Independent cycles of exocrine pancreatic secretion, hormones and gastroduodenal motility in healthy fasting humans: reassessment of a complex partnership

Background: interdigestive pancreatic secretion cycles in close association with the phases of the migrating motor complex (MMC) and release of regulatory hormones. The extrinsically denervated pancreas exhibits an intrinsic cyclic rhythm. We hypothesized that this intrinsic rhythm is normally present in the intact human pancreas. Methods: 19 healthy males (age range 26–35 years) were studied after 12 h fasting. A manometry catheter was positioned with four pressure ports in the antrum and three in the duodenum, and motility was recorded for a complete MMC cycle or 5 h. Duodenal aspirates were sampled at 15-min intervals, and immediately analysed for amylase, lipase and chymotrypsin activities; enzyme outputs were calculated by standard marker perfusion techniques. Plasma levels of pancreatic polypeptide (PP) and motilin were also determined (RIA) at 15-min intervals. Results: output of amylase, lipase and chymotrypsin occurred in parallel. All phase III motility fronts were accompanied by a pancreatic secretory peak. However, in 12 subjects at least one secretory peak was observed without the concomitant occurrence of phase III. A total of 16 out of 51 secretory peaks identified across all subjects were independent (31%). These phase III-independent peaks of pancreatic secretion occurred in subjects with a longer MMC cycle (160 ± 19 min vs 102 ± 13 min, P < 0.05). Phase III-associated and -independent peaks had a similar magnitude (amylase output: 21.6 ± 3.9 kU h⁻¹ vs 21.1 ± 2.8 kU h⁻¹, respectively). Irrespective of MMC phases, antral but not duodenal motor activity was closely correlated with fluctuations of pancreatic secretion (P < 0.05). Cycling of PP and motilin were also closely coordinated with pancreatic enzymes, with a particularly tight link between endocrine and exocrine secretion from the pancreas. Conclusions: peaks of pancreatic secretion invariably occur when a phase III motor activity occurs, but additional secretory peaks occur without a concomitant phase III. Interdigestive phasic pancreatic secretion is tightly coordinated with PP and motilin release as well as with antral motor activity. An intrinsic rhythm of the pancreas distinct from other cyclic activity may be present in healthy humans, expressed as peaks of pancreatic secretion independent of a motor phase III.     

Effects of motilin on human interdigestive gastrointestinal and gallbladder motility, and involvement of 5HT3 receptors.

A plasma motilin peak and a partial gallbladder emptying precede the antral phase III of the migrating motor complex (MMC). To clarify the causal relationship between these factors, we aimed to study the role of motilin in interdigestive gastrointestinal and gallbladder motility simultaneously. In addition, involvement of 5HT3 receptors in the action of motilin was studied. Eight fasting, healthy male volunteers received 13Leu-motilin or 0.9% NaCl i.v. for 30 min, in randomized order on two separate occasions, from 30 min after phase III. Seven of the eight subjects also received the 5HT3 receptor antagonist ondansetron in addition to motilin, on a third occasion. Antroduodenal motility, gallbladder volumes and plasma motilin were measured. The interval between the start of infusion and phase III was 95.0 (57.6-155.7) min for saline, 28.7 (21.0-33.2) min for motilin, and 39.3 (30.7-100.5) min for motilin + ondansetron (P < 0.05). Gallbladder volume decreased by one-third from 10 min after both motilin and motilin + ondansetron infusion (P < 0.05), and returned to baseline with duodenal passage of phase III. In two of the seven subjects phase III was absent after motilin + ondansetron, although gallbladder volume decreased and only refilled during a later spontaneous phase III. We conclude that motilin induces both partial gallbladder emptying and antral phase III. Indeed, although gallbladder emptying clearly precedes antral phase III, ondansetron only prevented phase III in some cases and had no effect on gallbladder emptying. Passage of phase III in the duodenum makes an important contribution to gallbladder refilling.     

