AE9C90CB: a novel, bladder-selective muscarinic receptor antagonist for the treatment of overactive bladder

Background and purpose:

AE9C90CB (N- [(1R, 5S, 6R)-3-azabicyclo [3.1.0] hex-6-ylmethyl]-2-hydroxy-N-methyl-2, 2-diphenylacetamide), a novel muscarinic receptor antagonist, was synthesized for the treatment of overactive bladder. Here we describe the in vitro and in vivo profiles of AE9C90CB for action in bladder over salivary gland and compare it with four agents already in clinical use (tolterodine, oxybutynin, solifenacin and darifenacin).

Experimental approach:

Radioligand binding assay and isolated tissue-based functional assay were used to evaluate affinity, potency, and receptor subtype selectivity of compounds. Inhibition of carbachol-induced increase in intravesicular pressure and salivary secretion were measured in anaesthetized rabbits to assess the functional selectivity.

Key results:

In vitro radioligand binding study using human recombinant muscarinic receptors showed that AE9C90CB had greater affinity for M₃ muscarinic receptors with pKi of 9.90 ± 0.11 and was 20-fold more selective for M₃ than for M₂ muscarinic receptors. AE9C90CB exhibited an unsurmountable antagonism on rat bladder strips (pK_B, 9.13 ± 0.12). In anaesthetized rabbits after intravenous administration, AE9C90CB dose dependently inhibited carbachol-induced increase in intravesicular pressure and salivary secretion, and exhibited functional selectivity for urinary bladder over salivary gland which was ninefold better than that of oxybutynin.

Conclusions and implications:

We have identified AE9C90CB, a compound exhibiting moderate selectivity for M₃ over M₂ receptors but greater selectivity for urinary bladder over salivary gland than oxybutynin, tolterodine, solifenacin and darifenacin. Therefore, AE9C90CB may be a promising compound for the treatment of overactive bladder with reduced potential to cause dry mouth than currently available antimuscarinic drugs.     

Fesoterodine: a novel muscarinic receptor antagonist for the treatment of overactive bladder syndrome

Background: Fesoterodine is a newly approved drug for the treatment of overactive bladder syndrome. Objective: The aim of this study was to review the preclinical and clinical data on fesoterodine. Methods: The study involved a search of the Medline database and the proceedings volumes of urological congresses. Results/conclusions: Fesoterodine functions as an orally active prodrug that is converted to the active metabolite 5-hydroxymethyltolterodine by non-specific esterases. 5-Hydroxymethyltolterodine is a muscarinic receptor antagonist. Fesoterodine is primarily eliminated as inactive metabolites along with significant renal excretion as the unchanged active metabolite 5-hydroxymethyltolterodine. Fesoterodine is indicated for use at doses of 4 and 8 mg once daily. In clinical studies both doses of fesoterodine were consistently superior to placebo in improving the symptoms of overactive bladder syndrome, with 8 mg/day having significantly greater effects than 4 mg/day.     

Tolterodine: a new antimuscarinic agent for the treatment of the overactive bladder

Bladder hyperactivity is a debilitating problem that affects many individuals. A plethora of therapeutic options have been investigated to combat this condition, antimuscarinic therapy being the most widely used. Nevertheless, this medication group has historically been of limited benefit, due to its side-effect profile. Tolterodine is a new muscarinic receptor antagonist that has been shown to be equally effective when compared to oxybutynin. However, the side-effect profile for tolterodine is much better than this commonly used anticholinergic. It has reduced affinity for the salivary glands in animal studies, and, in clinical trials, there has been a reduced incidence of dry mouth with this medication. In Phase III studies, tolterodine has been shown to decrease the number of micturitions per day, decrease the number of incontinence episodes per day and increase the mean volume voided per micturition. The maximal effect of this medication may not be seen for 6 - 8 weeks after initiation of the drug although the exact explanation for this finding has yet to be completely elucidated. The recommended dose is 2 mg b.i.d., which should be adjusted for those with liver failure or those on drugs that inhibit the cytochrome P450 isoenzyme known as CYP3A4. In summary, tolterodine is an effective well-tolerated antimuscarinic which should be considered as a first-line treatment due to its more favourable side-effect profile when than other available medications.     

