Exploring the Role of Overactive Bladder Acting Medications on Different Targets: A Pharmacological Intervention

Effect of Pharmacotherapy for Overactive Bladder on the Incidence of and Factors Related to Urinary Tract Infection: A Systematic Review and Meta-analysis.

Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults: AUA/SUFU Guideline

New ideas in urology: 2014 update

Mirabegron: Beta-3 agonist approved for OAB

Results of a Randomized Phase III Trial of Mirabegron in Patients with Overactive Bladder

Fesoterodine is a new antimuscarinic agent developed for the treatment of overactive bladder. Fesoterodine itself is inactive and is rapidly and extensively converted by ubiquitous esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is formed via biotransformation of both fesoterodine and tolterodine, albeit by different metabolising enzymes, viz. esterases and CYP2D6 respectively. Tolterodine is a potent muscarinic receptor antagonist and has been used for the treatment of overactive bladder for over ten years. The objective of this study was to establish the pharmacokinetic profile of fesoterodine and to highlight ist potential pharmacokinetic advantages over tolterodine. Single-centre, open-label, randomised, 4-way crossover study in a total of 24 healthy male volunteers. Single oral doses of 4, 8, or 12 mg fesoterodine were administered after an overnight fast. In addition, the 8 mg dose was also administered after a standard high-fat and high-calorie breakfast. Blood and urine samples for the analysis of 5-HMT were collected before and multiple times after drug administration for pharmacokinetic analysis. The mean peak plasma concentration (Cmax) of 5-HMT and the mean area under the time versus concentration curve (AUC) increased proportionally with the fesoterodine dose. These two parameters were some 2-fold higher in CYP2D6 poor metabolisers, whereas the time to peak plasma concentration (tmax) and half life (t1/2) were not influenced by the dose or the CYP2D6 metaboliser status. If fesoterodine was taken following a high-fat breakfast, we observed small increases in Cmax and AUC. In spite of these modest genetic influences and food effects on the pharmacokinetics of fesoterodine, the overall interindividual variability in Cmax levels was relatively little compared to previously published reports using tolterodine. Due to the esterase-mediated cytochrome P450-independent formation of 5-HMT and involvement of multiple metabolic and renal excretion pathways in the elimination of 5-HMT, the effects of patient-intrinsic and -extrinsic factors on the pharmacokinetics of fesoterodine are only modest, with some 2-fold higher 5-HMT exposure. Therefore, in contrast to tolterodine, no reduction of fesoterodine dosage is required under conditions of reduced elimination. In most cases of drug interaction or renal/hepatic impairment, the fesoterodine dose may be increased to 8 mg/day based on individual patients' response, or patients may be required to remain at the initial recommended dose of 4 mg/day.

Background: Overactive bladder (OAB) syndrome is defined as urinary urgency, with or without urge incontinence in the absence of an underlying pathological or metabolic cause. Treatment for OAB involves anti-muscarinic agents and beta 3-adrenoceptor agonists. As a previous study showed that treatment may increase the risk of urinary tract infection (UTI), we conducted a nationwide, population-based, retrospective study to assess UTI risk associated with OAB medication adherence, and different types of OAB medication. Methods: The source of data was medical records from National Health Insurance Research Database (NHIRD). Patients who were diagnosed with OAB in outpatient records from January 1, 2014 to December 31, 2016 were included. Outpatient visits included an attendance at primary care or the emergency department. The index date was the first prescription medication for OAB treatment after diagnosis. The targeted population was those diagnosed with OAB, and targeted drugs were anti-muscarinic agent (including flavoxate, oxybutynin, propiverine, solifenacin, tolterodine, and trospium) and mirabegron. Adherence was assessed based on the proportion of days covered in 12 months among mirabegron and anti-muscarinic agents. A multivariate Cox proportional-hazards model was used to compare the risk of UTI with OAB medication adherence, and different types of OAB medication. Results: There were 39,975 outpatients diagnosed with OAB in the database from 2014 to 2016. Excluding those younger than 20 years old and for whom the information was incomplete in the database, 21,869 patients were included in the final OAB cohort. Overall, risk of UTI was not influenced by the targeted drugs or adherence during the follow-up period, regardless of UTI history or sex. Conclusion: OAB is a common problem in Taiwan. After 12 months of follow-up, there was no difference between anticholinergic medications and beta-3 agonists, nor between high and low adherence in the risk of UTI.

Overactive bladder (OAB) is clinically defined as urinary urgency with or without urinary incontinence. It is associated with daytime frequency or constipation and has a prevalence of approximately 5%–12% among 5- to 10-year-olds. The appropriate functional exchange between the pontine micturition center, periaqueductal gray matter, and prefrontal cortex is important for proper micturition control. Several studies on pediatric cases observed a link between OAB and neuropsychiatric problems, such as anxiety, depression, and attention deficit, and treatment of these comorbidities improved patient symptoms. In this review, we present the pathophysiology of OAB, its associated conditions, and aspects related to updates in OAB treatment, and we propose a step-by-step treatment approach following this sequence: behavioral therapy, medical treatment, and invasive treatment. Although anticholinergic drugs are the mainstay of OAB medical treatment, beta-3 agonists and alpha-blockers are now recommended as a result of significant advancements in pharmacologic treatment in the last 10 years. Electrical stimulation techniques and botulinum toxin are also effective and can be used, especially in conventional treatment-refractory cases.

