Comparative Influence of Imidafenacin and Oxybutynin on Voiding Function in Rats with Functional Urethral Obstruction

306 Original Article Comparative Influence of Imidafenacin and Oxybutynin on Voiding Function in Rats with Functional Urethral Obstruction Authors A. Fukata, T. Yamazaki Affiliation Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan Key words Abstract Intravenous imidafenacin and oxybutynin pro- ●▶ overactive bladder ▼ duced a significant dose-dependent decrease in ●▶ benign prostatic hyperplasia An antimuscarinic therapy may increase the risk Qmax with the minimum doses of 0.03 and 1 mg/ ●▶ imidafenacin of voiding dysfunction. However, it is unclear kg, respectively. Imidafenacin and oxybutynin ●▶ oxybutynin ●▶ urinary flow whether the relative risk of voiding dysfunction markedly increased BC, with minimum doses is different among antimuscarinics. Therefore of 0.01 and 3 mg/kg, respectively. At the mini- we determined the potencies both in enhanc- mum dose to increase BC, oxybutynin caused ing the bladder capacity (BC), effectiveness, and a significant increase in residual urine volume in decreasing the maximum urinary flow rate with a significant decrease in voiding efficiency, (Qmax), voiding dysfunction, to compare their whereas imidafenacin had no influence on these therapeutic indices. values. The relative influence index, which is the Under urethane anesthesia, urinary flow rate ratio of the minimum influence dose between was measured at distal urethra using an ultra- in decreasing of Qmax and in increasing of BC, sonic flow meter in female Sprague-Dawley rats of imidafenacin was 10 fold higher than that of with functional urethral obstruction induced by oxybutynin. a continuous i. v. infusion of α1-adrenoceptor This study suggests that imidafenacin has a lower agonist A-61603 (0.03 μg/kg/min). In a separate relative risk of voiding difficulty compared with group of urethane-anesthetized rats without oxybutynin in rats. These results provide new received 29.10.2015 urethral obstruction, an intermittent cystometry information that antimuscarinics may have vary- accepted 11.02.2016 was performed to determine BC. ing degrees of impact on voiding difficulty. Bibliography DOI http://dx.doi.org/ Introduction antimuscarinics theoretically have an ability to 10.1055/s-0035-1569410 induce AUR [5]. In addition, BPH per se is typi- Published online: ▼ March 15, 2016 Antimuscarinic drugs are widely used for treat- cally responsible for AUR because of intrinsically Drug Res 2016; ment of overactive bladder (OAB), which is char- narrowed urethra. Thus, prescribing antimus- 66: 306–311 acterized by storage symptoms, such as urinary carinics for BPH patients could further aggravate This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. © Georg Thieme Verlag KG urgency. Although the clinical efficacy of anti- voiding dysfunction. Nevertheless, some data Stuttgart · New York muscarinics has been well established, their from recent clinical trials suggest that the inci- ISSN 2194-9379 mechanism-based adverse reactions often result dence of AUR in antimuscarinic therapy is infre- in poor compliance and in turn limiting their quent ( < 1 %), even in male patients with BPH [1]. Correspondence clinical usefulness. The most common and both- However, the results reported may have underes- A. Fukata Watarase Research Center ersome of such adverse reactions include dry timated the true incidence of this adverse reac- Kyorin Pharmaceutical Co., Ltd. mouth and constipation [1]. Another significant tion, because these trials were of short duration 1848 Nogi concern and potentially harmful reaction of anti- and included the patients with low post-void Nogi-machi muscarinics is acute urinary retention (AUR) in residual urine volume (RV) at baseline. Indeed, Shimotsuga-gun male patients, especially those with bladder out- Radomski [6] described, according to his data- Tochigi 329-0114 let obstruction due to benign prostatic hyperpla- base study that AUR risk is somewhat higher (the Japan sia (BPH), and indeed OAB symptoms frequently rate of 2.5 %) in real life clinical practice. Further- Tel.: + 81/280/57 1551 Fax: + 81/280/57 2336 accompany BPH [2–4]. Because muscarinic more, above-mentioned clinical trials have con- [email protected] receptors (mainly via M3 subtype) play a pivotal sistently been reported to increase the post-void pharm.co.jp role in contracting detrusor smooth muscles, RV in antimuscarinic therapy, indicating the Fukata A, Yamazaki T. Influence of Antimuscarinics on Voiding … Drug Res 2016; 66: 306–311 Original Article 307 impairment of voiding function [1]. Therefore, despite the ing dysfunction in terms of relative therapeutic index. Oxybu- absence of definitive evidence, it is recommended that OAB tynin was selected for comparison because it was a