Future trends in the treatment of urinary incontinence

Anticholinergic drugs act on efferent nerves to counteract overactive bladder (OAB) after it occurs. To prevent the occurrence of OAB, therapies should be directed at blocking the afferent nerves that control the bladder. Tachykinin-receptor antagonists hold great promise in this regard, since they can be administered orally and do not increase the risk of urinary retention that occurs with anticholinergics. Advanced drug delivery systems, such as controlled-release oral oxybutynin (oxybutynin-XL) can reduce the incidence of anticholinergic side effects. In a similar manner intravesical therapy for OAB is site specific, and thus also reduces the occurrence of adverse events. Moreover, the difficulties of intravesical therapy may now be overcome with advanced delivery techniques such as an implantable, long-acting drug-delivery pump. Another intravesical therapy that has met with great acceptance and success is the administration of chili pepper extracts, especially resiniferitoxin, which may be effective for up to 3 months with one application. Finally, gene therapy holds great promise for OAB, because it is possible to access all of the genitourinary organs via endoscopy and other minimally invasive techniques that are ideally suited for gene therapy.     

State of the art in intravesical therapy for lower urinary tract symptoms

Intravesical therapy is the routine first-line treatment for effectively delaying or preventing the recurrence of bladder cancer. This route of drug administration has also shown tremendous promise in the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS) and potentially overactive bladder to justify investments for further improvements. This review takes a bird's eye view into the current status of intravesical therapy, with emphasis on liposomal nanoparticles, in diseases associated with lower urinary tract symptoms (LUTS). Ongoing efforts to advance the field of intravesical drug delivery include development of sustained-release drug implants and efforts to improve delivery of biotechnological products including large protein acting as neurotoxins and small interfering RNAs.     

The future of bladder control-intravesical drug delivery, a pinch of pepper, and gene therapy

The incidence of urinary incontinence and overactive bladder problems will continue to grow as the population ages. Future treatments are likely to include an implantable drug delivery system, gene therapy, and the intravesical use of the vallinoids capsaicin and resiniferatoxin (RTX). An understanding of the urothelium is essential for effective design of these therapies. Intravesical anticholinergic drug treatment is currently not widely used, but intravesical pumps are under development to provide less cumbersome treatment methods and will provide nonsurgical options for patients who cannot tolerate oral anticholinergic agents. Research on the use of capsaicin as an intravesicular drug has had limited success, but trials have confirmed the efficacy of intravesical capsaicin for detrusor hyperreflexia. RTX is as effective as capsaicin but without side effects, such as pain and inflammatory neuropeptide release. RTX treatment may eliminate the need for surgical and other drug treatments of lower urinary tract dysfunction in patients with spinal cord injuries. Gene therapy will change the practice of urology by addressing the deficiencies that cause symptoms rather than attacking the symptoms themselves.     

Will the Evolution of Overactive Bladder Delivery Systems Increase Patient Compliance?

The negative impact of overactive bladder (OAB) on daily quality of life drives the large market of pharmacotherapy targeted at symptoms of urinary frequency and urgency, with or without urinary urge incontinence. Currently, the primary pharmacologic treatment modality is aimed at modulation of the efferent muscarinic receptors (M2 and M3) predominant in detrusor smooth muscle and responsible for involuntary or unwanted bladder contractions. However, due to drug effects in the muscarinic receptors of the salivary glands and intestinal smooth muscle, as well as extensive first-pass metabolism in the liver and intestinal tract yielding parent drug metabolites, adverse side effects are common and can be quite bothersome. These issues, encountered with many of the oral antimuscarinic formulations, limit their tolerability and affect long-term patient compliance and satisfaction. Thus, the benefit of pharmacotherapy for OAB must be a balance between efficacy and tolerability, also known as therapeutic index. This article reviews the current pharmacologic delivery systems available for the treatment of OAB, patient compliance, and reasons for discontinuation of medication.Key words: Overactive bladder, Pharmacotherapy, Compliance, Antimuscarinic agent, Transdermal delivery systemOveractive bladder syndrome (OAB) is a condition affecting millions of adults in the aging US population, with prevalence rates estimated at 17% in both men and women.¹ Quality of life and symptom bother have become important parameters in the treatment of many disease states, with efficacy of treatment measured by perceived improvements in these variables. OAB is largely characterized by its negative impact on daily quality of life. Specifically, the subjective impact of urinary frequency and urgency (with or without urge incontinence) on psychosocial and physical factors has become an important aspect of caring for this group of patients. The severity and degree of bother associated with OAB symptoms can directly influence a person’s mobility, degree of social isolation, and impairment in work-related productivity, and may also cause clinical depression, disruptions in sleep, and impairment in domestic and sexual life.² In addition, the patient may develop extreme coping strategies including severe, self-imposed fluid restrictions, avoidance of social events and travel, and dependence on costly protective undergarments. Although all of these factors drive patients to seek evaluation and treatment, persistence and compliance with medical OAB therapy remain astoundingly low both in the clinical setting and in large-scale clinical trials. High rates of discontinuation are multifactorial: adverse side effects, lack of perceived efficacy, polypharmacy, medication cost, poor counseling regarding compliance and successful treatment, and dosing frequency. Because adverse side effects are experienced by a significant portion of patients treated with oral antimuscarinic therapy, thereby limiting their long-term utilization, the development of new drug delivery systems for OAB pharmacotherapy has been critical. The focus has been on less frequent dosing intervals with longer acting formulations, reduction in side-effect profile by altering pharmacokinetics of both parent compound and active metabolites, and alternative methods of drug delivery that avoid first-pass liver metabolism.     

