demuth, S and Hanna, N. Suppressed IL-2 production and response in AA rats: role of suppressor cells and the effect of auranofin treatment. J Rheumatol, 12, 885–891Google Scholar
  253. 253.
    Weinblatt, ME, Coblyn, JS, Fraser, PA, Anderson, RJ, Spragg, J, Trentham, D and Austen, KF (1987). Cyclosporin A treatment of refractory rheumatoid arthritis. Arthritis and Rheumatism, 30, 11–17PubMedGoogle Scholar
  254. 254.
    Van Rijthoven, AWAM, Dijkmans, BAC, Goeithe, HS, Hermans, J, Montnor-Beckers, ZLMB, Jacobs, PCJ and Cats, A (1986). Cyclosporin treatment for rheumatoid arthritis: a placebo controlled, double blind, multicentre study. Ann Rheum Dis, 45, 736–731Google Scholar
  255. 255.
    Ichimura, O, Suzuki, S, Saito, M, Sugawara, Y and Ishida, N (1985). Augmentation of interleukin 1 and interleukin 2 production by OK-432. Immunopharmacol, 7, 263–270Google Scholar
  256. 256.
    Gilman, SC, Carlson, RP, Daniels, JF, Datko, L, Berner, PR, Chang, J and Lewis, AJ (1987). Immunological abnormalities in rats with adjuvant-induced arthritis — II. Effect of antiarthritic therapy on immune function in relation to disease development. Int J Immunopharmacol. 9, 9–16PubMedGoogle Scholar
  257. 257.
    Marder, P and Schmidtke, JR (1985). Cyclosporin A inhibits helper/inducer surface antigen expression on activated human lymphocytes. Int J Immunopharmacol, 7, 165–175PubMedGoogle Scholar
  258. 258.
    Palacios, R and Moller, G (1981). Cyclosporin A blocks receptors for HLA-DR antigens on T cells. Nature, 290, 792–794PubMedGoogle Scholar
  259. 259.
    Gauldie, J. (1989) Interleukin 6 in the inflammatroy response. In: Therapeutic Control of Inflammatory Diseases. 4th Int. Conference Inflammation Research Association, White Haven, PA, Oct 23–27, 1988. Plenum Press, in press Google Scholar
  260. 260.
    Andus, T, Geiger, T, Hirano, T, Kishimoto, T, Tran-Thi, T, Decker, K and Heinrich, PC (1988). Regulation fo synthesis and secretion of major rat acute-phase proteins by recombinant human interleukin-6 (BSF-2/IL-6) in hepatocyte primary cultures. Europ J Biochem, 173, 287–293PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1989

Authors and Affiliations

  • K. D. Rainsford
    • 1
  1. 1.Department of Biomedical SciencesMcMaster University Faculty of Health SciencesHamiltonCanada

Personalised recommendations