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.     

Altered neurogenic and mechanical responses to acetylcholine, ATP and substance P in detrusor from rat with outlet obstruction

The well-known side effects of anticholinergic compounds used to treat urinary incontinence caused by detrusor overactivity have addressed the interest on other pharmacological intervention. The purpose of the present work was to investigate the possible changes in purinergic and cholinergic components of parasympathetic neurotransmission in obstructed rat bladders with detrusor overactivity, and to examine the effect of the association of suramin, atropine and indomethacin on nerve-mediated responses to electrical field stimulation (EFS). Mechanical responses to exogenous acetylcholine, ATP and substance P were also evaluated. Altered sensitivities to acetylcholine and to the sensory neurotransmitter substance P, but unchanged sensitivity to the stable ATP analogue alpha,beta-methyleneATP were observed in bladders from obstructed rats. Suramin and atropine inhibited purinergic and cholinergic components of the neurogenic responses evoked by EFS in detrusor strips from control and obstructed rats. Interestingly, suramin enhanced the antagonistic effect of atropine on neurogenic responses of detrusor strips at all frequencies of stimulation tested. Our results suggest that the association between an antimuscarinic drug and an antagonist of P2X purinoceptors such as suramin might be helpful to reduce the therapeutic dosage of the antimuscarinic drug, along with its side effects. This approach may be of interest in the therapy of patients with bladder incontinence caused by detrusor overactivity, which do not even respond to a maximal dosage of antimuscarinic drug.     

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.     

Contemporary Management of Bulbar Urethral Strictures

Urethral stricture disease (USD) is a progressive scar-forming disease commonly encountered by urologists and is challenging to manage. USD most frequently occurs in the bulbar urethra. Patients typically present with chronic obstructive voiding symptoms but may develop recurrent urinary tract infections, detrusor failure, or renal disease. The authors review the pathophysiology, diagnostic workup, and evidence-based management of bulbar urethral strictures (BUS). There are multiple surgical options to treat BUS. Endoscopic techniques (eg, dilation and urethrotomy) are suitable for the initial management of short strictures but new evidence-based guidelines recommend against repeated endoscopic treatment. Urethroplasty is the gold standard treatment for BUS of all lengths, with anastomotic techniques appropriate for strictures <2 cm and tissue substitution performed for longer strictures. New techniques, such as non-transecting urethroplasty, lack long-term data but may represent a paradigm shift in the field. Future treatments may utilize tissue-engineered grafts and agents that inhibit inflammation and scar formation.     

Bulking agents in the treatment of stress urinary incontinence: history, outcomes, patient populations, and reimbursement profile

Stress urinary incontinence (SUI) can be defined as involuntary loss of urine during a period of increased abdominal pressure and in the absence of detrusor activity. Bulking agents used in the urethra are one of the newer but established technologies for the treatment of SUI. An understanding of the demographics of SUI will help in the selection of patients for bulking agent therapy. Knowledge of available materials, including their positive and negative aspects, is also required. Autologous fat, silicone beads, collagen, carbon particles, and polytetrafluoroethylene paste have all demonstrated success to some degree, but none have met both criteria for success (remaining efficacious over time and maintaining a low side-effect profile). An implantable solution of ethylene vinyl alcohol suspended in dimethyl sulfoxide, currently in clinical testing and review, shows minimal foreign body reaction and is one option being investigated to address patient needs for improved bulking therapy.     

Micturition and the mind: psychological factors in the aetiology and treatment of urinary symptoms in women.

