Tierarztl Prax Ausg K Kleintiere Heimtiere 2016; 44(03): 163-169
DOI: 10.15654/TPK-150039
Original Article
Schattauer GmbH

Effects of the neurokinin-1 antagonist maropitant on canine gastric emptying assessed by radioscintigraphy and breath test

Der Effekt des Neurokinin-1-Antagonisten Maropitant auf die mittels Radio-szintigraphie und Atemtest bestimmte Magenentleerung beim Hund
Silke Schmitz
1   Small Animal Hospital, Department Internal Medicine, Justus-Liebig University, Giessen, Germany
,
Tamara Fink
1   Small Animal Hospital, Department Internal Medicine, Justus-Liebig University, Giessen, Germany
,
Klaus Failing
2   Unit for Biomathematics and Data Processing, Veterinary Faculty, Justus-Liebig University, Giessen, Germany
,
Christian Borsch
3   Institute for Nutritional Science, Justus-Liebig University, Giessen, Germany
,
Clemens Kunz
3   Institute for Nutritional Science, Justus-Liebig University, Giessen, Germany
,
Richard Clemence
4   Zoetis France, Paris, France
,
Karine Savary-Bataille
4   Zoetis France, Paris, France
,
Reto Neiger
1   Small Animal Hospital, Department Internal Medicine, Justus-Liebig University, Giessen, Germany
› Author Affiliations
Further Information

Publication History

Received: 20 January 2015

Accepted after major revision: 29 April 2015

Publication Date:
18 December 2017 (online)

Summary

Objective: Delayed gastric emptying is a well-recognised phenomenon in a number of canine disease conditions. Only a limited number of drugs have been reported to have some gastrokinetic effect in the dog. The aim of this study was to investigate prokinetic effects of maropitant. Material and methods: In a cross-over study 24 healthy adult Beagle dogs were randomised to receive either maropitant (2 mg/kg q24 h PO), cisapride (1 mg/kg q12 h PO) or placebo (vitamin- B12, 10 μg/dog q24 h PO) for 7 days with a 7-day washout period between treatments. Gastric emptying was measured simultaneously via 99mTechnetium radioscintigraphy and 13C-sodium acetate breath testing for 6 hours post-feeding. The decrease in radioactive counts in the stomach and the increase in 13CO2 concentration in exhaled breath (measured via gas chromatography) were plotted against time. The area under the curve was determined for each test and the time to 25%, 50% and 75% gastric emptying was calculated for each method. Friedman test was used to compare gastric emptying times. Results: With both methods, no difference for gastric emptying times was observed for any treatment. Conclusion and clinical relevance: Neither maropitant nor cisapride were shown to have an effect on gastric emptying in healthy beagles using radioscintigraphy or breath test when compared to placebo. Consequently, neither drug can be recommended as a gastric prokinetic in dogs.

Zusammenfassung

Gegenstand und Ziel: Eine verzogerte Magenentleerung ist bei verschiedenen Erkrankungen des Hundes bekannt. Nur eine begrenzte Anzahl von Medikamenten wurden hinsichtlich ihres prokinetischen Effekts beim Hund untersucht. Das Ziel dieser Studie war, einen moglichen gastroprokinetischen Effekt von Maropitant zu untersuchen. Material und Methoden: Im Rahmen einer Cross-over Studie erhielten 24 gesunde Beagle randomisiert jeweils fur 7 Tage Maropitant (2 mg/kg p. o. einmal taglich), Cisaprid (1 mg/kg p. o. zweimal taglich) und ein Plazebo (Vitamin-B12, 10 μg/Hund p. o. einmal). Zwischen den Behandlungen lag jeweils eine Ruhephase von 7 Tagen. Am Ende jeder Medikamentengabe wurde die Magenentleerung simultan mittels 99mTechnetium-Radioszintigraphie und 13C-Natriumazetat-Atemtest uber 6 Stunden nach der Futterung gemessen. Die „Area-under-thecurve“ der radioaktiven Counts bzw. der Konzentration von 13CO2 in der Ausatemluft (bestimmt mittels Gaschromatographie) wurde gegen die Zeit aufgetragen und anhand dieser Kurve die 25-, 50- und 75%ige Magenentleerungszeit berechnet. Zum Vergleich der Magenentleerungszeiten diente der Friedman-Test. Ergebnisse: Mit beiden Methoden lies sich zwischen den Magenentleerungszeiten fur die eingesetzten Medikamente im Vergleich zum Plazebo kein signifikanter Unterschied feststellen. Schlussfolgerung und klinische Relevanz: Weder Maropitant noch Cisaprid zeigten einen prokinetischen Effekt auf den Magen. Der Einsatz dieser Substanzen zur Forderung der Magenentleerung beim Hund ist daher nicht empfehlenswert.

