Botulinum toxin A for the Treatment of Overactive Bladder

The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder.     

Liposome-Encapsulated Botulinum Toxin A in Treatment of Functional Bladder Disorders

Botulinum toxin A (BoNT-A) intravesical injections have been used to treat patients with refractory functional bladder disorders such as overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS), but the risk of adverse events and the need for repeated injections continue to prevent widespread application of this treatment. Liposomes are vesicles that comprise concentric phospholipid layers and an aqueous core; their flexible compositions enable them to adsorb and fuse with cell membranes and to deliver drugs or proteins into cells. Therefore, liposomes have been considered as promising vehicles for the less invasive delivery of BoNT-A. In previous placebo-controlled trials including patients with OAB refractory to medical treatment, it was shown that liposomal BoNT-A could significantly decrease the frequency and urgency of urination. In patients with IC/BPS, it was shown that liposomal BoNT-A could also improve bladder pain, but the therapeutic efficacy was not superior to that of the placebo. As the therapeutic mechanisms of BoNT-A include the decreased expression of nerve growth factors, P2X3 receptors, and vanilloid receptors on C-fibers, liposomal BoNT-A might play a more promising role in the treatment of bladder oversensitivity. This article features the contemporary literature regarding BoNT-A, liposomes, and liposomal BoNT-A treatment for functional bladder disorders and potential clinical applications in the future.     

Alternative use of botulinum toxin in urology

Botulinum toxin A is used in the treatment of lower urinary tract symptoms due to detrusor sphincter dysynergia and detrusor hyper-reflexia (neurogenic detrusor deficiency). The toxin acts by producing paralysis of muscle tissue and has been shown to be safe and effective in the treatment of conditions caused by increased muscle tonicity and spasticity. Here the literature is reviewed chronologically, the established and emerging indications for the urological use of botulinum toxin evaluated and future applications are also considered.     

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.     

Safety and efficacy of tramadol in the treatment of idiopathic detrusor overactivity: a double-blind, placebo-controlled, randomized study

AIM: To evaluate the efficacy and safety of tramadol in patients with idiopathic detrusor overactivity (IDO). METHODS: A total of 76 patients 18 years or older with IDO were randomly assigned to receive 100 mg tramadol sustained release (group 1, n = 38) or placebo (group 2, n = 38) every 12 h for 12 weeks. Clinical evaluation was performed at baseline and every 2 weeks during treatment. All patients underwent urodynamics and ice water test at baseline and 12-week treatment. Main outcome measures were number of voids per 24 h, urine volume per void and episodes of urge incontinence per 24 h on a frequency volume chart and detailed recording of adverse effect. RESULTS: After 12 weeks of treatment mean number of voids per 24 h +/- SD decreased from 9.3 +/- 3.2 to 5.1 +/- 2.1 (P < 0.001 vs. placebo) [95% confidence interval (CI) -5.1--0.4]. At that time mean urine volume per void increased from 158 +/- 32 to 198 +/- 76 ml (P < 0.001 vs. placebo) (95% CI 8-22), while mean number of incontinence episodes per 24 h decreased from 3.2 +/- 3.3 to 1.6 +/- 2.8 (P < 0.001 vs. placebo) (95% CI -2-0.3). Tramadol induced significant improvements in urodynamic parameters. More adverse effects were associated with tramadol treatment than with placebo (P < 0.05). The main adverse event with tramadol was nausea. CONCLUSIONS: In patients with non-neurogenic IDO tramadol provided beneficial clinical and urodynamic results. Further studies are required to draw final conclusions on the efficacy of this drug in IDO.     

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.     

The emerging role of solifenacin in the treatment of overactive bladder

Although antimuscarinic drug therapy has been proven to be effective in the management of patients with symptoms of the overactive bladder syndrome, compliance with medication is often affected by the antimuscarinic adverse effects of dry mouth, constipation, somnolence and blurred vision. The development of bladder-selective M₃-specific antagonists offers the possibility of increasing efficacy whilst minimising adverse effects. At present there are no M₃-specific antagonists currently available although solifenacin and darifenacin are both under development and are due to be launched in 2004. The purpose of this article is to review the pharmacology and clinical trial data available for solifenacin, in addition to examining its role in the treatment of the overactive bladder syndrome.     

