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NOTE Internal Medicine

Prokinetic Effect of the 5-HT4R Mosapride on Canine Gastric Motility

Atsushi TSUKAMOTO1), Koichi OHNO1)*, Shingo MAEDA1), Ko NAKASHIMA1), Kenjiro FUKUSHIMA1), Yasuhito FUJINO1) and Hajime TSUJIMOTO1)

1)Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1–1–1, Yayoi, Bunkyo-ku, Tokyo 113–8657, Japan

(Received 6 June 2011/Accepted 11 July 2011/Published online in J-STAGE 25 July 2011)

ABSTRACT. We assessed prokinetic action of gastroprokinetic agent, mosapride in dogs. Open-label cross-over study. Six healthy beagles were administered single oral mosapride at doses of 0.5, 0.75, 1, and 2 mg/kg 30 min prior to feeding, followed by 1-week interval. The motility index (MI) of gastric contraction was ultrasonographically evaluated by change rate of antral area and contraction number. Sig- nificant increases in MI were observed at doses of 0.75 mg/kg (mean  SEM, 11.11  0.19), 1 mg/kg (11.65  0.34), and 2 mg/kg (12.04  0.34), compared with that of the control (9.37  0.51). Mosapride administration (2.0 mg/kg, BID) for 1 week had no adverse effects on blood tests or health of the animals. In conclusion, 0.75 to 2 mg/kg of mosapride produces gastric prokinetic actions without adverse effects. KEY WORDS: canine, gastrointestinal clinical symptoms, . J. Vet. Med. Sci. 73(12): 1635–1637, 2011

Gastric motility disorders are induced by various patho- body weight ranged from 10.5 to 15.0 kg (median, 12.5 kg). logical conditions and may be associated with upper gas- Three dogs were male and 3 were female. None of the dogs trointestinal clinical symptoms, such as anorexia, nausea, or displayed any clinical symptoms prior to the experiments. vomiting [2, 12]. A prokinetic agent promotes gastrointesti- Food was offered twice daily. Experiments and animal care nal motor activity and is used for symptomatic treatment of complied with the policies outlined in the Guide to Animal gastrointestinal motility disorders. Several prokinetic Use and Care of the University of Tokyo. This study was agents have been developed in humans and some of them performed with open-label cross-over study design. The are utilized in dogs [7, 12]. dogs received mosapride at doses of 0.5, 0.75, 1, and 2 mg/ Mosapride citrate (mosapride), a selective 5-hydroxy- kg (Pronamid; DS Pharma Animal Health Co., Ltd.) fol- -4 receptor (5-HT4R) agonist, promotes the lowed by 1-week washout period. The gastric antral motil- release of acetylcholine from enteric nerves by activating 5- ity was ultrasonographically assessed after single HT4R, thereby enhancing gastrointestinal motility [5]. This administration of mosapride according to a previous report drug is widely used in humans as a prokinetic agent for the in dogs [11]. The tablet drug was ground into powder and control of dyspeptic symptoms of gastrointestinal disorders, dissolved in 15 ml of distilled water. Administration of dis- including chronic , functional dyspepsia, irritable tilled water (15 ml) was used as control. Gastric motility bowel syndrome (IBS), and gastroesophageal reflux disease after the single administration of mosapride at each dose (GERD) [5]. Mosapride is also registered as a prokinetic was compared with that of control. The order of the assess- agent in dogs (Pronamid; DS Pharma Animal Health Co., ment in the 6 dogs was randomly assigned and a washout Ltd., Osaka, Japan) in Japan and has been used for the con- period of at least 1 week was set between each experiment. trol of upper gastrointestinal symptoms, such as anorexia Thirty minutes after mosapride was administered, 10 g/kg of and vomiting, associated with gastrointestinal motility dis- commercial wet food (CIW; Intervet Schering-Plough Ani- orders. Previous reports demonstrated that mosapride (1 mal Health, Tokyo, Japan) was offered. Gastric antral mg/kg) enhanced gastric antral motility in dogs [8, 15], but motility was evaluated 30 min after feeding by using an the appropriate oral dose that produces prokinetic action ultrasound (Aplio 80 SSA-770A; Toshiba Medical Systems without any adverse effects has not been determined. The Corporation, Co., Ltd., Tochigi, Japan) with a 7.5-MHz main purpose of the present study was to assess the dose of phased array sector transducer. Dogs were restrained in the mosapride as oral drug that had gastric prokinetic action in right recumbent position, and the probe was adjusted for dogs. A safety evaluation in repeated administration of maximum visualization of the transverse image of the gas- mosapride was also performed. tric antrum close to the left lobe of the liver. The cross sec- Six healthy beagles were used in this study. The age of tion of the antral area was measured by tracing the serosal the dogs ranged from 5 to 6 years (median, 5.1 years) and margin of the antrum by using the built-in caliper. The antral area was measured 3 times in both the contracted and *CORRESPONDENCE TO: OHNO, K., Department of Veterinary Inter- nal Medicine, Graduate School of Agricultural and Life Sci- relaxed phases, and amplitude was calculated with the fol- ences, The University of Tokyo, 1–1–1 Yayoi, Bunkyo-ku, lowing formula: (mean area relaxed – mean area con- Tokyo 113–8657, Japan. tracted)/mean area relaxed. Next, frequency was e-mail: [email protected] determined by counting the number of antral contractions in 1636 A. TSUKAMOTO ET AL.

