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Drug Res (Stuttg) 2016; 66(06): 306-311
DOI: 10.1055/s-0035-1569410
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

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

A. Fukata
1   Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan
,
T. Yamazaki
1   Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan
› Author Affiliations
Further Information

Publication History

received 29 October 2015

accepted 11 February 2016

Publication Date:
15 March 2016 (online)

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Abstract

An antimuscarinic therapy may increase the risk of voiding dysfunction. However, it is unclear whether the relative risk of voiding dysfunction is different among antimuscarinics. Therefore we determined the potencies both in enhancing the bladder capacity (BC), effectiveness, and in decreasing the maximum urinary flow rate (Qmax), voiding dysfunction, to compare their therapeutic indices.

Under urethane anesthesia, urinary flow rate was measured at distal urethra using an ultrasonic flow meter in female Sprague-Dawley rats with functional urethral obstruction induced by a continuous i. v. infusion of α1-adrenoceptor agonist A-61603 (0.03 μg/kg/min). In a separate group of urethane-anesthetized rats without urethral obstruction, an intermittent cystometry was performed to determine BC.

Intravenous imidafenacin and oxybutynin produced a significant dose-dependent decrease in Qmax with the minimum doses of 0.03 and 1 mg/kg, respectively. Imidafenacin and oxybutynin markedly increased BC, with minimum doses of 0.01 and 3 mg/kg, respectively. At the minimum dose to increase BC, oxybutynin caused a significant increase in residual urine volume with a significant decrease in voiding efficiency, whereas imidafenacin had no influence on these values. The relative influence index, which is the ratio of the minimum influence dose between in decreasing of Qmax and in increasing of BC, of imidafenacin was 10 fold higher than that of oxybutynin.

This study suggests that imidafenacin has a lower relative risk of voiding difficulty compared with oxybutynin in rats. These results provide new information that antimuscarinics may have varying degrees of impact on voiding difficulty.

Key words

overactive bladder - benign prostatic hyperplasia - imidafenacin - oxybutynin - urinary flow
 

