T.L. Peeters
Faculty of Medicine University of Leuven Kasteeldreef 38 Gasthuisberg ON-1 Box 701 B-3000 LEUVEN Belgium

Abstract:

The demonstration that erythromycin accelerates gastric emptying in patients with diabetic gastroparesis, has stimulated several companies to develop derivatives of erythromycin without antibacterial properties. The prokinetic properties of erythromycin are due to its interaction with the motilin receptor, and derivatives of erythromycin with motilin agonist properties are called motilides. However the past 20 years, several motilides were abandoned during development. Low bio-availability (EM-523, EM-574 Takeda), lack of efficacy (KC-11458, Kali-Chemie) and worsening of symptoms (ABT-229, Abbott) were deciding points.  Patient selection, desensitization and impediment of fundic accommodation have been evoked as possible underlying causes of the worsening of symptoms. Presently two motilides are still candidate drugs. Promising results have been obtained in fase 2 clinical trials with GM-611 (mitemcinal, Chugai) in a subgroup of patients with gastroparesis.  PF-04548043 (Pfizer) increases gastric emptying in healthy volunteers.  In the mean time the potential of motilides continues to be confirmed in clinical studies with erythromycin and in the everyday prescription of low dose erythromycin by many gastroenterologists.

It is generally accepted that in normal physiology motilin plays little or no role in gastric emptying, but is an important regulator of the migrating motor complex (MMC).  The MMC is a motor pattern typical for the fasted state. The MMC has been called the “housekeeper” of stomach and small intestine, because it clears the lumen of debris and meal remnants. The occurrence of an MMC pattern in the postprandial state was recognized from the beginning of the discovery of the motilides as a possible disadvantage as it could induce dumping symptoms. Dr.Z.Itoh, who discovered the prokinetic properties of erythromycin, considers their application in gastroparesis conditions as a mistake and proposed that the special property of the motilides to induce the MMC should be considered.  However the only pathological condition that has been linked to the absence of the MMC is bacterial overgrowth. On the other hand present feeding patterns in humans prevent the occurrence of the MMC during most of the day, and this may have subtle effects contributing to such pathologies as IBS, ulcer and reflux disease. Considering the nature of the MMC, and the nature of these pathologies, this point may be hard to prove, although there is increasing evidence for an involvement of bacterial overgrowth in IBS. Proving the benefit of the induction of an MMC may be still harder to prove, except perhaps in reflux disease.

Although motilides did not have a beneficial effect in trials in patients with reflux disease, it may be noted that the (in our opinion inappropriate) treatment schedule did not aim at the induction of an MMC, and may even have prevented it.   Today the standard treatment of reflux disease involves PPI’s, but for an important subgroup of patients this treatment is inadequate.  It is known that in reflux disease nighttime reflux is an important problem and a contributing factor to the extent of the disease. The benefit of MMC induction may therefore most easily be shown by treating these patients with motilides at bedtime. In addition motilides could be taken on demand when a patient wakes up and experiences nighttime symptoms. It may also be noted that recent studies suggest that long term use of PPI’s may contribute to bacterial overgrowth.  Motilides may therefore find a useful application in a combination therapy with PPI’s and in a treatment schedule adapted to patient need.

Ideally motilides with a short half-life should be considered for this purpose. SAR studies have shown that the macrolide ring, the desosamine and the cladinose sugar each play a role in the interaction with the motilin receptor, offering a simple way to achieve this goal. The profile of second generation motilides then follows from earlier experience and these new insights. In this way motilin agonism may finally be applied for the benefit of the patient.