Presentation Authors: Min Jung Lee*, Jun-Hwan Moon, Hyung Keun Lee, Yongin, Korea, Republic of, Yoo Mi Shin, Hyun Soo Park, Young Nang Kim, Gi Seon Park, Byung Seok Moon, Byung Chul Lee, Sang Eun Lee, Seoul, Korea, Republic of
Introduction: Antimuscarinic agents are widely used as the first line therapy for overactive bladder (OAB). However, concerns have emerged about side effects of antimuscarinics in central nervous system (CNS). The aim of this study is to investigate the bladder selectivity of DA-8010, a novel antimuscarinic agent being developed for the treatment of OAB, over the brain in mice.
Methods: Carbachol-induced intravesical pressure (IVP) elevation was measured in female ICR mice administered intravenously at 5 min or orally at each time points (1, 2, 6, 12 and 24 h) with antimuscarinics prior to treatment of carbachol. Dynamic [11C](+)3-MPB PET studies were performed in mice intravenously administered with antimuscarinics, and regional brain non-displaceable binding potential of [11C](+)3-MPB to muscarinic receptors was calculated compared to control. The Y-maze test was conducted at 30 min after oral administration of antimuscarinics.
Results: Intravenous administration of DA-8010 and solifenacin produced dose-dependent decreases on carbachol-induced IVP elevation in mice, with mean ID30 of 0.012 and 0.637 mg/kg, respectively. Oral DA-8010 was effective on bladder for 12 h at 1 mg/kg and for 24 h at 3 mg/kg. In a PET study, there was a dose-dependent decrease in specific binding of [11C](+)3-MPB in brain regions of mice after i.v. injection of DA-8010 and solifenacin. The doses for 30% receptor occupancy (RO30) of DA-8010 and solifenacin in striatum, cortex, hippocampus, thalamus, and hypothalamus (Table 1) were higher than the ID30 on carbachol-induced IVP increases. In a Y-maze test, oral DA-8010 at 10 and 30 mg/kg had no effect on spontaneous alternation. There was no decrease in the number of total arm entries at any dose level for DA-8010, but it was significantly decreased in mice treated with 100 mg/kg solifenacin.
Conclusions: DA-8010 is highly selective for the urinary bladder over the brain, demonstrating that DA-8010 at a dose displaying significant effects on the bladder did not bind muscarinic receptors in the mouse brain regions, without any influence on locomotor activity and spatial short-term memory. The wide safety margin of DA-8010 suggests a decreased potential for CNS adverse effects in the treatment of OAB.