Reproducibility of antroduodenal motility during prolonged ambulatory recording

Ambulatory recording of antroduodenal manometry is a novel technique with several advantages over standard stationary manometry recording. Although the feasibility of this technique in clinical practice has been demonstrated, reproducibility of antroduodenal motility recorded by means of ambulatory manometry has not been investigated. To test whether antroduodenal motility recorded by ambulatory manometry is reproducible, we performed two 24-h ambulatory antroduodenal manometry recordings in 18 healthy subjects according to an identical protocol with a 1-week interval. Motility was recorded with a five-channel solid-state catheter. Postprandial motility was recorded after consumption of two test meals and interdigestive motility was recorded nocturnally. Postprandial antroduodenal motor characteristics were identical between the separate recordings. The number and duration of nocturnal cycles of the interdigestive migrating motor complex were also in the same range. Phase III characteristics in general were not different between the two recordings. Only minor alterations were observed in the duration of phase III motor fronts with duodenal onset and in the number of interdigestive cycles concluded by duodenal onset phase III. Parameters obtained by qualitative analysis were comparable between the two recordings. The antroduodenal motility pattern, when measured by ambulatory recording with solid state catheters under standardized conditions, is very reproducible.     

Postprandial peristalsis in the human duodenum

MMC-related retroperistalsis is a cyclical phenomenon in the duodenum linked to phase III. The aim of this study was to elucidate the direction of propagation of juxtapyloric duodenal pressure waves in the postprandial state in healthy humans and to compare with the contractions in the interdigestive phase II. Antroduodenal manometry was performed in 11 healthy subjects. Individual pressure waves propagating along a 6-cm duodenal segment were analysed with respect to the proportions of antegrade and retrograde propagation in the four duodenal subsegments (D1–D2) to (D4–D5), each subsegment being 15 mm. A test meal was given 30 min after a phase III had passed and motility recording continued for 60 min after the meal. During both the first and the second 30-min period of postprandial recording the proportion of retrograde pressure waves was larger just distal to the pylorus, (D1–D2), 40% (23–68) and 50% (23–68), respectively, compared to the distal part, (D4–D5), of the duodenal segment, 29% (12–30) and 10%(10–24), respectively (P < 0.05 and 0.01). In contrast, during late phase II of the interdigestive state antegrade pressure waves predominated in all four duodenal subsegments. We conclude that in the postprandial state a high proportion of the duodenal pressure waves (40–50%) is retrograde in the immediate juxtapyloric area while antegrade contractions predominate at a distance 5–6 cm distal to the pylorus. These manometric data together with recent observations of postprandial transpyloric liquid flow, indicate that retrograde duodenogastric propelling of contents may be an important determinant for the gastric emptying rate.     

Gastric myoelectrical and antroduodenal motor activity in patients with achalasia

Achalasia is a primary motor disorder of the oesophagus, in which the myenteric plexus is involved. However, abnormalities in other parts of the digestive tract have also been described in achalasia. Whether gastric myoelectrical and duodenal motor activity in these patients is also affected is unknown. Therefore, interdigestive and postprandial gastric myoelectrical and antroduodenal motor activity were studied in 11 patients with achalasia, using electrogastrography (EGG) and stationary antroduodenal manometry.
Electrogastrographically, no differences were found in the gastric frequency, incidence of dysrhythmias and postprandial/fasting power ratio. In the interdigestive state a lower propagation velocity of phase III episodes was found in the achalasia patients, but other parameters were unaltered. Postprandially, no differences were found in the number of pressure waves, in the amplitude of pressure waves or in antro-duodenal coordination.
We conclude that gastric myoelectrical activity and antral motor activity in patients with achalasia is normal, suggesting an intact extrinsic and intrinsic neural innervation of the distal stomach. Although postprandial duodenal motility is normal, a lower propagation velocity of phase III suggests involvement of the small intestine in achalasia.     

49Sibutramine accelerates gastric emptying, inhibits intestinal motility in conscious dogs