3 min. Motility index (MI), an indicator of gastric motility, examinations. was determined by the multiplication of amplitude and fre- Our study demonstrated that oral administration of quency. The same investigator performed all ultrasono- mosapride increases canine postprandial gastric motility in a graphic examinations. dose-dependent fashion within the dose of 2 mg/kg. How- Next, we evaluated the safety of repeated administration ever, a significant increase in gastric motility was not of mosapride in these dogs according to the result of blood observed when 0.5 mg/kg of mosapride was orally adminis- tests and clinical assessments. Dogs were administered tered to the dogs. This result is consistent with that of a pre- mosapride at a dose of 2 mg/kg twice daily for 1 week. vious report that evaluated the intravenous administration of Blood testing was performed before and after 1-week mosapride (AS-4370) in dogs. In that report, more than 1 administration of mosapride. Venous blood samples were mg/kg, but not 0.5 mg/kg, of mosapride enhanced the motil- collected into EDTA tubes for the measurement of red blood ity of the gastric antrum and duodenum in conscious dogs cell (RBC) counts, white blood cell (WBC) counts, differen- [15]. In humans, mosapride is usually prescribed at 5 mg tial WBC counts, hematocrit, hemoglobin concentration and TID for the treatment of gastrointestinal discomfort [5]. The platelet counts. Additional blood samples were collected dose of mosapride appears to be higher in dogs than that in into heparin tubes for analysis of blood chemistry (blood humans. This dose difference may be associated with dis- urea nitrogen, creatinine, alkaline phosphatase, alanine ami- similar bioavailability or metabolism. A previous report notransferase, aspartate aminotransferase, total bilirubin, indicated that the bioavailability of mosapride in dogs was glucose, total cholesterol, triglyceride, calcium, phosphate, lower than that in other species, such as monkeys [10]. Con- sodium, chloride, potassium, albumin, and total protein lev- sidering the present results and previous reports [8, 15], the els). During the medication period, the dogs were assessed recommended dose of mosapride in dogs is 0.75 to 2 mg/kg. for clinical symptoms 3 times a day, and physical examina- Doses of up to 2 mg/kg may be required in low-response tion was also performed. The clinical assessments were per- patients or cases of severe gastric motility disorders, such as formed by a veterinarian. gastroparesis. Further studies are required to evaluate the The difference in MI for each treatment was analyzed by prokinetic action of mosapride in gastric motility disorders one-way repeated measures of ANOVA. When significant, in dogs and the effect of oral mosapride administration on multiple comparisons were adjusted using Dunnett’s t test. canine intestinal motility. Results were expressed as mean ± SEM. P<0.05 was con- We evaluated the prokinetic action of mosapride by sidered as a significant difference. assessing the postprandial gastric antral motility in dogs. The difference in MI after administration of mosapride at Postprandial gastric motility function could be assessed each dose is shown in Fig. 1. The mean ± SEM of MI was either by gastric emptying assessment or gastric antral 9.37 ± 0.51 in the control, 9.99 ± 0.53 at 0.5 mg/kg, 11.11 ± motility evaluation. Gastric antral motility is regarded as 0.19 at 0.75 mg/kg, 11.65 ± 0.34 at 1 mg/kg, and 12.04 ± one of the major regulator of the gastric transit [4]. The 0.34 at 2 mg/kg. The MI increased dose-dependently and