Improved Non-Steroid Anti-Inflammatory Drugs: COX-2 Enzyme Inhibitors

1. Front Matter

   Pages i-ix

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2. Overview — mechanisms of action of anti-inflammatory drugs

   • J. R. Vane, R. M. Botting

   Pages 1-27

3. The three-dimensional structure of cyclooxygenases

   • R. M. Garavito

   Pages 29-43

4. The dilemma of two cyclooxygenases: identifying the roles of COX-1 and COX-2 in inflammation and apoptosis

   • D. L. Simmons, X. Lu, W. S. Bradshaw, W. Xie

   Pages 45-65

5. Inducible enzymes with special reference to COX-2 in inflammation and apoptosis

   • D. A. Willoughby, A. Tomlinson, D. Gilroy, D. Willis

   Pages 67-83

6. NSAID mechanism of action: the role of intracellular pharmacokinetics

   • L. G. Herbette, M. Vecchiarelli, G. Trummlitz

   Pages 85-102

7. Differential inhibition of COX-1 and COX-2 in vitro and pharmacological profile in vivo of NSAIDs

   • M. Pairet, G. Engelhardt

   Pages 103-119

8. COX-2 expression and inhibition in human monocytes

   • C. Patrono, P. Patrignani, M. R. Panara, F. Cipollone, G. Santini, M. G. Sciulli et al.

   Pages 121-131

9. Expression and regulation of COX-2 in synovial tissues of arthritic patients

   • L. J. Crofford

   Pages 133-143

10. An inhibitor of injury-induced COX-2 transcriptional activation elicits neuroprotection in a brain damage model

    • N. G. Bazan, G. Allan, V. L. Marcheselli

    Pages 145-166

11. COX-2 expression in labour

    • P. Bennett, D. Slater

    Pages 167-188

12. Re-evaluation of gut toxicity of NSAIDs

    • D. N. Bateman

    Pages 189-201

13. NSAID: can renal side effects be avoided?

    • J. C. Frölich, D. O. Stichtenoth

    Pages 203-228

14. Pharmacology, safety data and therapeutics of COX-2 inhibitors

    • P. Emery

    Pages 229-241

15. Back Matter

    Pages 243-248

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In 1971, Vane proposed that the mechanism of action of the aspirin-like drugs was through their inhibition of prostaglandin biosynthesis. Since then, there has been intense interest in the interaction between this diverse group of inhibitors and the enzyme known as cyclooxygenase (COX). It exists in two isoforms, COX-l and COX-2 (discovered some 5 years ago). Over the last two decades several new drugs have reached the market based on COX-l enzyme screens. Elucidation of the three-dimensional structure of COX-l has provided a new understanding for the actions of COX inhibitors. The constitutive isoform of COX, COX-l has clear physiological functions. Its activation leads, for instance, to the production of prostacyclin which when released by the endothelium is anti-thrombogenic and anti-atherosclerotic, and in the gastric mucosa is cyto­ protective. COX-l also generates prostaglandins in the kidney, where they help to maintain blood flow and promote natriuresis. The inducible isoform, COX-2, was discovered through its activity being increased in a number of cells by pro­ inflammatory stimuli. A year or so later, COX-2 was identified as a distinct isoform encoded by a different gene from COX-I. COX-2 is induced by inflammatory stimuli and by cytokines in migratory and other cells. Thus the anti-inflammatory actions of non-steroid anti-inflammatory drugs (NSAIDs) may be due to the inhibition of COX-2, whereas the unwanted side-effects such as irritation of the stomach lining and toxic effects on the kidney are due to inhibition of the constitutive enzyme, COX-I.

• cardiovascular disease
• inflammation
• kidney
• kinetics
• pharmacokinetics
• pharmacology
• research
• toxicity

• The William Harvey Research Institute, Saint Bartholomew’s Hospital Medical College, London, UK

  John Vane, Jack Botting, Regina Botting

Sir John Vane is the Director General at the William Harvey Research Institute, an independent charitable foundation within Queen Mary and Westfield College of the University of London, UK.
Sir John Vane shared the Nobel Prize in Physiology or Medicine in 1982 for his discoveries of the mechanism of action of aspirin and of prostacyclin, as well as his work on other prostanoids. Jack Botting is Consultant at the William Harvey Research Institute, an independent charitable foundation within Queen Mary and Westfield College of the University of London, UK.

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