A new strategy for metabolic stabilization of motilin using the C-terminal part of ghrelin.

Ghrelin consists of 28 amino acid residues with an octanoyl modification at the third serine residue. Recently we have found that the C-terminal part of ghrelin protects the ester bond of 3-octanoyled serine from plasma esterases and plays the essential role to prolong the plasma half-life and to show its biological activity in vivo. In the present study, we researched whether the C-terminal part of ghrelin has a potential to prolong the plasma half-life of motilin, by comparing the pharmacokinetics of various chimeric peptides of ghrelin and motilin. Motilin is another gastro-intestinal peptide hormone related with ghrelin structurally, binding to the same family of G protein-coupled receptors. Chimeric peptides were designed to be composed of motilin(1-12) fragment, the active core binding to the motilin receptor, GPR38, and C-terminal part of ghrelin. The modification of motilin(1-12) fragment by C-terminal part of ghrelin hardly influenced its agonist activity to GPR38 and almost all these chimeric peptides showed more than two times longer plasma half-lives than motilin in rats. From the relationship between structures of chimeric peptides and their corresponding plasma half-lives, the mid-region of ghrelin rich in basic amino acids ((15)RKESKK(20)) was considered to be the most important in prolonging the plasma half-life of motilin. The deletion of these fragments or replacement of 17th glutamic acid with a neutral amino acid resulted in short plasma half-lives. In conclusion, our data suggested that the C-terminal part of ghrelin has a potential to improve the biokinetics of motilin probably by a metabolic stabilizing effect.

Efficacy of mitemcinal, a motilin agonist, on gastrointestinal symptoms in patients with symptoms suggesting diabetic gastropathy: a randomized, multi-center, placebo-controlled trial.

BACKGROUND: Mitemcinal, an oral motilin agonist, accelerates gastric emptying. AIM: To investigate if mitemcinal was superior to placebo in relief of symptoms attributed to gastroparesis. METHODS: In a randomized, double-blind design, 392 insulin-requiring diabetics with symptoms attributable to gastroparesis were treated for 3 months with placebo, mitemcinal 5 or 10 mg bid. On a weekly basis, patients assessed whether there was adequate relief of their gastroparesis symptoms. Patients were classified as Complete Responders (CR) if there were three consecutive positive monthly responses, which required at least 50% of their weekly responses in a month being positive. An Overall Responder (OR) had at least 75% positive weekly responses for the whole treatment period. RESULTS: Mitemcinal 10 mg produced a significantly better response rate than placebo with a 10.6% increase in the OR (P < 0.05 vs. placebo). Mitemcinal 10 mg also produced statistically significant increases in the CR and OR in the subgroup identified by baseline body mass index (<35 kg/m(2)) and haemoglobin A(1c) (<10%) (P < 0.01 vs. placebo). Adverse events did not differ from placebo frequency levels. CONCLUSIONS: Mitemcinal can induce a statistically significant response to treatment in a subset of diabetic gastroparesis where future prokinetic clinical trials should be focused.

Effects of a nonpeptide motilin receptor antagonist on proximal gastric motor function.

AIM: To assess the effects of the motilin receptor antagonist RWJ-68023 on basal and motilin-stimulated proximal gastric volume. METHODS: Eighteen healthy male volunteers received RWJ-68023 in two different doses or placebo for 135 min. After 45 min, subjects received a motilin infusion for 90 min. Proximal gastric volume was measured with a barostat at constant pressure and during isobaric distensions. Abdominal symptoms were scored using visual analogue scales. Motilin and RWJ-68023 concentrations were assessed by radioimmunoassay and liquid chromatography-mass spectrometry, respectively. RESULTS: Both dosages of RWJ-68023 were safe and well tolerated. The most common adverse events were of gastrointestinal origin. RWJ-68023 did not affect basal proximal gastric volume, but the high-dose RWJ-68023 reduced the contractile effect of motilin on the stomach. This antagonizing effect of RWJ-68023 was only significant (P = 0.014) during the distension procedure. CONCLUSIONS: The RWJ-68023 doses used in this study were selected to accomplish plasma concentrations that would block the motilin effect entirely. However, the antagonizing effect of RWJ-68023 was partial and only present when the tonic condition of the stomach was modulated by motilin.