Goto-Kakizaki (GK) rats with type 2 diabetes mellitus respond to low temperature (LT) environments with bladder overactivity, including increased voiding frequency and decreased voiding interval and micturition volume. We determined if bladder overactivity could be inhibited by treatment with the combination of a M3 -muscarinic receptor antagonist and a β3 -adrenergic receptor agonist. Ten-week-old female GK rats were fed a high-fat diet for 4 weeks. Cystometric investigations were conducted at room temperature (RT, 27 ± 2°C). The rats were then intraperitoneally administered the vehicle, the M3 -muscarinic receptor antagonist solifenacin, the β3 -adrenergic agonist mirabegron, or a combination of solifenacin and mirabegron. Ten minutes after the administrations, the rats were transferred to the LT environment (4 ± 2°C), where the cystometric measurements were continued. The expressions of both M3 -muscarinic and β3 -adrenergic receptors were investigated. After transfer from RT to LT, both voiding interval and bladder capacity of the vehicle-, solifenacin-, or mirabegron-treated rats were significantly decreased. However, the combination of solifenacin and mirabegron significantly mitigated the bladder overactivity. While both M3 -muscarinic and β3 -adrenergic receptors were detected, the expression of M3 -muscarinic receptor mRNA was significantly higher than that of β3 -adrenergic receptor mRNA. The cold stress-induced bladder overactivity was not improved by either the M3 -muscarinic receptor antagonist or the β3 -adrenergic receptor agonist alone. However, the combined treatment mitigated the cold stress responses. Combined therapy with M3 -muscarinic antagonists and β3 -adrenergic agonists could reduce side effects and improve the quality of life for diabetic patients with bladder overactivity.

Metabolic syndrome (MetS) is defined by a group of cardiovascular risk factors, including impaired glucose tolerance, central obesity, hypertension, and dyslipidemia. Overactive bladder (OAB) syndrome consists of symptoms such as urinary urgency, frequency, and nocturia with or without urge incontinence. The high prevalences of metabolic syndrome (MetS) and overactive bladder (OAB) worldwide affect quality of life and cause profound negative impacts on the social economy. Accumulated evidence suggests that MetS might contribute to the underlying mechanisms for developing OAB, and MetS-associated OAB could be a subtype of OAB. However, how could these two syndromes interact with each other? Based on results of animal studies and observations in epidemiological studies, we summarized the common pathophysiologies existing between MetS and OAB, including autonomic and peripheral neuropathies, chronic ischemia, proinflammatory status, dysregulation of nutrient-sensing pathways (e.g., insulin resistance at the bladder mucosa and excessive succinate intake), and the probable role of dysbiosis. Since the MetS-associated OAB is a subtype of OAB with distinctive pathophysiologies, the regular and non-specific medications, such as antimuscarinics, beta-3 agonist, and botulinum toxin injection, might lead to unsatisfying results. Understanding the pathophysiologies of MetS-associated OAB might benefit future studies exploring novel biomarkers for diagnosis and therapeutic targets on both MetS and OAB.

Medical Management of Overactive Bladder

The overactive bladder (OAB) is a debilitating condition in which patients suffer from urinary urgency, frequency and nocturia with or without urge urinary incontinence. The mainstay of pharmacotherapy for OAB is muscarinic receptor antagonists, which have been shown to be effective treatments for the symptoms of OAB. The mechanism underlying the efficacy of antimuscarinic agents against the symptoms of OAB is not completely understood. This review explores the role of bladder mucosal muscarinic receptors in the signaling pathways that are activated in response to bladder filling. The cholinergic system is seen to be involved in bladder afferent signaling at many levels and as such muscarinic receptor antagonists may affect bladder signaling via numerous pathways including release of mediators from the bladder urothelium and activation of suburothelial myofibroblasts and afferent nerves. Therefore the mucosal cholinergic system may represent another target for the antimuscarinic agents used to treat OAB.

New perspectives of treatment with fesoterodine fumarate in patients with overactive bladder

The purpose of this study was to validate a short awareness tool to assist patients in identifying if they have bothersome overactive bladder (OAB) symptoms. This secondary analysis study utilised data from a cross-sectional study of adult patients presenting for primary care visits. Patients completed an 8-item OAB screener. The clinician probed for urinary frequency, urgency, nocturia and urgency urinary incontinence. If the patient screened positive or reported the presence of at least one OAB symptom, additional questions were asked regarding lifestyle and coping issues. The clinician then diagnosed the patient as having No OAB, Possible OAB, or Probable OAB. Multivariate logistic regressions were performed to assess the feasibility of deriving a shorter screener to raise awareness of OAB among primary care patients. The 1,260 patients in this study were 51.6±17.0 years old; 62% were women; and most (89%) were Caucasian. Clinicians diagnosed 12.1% of patients with Probable OAB, 19.7% with Possible OAB and 68.3% with No OAB. The logistic regression models were performed with OAB clinical diagnosis as the dependent variable comparing No OAB versus Probable OAB. Three items which included the symptoms of urinary frequency, urinary urgency and urine loss associated with a strong desire to urinate performed well as an awareness tool. A cut-point of four provided the most appropriate sensitivity (82%) and specificity (91%) when identifying Probable OAB and yielded adequate model fit. The final 3-item OAB Awareness Tool (OAB-V3) is gender neutral. The 3-item OAB Awareness Tool (OAB-V3) correctly identified patients with symptoms of OAB with high sensitivity and specificity and can be used as a conversation starter for patients with symptoms of OAB.

Defining and Managing Overactive Bladder: Disagreement Among the Experts