坦索罗辛联合溴吡啶斯的明治疗合并逼尿肌功能低下的BPH

目的 探讨坦索罗辛联合吡啶斯的明治疗合并逼尿肌功能低下的前列腺增生(BPH)的有效性.方法 93例BPH患者分三组:A组30例,坦索罗辛0.2mg,每日一次;B组32例,吡啶斯的明60 mg,每日二次;C组31例,按A、B组方案两药联合使用.治疗4周,比较疗效.结果 与治疗前比较,A、C组治疗后国际前列腺症状评分(IPSS)评分明显下降(P<0.05,P<0.01),C组最大尿流率(Qmax)明显上升(P<0.01),A组残余尿(PVR)明显下降(P<0.05),C组下降更明显(P<0.01).结论 对于合并逼尿肌功能低下的BPH,坦索罗辛与吡啶斯的明联合用药比单一用药更为有效.     

Effectiveness and Safety of Intradetrusor OnabotulinumtoxinA Injection for Neurogenic Detrusor Overactivity and Overactive Bladder Patients in Taiwan—A Phase IV Prospective,Interventional, Multiple-Center Study (Restore Study)

We conducted a phase IV, pre/post multi-center study to evaluate the efficacy and safety of intradetrusor onabotulinumtoxinA injection in patients with neurogenic detrusor overactivity (NDO, n = 119) or overactive bladder (OAB, n = 215). Patients received either 200U (i.e., NDO) and 100U (i.e., OAB) of onabotulinumtoxinA injection into the bladder, respectively. The primary endpoint for all patients was the change in the PPBC questionnaire score at week 4 and week 12 post-treatment compared with baseline. The secondary endpoints were the changes in subjective measures (i.e., questionnaires: NBSS for patients with NDO and OABSS for those with OAB) at week 4 and week 12 post-treatment compared with baseline. Adverse events included symptomatic UTI, de novo AUR, gross hematuria and PVR > 350mL were recorded. The results showed that compared with baseline, PPBC (3.4 versus 2.4 and 2.1, p < 0.001) and NBSS (35.4 versus 20.4 and 18.1, p < 0.001) were significantly improved at 4 weeks and 12 weeks in NDO patients. In addition, compared with baseline, PPBC (3.5 versus 2.3 and 2.0, p < 0.001) and OABSS (9.1 versus 6.2 and 5.7, p < 0.001) were significantly improved at 4 weeks and 12 weeks in OAB patients. Eight (6.7%) had symptomatic UTI and 5 (4.2%) had de novo AUR in NDO patients. Twenty (9.3%) had symptomatic UTI but no de novo AUR in OAB patients. In conclusion, we found that intradetrusor onabotulinumtoxinA injections were safe and improved subjective measures related to NDO or OAB in our cohort.     

Botulinum toxin for the treatment of cervical dystonia

Cervical dystonia (CD) manifests clinically through involuntary spasms of neck muscles, producing abnormal head and neck movements and postures, which is often associated with pain. CD is the most common form of focal dystonia presenting to movement disorders clinics. Chemodenervation with botulinum toxin (BTX) has become the first-line treatment for CD, producing satisfactory relief of symptoms in > 80% of cases. Unresolved issues that may impact on the overall results include the method of selection for injection sites (clinical vs. electromyography), dosing, dilution and the role and relative efficacy of the different BTX serotypes. A guiding therapeutic principle of BTX injections is to achieve optimal results with the lowest possible dosage and frequency of administration. This strategy is critical in order to keep the risk of immunoresistance at a minimum. Development of antibodies that block the effects of BTX, usually associated with frequent injections of high doses, is the main reason for secondary unresponsiveness to this treatment. Although the mechanism of denervation at the neuromuscular junction by BTX is relatively well understood, the role of changes in muscle spindles and myopathic pain mechanisms, as well as secondary changes at the level of the basal ganglia, thalamus and cortex and their role in response to BTX, all need further exploration.     

Botulinum toxin for the treatment of cervical dystonia

Cervical dystonia (CD) manifests clinically through involuntary spasms of neck muscles, producing abnormal head and neck movements and postures, which is often associated with pain. CD is the most common form of focal dystonia presenting to movement disorders clinics. Chemodenervation with botulinum toxin (BTX) has become the first-line treatment for CD, producing satisfactory relief of symptoms in > 80% of cases. Unresolved issues that may impact on the overall results include the method of selection for injection sites (clinical vs. electromyography), dosing, dilution and the role and relative efficacy of the different BTX serotypes. A guiding therapeutic principle of BTX injections is to achieve optimal results with the lowest possible dosage and frequency of administration. This strategy is critical in order to keep the risk of immunoresistance at a minimum. Development of antibodies that block the effects of BTX, usually associated with frequent injections of high doses, is the main reason for secondary unresponsiveness to this treatment. Although the mechanism of denervation at the neuromuscular junction by BTX is relatively well understood, the role of changes in muscle spindles and myopathic pain mechanisms, as well as secondary changes at the level of the basal ganglia, thalamus and cortex and their role in response to BTX, all need further exploration.     