Fasting interdigestive myoelectric complex (IMC) and postprandial gastroduodenal myoelectric activities are regulated by motilin and leptin, respectively (L. Zhou 2005). This study is to observe whether electrical acupuncture points could increase fasting gastroduodenal IMC and postprandial activities, as well as increase the release of motilin and leptin. Methods: Bipolar platinum electrodes were implanted on the serosa of antrum and duodenum in 10 conscious Wistar rats to record IMC and postprandial digestive myoelectric activities. We acupunctured Points Zusanli (S‐36), Tianshu (S‐25), and Liangmen (S‐21) during phase I of IMC (Frequency 20~100 Hz, Strengthen 12~16 mA, period 90 min) and compared with non‐specific electric stimulation (sham acupuncture) group. Serum motilin and leptin level was measured by RIA. Results: (1) Acupuncture points could shorten markedly phase I of antroduodenal IMC and increase the period of phase III (P < 0.01). Acupuncture points also increased the number of spike burst of antral and duodenal slow wave by (121.24 ± 20.0)% and (97.34 ± 15.20)% (compared with control group, P < 0.01). In postprandial period, acupuncture points could increase the number of spike burst of antral and duodenal slow wave by (142.52 ± 23.50)% and (102.48 ± 13.25)% (compared with control group, P < 0.01). (2) When acupuncture points increased the number of spike burst of IMC in fasting state, serum motilin concentration also increased, which was (74.56 ± 8.20)% more than control group (P < 0.01). When acupuncture points with meal, serum leptin concentration increased with myoelectric activity, which was (139.84 ± 20.25)% more than control group (P < 0.01). There was no change of motilin and leptin concentration in non‐specific electric stimulation group. (3) Cutting off subphrenic vagus nerves could totally block the effect of acupuncture points on antroduodenal myoelectric activities and release of motilin and leptin. Conclusions: Acupuncture points could effectively increase fasting and postprandial antroduodenal myoelectric activities. This effect is mediated by motilin and leptin, respectively.     

Sham feeding disrupts phase III of the duodenal migrating motor complex in humans

The role of the vagus nerve in the control of the intestinal migrating motor complex (MMC) is unclear. This study aimed to evaluate the effect of physiological vagal stimulation with sham feeding on phase III of the MMC. Antroduodenal motility was recorded in six healthy volunteers. The first phase III was used as a control, and sham feeding was performed during the second phase III. The MMC was disrupted within 1.5 ± 0.4 min of sham feeding and its duration was shorter than the control phase III. Phase III propagation was inhibited in all subjects, most of them exhibiting no propagation beyond the third duodenal recording site. During sham feeding, the antrum exhibited transient phasic contractions in five out of six subjects. The duodenal motility index recorded for up to 30 min after the onset of the sham feeding was unchanged in five out of six subjects. We conclude that sham feeding consistently interrupted phase III of the duodenal MMC and induced antral contractions, but failed to provoke significant motor events in the duodenum.     

Mechanisms underlying duodeno-gastric reflux in man

BACKGROUND: Recent studies suggest that duodeno-gastro-oesophageal reflux (DGER) contributes to the occurrence of reflux oesophagitis and Barrett's oesophagus. The mechanisms underlying duodeno-gastric reflux (DGR), a prerequisite for DGER, are poorly understood. AIMS: To study the occurrence of DGR in relation to interdigestive and postprandial gastroduodenal motility. SUBJECTS AND METHODS: Ten healthy subjects underwent stationary gastroduodenal manometry with simultaneous duodenal and antral Bilitec recording 4 h before and 5 h after ingestion of a liquid meal. Eight volunteers underwent the same study, with administration of erythromycin postprandially. RESULTS: During the interdigestive phase II, all volunteers had short DGR episodes. Postprandially, DGR occurred in all subjects, on average 39 +/- 28 min after the start of the meal, and was cleared from the stomach after 242 +/- 23 min. Induction of increased antral motility and of a premature phase III, by administration of erythromycin, was associated with faster gastric DGR clearance. However, there was no direct temporal relationship between erythromycin-induced gastric phase III and erythromycin-induced DGR clearance. CONCLUSION: In healthy subjects, duodenogastric reflux occurs sporadically in the interdigestive state and is a normal phenomenon in the postprandial period. Erythromycin induces faster clearance of DGR from the stomach, which depends on enhanced antral contractile activity rather than premature phase III.     

Phase III of the migrating motor complex: associated with endogenous xenin plasma peaks and induced by exogenous xenin

Xenin, a recently discovered peptide produced by specific endocrine cells of the duodenal mucosa, has shown exocrine, endocrine and motility effects in the gastroenteropancreatic system in animal experiments. The aim of the present investigation was to study the role of xenin in the regulation of duodenojejunal motility of humans. Twenty-nine healthy volunteers from the hospital staff gave informed consent to participate in this investigation. In 20 volunteers, we determined plasma concentrations of immunoreactive xenin at 15 min intervals over a mean time period of 8 h fasting and recorded the interdigestive motor activity of the duodenojejunum. In a double-blind randomized crossover study on other nine subjects, synthetic xenin in a dose of 4 pmol kg-1 min-1 or placebo was infused for 10 min intravenously in the interdigestive period and postprandially after a liquid meal. Duodenojejunal motility was recorded simultaneously. Predefined interdigestive xenin plasma peaks were found to be significantly associated with the phases III of the migrating motor complex. In the interdigestive period, xenin induced a premature phase III activity in each volunteer; this was followed by a second phase III in five out of nine subjects. In the postprandial state, xenin significantly increased contraction frequency and the percentage of aborally propagated contractions. These findings suggest a role of the peptide hormone xenin in modulating interdigestive and postprandial duodenojejunal motility in humans.     

