Effect of the Motilin Receptor Agonist, Erythromycin, on Hunger and Food Intake; Study of Role of Cholinergic Pathways

The role of induced phase 3 contractions in the control of hunger and food intake

• Background In between meals the motor activity of the upper gastrointestinal tract is characterized by a cyclical pattern of contractions that consists of 3 phases: maximal contractile activity originating in the stomach and migrating down the small intestine (phase 3), followed by a phase of motor quiescence (phase 1) and a phase of progressively increasing motor activity (phase 2). In 1975 Itoh et. al. linked the phase 3 contractions of the migrating motor complex (MMC) to hunger sensations, by increasing the hunger sensations through exogenously administered motilin. The investigators previously demonstrated that phase 3 is associated with a 'hunger pang'. The trigger for the phase 3 initiation is unclear, but the gut hormones ghrelin and motilin are presumed to play a role. If either of these substances are administered intravenously, they induce a premature phase 3 in humans.

In previous studies, 'hunger pangs' could objectively be detected as peaks in subjective hunger ratings on a visual analog scale (VAS) using a custom made algorithm. A close association between phase 3 contractions of gastric origin and hunger peaks was observed and spontaneous food intake was also found to be associated with hunger peaks. By inducing phase 3 contractions through the administration of IV erythromycin, the time of food intake could be manipulated.

In a new study the investigators will evaluate if the food intake associated with the infusion of erythromycin is caused by the phase 3 contractions or by another yet unknown effect of erythromycin. To obtain this the investigators will use atropine, a muscarinic receptor antagonist, to inhibit the formation of contractions induced by a low dose of erythromycin. Since food intake is no longer a pure physiological act to still hunger sensations, it has obtained a social and emotional status in modern times where palatable food is abundant, the relationship of the subject towards food using multiple questionnaires will also be evaluated.

• Aim To investigate whether contractions in the antrum are necessary to induce food intake with erythromycin or if erythromycin has a secondary effect to stimulate food intake.
• Methodology 3.1. Subject selection Healthy volunteers will be recruited. See eligibility criteria for details

3.2. Questionnaires

Dutch eating behaviour questionnaire (DEBQ):

The DEBQ will be administered as a measure of dietary restraint and disinhibition. The DEBQ investigates three fields of behavioral eating: restrained eating, emotional eating and external eating.

Council of nutrition appetite questionnaire (CNAQ):

This questionnaire is an appetite-monitoring instrument developed by the Council for Nutritional Strategies in Long-Term Care.

Hospital Anxiety & Depression Scale (HAD):

This questionnaire will be used to exclude subjects with mood & anxiety disorders.

Power of food scale (PFS):

The PFS evaluates the psychological impact of living in an environment where palatable food is abundant.

3.3. Protocol Study design Gastric motility will be registered for 7h after an overnight fast (see below). During this period the volunteers are allowed to ingest a standardized liquid meal twice at time points of their choice. The volunteers are exposed to the liquid meal before the start of the experiment and the palatability of the meal is scored; this is done in a standardized way (same cup, temperature, duration, only smelling not tasting). The liquid meal is a low-caloric soup with a similar composition as the one used by Hjelland et. al. The volunteers are not aware that the investigators want to study the association between gastric motility, hunger and food intake; they receive the information that the investigators want to examine the effect of fasting on the motility of the stomach and hunger. During the experiment they will watch standardized movies with a neutral emotional content at standardized time points. They will rate hunger every 5 minutes and they will be offered the opportunity to drink the meal at a time point of their choice. At the start of the experiment two intravenous catheters will be placed in separate arms of the subject. During the entire study saline will be administered intravenously at a low rate to blind the subject towards the time of drug administration. The infusion bag will be positioned behind a curtain, in this way the time of drug administration will be blind for the subject. The administration of the drug, 40 mg of the motilin receptor agonist erythromycin lactobionate (Erythrocine; Abbott, Ottignies-Louvain-la-Neuve, Belgium), will be given in a randomized fashion at time point 90, 180, 270 or 360 min after the start of the study. An infusion of this macrolide antibiotic will be given at two of the above time points, one of these erythromycin infusions will be preceded by a 15 µg/kg IV bolus of atropine (Stellatropine; Pharmacobel, Brussels, Belgium) plus a 30 min infusion of 15 µg/kg/hr of atropine. The administration of atropine will be given 10 minutes before the infusion of erythromycin in the opposite arm of the erythromycin infusion. The arterial pulse frequency will be monitored continuously during the administration of atropine. If the start point of an infusion coincides with a spontaneous phase 3, then the infusion will be postponed for 15 min until the phase 3 is passed.

Manometry Recording of antroduodenal intraluminal pressures will be performed using a Manoscan® high resolution manometry catheter (outer diameter 4.2 mm, 36 channels spaced 1 cm apart). The catheter will be introduced via the nose and the position of the catheter, see figure 1, will be briefly checked by fluoroscopy (typically 5 seconds, never more than 25 seconds). This part will comply with the relevant guidelines of radioprotection and participants will be protected by a leaden shield that covers the lower abdomen, Personnel will carry a leaden jacket, will not be exposed to the primary beam and will wear dosimeters at all time. The catheter will be placed in such a way, that there are measuring points in the antrum and just distal to the pylorus to accurately record the migrating motor complex. The output of the manometry channels is recorded and monitored on-line via the ManoScan 360™ (Sierra Scientific Instruments, Los Angeles, CA). After an overnight fast, the manometry assembly will be introduced as described above and secured to the subject's nose with adhesive tape. The subjects will then be positioned in a comfortable sitting position with the knees bent (80°) and the trunk upright in a specifically designed bed.

Behavioural ratings At 5-minute intervals, volunteers will indicate scores for hunger and expected amount to eat on a 10cm VAS. Emotions will be scored at a 15-minute interval on an electronic grid mood scale.

Inclusion criteria

• Female or male subjects aged 18 to 60
• Subject is capable and willing to give informed consent
• Female volunteers of child bearing potential must use oral, injected or implanted hormonal methods of contraception

Exclusion criteria

• Female volunteer is pregnant or breastfeeding
• Gastrointestinal diseases, major abdominal surgery
• Major psychiatric illnesses
• Volunteers that use drugs affecting the gastrointestinal tract or the central nervous system
• Allergy for macrolide antibiotics
• Allergy for atropine
• Severe heartburn
• Enlarged prostate
• Blockage of urinary tract
• Acute closed-angle glaucoma
• Myasthenia gravies
• Severe heart disease
• Thyrotoxicosis
• Fever
• Liver problems
• High blood pressure or fast heart rate
• Lung disease