Development of motilides

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 Talleyet 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 …