[Gastroparesis: pathophysiology and management]. / Gastroparésie : physiopathologie et traitement.

The prevalence of gastroparesis is increasing. Diabetes mellitus and sequelae of œsogastric surgery are the two main causes of gastroparesis. In some patients, gastroparesis seems a postinfectious disease after its sudden onset after a viral infection. In about one third of the patients, gastroparesis is considered as idiopathic. In diabetic patients, gastroparesis impairs glycaemic control. Due to the low positive predictive value of symptoms, a gastric emptying study is often necessary to confirm a suspected diagnosis of gastroparesis. The symptomatic efficacy of erythromycin is higher than that of other prokinetics. This efficacy is higher when erythromycin is given intravenously. Hyperglycaemia impairs this symptomatic effect. Due to a tachyphylaxis phenomenon, the clinical effect of erythromycin decreases with the duration of treatment. In refractory gastroperis, either duodenal or jejunal enteral feeding, or high-frequency gastric electrical stimulation are possible therapeutic options while endoscopic alternatives (intrapyloric botulinum injection or pyloric balloon dilation) give unsatisfactory results.

GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility.

There is an urgent clinical need for a safe, efficacious stimulant of gastric emptying; current therapies include erythromycin (an antibiotic with additional properties which preclude chronic use) and metoclopramide (a 5-hydroxytryptamine type 4 receptor agonist and an antagonist at brain D2 receptors, associated with movement disorders). To move away from the complex motilide structure of erythromycin, a small molecule motilin receptor agonist, GSK962040, was identified and characterized. The compound was evaluated using recombinant human receptors, rabbit and human isolated stomach preparations known to respond to motilin and in vivo, by measuring its ability to increase defecation in conscious rabbits. At the human motilin receptor, the pEC50 (the negative logarithm to base 10 of the EC50 value, the concentration of agonist that produces 50% of the maximal response) values for GSK962040 and erythromycin as agonists were, respectively, 7.9 and 7.3; GSK962040 had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L(-1)-10 micromol L(-1) caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 +/- 47% at 3 micromol L(-1). In human-isolated stomach, GSK962040 10 micromol L(-1), erythromycin 10 micromol L(-1) and [Nle13]-motilin 100 nmol L(-1), each caused muscle contraction of similar amplitude. In conscious rabbits, intravenous doses of 5 mg kg(-1) GSK962040 or 10 mg kg(-1) erythromycin significantly increased faecal output over a 2-h period. Together, these data show that GSK962040, a non-motilide structure, selectively activates the motilin receptor. Simplification of the structural requirements to activate this receptor greatly facilitates the design of potentially new medicines for gastroparesis.

Mitemcinal (GM-611), an orally active motilin receptor agonist, accelerates colonic motility and bowel movement in conscious dogs.

The prokinetic effects of mitemcinal, an orally active motilin receptor agonist, on the lower gastrointestinal tracts were investigated in conscious dogs. Oral administration of mitemcinal (0.1-1 mg/kg) stimulated colonic motility, which was measured by chronically implanted force-transducers, as well as gastric motility in a dose-dependent manner. The gastrointestinal contractile activities induced by mitemcinal were inhibited by the continuous intravenous infusion of GM-109, a selective motilin receptor antagonist. Oral administration of mitemcinal (0.3-3 mg/kg) also accelerated bowel movement after feeding without inducing diarrhea in dogs. The results demonstrate that mitemcinal stimulates colonic motility via motilin receptors and the effect of mitemcinal on colonic motility may reflect bowel movement after feeding. Thus, mitemcinal could be a promising agent for treatment of not only the upper but also the lower gastrointestinal motility disorders.

Prokineticin-2, motilin, ghrelin and metoclopramide: prokinetic utility in mouse stomach and colon.