Darifenacin: a muscarinic M3-selective receptor antagonist for the treatment of overactive bladder

Darifenacin is a novel, muscarinic M(3)-selective receptor antagonist with up to 59-fold selectivity for M(3) receptors compared with other muscarinic receptor subtypes and a low relative affinity for M(1) and M(2) receptors. This profile may explain its clinical efficacy in overactive bladder (OAB), the observed absence of adverse effects on cognitive function and reduced cardiovascular risks. Large-scale clinical trials have confirmed that darifenacin 7.5 and 15 mg/day provide rapid and meaningful improvement across a range of OAB symptoms, but with CNS and cardiac adverse event rates comparable to placebo. On this basis, darifenacin seems to meet the standard for an effective OAB pharmacotherapy that is well-tolerated and, more importantly, minimises the risk of safety-related adverse effects.     

Darifenacin: a novel M3 muscarinic selective receptor antagonist for the treatment of overactive bladder

Darifenacin is a novel M₃ muscarinic selective receptor antagonist for once-daily treatment of overactive bladder (OAB), a highly prevalent, chronic and debilitating disease defined by urinary urgency with or without urge incontinence, usually with increased frequency of micturition and nocturia. In vitro, darifenacin is a potent and specific muscarinic receptor antagonist with ≤ 59-fold higher selectivity for muscarinic M₃ receptors relative to other muscarinic receptor subtypes. This profile may, therefore, confer clinical efficacy in the treatment of OAB, with a lower propensity for adverse effects and safety issues related to blockade of other muscarinic receptor subtypes. Indeed, consistent with its low relative affinity for M₁ and M₂ receptors, no effects on cognitive function and heart-rate variability, respectively, have been observed with darifenacin. Subsequent large-scale clinical trials have confirmed that darifenacin (at doses of 7.5 and 15 mg/day) results in central nervous system and cardiac adverse events comparable to placebo, and provides early and meaningful improvement across a range of OAB symptoms including incontinence episodes, urgency and urinary frequency. On the basis of such findings, darifenacin would appear to meet the current need for an effective OAB pharmacotherapy that is efficacious, well-tolerated and, more importantly, minimises the risk of safety-related adverse effects.     

Darifenacin: a novel M3 muscarinic selective receptor antagonist for the treatment of overactive bladder

Darifenacin is a novel M3 muscarinic selective receptor antagonist for once-daily treatment of overactive bladder (OAB), a highly prevalent, chronic and debilitating disease defined by urinary urgency with or without urge incontinence, usually with increased frequency of micturition and nocturia. In vitro, darifenacin is a potent and specific muscarinic receptor antagonist with 相似文献   

Tolterodine for the treatment of overactive bladder

Background: The overactive bladder syndrome is a common condition affecting ～ 12% of men and women. It is extremely disturbing with a great impact on quality of life. Its treatment involves a combination of behavioural and pharmacological therapy. The latter includes antimuscarinic drugs such as tolterodine. Objective: To review the safety and efficacy of tolterodine in the treatment of overactive bladder in comparison with other available antimuscarinic agents. Methods: A Pubmed search was carried out differentiating randomised, clinical trials; longitudinal, retrospective studies; and metanalysis on the use of tolterodine for overactive bladder treatment. In the comparison with other antimuscarinic agents, only randomised, clinical trials were considered. Results/conclusion: Tolterodine is available as immediate- or extended-release formulations. It has been extensively evaluated with long-term, randomised trials for safety and efficacy showing a significant improvement in overactive bladder symptoms with an excellent tolerability profile.     

