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The effects of oral administration of the novel muscarinic receptor antagonist DA-8010 on overactive bladder in rat with bladder outlet obstruction.

ABSTRACT: BACKGROUND:DA-8010 is a novel compound developed for the treatment of overactive bladder (OAB) and urinary incontinence. The aims of this study were to investigate the effects of DA-8010 on OAB in a rat model. METHODS:Study animals were divided into the following five groups of seven animals each: a sham-operated control group, a control group with partial bladder outlet obstruction (BOO) (OAB group), and three DA-8010 (doses of 0.3?mg/kg/day, 1?mg/kg/day, and 3?mg/kg/day, respectively) with partial BOO groups. Oral administration of the drugs was continued for 14?days after 2 weeks of partial BOO. After 4 weeks of partial BOO, cystometrography was performed in all groups. Additionally, pro-inflammatory cytokines, Rho-kinases, and histology of the bladder were analyzed. RESULTS:There was a significant increase in the contraction interval and a decrease in contraction pressure in the 3?mg/kg/day DA-8010 group versus those in the OAB group. Rho kinase was also significantly decreased in the DA-8010 3?mg/kg/day dosage treatment group. The increased ratio of collagen to smooth muscle after partial BOO was significantly attenuated in the DA-8010 3?mg/kg/day dosage group. CONCLUSIONS:Oral administration of DA-8010 at 3?mg/kg/day improved findings in an OAB rat model induced by partial BOO. Our results suggest that the novel muscarinic receptor antagonist DA-8010 may be a promising drug for treating patients with OAB.

SUBMITTER: Choi JB

PROVIDER: S-EPMC7164290 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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The effects of oral administration of the novel muscarinic receptor antagonist DA-8010 on overactive bladder in rat with bladder outlet obstruction.

Choi Jin Bong JB Jeon Seung Hwan SH Kwon Eun Bi EB Bae Woong Jin WJ Cho Hyuk Jin HJ Ha U-Syn US Hong Sung-Hoo SH Lee Ji Youl JY Kim Sae Woong SW

BMC urology 20200417 1

<h4>Background</h4>DA-8010 is a novel compound developed for the treatment of overactive bladder (OAB) and urinary incontinence. The aims of this study were to investigate the effects of DA-8010 on OAB in a rat model.<h4>Methods</h4>Study animals were divided into the following five groups of seven animals each: a sham-operated control group, a control group with partial bladder outlet obstruction (BOO) (OAB group), and three DA-8010 (doses of 0.3 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day, respect ...[more]

PMID: 32303205

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Project description:PurposeDA-8010 is a novel muscarinic M3 receptor antagonist with significant selectivity for bladder over salivary gland in preclinical studies. We evaluated the clinical efficacy and safety of DA-8010 in overactive bladder (OAB) patients.MethodsThis phase 2, randomized, double-blind, parallel-group, active reference- and placebo-controlled trial was conducted at 12 centers in South Korea (NCT03566134). Patients aged ≥19 years with OAB symptoms for ≥3 months were enrolled. Three hundred six patients (30.07% male) were randomized to 12 weeks of treatment among 4 groups; 2 experimental groups (DA-8010 2.5 or 5 mg), an active reference group (solifenacin 5 mg), and a placebo group. The change from the baseline of (=∆) 24-hour frequency at 12 weeks (primary endpoint), episodes of urgency, overall/urgency urinary incontinence, average/ maximum voided volume, nocturia, and patients' subjective responses were analyzed.ResultsIn the full analysis set, the mean (standard deviation) [median] values for ∆ 24-hour frequency at 12 weeks were -1.01 (2.44) [-1.33] for placebo, -1.22 (2.05) [-1.33] for DA-8010 2.5 mg, and -1.67 (2.25) [-1.67] for DA-8010 5 mg; DA-8010 5 mg showed a significant decrease compared with placebo (P=0.0413). At 4 and 8 weeks, both DA-8010 2.5 mg (P=0.0391 at 4 weeks, P=0.0335 at 8 weeks) and DA-8010 5 mg (P=0.0001 at 4 weeks, P=0.0210 at 8 weeks) showed significant decrease in ∆ 24-hour frequency compared with placebo. DA-8010 5 mg achieved a significant decrease in ∆ number of urgency episodes, compared with placebo at 4 (P=0.0278) and 8 (P=0.0092) weeks. Adverse drug reactions (ADRs) were observed in 3.95% of placebo, 6.67% of DA-8010 2.5 mg, 18.42% of DA-8010 5 mg, and 17.33% of solifenacin 5 mg groups. No serious ADRs were observed in any patient.ConclusionBoth DA-8010 2.5 mg and 5 mg showed therapeutic efficacy for OAB without serious ADRs. Therefore, both dosages of DA-8010 can advance to a subsequent large-scale phase 3 trial.

Dataset Information

The effects of oral administration of the novel muscarinic receptor antagonist DA-8010 on overactive bladder in rat with bladder outlet obstruction.

Publications

The effects of oral administration of the novel muscarinic receptor antagonist DA-8010 on overactive bladder in rat with bladder outlet obstruction.

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