Differential effects of motilin on interdigestive motility of the human gastric antrum, pylorus, small intestine and gallbladder

Motilin was infused in this study with the aim of examining refractory characteristics for motilin stimulation of antral phase III and fasting gallbladder emptying. Moreover, interdigestive pyloric and small intestinal motility from duodenum to ileum were studied, as these may be target organs for motilin. Eight fasting, healthy male volunteers received, on separate subsequent days, repeated infusions of 13leucine-motilin (8 pmol (kg min)(-1) for 5 min) or saline at 30 min after phase IIIs in the duodenum. Interdigestive motility of the antrum, pylorus, duodenum, jejunum and ileum was measured for maximum 10 h by using a 21-lumen perfused catheter. Gallbladder motility was measured by ultrasonography. Motilin infusions induced antral phase IIIs, but only after a preceding phase III of duodenal origin. Under this condition, time-interval to phase III at the duodenal recording site was 30 +/- 13 (SEM) min after motilin, compared with 79 +/- 14 min after saline (P < 0.01), and compared with 121 +/- 13 min for motilin infusion following an antral phase III (P < 0.001). Motilin did not affect small intestinal motility or isolated pyloric pressure waves (IPPWs). However, the number of IPPWs was significantly affected by the origin of the preceding phase III, irrespective of whether motilin or saline was infused. Gallbladder volume decreased significantly within 10 min after each motilin infusion. We conclude that this study clearly demonstrates differential regional effects of motilin. Motilin initiates antral phase IIIs, but stimulation is subject to a refractory period which is clearly prolonged after a preceding antral phase III. Motilin induced gallbladder emptying, however, is not subject to a refractory state. Small intestinal phase IIIs as well as pyloric IPPWs are not affected by motilin.     

Gastrointestinal Electrical Activity in the Prairie Dog During Fasting, Feeding, and After High-Cholesterol Diet

This study describes the electromyographic characteristics of the gastrointestinal tract of prairie dogs, and examines the effects of a 1.2% cholesterol diet on intestinal myoelectrical activity. Twelve prairie dogs were implanted with eight bipolar electrodes in the stomach and small bowel. Recordings were obtained during fasting (n = 12), gastric instillation of food (n = 7), and chronic cholesterol feeding for 3 weeks (n = 7). Gastric slow waves had a frequency per minute of 4.9 ± 1. Intestinal slow waves had a frequency per minute of 19.1 ± 2 in the duodenum, and of 16.8 ± 1 in the ileum. The migrating myoelectric complex (MMC) was identified, with an interval between two consecutive phases I of 145 ± 33 minutes. The delivery of diets of equal weight into the stomach interrupted fasting activity for approximately 3 hours. This was followed by a duodenal phase III and return of the fasted pattern. The interval between the first two postprandial phases I of the MMC not only was shorter than in the fasted state, but also was shorter after cholesterol diet than after regular diet (89 ± 33 min versus 116 ± 24 min, p ≤ 0.05). Chronic feeding of cholesterol diet did not affect the length of the MMC. In conclusion, the gastrointestinal tract of prairie dogs exhibits slow waves, spike bursts, and an MMC that is interrupted by feeding. High-cholesterol diet does not induce significant changes in the pattern of electrical activity.     

Recovery of gastrointestinal motility from post-operative ileus in dogs: effects of Leu13-motilin (KW-5139) and prostaglandin F2α

