J Janssens

Improvement of gastric emptying in diabetic gastroparesis by erythromycin. Preliminary studies

Erythromycin mimics the effect of the gastrointestinal polypeptide motilin on gastrointestinal motility, probably by binding to motilin receptors and acting as a motilin agonist. Erythromycin may thus have clinical application in patients with disturbances of gastroduodenal motility, such as diabetic gastroparesis. To examine this possibility, we studied the effect of erythromycin on gastric emptying in 10 patients with insulin-dependent diabetes mellitus and gastroparesis. We studied the emptying of liquids and solids simultaneously on separate days after the intravenous administration of erythromycin (200 mg) or placebo, using a double-isotope technique and a double-blind, crossover design. Erythromycin shortened the prolonged gastric-emptying times for both liquids and solids to normal. For example, 120 minutes after the ingestion of a solid meal, mean (+/- SE) retention was 63 +/- 9 percent with placebo and 4 +/- 1 percent with erythromycin, as compared with 9 +/- 3 percent in 10 healthy subjects. The corresponding values 120 minutes after the ingestion of a liquid meal were 32 +/- 4, 9 +/- 3, and 4 +/- 1 percent, respectively. Gastric emptying also improved, but to a lesser degree, in the 10 patients after four weeks of treatment with oral erythromycin (250 mg three times a day). These preliminary results suggest that erythromycin may have therapeutic value in patients with severe diabetic gastroparesis.

Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring

Background and aims: Acid gastro-oesophageal reflux is one of the most important causes of chronic cough. The response to acid suppression in these patients is not as good as in patients with heartburn but improvement with antireflux surgery has been reported, suggesting the involvement of a non-acidic gastric component in the refluxate. Less acidic reflux may produce symptoms such as regurgitation or chest pain. We investigated whether chronic cough might be associated with weakly acidic reflux. Methods: We studied 28 patients with chronic cough using 24 hour ambulatory pressure-pH-impedance monitoring. Manometry was used for precise recognition of cough and impedance-pHmetry to detect acid (pH <4), weakly acidic (pH 7–4), and weakly alkaline (impedance drops, pH ⩾7) reflux. A symptom association probability (SAP) analysis was performed for each type of reflux. Results: Analysis was completed in 22 patients with 24 cough events (5–92)/patient. The majority of cough events (69.4%) were considered “independent” of reflux whereas 30.6% occurred within two minutes of a reflux episode. Half of these (49%) were “reflux cough” sequences, involving acid (65%), weakly acidic (29%), and weakly alkaline (6%) reflux. Ten patients (45%) had a positive SAP between reflux and cough: five with acid, two with acid and weakly acidic, and three only with weakly acidic reflux. Conclusions: Ambulatory pressure-pH-impedance monitoring with SAP analysis allowed precise determination of the temporal association between cough and gastro-oesophageal reflux (acid, weakly acidic, and weakly alkaline) and identification of a subgroup of patients with chronic cough clearly associated with weakly acidic gastro-oesophageal reflux.