The ability of agents described as gastrointestinal prokinetics (prokineticin-2, [Nle(13)]-motilin, ghrelin), to modulate nerve-mediated contractions of mouse isolated stomach and colon was determined and compared with the prokinetic and 5-HT(4) receptor agonist, metoclopramide. Circular muscle preparations were electrically field-stimulated (EFS) to evoke cholinergically mediated contractions. Metoclopramide 10-100 microM facilitated EFS-evoked contractions in forestomach (n = 5-11, P < 0.05); 1 mM inhibited. Metoclopramide had no effects in colon, apart from 100 microM which reduced contractions. Prokineticin-2 0.001 nM-0.1 microM (n = 3-7) or [Nle(13)]-motilin 0.1 nM-1 microM (n = 4-8) had no effects in forestomach or colon. Ghrelin 0.01-1 microM facilitated EFS-evoked contractions in forestomach (n = 5-7, P < 0.05) but not in colon (n = 5-8). We conclude that ghrelin and metoclopramide facilitate excitatory nerve activity because neither affected inhibitory responses to EFS in the presence of atropine, or contractions to carbachol. Further, prokineticin-2 and [Nle(13)]-motilin are unlikely to exert gastric prokinetic activity in this species, the inactivity of the latter being consistent with an absence of the motilin receptor in rodents.

Demonstration of a specific site of covalent labeling of the human motilin receptor using a biologically active photolabile motilin analog.

The motilin receptor belongs to a group of class I G protein-coupled receptors that also includes the growth hormone secretagogue and ghrelin receptors. These represent clinically useful targets for pharmacotherapy. Their potentially unique structures and the molecular basis of their binding are not yet clear. We previously reported the initial affinity labeling of a region within this receptor (a cyanogen bromide fragment extending from the first to the second extracellular loop) using a position 1 photolabile motilin analog. To extend our understanding of the molecular basis of motilin binding, we have developed an additional radioiodinatable motilin analog probe having site of covalent attachment in position 5. This was a full agonist that bound to the motilin receptor specifically and with high affinity, and that efficiently established a single covalent bond to its receptor. Sequential chemical and enzymatic cleavage of labeled wild-type and mutant motilin receptor constructs established that the region of labeling was within the third extracellular loop. This was further localized to Phe(332) using radiochemical Edman degradation sequencing. These data provide the first spatial approximation constraint that can be used in the docking of this peptide ligand to its receptor. We hope that a series of such constraints can be determined to provide adequate structural information to begin to elucidate the conformation of this agonist-bound receptor and to ultimately be useful in the rational design of drugs acting at this important target.

Pharmacokinetic and pharmacodynamic studies of SK-896, a new human motilin analogue, in healthy male volunteers.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of SK-896 ([Leu(13)]motilin-Hse) after intravenous administration to healthy male volunteers. DESIGN AND SETTING: This was a non-blinded phase I study. PARTICIPANTS: Thirty male Japanese volunteers (mean age 30.6 years) participated in this study. The volunteers were divided into five groups receiving different doses of SK-896. METHODS: The pharmacokinetics and pharmacodynamics of SK-896 were evaluated after single intravenous infusions of doses of 10, 20, 40 and 80 micro g over 20 minutes to fasting volunteers, or after multiple intravenous infusions (twice a day for 3 days) of doses of 40 micro g over 20 minutes to volunteers in the morning (fasting) and afternoon (non-fasting). Plasma concentrations of immunoreactive SK-896 were determined by radioimmunoassay, and borborygmus was measured as an indicator of drug effect (acceleration of gastrointestinal motility) with an improved Holter electrocardiograph attached to the abdomen. RESULTS: When SK-896 was given by single intravenous infusion at each dose, the plasma concentration of immunoreactive SK-896 rapidly increased to a maximum at the end of the infusion. After the infusion was completed, plasma concentrations declined monoexponentially with an elimination half-time of 4.57-5.64 minutes. The area under the concentration-time curve and the maximum concentration (1.04-9.08 microg-equiv./L) increased in proportion to the dose, and there were no dose-related changes in plasma clearance (7.59-9.34 mL/min/kg), mean residence time (7.83-9.51 minutes) or steady-state volume of distribution (62.9-73.9 mL/kg), indicating that SK-896 plasma concentrations can be described by a linear pharmacokinetic model within the dose range of the present study. After beginning administration, an increase in borborygmus was observed. At doses of 40 and 80 micro g, the borborygmus did not continue even when the plasma concentration was maintained, suggesting that tachyphylaxis occurs at a higher dose. When SK-896 was given as multiple intravenous infusions, the pharmacokinetics did not change with repeated administration. The intensity of borborygmus was low with afternoon administration, reaching only one-third to one-half that with morning administration, suggesting that, like native motilin, SK-896 does not stimulate gastrointestinal motility in the non-fasting state. CONCLUSIONS: The appropriate dose and administration period (fasting or non-fasting) are important factors in stimulating and maintaining gastrointestinal motility when treating gastroparalysis with SK-896.