ultrasonographic method we used in the present study had significant increases in MI were observed at the doses of already confirmed the correlation with gastric emptying 0.75, 1, and 2 mg/kg, compared with that of the control. time determined by 13C-octanoic acid breath test in advance None of the dogs had any blood test abnormalities before [11]. Following our studies, further studies may be required or after the 1-week administration of mosapride (data not to investigate whether mosapride enhance the gastric emp- shown). Clinical adverse events were not observed in any of tying rate as well. the dogs, and there were no abnormalities on the physical We confirmed that repeated administration of mosapride in dogs for 1 week did not cause any adverse clinical effects or blood test abnormalities. The advantage of mosapride over several prokinetic agents in humans is its safety. Some gastroprokinetic agents, like , may cause sedation through receptors in the central nervous system [1, 6]. Mosapride has a high affinity for the 5-HT4R in the gastrointestinal tract and does not have affinity for the 5-hydroxytryptamine-1 (5-HT1), 5-hydroxytryptamine-2 (5- HT2), or Dopamine-2 (D2) receptors in the central nervous system [16]. Further to this study, longer safety assessments should be conducted in cases of canine gastric motility dis- order receiving mosapride. The pharmacological action of mosapride is similar to that of . Both agents enhance gastrointestinal motility by triggering acetylcholine release from enteric nerves subsequent to 5-HT4R stimula- Fig. 1. Difference in motility index (MI) after administration of tion. Cisapride had been used for the treatment of gas- mosapride at several doses in 6 dogs. Data are expressed as mean  SEM. * and ** indicate significant difference from the trointestinal motility disorders in humans and dogs [3, 12]. control at P<0.05 and P<0.01, respectively. However, cisapride has potent action on cardiac tissue, MOSAPRIDE IN DOGS 1637 which may inhibit the K+ channel, leading to cardiac adverse 6. Donald, C. and Plumb, P. D. 2008. Veterinary Drug Handbook, effects such as QT prolongation [9, 13]. Due to the cardiac Blackewell Publishing Proffesional, Iowa. adverse effects in human, cisapride was withdrawn from 7. Karamanolis, G. and Tack, J. 2006. Promotility medications— market and only available in experimental use [7, 13]. In now and in the future. Dig. Dis. 24: 297–307. contrast, it has been confirmed that mosapride has no effect 8. Kubota, K., Tatsutomi, Y., Kitajima, M., Mafune, K., Ohta, K., + Yoshida, M., Suwa, T., Kuroda, J., Hiki, N., Seto, Y. and on cardiac K channel and do not cause any cardiac adverse Kaminishi, M. Physiological evaluation of residual effects in both humans and dogs [5, 9, 14]. Mosapride can motility after local resection in conscious dogs. Surg. Today be an alternative prokinetic agent to cisapride for the treat- 41: 680–687. ment of gastrointestinal discomfort associated with upper 9. Potet, F., Bouyssou, T., Escande, D. and Baro, I. 2001. Gas- gastrointestinal motility disorders in dogs. trointestinal prokinetic drugs have different affinity for the In summary, oral mosapride administration dose-depen- human cardiac human ether-a-gogo K(+) channel. J. Pharma- dently increased canine postprandial gastric motility with- col. Exp. Ther. 299: 1007–1012. out causing any adverse effects within the dose of 2 mg/kg. 10. Sakashita, M., Mizuki, Y., Yamaguchi, T., Miyazaki, H. and We hope that this study will facilitate appropriate prescrip- Sekine, Y. 1993. 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