托特罗定缓释片治疗膀胱过度活动症的临床研究

目的评价酒石酸托特罗定缓释片治疗膀胱过度活动症的有效性与安全性。方法采用随机、双盲、双模拟平行对照的方法对膀胱过度活动症220例进行托特罗定缓释片剂型组（观察组,110例）和托特罗定原剂型组（对照组,110例）对比研究。托特罗定缓释片,每片4 mg,每日1次,口服;托特罗定片,每片2 mg,每日2次,口服。各连服6周。结果治疗后观察组24 h平均排尿次数由（12.21±3.10）次降至（8.50±2.31）次,24 h平均每次排尿量由（119.80±30.54）ml增至（215.50±68.52）ml、24 h平均尿失禁次数由（2.88±2.5）次减至（0.07±0.38）次。治疗前后比较,有极显著差异（P〈0.01）。两组治疗后相比较,无显著性差异。观察组对药物不良反应发生率为38.0%,中毒发生率为18.5%;对照组分别为40.8%和20.0%,总发生率两者无显著性差异（P〉0.05）。结论托特罗定缓释片与托特罗定片,其疗效与不良反应基本相同。但托特罗定缓释片,用药次数少,服用方便,为膀胱过度活动症治疗药物的最佳选择。     

Evidence for the efficacy and safety of tolterodine in the treatment of overactive bladder

Overactive bladder (OAB) is a chronic and prevalent condition, the symptoms of which (urinary frequency and urgency, with or without urge incontinence) can exert a profound negative effect on a person’s daily life activities. Tolterodine (Detrol^® in North America and Detrusitol^® in the rest of the world, Pharmacia), a competitive muscarinic antagonist, is the first agent of this class to be specifically developed for the treatment of OAB. This agent displays in vivo functional selectivity for the bladder over other tissues that contain muscarinic receptors (e.g., salivary glands, eye), which translates into good efficacy and tolerability in patients with OAB (including the elderly). Comparative, randomised, double-blind studies show that tolterodine (administered as immediate-release [IR] tablets 2 mg b.i.d.) is as effective as oxybutynin (5 mg t.i.d.) in improving all of the troublesome symptoms of OAB but with a significantly lower incidence and severity of dry mouth. The advent of a new extended-release (ER) capsule formulation of tolterodine (4 mg) for convenient once-daily treatment builds upon these findings, with significantly improved efficacy for reducing urge incontinence episodes and a lower frequency of dry mouth relative to the existing IR tablet (2 mg b.i.d.). Tolterodine can therefore be considered a valuable, well-tolerated treatment option for patients with OAB, providing improvements in symptoms that are both clinically meaningful to patients and sustained during long-term treatment.     

Pharmacological agents for the treatment of urinary incontinence due to overactive bladder

Although the exact aetiology of overactive bladder is unknown to date, pharmacological therapy has been targeted to both the central and peripheral nervous systems. Potential CNS targets include GABA, opioid, serotonin (5-HT), dopamine and glutaminergic receptors as well as the α-adrenoceptors. Potential PNS targets include muscarinic receptors, calcium and potassium channels and α- and β-adrenergic receptors. Since acetylcholine is the primary excitatory neurotransmitter involved in bladder (detrusor) contraction and emptying, anticholinergic agents are the primary compounds used clinically to decrease involuntary detrusor contractions. Anticholinergic therapy has a stabilising effect on the bladder (detrusor muscle); increases bladder capacity; decreases frequency of involuntary detrusor contractions; and delays the initial urge to void, but does not affect warning time. However, the clinical utility of antimuscarinic therapy is limited by the lack of receptor selectivity, resulting in the classic anticholinergic side effects of dry mouth, blurred vision, constipation and potentially, CNS effects such as somnolence and impaired cognitive function. These unwanted side effects often result in premature discontinuation of therapy and poor compliance. Previous attempts to develop uroselective α-adrenergic receptor antagonists have not been successful and although research continues, the hope that this class of agents would be viable alternatives to the anticholinergics remains to be proven in the clinical setting. The recent demise of several potassium channel openers does not augur well for the future of this class of agent. The reasons for the discontinuation of trials with these agents have not been fully elucidated, but one must assume that they were not uroselective and the cardiovascular side effects rendered them less than useful clinically. The serotonin re-uptake inhibitors appear to be promising novel therapeutic agents aimed at controlling bladder over-activity through specific CNS pathways. The sensory side of the micturition reflex is a potential therapeutic target. Agents to desensitise afferent nerve endings involved in C-fibre afferent reflexes include capsaicin and resiniferatoxin. Their clinical applicability is currently being evaluated. Finally, the recent findings related to the role of the P2X3 receptor in the sensory aspects of bladder filling have created new interest in the future development of agents that will improve the management of this prevalent and debilitating condition.     

