Effects of Oral Mitemcinal (GM-611), Erythromycin, EM-574 and Cisapride on Gastric Emptying in Conscious Rhesus Monkeys

Onoma, Mitsu; Koto, Masao; Ōmura, Satoshi; Takanashi, Hisanori

doi:10.1007/s10620-007-9951-9

Cited by 18 publications

(12 citation statements)

References 31 publications

(48 reference statements)

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“…Bell-shaped dose-response curves have been reported in experimental animal models when evaluating the therapeutic efficacy of prokinetic drugs such as cisapride, itopride, and tegaserod. [25][26][27] The reason for these dose-dependent effects of CTE and corydaline on GI motility is not clear, although there are several Fig. 3.…”

Section: )mentioning

confidence: 99%

Effects of Corydaline from Corydalis Tuber on Gastric Motor Function in an Animal Model

Lee

Son

Kim

2010

Biological & Pharmaceutical Bulletin

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Functional dyspepsia (FD) is a highly prevalent chronic gastrointestinal (GI) disorder that causes a considerable burden to both the patient and society. Although the etiology and pathogenesis of FD are poorly understood, FD is associated with pathophysiologic abnormalities including delayed gastric emptying (GE), impaired gastric accommodation, and visceral hypersensitivity.1,2) Delayed GE has been reported in 30-40% of FD patients, 3) and a number of studies have demonstrated impaired gastric accommodation after meals in approximately 40% of patients. 4) Given these results, we hypothesized that GE of a semi-solid meal, GI transit, and gastric accommodation would be suitable markers for evaluating motor effects in animal models.Corydalis tubers, the roots of Corydalis yahusuo W.T. WANG (Papaveraceae), have long been used as herbal medicine for their analgesic and anti-ulcer effects. It has been reported that Corydalis tuber extracts exhibit several biological activities, acting as both an anti-spasmodic agent in the GI tract and as an analgesic. [5][6][7][8] Previous phytochemical studies reported that Corydalis tubers are made up primarily of alkaloid compounds including corydaline, berberine, protopine, and palmatine. [8][9][10][11][12] These alkaloid compounds are reported to provide the analgesic, anti-spasmodic, and anti-acetylcholinesterase activities associated with Corydalis tubers. Of these compounds, corydaline is considered the marker compound for quality control of Corydalis extract; however, the pharmacological effects of corydaline on GI motor function have not yet been studied.We previously investigated the prokinetic activities of corydaline to determine its potential bioactivity in FD and elucidated the basis of the selection of corydaline as the principal marker compound for quality control. 13) In the present study, we evaluated the effects of corydaline on GE and GI transit in rats and gastric accommodation in conscious dogs. MATERIALS AND METHODS Plant MaterialPlant material was commercially purchased at Kyungdong herbal market (Seoul, Korea) and identified by Dr. S. Choi at the Research Center of Dong-A Pharm. Co., Ltd. (Yongin-si, Korea). A voucher specimen has been deposited in our laboratory at Kyung Hee University.Extraction and Isolation Dried Corydalis tuber (30 kg) was extracted with 50% aqueous ethanol three times at room temperature. Upon removal of the solvent under vacuum, the ethanolic extract yielded 2.85 kg of material (Corydalis tuber extract, CTE; 7.6% by dry weight). We found that the CTE contained corydaline, palmatine, berberine, and other isoquinoline alkaloids. Based on HPLC analysis, the prescribed range of index components including corydaline and palmatine was detected in the CTE. The CTE was suspended in H 2 O and partitioned successively with n-hexane, ethyl acetate (EtOAc), and n-butanol. The EtOAc-soluble fraction (15 g) of the extract was subjected to a silica gel column using mixtures of n-hexane-EtOAc of increasing polarity as eluents to give 12 sub-fraction...

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Section: )mentioning

confidence: 99%

Effects of Corydaline from Corydalis Tuber on Gastric Motor Function in an Animal Model

Lee

Son

Kim

2010

Biological & Pharmaceutical Bulletin

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“…In fact, abnormalities of GI function are frequently modeled in nonhuman primates. These experiments have included models of simian immunodeficiency virus-induced enteropathy (Orandle et al, 2007; Raffatellu et al, 2008) and inflammatory bowel disease and colitis (McKenna et al, 2008; Raffatellu et al, 2009), as well as study of pharmacological agents affecting GI motility (Yogo et al, 2008). Additionally, extensive investigation into neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease has been performed in nonhuman primates.…”

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Neurochemical phenotypes of myenteric neurons in the rhesus monkey