The mental state of 211 women attending a urodynamic clinic was assessed using questionnaires. Patients with genuine stress incontinence had scores comparable with other patients with longstanding physical complaints. Patients with sensory urgency were more anxious than those with genuine stress incontinence. Patients with detrusor instability were as anxious as patients with sensory urgency and in addition had higher scores on the hysteria scale. A subset of patients (roughly a quarter of the total) was identified, comprising members of all three diagnostic groups, for whom urinary symptoms rendered life intolerable. These patients were as anxious, depressed, and phobic as psychiatric inpatients, emphasising the serious psychological morbidity experienced by patients with urinary symptoms. Fifty patients with detrusor instability or sensory urgency entered a randomised trial comparing psychotherapy, bladder drill, and propantheline. The psychotherapy group significantly improved on measures of urgency, incontinence, and nocturia, though not on frequency. Bladder training was an effective treatment for frequency and patients became less anxious and depressed. There was a modest improvement in frequency of micturition in patients given propantheline. Frequency may be a learnt disorder which responds to the direct symptom oriented approach of bladder training. Patients with urgency and nocturia predominating might derive more benefit from psychotherapy.     

Hypnotherapy for incontinence caused by the unstable detrusor.

Fifty incontinent women with proved detrusor instability completed 12 sessions of hypnosis (symptom removal by direct suggestion and "ego strengthening") over one month. This was continued at home with a prerecorded cassette, and all patients were followed up for at least six months. At the end of the 12 sessions 29 patients were entirely symptom free, 14 improved, and seven unchanged. Three months later cystometry in 44 of the patients showed conversion of the cystometrogram to stability in 22 and a significant improvement in a further 16; only six showed no objective improvement. Seven patients relapsed (three after bereavement). Further treatment was given and five out of six patients were rendered symptom free again. Patients with detrusor instability were not found to have a noticeably increased susceptibility to hypnosis. It is concluded that psychological factors are very important in "idiopathic" detrusor instability and that hypnotherapy is effective for incontinence due to this disorder.     

Behavioural treatment of urinary incontinence in geriatric patients.

Urinary incontinence and a program to treat it were studied in a geriatric hospital. Of 161 men, 58 (36%) were incontinent. The most common probable causes were cerebrovascular accident and organic brain syndrome. Evaluation by cystometry (after treatment of infections) in 30 patients showed 24 (80%) to have detrusor hyperreflexia. Twenty patients with hyperreflexia completed a timed-voiding routine, which benefited 17 of them (85%).     

Evaluation of flurbiprofen in detrusor instability.

Thirty women with detrusor instability (27 cases idiopathic, and three secondary to multiple sclerosis) completed a double-blind, cross-over trial of the prostaglandin synthetase inhibitor flurbiprofen and a placebo, results being evaluated by questionnaire and cystometry. Frequency, urgency, and urge incontinence were all significantly reduced with flurbiprofen (P less than 0.001, P less than 0.025, and P less than 0.025 respectively), as was the detrusor-pressure rise during bladder filling (P less than 0.01). Side effects, however, occurred in 13 patients while taking flurbiprofen compared with five while taking placebo (P less than 0.025). After the trial 19 patients wished to continue with flurbiprofen. Flurbiprofen is a useful treatment for idiopathic detrusor instability and is well tolerated by most patients.     

Botulinum toxin for the treatment of idiopathic and neurogenic overactive bladder: state of the art

The pharmacologic treatment of overactive bladder and detrusor overactivity, whether idiopathic or neurogenic, has centered around blocking muscarinic receptors on the detrusor muscle. Although newer agents have been developed with better tolerability and safety, the basic mechanism by which the "irritable" detrusor is treated has not changed in decades. Although effective in many cases of idiopathic and neurogenic detrusor overactivity and overactive bladder, antimuscarinic agents fall short in many other cases because of lack of efficacy and/or tolerability. For the past several years, there has been increasing evidence to support the use of botulinum toxin for the treatment of detrusor overactivity and overactive bladder syndrome not effectively treated by anticholinergics. From early open-label studies to the more recent randomized, controlled trials, efficacy and tolerability data have been very encouraging. Botulinum toxin is not yet approved by the US Food and Drug Administration for the treatment of detrusor overactivity and overactive bladder, but the positive results seen thus far cannot be ignored.     