Gallbladder volume as a biomarker for the motilin effect in healthy volunteers and patients with functional dyspepsia.

AIM: To investigate a motilin effect on gallbladder volume in healthy volunteers and patients with functional dyspepsia. METHODS: Forty-three healthy volunteers and 10 patients with functional dyspepsia received motilin (4 pmol.min/kg) or placebo in four separate double-blind, randomized, placebo-controlled, cross-over studies. The gallbladder volume was measured by ultrasonography. Analysis of variance of the combined data of these studies was performed to investigate a motilin effect on gallbladder volume and potential differences between patients and healthy volunteers. RESULTS: The baseline gallbladder volume was similar for placebo and motilin treatment, as well as for patients and healthy volunteers. Motilin, compared with placebo, significantly decreased the gallbladder volume in healthy volunteers (P = 0.003) and patients (P < 0.0001). A linear concentration-response relationship was observed. The decrease in gallbladder volume by motilin was greater in patients (P = 0.03). The motilin effect was consistent between studies. CONCLUSION: The interdigestive gallbladder volume is a non-invasive end-point for motilin activity, displaying a consistent response across studies, a clear response to motilin and a clear concentration-response relationship. However, it is less suitable as a biomarker for future pharmacological studies on motilin agonists or antagonists as the effect is probably indirect, and a relatively large study population of 27 subjects is required to demonstrate a 15% decrease in gallbladder volume. Further investigation is required to confirm altered gallbladder motility as a feature of functional dyspepsia.

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.

Motilin effects on the proximal stomach in patients with functional dyspepsia and healthy volunteers.

This study investigates motilin effects on the proximal stomach in patients with functional dyspepsia (FD) and healthy volunteers. Eight healthy volunteers and 12 patients with FD were infused with synthetic motilin or placebo. Proximal gastric volume was measured with a barostat at constant pressure and during isobaric distensions. Abdominal symptoms were scored by visual analog scales. Plasma motilin concentrations were measured by radioimmunoassay. Motilin concentrations and baseline gastric volumes were similar for patients and healthy volunteers. Motilin, compared with placebo, reduced gastric volume by 112 ml [F(29,195); confidence interval (CI) 95%] in patients and by 96 ml [F(-7,200); CI 95%] in healthy volunteers. In patients, motilin decreased compliance by 76 ml/mmHg [F(9,143); CI 95%] compared with placebo, which was similar in volunteers [66 ml/mmHg; F(11,120); CI 95%]. Patients were more nauseous during motilin compared with placebo (P = 0.04), whereas healthy volunteers did not experience nausea. We conclude that in a fasted condition, FD patients have a similar proximal gastric motor response to motilin as healthy volunteers, but experience an exaggerated sensation of nausea.

Exogenous motilin affects postprandial proximal gastric motor function and visceral sensation.

Our aim was to investigate the effect of motilin on postprandial proximal gastric motor and sensory function in healthy volunteers. Ten fasted, healthy volunteers were infused intravenously with synthetic motilin or placebo over 90 min. A liquid meal (200 ml) was ingested within 2 min at the start of the infusion. Proximal gastric volume was measured with a barostat device. Abdominal symptoms were scored by visual analog scales. Plasma motilin concentrations were measured using RIA. Endogenous motilin levels were not affected by meal ingestion. After meal intake, gastric relaxation was similar for motilin and placebo. After postprandial relaxation, motilin resulted in a faster return of gastric volume to baseline (P = 0.007). Motilin significantly increased postprandial feelings of nausea (P = 0.03) and tended to increase abdominal pain and abdominal tension. In conclusion, after normal postprandial gastric relaxation, motilin accelerated the return of gastric volume to baseline. In addition, motilin increased postprandial feelings of nausea.