Use of Botulinum Toxin A in the Treatment of Lower Urinary Tract Disorders: A Review of the Literature.
ABSTRACT: Botulinum neurotoxin (BoNT) is used to treat a variety of ailments, and its therapeutic application in lower urinary tract disorders (LUTDs) is well studied. Robust evidence supporting the efficacy and tolerability of BoNT in the treatment of neurogenic detrusor overactivity (NDO) and non-neurogenic overactive bladder (OAB) has led to regulatory approval for these conditions. Use of BoNT in the treatment of interstitial cystitis/bladder pain syndrome, chronic pelvic pain, and detrusor sphincter dyssynergia has demonstrated some promise, but is still evolving and off-label for these indications. Trials to date do not support the use of BoNT for benign prostatic hyperplasia. This comprehensive review outlines the mechanisms of BoNT in the treatment of LUTDs in adults and presents background and updated data examining the efficacy and adverse events associated with the use of BoNT in common urologic applications.
Project description:To assess the effectiveness and safety of botulinum toxin A (BTX-A) at different dosages for overactive bladder (OAB).The MEDLINE, EMBASE, and Cochrane Controlled Trials Register databases were searched through November 3, 2016 to identify relevant randomized controlled trials (RCTs).Eleven studies were identified in this meta-analysis. Compared with placebo, the urinary incontinence (UI) episodes per week as the primary outcomes, urodynamic parameters including maximum cystometric capacity (MCC), and maximum detrusor pressure (MDP) for neurogenic detrusor overactivity (NDO) at 6 weeks, and for idiopathic detrusor overactivity (IDO) at 36 weeks were evaluated. These and other outcomes for effectiveness of BTX-A at different dosages in two observation periods indicate that a dose greater than 50 U is significantly more effective for certain symptoms of OAB compared with placebo. However, there were no significant differences between some dosages. Compared with placebo, the outcomes of total adverse events for NDO and for IDO show that doses of 300 U and 200 U for NDO are associated with more complications.In consideration that the treatments of BTX-A were with minimal, local, and manageable adverse effects, this meta-analysis demonstrates that BTX-A 200 U is recommended for management of NDO for short-term treatment for there was no significant difference from the larger dose of 300U. The short-term efficacies of BTX-A for IDO remain to be investigated.
Project description:Diabetes mellitus (DM) is an independent risk factor for overactive bladder (OAB). The pathophysiology of DM-associated OAB is multifactorial and time-dependent. Diabetic bladder dysfunction is highly associated with diabetic complications, mainly including diabetic neuropathy and atherosclerosis. Chronic systemic inflammation and bladder urothelial inflammation may contribute to the onset of OAB. Intravesical botulinum toxin A (BoNT-A) injection has proved to be a successful treatment for idiopathic and neurogenic OAB. BoNT-A can inhibit the efferent pathways of the bladder as well as the chronic inflammation and hypersensitivity via the afferent pathways. We conducted a review of the published literature in Pubmed using a combination of two keywords, namely "botulinum toxin A" (BoNT-A) and "overactive bladder", with or without the additional keywords "detrusor overactivity", "diabetes mellitus", "inflammation", and "urodynamic study". We also reviewed the experience of our research teams, who have published several studies of the association between DM and OAB. Since limited data support the effectiveness and safety of BoNT-A for treating patients with DM-associated OAB, a comprehensive evaluation of diabetic complications and urodynamic study is needed before treatment. In the future, it is imperative to explore the clinical characteristics and inflammatory biomarkers of diabetes as determining predictors of the treatment efficacy.
