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PubMed2004

Corticotropin releasing factor: a mediator of emotional influences on bladder function.

PURPOSE: We review evidence linking overactive bladder (OAB) and interstitial cystitis with anxiety and depression, and highlight the importance of corticotropin releasing factor (CRF) as a potential mediator of these conditions. MATERIALS AND METHODS: We review the literature and describe ongoing experiments. RESULTS: CRF is expressed in areas of the central nervous system that control voiding and response to stress. CRF is increased during anxiety, depression and pain as well as functional disorders of the pelvic viscera. Epidemiological studies reveal an association between anxiety and voiding disorders. Experiments in our laboratory show that CRF stimulates bladder activity while CRF antagonists inhibit OAB. CONCLUSIONS: Epidemiological, genetic and neuropharmacological evidence links disorders of voiding and anxiety. CRF may participate in these events and warrants further investigation as a therapeutic target in the treatment of OAB and interstitial cystitis.

Animals↗

PubMed2004

Current perspectives on management of urgency using bladder and behavioral training.

Behavioral interventions for overactive bladder (OAB) include bladder training and behavioral training. Bladder training focuses on modifying bladder function by changing voiding habits; a bladder diary is indispensable. Behavioral training focuses on improving voluntary control rather than bladder function. It works through modification of the bladder outlet using methods, such as pelvic floor muscle training and urge suppression strategies to inhibit detrusor (bladder) muscle contraction. Behavioral methods--with biofeedback (which requires instrumentation), verbal feedback during a pelvic examination (using vaginal or anal palpation), or electrical stimulation--appear to be at least as effective in terms of reducing incontinence episodes as currently available drug therapy. However, evidence suggests that combining behavioral and drug therapy may produce better results than either approach alone. More research is needed to elucidate the role of behavioral modification in reducing urgency, frequency, and nocturia.

Behavior Therapy↗

PubMed1999

[Bladder dysfunction in dementia patients showing urinary incontinence: evaluation with cystometry and treatment with propiverine hydrochloride].

In a total of 46 dementia patients with urinary incontinence, filling cystometry was performed to evaluate bladder function, followed by peroral administration of propiverine hydrochloride. Therapeutic effects were evaluated in terms of changes in cystometric bladder capacity and urinary incontinence. Based on cystometric findings, 58.1%, 35.3% and 6.4% of Alzheimer dementia patients proved to have overactive bladder, normoactive bladder and low compliant bladder, respectively. Similarly, 90.9% and 9.1% of vascular dementia patients had overactive detrusor and low compliance, respectively. As a result of propiverine hydrochloride administration for 2 weeks, both bladder capacity and incontinence improved in around 40%, irrespective of the dementia type (Alzheimer vs vascular). It is of interest, however, that patients with overactive bladder demonstrated more satisfactory response to the treatment than those with normoactive bladder. It is accordingly suggested that propiveline hydrochrolide is a promising treatment option for urinary incontinence in demented elderly and cystometry could be useful in predicting treatment outcome.

Aged↗

PubMed2006

Muscarinic receptors in the bladder: from basic research to therapeutics.

Muscarinic receptor antagonists (antimuscarinics) serve as the cornerstone in the pharmacological management of overactive bladder (OAB) by relieving the symptoms of urgency, frequency and incontinence. These drugs operate primarily by antagonizing post-junctional excitatory muscarinic receptors (M(2)/M(3)) in the detrusor. The combination of pharmacological and gene knockout studies has greatly advanced our understanding of the functional role of muscarinic receptors in the bladder. M(3) receptors produce direct smooth muscle contraction by a mechanism that relies on entry of extracellular calcium through L-type channels and activation of a rho kinase. M(2) receptors, which predominate in number, appear to facilitate M(3)-mediated contractions. M(2) receptors can also produce bladder contractions indirectly by reversing cAMP-dependent beta-adrenoceptor-mediated relaxation, although the physiological role of beta-adrenoceptors in detrusor relaxation is controversial. Emerging evidence suggests that muscarinic receptors in the urothelium/suburothelium can modulate the release of certain factors, which in turn may affect bladder function at the efferent or afferent axis. Currently, oxybutynin, tolterodine, darifenacin, solifenacin and trospium are the five major antimuscarinics approved for the treatment of OAB. Comparative clinical studies have shown that oxybutynin and solifenacin may be marginally more effective than tolterodine, although the latter seems to be better tolerated. Pharmacokinetic-pharmacodynamic analyses using plasma concentrations of 'total drug' indicate that, at therapeutic doses, the clinical efficacy of darifenacin and solifenacin may be driven primarily by selective M(3) receptor occupation, whereas the pharmacodynamic effects of pan-selective molecules (such as tolterodine, trospium) may potentially involve multiple receptors, including M(2) and M(3). Furthermore, high M(3) receptor occupation is the likely explanation for the greater propensity of darifenacin and oxybutynin to cause dry mouth and/or constipation. Although the recently introduced drugs represent a significant improvement over older drugs, especially with respect to the convenience of dosing schedule, their overall efficacy and tolerability profile is still less than optimal and patient persistence with therapy is low. Recent advances in basic research have not yet offered a clear discovery path for improving the therapeutic index of antimuscarinic molecules. There is still an unmet need for an antimuscarinic medicine with superior clinical effectiveness that can translate into better persistence on therapy.

