Michael B. Chancellor

Efficacy and Safety of OnabotulinumtoxinA for Idiopathic Overactive Bladder: A Double-Blind, Placebo Controlled, Randomized, Dose Ranging Trial

PURPOSE Treatment options for patients with overactive bladder refractory to anticholinergics are limited. We assessed the dose response across a range of doses of onabotulinumtoxinA (BOTOX®) in patients with idiopathic overactive bladder and urinary urgency incontinence whose symptoms were not adequately managed with anticholinergics. MATERIALS AND METHODS In a phase 2, multicenter, randomized, double-blind study, 313 patients with idiopathic overactive bladder and urinary urgency incontinence experiencing 8 or more urinary urgency incontinence episodes a week and 8 or more micturitions daily at baseline received 50, 100, 150, 200 or 300 U intradetrusor onabotulinumtoxinA, or placebo. Symptoms were recorded using a 7-day bladder diary. The primary efficacy variable was weekly urinary urgency incontinence episodes and the primary end point was week 12. RESULTS Demographics and baseline characteristics were balanced across the treatment groups. Durable efficacy was observed for all onabotulinumtoxinA dose groups of 100 U or greater for primary and secondary efficacy measures, including the proportion of incontinence-free patients. When the dose response curves were analyzed, doses greater than 150 U contributed minimal additional or clinically relevant improvement in symptoms. This finding was also reflected in health related quality of life assessments. Dose dependent changes in post-void residual urine volume were observed and the use of clean intermittent catheterization was also dose dependent. The only adverse events significantly greater with onabotulinumtoxinA than with placebo were urinary tract infection and urinary retention. CONCLUSIONS OnabotulinumtoxinA at doses of 100 U or greater demonstrated durable efficacy in the management of idiopathic overactive bladder and urinary urgency incontinence. A dose of 100 U may be the dose that appropriately balances the symptom benefits with the post-void residual urine volume related safety profile.

Comparison of intravesical botulinum toxin type A injections plus hydrodistention with hydrodistention alone for the treatment of refractory interstitial cystitis/painful bladder syndrome

To compare the clinical effectiveness of botulinum toxin type A (BoNT‐A) injections followed by hydrodistention (HD) with HD alone in patients with interstitial cystitis/painful bladder syndrome (IC/PBS).

Rehabilitation and medical management of the adult with spina bifida

Dicianno BE, Kurowski BG, Yang JMJ, Chancellor MB, Bejjani GK, Fairman AD, Lewis N, Sotirake J: Rehabilitation and medical management of the adult with spina bifida. Am J Phys Med Rehabil 2008;87:1026–1050. As the life expectancy of individuals with spina bifida increases, a lifelong need for management of many health issues in a rehabilitation setting has emerged in recent years. Physiatrists, in consultation with a variety of adult specialists, are particularly well suited to manage the common musculoskeletal, skin, bowel, bladder, renal, neurological, and other issues that arise in the adult population. This article reviews the last 20 yrs of literature pertinent to the rehabilitative care of this population, summarizes current evidence-based practice, and identifies key areas in which scientific evidence is lacking and future research is needed.

Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

Botulinum toxins can effectively and selectively disrupt and modulate neurotransmission in striated muscle. Recently, urologists have become interested in the use of these toxins in patients with detrusor overactivity and other urological disorders. In both striated and smooth muscle, botulinum toxin A (BTX-A) is internalized by presynaptic neurons after binding to an extracellular receptor (ganglioside and presumably synaptic vesicle protein 2C). In the neuronal cytosol, BTX-A disrupts fusion of the acetylcholine-containing vesicle with the neuronal wall by cleaving the SNAP-25 protein in the synaptic fusion complex. The net effect is selective paralysis of the low-grade contractions of the unstable detrusor, while still allowing high-grade contraction that initiates micturition. Additionally, BTX-A seems to have effects on afferent nerve activity by modulating the release of ATP in the urothelium, blocking the release of substance P, calcitonin gene-related peptide and glutamate from afferent nerves, and reducing levels of nerve growth factor. These effects on sensory feedback loops might not only help to explain the mechanism of BTX-A in relieving symptoms of overactive bladder, but also suggest a potential role for BTX-A in the relief of hyperalgesia associated with lower urinary tract disorders.