Expectations of Stress Urinary Incontinence Surgery in Patients With Mixed Urinary Incontinence

Mixed urinary incontinence is estimated to affect 30% of all women who have urinary incontinence, and it has been shown to be more bothersome to women than pure stress incontinence. Given the degree of bother, many women will undergo surgical correction for incontinence. Patients have high expectations about the success of these interventions. Understanding mixed incontinence and the effects of our interventions can help guide therapeutic choices and manage patients’ expectations.Key words: Urodynamics, Mixed urinary incontinence, Sling, Anti-incontinence surgery, Urgency incontinenceIt has been estimated that approximately 30% of women with urinary incontinence have mixed urinary incontinence (MUI). Degree of bother is higher among women with MUI compared with those who have pure stress urinary incontinence (SUI).¹ MUI can be a very challenging and costly condition to treat.^2,3 Patients with MUI are often offered conservative therapy such as physical therapy, weight-loss strategies, and behavioral modification. Some patients also benefit from treatments aimed directly at urgency, frequency, and urgency incontinence (overactive bladder), which currently include pharmacologic therapy (antimuscarinic or β-3 agonists), chemodenervation (botulinum toxin), or neuromodulation (sacral or posterior tibial nerves).⁴ However, many patients with MUI progress to surgical therapies for treatment of SUI. This article reviews the literature available that can help clinicians manage expectations of SUI surgeries on patients with MUI.     

Urodynamic biofeedback treatment of urinary incontinence in children with myelomeningocele

Eight children with myelomeningocele and chronic neurogenic urinary incontinence were provided urodynamic biofeedback training. During urodynamic biofeedback, six of the eight children demonstrated improved self-regulation of detrusor and/or sphincter functioning. However, substantial improvements in clinical symptomatology (i.e., urinary incontinence) were clearly shown by only one child. Unexpectedly, chronic neurogenic fecal incontinence was reduced in four children. Several methodological modifications are discussed which may improve clinical symptomatology and which may facilitate further urodynamic biofeedback research for these children with congenital neurogenic urinary incontinence.     

Urodynamic biofeedback treatment of urinary incontinence in children with myelomeningocele

Eight children with myelomeningocele and chronic neurogenic urinary incontinence were provided urodynamic biofeedback training. During urodynamic biofeedback, six of the eight children demonstrated improved self-regulation of detrusor and/or sphincter functioning. However, substantial improvements in clinical symptomatology (i.e., urinary incontinence) were clearly shown by only one child. Unexpectedly, chronic neurogenic fecal incontinence was reduced in four children. Several methodological modifications are discussed which may improve clinical symptomatology and which may facilitate further urodynamic biofeedback research for these children with congenital neurogenic urinary incontinence.This work was supported by a grant from The Crippled Children's Guild through the Behavioral Pediatrics Program at Orthopaedic Hospital.     

Outcome of elective prostatectomy.

OBJECTIVES--To determine the symptomatic and urodynamic outcome of elective prostatectomy and to establish whether the outcome is influenced or can be predicted by preoperative urodynamic measurements. DESIGN--Prospective non-randomised study with follow up at a mean of 11 months after operation. Most men were assessed jointly by a urologist and a general practitioner. SETTING--Department of urology in a teaching hospital serving a large district population. PATIENTS--253 Men listed for elective prostatectomy because of symptoms and low urinary flow rates (less than 15 ml/s) and excluding those already on a waiting list or with acute urinary retention, clinically apparent prostatic cancer, and neurological or cerebrovascular disease; 217 (86%) were followed up. INTERVENTION--Elective prostatectomy. MAIN OUTCOME MEASURE--Classification on the basis of relief of symptoms assessed by patients and urologist and general practitioner and of symptom scores obtained by questionnaire. RESULTS--Of the 217 men followed up, 171 (79%) had a satisfactory subjective review and 155 (72%) had a satisfactory review and also low symptom scores. An unsatisfactory outcome was associated with preoperative symptoms of urge incontinence, small prostatic size and resected weight, low voiding pressures, and low urethral resistance. Preoperative maximum urinary flow rates did not predict outcome. Men with poor outcome could be classified into two groups: those with irritative symptoms who were more likely before operation to have had urge incontinence and detrusor instability and men with symptoms of poor urinary flow who were more likely before operation to have had a small prostate, low voiding pressures, and low urethral resistance. In patients in the second group flow rates or voiding pressures improved little after operation. Men with stable detrusors and either low urethral resistance or low voiding pressures were less likely to do well after prostatectomy, but despite these associations preoperative urodynamic measurements were unable to predict outcome accurately. CONCLUSIONS--Prostatectomy was satisfactory in relieving symptoms and improving urodynamic measurements in most men, but even in those with classic symptoms and low urinary flow rates a substantial minority experienced little improvement afterwards and urodynamic measurements did not accurately predict outcome in individual patients.     

