Efficacy of acotiamide hydrochloride hydrate added to α‐blocker plus cholinergic drug combination therapy

Excitatory effect of acotiamide on rat and human bladder: Implications for underactive bladder treatment

“…The excitatory effect of acotiamide is linked to the acceleration of TTX-sensitive and extracellular Ca 2+ dependent EFS evoked ACh release in the [ 3 H]-choline-preincubated gastric antrum and body of rat and dog at doses greater than 10 −6 M (Ogishima et al, 2000). Moreover, acotiamide mediated enhancement of EFS evoked ACh release was higher in the presence of physostigmine, which suggests that direct AChE inhibition by acotiamide (Doi et al, 2004) may have modest contribution to the efficacy of acotiamide in DU patients (Sugimoto et al, 2019, Sugimoto et al, 2017, Sugimoto et al, 2015 and in the findings described here.…”

“…Taking our experimental findings and the clinical results (Sugimoto et al, 2019, Sugimoto et al, 2017, Sugimoto et al, 2015 together, it is likely that the excitatory effect of acotiamide in bladder may involve action on nicotinic autoreceptors on cholinergic nerve terminals (Prior and Singh, 2000), which warrants investigation in future studies. Several clinical studies have now compared the direct and indirect cholinergic agonists in UAB patients with intact voiding reflex and reported that indirect cholinergic agonist like Distigmine works better than Bethanechol (Izumi et al, 2014).…”

“…This is a first report demonstrating a direct excitatory effect of Acotiamide on the neural modulation of rat and human bladder contractility mainly through prejunctional mechanisms (Ogishima et al, 2000). Acotiamide is known to decrease the PVR of DU patients and resolve urinary retention of female patients with thrice daily oral treatment of 100 mg for 2 weeks (Sugimoto et al, 2019, Sugimoto et al, 2017, Sugimoto et al, 2015. Clinically used dose of acotiamide (Sugimoto et al, 2017, Sugimoto et al, 2015 is said to generate plasma concentration in the range of 2μM (Yoshii et al, 2016).…”

“…1) in its pharmacophore instead of an ester bond of acetylcholine and the carbamate bond of Bethanechol or cholinesterase inhibitors failed to functionally antagonize recombinant M3 receptors expressed on oocytes in concentrations upto 100 μM (Doi et al, 2004). Furthermore, daily oral treatment of acotiamide (approved gastroprokinetic agent in Asian countries) led to a significant reduction of PVR in DU patients (Sugimoto et al, 2019, Sugimoto et al, 2017, Sugimoto et al, 2015 without the blockade of post-junctional M 3 receptor signaling. Following study seeks to answer the question, whether acotiamide (Z-338) (Tyagi et al, 2019) has a direct excitatory action on nerve-mediated bladder contractions via pharmacological antagonism of prejunctional muscarinic receptors.…”