Urodynamic and Immunohistochemical Evaluation of Intravesical Botulinum Toxin A Delivery Using Liposomes

PURPOSE Botulinum toxin A (Allergan, Irvine, California) is a high molecular weight neurotoxin used to treat hypersensitive bladder by direct injection to pass the urothelial barrier. We investigated the feasibility of intravesical botulinum toxin A delivery using liposomes (Lipella Pharmaceuticals, Pittsburgh, Pennsylvania), which are phospholipid bilayered vesicles, and evaluated the urodynamic and immunohistochemical effect on acetic acid induced bladder hyperactivity in rats. MATERIALS AND METHODS Liposomes (1 ml), botulinum toxin A (20 U/1 ml saline) or botulinum toxin A encapsulated in liposomes (lipotoxin, that is 20 U botulinum toxin A plus 1 ml liposomes) was administered in the bladder and retained for 1 hour on day 1 after baseline cystometrogram. Continuous cystometrogram was performed on day 1 by filling the bladder with saline and on day 8 by filling the bladder with saline, followed by 0.3% acetic acid. The bladder was then harvested. Cystometrogram parameters, histology, SNAP25 and calcitonin gene-related peptide expression were measured by Western blotting or immunostaining. RESULTS The intercontraction interval was decreased 57.2% and 56.0% after intravesical acetic acid instillation in liposome and botulinum toxin A pretreated rats, respectively. However, rats that received lipotoxin showed a significantly decreased intercontraction interval response (21.1% decrease) to acetic acid instillation but without compromised voiding function. Also, lipotoxin pretreated rats had a better decrease in the inflammatory reaction and SNAP-25 expression, and increase in calcitonin gene-related peptide immunoreactivity than those in liposome or botulinum toxin A pretreated rats. CONCLUSIONS Intravesical lipotoxin administration cleaved SNAP-25, inhibited calcitonin gene-related peptide release from afferent nerve terminals and blocked the acetic acid induced hyperactive bladder. These results support liposomes as an efficient vehicle for delivering botulinum toxin A without injection.

Urinary nerve growth factor but not prostaglandin E2 increases in patients with interstitial cystitis/bladder pain syndrome and detrusor overactivity

Study Type – Aetiology (case series)
Level of Evidence 4

Extended‐release tolterodine with or without tamsulosin in men with lower urinary tract symptoms and overactive bladder: effects on urinary symptoms assessed by the International Prostate Symptom Score

To evaluate the efficacy of tolterodine extended‐release (ER) plus tamsulosin on lower urinary tract symptoms (LUTS) as assessed by changes in the International Prostate Symptom Score (IPSS) in men who met symptom entry criteria for both overactive bladder (OAB) and benign prostatic hyperplasia (BPH) trials.

Dynamic Progression of Overactive Bladder and Urinary Incontinence Symptoms: A Systematic Review

CONTEXT Overactive bladder (OAB) and urinary incontinence (UI) are worldwide public health problems. Longitudinal epidemiologic studies that assess the natural history of OAB and UI are valuable in making accurate prognoses, determining causes and consequences, and predicting resource utilization. OBJECTIVE Our aim was to assess whether the severity of OAB and UI symptoms progress dynamically over time, with the secondary aim of assessing factors that may be associated with symptom progression and regression. EVIDENCE ACQUISITION A systematic review of English articles published between January 1, 1990, and September 20, 2009, was conducted using PubMed and Embase. Search terms included longitudinal, natural history, overactive bladder, incontinence, progression, remission, and regression. Eligibility was assessed by Dr. Irwin with editorial assistance. Studies were required to be longitudinal and population based; meeting abstracts and conference proceedings were excluded. Results were assessed qualitatively. EVIDENCE SYNTHESIS Overall, the 7 longitudinal studies of OAB and 14 longitudinal studies of UI reviewed reported an increase in the incidence and remission/regression of both OAB and UI symptoms over time that varied across studies (eg, OAB incidence, 3.7-8.8%; UI incidence, 0.8-19%). The studies provide evidence for a dynamic progression of OAB and UI symptoms (eg, among women with OAB without urge urinary incontinence [UUI], 28% reported OAB with UUI 16 yr later) and also show that although symptom severity progresses dynamically, for many individuals symptoms also persist over long time periods. CONCLUSIONS The results support the hypothesis that OAB and UI symptom severity progress dynamically and are also sustained over time. However, the variations in symptom definitions and methods used across studies prevent statistical determinations of overall incidence rates. The recognition of OAB and UI as progressive conditions allows for a shift from the current treatment paradigm of symptom control alone to one of symptom management.

