Pharmacological targets in gastro-oesophageal reflux disease

Although proton pump inhibitors have become the mainstay of treatment in gastro-oesophageal reflux disease (GORD), there are still unmet needs in the management of this very common disorder. For example, all current proton pump inhibitors have a relatively slow onset of action and their activity is limited mainly to the post-prandial period with far less effective inhibition of nocturnal acid secretion. In order to achieve more potent, rapid and sustained acid inhibition several compounds are currently under development, such as new proton pump inhibitors with a prolonged plasma half-life, potassium competitive ATPase blockers (PCABs), histamine H3 agonists, and gastrin antagonists. Acid suppression does not, however, cure the disease and relapses are frequently observed after discontinuation of proton pump inhibitor therapy. Among the different abnormalities involved in the pathophysiology of this multifactorial disease, transient lower oesophageal sphincter relaxations represent the major mechanism responsible for episodes of reflux. Baclofen, the prototype GABA(B) receptor agonist, is one of the most potent inhibitors of transient lower oesophageal sphincter relaxations identified. To date the transfer of these relaxation-controlling pharmacological agents into clinical practice has however been hampered by the occurrence of unacceptable side effects. Beside "anti-relaxation therapy", the potential of novel prokinetics such as motilin agonists has been explored, especially since the motilin receptor has been cloned. Thus far the broad therapeutic value of prokinetics in GORD does, however, seem very limited in terms of efficacy with respect to oesophageal motility and acid exposure. Lastly, further research is necessary to better understand the complex mechanisms involved in oesophageal sensitivity and mucosal defence.