Effect of the GABA B agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors

Background and aims: A subset of patients with gastro-oesophageal reflux disease (GORD) with refractory symptoms during therapy with proton pump inhibitors (PPIs), have persistent non-acid duodeno-gastro-oesophageal reflux (duodenal reflux). The aim of the present study was to investigate the effect of the GABAB receptor agonist baclofen, which was shown to inhibit the occurrence of transient lower oesophageal sphincter relaxations (TLOSRs) in patients with persistent non-acid duodenal reflux during PPI therapy. Methods: Patients were eligible for the study if they had persistent reflux symptoms, normal pH monitoring, and pathological Bilitec monitoring during PPI treatment. Upper gastrointestinal endoscopy and reflux symptom score were performed at the beginning of the study. Baclofen 5 mg three times daily was associated with treatment, and was increased by 5 mg every fourth day until a maintenance dose of 20 mg three times daily was reached. A reflux symptom questionnaire, ambulatory pH monitoring, and Bilitec monitoring were repeated four days later while PPI and baclofen were continued. All data are given as mean (SEM) or median (interquartile range) and were compared using the Student’s t test or the Mann-Whitney U test. Results: Sixteen patients (11 women, mean age 46 (3) years) with persistent heartburn or regurgitation for at least three months, in spite of PPI therapy, were included in the study. Erosive oesophagitis was present in seven patients (five with grade 1, two with grade 2). Under PPI therapy alone, all patients had normal acid exposure (0.3 (0.05; 2.2)% of the time) but pathological duodenal reflux exposure (13.8 (11.8; 15.5)% of the time). After addition of baclofen 20 mg three times daily, acid exposure was similar (0.4 (0.15; 2.3)% of the time; NS) but duodenal reflux had significantly decreased (6.1 (0.8; 10.3)% of the time; p<0.05). The number of duodenal reflux episodes and the number of longlasting duodenal reflux episodes (>5 minutes) was decreased, respectively, from 23 (14.5; 34) to 12 (5; 21) (p = 0.06) and from 5 (3; 8) to 2 (0.5;4.5) (p<0.05). The cumulative severity score for 14 reflux symptoms decreased from 10.3 (1.7) to 5.8 (1.3) (p<0.01). Four patients reported mild side effects of nausea or drowsiness. Conclusions: The GABAB receptor agonist baclofen improves duodenal reflux and associated reflux symptoms that persist during PPI therapy.

Influence of sumatriptan on gastric fundus tone and on the perception of gastric distension in man

BACKGROUND In animals, activation of 5-HT1 like receptors causes a relaxation of the gastric fundus through the activation of intrinsic inhibitory neurones. AIMS To investigate the effect of sumatriptan, an agonist at enteric neuronal 5-HT1receptors, on fasting fundus tone and sensitivity to gastric distension in man. METHODS A gastric barostat was used to study the effect of placebo and sumatriptan, 6 mg subcutaneously, on basal fundic tone in healthy subjects. In addition, stepwise isobaric and isovolumetric gastric distensions were performed and perception was measured before and after the administration of placebo and sumatriptan. RESULTS Placebo had no significant effects on gastric tone and on perception. Sumatriptan induced an immediate relaxation of the gastric fundus, reflected by an intragastric volume increase of 209 (39) ml (p<0.0005). After sumatriptan, intragastric pressures at the thresholds for perception or discomfort were not significantly altered. However, the intragastric volumes and the corresponding calculated wall tensions at perception and discomfort thresholds were significantly increased. CONCLUSIONS Administration of the 5-HT1 receptor agonist sumatriptan induces a relaxation of the gastric fundus in man, allowing larger intragastric volumes before thresholds for perception or discomfort are reached. The effects of sumatriptan on the gastric fundus may have therapeutic potential in the treatment of patients with functional dyspepsia.

Composition of the postprandial refluxate in patients with gastroesophageal reflux disease

OBJECTIVE:It is not known whether the characteristics of the postprandial refluxate in patients with gastroesophageal reflux disease (GERD) differ from those observed in normal subjects. The aim of this study was to characterize the postprandial refluxate in adult patients with GERD using combined intraluminal electrical impedance and pH measurements.METHODS:Postprandial gastroesophageal reflux was assessed in 16 patients with GERD and 15 controls. pH and intraluminal electrical impedance were used to identify acid and nonacid reflux of liquid, mixed (liquid + gas) or gas.RESULTS:Transient lower esophageal sphincter relaxations (TLESRs) and reflux of gastric contents were equally frequent in both groups. However, patients with GERD had more acid reflux [8 (4.7–10.5)/h vs 3.5 (2.6–6)/h, p < 0.05], and normal subjects had more nonacid reflux [5 (4.3–6.7)/h vs 3 (1–3.5)/h, p < 0.05]. Gas reflux was less frequent in GERD than in controls (51% vs 68%; p < 0.05). Pure liquid reflux, however, was more frequent (40% vs 26%, p < 0.05) and twice as likely to be acid in GERD. During TLESRs, liquid acid reflux was more frequent in GERD than in controls.CONCLUSIONS:TLESRs and reflux of gastric contents are similarly frequent in patients with GERD and controls. However, patients with GERD have more acid reflux and less nonacid reflux. Differences in the air–liquid composition of the refluxate may contribute to the higher rate of acid reflux observed in these patients.

