Improving on PPI-based therapy of GORD

Blockade of the gastric acid pump, hydrogen-potassium adenosine triphosphat ase (H+,K+-ATPase), by proton pump inhibitors (PPIs) is one of the most eff ective treatments for gastro-oesophageal reflux disease (GORD), In ideal te rms, however, the inhibition of acid secretion should occur rapidly, on the first dose, and remain virtually complete in a dose-dependent manner, Seve ral aspects of PPI biochemistry prevent the achievement of this ideal. PPIs target the final step of acid secretion and, due to the covalent nature of their inhibition of H+,K(+-)ATPase, cause suppression of acid secretion lo ng after the drug has been eliminated. Their disadvantages stem from their mechanism of action: they require accumulation and activation in active par ietal cells and have short plasma half-lives, hence a relatively slow onset of action, An extension of PPI plasma half-lives is an obvious goal, possi bly via exploitation of probable differences in the metabolism of the two e nantiomers (structural mirror images) present in current PPI formulations: e,g., clinical data on the S-enantiomer of omeprazole (esomeprazole) sugges t some improvement in acid control, An alternative is to generate a pro-dru g of a PPI; plasma levels of the PPI would thus depend on release of the ac tive metabolite from the pro-drug, again extending drug half-life. Another area of active investigation is the development of acid-pump antagonists to inhibit acid secretion at its final step. Eur J Gastroenterol Hepatol 13 ( suppl 1):S35-S41 (C) 2001 Lippincott Williams & Wilkins.