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Research ArticleArticle

Effects of EM574 and Cisapride on Gastric Contractile and Emptying Activity in Normal and Drug-Induced Gastroparesis in Dogs

Toshiyuki Tanaka, Akiyoshi Mizumoto, Erito Mochiki, Hideki Suzuki, Zen Itoh and Satoshi Omura
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 712-719;
Toshiyuki Tanaka
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Akiyoshi Mizumoto
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Erito Mochiki
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Hideki Suzuki
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Zen Itoh
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Satoshi Omura
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Abstract

EM574, an erythromycin derivative and potent motilin receptor agonist, is now undergoing clinical trials as a gastroprokinetic drug. The aim of this study was to compare the effect of EM574 with that of cisapride on gastric motility and emptying in normal and gastroparesis dogs. Six dogs were each implanted with two duodenal cannulas for infusion of phenolsulfonphthalein into the proximal duodenum and for aspiration of luminal samples from the distal duodenum. Both solid and liquid gastric emptying were determined by a novel freeze-drying method developed in our laboratory. A freeze-dried standard meal (100 g, 400 kcal) was given with 100 ml normal saline containing 15 g of polyethylene glycol as a liquid marker. Gastric muscle contractility was measured by means of a force transducer implanted on the gastric antrum. EM574 (3–30 μg/kg) and cisapride (0.3–3.0 mg/kg) were administered intraduodenally at the start of feeding. Clonidine (3–30 μg/kg) was injected subcutaneously 15 min before feeding to induce gastroparesis. EM574 and cisapride both enhanced gastric muscle contractility in a dose-dependent manner. EM574 (30 μg/kg and 10 μg/kg) significantly accelerated gastric emptying of solids and liquids, respectively. Cisapride (1 mg/kg) significantly accelerated solid gastric emptying, but 3.0 mg/kg significantly delayed liquid gastric emptying. Clonidine (10 and 30 μg/kg) significantly delayed solid and liquid gastric emptying and reduced gastric muscle contractility. EM574, at a dose of 30 μg/kg, completely restored solid and liquid gastric emptying and muscle contractility to the normal range in dogs with clonidine-induced gastroparesis. Cisapride (1 mg/kg) restored liquid gastric emptying in dogs with gastroparesis to the normal range and partially restored solid emptying. EM574 accelerated gastric muscle contractility and emptying of solids and liquids in normal dogs. The stimulating activity of EM574 on gastric muscle contractility and emptying was comparable to that of cisapride, but EM574 was as effective as cisapride in normalizing gastric muscle contractility and emptying in dogs with clonidine-induced gastroparesis.

Footnotes

  • Send reprint requests to: Toshiyuki Tanaka, M.D., The Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.

  • ↵1 T.T. is a research fellow from the Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.

  • Abbreviations:
    EM574
    De(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal
    PSP
    phenolsulfonphthalein
    PEG
    polyethylene glycol
    EM523
    De(N-methyl)-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal
    5-HT
    5-hydroxytryptamine
    EMA
    erythromycin A
    t1/2
    half-emptying time
    MI
    motor index
    Tc
    technetium
    L-NNA
    Nω-nitro-l-arginine
    • Received February 19, 1998.
    • Accepted June 8, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Effects of EM574 and Cisapride on Gastric Contractile and Emptying Activity in Normal and Drug-Induced Gastroparesis in Dogs

Toshiyuki Tanaka, Akiyoshi Mizumoto, Erito Mochiki, Hideki Suzuki, Zen Itoh and Satoshi Omura
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 712-719;

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Research ArticleArticle

Effects of EM574 and Cisapride on Gastric Contractile and Emptying Activity in Normal and Drug-Induced Gastroparesis in Dogs

Toshiyuki Tanaka, Akiyoshi Mizumoto, Erito Mochiki, Hideki Suzuki, Zen Itoh and Satoshi Omura
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 712-719;
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