Abstract. To construct a non-clinical database for drug-induced QT interval prolongation, the electrophysiological effects of 11 positive and 10 negative compounds on action potentials (AP) in guinea-pig papillary muscles were investigated in a multi-site study according to a standard protocol. Compounds with a selective inhibitory effect on the rapidly activated delayed rectifier potassium current (I Kr ) prolonged action potential duration at 90% repolarization (APD 90 ) in a concentration-dependent manner, those showing Ca 2+ current (I Ca ) inhibition shortened APD 30 , and those showing Na + current (I Na ) inhibition decreased action potential amplitude (APA) and V max . Some of the mixed ion-channel blockers showed a bell-shaped concentration-response curve for APD 90 , probably due to their blockade of I Na and / or I Ca , sometimes leading to a falsenegative result in the assay. In contrast, all positive compounds except for terfenadine and all negative compounds with I Kr -blocking activity prolonged APD 30-90 regardless of their I Na -and / or I Ca -blocking activities, suggesting that APD 30-90 is a useful parameter for evaluating the I Krblocking activity of test compounds. Furthermore, the assay is highly informative regarding the modulation of cardiac ion channels by test compounds. Therefore, when APD 90 and APD 30-90 are both measured, the action potential assay can be considered a useful method for assessing the risk of QT interval prolongation in humans in non-clinical safety pharmacology studies. Supplementary material (Appendix): available only at http://dx

Imidafenacin (KRP-197) is a novel antimuscarinic agent for overactive bladder treatment. The inhibitory effect of imidafenacin on detrusor contraction has been adopted for assessing their bladder selectivity, but this is becoming less convincing as an effectiveness index. We, therefore, reevaluated the bladder selectivity of imidafenacin and other antimuscarinics using their effects on the bladder capacity as an effectiveness index. Bladder capacity was measured by intermittent cystometry in urethane-anesthetized rats. In the tissues related to antimuscarinic side effects, the inhibitory actions were measured each on salivary secretion by electrical stimulation of chorda tympani, on rhythmical contractions in colon, and on carbamylcholine-induced bradycardia. Imidafenacin, solifenacin succinate, tolterodine tartrate, and propiverine hydrochloride significantly increased the bladder capacity, with minimum effective doses of 0.003, 1, 0.03, and 3 mg/kg (i.v.), respectively. The antimuscarinics tested, except for propiverine hydrochloride, shared a common property of increasing bladder capacity at a dose which did not affect micturition pressure. The relative bladder selectivity of imidafenacin, solifenacin succinate, and tolterodine tartrate was 15-, 1.7-, and 2.5-fold higher over salivary gland; 150-, 1.9-, and 9.2-fold higher over colon; and 50-, 12-, and 4.6-fold higher over heart, respectively, than that of propiverine hydrochloride. Thus, imidafenacin shows the most highly selective for bladder over the tissues related to major antimuscarinic side effects, compared to the other three well-known antimuscarinics tested in the rat.

Imidafenacin (CAS 170105-16-5, KRP-197, ONO-8025) has been developed for the treatment of overactive bladder as a new anti-cholinergic with high affinities for muscarinic acetylcholine M3 and M1 receptors. The pharmacological profiles of imidafenacin on the urinary bladder function by determining carbamylcholine (CCh)-induced decrease in bladder capacity and distention-induced rhythmic bladder contraction in conscious rats were investigated. In addition, effects of imidafenacin on CCh-induced salivary secretion and performance in the Morris water maze task in rats were investigated to evaluate side effects, such as dry mouth and cognitive dysfunction in the central nervous system (CNS). Imidafenacin prevented the CCh-induced decrease in bladder capacity dose-dependently with an ID50 of 0.055 mg/kg. On the distention-induced rhythmic bladder contraction, imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects with ID30's of 0.17, 15, 3.0, 3.2 and 0.85 mg/kg, respectively. The rank order of inhibitory potency was: imidafenacin > darifenacin > tolterodine > or = oxybutynin > propiverine. Imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects on the CCh-stimulated salivary secretion with ID50's of 1.5, 14, 15, 4.4 and 1.2 mg/kg, respectively. The rank order of inhibitory potency was: darifenacin > or = imidafenacin > oxybutynin > propiverine > or = tolterodine. Imidafenacin at the doses of 1 and 10 mg/ kg did not affect the escape latencies in the Morris water maze task compared with those in vehicle controls. Oxybutynin at the dose of 100 mg/kg induced a significant increase in the escape latencies, but propiverine at the dose of 100 mg/kg did not induce significant changes. These results suggest that imidafenacin inhibits urinary bladder contraction to a greater extent than the salivary secretion (compared with the M3 receptor selective antagonist, darifenacin, and the non-selective antagonists, propiverine, tolterodine and oxybutynin) or the CNS functions, such as performance in the Morris water maze task (compared with oxybutynin). In conclusion, imidafenacin has organ selectivity for the bladder over the salivary gland, without influence on the central nervous system such as spatial learning and memory.

Abstract. Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayedrectifier potassium currents (I Kr ) and / or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on I Kr and / or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD 30-60 , APD 60-90 , and APD 30-90 , respectively) were calculated as the new parameters. All the 15 I Kr and / or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD 30-60 , APD 60-90 , and / or APD 30-90 ; and 8 of the 15 inhibitors prolonged APD 30-60 , APD 60-90 , and / or APD 30-90 more potently than APD 90 . The APD 30-60 , APD 60-90 , and APD 30-90 measurements revealed no difference in sensitivity when evaluating the effects of the I Kr and / or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD 30-60 , APD . Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD 30-60 , APD 60-90 , and APD 30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on I Kr and / or hERG currents. Supplementary material (Appendix): available only at http://dx