Noorian

Taylor

Annerino

et al. 2011

J of Comparative Neurology

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Understanding the neurochemical composition of the enteric nervous system (ENS) is critical for elucidating neurological function in the gastrointestinal (GI) tract in health and disease. Despite their status as the closest models of human neurological systems, relatively little is known about enteric neurochemistry in nonhuman primates. We describe neurochemical coding of the enteric nervous system, specifically the myenteric plexus, of the rhesus monkey (Macaca mulatta) by immunohistochemistry and directly compare it to human tissues. There are considerable differences in the myenteric plexus along different segments of the monkey GI tract. While acetylcholine neurons make up the majority of myenteric neurons in the stomach (70%), they are a minority in the rectum (47%). Conversely, only 22% of gastric myenteric neurons express nitric oxide synthase (NOS) compared to 52% in the rectum. Vasoactive intestinal peptide (VIP) is more prominent in the stomach (37%) versus the rest of the GI tract (10%), and catecholamine neurons are rare (1%). There is significant coexpression of NOS and VIP in myenteric neurons that is more prominent in the proximal GI tract. Taken as a whole, these data provide insight into the neurochemical anatomy underlying GI motility. While overall similarity to other mammalian species is clear, there are some notable differences between the ENS of rhesus monkeys, humans, and other species that will be important to take into account when evaluating models of human diseases in animals.

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“…This method gives a good picture of gastric emptying because paracetamol is not absorbed from the stomach, but is rapidly absorbed from the small intestine 26 . The paracetamol method has been widely used to assess gastric emptying in humans and in several animal species, including dogs 16,18,26,30–36 . However, plasma paracetamol may be affected by liver or renal dysfunction because, after absorption from the small intestine, paracetamol is predominantly metabolised in the liver and excreted from the kidney 37 .…”

Section: Discussionmentioning

confidence: 99%

“…Mitemcinal (GM‐611), a new erythromycin‐derived motilin agonist, has the advantages of being orally active and devoid of antibacterial activity 14–17 . This agent has been shown to stimulate gastrointestinal motility and accelerate gastric empting better than erythromycin and other erythromycin derivatives, even after oral administration, in conscious dogs and monkeys 17,18 . In clinical studies, mitemcinal has improved both delayed gastric emptying 19 and symptoms in patients with diabetic gastroparesis, with minimal side‐effects 20 …”

Section: Introductionmentioning

confidence: 99%

Mitemcinal (Gm‐611), an Orally Active Motilin Receptor Agonist, Improves Delayed Gastric Emptying in a Canine Model of Diabetic Gastroparesis

Onoma

Monnai²,

Muramatsu

et al. 2008

Clin Exp Pharma Physio

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1. The aim of the present study was to evaluate the effects of mitemcinal (GM-611), an orally active motilin receptor agonist, on delayed gastric emptying in a canine model of diabetic gastroparesis and to compare these effects with those of cisapride. 2. Moderate hyperglycaemia was induced by a single intravenous injection of a mixture of streptozotocin (30 mg/kg) and alloxan (50 mg/kg). Dogs that maintained moderate hyperglycaemia (fasting plasma glucose 200-300 mg/dL) without insulin treatment were selected and gastric emptying in these dogs was determined by the paracetamol method. 3. One year after the onset of diabetes, there was no difference in the gastric emptying of normal and diabetic dogs. However, after 5 years, the diabetic dogs showed delayed gastric emptying. The motor nerve conduction velocity of the tibial nerve was significantly lower in diabetic dogs compared with normal dogs at both time points. 4. Histopathological examination at the end of the study showed that there were fewer nerve fibres in both dorsal vagal and tibial nerves of diabetic dogs compared with normal dogs. The onset of delayed gastric emptying is thought to have occurred gradually, in parallel with abnormal autonomic nerve function induced by the long period of moderate hyperglycaemia. 5. Oral administration of mitemcinal (0.125, 0.25 or 0.5 mg/kg) dose-dependently accelerated delayed gastric emptying, significant at 0.5 mg/kg, in diabetic dogs, whereas cisapride (1, 3 or 10 mg/kg) had no significant effect. These results add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis.

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Effects of Oral Mitemcinal (GM-611), Erythromycin, EM-574 and Cisapride on Gastric Emptying in Conscious Rhesus Monkeys

Cited by 18 publications

References 31 publications

Effects of Corydaline from Corydalis Tuber on Gastric Motor Function in an Animal Model

Effects of Corydaline from Corydalis Tuber on Gastric Motor Function in an Animal Model

Neurochemical phenotypes of myenteric neurons in the rhesus monkey

Mitemcinal (Gm‐611), an Orally Active Motilin Receptor Agonist, Improves Delayed Gastric Emptying in a Canine Model of Diabetic Gastroparesis

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