Hyposensitivity of C-fiber Afferents at the Distal Extremities as an Indicator of Early Stages Diabetic Bladder Dysfunction in Type 2 Diabetic Women

Purpose

To investigate the relationship between distal symmetric peripheral neuropathy and early stages of autonomic bladder dysfunction in type 2 diabetic women.

Materials and Methods

A total of 137 diabetic women with minimal coexisting confounders of voiding dysfunction followed at a diabetes clinic were subject to the following evaluations: current perception threshold (CPT) tests on myelinated and unmyelinated nerves at the big toe for peroneal nerve and middle finger for median nerve, uroflowmetry, post-void residual urine volume, and overactive bladder (OAB) symptom score questionnaire. Patients presenting with voiding difficulty also underwent urodynamic studies and intravesical CPT tests.

Results

Based on the OAB symptom score and urodynamic studies, 19% of diabetic women had the OAB syndrome while 24.8% had unrecognized urodynamic bladder dysfunction (UBD). The OAB group had a significantly greater mean 5 Hz CPT test value at the big toe by comparison to those without OAB. When compared to diabetic women without UBD, those with UBD showed greater mean 5 Hz CPT test values at the middle finger and big toe. The diabetic women categorized as C-fiber hyposensitivity at the middle finger or big toe by using CPT test also had higher odds ratios of UBD. Among diabetic women with UBD, the 5 Hz CPT test values at the big toe and middle finger were significantly associated with intravesical 5 Hz CPT test values.

Conclusions

Using electrophysiological evidence, our study revealed that hyposensitivity of unmyelinated C fiber afferents at the distal extremities is an indicator of early stages diabetic bladder dysfunction in type 2 diabetic women. The C fiber dysfunction at the distal extremities seems concurrent with vesical C-fiber neuropathy and may be a sentinel for developing early diabetic bladder dysfunction among female patients.     

Efficacy and Safety of Intravesical OnabotulinumtoxinA Injection on Elderly Patients with Chronic Central Nervous System Lesions and Overactive Bladder

Purpose

Intravesical injection of onabotulinumtoxinA is an effective treatment for overactive bladder (OAB). Nonetheless, the treatment outcome is unclear in OAB patients with central nervous system (CNS) lesions. This study evaluated the efficacy and safety of intravesical onabotulinumtoxinA treatment in elderly patients with chronic cerebrovascular accidents (CVAs), Parkinson’s disease (PD) and dementia.

Materials and Methods

Patients with CVA, PD, dementia, and OAB refractory to antimuscarinic therapy were consecutively enrolled in the study group. Age-matched OAB patients without CNS lesions were selected to serve as a control group. OnabotulinumtoxinA (100 U) was injected into the bladder suburothelium at 20 sites. The clinical effects, adverse events, and urodynamic parameters were assessed at baseline and 3 months post-treatment. The Kaplan-Meier method was used to compare long-term success rates between groups.