Effects of SK-896, a new human motilin analogue ([Leu13]motilin-Hse), on postoperative ileus in dogs after laparotomy.

The effects of SK-896, a new human motilin analogue ([Leu13]motilin-Hse), on digestive tract motility in postoperative ileus were evaluated in a dog model of ileus after laparotomy. SK-896 was intravenously administered at 0.17, 0.33 and 0.67 microg/kg starting soon after operation and then at 6-h intervals, for a total of 9 times. SK-896 progressively, dose-dependently and significantly increased the duodenal motility from 1 h after operation. The recovery time of the gastrointestinal-interdigestive migrating complex (GI-IMC) activity, which is an indicator of normal gastrointestinal tract activity after laparotomy, was 56.5 +/- 5.0 h in the control group. SK-896 significantly shortened this recovery time. On the other hand, the plasma SK-896 concentrations declined diexponentially after administration, and can be described by a linear pharmacokinetic model within the dose range used. In addition, the pharmacokinetics of SK-896 did not change significantly at any postoperative time. There was no correlation between the plasma SK-896 concentrations and the intensity of duodenal motility, because the activity in the duodenum decreased transiently 13 h after laparotomy and increased with time thereafter. The changes in the activity are considered to reflect the progressive changes in the state of ileus. In conclusion, SK-896 increased the duodenal motility significantly, shortening the recovery time of GI-IMC-like activity in dogs with post-laparotomy ileus. Therefore, it is expected from these results that SK-896 would be useful and effective for the treatment of gastroparalysis after abdominal surgery.

Gastroprokinetic effect and mechanism of SK-896, a new motilin analogue, during the interdigestive period in conscious dogs.

SK-896 [(Leu(13))motilin-Hse] is a new human motilin analogue synthesized from Escherichia coli using a biotechnological method. We investigated the gastrointestinal motor-stimulating effect of SK-896 and the mechanism of this effect using implanted force transducers in conscious dogs. Infusion of SK-896 during phase I in the interdigestive state induced interdigestive migrating contractions like motility in the gastroduodenum. The motility index (MI(0-20)) of gastric antrum motor activity induced by SK-896 was increased dose dependently (r = 0.830, p < 0.001), and the MI(0-20) induced by SK-896 at a dose of 0.25 microg/kg/h for 20 min was the same as that for spontaneous phase III contractions. The SK-896-induced MI(0-20) was significantly decreased by atropine, hexamethonium, dopamine, granisetron, and yohimbine. Conversely, ketanserin, phentolamine, timolol, and naloxone did not have significant effects on SK-896-induced MI(0-20). The effects of these drugs on human motilin (0.25 microg/ kg/h for 20 min) induced MI(0-20) were the same as those of SK-896. These results indicate that SK-896 induces gastrointestinal motility during the interdigestive period in dogs with regulation of acetylcholine release from the cholinergic nerve terminal via the parasympathetic nervous system in the same fashion as human motilin.

The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound.

Prucalopride is a novel enterokinetic compound and is the first representative of the benzofuran class. We set out to establish its pharmacological profile in various receptor binding and organ bath experiments. Receptor binding data have demonstrated prucalopride's high affinity to both investigated 5-HT(4) receptor isoforms, with mean pK(i) estimates of 8.60 and 8.10 for the human 5-HT(4a) and 5-HT(4b) receptor, respectively. From the 50 other binding assays investigated in this study only the human D(4) receptor (pK(i) 5.63), the mouse 5-HT(3) receptor (pK(i) 5.41) and the human sigma(1) (pK(i) 5.43) have shown measurable affinity, resulting in at least 290-fold selectivity for the 5-HT(4) receptor. Classical organ bath experiments were done using isolated tissues from the rat, guinea-pig and dog gastrointestinal tract, using various protocols. Prucalopride was a 5-HT(4) receptor agonist in the guinea-pig colon, as it induced contractions (pEC(50)=7.48+/-0.06; insensitive to a 5-HT(2A) or 5-HT(3) receptor antagonist, but inhibited by a 5-HT(4) receptor antagonist) as well as the facilitation of electrical stimulation-induced noncholinergic contractions (blocked by a 5-HT(4) receptor antagonist). Furthermore, it caused relaxation of a rat oesophagus preparation (pEC(50)=7.81+/-0.17), in a 5-HT(4) receptor antagonist sensitive manner. Prucalopride did not cause relevant inhibition of 5-HT(2A), 5-HT(2B), or 5-HT(3), motilin or cholecystokinin (CCK(1)) receptor-mediated contractions, nor nicotinic or muscarinic acetylcholine receptor-mediated contractions, up to 10 microM. It is concluded that prucalopride is a potent, selective and specific 5-HT(4) receptor agonist. As it is intended for treatment of intestinal motility disorders, it is important to note that prucalopride is devoid of anti-cholinergic, anticholinesterase or nonspecific inhibitory activity and does not antagonise 5-HT(2A), 5-HT(2B) and 5-HT(3) receptors or motilin or CCK(1) receptors.