Animals↗

PubMed2006

A meta-analysis comparing trials of antimuscarinic medications funded by industry or not.

OBJECTIVE: To determine if there is a significant difference in outcomes of clinical trials funded by industry or not of antimuscarinic medications used to treat overactive bladder (OAB) symptoms and detrusor overactivity (DOA). METHODS: A Medline search was conducted from January 1966 to June 2003 to identify human clinical trials of oxybutynin and tolterodine published in English. Randomized controlled trials on subjects aged > or = 16 years who were being treated with oxybutynin or tolterodine for OAB symptoms or DOA; 24 studies were identified. The endpoints assessed were OAB symptoms or changes in uninhibited detrusor contractions on cystometrography. The outcome variables were dichotomized as 'improvement' or 'no improvement'. Odds ratios and 95% confidence intervals were calculated for each study based on data derived or extracted from tables and figures. RESULTS: Meta-analysis showed no significant difference in the outcomes trails funded by industry or not. Trials were then reviewed to determine their adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines for randomized trials. CONCLUSIONS: Clinical trials are important for clinicians when selecting medical therapies. In this analysis we found no difference in outcomes when comparing studies funded by industry or not for tolterodine and oxybutynin. The quality of all trials would be improved by close adherence to the CONSORT guidelines for randomized clinical trials.

Benzhydryl Compounds↗

PubMed2003

Alpha blocker therapy for children with dysfunctional voiding and urinary retention.

PURPOSE: Alpha blocker therapy has been successfully used to decrease residual urine in children with complex neuropathic and nonneuropathic voiding dysfunction. We evaluated the safety and efficacy of using selective alpha blocker therapy for children with uncomplicated voiding dysfunction and underlying poor bladder emptying. MATERIALS AND METHODS: A total of 55 patients with a mean age of 7.9 years presented with symptoms of urinary incontinence, urgency and urinary tract infection. All patients had increased post-void residual (PVR) on bladder ultrasound, with a mean residual volume of 65 ml (22% of age expected capacity). All patients were treated with doxazosin, a selective alpha-1 adrenergic antagonist, at dosages of 0.5 mg to 2.0 mg daily. Of the patients 38 were treated at presentation with a regimen of anticholinergics, timed voiding and antibiotic prophylaxis before initiating alpha blocker therapy. Patients were reevaluated with post-void ultrasound of the bladder 6 weeks after initiating alpha blocker therapy. RESULTS: After starting doxazosin average PVR decreased to 8 ml (p <0.0001), representing an 88% reduction in residual urine (or reduction to only 2.7% of age expected bladder capacity). Medication was discontinued in 2 patients due to minor side effects. CONCLUSIONS: Selective alpha blocker therapy appears to be effective for improving bladder emptying in children with an overactive bladder, wetting, recurrent infection and increased PVR urine. This therapy may be used as either a replacement or in addition to biofeedback in patients with urinary retention. Further investigation, including a prospective randomized trial of alpha blocker therapy in children with urinary tract dysfunction, is warranted based on the findings of our study.

Adolescent↗

PubMed2004

[Urodynamic phenomena in the aging bladder].

Lower urinary tract symptoms increase with age in both sexes and are a major problem in the elderly due to the medical and bio-psycho-social consequences involved. Lower urinary tract dysfunctions in the elderly are generally multifactorial in origin and are classifiable to a large extent by age and pathology related changes. Urodynamic findings should never be interpreted without considering the medical history, bladder diary, clinical examination and other findings. Age related changes involve a decrease of voided volume and urinary flow and an increase in overactive bladder symptoms and post void residuals. Consequently, decreased maximum bladder capacity, terminal detrusor overactivity and detrusor overactivity with impaired contractile function are typically found in the elderly. Patients with terminal detrusor overactivity are well treated by bladder training and timed voiding, sometimes combined with anticholinergic drugs, whereas patients with phasic detrusor overactivity are often good candidates for non-invasive electrical neuromodulation.

Aged↗

PubMed2003

Effects of ylang-ylang essential oil on the relaxation of rat bladder muscle in vitro and white rabbit bladder in vivo.