  • References

  • 1 Athanasopoulos A, Giannitsas K. An overview of the clinical use of antimuscarinics in the treatment of overactive bladder. Advances in urology 2011;
    PubMedGoogle Scholar
  • 2 Martín-Merino E, García-Rodríguez LA, Massó-González EL et al. Do oral antimuscarinic drugs carry an increased risk of acute urinary retention?. The Journal of urology 2009; 182: 1442-1448
    CrossrefPubMedGoogle Scholar
  • 3 Verhamme KMC, Sturkenboom MCJM, Stricker BHC et al. Drug-induced urinary retention: incidence, management and prevention. Drug safety 2008; 31: 373-388
    CrossrefPubMedGoogle Scholar
  • 4 Afonso ASM, Verhamme KMC, Stricker BHC et al. Inhaled anticholinergic drugs and risk of acute urinary retention. BJU international 2011; 107: 1265-1272
    CrossrefPubMedGoogle Scholar
  • 5 Loke YK, Singh S. Risk of acute urinary retention associated with inhaled anticholinergics in patients with chronic obstructive lung disease: systematic review. Therapeutic advances in drug safety 2013; 4: 19-26
    CrossrefPubMedGoogle Scholar
  • 6 Radomski SB. Update on medical therapy for male LUTS. Canadian Urological Association journal=Journal de l’Association des urologues du Canada 2014; 8: S148-S150
    PubMedGoogle Scholar
  • 7 Hao N, Tian Y, Liu W et al. Antimuscarinics and α-blockers or α-blockers monotherapy on lower urinary tract symptoms – a meta-analysis. Urology 2014; 83: 556-562
    CrossrefPubMedGoogle Scholar
  • 8 Woderich R, Fowler CJ. Management of lower urinary tract symptoms in men with progressive neurological disease. Current opinion in urology 2006; 16: 30-36
    PubMedGoogle Scholar
  • 9 Andersson K-E. Storage and voiding symptoms: pathophysiologic aspects. Urology 2003; 62: 3-10
    PubMedGoogle Scholar
  • 10 Finney SM, Andersson K-E, Gillespie JI et al. Antimuscarinic drugs in detrusor overactivity and the overactive bladder syndrome: motor or sensory actions?. BJU international 2006; 98: 503-507
    CrossrefPubMedGoogle Scholar
  • 11 Yokoyama O, Tanaka I, Kusukawa N et al. Antimuscarinics suppress adenosine triphosphate and prostaglandin E2 release from urothelium with potential improvement in detrusor overactivity in rats with cerebral infarction. The Journal of urology 2011; 185: 2392-2397
    CrossrefPubMedGoogle Scholar
  • 12 Kobayashi F, Yageta Y, Segawa M et al. Effects of imidafenacin (KRP-197/ONO-8025), a new anti-cholinergic agent, on muscarinic acetylcholine receptors. High affinities for M3 and M1 receptor subtypes and selectivity for urinary bladder over salivary gland. Arzneimittel-Forschung 2007; 57: 92-100
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Yamazaki T, Muraki Y, Anraku T. In vivo bladder selectivity of imidafenacin, a novel antimuscarinic agent, assessed by using an effectiveness index for bladder capacity in rats. Naunyn-Schmiedeberg’s archives of pharmacology 2011; 384: 319-329
    PubMedGoogle Scholar
  • 14 Homma Y, Yamaguchi O. A randomized, double-blind, placebo- and propiverine-controlled trial of the novel antimuscarinic agent imidafenacin in Japanese patients with overactive bladder. International journal of urology 2009; 16: 499-506
    CrossrefPubMedGoogle Scholar
  • 15 Nishizawa O, Yamaguchi O, Takeda M et al. Randomized controlled trial to treat benign prostatic hyperplasia with overactive bladder using an alpha-blocker combined with anticholinergics. LUTS: Lower Urinary Tract Symptoms 2011; 3: 29-35
    CrossrefPubMedGoogle Scholar
  • 16 Chapple C, Herschorn S, Abrams P et al. Tolterodine treatment improves storage symptoms suggestive of overactive bladder in men treated with alpha-blockers. European urology 2009; 56: 534-543
    CrossrefPubMedGoogle Scholar
  • 17 Yamaguchi O, Kakizaki H, Homma Y et al. Solifenacin as add-on therapy for overactive bladder symptoms in men treated for lower urinary tract symptoms–ASSIST, randomized controlled study. Urology 2011; 78: 126-133
    PubMedGoogle Scholar
  • 18 Takeda M, Nishizawa O, Gotoh M et al. Clinical efficacy and safety of imidafenacin as add-on treatment for persistent overactive bladder symptoms despite α-blocker treatment in patients with BPH: the ADDITION study. Urology 2013; 82: 887-893
    CrossrefPubMedGoogle Scholar
  • 19 Homma Y, Paick JS, Lee JG et al. Clinical efficacy and tolerability of extended-release tolterodine and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: a randomized, placebo-controlled trial. BJU international 2003; 92: 741-747
    CrossrefPubMedGoogle Scholar
  • 20 Streng T, Santti R, Talo A. Similarities and differences in female and male rat voiding. Neurourology and urodynamics 2002; 21: 136-141
    CrossrefPubMedGoogle Scholar
  • 21 Nagabukuro H, Hashimoto T, Iwata M et al. Effects of TAK-802, a novel acetylcholinesterase inhibitor, and tamsulosin, an alpha1-adrenoceptor antagonist, and their synergistic effects on the urodynamic characteristics in a guinea-pig model of functional bladder outlet obstruction. BJU international 2005; 95: 1071-1076
    CrossrefPubMedGoogle Scholar
  • 22 Knepper SM, Buckner SA, Brune ME et al. A-61603, a potent alpha 1-adrenergic receptor agonist, selective for the alpha 1A receptor subtype. The Journal of pharmacology and experimental therapeutics 1995; 274: 97-103
    PubMedGoogle Scholar
  • 23 Ney P, Pandita RK, Newgreen DT et al. Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivo. BJU international 2008; 101: 1036-1042
    CrossrefPubMedGoogle Scholar
  • 24 Nagabukuro H, Villa KL, Wickham LA et al. Comparative analysis of the effects of antimuscarinic agents on bladder functions in both nonhuman primates and rodents. Journal of pharmacology and experimental therapeutics 2011; 338: 220-227
    CrossrefPubMedGoogle Scholar
  • 25 Yamada S, Seki M, Ogoda M et al. Selective binding of bladder muscarinic receptors in relation to the pharmacokinetics of a novel antimuscarinic agent, imidafenacin, to treat overactive bladder. The Journal of pharmacology and experimental therapeutics 2011; 336: 365-371
    CrossrefPubMedGoogle Scholar
  • 26 Mansfield K. Muscarinic receptor antagonists, the overactive bladder and efficacy against urinary urgency. Clinical Medicine Insights: Therapeutics 2010; 2: 471-480
    PubMedGoogle Scholar
  • 27 Ohno T, Nakade S, Nakayama K et al. Absolute bioavailability of imidafenacin after oral administration to healthy subjects. British journal of clinical pharmacology 2008; 65: 197-202
    CrossrefPubMedGoogle Scholar
  • 28 Andersson K-E, Fullhase C, Soler R. Urothelial effects of oral agents for overactive bladder. Current urology reports 2008; 9: 459-464
    CrossrefPubMedGoogle Scholar
  • 29 Yono M, Yoshida M, Wada Y et al. Pharmacological effects of tolterodine on human isolated urinary bladder. European journal of pharmacology 1999; 368: 223-230
    CrossrefPubMedGoogle Scholar
  • 30 Davila GW, Daugherty CA, Sanders SW. A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. The Journal of urology 2001; 166: 140-145
    CrossrefPubMedGoogle Scholar