Project description:PURPOSE:OnabotulinumtoxinA has demonstrated efficacy and safety in the treatment of urinary incontinence (UI) associated with neurogenic detrusor overactivity (NDO) and idiopathic overactive bladder (OAB); however, real-world evidence is limited. This postmarketing surveillance study aimed to assess the effectiveness and safety of onabotulinumtoxinA in Korean patients with UI associated with NDO or OAB with an inadequate response or intolerance to anticholinergics. METHODS:Patients received 200 U (NDO) or 100 U (OAB) of onabotulinumtoxinA. Effectiveness (assessed using the validated International Consultation on Incontinence Questionnaire-Short Form [ICIQ-SF]) and safety were assessed for 1-4 months after onabotulinumtoxinA administration. RESULTS:Overall, 686 patients (NDO, 161; OAB, 525) comprised the safety population; of these, 612 patients were analyzed for effectiveness. There was a significant decrease (P<0.0001) in the mean (standard deviation) ICIQ-SF scores in the NDO (-6.8±5.5) and OAB (-6.0±6.4) groups after onabotulinumtoxinA administration. A decrease of >5 points from baseline in the ICIQ-SF score was observed in 64.9% and 47.3% of patients in the NDO and OAB groups, respectively. Following treatment, 59.9% in the NDO group and 43.0% in the OAB group were dry. There was no effect of age on effectiveness in either group. Only 10 adverse drug reactions (ADRs) were reported in 5.6% of NDO patients and 20 ADRs in 3.2% of OAB patients. Most ADRs in both groups were related to the lower urinary tract such as dysuria (NDO, 1.2%; OAB, 0.6%) and urinary retention (NDO, 0.6%; OAB, 1.5%). CONCLUSION:Effectiveness and safety of onabotulinumtoxinA in Korea in a real-world setting was demonstrated.
Project description:Botulinum toxins were primary suggested for the neurogenic lower urinary tract dysfunction (LUTD) treatment about thirty years ago. The application of BTX-A in LUTD have just developed and the approval of BTX-A injection confirmed in for patients with both overactive bladders (OAB) and neurogenic detrusor overactivity (NDO). Actually the BTX-A medication in interstitial cystitis/bladder pain syndrome (IC/BPS) is not licensed, but there is under consideration. Despite BTX-A is recommended to treat patients with interstitial cystitis/bladder pain syndrome (ICBPS) under different occasions, its efficacy and safety in the cure of (IC/BPS) is under consideration. One difficulty is related to the toxin delivering systems. It is shown that there is no difference in BTX-A injection to body or trigone but there is a need on further large-scale studies over this subject. Moreover, Hydro distention can boost the therapeutic effect of BTX-A for IC/BPS patients. Additional studies should consider the safety and efficacy of BTX-A injection in the treatment of BTX-A.
Project description:INTRODUCTION:Neurogenic lower urinary tract dysfunction (NLUTD), including neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia, is one of the most frequent and devastating sequelae of spinal cord injury (SCI), as it can lead to urinary incontinence and secondary damage such as renal failure. Transcutaneous tibial nerve stimulation (TTNS) is a promising, non-invasive neuromodulatory intervention that may prevent the emergence of the C-fibre evoked bladder reflexes that are thought to cause NDO. This paper presents the protocol for TTNS in acute SCI (TASCI), which will evaluate the efficacy of TTNS in preventing NDO. Furthermore, TASCI will provide insight into the mechanisms underlying TTNS, and the course of NLUTD development after SCI. METHODS AND ANALYSIS:TASCI is a nationwide, randomised, sham-controlled, double-blind clinical trial, conducted at all four SCI centres in Switzerland. The longitudinal design includes a baseline assessment period 5-39 days after acute SCI and follow-up assessments occurring 3, 6 and 12 months after SCI. A planned 114 participants will be randomised into verum or sham TTNS groups (1:1 ratio), stratified on study centre and lower extremity motor score. TTNS is performed for 30?min/day, 5?days/week, for 6-9 weeks starting within 40 days after SCI. The primary outcome is the occurrence of NDO jeopardising the upper urinary tract at 1?year after SCI, assessed by urodynamic investigation. Secondary outcome measures assess bladder and bowel function and symptoms, sexual function, neurological structure and function, functional independence, quality of life, as well as changes in biomarkers in the urine, blood, stool and bladder tissue. Safety of TTNS is the tertiary outcome. ETHICS AND DISSEMINATION:TASCI is approved by the Swiss Ethics Committee for Northwest/Central Switzerland, the Swiss Ethics Committee Vaud and the Swiss Ethics Committee Zürich (#2019-00074). Findings will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER:NCT03965299.