Results

A total of 40 patients with OAB due to CVA (23), PD (9), dementia (8) and 160 control patients were included in this retrospetive analysis. Improvement of urgency severity scale, increased bladder capacity and increased post-void residual volume were comparable between the groups at 3 months. Patients with CNS lesions did not experience increased risks of acute urinary retention and urinary tract infection; nonetheless, patients with CVA experienced a higher rate of straining to void. Long-term success rates did not differ between the patients with and without CNS lesions.

Conclusion

Intravesical injection of 100 U of onabotulinumtoxinA effectively decreased urgency symptoms in elderly OAB patients with CNS lesions. The adverse events were acceptable, and long-term effects were comparable to OAB patients in general. Nonetheless, the possibility of longstanding urinary retention and chronic catheterization need careful evaluation for this very vulnerable population before choosing intravesical onabotulinumtoxinA treatment.     

Inhibition of bladder overactivity by a combination of tibial neuromodulation and tramadol treatment in cats

Our recent study in cats revealed that inhibition of bladder overactivity by tibial nerve stimulation (TNS) depends on the activation of opioid receptors. TNS is a minimally invasive treatment for overactive bladder (OAB), but its efficacy is low. Tramadol (an opioid receptor agonist) is effective in treating OAB but elicits significant adverse effects. This study was to determine if a low dose of tramadol (expected to produce fewer adverse effects) can enhance the TNS inhibition of bladder overactivity. Bladder overactivity was induced in α-chloralose-anesthetized cats by an intravesical infusion of 0.25% acetic acid (AA) during repeated cystometrograms (CMGs). TNS (5 Hz) at two to four times the threshold intensity for inducing toe movement was applied during CMGs before and after tramadol (0.3-7 mg/kg iv) to examine the interaction between the two treatments. AA irritation significantly reduced bladder capacity to 24.8 ± 3.3% of the capacity measured during saline infusion. TNS alone reversibly inhibited bladder overactivity and significantly increased bladder capacity to 50-60% of the saline control capacity. Tramadol administered alone in low doses (0.3-1 mg/kg) did not significantly change bladder capacity, whereas larger doses (3-7 mg/kg) increased bladder capacity (50-60%). TNS in combination with tramadol (3-7 mg/kg) completely reversed the effect of AA. Tramadol also unmasked a prolonged (>2 h) TNS inhibition of bladder overactivity that persisted after termination of the stimulation. The results suggest a novel treatment strategy for OAB by combining tibial neuromodulation with a low dose of tramadol, which is minimally invasive with a potentially high efficacy and fewer adverse effects.     

Beyond traditional therapy: Mucoadhesive polymers as a new frontier in oral cancer management

In recent times mucoadhesive drug delivery systems are gaining popularity in oral cancer. It is a malignancy with high global prevalence. Despite significant advances in cancer therapeutics, improving the prognosis of late-stage oral cancer remains challenging. Targeted therapy using mucoadhesive polymers can improve oral cancer patients' overall outcome by offering enhanced oral mucosa bioavailability, better drug distribution and tissue targeting, and minimizing systemic side effects. Mucoadhesive polymers can also be delivered via different formulations such as tablets, films, patches, gels, and nanoparticles. These polymers can deliver an array of medicines, making them an adaptable drug delivery approach. Drug delivery techniques based on these mucoadhesive polymers are gaining traction and have immense potential as a prospective treatment for late-stage oral cancer. This review examines leading research in mucoadhesive polymers and discusses their potential applications in treating oral cancer.     

Enhancement of intravesical delivery with Syn3 potentiates interferon-alpha2b gene therapy for superficial bladder cancer

Intravesical administration of interferon alpha-2b protein (IFN) has been successfully used in the treatment of patients with superficial bladder tumors. Local dosing of IFN minimizes well-known systemic side effects of the drug, but exposure to bladder tumors is limited by the duration of instillation and transient concentrations achieved in the urothelium. Intravesical delivery of the gene encoding interferon results in an alternative strategy for IFN-based therapy of the disease, enabling sustained exposure of IFN protein that results from production by tumor and non-tumor cells in the urothelium. Efficient gene delivery and expression of IFN has been achieved using a recombinant adenovirus gene delivery system (rAd-IFN) in conjunction with the novel small molecule excipient Syn3. Studies with rAd-IFN/Syn3 in animal models result in urine concentrations of IFN that persisted for weeks and correlated with potent anti-tumor effects. The objective of this review is to communicate the rationale and preclinical findings that support ongoing clinical investigation of intravesical rAd-IFN/Syn3 in superficial bladder cancer.     

