Gastroprokinetic Effect and Mechanism of SK-896, a New Motilin Analogue, during the Interdigestive Period in Conscious Dogs

Tsukamoto, Katsura; Tagi, Yoshihiko; Nakazawa, Toru; Takeda, Motohiro

doi:10.1159/000056119

Cited by 7 publications

(3 citation statements)

References 17 publications

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“…It has been demonstrated 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. 32) It is postulated from this finding that a factor exists which regulates this parasympathetic nervous system activity. In addition, the fact that the GI-IMC-like activity does not occur in the early postoperative period may be a biophylaxis reaction to hasten the healing by restraining the enterokinesis.…”

Section: Discussionmentioning

confidence: 98%

Effects of SK-896, a New Human Motilin Analogue ([Leu13]motilin-Hse), on Postoperative Ileus in Dogs after Laparotomy.

Furuta

Takeda

Nakayama

et al. 2002

Biological & Pharmaceutical Bulletin

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The effects of SK-896, a new human motilin analogue ([Leu 13 ]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 m mg/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.

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Section: Discussionmentioning

confidence: 98%

Effects of SK-896, a New Human Motilin Analogue ([Leu13]motilin-Hse), on Postoperative Ileus in Dogs after Laparotomy.

Furuta

Takeda

Nakayama

et al. 2002

Biological & Pharmaceutical Bulletin

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“…The oligopeptide SK-896 binds with similar affinity to the motilin receptor as motilin and contracted smooth muscle in in vitro preparations of the rabbit gastrointestinal tract with the same pharmacological profile as motilin 220 . In dogs, SK-896 induced interdigestive migrating contractions 221 . Moreover, SK-896 improved gastrointestinal motility in postoperative ileus in dogs 222,223 .…”

Section: Small-molecule Motilin Receptor Agonistsmentioning

confidence: 97%

Motilin: from gastric motility stimulation to hunger signalling

et al. 2019

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After the discovery of motilin in 1972, motilin and the motilin receptor were studied intensely for their role in the control of gastrointestinal motility and as targets for treating hypomotility disorders. The genetic revolution -with the use of knockout models -sparked novel insights into the role of multiple peptides but contributed to a decline in interest in motilin, as this peptide and its receptor exist only as pseudogenes in rodents. The past 5 years have seen a major surge in interest in motilin, as a series of studies have shown its relevance in the control of hunger and regulation of food intake in humans in both health and disease. Luminal stimuli, such as bitter tastants, have been identified as modulators of motilin release, with effects on hunger and food intake. The current state of knowledge and potential implications for therapy are summarized in this Review.

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“…A case report concluded that even as monotherapy, cisapride may pose dangers for high-risk diabetic patients ( 29 ). Although cisapride may even not usable in gastric emptying in diabetic gastroparetic dogs, it is available in the United States and Canada for use in animals ( 30 ). Studies on reducing the side effects while maintaining the efficiency of binding to targets may allow some drugs to return to the market.…”

Section: Discussionmentioning

confidence: 99%

Cisapride induced hypoglycemia via the KCNH6 potassium channel

Lü

Shi²,

Yuan³

et al. 2022

Front. Endocrinol.

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Mutations in KCNH6 has been proved to cause hypoinsulinemia and diabetes in human and mice. Cisapride is a stomach–intestinal motility drug used to treat gastrointestinal dysfunction. Cisapride has been reported to be a potential inhibitor of the KCNH family, but it remained unclear whether cisapride inhibited KCNH6. Here, we discovered the role of cisapride on glucose metabolism, focusing on the KCNH6 potassium channel protein. Cisapride reduced blood glucose level and increased serum insulin secretion in wild-type (WT) mice fed standard normal chow/a high-fat diet or in db/db mice, especially when combined with tolbutamide. This effect was much stronger after 4 weeks of intraperitoneal injection. Whole-cell patch-clamp showed that cisapride inhibited KCNH6 currents in transfected HEK293 cells in a concentration-dependent manner. Cisapride induced an increased insulin secretion through the disruption of intracellular calcium homeostasis in a rat pancreatic β-cell line, INS-1E. Further experiments revealed that cisapride did not decrease blood glucose or increase serum insulin in KCNH6 β-cell knockout (Kcnh6-β-KO) mice when compared with WT mice. Cisapride also ameliorated glucose-stimulated insulin secretion (GSIS) in response to high glucose in WT but not Kcnh6-β-KO mice. Thus, our data reveal a novel way for the effect of KCNH6 in cisapride-induced hypoglycemia.

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Gastroprokinetic Effect and Mechanism of SK-896, a New Motilin Analogue, during the Interdigestive Period in Conscious Dogs

Cited by 7 publications

References 17 publications

Effects of SK-896, a New Human Motilin Analogue ([Leu13]motilin-Hse), on Postoperative Ileus in Dogs after Laparotomy.

Effects of SK-896, a New Human Motilin Analogue ([Leu13]motilin-Hse), on Postoperative Ileus in Dogs after Laparotomy.

Motilin: from gastric motility stimulation to hunger signalling

Cisapride induced hypoglycemia via the KCNH6 potassium channel

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