Improving on PPI-based therapy of GORD.

Blockade of the gastric acid pump, hydrogen-potassium adenosine triphosphatase (H+,K+-ATPase), by proton pump inhibitors (PPIs) is one of the most effective treatments for gastro-oesophageal reflux disease (GORD). In ideal terms, however, the inhibition of acid secretion should occur rapidly, on the first dose, and remain virtually complete in a dose-dependent manner. Several 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 long after the drug has been eliminated. Their disadvantages stem from their mechanism of action: they require accumulation and activation in active parietal 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, possibly via exploitation of probable differences in the metabolism of the two enantiomers (structural mirror images) present in current PPI formulations: e.g., clinical data on the S-enantiomer of omeprazole (esomeprazole) suggest some improvement in acid control. An alternative is to generate a pro-drug of a PPI; plasma levels of the PPI would thus depend on release of the active 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.