Relevance of ineffective oesophageal motility during oesophageal acid clearance

Background: Oesophageal clearance of acid reflux consists of an initial volume clearance followed by neutralisation of the acidified mucosa by swallowed saliva (chemical clearance). Ineffective oesophageal motility (IOM), a frequent finding in patients with gastro-oesophageal reflux disease (GORD), has been claimed to underlie prolonged acid clearance by affecting oesophageal emptying and saliva transport. Intraluminal impedance allows non-radiological monitoring of movement of oesophageal liquids. Aims: To evaluate the relevance of IOM during oesophageal volume and chemical clearance using combined pH impedance measurements. Subjects: Impedance was validated with fluoroscopy to study volume clearance in three healthy subjects. Acid clearance tests were performed in 10 healthy subjects in the upright and supine positions, before and after oesophageal peristaltic disruption with sildenafil 50 mg. Methods: After instillation of an acid bolus, simultaneous manometry, pH, and impedance were used to study oesophageal motility, chemical clearance, and volume clearance, respectively. Results: Impedance allowed assessment of volume clearance accurately, showing a strong correlation with fluoroscopy (r2=0.89). Sildenafil provoked a graded impairment in oesophageal motility in healthy subjects without affecting saliva secretion. In the upright position, volume clearance was slightly prolonged only with severe IOM (>80% abnormal peristaltic sequences). In the supine position, severe IOM significantly prolonged chemical and volume clearance. Moderate IOM (30–80% abnormal peristalsis) had no effect. With normal peristalsis and moderate IOM, clearance times were similar in the upright and supine positions. Severe IOM however had a greater impact on clearance in the supine than in the upright position. Conclusion: Ineffective oesophageal motility has little effect on oesophageal clearance during upright acid reflux. With supine reflux, only severe IOM is associated with prolonged oesophageal clearance.

Effect of Erythromycin On Gastric-motility in Controls and in Diabetic Gastroparesis

The effect of three doses of erythromycin on interdigestive gastrointestinal motility and on plasma motilin levels was studied in healthy volunteers and patients with diabetic gastroparesis. Abnormalities of interdigestive motility were observed in 40% of the patients. In healthy volunteers, 40 mg erythromycin elicited a premature phase 3 that started in the stomach. In contrast to the spontaneous gastric phase 3, this erythromycin-induced phase 3 was not accompanied by a motilin peak. In patients with diabetic gastroparesis, 40 mg erythromycin induced a premature phase 3 in three patients, no response in one patient, and a burst of antral contractions in another patient. Doses of 200 and 350 mg erythromycin elicited a burst of antral phase-3-like contractions in both volunteers and patients, which was not accompanied by a motilin peak. This phase-3-like activity did not migrate to the small intestine and was not followed by a phase 1, but by a prolonged period of antral contractile activity. The number and amplitude of antral contractions after 200 or 350 mg erythromycin were significantly higher than after 40 mg. The motor patterns induced by different doses of erythromycin offer potential therapeutic applications.