Change of the involvement of 5-HT3 receptor in the gastric motor stimulating actions of KW-5139 (Leu13-motilin acetate) in the recovered and post-operative periods in dogs.

We have previously reported that KW-5139, a motilin analogue, evokes gastrointestinal motor stimulating action in the post-operative period as well as in the recovered period of conscious dogs. In this report, we compared the mechanisms of the KW-5139-induced contractions in the post-operative period with those in the recovered period using beagle dogs implanted force transducers in the gastric antrum, duodenum, jejunum, ileum and colon. In addition, we also examined the mechanisms of the prostaglandin F2alpha-induced contractions in both periods. The gastric contractions evoked by KW-5139 (0.5 microg kg(-1), i.v.) were inhibited by the pretreatment of ondansetron (0.1 mg kg(-1), i.v.), a 5-HT3 receptor antagonist, in the recovered period, but were not affected in the post-operative period even by higher doses of ondansetron (0.3-1 mg kg(-1), i.v.). The KW-5139-induced contractions in the small and large intestine were not inhibited by ondansetron in the both periods. The contractions evoked by KW-5139 (0.5 microg kg(-1), i.v.) in the gastric antrum, duodenum, jejunum and colon were significantly inhibited by the pretreatment with atropine (0.05 mg kg(-1), i.v.), a muscarinic receptor antagonist, in the recovered period as same extent as in the post-operative period. The contractions evoked by prostaglandin F2alpha (50 microg kg(-1), i.v.) in the any recording sites were not affected by the pretreatment with ondansetron (0.1 mg kg(-1), i.v.) in the recovered period. On the other hand, atropine (0.05 mg kg(-1), i.v.) tended to inhibit the gastric and colonic contractions. These effects of ondansetron and atropine on the prostaglandin F2alpha-induced contractions were not different between in the post-operative and recovered periods. The present results indicate that 5-HT3 receptors are involved in the KW-5139-induced motor stimulating action in the recovered period but not in the post-operative period. The mechanisms of the alteration were discussed.

Three-dimensional structure-activity relationship analysis between motilin and motilide using conformational analysis and a novel molecular superposing method.

Motilide, an erythromycin derivative, has been shown to equal activity to that of motilin as an agonist at the motilin receptor. However, there is little information on the three-dimensional (3D) structure-activity relationship between these two molecules, largely because they have quite different structures. In this study, we applied a rational computational procedure consisting of conformational analysis and a novel superposing method to investigate the 3D structure-activity relationship between motilide and motilin. We propose common 3D structural features between these molecules, which may be important for their similar activity.

The effect of SK-896 on post-operative ileus in dogs: gastrointestinal motility pattern and transit.

The aim of this study was to investigate the effect of SK-896 (Phe-Val-Pro-Ile-Phe-Thr-Try-Gly-Glu-Leu-Gln-Arg-Leu-Gln-Glu-Lys-Glu- Arg-Asn-Lys-Gly-Gln-Hse), a new motilin analogue, on gastrointestinal motility and transit in dogs with post-operative ileus, and to compare the effects of this agent on these parameters with the effects of prostaglandin F(2alpha), a well-known gastroprokinetic agent. We used chronically implanted force transducers to measure motility and radiography of radio-opaque markers to measure transit. Infusion of SK-896 1 microgram/kg/h, for 20 min twice a day induced interdigestive migrating contractions-like motility. Infusion of prostaglandin F(2alpha), 20 microgram/kg/h, for 1 h twice a day induced continuous contractions in the distal part of the small intestine. The time of first appearance of interdigestive migrating contractions in the stomach (gastric-interdigestive migrating contractions) and the gastric emptying time of the solid marker with the administration of SK-896 were significantly less than those noted with the administration of prostaglandin F(2alpha). It appears that gastric-interdigestive migrating contractions play an important role in the transit of substances, especially solid substances, in the gastrointestinal tract. We conclude that SK-896, which induced gastric-interdigestive migrating contractions, is effective to induce early recovery from post-operative ileus.