In vivo and in vitro pharmacological characterization of SVT-40776, a novel M3 muscarinic receptor antagonist,for the treatment of overactive bladder

Background and purpose:

Highly selective M₃ muscarinic receptor antagonists may represent a better treatment for overactive bladder syndrome, diminishing side effects. Cardiac side effects of non-selective antimuscarinics have been associated with activity at M₂ receptors as these receptors are mainly responsible for muscarinic receptor-dependent bradycardia. We have investigated a novel antimuscarinic, SVT-40776, highly selective for M₃ over M₂ receptors (Ki = 0.19 nmol·L⁻¹ for M₃ receptor affinity). This study reports the functional activity of SVT-40776 in the bladder, relative to its activity in atria.

Experimental approach:

In vitro and ex vivo (oral dosing) inhibition of mouse detrusor and atrial contractile responses to carbachol were used to study the functional activity of SVT-40776. The in vivo efficacy of SVT-40776 was characterized by suppression of isovolumetric spontaneous bladder contractions in anaesthetized guinea pigs after intravenous administration.

Key results:

SVT-40776 was the most potent in inhibiting carbachol-induced bladder contractions of the anti-cholinergic agents tested, without affecting atrial contractions over the same range of concentrations. SVT-40776 exhibited the highest urinary versus cardiac selectivity (199-fold). In the guinea pig in vivo model, SVT-40776 inhibited 25% of spontaneous bladder contractions at a very low dose (6.97 µg·kg⁻¹ i.v), without affecting arterial blood pressure.

Conclusions and implications:

SVT-40776 is a potent inhibitor of M₃ receptor-related detrusor contractile activity. The absence of effects on isolated atria preparations represents an interesting characteristic and suggests that SVT-40776 may lack unwanted cardiac effects; a feature especially relevant in a compound intended to treat mainly elderly patients.British Journal of Pharmacology (2009) doi:10.1111/j.1476-5381.2008.00082.x     

QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M3 selective receptor antagonist for the treatment of overactive bladder

Prolongation of QT interval on an electrocardiogram is a valuable predictor of a drug's ability to cause potentially fatal ventricular tachyarrhythmia (torsades de pointes). Darifenacin is a muscarinic M3 selective receptor antagonist developed for the treatment of overactive bladder, a debilitating condition that is particularly prevalent in the older population. This 7-day, randomized, parallel-group study (n=188) measured QT/QTc interval in healthy volunteers receiving once-daily darifenacin at steady-state therapeutic (15 mg) and supratherapeutic (75 mg) doses, alongside controls receiving placebo or moxifloxacin (positive control, 400 mg) once daily. There was no significant increase in QTcF interval with darifenacin treatment compared with placebo. Mean changes from baseline at pharmacokinetic Tmax versus placebo were -0.4 and -2.2 milliseconds in the darifenacin 15 mg and 75 mg groups, respectively, compared with +11.6 milliseconds in the moxifloxacin group (P<.01). This study demonstrates that darifenacin does not prolong QT/QTc interval.     

Transdermal oxybutynin: a new treatment for overactive bladder

Overactive bladder has been successfully treated with oral anticholinergic drugs such as oxybutynin chloride. Although oral oxybutynin has been effective in controlling urinary urge incontinence and in decreasing incontinence episodes, adverse events, particularly dry mouth, often cause patients to discontinue oral therapy and to endure incontinence. Transdermal oxybutynin (Oxytrol, Watson Pharmaceuticals) is applied twice-weekly to maintain the efficacy of oral oxybutynin while significantly minimising side effects (e.g., dry mouth) that complicate therapy. By avoiding hepatic and gastrointestinal metabolism of oxybutynin, less N-desethyloxybutynin (N-DEO), the compound thought to be responsible for anticholinergic side effects, such as dry mouth, is produced. The new transdermal oxybutynin formulation offers patients with urinary incontinence an effective, safe and well-tolerated option for managing the symptoms of overactive bladder.     