 
  • Literatur

  • 1 Ehrlein H, Kaske M. Motorik des Magen-Darm-Kanals. Physiologie der Haustiere.. Engelhardt W, Breves G. Stuttgart: Enke; 2000
  • 2 Washabau RJ. Gastrointestinal motility disorders and gastrointestinal prokinetic therapy. Vet Clin North Am Small Anim Pract 2003; 33 (05) 1007-1228 vi
  • 3 Cullen JJ, Titler S, Ephgrave KS, Hinkhouse MM. Gastric emptying of liquids and postprandial pancreatobiliary secretion are temporarily impaired during endotoxemia. Dig Dis Sci 1999; 44 (11) 2172-2177.
  • 4 Fioramonti J, Bueno L. Gastrointestinal myoelectric activity disturbances in gastric ulcer disease in rats and dogs. Dig Dis Sci 1980; 25 (08) 575-580.
  • 5 Johnson CS, Fales-Williams AJ, Reimer SB, Lotsikas PJ, Haynes JS. Fibrosing gastrointestinal leiomyositis as a cause of chronic intestinal pseudo-obstruction in an 8-month-old dog. Vet Pathol 2007; 44 (01) 106-109.
  • 6 Takeda M, Mizutani Y, Yamano M, Tsukamoto K, Suzuki T. Gastric emptying in diabetic gastroparetic dogs: Effects of SK-951, a novel prokinetic agent. Pharmacology 2001; 62 (01) 23-28.
  • 7 Schmitz S, Jansen N, Failing K, Neiger R. 13C-sodium acetate breath test for evaluation of gastric emptying times in dogs with gastric dilatation-volvulus. Tierärztl Prax 2013; 41(K): 87-92.
  • 8 Boscan P, Cochran S, Monnet E. et. al. Effect of prolonged general anesthesia with sevoflurane and laparoscopic surgery on gastric and small bowel propulsive motility and pH in dogs. Vet Anaesth Analg 2014; 41 (01) 73-81.
  • 9 Hall J, Washabau R. Gastrointestinal prokinetic therapy: Dopaminergic antagonist drugs. Compend Contin Educ Pract Vet 1997; 19 (02) 214.
  • 10 Gué M, Fioramonti J, Bueno L. A simple double radiolabeled technique to evaluate gastric emptying of canned food meal in dogs. Application to pharmacological tests. Gastroentérologie Clin Biol 1988; 12 (05) 425-430.
  • 11 Hall JA, Solie TN, Seim HB, Twedt DC. Effect of metoclopramide on fed-state gastric myoelectric and motor activity in dogs. Am J Vet Res 1996; 57 (11) 1616-1622.
  • 12 Platteborse R, Hermans C, Loots W, Van Loon J, Van Gorp A, Smet F. et al. The effect of domperidone on pyloric activity in dog and in man. Postgrad Med J 1979; 55 (Suppl. 01) 15-18
  • 13 Edelbroek M, Schuurkes J, De Ridder W, Horowitz M, Dent J, Akkermans L. Effect of cisapride on myoelectrical and motor responses of antropyloroduodenal region during intraduodenal lipid and antral tachygastria in conscious dog. Dig Dis Sci 1995; 40 (04) 901-911.
  • 14 Manini ML, Camilleri M, Goldberg M, Sweetser S, McKinzie S, Burton D. et al. Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation. Neurogastroenterol Motil 2010; 22 (01) 42-49 e7-8
  • 15 Seto Y, Yoshida N, Kaneko H. Effects of mosapride citrate, a 5-HT4-receptor agonist, on gastric distension-induced visceromotor response in conscious rats. J Pharmacol Sci 2011; 116 (01) 47-53.
  • 16 Tsukamoto A, Ohno K, Maeda S, Nakashima K, Fukushima K, Fujino Y. et al. Effect of mosapride on prednisolone-induced gastric mucosal injury and gastric-emptying disorder in dog. J Vet Med Sci 2012; 74 (09) 1103-1108.