Neural and muscular receptors for motilin in the rabbit colon.

Motilin receptors were classically recognized in the gastroduodenal area, where they help to regulate interdigestive motility. More recently, motilin receptors were identified in the colon where their biologic significance remains unclear. We aimed here to characterize the motilin receptors of the rabbit colon. Distal colon and duodenum were obtained from sacrificed rabbits. Tissues homogenized by Polytron were submitted to differential centrifugation to obtain neural synaptosomes or smooth muscle plasma membranes enriched solutions. Motilin binding to these membranes was determined by the displacement of (125)I MOT by the native peptide MOT 1-22, or by peptide analogues MOT 1-12 [CH(2)NH](10-11) or GM-109 and by erythromycin derivative GM-611. Motilin binding capacity was maximum in colon nerves (49.5 +/- 6.5 fmol/mg protein vs. 19.9 +/- 2.5 in colon muscles or 9.4 +/- 2.8 and 6.6 +/- 1.2 in duodenal muscles and antral nerves respectively); all tissues expressed similar affinity for MOT 1-22, and the motilin agonist GM-611 bound equally to neural or muscle tissues from the rabbit colon; the synthetic antagonist MOT 1-12 [CH(2)NH](10-11) showed greater affinity for colon nerves than for colon muscles (plC50: 7.23 +/- 0.07 vs. 6.75 +/- 0.03). Similar results were obtained with the peptide antagonist GM-109; receptor affinity toward MOT 1-12 [CH(2)NH(10-11)] was always five times superior in neural tissues, whether they came from the colon or the antrum, than in muscle tissues, whether they were obtained from colon or from duodenum. Motilin receptors are found in very high concentration in nerves and in muscles from rabbit colon; specific motilin receptor subtypes are identified in nerves (N) and muscles (M) of the rabbit colon; N and M receptor subtypes seem independent of the organ location.

In vitro pharmacological profile of SK-896, a new human motilin analogue.

SK-896 ([Leu(13)]motilin-Hse) is a new human motilin analogue synthesized by Escherichia coli using a biotechnological method. We investigated the binding of SK-896 to motilin receptors and the contractile effect of SK-896 on smooth muscle preparations isolated from the gastrointestinal tract and various regional organs in order to clarify its in vitro pharmacological profile. SK-896 inhibited the binding of (125)I-human motilin to rabbit gastroduodenal motilin receptors with the same potency as unlabeled human motilin. The IC(50) values of SK-896 and human motilin were 3.5 +/- 1.5 and 3.1 +/- 1.8 nmol/l, respectively. The K(d) of human motilin was 3.0 +/- 1.5 nmol/l, and the Ki of SK-896 was 3.4 +/- 1.5 nmol/l. SK-896 induced contraction of smooth muscle preparations isolated from rabbit duodenum in a concentration-dependent manner. However, there was no effect of SK-896 on duodenal preparations isolated from the dog and the rat. SK-896 thus exhibited species specificity in its contractile effect. We next investigated the effect of SK-896 on various smooth muscle preparations isolated from rabbit gastrointestinal tract, trachea, bladder, gallbladder, uterus, vas deferens and artery. Results showed that SK-896 induced contraction of smooth muscle preparations isolated from gastrointestinal tract, with potencies in the order duodenum > gastric pylorus = jejunum = descending colon > ascending colon >/= ileum. However, there was no effect of SK-896 on smooth muscle preparations from gastric fundus and other regional organs. SK-896 thus exhibited regional specificity in its contractile effect. Moreover, the effects of SK-896 on smooth muscle preparations from rabbit duodenum were the same as those of human motilin, and were not inhibited by pretreatment with tetrodotoxin and atropine but were inhibited by verapamil. These findings indicate that SK-896 has the same pharmacological profile as human motilin. They suggest that SK-896 acts on gastrointestinal smooth muscle isolated from rabbit directly and specifically.

