Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial

Abstract

Introduction-Erythromycin, a motilin agonist, is a potent prokinetic. ABT-229 is a specific motilin agonist that dose dependently accelerates gastric emptying. Dyspepsia and gastroparesis are common problems in type 1 diabetes mellitus. We aimed to evaluate the eYcacy of ABT-229 in symptomatic diabetic patients with and without delayed gastric emptying. Methods-Patients with type 1 diabetes and postprandial symptoms were randomised (n=270). Based on a validated C 13 octanoic acid breath test, patients were assigned to either the delayed or normal gastric emptying strata. Patients received one of four doses of ABT-229 (1.25, 2.5, 5, or 10 mg twice daily before breakfast and dinner) or placebo for four weeks following a two week baseline. A self report questionnaire measured symptoms on visual analogue scales; the primary outcome was assessment of change in the total upper abdominal symptom severity score (range 0-800 mm) from baseline to the final visit. Results-The treatment arms were similar regarding baseline characteristics. There was symptom improvement on placebo and a similar level of improvement on active therapy for the upper abdominal discomfort severity score (mean change from baseline −169, −101, −155, −143, and −138 mm for placebo, and 1.25, 2.5, 5, and 10 mg ABT-229, respectively, at four weeks by intent to treat). The results were not significantly diVerent in those with and without delayed gastric emptying. The severity of bloating, postprandial nausea, epigastric discomfort, heartburn, and acid regurgitation worsened dose dependently in a greater number of patients receiving ABT-229 than placebo. Overall, 63% of patients on placebo reported a good or excellent global response, and this was not diVerent from the active treatment arms. Conclusions-The motilin agonist ABT-229 was not eYcacious in the relief of postprandial symptoms in diabetes mellitus in the presence or absence of delayed gastric emptying. (Gut 2001;49:395-401)

Effect of the motilin agonist KC 11458 on gastric emptying in diabetic gastroparesis

“…After 4 weeks, ABT-229 in a dose of 10 mg b.d., exacerbated symptoms when compared with placebo and this was the case irrespective of whether patients had delayed gastric emptying or not. 20 Mechanisms that may be relevant to the generation of symptoms in patients with diabetes include slow gastric emptying, changes in antral or fundic tone, and visceral hypersensitivity which may all be influenced by hyperglycaemia. 1, 2 It has been suggested that the effect of motilin agonists on upper gastrointestinal symptoms may relate to an adverse effect on postprandial fundic relaxation.…”

“…[2][3][4] In view of the potency of intravenous erythromycin in accelerating gastric emptying when administered acutely in diabetic gastroparesis, motilides that lack antibiotic activity have been developed. 4,20 Both animal and human studies have established that KC 11458 accelerates gastric emptying. [22][23][24][25][26] In healthy volunteers, single oral doses of KC 11458 ranging from 4 to 32 mg accelerated gastric emptying of solids as assessed by a breath test.…”

“…4,20 A recent study using one of these drugs for the treatment of upper gastrointestinal symptoms in a large cohort of type 1 patients was, however, negative.…”

Desensitization of the Human Motilin Receptor by Motilides

“…As a result, more potent motorstimulating EM derivatives were developed without antibiotic activity: the motilides (Omura et al, 1987). Recently the clinical development of the most promising motilide ABT-229 was stopped because of its failure to improve symptoms in patients with functional dyspepsia with normal or delayed gastric emptying (Talley et al, 2000) and in patients with type 1 diabetes mellitus (Talley et al, 2001). The authors of the studies with ABT-229 concluded that there was no future for drugs with the prokinetic profile of the motilides, but others have argued that ABT-229 had undesirable properties that may be avoided in new motilides (Tack and Peeters, 2001;Camilleri, 2002).…”

Pharmacological therapy of feed intolerance in the critically ills

“…In order to overcome this issue, a number of motilin derivatives that have no antibiotic property have been developed. Unfortunately, the prokinetic effects of these new agents are less durable, and are most likely due to the rapid development of drug tachyphylaxis [74][75][76] .…”