The role of the urologist in treating patients with hormone-refractory prostate cancer

Objectives: To ascertain what percentage of urologists' oncology practice is dedicated to the care of prostate cancer patients and to determine urologists' attitudes towards the treatment of patients with metastatic and hormone-refractory prostate cancer (HRPC). An additional objective is to determine urologists' interest in administering various types of chemotherapy in HRPC patients.Materials and Methods: The American Urological Association (AUA) directory of practicing urologists was obtained, and 3000 randomly selected members of the AUA, as well as the complete list of 168 Society of Urologic Oncology (SUO) members, were chosen for the mailing of a 16-item questionnaire. The urologists were asked about how many of their patients have prostate cancer, how many have metastatic disease, and how many have HRPC and are currently receiving intravenous (IV) chemotherapy. In addition, the urologists were queried regarding their level of interest in learning about chemotherapy options as well as learning how to administer chemotherapy.Results: A total of 654 survey questionnaires were completed and returned for tabulation, resulting in a 21% effective response rate. Sixty-four percent of the responding urologists' cancer patients had prostate cancer, 21% had metastatic disease, and 19% had HRPC; only 4% of the urologists currently administer IV chemotherapy themselves. When asked to describe their interest in learning how to deliver and be reimbursed for IV chemotherapy, 26% expressed an extremely low level of interest, 23% a low level of interest, 31% a high level of interest, and 17% an extremely high level of interest. The results of other questions are presented and correlated with the number of years the urologists have been in practice and other demographic data.Conclusions: The management of prostate cancer comprises a major portion of urologists' practices. Almost one half (48%) of the urologists in this survey were interested in administering and being reimbursed for IV chemotherapy. Several chemotherapy regimens have been shown to improve quality of life in patients with HRPC, yet only about 30% of these patients were referred for chemotherapy. If more urologists were able to deliver these drugs, then the number of patients referred for chemotherapy would likely increase, as would accrual to important clinical trials in HRPC. The results of this survey suggest that methods to implement the training and reimbursement of urologists in the use of chemotherapy regimens should be investigated.     

Is There a Role for alpha-Blockers for the Treatment of Voiding Dysfunction Unrelated to Benign Prostatic Hyperplasia?

alpha-Adrenoreceptor antagonists have become the primary medical treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). It was presumed that the primary mechanism by which alpha-blockers reduced lower urinary tract symptoms (LUTS) was by relaxation of smooth muscle in the prostate through a sympathetic response. Reduction of outlet resistance leads to changes in bladder function, thus improving both storage and voiding symptoms. However, it was observed that many patients with BPH-associated LUTS had significant improvement in storage symptoms without subjective or objective improvement in voiding. Storage symptoms associated with detrusor overactivity (frequency, urgency, and urge incontinence) are typically thought of as being parasympathetically mediated, and therefore anticholinergic medications have been the mainstay of pharmacological treatment, but recent work has suggested that several nonparasympathetic-mediated mechanisms may cause detrusor overactivity. Because alpha receptors appear to play a role in lower urinary tract function at multiple sites and levels, alpha-blockers could be used to treat voiding dysfunction not related to BPH. In addition, these nonprostate effects should be gender-independent, making the use of alpha-blockers plausible in women with specific types of voiding dysfunction.     

