In vitro Pharmacological Profile of SK-896, a New Human Motilin Analogue

Tsukamoto, Katsura; Kuboyama, Noboru; Yamano, Masaya; Nakazawa, Toru; Suzuki, Tsunemasa

doi:10.1159/000028357

Cited by 12 publications

(7 citation statements)

References 23 publications

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“…Since the discovery that the antibiotic erythromycin could activate the motilin‐R, several derivatives of erythromycin have been identified as being more potent activators of this receptor and effective stimulants of gastric motility. A common feature in the characterisation of these compounds has been the use of rabbit isolated gastrointestinal preparations for radioligand binding or functional pharmacological assays of the receptor (e.g., Sato et al , 1997 ; Clark et al , 1999 ; Tsukamoto et al , 2000 ; Beavers et al , 2001 ; Van Vlem et al , 2002 ). The selection of this species followed the identification of motilin receptors in the gastrointestinal tract of the rabbit ( Bormans et al , 1986 ), but its importance as an assay tool may also be at least partly due to the apparent absence of a functional motilin‐R in rodent species ( Hill et al , 2002 ), commonly used as small laboratory animals.…”

Section: Introductionmentioning

confidence: 99%

The rabbit motilin receptor: molecular characterisation and pharmacology

Dass

Hill

Muir

et al. 2003

British J Pharmacology

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1 Following identification of the human motilin receptor, we isolated the rabbit orthologue by PCR amplification and found this to be 85% identical to the open reading frame of the human receptor. The protein encoded was 84% identical to the human polypeptide. ]-motilin faded rapidly during its continual presence. Rat or human ghrelin 0.01 -10 mM were without activity. 4 Erythromycin 30 -3000 nM and 10 mM, respectively, increased neuronal activity and muscle tension in rabbit stomach. Unlike [Nle 13 ]-motilin, the increase in neuronal activity did not fade during continual presence of submaximally-effective concentrations of erythromycin; some fade was observed at higher concentrations. 5 We conclude that the pharmacology of the rabbit motilin receptor is similar to the human orthologue and, when expressed as a recombinant, comparable to the native receptor. However, in terms of their ability to increase neuronal activity in rabbit stomach, [Nle 13 ]-motilin and erythromycin are distinguished by different response kinetics, reflecting different rates of ligand degradation and/or interaction with the receptor.

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Section: Introductionmentioning

confidence: 99%

The rabbit motilin receptor: molecular characterisation and pharmacology

Dass

Hill

Muir

et al. 2003

British J Pharmacology

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“…A pharmacological profile of SK-896 in rabbits, rats and dogs was developed from tests using in vitro techniques, and it was revealed that SK-896 bound to motilin receptors in the rabbit duodenum and induced the contraction of smooth muscle preparations isolated from the rabbit gastrointestinal tract but not those isolated from the rat or the dog. 18) In addition, from an in vivo study it was reported that treatment with SK-896 significantly shortened the time to the first appearance of IMC in the stomach as well as the gastric emptying time in dogs with operative ileus, as compared with treatment with prostaglandin F 2a , which is currently used to treat of gastroparalysis. 19) SK-896 has the same pharmacological profile as human motilin in vitro 18) and is more effective than prostaglandin F 2a in vivo.…”

mentioning

confidence: 99%

“…18) In addition, from an in vivo study it was reported that treatment with SK-896 significantly shortened the time to the first appearance of IMC in the stomach as well as the gastric emptying time in dogs with operative ileus, as compared with treatment with prostaglandin F 2a , which is currently used to treat of gastroparalysis. 19) SK-896 has the same pharmacological profile as human motilin in vitro 18) and is more effective than prostaglandin F 2a in vivo. 19) Clinically, intravenously administered motilin or motilin analogue enhances GI motility without serious side effects.…”

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confidence: 99%

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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“…It has been previously reported [16][17][18] that injection or infusion of motilin (0.1-1.0 Ìg/kg) induced phase III contractile activity in the gastric antrum. Moreover, we reported earlier [4] that SK-896 and human motilin bind the rabbit gastroduodenal motilin receptor with equal ability and that the 50% inhibitory concentrations for binding of 125 I-motilin to this receptor were 3.5 B 1.5 and 3.1 B 1.8 nmol/l, respectively. We, therefore, used the same dose of human motilin as of SK-896 in the present study.…”

Section: Discussionmentioning

confidence: 78%

“…In a preliminary study (data not shown), SK-896 had a longer half-life in the blood in dogs than did human motilin, and it produced no evidence of anaphylactic shock in either mice or guinea pigs. In a previous study Tsukamoto/Tagi/Nakazawa/Takeda [4], we examined the pharmacological profile of SK-896 in rabbits, rats, and dogs using in vitro techniques. We found that SK-896 bound motilin receptors in the rabbit duodenum and induced contraction of smooth muscle preparations isolated from rabbit gastrointestinal tract, but not of those isolated from either rat or the dog.…”

Section: Introductionmentioning

confidence: 99%

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

Tsukamoto

Tagi²,

Nakazawa³

et al. 2001

Pharmacology

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SK-896 [(Leu¹³)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 µg/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 µg/ 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.

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In vitro Pharmacological Profile of SK-896, a New Human Motilin Analogue

Cited by 12 publications

References 23 publications

The rabbit motilin receptor: molecular characterisation and pharmacology

The rabbit motilin receptor: molecular characterisation and pharmacology

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

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

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