Enhancement of intravesical delivery with Syn3 potentiates interferon-α2b gene therapy for superficial bladder cancer

Intravesical administration of interferon alpha-2b protein (IFN) has been successfully used in the treatment of patients with superficial bladder tumors. Local dosing of IFN minimizes well-known systemic side effects of the drug, but exposure to bladder tumors is limited by the duration of instillation and transient concentrations achieved in the urothelium. Intravesical delivery of the gene encoding interferon results in an alternative strategy for IFN-based therapy of the disease, enabling sustained exposure of IFN protein that results from production by tumor and non-tumor cells in the urothelium. Efficient gene delivery and expression of IFN has been achieved using a recombinant adenovirus gene delivery system (rAd-IFN) in conjunction with the novel small molecule excipient Syn3. Studies with rAd-IFN/Syn3 in animal models result in urine concentrations of IFN that persisted for weeks and correlated with potent anti-tumor effects. The objective of this review is to communicate the rationale and preclinical findings that support ongoing clinical investigation of intravesical rAd-IFN/Syn3 in superficial bladder cancer.     

Selective binding of lectins to normal and neoplastic urothelium in rat and mouse bladder carcinogenesis models

Bladder cancer adjuvant intravesical therapy could be optimized by more selective targeting of neoplastic tissue via specific binding of lectins to plasma membrane carbohydrates. Our aim was to establish rat and mouse models of bladder carcinogenesis to investigate in vivo and ex vivo binding of selected lectins to the luminal surface of normal and neoplastic urothelium. Male rats and mice were treated with 0.05 % N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water and used for ex vivo and in vivo lectin binding experiments. Urinary bladder samples were also used for paraffin embedding, scanning electron microscopy and immunofluorescence labelling of uroplakins. During carcinogenesis, the structure of the urinary bladder luminal surface changed from microridges to microvilli and ropy ridges and the expression of urothelial-specific glycoproteins uroplakins was decreased. Ex vivo and in vivo lectin binding experiments gave comparable results. Jacalin (lectin from Artocarpus integrifolia) exhibited the highest selectivity for neoplastic compared to normal urothelium of rats and mice. The binding of lectin from Amaranthus caudatus decreased in rat model and increased in mouse carcinogenesis model, indicating interspecies variations of plasma membrane glycosylation. Lectin from Datura stramonium showed higher affinity for neoplastic urothelium compared to the normal in rat and mouse model. The BBN-induced animal models of bladder carcinogenesis offer a promising approach for lectin binding experiments and further lectin-mediated targeted drug delivery research. Moreover, in vivo lectin binding experiments are comparable to ex vivo experiments, which should be considered when planning and optimizing future research.     

Aerosol gene therapy

Gene therapy is a novel field of medicine that holds tremendous therapeutic potential for a variety of human diseases. Targeting of therapeutic gene delivery vectors to the lungs can be beneficial for treatment of various pulmonary diseases such as lung cancer, cystic fibrosis, pulmonary hypertension, alpha-1 antitrypsin deficiency, and asthma. Inhalation therapy using formulations delivered as aerosols targets the lungs through the pulmonary airways. The instant access and the high ratio of the drug deposited within the lungs noninvasively are the major advantages of aerosol delivery over other routes of administration. Delivery of gene formulations via aerosols is a relatively new field, which is less than a decade old. However, in this short period of time significant developments in aerosol delivery systems and vectors have resulted in major advances toward potential applications for various pulmonary diseases. This article will review these advances and the potential future applications of aerosol gene therapy technology.     

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.     

Presence of Cleaved Synaptosomal-Associated Protein-25 and Decrease of Purinergic Receptors P2X3 in the Bladder Urothelium Influence Efficacy of Botulinum Toxin Treatment for Overactive Bladder Syndrome

Objectives

To evaluate whether botulinum toxin A (BoNT-A) injection and Lipotoxin (liposomes with 200 U of BoNT-A) instillation target different proteins, including P2X3, synaptic vesicle glycoprotein 2A, and SNAP-25, in the bladder mucosa, leading to different treatment outcomes.

