Effect of an ATP-Sensitive Potassium Channel Opener in Subjects with Overactive Bladder: A Randomized, Double-Blind, Placebo-Controlled Study (ZD0947IL/0004)

Chapple, Christopher R.; Patroneva, Albena; Raines, Shane

doi:10.1016/j.eururo.2006.01.037

Cited by 50 publications

(17 citation statements)

References 17 publications

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“…Treatment was generally safe and well tolerated, but ZD0947 was not superior to placebo [93]. Newer KCOs, such as ZD6169, have been claimed to be more selective for the bladder than first-generation KCOs [91,92], although other investigators did not confirm this selectivity.…”

Section: Fig 1 Hypothetical Model That Depicts the Possible Interactmentioning

confidence: 92%

“…ZD0947, a novel KCO, also markedly inhibited myogenic phasic contractility in HBSM strips and a randomized, double-blind, placebo-controlled phase II study evaluated its efficacy and safety (25 mg/day for 12 weeks) in patients with OAB [93]. Treatment was generally safe and well tolerated, but ZD0947 was not superior to placebo [93].…”

Section: Fig 1 Hypothetical Model That Depicts the Possible Interactmentioning

confidence: 99%

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Emerging pharmacological targets in overactive bladder therapy: experimental and clinical evidences

2008

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Antimuscarinics are the mainstay of the medical therapy for overactive bladder, but their side effects and often modest success have prompted studies on novel pharmacological approaches. In this paper, we give a systematic literature review of peer-reviewed papers on the subject. Effective nonantimuscarinic treatments are currently scarce, but many new promising compounds are emerging, which target key molecular pathways involved in micturition control. The most promising potential therapeutic targets include: nervous GABAergic, glycinergic, dopaminergic, and serotonergic systems; b-adrenoceptors and cAMP metabolism; nonadrenergic-noncholinergic mechanisms such as purinergic and neuropeptidergic systems; vanilloid receptors; bladder afferent nerves; nonneuronal bladder signaling systems including urothelium and interstitial cells; prostanoids; Rho-kinase; and different subtypes of potassium and calcium channels. Despite the enormous amount of new biologic insight, very few drugs with mechanism of action other than antimuscarinics have passed as yet the proof-of-concept stage. Further preclinical and clinical studies are urgently needed in this rapidly moving field.

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Section: Fig 1 Hypothetical Model That Depicts the Possible Interactmentioning

confidence: 92%

Section: Fig 1 Hypothetical Model That Depicts the Possible Interactmentioning

confidence: 99%

Emerging pharmacological targets in overactive bladder therapy: experimental and clinical evidences

2008

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“…Activation of big potassium channels in the human bladder has shown to reduce neurogenic contractions but has no effect on myogenic contractions [95]. A double-blind randomized placebocontrolled trial with 229 participants failed to show that ZD0947 25 mg was superior to placebo in treating OAB [96]. Another Phase II trial was terminated due to unexpected frequent hepatotoxicity [97].…”

Section: Gene Therapymentioning

confidence: 98%

Emerging drugs for overactive bladder

Karmarkar

Khullar

2015

Expert Opinion on Emerging Drugs

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“…The potential sites of action have made K + channels attractive targets and have also made K + channel openers promising candidates for the treatment of detrusor overactivity and overactive bladder (OAB) syndrome. However, K ATP channel openers, which have been reported to exert a relaxing effect on the rat bladder and reduce detrusor activity in various models [13][14][15][16], did not have any clinical efficacy in patients with OAB syndrome [17].…”

Section: Discussionmentioning

confidence: 99%

Effect of the SK/IK channel modulator 4,5‐dichloro‐1,3‐diethyl‐1,3‐dihydro‐benzoimidazol‐2‐one (NS4591) on contractile force in rat, pig and human detrusor smooth muscle

Nielsen¹,

Rode²,

Rahbek³

et al. 2011

BJU International

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minimum force between oscillations by 30 ± 5% ( n = 9) in pig detrusor strips ( P < 0.005). In the presence of 10 μ M NS4591, carbachol (1 μ M) induced rhythmic contractions with an amplitude and normalized mean power frequency (nmeanPF) of 8.4 ± 5.1% and 0.11 ± 0.06 mN root mean square (rms) Hz ( n = 12), respectively, vs. 21 ± 3.4% and 0.17 ± 0.04 mN rms Hz in control strips ( n = 13). Apamin induced 6-and 11-fold increases in amplitude and nmeanPF vs. 1.3-and 2-fold increases in control strips.• In human detrusor strips ( n = 15), the cumulative addition of NS4591 (1-30 μ M) significantly reduced the amplitude by 69 ± 11%, the nmeanPF by 78 ± 6% and the minimum force between carbachol-induced oscillations by 59 ± 5% ( P < 0.008). The addition of apamin (0.3 μ M) before application of 1 μ M carbachol abolished the effects of NS4591 on amplitude and partially abolished its effect on nmeanPF by 41 ± 7%, vs. a 78 ± 6% reduction in the absence of apamin ( n = 8).• In spontaneously active detrusor preparations, NS4591 reduced or abolished contractions.• Furthermore, NS4591 (10 μ M) decreased the carbachol-induced increase in the fura-2 ratio by 43 ± 3% compared with control ( n = 12) ( P < 0.03). CONCLUSIONS• The SK/IK channel modulator NS4591 inhibits EFS-and carbachol-induced contractions in rat, pig and human detrusor muscle.• NS4591 may have therapeutic potential for treatment of detrusor overactivity. KEYWORDS detrusor, SK channels, NS4591, OABWhat's known on the subject? and What does the study add? Increased urinary bladder detrusor smooth muscle phasic contractility has been suggested to be associated with idiopathic bladder overactivity. Small conductance Ca2 + -activated K + (SK 1-3) channels have attracted considerable interest as putative target for new therapeutic strategy for treating overactive bladder. These channels play an important role in regulating the function and activity of urinary bladder smooth muscle (UBSM), and the loss of SK channel function has been shown to increase UBSM excitability and contractility. However, it is not known whether activation of SK channels has the converse effect of reducing UBSM excitability and contractility. In this paper, we investigated this possibility in the rat, pig and human UBSM by using the novel SK channel opener NS4591. These studies demonstrate that the SK channel modulator NS4591 has a potential role as a pharmacological tool to study the involvement of SK (and IK) channels in mammals and rodents urinary bladder. NS4591 may have therapeutic potential for treatment of detrusor overactivity. OBJECTIVE • To investigate the importance of small (SK)-and intermediate (IK)-conductance Ca2+ -activated K + channels on bladder function, by studying the effects of 4,5-dichloro-1,3-diethyl-1,3-dihydrobenzoimidazol-2-one (NS4591), a new modulator of SK/IK channels, on contractions induced by electrical field stimulation (EFS) and carbachol in rat, pig and human detrusor. PATIENTS AND METHODS• Detrusor biopsies were obtained from rats, pigs and male patients unde...

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Effect of an ATP-Sensitive Potassium Channel Opener in Subjects with Overactive Bladder: A Randomized, Double-Blind, Placebo-Controlled Study (ZD0947IL/0004)

Cited by 50 publications

References 17 publications

Emerging pharmacological targets in overactive bladder therapy: experimental and clinical evidences

Emerging pharmacological targets in overactive bladder therapy: experimental and clinical evidences

Emerging drugs for overactive bladder

Effect of the SK/IK channel modulator 4,5‐dichloro‐1,3‐diethyl‐1,3‐dihydro‐benzoimidazol‐2‐one (NS4591) on contractile force in rat, pig and human detrusor smooth muscle

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