Why is the elderly female at high risk for NSAID-induced gastric damage?

A H Robins; Wyeth

Cutting-edge science and differentiation

In the early 80s, McCormack’s evolving methods of correlation and association, that were later developed into CEME, show that the chemical structure and ionization behaviour of azapropazone distinguish this compound from other NSAIDs. These previously-unknown relationships between physico-chemical character and clinical outcomes imply that at normal dosing azapropazone has little or no capacity to accumulate directly within the gastric mucosa (subsequent studies in humans supported this).

Clinical implications of new teachings

In an era (1980s) when manufacturers were competing in their efforts to develop gastric-sparing NSAID formulations, McCormack’s new teachings positioned azapropazone as the NSAID of choice, particularly within the most vulnerable subpopulation of arthritis patients, the elderly female. McCormack’s initial characterization of azapropazone’s amphiprotic behaviour was followed with the development by Keith McCormack of the first unifying hypothesis to explain how NSAIDs accumulated within the pyloric antrum of the stomach by systemic transfer, and why the elderly female was apparently more prone to this local accumulation.

Taken together, these new teachings positioned A H Robins as a leader and pioneer in defining a new category of gastric-sparing NSAID. The so-called pH partition hypothesis within which the novel amphiprotic behaviour of azazpropazone is accommodated, was later to become prominent in the development of several major therapeutics that for example include the proton pump inhibitor class of drugs. McCormack’s new teachings strongly differentiated azaopropazone by a unique classification and additionally distinguished A H Robins as a company that had made a major contribution in furthering understanding of NSAID-associated gastric toxicity.

Elderly woman lies in a hospital bed; a nurse sits with her
© Shutterstock

Key outcomes

  • Expansion of use within an approved indication

Formal presentations of new teachings by Keith McCormack

  • Mathematical model for assessing risk of gastrointestinal reactions to NSAIDs. A special meeting to celebrate twenty years of azapropazone in clinical use. Lucerne, Switzerland. November 1989. Organized and sponsored by Siegfried AG, Zofingen, Switzerland.
  • The role of NSAIDs in managing musculoskeletal pain. NSAIDs and Pain. A special meeting at Exeter College, Oxford University, UK. May 1992. Organized by McCormack Pharma with sponsorhip from Wyeth (UK) and Siegfried AG, Zofingen, Switzerland.

Published new teachings

  • McCormack K, Brune K. Classical absorption theory and the development of gastric mucosal damage associated with the nonsteroidal antiinflammatory drugs. Arch Toxicol 1987 60 261-269.
  • McCormack & Brune The amphiprotic character of azapropazone and its relevance to the gastric mucosaArch Toxicol 1990 64(1) 1-6.
  • McCormack K. Mathematical model for assessing risk of gastrointestinal reactions to NSAIDs. In: Azapropazone, 20 Years of Clinical Use. Ed: Rainsford KD. Publisher: Kluwer Academic, Lancaster, UK. 1989, pp. 81-94.
  • McCormack K. Mathematical model for assessing risk of gastrointestinal reactions to NSAIDs. EULAR Bulletin 1989 XIX(1) 7-8.
  • McCormack K, Urquhart E. NSAIDs: is prostaglandin synthetase inhibition essential for efficacy? Medical Dialogue 1990 No. 295 1-4.
  • McCormack K, Brune K. Dissociation between the antinociceptive and the antiinflammatory effects of the nonsteroidal antiinflammatory drugs. A survey of their analgesic efficacy. Drugs 1991 41(4) 533-547.