Transdermal oxybutynin: a new treatment for overactive bladder

Overactive bladder has been successfully treated with oral anticholinergic drugs such as oxybutynin chloride. Although oral oxybutynin has been effective in controlling urinary urge incontinence and in decreasing incontinence episodes, adverse events, particularly dry mouth, often cause patients to discontinue oral therapy and to endure incontinence. Transdermal oxybutynin (Oxytrol^®, Watson Pharmaceuticals) is applied twice-weekly to maintain the efficacy of oral oxybutynin while significantly minimising side effects (e.g., dry mouth) that complicate therapy. By avoiding hepatic and gastrointestinal metabolism of oxybutynin, less N-desethyloxybutynin (N-DEO), the compound thought to be responsible for anticholinergic side effects, such as dry mouth, is produced. The new transdermal oxybutynin formulation offers patients with urinary incontinence an effective, safe and well-tolerated option for managing the symptoms of overactive bladder.     

酒石酸托特罗定缓释片治疗膀胱过度活动症的多中心双盲双模拟随机对照临床研究

目的 评价国产酒石酸托特罗定缓释片（抗膀胱过度活动症药）治疗膀胱过度活动症的有效性和安全性.方法 用随机双盲双模拟多中心临床试验设计,232例（试验组和对照组均为116例）托特罗定缓释片每日1次,每次4 mg;对照组口服托特罗定片每日2次,每次2 mg.均服药6周.结果 试验组（n=111）和对照组（n=112）24 h平均排尿次数减少、平均尿失禁次数均减少;平均每次尿量均增加,2组比较无统计学意义（P＞0.05）.试验组和对照组总药物不良反应发生率分别为39.3%和41.2%,主要表现为口干,发生率分别为35.7%,30.7%,经比较无统计学意义（P＞0.05）.结论 酒石酸托特罗定缓释片治疗膀胱过度活动症的疗效及安全性与其普通片相当.     

Tolterodine: a new antimuscarinic agent for the treatment of the overactive bladder

Bladder hyperactivity is a debilitating problem that affects many individuals. A plethora of therapeutic options have been investigated to combat this condition, antimuscarinic therapy being the most widely used. Nevertheless, this medication group has historically been of limited benefit, due to its side-effect profile. Tolterodine is a new muscarinic receptor antagonist that has been shown to be equally effective when compared to oxybutynin. However, the side-effect profile for tolterodine is much better than this commonly used anticholinergic. It has reduced affinity for the salivary glands in animal studies, and, in clinical trials, there has been a reduced incidence of dry mouth with this medication. In Phase III studies, tolterodine has been shown to decrease the number of micturitions per day, decrease the number of incontinence episodes per day and increase the mean volume voided per micturition. The maximal effect of this medication may not be seen for 6 - 8 weeks after initiation of the drug although the exact explanation for this finding has yet to be completely elucidated. The recommended dose is 2 mg b.i.d., which should be adjusted for those with liver failure or those on drugs that inhibit the cytochrome P450 isoenzyme known as CYP3A4. In summary, tolterodine is an effective well-tolerated antimuscarinic which should be considered as a first-line treatment due to its more favourable side-effect profile when than other available medications.     