Development of a sensitive liquid chromatography-electrospray ionization mass spectrometry method for the measurement of KW-5139 in rat plasma.

A sensitive method for the determination of a prokinetic peptide, KW-5139 (Leu(13)-motilin), in rat plasma has been developed utilizing liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS). KW-5139 was separated by reversed-phase HPLC, with a mixture of 75 mM ammonium formate (pH 3.0) and acetonitrile (4:1, v/v), and monitored by single ion recording (SIR)-ESI-MS at m/z 894 ([M+3H](3+)). Simple protein precipitation and the LC-ESI-MS analysis allowed the determination of KW-5139 in rat plasma with the mean precision and accuracy at the lower limit of quantitation (LLOQ, 0.5 ng/mL) of 5.7 and 11.2%, respectively. The method was applied to the monitoring of the plasma time-concentration profile of KW-5139, intravenously administered to rats at a dose of 1 microg/kg.

Receptor for motilin identified in the human gastrointestinal system.

Motilin is a 22-amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum and duodenal contractions. A heterotrimeric guanosine triphosphate-binding protein (G protein)-coupled receptor for motilin was isolated from human stomach, and its amino acid sequence was found to be 52 percent identical to the human receptor for growth hormone secretagogues. The macrolide antibiotic erythromycin also interacted with the cloned motilin receptor, providing a molecular basis for its effects on the human GI tract. The motilin receptor is expressed in enteric neurons of the human duodenum and colon. Development of motilin receptor agonists and antagonists may be useful in the treatment of multiple disorders of GI motility.

Erythromycin derivatives ABT 229 and GM 611 act on motilin receptors in the rabbit duodenum.

1. The present study was undertaken to determine whether the macrolide antibiotic erythromycin, its stable motilide derivatives ABT 229 and GM 611 and motilin act at the same receptors on intestinal muscle 2. Each compound contracted the longitudinal muscle of the rabbit duodenum in a concentration-dependent manner that was unaffected by 1 mumol/L tetrodotoxin. The potency order (pEC50 values in brackets) was motilin (8.4), ABT 229 (7.6), GM 611 (7.5) and erythromycin (6.0). 3. The motilin receptor antagonists GM 109 and [phe3, leu13]-motilin, both shifted the concentration-response curves for each agonist to the right, but did not affect concentration-response relationships for the muscarinic agonist carbachol. Schild regression analysis yielded similar pA2 values for GM 109 (in the range 7.2-7.5) for all agonists. This analysis was not done for [phe3, leu13]motilin, which was a non-competitive antagonist and partial agonist. 4. It is concluded that erythromycin, the motilides and motilin act at the same (motilin) receptor on rabbit duodenal muscle and do not have any detectable actions at other receptors in this preparation.

Pyloric opening and closure evaluated by means of strain gauge force transducers.

Recently, gastrointestinal motility research and various studies to measure motility have been conducted. However, it is not easy to measure the pyloric sphincter motility, especially its open and closed motility. There are few reports on the opening and closed motility of the pyloric ring. In this study, I examined the pyloric motility with strain gauge force transducers (SGTs). SGTs were implanted onto the antrum, pyloric ring and duodenum of a dog. In order to clarify the relationship between the opening and closed motility of the pylorus and SGTs recordings, the pyloric ring was observed with a gastrofiberscope while measurements were taken using the SGTs in anesthetized dogs. In addition, the pyloric ring was extended mechanically with a balloon and measurement were taken using the SGTs. In conscious dogs, the natural gastropyloroduodenal motility was recorded. Then, cisapride, erythromycin, and Leu13-motilin were administered in the interdigestive state and the motility was recorded. The pyloric opening and closed motility could be monitored using SGTs. The pyloric ring opened when the pyloric motility recorded using the SGTs showed a negative deflection. In addition, in phase III, when intense contraction of the antrum was observed, relaxation and opening of the pyloric ring could be observed. Erythromycin and Leu13-motilin induced phase III-like motility and relaxation of the pyloric ring. However, in cisapride-induced motility, relaxation of the pyloric ring was not observed. The pyloric ring opening and closed motility can be monitored using SGTs and this method is effective for the evaluation of the pyloric function.