representative patients, especially those associated with BPH, should be care- of the first-generation of antimuscarinic drugs that has been fully monitored for post-void RV to avoid inadvertent AUR dur- intensively investigated for the AUR [19]. ing the antimuscarinic therapy [7]. Adverse reaction profiles of the existing antimuscarinics may be different depending on their selectivity for specific subtypes of Materials and Methods muscarinic receptor, their tissue selectivity (organ specificity) ▼ for bladder, their physicochemical properties, as well as their Animals pharmacokinetic properties [1]. In fact, clinical studies have Female Sprague-Dawley rats (Charles River Laboratories Japan, shown that a new generation of antimuscarinics with higher Kanagawa, Japan), weighing 210–280 g, were housed in a room selectivity for the M3 muscarinic receptor subtype and/or blad- maintained under controlled conditions 23 ± 3 °C, 55 ± 15 % RH, der tissue has a comparable efficacy with first-generation anti- and 12:12-h light-dark cycle. The rats had free access to food muscarinic oxybutynin but has fewer adverse reactions, mainly pellets and tap water. All animal care/experiments and the study dry mouth [8]. On the other hand, diminishing adverse effects protocol complied with the guidelines of the Committee for the on voiding function was probably considered more difficult to Purpose of Control and Supervision of Experiments on Animals achieve, because antimuscarinics had been traditionally believed and were approved, prior to the study, by the Institutional Ani- to exert their therapeutic action on OAB by reducing detrusor mal Ethics Committee at Kyorin Pharmaceutical Co., Ltd. Our muscle contraction via blockade of M3 subtype [9]. More facility is certified as an animal testing research institute by the recently, however, Finney et al. [10] found that at least in a range Japan Health Sciences Foundation, established under the juris- of usual therapeutic doses, antimuscarinics primarily act during diction of the Japanese Ministry of Health, Labor and Welfare. storage phase of micturition cycle, resulting in decreasing urgency and increasing bladder capacity (BC), whereas they Pressure-flow measurement in urethane-anesthetized have little or no influence on detrusor muscle contraction dur- rats with functional urethral obstruction ing voiding phase. Similarly basic researches with experimental Pressure-flow study (a simultaneous recording of urinary flow animal models of OAB have reported that low doses of antimus- rate and intravesical pressure) was performed by a slight modi- carinics significantly increase BC without influence on voiding fication of the method reported by Streng et al. [20]. Although contractions, and their increasing effect is significantly inhibited Streng et al. used the continuous cystometry in their study, we by sensory denervation induced by resiniferatoxin [11]. These used the intermittent cystometry, because the continuous cys- findings suggest that some regulatory involvement of antimus- tometry does not allow to measure the residual urine volume. In carinics in afferent nerve activity during the storage phase con- brief, under urethane anesthesia (1.2 g/kg, s.c.), a lower abdomi- tributes to their therapeutic effect, but such involvement may be nal midline incision was made to expose the bladder. A saline- absent in efferent activity during voiding phase. filled polyethylene catheter (PE50; Japan Becton Dickinson, Imidafenacin, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbu- Tokyo, Japan) was inserted into the bladder dome. The catheter tanamide, belongs to a new generation of antimuscarinics with was connected via a 3-way cock to a pressure transducer (Nihon high affinity for the1 M /M3 muscarinic receptor subtypes and Kohden, Tokyo, Japan) for measurement of the intravesical pres- high bladder selectivity [12, 13], and was approved for treating sure and to a syringe pumps (Harvard Apparatus, Holliston, MA, OAB in Japan in 2007. A randomized, double-blind, controlled USA) for saline infusion. The bone of symphysis pubis was cut trial (RCT) demonstrated that imidafenacin is as efficacious as a vertically to expose the urethra. An ultrasonic flow probe first-generation antimuscarinic drug propiverine but has better (MC2.5PSB; Transonic Systems, Ithaca, NY, USA) was placed adverse reaction profiles [14]. Antimuscarinics are currently around the distal urethra and connected to a transit-time flow recommended as a useful addition to drug regimens for BPH meter (TS420, Transonic Systems) for the measurement of actual patients with predominantly OAB symptom. Recent RCTs in urinary flow rate. The intravesical pressure and the urinary flow male BPH patients with OAB symptoms reported that antimus-

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