Abstract Cyclical motor activity of the gastrointestinal tract, normally occurring during the interdigestive period in several mammals, is disrupted in the post-operative ileus. We determined the recovery from the disappearance of cyclical motor activity, from the stomach to the colon, in dogs after laparotomy with the force transducers. Moreover, we examined the effects of Leu¹³-motilin (KW-5139) and prostaglandin F2a (PGF2a), administered in the early post-operative period, on the gastrointestinal motility. Following laparotomy, the cyclical motor activity reappeared firstly in the ileum and the colon, then in the jejunum and the duodenum, and finally in the stomach. The reappearance time of the phase III contractions in the stomach was 105.8 ± 10.6 h (n = 4). In the early postoperative period, KW-5139 (0.5 μg kg^?1, i.v.) induced phase-III-like contractions, whereas PGF2a (50 μg kg^?1, i.v.) induced simultaneously occurring contractions over the whole gastrointestine. The treatment with KW-5139 (0.5 μg kg^?1, i.v.) four times (twice daily on the first and the second post-operative day) significantly (P < 0.05) shortened the time required to recover the phase III contractions in the stomach (64.2 ± 2.2 h, n = 4), whereas that with PGF2a (50 μg kg^?1, i.v.) four times did not (111.3 ± 17.2 h, n = 4). The present results indicate that, after laparotomy, the cyclical motor activity recovers faster in the distal intestine than in the proximal intestine and the stomach, and that KW-5139, but not PGF2a, shortens the reappearance time of the phase III activity in the stomach.     

The migrating motor complex modulates intestinal motility response and rate of gastric emptying of caloric meals

Abstract The present study elucidates whether the phase of the migrating motor complex (MMC) present at the moment of food intake modulates postprandial motor response and rate of gastric emptying of caloric meals. Eight healthy male volunteers with a mean age of 26 years were examined twice. During water-perfused gastroduodenal manometry, a liquid meal with paracetamol added as a marker was orally administered during phase I and late phase II. Paracetamol appeared in serum 14.1 ± 3.8 min and 9.1 ± 4.0 (mean ± SD) min, respectively, after intake of the meal (P < 0.02). The area under the curve of s-paracetamol until 25 min after intake was 232 ± 169 μmoll_-1 min and 362 ± 130 (P < 0.05), respectively. When taken during late phase II, a phase III-like activity occurred within 2.1 ± 1.3 min in the duodenum, and was succeeded by quiescence. During phase I, the meal invariably initiated irregular contractions within 4 min. The phase of MMC during which a caloric meal is ingested modulates duodenal motor response and rate of gastric emptying during the initial postprandial period. Initial postprandial motor activity thus represents the combined effect of nutrient stimulation and the underlying enteric biorhythm as reflected by phase of MMC.     

Effect of cholecystokinin octapeptide and somatostatin on the mechanical and electrical activity of the colon of conscious dogs

Intraluminal pressure and electrical activity of the colon of conscious dogs were recorded using silver bipolar electrodes and a pressure transducer. Two phases in the mechanogram of the transverse colon were observed: a quiescent phase (lack of contractions) lasting 12.05 ± 0.54 min and a contractile phase lasting 14.46 ± 0.88 min. The electrical activity was characterized by a quiescent phase (only slow waves in the electrogram) with a duration of 13.55 ± 1.73 min. Groups of spike potentials bursting in the rhythm of the slow waves appeared during the activity phase lasting 15.60 ± 2.02 min. Cholecystokinin octapeptide (CCK₈) (10–20 ng/kg i.v.) significantly increased the duration of 1–3 active phases and shortened the duration of the quiescent phases. The percentage of slow waves with spike potentials during the active phase in the electro-gram increased. Colonic contractions also increased, i.e. CCK₈ evoked an enhanced motility of the colon. Somatostatin (1–2 μg/kg i.v.) increased by two to three times the duration of the quiescent phases. Atropine (50–100 μg/kg i.v.) or somatostatin (1–2 μg/kg i.v.) inhibited both the spontaneous and the CCK₈-induced colonic motility. It is suggested that the inhibitory effect of somatostatin on spontaneous and CCAV induced colonic activity in conscious dogs is mediated by a decrease in cholinergic neurotransmission.     

Ghrelin regulates gastric phase III-like contractions in freely moving conscious mice

Abstract  In humans and dogs, motilin regulates phase III contractions of migrating motor complex (MMC) in the interdigestive state, while ghrelin regulates MMC in rats. It still remains unclear whether ghrelin regulates phase III contractions of the mouse stomach. A miniature strain gauge transducer was sutured on the antrum to detect circular muscle contractions and gastric contractions of the interdigestive state were evaluated. Effects of ghrelin, a ghrelin receptor antagonist, and atropine on spontaneous gastric contractions were studied in freely moving conscious mice. Similar to the rat stomach, phase III-like contractions were observed in the interdigestive state, which disappeared immediately after the feeding. Ghrelin augmented spontaneous phase III-like contractions, while growth-hormone secretagogue receptor antagonists and atropine abolished the occurrence of spontaneous phase III-like contractions. The spontaneous phase III-like contractions were no more observed in vagotomized mice. These results suggest that ghrelin regulates phase III-like contractions in mice stomach via its own receptors. Ghrelin-induced gastric phase III-like contractions are mediated via vagal cholinergic pathways in mice. Our recording system of mice gastric motility may be useful to study the functional changes in gene knockout mice, in the future.     

