New frontiers in the treatment of overactive bladder and incontinence

In this article the author tries to forecast how urologists will treat the overactive bladder (OAB) in the next decade. He reviews drugs currently under development and also logical and exciting pharmacological targets that would be suitable targets for treating OAB in the future. The author also discusses intravesical therapy and alternative drug delivery methods, such as intravesical capsaicin and botulinum toxin. There are many advantages to advanced drug delivery systems, including the achievement of long-term therapeutic efficacy, decreased incidence and severity of side effects, and improved patient compliance. Special emphasis is placed on approaches to modulating bladder afferent nerve function to prevent OAB. Speculation on future techniques such as gene therapy can also be considered for treating OAB, because they may make it possible to access all of the genitourinary organs via minimally invasive techniques. Traditional anticholinergic therapies are limited in their effectiveness. There is great hope for future research and therapy for OAB and urinary incontinence.     

Pathophysiology of overactive bladder and urge urinary incontinence

Storage symptoms such as urgency, frequency, and nocturia, with or without urge incontinence, are characterized as overactive bladder (OAB). OAB can lead to urge incontinence. Disturbances in nerves, smooth muscle, and urothelium can cause this condition. In some respects the division between peripheral and central causes of OAB is artificial, but it remains a useful paradigm for appreciating the interactions between different tissues. Models have been developed to mimic the OAB associated with bladder instability, lower urinary tract obstruction, neuropathic disorders, diabetes, and interstitial cystitis. These models share the common features of increased connectivity and excitability of both detrusor smooth muscle and nerves. Increased excitability and connectivity of nerves involved in micturition rely on growth factors that orchestrate neural plasticity. Neurotransmitters, prostaglandins, and growth factors, such as nerve growth factor, provide mechanisms for bidirectional communication between muscle or urothelium and nerve, leading to OAB with or without urge incontinence.     

Maximizing the treatment of overactive bladder in the elderly

Overactive bladder syndrome affects millions of elderly people in the United States and is equally prevalent in men and women. Its impact on quality of life can be devastating, especially to elderly patients with other medical comorbidities. In order to maximize care, health care providers must be able to make the correct diagnosis and have a working knowledge of available therapies. Data exist supporting the efficacy and safety of nonpharmacologic and pharmacologic therapies.     

The role of geriatricians and family practitioners in the treatment of overactive bladder and incontinence

Although the prevalence of overactive bladder (OAB) and that of its symptoms (urinary urge incontinence, urgency, and frequency) increase with age, these conditions are not necessarily normal consequences of aging. Patients who present with urinary symptoms should be evaluated and treated, whether they are living on their own or in a residential, assisted-care, or long-term-care environment. Effective treatment for OAB and urinary incontinence (UI) is available and improves quality of life for the elderly. The primary care physician and geriatrician can accomplish a basic evaluation for UI using a systematic approach, as detailed in the following pages.     

Association of overactive bladder and stress urinary incontinence in rats with pudendal nerve ligation injury

Approximately one-third of patients with stress urinary incontinence (SUI) also suffer from urgency incontinence, which is one of the major symptoms of overactive bladder (OAB) syndrome. Pudendal nerve injury has been recognized as a possible cause for both SUI and OAB. Therefore, we investigated the effects of pudendal nerve ligation (PNL) on bladder function and urinary continence in female Sprague-Dawley rats. Conscious cystometry with or without capsaicin pretreatment (125 mg/kg sc), leak point pressures (LPPs), contractile responses of bladder muscle strips to carbachol or phenylephrine, and levels of nerve growth factor (NGF) protein and mRNA in the bladder were compared in sham and PNL rats 4 wk after the injury. Urinary frequency detected by a reduction in intercontraction intervals and voided volume was observed in PNL rats compared with sham rats, but it was not seen in PNL rats with capsaicin pretreatment that desensitizes C-fiber-afferent pathways. LPPs in PNL rats were significantly decreased compared with sham rats. The contractile responses of detrusor muscle strips to phenylephrine, but not to carbachol, were significantly increased in PNL rats. The levels of NGF protein and mRNA in the bladder of PNL rats were significantly increased compared with sham rats. These results suggest that pudendal nerve neuropathy induced by PNL may be one of the potential risk factors for OAB, as well as SUI. Somato-visceral cross sensitization between somatic (pudendal) and visceral (bladder) sensory pathways that increases NGF expression and alpha(1)-adrenoceptor-mediated contractility in the bladder may be involved in this pathophysiological mechanism.     