Autologous Muscle Derived Cell Therapy for Stress Urinary Incontinence: A Prospective, Dose Ranging Study

PURPOSE In this feasibility study we assessed the 12-month safety and potential efficacy of autologous muscle derived cells (Cook MyoSite Incorporated, Pittsburgh, Pennsylvania) as therapy for stress urinary incontinence. MATERIALS AND METHODS A total of 38 women in whom stress urinary incontinence had not improved with conservative therapy for 12 or more months underwent intrasphincter injection of low doses (1, 2, 4, 8 or 16 × 10(6)) or high doses (32, 64 or 128 × 10(6)) of autologous muscle derived cells, which were derived from biopsies of their quadriceps femoris. All patients could elect a second treatment of the same dose after 3-month followup. Assessments were made at 1, 3, 6 and 12 months after the last treatment. The primary end point was the incidence and severity of adverse events. In addition, changes in stress urinary incontinence severity were evaluated by pad test, diary of incontinence episodes and quality of life surveys. RESULTS Of the 38 patients 33 completed the study. Treatment related complications were limited to minor events such as pain/bruising at the biopsy and injection sites. Of patients who received 2 treatments of autologous muscle derived cells who were eligible for analysis, a higher percentage of those in the high dose vs the low dose group experienced a 50% or greater reduction in pad weight (88.9%, 8 of 9 vs 61.5%, 8 of 13), had a 50% or greater reduction in diary reported stress leaks (77.8%, 7 of 9 vs 53.3%, 8 of 15) and had 0 to 1 leaks during 3 days (88.9%, 8 of 9 vs 33.3%, 5 of 15) at final followup. CONCLUSIONS Injection of autologous muscle derived cells in a wide range of doses appears safe with no major treatment related adverse events reported. In addition, treatment with autologous muscle derived cells shows promise for relieving stress urinary incontinence symptoms and improving quality of life.

Prevalence of Overactive Bladder and Associated Risk Factors in 1359 Patients With Type 2 Diabetes

OBJECTIVE To evaluate overactive bladder (OAB, dry and wet) and the associated risk factors of OAB wet (with incontinence) in type 2 diabetes. METHODS A self-administered questionnaire containing the OAB symptom score (OABSS, 0-15, with higher numbers indicating an increasing severity of symptoms) was obtained from subjects with type 2 diabetes at a dedicated diabetic center. The association of age, sex, duration of diabetes, body mass index, waist circumference, glycated hemoglobin level, high-sensitive C-reactive protein level, and diabetes-associated complications to the risk of OAB and OAB wet was evaluated. RESULTS Of 1359 consecutive subjects, 22.5% reported having OAB, with 11.7% reporting OAB dry and 10.8% OAB wet. The difference in symptom severity was statistically significant among those without OAB and those with OAB dry and OAB wet (OABSS 2.5 ± 1.4, 5.9 ± 1.6, and 8.9 ± 2.6, respectively). The prevalence of OAB and OAB wet was 2.4-fold and 4.2-fold greater, respectively, in patients with a diabetes duration >10 years and age >50 years. Age and male sex and age and waist circumference were independent risk factors for OAB and OAB wet, respectively, after multivariate analysis. Glycated hemoglobin and high-sensitivity C-reactive protein levels were similar between patients with diabetes patients with and without OAB. CONCLUSION In the dedicated diabetic center in which all patients were screened, 22.5% had OAB, and 48.0% of those with OAB had incontinence. These findings can help guide the collaboration between urologists and diabetologists to work toward developing screening for, and early treatment of, urologic complications in higher risk patients.