Acute intraduodenal bile salt depletion leads to strong gallbladder contraction, altered antroduodenal motility and high plasma motilin levels in humans.

Cholecystokinin is the main hormone involved in postprandial gallbladder contraction. There is also considerable gallbladder contraction in the fasting state, associated with phase III of the gastrointestinal migrating motor complex and release of the hormone motilin. It has been proposed that intraduodenal bile salts exert a negative-feedback control on postprandial cholecystokinin release and resulting gallbladder contraction. We wanted to elucidate whether a similar control mechanism on gallbladder contraction exists in the fasting state. We therefore performed gallbladder ultrasonography and 24-h antroduodenal motility registrations and determined plasma cholecystokinin and motilin levels in six healthy subjects before and after acute (4 g) and chronic (8 days; 8 g day(-1)) oral cholestyramine. Acute cholestyramine strongly decreased gallbladder volumes and increased motilin without changed cholecystokinin levels. There was a negative relationship between gallbladder volumes and plasma motilin levels. Although there was a persistent fasting pattern of antroduodenal motility, its cycle length was increased (P < 0.03) with markedly longer phase II (P < 0. 005). Fasting gallbladder volumes 24 h later were still strongly decreased but gradually increased to pretreatment levels. Before and after 8 days cholestyramine, interdigestive and postprandial gallbladder emptying, intestinal migrating motor complex and hormone levels did not differ. We conclude that acute (but not chronic) intraduodenal bile salt depletion with cholestyramine affects gallbladder and antroduodenal motility, possibly partly related to motilin release.     

The Rectal Motor Complex

To identify patterns of motility in the rectum of humans during the day while awake and at night during sleep, and to correlate the patterns with interdigestive duodenal motor complexes and sleep cycles, intraluminal rectal pressure was recorded in 12 healthy subjects (five female, seven male; mean age, 28 years) using a flexible, noncompliant, silastic catheter and an Arndorfer system with a single perfused rectal port 6 cm above the anorectal junction, duodenal motility was recorded via a perfused oroduodenal tube, and sleep stages were determined electroencephalographically. Discrete bursts of rectal motor waves, called rectal motor complexes (RMCs), were identified on 72 occasions in 11 of the 12 subjects during 157 hours of recording. The RMCs were found in daytime during fasting or after feeding (0.2 ± 0.1 RMCs/hour), but were more easily and frequently identified at night during sleep (0.8 RMCs/hour, p < .01). The complexes had a distinct onset, a mean duration ± SEM of 9.5 ± 1.0 minutes, and a distinct decline. Within each complex, the waves had a mean frequency of 3.8 ± 0.3 per minute and a mean amplitude of 19 ± 2.7 mm Hg. Complex-to-complex intervals at night averaged 74 ± 15 minutes. No clear-cut temporal association was present between the complexes and phase III of interdigestive duodenal motor complex or the REM stage of sleep.     

Evaluation of the refractory period of the human migrating motor complex through induction of premature Phase III

We examined the refractory period of the migrating motor complex and the ability of somatostatin to increase the oscillation frequency of the complex through the initiation of premature phase HI activity. Fifteen normal human subjects were studied by means of a naso-intestinal motility probe and divided in three groups of five subjects each. After recording three spontaneous migrating motor complexes, somatostatin was infused at a time interval from the last spontaneous Phase III that corresponded to 10% (Group A), 20% (Group B) and 30% (Group C) of the previous mean cycle length. Eleven successive somatostatin infusions were given with the interval between each infusion being altered in a fashion designed to identify the refractory period of the MMC. The results show a spontaneous cycle length of 121.3 ± 15.8 min (mean ± SD). When given at 10% (12 min) of the previous cycle somatostatin did not elicit any response, when given at 20% (24 min) of the cycle somatostatin induced a premature Phase III activity in three of five subjects; when given at 30% (36 min) of the cycle somatostatin induced a premature Phase III in all five subjects examined. Each somatostatin infusion was associated with the onset of a premature Phase III activity in 50% of the trials when the time interval was 20% of the ideal cycle (24 ± 4 min). When the time interval was increased to 30% of the ideal cycle a premature Phase III could be recorded after each somatostatin infusion in all trials. Motilin and pancreatic polypeptide plasma levels were significantly lowered by somatostatin. It is concluded that the migrating motor complex of the human gastrointestinal tract shows an absolute and a relative refractory state. Repetitive infusions of somatostatin for short periods may increase the occurrence of Phase III activity up to four-fold.     

