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

Q3 · MEDICINE

Article

Author: Takasaki, Kotaro ; Karasawa, Akira ; Kusaka, Hideaki ; Kitazawa, Takio ; Yokoyama, Toshihide

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.

01 Apr 2000·Biomedical ChromatographyQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Michio Takashima ; Tatsuo Uchimura ; Satoshi Kobayashi ; Kazuo Yamaguchi

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.

01 Apr 1998·Annals of SurgeryQ1 · MEDICINE

Effect of Leucine 13-Motilin (KW5139) on Early Gastric Stasis After Pylorus-Preserving Pancreatoduodenectomy

Q1 · MEDICINE

Article

Author: Koji Yamaguchi ; Hiroaki Matsunaga ; Kazunori Yokohata ; Masao Tanaka ; Kazuo Chijiiwa ; Gen Naritomi

OBJECTIVETo test a hypothesis that exogenously administered motilin would improve early gastric stasis after pylorus-preserving pancreatoduodenectomy (PPPD).SUMMARY BACKGROUND DATAProlonged 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.METHODSTen 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.RESULTSThe 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).CONCLUSIONSThese data indicate that KW5139 is a safe and effective prokinetic drug for the treatment of early gastric stasis after PPPD.

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Indication	Highest Phase	Country/Location	Organization	Date
Gastrointestinal Diseases	Phase 2	JP	Kyowa Kirin Co., Ltd.	-

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