Clinical impact of overactive bladder

Overactive bladder (OAB) is a medical condition with the symptoms of urinary frequency and urgency, with or without urge incontinence. Traditionally, epidemiologic studies have focused on the symptom of incontinence, and therefore the prevalence and clinical impact have been grossly underestimated. Recently, several population-based studies have been conducted that have provided insight into the true magnitude of OAB. This article will review the latest data on the prevalence of OAB and discuss the impact of the condition on quality of life. Furthermore, it will examine some of the comorbidities associated with OAB and look at the potential economic impact of OAB.     

Management of overactive bladder with transdermal oxybutynin

In clinical trials, transdermal oxybutynin (OXY-TDS) has shown comparable efficacy and improved tolerability when compared with conventional pharmacotherapy. Systemic anticholinergic adverse effects are comparable to those with placebo, most likely owing to avoidance of first-pass hepatic metabolism and conversion of oxybutynin to N-desethyloxybutynin. OXY-TDS has predictable pharmacokinetic absorption and elimination parameters, as shown in both in vitro and in vivo studies. Consistent plasma concentrations of oxybutynin avoid labile peak and trough concentrations seen with immediate-release formulations, paralleling extended-release drug delivery. This novel drug delivery system has unique dermatologic skin application site reactions, including erythema and pruritus. Skin reactions are usually mild and can be minimized by varying the site of patch application. Most eczematous dermatologic reactions can be appropriately treated with a moderately potent topical corticosteroid cream. A small percentage of patients will discontinue therapy as a result of bothersome application site skin reactions.     

Selecting a medical therapy for overactive bladder

Immediate-release oxybutynin was the gold standard for pharmacologic treatment of overactive bladder for nearly 30 years. Intolerable systemic side effects, in particular dry mouth, limited its clinical utility, resulting in poor patient compliance with dosing regimens. Multiple studies have demonstrated the vastly superior tolerability of tolterodine, extended-release tolterodine, and extended-release oxybutynin over that of immediate-release oxybutynin at equivalent doses, and in the case of extended-release oxybutynin even to twice the dose of the original immediate-release form. With different drug delivery systems and, perhaps, with better bladder selectivity, these new oral agents have favorable side effect profiles, which translate into higher patient compliance and fewer treatment withdrawals or dosage reductions.     

Diagnosis of interstitial cystitis/ painful bladder syndrome in patients with overactive bladder symptoms

Overactive bladder (OAB) and interstitial cystitis (IC) have similar symptoms, including urinary urgency/frequency and nocturia, making them difficult to differentiate on the basis of clinical presentation alone. Both conditions may represent a clinical manifestation of a hypersensitive bladder and should be included in the differential diagnosis for patients who present with urgency/ frequency. It is especially important that IC be considered in patients with OAB that is refractory to treatment. The proposed diagnostic framework may be useful for differentiating IC from OAB and for facilitating appropriate treatment.     

The efficacy and safety of solifenacin in patients with overactive bladder syndrome

The aim of the randomised, double blind, placebo controlled study was to evaluate the efficacy, tolerability and safety of solifenacin, a once-daily M3 selective receptor antagonist, in patients with overactive bladder syndrome. Following a single blind 2-week placebo run in period, patients who complained from symptoms of OAB for at least 6 months, were randomized to 4 weeks of solifenacin in 5 mg once daily doses or placebo. 171 patients were enrolled in the study and 157 patients completed the study. Patients with solifenacin had significantly improved micturitions per 24 hours after first week of treatment (1.75 +/- 0.63 vs. 2.64 +/- 0.48, p < 0.001), and after four weeks (1.56 +/- 0.58 vs. 2.71 +/- 0.45, p < 0.001) compared to placebo group. The mean number of urgency episodes per 24 hours had significantly decreased in patients with solifenacin compared to placebo after first week (5.75 +/- 1.43 vs. 6.65 +/- 0.65, p < 0.001), and after four weeks of treatment (5.77 +/- 1.33 vs. 6.54 +/- 0.50, p < 0.001). Solifenacin was also significantly more effective than placebo in reducing the mean number of episodes of severe urgency from baseline to end point (5.83 +/- 1.16 vs. 6.48 +/- 0.50, p < 0.001). Compared with changes obtained with placebo, episodes of urinary frequency were significanlty reduced after first week (0.3 vs. -0.5, p < 0.001) and four weeks check up periods in patients treated with solifenacin (0.19 vs. -0.15, p < 0.001). Episodes of nocturia was significantly reduced in patients treated with solifenacin after first week (0.3 vs. -0.5, p < 0.001), and after four weeks treatment period (0.45 vs. -0.50, p < 0.001). The number of incontinence episodes was also significantly decreased in solifenacin group compared to placebo group after first week (1.06 +/- 0.57 vs. 2.74 +/- 0.47, p < 0.001) and four weeks check up (0.96 +/- 0.57 vs. 2.75 +/- 0.43, p < 0.001). The most common adverse effects with solifenacin were dry mouth and constipation. Adverse effects were mild or moderate severity. The discontinuation rate owing to adverse effects was 4.5%-6.7% with solifenacin and 3.8%-6.1% with placebo, respectively. According to subjective estimation, significant improvement was achieved in 71 (92.21%) of patients treated with solifenacin and in 68 (85%) patients treated with placebo there was no change in OAB symptoms compared to baseline values. UDI score was significantly improved after solifenacin (22.26 +/- 5.91 vs. 29.61 +/- 8.45, p < 0.001) compared to placebo. IIQ score was significantly decreased in patients with solifenacin (36.25 +/- 10.34 vs. 46.86 +/- 6.81, p < 0.001) compared to placebo. In conclusion, solifenacin is a safe and effective treatment alternative for patients with overactive bladder symptoms.     