A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis

Central neuropathic pain (CNP) occurs in many multiple sclerosis (MS) patients. The provision of adequate pain relief to these patients can very difficult. Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP. Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment, in a double-blind manner, for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain. This parallel-group phase of the study was then followed by an 18-week randomized-withdrawal study (14-week open-label treatment period plus a double-blind 4-week randomized-withdrawal phase) to investigate time to treatment failure and show maintenance of efficacy. A total of 339 patients were randomized to phase A (167 received THC/CBD spray and 172 received placebo). Of those who completed phase A, 58 entered the randomized-withdrawal phase. The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met, with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo (p = 0.234). However, an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point (p = 0.046). During the randomized-withdrawal phase, the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray, with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group (p = 0.04). The mean change from baseline in Pain Numerical Rating Scale (NRS) (p = 0.028) and sleep quality NRS (p = 0.015) scores, both secondary endpoints in phase B, were also statistically significant compared to placebo, with estimated treatment differences of ?0.79 and 0.99 points, respectively, in favor of THC/CBD spray treatment. The results of the current investigation were equivocal, with conflicting findings in the two phases of the study. While there were a large proportion of responders to THC/CBD spray treatment during the phase A double-blind period, the primary endpoint was not met due to a similarly large number of placebo responders. In contrast, there was a marked effect in phase B of the study, with an increased time to treatment failure in the THC/CBD spray group compared to placebo. These findings suggest that further studies are required to explore the full potential of THC/CBD spray in these patients.     

12Effects of synchronized intestinal electrical stimulation on small intestinal motility in dogs

Our previous studies showed that synchronized gastric electrical stimulation enhanced antral contractions, accelerated gastric emptying in dogs. It has never been reported whether synchronized electrical stimulation could improve small intestinal motility. The aim of this study was to investigate the effects of synchronized intestinal electrical stimulation (SIES) on small bowel motility in both fasting and fed states in dogs. Methods: Five healthy female dogs (18–24 kg) were equipped with a duodenal cannula for the measurement of small bowel motility using manometry. Two pairs of bipolar electrodes were implanted on the small intestinal serosa with an interval of 25 cm; the first one was 10 cm beyond the pylorus and used for stimulation. The experiment was consisted of four sessions in each dog with a randomized order. In the fasting state, 20 min after occurrence of phase III, SIES was initiated and maintained for 45 min, small bowel motility was recorded during the entire experiment, and no stimulation was performed in the control session. In other two sessions, dogs were fed with solid meal at the beginning of the experiment; glucagon (0.1 mg kg^­1) was injected 20 min after feeding, SIES was initiated at the same time for 20 min followed by 20 min recovery period. The stimulus was composed of train of pulses with on‐time of 0.5 s, frequency of 20 Hz, pulse width of 2 ms and amplitude of 4 mA. Results: 1). In the fasting state, SIES induced small intestinal contractions during phase I. The motility index was 5.2 ± 0.6 in the control session and significantly increased to 10.3 ± 0.7 with SIES (P = 0.003). 2). In the fed state, glucagon substantially and significantly inhibited small intestinal motility. The motility index was 11.3 ± 0.7 after feeding and reduced to 3.4 ± 0.5 with glucagon injection (P < 0.001). SIES significantly enhanced glucagon‐induced small intestinal postprandial hypomotility. The motility index was 3.4 ± 0.5 in the control session and increased to 6.0 ± 0.3 with the presence of SIES (P = 0.03). Conclusions: Intestinal electrical stimulation synchronized with intestinal slow waves induces intestinal contractions during phase I and enhanced small intestinal postprandial hypomotility induced by glucagon. SIES may have the therapeutic potential for treating small intestinal motility disorders. (Supported by a grant from American Diabetes Association).