  • 17 Briejer MR, Prins NH, Schuurkes JAJ. Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs. Neurogastroenterol Motil 2001; 13 (05) 465-472.
  • 18 Tanaka T, Mizumoto A. Mochiki et. al. Effects of EM574 and cisapride on gastric contractile and emptying activity in normal and drug-induced gastroparesis in dogs. J Pharmacol Exp Ther 1998; 287 (02) 712-719.
  • 19 Bertaccini G, Coruzzi G, Poli E. Histamine H2 receptor antagonists may modify dog intestinal motility independently of their primary action on the H2 receptors. Pharmacol Res Commun 1985; 17 (03) 241-254.
  • 20 McCord K, Boscan P, Dowers K, Bradley A, Cosgrove S, Dame K. et al. Comparison of gastrointestinal motility in dogs treated with metoclopramide, cisapride, erythromycin or maropitant using the SMART-PillTM. J Vet Int Med ACVIm Forum Proceedings. 2009: 735-736
  • 21 Bogard K, Gaschen F, Olsen E. et. al. Double-blind, placebo-controlled ultrasonographic evaluation of the effects of anti-emetic drugs on antral motility and gastric emptying in healthy dogs. J Vet Int Med ACVIM Forum Proc. 2015: 1184
  • 22 Conder GA, Sedlacek HS, Boucher JF, Clemence RG. Efficacy and safety of maropitant, a selective neurokinin 1 receptor antagonist, in two randomized clinical trials for prevention of vomiting due to motion sickness in dogs. J Vet Pharmacol Ther 2008; 31 (06) 528-532.
  • 23 Gardner CJ, Twissell DJ, Dale TJ, Gale JD, Jordan CC, Kilpatrick GJ. et al. The broad-spectrum anti-emetic activity of the novel non-peptide tachykinin NK1 receptor antagonist GR203040. Br J Pharmacol 1995; 116 (08) 3158-3163.
  • 24 Ramsey DS, Kincaid K, Watkins JA, Boucher JF, Conder GA, Eagleson JS. et al. Safety and efficacy of injectable and oral maropitant, a selective neurokinin 1 receptor antagonist, in a randomized clinical trial for treatment of vomiting in dogs. J Vet Pharmacol Ther 2008; 31 (06) 538-543.
  • 25 Mantyh PW, Mantyh CR, Gates T, Vigna SR, Maggio JE. Receptor binding sites for substance P and substance K in the canine gastrointestinal tract and their possible role in inflammatory bowel disease. Neuroscience 1988; 25 (03) 817-837.
  • 26 Pearse AG, Polak JM. Immunocytochemical localization of substance P in mammalian intestine. Histochemistry 1975; 41 (04) 373-375.
  • 27 Mangel AW, Koegel A. Effects of peptides on gastric emptying. Am J Physiol 1984; 246 (4 Pt 1) G342-345.
  • 28 Holzer P. Stimulation and inhibition of gastrointestinal propulsion induced by substance P and substance K in the rat. Br J Pharmacol 1985; 86 (01) 305-312.
  • 29 Valdovinos MA, Thomforde GM, Camilleri M. Effect of putative carcinoid mediators on gastric and small bowel transit in rats and the role of 5-HT receptors. Aliment Pharmacol Ther 1993; 7 (01) 61-66.
  • 30 Schmitz S, Failing K, Neiger R. Solid phase gastric emptying times in the dog measured by 13C-sodium-acetate breath test and 99mTechnetium radioscintigraphy. Tierärztl Prax 2010; 38(K): 211-216.
  • 31 Wyse CA, McLellan J, Dickie AM, Sutton DGM, Preston T, Yam PS. A review of methods for assessment of the rate of gastric emptying in the dog and cat: 1898-2002. J Vet Intern Med 2003; 17 (05) 609-621.