Food does not affect the pharmacokinetics of solifenacin, a new muscarinic receptor antagonist: results of a randomized crossover trial

AIM: To determine the effect of food ingestion on the pharmacokinetic profile of solifenacin succinate (YM905; Vesicare, a new bladder selective muscarinic receptor antagonist for the treatment of overactive bladder, a chronic disease usually caused by involuntary detrusor muscle contractions during bladder filling. METHODS: A randomized, two-period, crossover study in two groups of 12 healthy men (aged 18-45 years, body weight 60-100 kg, body mass index < or =30). A single 10-mg dose of solifenacin was administered to the first group in the fasting state during period 1 and in the fed state during period 2, and to the second group in the fed state during period 1 and in the fasting state during period 2 (10 mg is two times the suggested starting dose). There was a 14-day washout between treatment periods. Parameters obtained included C(max), AUC(last), and AUC(0-inf), as well as t(1/2), t(max), and t(lag). RESULTS: One subject withdrew during the first period for personal reasons. No statistically or clinically significant pharmacokinetic differences occurred between subjects in the fed and fasting states. All geometric mean ratios were close to 1 (C(max), 1.033; AUC(last), 1.068; AUC(0-inf), 1.040). The 90% confidence intervals (CIs) fell in the predefined no-food-effect boundaries of 0.8-1.25 (C(max), 0.953-1.120; AUC(last), 0.990-1.153; AUC(0-inf), 0.976-1.109). The mean difference in t(1/2) was -3.8 h (90% CI 7.6-0.0). There were no significant differences between the fed and fasting states with regard to t(max) and t(lag) (P > 0.05). CONCLUSIONS: The pharmacokinetics of oral solifenacin was not affected by food ingestion, suggesting that this drug may be administered with or without food. The results observed in this investigation are consistent with those of previous studies of solifenacin.     

Oxybutynin chloride topical gel: a new formulation of an established antimuscarinic therapy for overactive bladder

Background: Oxybutynin, a cholinergic-muscarinic receptor antagonist, is established as a safe and effective pharmacological treatment for patients with overactive bladder syndrome (OAB). Oxybutynin is available in multiple immediate- and extended-release oral and two transdermal formulations. Oxybutynin chloride topical gel (OTG) (Gelnique^®, Watson Pharmaceuticals, Corona, CA, USA) was approved in January 2009 by the US FDA. OTG was designed to provide consistent plasma oxybutynin levels with daily application, favorably altering the circulating N-desethyloxybutynin metabolite:oxybutynin ratio, and to utilize a biocompatible delivery system, thus minimizing both the anticholinergic adverse effects of oral formulations and the application-site skin reactions associated with other available forms of transdermal delivery. Objective/methods: This review summarizes the pharmacological properties and the clinical efficacy and safety profile of OTG based on the published literature and unpublished data provided by the manufacturer upon request. Results/conclusion: OTG represents an efficacious, safe, and convenient alternative to other oxybutynin formulations and other oral anticholinergic medications for the treatment of OAB. Future studies and broad clinical experience should confirm the promising early experience observed with this formulation.     

Imidafenacin for the treatment of overactive bladder

Introduction: Imidafenacin (KRP-197/ONO-8025) is the latest antimuscarinic (AM) developed for the treatment of overactive bladder syndrome (OAB) and, at the moment, it is marketed only in Japan. This compound has been developed to improve the tolerability of AM therapy by binding specifically the M₃ receptor subtype, thus limiting undesirable adverse events (AEs).

Areas covered: This systematic review offers a brief explanation of the mechanism of action and of the pharmacokinetics of imidafenacin and helps readers to understand the clinical efficacy, tolerability, and safety of the compound in the setting of OAB therapy.

Expert opinion: Imidafenacin is an AM drug with excellent efficacy, tolerability, and safety. It is indicated for patients with nocturia, nocturnal polyuria, and benign prostatic hyperplasia. This compound, due to its pharmacokinetic properties, gives the opportunity to be easily adjusted in its dosages. Further studies should assess the pharmacokinetics, clinical efficacy, safety, and tolerability of imidafenacin in Caucasian and African populations because this AM agent, at the moment, has been evaluated just in Asian populations. More studies should evaluate and compare efficacy, safety, and tolerability of imidafenacin also with other largely utilized AMs, such as oxybutynin, tolterodine, and fesoterodine, or with the other M3 selective compound, darifenacin.