What comes after macrolides and other motilin stimulants?

Delayed gastric emptying is often considered the major pathophysiological mechanism underlying symptoms in both functional dyspepsia and diabetic gastroparesis. Studies have reported a significant delay in the gastric emptying rate of solids in up to 50% of patients with functional dyspepsia and in up to 75% of patients with type 1 diabetes.1 2 Prokinetic agents, including metoclopramide, domperidone, and cisapride, have traditionally been used to enhance gastric emptying rate and to improve symptoms in these patients. However, their prokinetic effect was moderate and the symptomatic response was often poor.1 In view of the limited options to treat these patients, the report of the strong gastrokinetic effect of erythromycin3 was met with great enthusiasm. This surprising effect of erythromycin relates to its ability to act as a motilin receptor agonist,4 and several motilides (motilin agonists) lacking antibiotic activity were developed, including ABT-229. However, the outcomes of clinical trials with ABT-229 were unequivocally disappointing with regard to symptom improvement. In a large double blind placebo controlled study of 612 patients with functional dyspepsia assigned to placebo, or 1.25, 2.5, 5.0, or 10 mg of ABT-229, symptoms did not improve. On the contrary, an inverse dose-response occurred for postprandial fullness and ABT-229 apparently prevented the beneficial placebo effect.5 Similarly, as reported in this issue of Gut by Talley et al , a study with a comparable design in 270 patients with diabetes mellitus had an adverse effect and increased the severity of dyspeptic symptoms (see page 395).6 This led the authors to conclude that motilides will not be helpful in treating gastroparesis, and that acceleration of gastric emptying is apparently not the right therapeutic target. These are far reaching conclusions which may not be warranted. Several factors may have contributed to the negative outcome of both …