Project description:The aim of this investigation was to characterize and compare the pharmacokinetics (PK) of the antimuscarinic drug solifenacin in pediatric patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) utilizing data from three phase III trials. LION was a placebo-controlled, 12-week trial in children (5-<12 years) and adolescents (12-<18 years) with OAB. MONKEY and MARMOSET were open-label, 52-week trials in children and adolescents or younger children (6 months-<5 years), respectively, with NDO. During the trials, solifenacin doses could be titrated to weight-adjusted pediatric equivalent doses (PEDs) of 2.5, 5, 7.5, or 10 mg day<sup>-1</sup> . Nonlinear mixed effects modeling was used to develop population PK models to characterize the PK in patients with either OAB or NDO. Overall, 194 children and adolescents received solifenacin. At the time of PK sampling, the majority (119/164 [72.6%] patients) were receiving PED10 once daily. All population models included first-order oral absorption, a lag time, and interindividual variability. PK analysis showed that apparent clearance was similar in both patient populations. Mean apparent oral plasma clearance (CL/F), apparent volume of distribution during the terminal phase (V<sub>z</sub> /F), and terminal half-life (t<sub>1/2</sub> ) were higher in adolescents than in children, but median time to maximum plasma concentration (t<sub>max</sub> ) was similar. Dose-normalized exposure results were similar for both younger and older patients with OAB or NDO. In conclusion, population PK modeling was used to successfully characterize solifenacin PK in pediatric patients with OAB or NDO. Similar solifenacin PK characteristics were observed in both populations.
Project description:Urothelium and Lamina Propria (LP) are considered an integrate sensory system which is able to control the detrusor activity. Complete supra-sacral spinal cord lesions cause Neurogenic Detrusor Overactivity (NDO) whose main symptoms are urgency and incontinence. NDO therapy at first consists in anti-muscarinic drugs; secondly, in intra-vesical injection of botulinum toxin. However, with time, all the patients become insensitive to the drugs and decide for cystoplastic surgery. With the aim to get deeper in both NDO and drug's efficacy lack pathogenesis, we investigated the innervation, muscular and connective changes in NDO bladders after surgery by using morphological and quantitative methodologies. Bladder innervation showed a significant global loss associated with an increase in the nerve endings located in the upper LP where a neurogenic inflammation was also present. Smooth muscle cells (SMC) anomalies and fibrosis were found in the detrusor. The increased innervation in the ULP is suggestive for a sprouting and could condition NDO evolution and drug efficacy length. Denervation might cause the SMC anomalies responsible for the detrusor altered contractile activity and intra-cellular traffic and favour the appearance of fibrosis. Inflammation might accelerate these damages. From the clinical point of view, an early anti-inflammatory treatment could positively influence the disease fate.
Project description:The use of botulinum toxin A (BTX-A) has revolutionized the treatment of neurogenic lower urinary tract dysfunction (NLUTD) over the past three decades. Initially, it was used as a sphincteric injection for detrusor sphincter dyssynergia but now is used mostly as intradetrusor injection to treat neurogenic detrusor overactivity (NDO). Its use is supported by high-level-of-evidence studies and it has become the gold-standard treatment for patients with NDO refractory to anticholinergics. Several novelties have emerged in the use of BTX-A in neurourology over the past few years. Although onabotulinumtoxinA (BOTOX®, Allergan, Inc., Irvine, CA) remains the only BTX-A for which use is supported by large, multicenter, randomized, controlled trials (RCT), and is therefore the only one to be licensed in the United States and Europe, a second BTX-A, abobotulinumtoxinA (Dysport®, Ipsen Biopharmaceuticals, Basking Ridge, NJ), is also supported by high-level-of-evidence studies. Other innovations in the use of BTX-A in neurourology during the past few years include the BTX switch (from abobotulinumtoxinA to onabotulinumtoxinA or the opposite) as a rescue option for primary or secondary failures of intradetrusor BTX-A injection and refinements in intradetrusor injection techniques (number of injection sites, injection into the trigone). There is also a growing interest in long-term failure of BTX-A for NDO and their management, and a possible new indication for urethral sphincter injections.