Hyperosmolarity alters micturition: a comparison of urinary bladder motor activity in hyperosmolar and cyclophosphamide-induced models of overactive bladder

Hyperosmolar factors induce the neurogenic inflammatory response, leading to bladder overactivity (OAB). The aim of the study was to compare the bladder motor activity in a hyperosmolar and acute cyclophosphamide (CYP)-induced model of OAB. Furthermore, we set our sights on defining the most physiological model of OAB in experimental practice. Forty-two female rats were divided randomly into 5 groups. All animals underwent cystometry with the usage of isotonic saline or saline of increasing concentration. Acute chemical cystitis was induced by CYP to elicit OAB. The following cystometric parameters were analyzed: basal pressure, threshold pressure, micturition voiding pressure, intercontraction interval, compliance, functional bladder capacity, motility index, and detrusor overactivity index. CYP and hypertonic saline solutions induced OAB. Having been compared with CYP OAB, none of the rats infused with hypertonic solution exhibited macroscopic signs of bladder inflammation. The comparison of CYP and hyperosmolar models of OAB revealed that the greatest similarity existed between the 2080 mOsm/L OAB model and the acute CYP-induced model. We postulate that the 2080 mOsm/L model of OAB can be established as being a less invasive and more physiological model when compared with the CYP-induced OAB model. Additionally, it may also be a more reliable experimental tool for evaluating novel therapeutics for OAB as compared with CYP-induced models.     

Modulation of spontaneous activity in the overactive bladder: the role of P2Y agonists

Spinal cord transection (SCT) leads to an increase in spontaneous contractile activity in the isolated bladder that is reminiscent of an overactive bladder syndrome in patients with similar damage to the central nervous system. An increase in interstitial cell number in the suburothelial space between the urothelium and detrusor smooth muscle layer occurs in SCT bladders, and these cells elicit excitatory responses to purines and pyrimidines such as ATP, ADP, and UTP. We have investigated the hypothesis that these agents underlie the increase in spontaneous activity. Rats underwent lower thoracic spinal cord transection, and their bladder sheets or strips, with intact mucosa except where specified, were used for experiments. Isometric tension was recorded and propagating Ca(2+) and membrane potential (E(m)) waves were recorded by fluorescence imaging using photodiode arrays. SCT bladders were associated with regular spontaneous contractions (2.9 ± 0.4/min); ADP, UTP, and UDP augmented the amplitude but not their frequency. With strips from such bladders, a P2Y(6)-selective agonist (PSB0474) exerted similar effects. Fluorescence imaging of bladder sheets showed that ADP or UTP increased the conduction velocity of Ca(2+)/E(m) waves that were confined to regions of the bladder wall with an intact mucosa. When transverse bladder sections were used, Ca(2+)/E(m) waves originated in the suburothelial space and propagated to the detrusor and urothelium. Analysis of wave propagation showed that the suburothelial space exhibited properties of an electrical syncitium. These experiments are consistent with the hypothesis that P2Y-receptor agonists increase spontaneous contractile activity by augmenting functional activity of the cellular syncitium in the suburothelial space.