Pharmacological treatment of GERD – a look beyond PPIs?

Abstract

Zusammenfassung. Grundlagen: Etwa 20-30% der Patienten mit gastroösophagealer Refluxkrankheit haben immer noch Beschwerden, trotz Therapie mit einem Protonenpumpenhemmer (PPI). Bei diesen Patienten können in 40-50% der Fälle auch unter PPI-Therapie saure und nicht saure Refluxe nachgewiesen werden und somit die Therapie nicht voll ausgeschöpft erscheint. Transiente Erschlaffungen des LES (TLESRs) sind die Ursache für Refluxe. Deshalb bieten die TLESRs einen zusätzlichen therapeutischer Ansatz in der GERD-Therapie.Methodik: Ü bersicht zur medikamentösen Therapie der TLESRs.Ergebnisse: Unter den Medikamenten, welche die TLESRs hemmen, ist der GABA B -Agonist Baclofen der vielversprechendste Ansatz, da er durch Hemmung der Säureexposition der Speiseröhre die Beschwerden lindert. Auch ADX10059, ein mGluR5-Antagonist, zeigt Wirksamkeit in der GERD-Therapie. Limitierend sind derzeit noch die Nebenwirkungen wie Ü belkeit, Erbrechen und Schwindel, welche durch ein entsprechendes Drug Design ausgeräumt werden sollten.Schlussfolgerungen: Substanzen, welche die TLESRs hemmen, stellen einen vielversprechenden neuen Ansatz in der GERD Therapie dar.Schlüsselwörter: Gastroesophagealer Reflux, Baclofen, GERD, Protonenpumpenhemmer, Manometrie, pHMetrie. Summary.Background: Approximately 20-30% of patients with gastro-esophageal reflux symptoms report inadequate symptom relief while on PPI therapy. Persisting acid or nonacid reflux can be demonstrated in 40-50% of them suggesting that there is room for anti-reflux therapy in these patients. Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism of all type of reflux, i.e. both acid and weakly acidic reflux episodes. Therefore, controlling the occurrence of TLESRs appears to be a relevant therapeutic objective in GERD.Methods: Review on the pharmacological therapy of TLESRs for GERD management.Results: Many compounds have been shown to decrease the number of TLESRs, but the most promising classes are GABA B agonists and mGluR5 antagonists both of which have orally formulations available for human use. The GABA B agonist baclofen, prescribed for the treatment of spasticity for many years, has been shown to decrease the number of TLESRs, esophageal acid exposure, and reflux symptoms. Considering the poor tolerability of this compound, more selective GABA B agonists are currently in development. ADX10059, a mGluR5 negative allosteric modulator, has been shown to decrease GER in both healthy subjects and GERD patients and has entered in phase IIb studies.Conclusions: Compounds that target TLESR activity represent a promising new therapeutic option for patients who suffer from GERD symptoms. These drugs will probably be developed as add-on therapy in combination with PPIs provided the tolerability and safety issues are resolved.

Esophagology 2009: Tubes, trumpets and treatments

“…Zerbib summarizes our novel understanding of the pathogenesis of the transient LES relaxations and how they contribute to GERD. In addition Zerbib describes novel pharmacological approaches to inhibit these LES relaxations and how this improves the novel GERD therapy [2]. Taken together, this excellent paper opens up a new field in GERD management.…”

“…Gastric induced dilatations cause repeated, transient dilations and shortenings of the lower esophageal sphincter, where the sphincter is taken up by the contour of the distended stomach: during manometry this phenomenon may manifest as so-called transient LES relaxations, as described by Zerbib [2], in this issue of European Surgery (technically, during dilatations, the manometry catheter loses its contact to the esophageal wall and indicates a drop of pressure). Over time, dilations of the LES become permanent (Fig.…”

“…The next stop on our journey comes from Frank Zerbib [2], a highly motivated, open-minded gastroenterologist with great reputation in the medical management of esophageal disorders. His paper deals with a novel approach to ''attack'' GERD-induced impairment of the function of the lower esophageal sphincter [2].…”

“…His paper deals with a novel approach to ''attack'' GERD-induced impairment of the function of the lower esophageal sphincter [2]. The pathogenesis of GERD involves transient relaxations of the lower esophageal sphincter.…”

“…In GERD patients the LES also relaxes independent of swallowing. These transient LES relaxations are responsible for postprandial GERD symptoms and reflux [2]. Zerbib summarizes our novel understanding of the pathogenesis of the transient LES relaxations and how they contribute to GERD.…”