Project description:To evaluate the effects of onabotulinumtoxinA on patient-reported outcomes including health-related quality of life (HRQOL), treatment satisfaction, and treatment goal attainment in patients with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO).In this multicenter, double-blind, randomized, placebo-controlled, phase III, 52-week study (ClinicalTrials.gov NCT00311376), patients with UI due to NDO who were not adequately managed with anticholinergic therapy were treated with intradetrusor injections of onabotulinumtoxinA (200 or 300 U) or placebo (0.9% saline). HRQOL measures included the Incontinence Quality of Life (I-QOL) Questionnaire total score, and the 3 domain scores (avoidance and limiting behavior, psychosocial, and social embarrassment), the modified Overactive Bladder Patient Satisfaction with Treatment Questionnaire (OAB-PSTQ), and Patient Global Assessment. Assessments were made at baseline, posttreatment week 6 (primary time point), week 12, and at 12-week intervals.Patients (mean age of 46 years with 30.5 weekly UI episodes at baseline) were randomized to receive placebo (n = 149) or onabotulinumtoxinA (200 U [n = 135] or 300 U [n = 132]). At week 6, improvements from baseline in I-QOL Questionnaire total score were greater (p < 0.001) in both onabotulinumtoxinA-treated groups vs placebo. Responses to the OAB-PSTQ also demonstrated greater mean improvements from baseline (p < 0.001) in both onabotulinumtoxinA-treated groups vs placebo at week 6. Patients who received onabotulinumtoxinA also reported greater improvement in the Patient Global Assessment than those in the placebo group (p ? 0.001 vs placebo).Patients with UI due to NDO reported greater improvement in HRQOL and treatment satisfaction with onabotulinumtoxinA than with placebo consistently across several patient-reported outcome instruments.This study provides Class I evidence that onabotulinumtoxinA intradetrusor injections (200 or 300 U) can improve quality of life measures in patients with NDO not adequately managed with anticholinergic therapy.
Project description:Intradetrusor injections of Botulinum toxin A-currently onabotulinumtoxinA-is registered as a second-line treatment to treat neurogenic detrusor overactivity (NDO). The common clinical practice is 30 × 1 mL injections in the detrusor; however, protocols remain variable and standardization is warranted. The effect of reducing the number of injection sites of Dysport(®) abobotulinumtoxinA (aboBoNTA) was assessed in the spinal cord-injured rat (SCI). Nineteen days post-spinalization, female rats received intradetrusor injections of saline or aboBoNTA 22.5 U distributed among four or eight sites. Two days after injection, continuous cystometry was performed in conscious rats. Efficacy of aboBoNTA 22.5 U was assessed versus aggregated saline groups on clinically-relevant parameters: maximal pressure, bladder capacity, compliance, voiding efficiency, as well as amplitude, frequency, and volume threshold for nonvoiding contractions (NVC). AboBoNTA 22.5 U significantly decreased maximal pressure, without affecting voiding efficiency. Injected in four sites, aboBoNTA significantly increased bladder capacity and compliance while only the latter when in eight sites. AboBoNTA significantly reduced NVC frequency and amplitude. This preclinical investigation showed similar inhibiting effects of aboBoNTA despite the number of sites reduction. Further studies are warranted to optimize dosing schemes to improve the risk-benefit ratio of BoNTA-based treatment modalities for NDO and further idiopathic overactive bladder.