Materials and Methods

This was a retrospective study performed in a tertiary teaching hospital. We evaluated the clinical results of 27 OAB patients treated with intravesical BoNT-A injection (n = 16) or Lipotoxin instillation (n = 11). Seven controls were treated with saline. Patients were injected with 100 U of BoNT-A or Lipotoxinin a single intravesical instillation. The patients enrolled in this study all had bladder biopsies performed at baseline and one month after BoNT-A therapy. Treatment outcome was measured by the decreases in urgency and frequency episodes at 1 month. The functional protein expressions in the urothelium were measured at baseline and after 1 month. The Wilcoxon signed-rank test and ordinal logistic regression were used to compare the treatment outcomes.

Results

Both BoNT-A injection and Lipotoxin instillation treatments effectively decreased the frequency of urgency episodes in OAB patients. Lipotoxin instillation did not increase post-void residual volume. BoNT-A injection effectively cleaved SNAP-25 (p < 0.01). Liposome encapsulated BoNT-A decreased urothelial P2X3 expression in the five responders (p = 0.04), while SNAP-25 was not significantly cleaved.

Conclusions

The results of this study provide a possible mechanism for the therapeutic effects of BoNT-A for the treatment of OAB via different treatment forms. BoNT-A and Lipotoxin treatments effectively decreased the frequency of urgency episodes in patients with OAB.     

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.     

Factors Associated with Therapeutic Efficacy of Intravesical OnabotulinumtoxinA Injection for Overactive Bladder Syndrome

Objectives

To analyze the predictors of therapeutic efficacy after intravesical botulinum toxin A injection for overactive bladder syndrome (OAB) refractory to antimuscarinic therapy.

Methods

All consecutively OAB patients, who visited the urologic outpatient clinics of a medical center and refractory to antimuscarinic treatment, were prospectively enrolled. All enrolled patients received intravesical injection of 100 U onabotulinumtoxinA (Botox). The Global Response Assessment (GRA) score ≥ 2 at 3 months after Botox injection was defined as a successful treatment, otherwise failed.

Results

Overall, 89 patients received intravesical injection. Eighty patients, including 42 men and 38 women, had received follow-up at 3 months. The overall success rate was 63.8%. The global response assessment, urgency severity score, urgency, urgency urinary incontinence and frequency episodes, and functional bladder capacity improved after treatment. However, post-void residual volume (PVR) increased, and voiding efficiency (VE) decreased after treatment. Female gender (odds ratio = 3.75) was the only independent factor associated with the success. Female gender (coefficient = 0.74), low baseline overactive bladder symptoms score (coefficient = -0.12) and the presence of OAB-wet (coefficient = 0.79) were independent factors associated with therapeutic efficacy (i.e., GRA score). VE (odds ratio = 0.062) was the only predictor for a large PVR at 3 months. The optimum cutoff value of VE was <87% with the area under the ROC curve being 0.64 (sensitivity = 63.8%, specificity = 57.1%).

Conclusions

The therapeutic effects of Botox can persist till 6 months after treatment. Female gender, low overactive bladder symptoms score and OAB-wet are associated better therapeutic efficacy, and low baseline VE is associated with large PVR. These findings can serve as an initial guide or assist in consultation regarding the treatment of OAB patients with Botox injection.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01657409","term_id":"NCT01657409"}}NCT01657409     

Endocytosis in cellular uptake of drug delivery vectors: Molecular aspects in drug development

Drug delivery vectors are widely applied to increase drug efficacy while reducing the side effects and potential toxicity of a drug. They allow for patient-tailored therapy, dose titration, and therapeutic drug monitoring. A major part of drug delivery systems makes use of large nanocarriers: liposomes or virus-like particles (VLPs). These systems allow for a relatively large amount of cargo with good stability of vectors, and they offer multiple options for targeting vectors in vivo. Here we discuss endocytic pathways that are available for drug delivery by large nanocarriers. We focus on molecular aspects of the process, including an overview of potential molecular targets for studies of drug delivery vectors and for future solutions allowing targeted drug delivery.     

