AbstractThe pharmacology of ecabapide (DQ-2511; 3-[2-(3,4-dimethoxyphenyl)ethylcarbamoylmethyl]amino-N-methylbenzamide) is reviewed.Evidence from basic studies in animal models suggests that the drug acts on peripheral mechanisms of neural control. In the stomach, ecabapide acts to suppress firing in vagal afferent nerves and thereby reduce the flow of sensory information into the dorsal vagal complex.The enhancement of the efferent discharge provoked by ecabapide was completely blocked by bilateral vagotomy, as suggested by increased firing in vagal efferent fibres, preceded by suppression of activity in the sensory limb of the putative vago-vagal reflex pathway.The mechanism of action of ecabapide in suppressing discharge in vagal afferent terminals appears to mimic that of nitric oxide by stimulating formation of cGMP and activation of an inhibitory transduction cascade in the sensory fibres. In this respect the mechanism of its pro-kinetic action differs from other promoter agents. In addition to selective actions in the stomach, evidence from electrophysiological studies of enteric neurons in the small intestine suggests that ecabapide might have actions similar to those of other substituted benzamides on synaptic transmission in the intramural nervous system of this specialized region of the digestive tract. These actions include enhanced release of acetylcholine at excitatory synapses and suppression of the release of noradrenaline at inhibitory synapses.

01 Jan 2000·Journal of the Autonomic Nervous System

Modulation of gastrointestinal afferent sensitivity by a novel substituted benzamide (ecabapide)

Article

Author: W Jiang ; D Grundy

The effects of ecabapide, a novel substituted benzamide compound (3-[2-(3,4-dimethoxyphenyl)ethylcarbamoylmethyl]amino-N-methylb enzamide) that has gastrointestinal prokinetic action, were examined on the discharge of extrinsic afferent nerves supplying the stomach and jejunum in anaesthetized rats. Ecabapide (60 and 180 microg kg(-1), i.v.) had no effect on the baseline discharge of vagal gastric distension-sensitive afferents or the stimulus-response profile to gastric distension. Ecabapide also had no effect on either spontaneous jejunal mesenteric afferent nerve discharge or responses to intestinal distension. Ecabapide (180 microg kg(-1)) significantly inhibited the maximum discharge of jejunal afferents induced by cholecystokinin (CCK8; 50 pmol, i.v.), whereas it failed to inhibit the excitatory action of 2-methyl-5-hydroxytryptamine (2Me-5-HT; 10 microg, i.v.), a selective 5-HT3 receptor agonist. A model of acute focal intestinal ischaemia was used to evaluate the actions of ecabapide on the discharge of activated jejunal afferents. Ischaemia produced a substantial increase in afferent discharge which was reproducible when the duration of ischaemia was limited to less than 10 min and repeated every 15 min. Ecabapide at doses of 60 and 180 microg kg(-1) significantly reduced ischaemia-induced increases in afferent discharge. In addition to its therapeutic efficacy as a gastrointestinal prokinetic agent, these findings show also that ecabapide may also have an inhibitory action on the discharge of intestinal afferents activated by ischaemia.

01 Jan 1999·XenobioticaQ4 · MEDICINE

Identification of cytochromes P450 involved in human liver microsomal metabolism of ecabapide, a prokinetic agent

Q4 · MEDICINE

Article

Author: Y Fujimaki ; T Inaba ; N Arai

1. In vitro studies identified the hepatic cytochrome P450 (CYP) enzyme(s) involved in the major metabolism of ecabapide in human. 2. Ecabapide mainly underwent N-dealkylation to form M1 and 6-hydroxylation of the benzamide moiety to form M6. 3. The rates of formation of the major metabolites M1 and M6 were significantly correlated with CYP3A-selective testosterone 6beta-hydroxylase activities in 14 different human liver microsomes. The formation of both metabolites was markedly decreased by ketoconazole, miconazole or troleandomycin (TAO), CYP3A-selective inhibitors, and also was inhibited by anti-CYP3A antibodies. 4. These results strongly indicate that CYP3A is the predominant isozyme responsible for the major metabolism of ecabapide in human liver microsomes. 5. Marginal inhibition of the formation of M1 and M6 by nifedipine, a substrate of CYP3A with a Ki > 100 microM, suggested that nifedipne has a limited potential to inhibit the major metabolic pathways of ecabapide.

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Indication	Highest Phase	Country/Location	Organization	Date
Gastritis	NDA/BLA	-	Daiichi Sankyo Co., Ltd.	-
Gastritis	Preclinical	JP	Daiichi Pharmaceutical Co., Ltd.	-

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