  • 32 Wyse CA, Preston T, Love S, Morrison DJ, Cooper JM, Yam PS. Use of the 13C-octanoic acid breath test for assessment of solid-phase gastric emptying in dogs. Am J Vet Res 2001; 62 (12) 1939-1944.
  • 33 Craig H. Isotopic standards for carbon and oxygen and correction factors for mass-spectrometric analysis of carbon dioxide. Geochim Cosmochim Acta 1957; 12 (12) 133-149.
  • 34 Allescher HD, Kostolanska F, Tougas G, Fox JE, Regoli D, Drapeau G. et al. The actions of neurokinins and substance P in canine pylorus, antrum and duodenum. Peptides 1989; 10 (03) 671-679.
  • 35 Milenov K, Oehme P, Bienert M, Bergmann J. Effect of substance P on mechanical and myoelectrical activities of stomach and small intestines in conscious dog. Arch Int Pharmacodyn Ther 1978; 233 (02) 251-260.
  • 36 Nakazato Y, Sekine H, Isogaya M, Ito S, Ohga A. Atropine- and hexamethonium-resistant motor response to greater splanchnic nerve stimulation in the dog stomach. J Auton Nerv Syst 1987; 20 (01) 35-42.
  • 37 Fox JE, McDonald TJ. Motor effects of gastrin releasing peptide (GRP) and bombesin in the canine stomach and small intestine. Life Sci 1984; 35 (16) 1667-1673.
  • 38 Itoh Z, Takeuchi S, Aizawa I, Couch EF. Inhibitory effect of pentagastrin and feeding natural and motilin-induced interdigestive contractions in the stomach of conscious dogs. Gastroenterol Jpn 1977; 12 (04) 284-288.
  • 39 Maggi CA, Schwartz TW. The dual nature of the tachykinin NK1 receptor. Trends Pharmacol Sci 1997; 18 (10) 351-355.
  • 40 Holzer P, Holzer-Petsche U. Tachykinin receptors in the gut: physiological and pathological implications. Curr Opin Pharmacol 2001; 1 (06) 583-590.
  • 41 Boillat CS, Gaschen FP, Gaschen L, Stout RW, Hosgood GL. Variability associated with repeated measurements of gastrointestinal tract motility in dogs obtained by use of a wireless motility capsule system and scintigraphy. Am J Vet Res 2010; 71 (08) 903-908.
  • 42 Richards RD, Valenzuela GA, Davenport KG. et. al. RW. Objective and subjective results of a randomized, double-blind, placebo-controlled trial using cisapride to treat gastroparesis. Dig Dis Sci 1993; 38 (05) 811-816.
  • 43 Takeda M, Tsukamoto K, Yamano M, Uesaka H. Effects of SK-951, a benzofuran derivative, as a prokinetic agent in rats and dogs. Jpn J Pharmacol 1999; 81 (03) 292-297.
  • 44 Iwanaga Y, Wen J, Thollander MS, Kost LJ, Thomforde GM, Allen RG. et al. Scintigraphic measurement of regional gastrointestinal transit in the dog. Am J Physiol 1998; 275 (5 Pt 1) G904-910.
  • 45 Peterson L, Gaschen L, Otamendi A, Stout R, Gaschen F. Ultrasound evaluation of the effects of various prokinetics administered intravenously on gastric and duodenal motility in healthy dogs. Journal of Veterinary Internal Medicine ACVIM Forum Proceedings. 2013: 709
  • 46 Ariga H, Nakade Y, Tsukamoto K, Imai K, Chen C, Mantyh C. et al. Ghrelin accelerates gastric emptying via early manifestation of antro-pyloric coordination in conscious rats. Regul Pept 2008; 146 (13) 112-116.
  • 47 Trudel L, Bouin M, Tomasetto C, Eberling P, St-Pierre S, Bannon P. et al. Two new peptides to improve post-operative gastric ileus in dog. Peptides 2003; 24 (04) 531-534.