Use of Herbal Supplements for Overactive Bladder

Anticholinergics, specifically antimuscarinic agents, are the most common medications prescribed for overactive bladder (OAB). The most common side effects of these agents are dry mouth and constipation, although other more concerning effects include changes in blood pressure, pulse rate, or heart rhythm when treatment is initiated. Herbal treatments are an increasingly popular alternative for treating OAB. A 2002 survey of US adults aged ≥ 18 years conducted by the Centers for Disease Control and Prevention indicated that 74.6% of those with OAB had used some form of complementary and alternative medicine. The World Health Organization estimates that 80% of the world’s population presently uses herbal medicine for some aspect of primary health care. Women were more likely than men to use complementary and alternative medicine. The authors review the most commonly used herbal medications for OAB.Key words: Overactive bladder, Herbal medicine, Gosha-jinki-gan, Hachi-mi-jio-gan, Buchu (Barosma betuline), Cleavers (Galium aparine), Cornsilk (Zea mays), Horsetail (Equisetum), Ganoderma lucidum, Resinferatoxin, CapsaicinOveractive bladder (OAB) is defined by the International Continence Society as a syndrome that includes urgency, with or without urge incontinence, frequency, and nocturia. The prevalence of OAB is estimated to range between 9% and 16%, depending on the population studied.^1–3 As symptoms of OAB increase with age, they can negatively impact quality of life (QoL).The cost of treating OAB is estimated to be approximately $12 billion annually in the United States.⁴ This estimate accounts for the direct cost of management, including protective undergarments, bedside commodes, and medical treatment, as well as indirect costs, such as those resulting from urinary tract infections and falls due to urgency and nocturia. There are also additional intangible costs that cannot be estimated such as pain, suffering, and poor QoL.The negative impact on health and the sense of well-being as well as the impairment in the ability to perform activities of daily living, has been well-documented. For example, elderly patients with OAB and subsequent incontinence are more likely to be admitted to nursing homes. Thom and colleagues reported a twofold increased risk of admission to a nursing facility for patients with incontinence.⁵ Urinary incontinence can also lead to anxiety, negative self-image, and isolation.⁴ Other problems associated with OAB include skin ulcerations and urinary tract infections. Nocturia is common with OAB and ranks among the most bothersome of lower urinary tract symptoms.⁶ In addition to sleep interruption and resulting fatigue, patients with nocturia may be more likely to suffer from falls and fractures, which are associated with high mortality in elderly patients. Approximately 33% of elderly people do not survive beyond 1 year after a hip fracture.⁷The impact of OAB was clearly reported in the National Overactive Bladder Evaluation (NOBLE) study.⁸ The NOBLE study represented a computer-assisted telephone interview survey that used health-related QoL (HRQoL) questionnaires to compare continent OAB patients, with incontinent OAB patients, and control groups in a nested case-control fashion. In this study, OAB was associated with lower QoL scores, higher scores on depression, and poorer sleep quality when compared with control subjects.⁸ Note that, although the prevalence of OAB increases with age, it should not be considered a normal consequence of aging.Anticholinergics, specifically antimuscarinic agents, represent the most common medications prescribed for OAB. The most common side effects are dry mouth and constipation.^9,10 Other more concerning side effects include changes in blood pressure, pulse rate, or heart rhythm when treatment is initiated. Additional adverse events (AEs) include memory loss, cognitive impairment, and balance problems. Thus, alternative therapies not involving standard medications and their associated risks are sought by patients to alleviate symptoms of OAB.Herbal treatments represent an increasingly popular alternative for treating OAB. A 2002 survey of US adults aged ≥ 18 years conducted by the Centers for Disease Control and Prevention indicated 74.6% of those with OAB had used some form of complementary and alternative medicine. The World Health Organization estimates that 80% of the world’s population presently uses herbal medicine for some aspect of primary health care. Women were more likely than men to use complementary and alternative medicine.^10,11 We review the most commonly used herbal medications used for OAB.     

Discovery of 2-(1H-indazol-1-yl)-thiazole derivatives as selective EP1 receptor antagonists for treatment of overactive bladder by core structure replacement

We have designed a series of potent EP₁ receptor antagonists. These antagonists are a series of 2-(1H-indazol-1-yl)-thiazoles in which the core structure was replaced with pyrazole-phenyl groups. In preliminary conscious rat cystometry experiments, two representative candidates, 2 and 22, increased bladder capacity. In particular, the increase using 22 was approximately 2-fold that of the baseline. More detailed profiling of this compound and further optimization of this series promises to provide a novel class of drug for treating overactive bladder (OAB).