Effect of leucine 13-motilin (KW5139) on early gastric stasis after pylorus-preserving pancreatoduodenectomy.

OBJECTIVE: To test a hypothesis that exogenously administered motilin would improve early gastric stasis after pylorus-preserving pancreatoduodenectomy (PPPD). SUMMARY BACKGROUND DATA: Prolonged gastric stasis is a frequent complication after PPPD. We demonstrated that this might at least in part be attributable to delayed recovery of phase III activity of the gastric migrating motor complex due to low concentrations of plasma motilin caused by resection of the duodenum. METHODS: Ten patients with a mean age of 54 years (range, 33-70) who underwent PPPD were studied. An assembly of manometric tubes was placed in the gastric antrum and jejunum (neoduodenum) at surgery. A gastrostomy tube was added for drainage and volume measurements of the gastric juice. After baseline recording, saline as a placebo was given intravenously on day 14 and 0.5 microg/kg of KW5139 (leucine-13 motilin) was given on days 17 and 18 every 2 hours, 6 times a day. The daily volume of gastric juice output and a gastric motility index were measured. RESULTS: The mean period until the first appearance of phase III activity in the stomach was 41 +/- 2 days. The injection of saline did not change the gastric motility index (7.3 +/- 1.1 to 7.1 +/- 1.3 mmHg; p = 0.72). In contrast, motilin resulted in a significant increase in the gastric motility index (7.5 +/- 1.0 to 17.7 +/- 2.0 mmHg; p < 0.001). The saline injection produced no change in the daily gastric juice output (1175 +/- 140 to 1393 +/- 193 mL; p = 0.09). Motilin significantly decreased the gastric juice output (1387 +/- 157 to 934 +/- 142 mL; p = 0.01). CONCLUSIONS: These data indicate that KW5139 is a safe and effective prokinetic drug for the treatment of early gastric stasis after PPPD.

Functional characterization of neural and smooth muscle motilin receptors in the chicken proventriculus and ileum.

To characterize the motilin receptors present in the chicken, the effects of chicken motilin (Phe-Val-Pro-Phe-Phe-Thr-Gln-Ser-Asp-Ile-Gln-Lys-Met-Gln-Glu-Lys-Glu-Arg -Asn-Lys-Gly-Gln), Leu13 porcine motilin, canine motilin and three erythromycin derivatives (EMA, EM523, GM611) on the contractility of the chicken gastrointestinal (GI) smooth muscles were investigated in vitro and compared with those in the rabbit duodenum. In the proventriculus longitudinal and circular muscle layers, chicken motilin (3 nM-1 microM) caused an atropine- and a tetrodotoxin-sensitive contraction (EC50 = 39-49 nM), and potentiated the EFS-induced contraction without affecting the responsiveness of acetylcholine. EM523 and GM611 (3-100 microM) contracted the proventriculus longitudinal muscle, and the maximum amplitudes of contraction were about 60% of that induced by chicken motilin. Chicken motilin (0.1 nM-100 nM) also caused contraction of the ileum (EC50 = 7 nM) through direct action on the smooth muscle cells. On the other hand, erythromycin derivatives showed only a weak contractile efficacy (about 20% of the maximum response of chicken motilin) even at high concentrations (10-100 microM). The rank order of potency in the ileum was chicken motilin > canine motilin > or = Leu13 porcine motilin > > GM611 > or = EM523 > or = EMA. GM109 slightly inhibited the ideal contractions induced by Leu13 porcine motilin at 100 microM (pA2 = 3.86). In the rabbit duodenum, chicken motilin was a full agonist with the same intrinsic activity as Leu13 porcine motilin, canine motilin and the erythromycin derivatives. However, the rank order of potency (Leu13 porcine motilin > or = canine motilin > chicken motilin > GM611 > or = EM523 > EMA) was different from that in the chicken ileum. In conclusion, chicken motilin causes an excitatory response in the chicken GI tract through activation of neural (proventriculus) and smooth muscle motilin receptors (ileum). The motilin receptor present in the ileum is different from that demonstrated in the rabbit intestine, because of a different rank order of motilin peptides in producing the contraction, low contracting activity of erythromycin derivatives and low antagonistic efficacy of GM109. Different pharmacological characteristics of the mechanical response induced by motilin peptides and erythromycin derivatives between the proventriculus and the ileum are discussed.