Comparative Analysis of the Effects of Antimuscarinic Agents on Bladder Functions in Both Nonhuman Primates and Rodents

Nagabukuro, Hiroshi; Villa, Katherine L.; Wickham, L. Alexandra; Kulick, Alison; Gichuru, Loise; Donnelly, Marcie J.; Voronin, Gregory; Pereira, Tony; Tong, Xinchun; Alves, Stephen E.; O’Neill, Gary P.; Johnson, Christopher V.; Hickey, Emily

doi:10.1124/jpet.111.179747

Cited by 11 publications

(12 citation statements)

References 38 publications

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“…Baseline values of urodynamic parameters in vehicle-and vibegron-treated animals are as follows: bladder capacity, 156.8 6 21.6 ml (vehicle), 123.7 6 10.7 ml (vibegron); micturition pressure, 36.7 6 1.6 cm H 2 O (vehicle), 35.5 6 2.8 cm H 2 O (vibegron); bladder compliance, 15.0 6 2.2 ml/cm H 2 O (vehicle), 16.6 6 2.8 ml/cm H 2 O (vibegron). As in the previous study (Nagabukuro et al, 2011), vehicle had no statistically significant effect on any of parameters. Vibegron increased bladder capacity in a dose-dependent manner (Fig.…”

Section: Resultssupporting

confidence: 70%

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Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder

Salvo

Nagabukuro

Wickham

et al. 2016

J Pharmacol Exp Ther

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Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of β-adrenergic receptors (βARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel βAR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of βAR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full βAR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a βAR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel βAR agonist probe, [H]MRL-037, that selectively labels β receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of βAR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

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Section: Resultssupporting

confidence: 70%

“…Cystometry in Rhesus Monkeys. Cystometry was performed as described previously (Nagabukuro et al, 2011). In brief, rhesus monkeys were anesthetized with an intramuscular injection of Telazol (5 mg/kg) or ketamine HCl (20 mg/kg) followed by intravenous constant rate infusion with ketamine HCl (0.2-0.3 mg/kg/min).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder

Salvo

Nagabukuro

Wickham

et al. 2016

J Pharmacol Exp Ther

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“…3b,c,d). Similar results have been reported using urethane-anesthetized rats and cerebral infarction rats [11,13,24]. As one of putative mechanisms behind these, Yamada et al [25] indicated that imidafenacin excreted in urine may contribute to its selective and long-lasting distribution in the bladder, because imidafenacin showed a significant binding to bladder muscarinic receptors in rats following intravesical injection at concentration levels similar to its urine concentrations after oral administration in rats as well as healthy volunteers.…”

supporting

confidence: 69%

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

Fukata¹,

Yamazaki²

2016

Drug Res (Stuttg)

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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 ?1-adrenoceptor agonist A-61603 (0.03??g/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.

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“…Antimuscarinics suppress detrusor smooth muscle activity and inhibit DO; however, urinary urgency and frequency, which are both alleviated by antimuscarinics, are bladder storage symptoms. Because parasympathetic activity is usually absent during bladder storage, antimuscarinics work to improve these symptoms by acting on afferents found within the urothelium 2 .…”

Section: Neuronal Control Of Micturitionmentioning

confidence: 99%

Past, Present and Future of Chemodenervation with Botulinum Toxin in the Treatment of Overactive Bladder

et al. 2017

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Purpose We systematically reviewed both pre-clinical and clinical studies on bladder chemodenervation with onabotulinumtoxin A to highlight current limitations and future drug delivery approaches. Materials and Methods We identified peer-reviewed basic and clinical research studies of onabotulinumtoxin A (onaBoNT-A) in the treatment of neurogenic bladder and refractory idiopathic overactive bladder (OAB) published between March 2000 and March 2016. Paired investigators independently screened 125 English language articles to identify controlled studies on onaBoNT-A administration in MEDLINE® database and abstracts presented at annual American Urological Association meetings. The review yielded an evidence base of over 50 articles relevant to the approach of injection free onaBoNT-A chemodenervation. Results The efficacy and safety of intradetrusor injection of onaBoNT-A for the treatment of OAB is sensitive to both injection volume and depth, and this issue has motivated researchers to study injection-free modes of drug delivery into the bladder. Urothelial denudation with protamine sulfate or dimethyl sulfoxide (DMSO), liposome encapsulated onaBoNT-A, and other physical approaches are all being studied to increase toxin permeability and avoid intradetrusor injections. Liposome encapsulated onaBoNT-A enhances toxin activity while reducing its toxin degradation. The safety and efficacy of liposome encapsulated onaBoNT-A was tested in a multi-center, placebo controlled study. Although this treatment successfully reduced urinary frequency and urgency, it did not significantly reduce urgency urinary incontinence episodes. Conclusions Intradetrusor injection of onaBoNT-A is safe and effective as reported in several large multicenter randomized controlled trials. Injection of the toxin into the bladder wall impairs both afferent and efferent nerves, but drug delivery approaches that avoid injections impair only bladder afferent nerves. Further studies are needed to develop better drug delivery platforms that overcome the drawbacks of intradetrusor injection, increase patient acceptance, and reduce the treatment costs.

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Comparative Analysis of the Effects of Antimuscarinic Agents on Bladder Functions in Both Nonhuman Primates and Rodents

Cited by 11 publications

References 38 publications

Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder

Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder

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

Past, Present and Future of Chemodenervation with Botulinum Toxin in the Treatment of Overactive Bladder

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