Can J Physiol Pharmacol. 2023 Jan 30. doi: 10.1139/cjpp-2022-0498. Online ahead of print.
ABSTRACT
The feasibility of eliciting defecation and urination after intranasal (IN) or sublingual (SL) delivery of a small peptide NK2 receptor agonist, [Lys5,MeLeu9,Nle10]-NKA(4-10) (LMN-NKA), was examined using prototype formulations in dogs. In anesthetized animals, administration of 100 or 300 μg/kg IN or 2.0-6.7 mg/kg SL increased colorectal peak pressure and area under the curve (AUC). Peak bladder pressure was also increased at the same doses, and this was accompanied by highly efficient voiding at normal physiological bladder pressures. The onset of these effects was rapid (<2.5 min), and the primary contractions lasted ~25 min, returning to baseline in <60 min. Slight hypotension lasting a few minutes and causing <10% change from baseline was detected after higher doses and was statistically significant after only 100 μg/kg IN. In conscious dogs, there was a dose-related increase in voiding responses and reduction in the latency to urinate and defecate after 300 and 1,000 μg/kg IN; emesis was also observed at these doses. SL administration of 6.7 mg/kg induced urination within 10 min, but not defecation or emesis. These findings support the feasibility of developing a convenient dosage form of small peptide NK2 receptor agonists as on-demand defecation or urination therapies.
PMID:36716436 | DOI:10.1139/cjpp-2022-0498
