Effects of an EP2 and EP3 Receptor Dual Agonist, ONO-8055, on a Radical Hysterectomy-Induced Underactive Bladder Model in Monkeys.

Abstract

OBJECTIVES:

The objective was to develop an underactive bladder (UAB) model in primates and to evaluate the potential of prostanoid EP2 and EP3 receptor dual agonist ONO-8055 to become a therapeutic agent for UAB.

METHODS:

A surgical procedure resembling radical hysterectomy was performed on female cynomolgus monkeys. Subsequently, in vitro muscle strip studies were performed using bladder muscle strips from normal monkeys and monkeys that underwent surgery. In addition, uroflowmetric data were obtained at specified days after the surgery. To evaluate the effects of ONO-8055 and distigmine (DIS) on voiding function in the UAB monkey model, uroflowmetry was performed approximately 1 week after the surgery, before and after the cumulative intravenous administration of the compounds at 2 h intervals.

RESULTS:

In the bladder muscle strip studies, the responses to potassium chloride at 2 months, and carbachol and electrical field stimulation from 2 weeks decreased significantly. Voided volume (VV), maximum flow rate (Qmax), and average flow rate (Qave) decreased after surgery, while voiding time (VT) increased. In this model, ONO-8055 and DIS significantly increased VV and Qmax. DIS prolonged VT, while ONO-8055 had no effect. The results also showed that ONO-8055 increased Qave.

CONCLUSIONS:

We developed a neurogenic UAB model in primates. As ONO-8055 improved voiding function in this model to at least the same degree as DIS, this EP2 and EP3 receptor dual agonist has the potential to be a candidate for neurogenic UAB pharmacotherapy.

• Authors: Hidekazu Matsuya, Noritoshi Sekido, Jun Kida, Hiroko Mashimo, Daisuke Wakamatsu, Hiroki Okada
• Journal: Lower urinary tract symptoms (Low Urin Tract Symptoms) Vol. 10 Issue 2 Pg. 204-211 (May 2018) ISSN: 1757-5672 [Electronic] Australia
• PMID: 28439968 (Publication Type: Journal Article)
• Copyright: © 2017 John Wiley & Sons Australia, Ltd.

Chemical References

• Cholinesterase Inhibitors
• ONO-8055
• Pyridinium Compounds
• Receptors, Prostaglandin E, EP2 Subtype
• Receptors, Prostaglandin E, EP3 Subtype
• Thiazoles
• distigmine

Topics

• Animals
• Cholinesterase Inhibitors (pharmacology)
• Disease Models, Animal
• Female
• Hysterectomy (methods)
• Macaca fascicularis
• Muscle Contraction (drug effects)
• Pyridinium Compounds (pharmacology)
• Receptors, Prostaglandin E, EP2 Subtype (antagonists & inhibitors)
• Receptors, Prostaglandin E, EP3 Subtype (antagonists & inhibitors)
• Rheology
• Thiazoles (pharmacology)
• Urinary Bladder, Neurogenic (drug therapy, physiopathology)
• Urination (drug effects)