Botulinum toxin A for the treatment of cervical dystonia

Idiopathic cervical dystonia (ICD) is the most common adult-onset focal dystonia. It is characterised by relatively sustained, involuntary contractions of neck muscles. Injections of botulinum toxin (BTX)-A are safe and effective for the treatment of ICD, and have substantially improved its treatment. BTX-A is manufactured by Allergan Pharmaceuticals in the US and Ireland, and is distributed as Botox^®. In Europe, BTX-A is manufactured and distributed by Ipsen Pharmaceuticals as Dysport^®. Success rates for BTX-A injections for ICD ranges 64 – 90%, with 76 – 93% of injected patients experiencing pain reduction. Side effects are generally mild and include dysphagia and neck weakness.     

Botulinum toxin type A for the treatment of migraine

Migraine is a common and debilitating disorder that often requires prophylactic therapy, particularly for those migraine patients who meet the diagnostic criteria for chronic daily headache (chronic migraine). Existing prophylactic treatments for migraine are inadequate for many patients due to their modest efficacy and/or systemic side effects. Alternative treatment strategies are needed, particularly in those with chronic migraine. Botulinum toxin type A is a locally injected protein complex that has been investigated as a treatment for episodic migraine and chronic daily headache. A systematic series of controlled trials has led to the identification of a subset of migraineurs with chronic daily headache who obtain demonstrated benefits of botulinum toxin type A over placebo that is maintained with repeated treatments.     

Botulinum toxin A for the treatment of cervical dystonia

Idiopathic cervical dystonia (ICD) is the most common adult-onset focal dystonia. It is characterised by relatively sustained, involuntary contractions of neck muscles. Injections of botulinum toxin (BTX)-A are safe and effective for the treatment of ICD, and have substantially improved its treatment. BTX-A is manufactured by Allergan Pharmaceuticals in the US and Ireland, and is distributed as Botox. In Europe, BTX-A is manufactured and distributed by Ipsen Pharmaceuticals as Dysport. Success rates for BTX-A injections for ICD ranges 64-90%, with 76-93% of injected patients experiencing pain reduction. Side effects are generally mild and include dysphagia and neck weakness.     

Botulinum toxin as an effective treatment of clozapine-induced hypersalivation

Hypersalivation is a common and frequently disabling side effect of atypical neuroleptics such as clozapine. Current treatment options of this adverse advent are limited by lack of efficacy or additional side effects. Botulinum toxin (BTX) injections into the parotid glands have been shown to be very effective in treating sialorrhea in the context of various neurological disorders, such as Parkinsons and motor neuron disease. Surprisingly, BTX treatment of drug-induced sialorrhea has not yet been described. We here report a patient with clozapine-induced hypersalivation and a good response to BTX injections lasting for more than 12 weeks, resulting in a marked reduction of the hypersalivation and consequently of his social withdrawal. Our patient serves to alert clinicians to the frequent problem of drug-induced sialorrhea and suggests that BTX injections should be considered as an effective and safe treatment for hypersalivation in psychiatric patients treated with clozapine.The first two authors contributed equally to this work.     

Discovery history and clinical development of mirabegron for the treatment of overactive bladder and urinary incontinence

Introduction: Overactive bladder (OAB) and urinary incontinence, although not life-threatening, are very bothersome chronic health conditions. The limitations of current pharmacological treatment urge the need for novel drugs with alternative mechanisms of action. Huge efforts in this area of research led to the synthesis of several selective and potent β3-adrenoceptor agonists that gained relevance through research during the late 80s and 90s. Mirabegron was the first compound of this new class of drugs that showed preclinical efficacy in several models of storage bladder dysfunction, together with a favorable human pharmacological profile. Having passed the proof-of-concept stage, an extensive clinical development and pharmacology program was performed during the last 10 years, involving > 10,000 individuals, before mirabegron was granted marketing approval.

Areas covered: In this case history, the authors review the milestones in mirabegron's discovery based on a systematic literature review.

Expert opinion: Thanks to its tolerability and safety/efficacy balance, mirabegron has potential to fill a need for new treatment options for OAB, and paves the way for further development of a completely new class of drugs aimed to treat this condition. However, the exact role of mirabegron in clinical practice has yet to be defined. Further studies are needed in order to clarify, together with post-launch information, critical safety issues and cost-effectiveness in head-to-head comparison with current standard treatments.