Comparative evaluation of DQ‐2511, a novel gastroprokinetic agent, with cisapride in ameliorative action on experimentally induced delayed gastric emptying

Abstract

We compared the main pharmacological effect of DQ-2511 (3-[[[2-(3,4-dimethoxyphenyl)- ethyl]carbamoyl]methyl]amino-N-methylbenzamide), a novel gastroprokinetic agent, with that of cisapride. Single oral administration of DQ-2511 (3-10 mg kg-1) caused similar significant improvements to delays in gastric emptying of semi-solid meals evoked by cholecystokinin-octapeptide (CCK8: 5 micrograms kg-1, i.v.) in monkeys, to that with cisapride (3 mg kg-1). A 2-week oral treatment of unilaterally vagotomized rats with DQ-2511 (1-10 mg kg-1) lessened delays in gastric emptying, whereas cisapride (0.3-10 mg kg-1) had no effect under the same experimental protocols. In anesthetized rats, bolus intravenous injection of either compound (60 micrograms kg-1) enhanced gastric motility determined by means of strain gauge force transducers. Electrophysiological investigations revealed that bolus injection of DQ-2511 (6-60 micrograms kg-1) depressed the afferent discharge rate of the ventral gastric branch of the vagus nerve, while cisapride showed no effect. These results suggest that the mechanism of ameliorative action of DQ-2511 on delayed gastric emptying may differ from that of cisapride.

Ecabapide, a Novel Gastroprokinetic Agent, Ameliorates Gastric Emptying of Stroke-Prone Spontaneously Hypertensive Rats(SHRSP).

“…The facilitation of gastric emptying involves the sensory component of gastric inhibitory vago-vagal reflex circuits [5,7,13]. The data were supported by the fact that the enhancement of the efferent discharge provoked by ecabapide was completely blocked by bilateral vagotomy.…”

“…In that study, even though the pharmacological efficacy of ecabapide was evaluated 24 hr after the last treatment, ameliorative effects were noted. This phenomenon may be explained by the finding that after 14-day repeated oral treatment with isotope-labeled ecabapide, radioactivity remained selectively in the stomach muscle until 24 hr later [5]. Moreover, ecabapide was continuously secreted from the serosal to the mucosal side in the stomach.…”

“…This may have been due to differences in body weight of SHRSP used, since the semi-solid meal utilized for the measurement of gastric emptying was administered at a constant volume of 2 ml/rat containing 20 mg APAP. Based on the previous data [3,4,5] and the present results, it is proposed that ecabapide shows no possibility of tachyphylaxis. The therapeutically relevant dose of ecabapide is inferred from 100 mg three times a day orally for 2 consecutive weeks in patients with non-ulcer dyspepsia.…”

“…SHRSP receiving either 0.5% CMC (5 ml/kg) solution or the F-2 diet alone served as the vehicle control. The dosage levels used in the present study were chosen on the previous published reports [3][4][5]. Data are expressed as the mean ± standard deviation (SD), and were analyzed by Student's t-test or Dunnett's multiple comparison test.…”

Possible Mechanisms Underlying the Suppression of Gastric Vagal Afferents Due to Ecabapide (DQ-2511), a Gastroprokinetic Agent, in Rats.

“…Although the binding affinity of ecabapide to selective receptors has been exhaustively explored, it showed no specific binding (2,5). On the ba sis of the above studies, ecabapide was considered to exert its action via suppression of activation of afferents in the sensory component of gastric inhibitory vago-vagal reflex pathways (3,4). More recently, ecabapide was reported to stimulate the intracellular production of guanosine 3",5' cyclic monophosphate (cGMP) content (5,6) at a con centration as low as 10-' M when rabbit gastric parietal cells were used (7).…”