INDICATIONS FOR DIFFERENT APPROACHES TO PROSTATECTOMY

Most urologists are definite and positive in their conviction as to which approach to prostatectomy is indicated in a given case. Their views are often so widely divergent that other physicians may be confused as to the best advice to give patients who need prostatic operation. Urologists who extol one approach or technique and deride another only add to the confusion and prejudice.The most important indication for the use of any approach or technique is the ability of the surgeon to carry it out.     

Sleep Cystometrography: A Preliminary Study of Bladder Function During Sleep

Bladder function during sleep was studied by the use of a cystometer which recorded detrusor contractions and intravesical pressure as urine accumulated in the bladder during diuresis. The cystometrographic tracing was obtained while the patient was awake. A detrusor contraction can occur during sleep. Results of such studies on five patients are presented, with photographs of representative cystometrographic tracings.The general pattern of the cystometrogram during sleep was found to be different from that obtained while the patient was awake. A detrusor contraction can occur during sleep and may subsequently: (a) subside without awakening the patient; (b) be associated with the involuntary escape of urine or flatus; or (c) cause the patient to awaken. It is suggested that detrusor contractions rather than increases in urinary volume are responsible for the individual''s awakening at night to urinate.In the light of these observations, further study of patients with enuresis and those with non-obstructive nocturia is required.     

膀胱过度活动症的抗胆碱治疗及其不良反应

膀胱过度活动症(overactive bladder,OAB)是一种令人烦恼的疾病,它影响着人们生活的质量。病人常常表现为尿急,伴有或不伴有急迫性尿失禁,通常有尿频和夜尿的症状。虽然膀胱过度活动症的病因不是很明确,但是抗胆碱药物作为其治疗的基石,在减少膀胱储尿期的收缩,增加膀胱的容量,起着重要的作用。这类药物具有一定的安全性,副作用小,并且有着相似的疗效。尽管如此,当治疗膀胱过度活动时,抗胆碱药物种类的选择,其治疗的预期利弊平衡也应在考虑之中,尤其是合并有中枢神经系统或者心脑血管系统疾病的老年患者。本文通过查阅国内外新近相关的文献,从受体的选择,临床应用和不良反应等方面对7种抗胆碱药物进行综述。     

Characterization of Gap Junction Proteins in the Bladder of Cx43 Mutant Mouse Models of Oculodentodigital Dysplasia

Oculodentodigital dysplasia (ODDD) is a rare developmental disease resulting from germline mutations in the GJA1 gene that encodes the gap junction protein connexin43 (Cx43). In addition to the classical ODDD symptoms that affect the eyes, teeth, bone and digits, in some cases ODDD patients have reported bladder impairments. Thus, we chose to characterize the bladder in mutant mouse models of ODDD that harbor two distinct Cx43 mutations, G60S and I130T. Histological assessment revealed no difference in bladder detrusor wall thickness in mutant compared to littermate control mice. The overall localization of Cx43 in the lamina propria and detrusor also appeared to be similar in the bladders of mutant mice with the exception that the G60S mice had more instances of intracellular Cx43. However, both mutant mouse lines exhibited a significant reduction in the phosphorylated P1 and P2 isoforms of Cx43, while only the I130T mice exhibited a reduction in total Cx43 levels. Interestingly, Cx26 levels and distribution were not altered in mutant mice as it was localized to intracellular compartments and restricted to the basal cell layers of the urothelium. Our studies suggest that these two distinct genetically modified mouse models of ODDD probably mimic patients who lack bladder defects or other factors, such as aging or co-morbidities, are necessary to reveal a bladder phenotype.