Assessment of meal induced gastric accommodation by a satiety drinking test in health and in severe functional dyspepsia

Aims: Impaired gastric accommodation is a major pathophysiological mechanism in functional dyspepsia. The aim of the present work was to assess a satiety drinking test in the evaluation of accommodation in health and dyspepsia. Methods: Twenty five controls and 37 severely dyspeptic patients seen at a tertiary care centre completed a dyspepsia questionnaire, and gastric emptying and gastric barostat studies. The amount of liquid meal ingested at maximum satiety during a slow satiety drinking test was determined. In controls, we studied the influence of caloric density and of pharmacological agents that influence accommodation. Results: In patients, satiety scores were higher and maximum satiety occurred at lower calories (542 (50) v 1508 (53) kcal; p<0.0001). Six patients had required nutritional support, but excluding these did not alter the correlations. With increasing severity of early satiety, less calories were ingested at maximum satiety. In multivariate analysis, the amount of calories was significantly correlated to accommodation but not to gastric emptying or sensitivity. Sensitivity and specificity of the satiety test in predicting impaired accommodation reached 92% and 86%, respectively. At different caloric densities, ingested volume rather than caloric load determined maximum satiety. Pharmacological agents (sumatriptan, cisapride, erythromycin) affected the satiety test according to their effect on accommodation. Conclusion: A slow caloric drinking test can be used to evaluate accommodation and early satiety. It provides a non-invasive method of predicting impaired accommodation and quantifying pharmacological influences on accommodation.

Role of nitric oxide in the gastric accommodation reflex and in meal induced satiety in humans

Aims: In humans, impaired gastric accommodation is associated with early satiety and weight loss. In animals, accommodation involves activation of gastric nitrergic neurones. Our aim was to study involvement of nitric oxide in gastric accommodation and in meal induced satiety in humans. Methods: The effect of NG-monomethyl-l-arginine (l-NMMA) 4 mg/kg/h and 8 mg/kg/h on gastric compliance, on sensitivity to distension, and on gastric accommodation was studied with a barostat in double blind, randomised, placebo controlled studies. The effect of l-NMMA 8 mg/kg/h on meal induced satiety was studied using a drinking test. Results:l-NMMA had no significant effect on fasting compliance and sensitivity. Ingestion of a meal induced a relaxation of 274 (15) ml which was significantly smaller after l-NMMA 4 mg/kg/h (132 (45) ml; p=0.03) or l-NMMA 8 mg/kg/h (82 (72) ml; p=0.03). l-NMMA 8 mg/kg/h significantly decreased the amount of food ingested at maximum satiety from 1058 (67) to 892 (73) kcal (p<0.01). Conclusion: In humans, fasting gastric tone and sensitivity to distension are not influenced by nitric oxide synthase inhibition, but the gastric accommodation reflex involves activation of nitrergic neurones. Inhibition of nitric oxide synthase impairs accommodation and enhances meal induced satiety.

Somatostatin and the interdigestive migrating motor complex in man

The relationship between somatostatin and the interdigestive migrating motility complex (MMC) was determined in human volunteers. Motor activity was monitored manometrically by means of seven perfused catheters: four in the stomach, one in the duodenum, two in the jejunum. Blood samples were drawn every 10 min and radioimmunoassayed for motilin, pancreatic polypeptide and somatostatin. In four volunteers two activity fronts (AF) were recorded and somatostatin levels correlated to the manometric data. The start of an AF in the upper duodenum was accompanied by somatostatin peaks. Peak values, taken as the mean of the levels in the sample obtained after the start of an AF, the preceding sample and the next one, averaged 32 +/- 4 pM compared to 12 +/- 2 pM in the remaining period. In four volunteers somatostatin was infused in doses of 1.2, 2.4 and 4.8 pM/kg per min over three consecutive periods of 90 min, causing dose-dependent increments in plasma somatostatin levels of 7, 32 and 76 pM. In all volunteers and for all doses all gastric activity was completely inhibited. In the intestine phase 2 was abolished but phase 3 stimulated: during somatostatin infusion phase 3 occurred with an interval of 39 +/- 6 min. Motilin and PP levels were decreased. As the two lowest infusion doses caused increases in somatostatin levels that might be considered as physiological, somatostatin seems to have a physiological role in the regulation of the migrating motor complex. We propose that it facilitates the progressing of the activity front into the small intestine.