Current and primary treatment modality in overactive bladder includes the administration of anticholinergics. The demand for new agents has been rising since anticholinergics have proven to come with many side effects. This study was designed to investigate the effects of ylang-ylang essential oil (YYEO) on the relaxation of urinary bladder muscle in vitro and in vivo. Effects of YYEO were assessed on resting tension, and electrical field stimulation- and various drug-induced contraction in vitro by checking the isometric tension changes of muscle strips and same procedures were repeated in the presence of methylene blue, Nw-Nitro-L-arginine methyl ester hydrochloride (L-NAME), or N-ethylmaleimide, and in vivo. YYEO decreased significantly the contractility of strips. There was no statistically significant difference between the treated group only with YYEO and the pretreated group with YYEO and methylene blue or L-NAME. When N-ethylmaleimide was employed, there was a statistically significant decrease in the rate of contraction. In vivo studies showed the same results compared with in vitro study. The results of this study indicate that YYEO has a relaxing effect on the bladder, and such mechanism is thought to be brought about by a pathway mediated by c-AMP.

Animals↗

PubMed2006

Local effects of antimuscarinics.

Overactive bladder (OAB) syndrome has been estimated to occur in nearly 17% of the population. The most common drug treatments for OAB are antimuscarinic agents that act to increase bladder capacity and decrease the urge to urinate during the storage phase. An increasing number of studies have focused on te role and mechanism of muscarinic acetylcholine receptors for the regulation of afferent activity during urine storage. Interactions between muscarinic receptors in the urothelium, afferent nerves, or myofibroblasts and locally released acetylcholine might be involved in the emergence of detrusor overactivity and OAB. Therefore, antimuscarinic agents may be effective in treating OAB not only by suppression of muscarinic receptor-mediated detrusor muscle contractions but also by modulation of muscarinic receptor-bladder afferent interactions.

Humans↗

PubMed2000

Urethral obstruction in patients with nighttime wetting: urodynamic evaluation and outcome of surgical incision.

The aim of this study was to investigate urodynamic findings and the outcome of surgical incision in patients with nighttime wetting due to urethral obstruction. A total of 239 patients with nighttime wetting (157 males and 82 females; mean age, 8.7; range, 4-18 years) was studied. One hundred and ten patients had monosymptomatic enuresis alone and 129 both nighttime wetting and daytime symptoms, that is, the majority was not simple bedwetters, but had signs of bladder overactivity. All patients were first treated with bladder training and fluid intake after dinner was restricted. The non-responders were then treated with tricyclic antidepressants, anticholinergics, or intra-nasal desmopressin and conditioning therapy. Ninety-seven patients who did not respond to these conventional treatments were investigated by voiding cystourethrography, bougie à boule, and urodynamic study. Urethral obstruction was noted in 34 patients (14.2%); posterior urethral valves in three males, ring stricture of the bulbar urethra in 26 males and distal urethral stenosis in five females. Detrusor instability was noted in 30 (94%) of 32 patients. Three patients had <15 mL/s of maximum flow rate and none had post-void residual urine. Pressure at maximum flow (PQ(max)) was 106.5 +/- 26.3 cm H(2)O in pressure/flow study. After surgery, nighttime wetting was cured in 25 patients (73.5%), improved in four (11.8%). Detrusor instability disappeared in six of 16 patients studied (37.5%) and improved in 8 (50%), and PQ(max) decreased significantly after operation (P = 0. 0034). In conclusion, most of the patients with urethral obstruction have detrusor instability and high pressure voiding, and these conditions improved after operation.

Adolescent↗

PubMed2006

Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management.

The advent of functional imaging methods has increased our understanding of the neural control of the bladder. This review examines current concepts of the role of brain function in urinary control with particular emphasis on the putative role of dopamine receptors. Dopaminergic mechanisms play a profound role in normal bladder control and the dysfunction of these may result in symptoms of overactive bladder in Parkinsonism. The importance of this nonmotor disorder has been overlooked. We address the problem of bladder dysfunction as it presents to patients and their neurologist. The prevalence of bladder symptoms in Parkinson's disease is high; the most common complaint is nocturia followed by frequency and urgency. In multiple-system atrophy, the combination of urge and urge incontinence and poor emptying may result in a complex combination of complaints. The management of bladder dysfunction in Parkinsonism addresses treatment of overactive detrusor as well as incontinence.

Brain↗

PubMed2006

Relaxation of phasic contractile activity of human detrusor strips by cyclic nucleotide phosphodiesterase type 4 inhibition.

OBJECTIVES: Detrusor smooth muscle relaxation is mainly mediated by the cyclic adenosine monophosphate (cAMP) pathway. Elevation of cAMP levels by phosphodiesterase type 4 (PDE4) inhibition relaxes smooth muscles of various origins. We aimed to determine the effect of a PDE4 inhibitor, rolipram, on human detrusor contractions. METHODS: Human bladder strips (from 20 different donors) with no known overactive bladder (OAB) were studied in organ baths. Detrusor samples with or without urothelium were incubated with carbachol 10(-6)mol/l (in presence or absence of forskolin, 3.10(-7)mol/l) or with KCl 10mmol/l to enhance phasic contractile activity. Concentration response curves for rolipram or vehicle were then performed. RESULTS: Rolipram (10(-9) to 3.10(-5)mol/l) induced a moderate relaxing effect on carbachol-induced contractions. This effect was enhanced when cAMP levels were increased by forskolin (the maximal effect was 53.0+/-5.1 vs. 83.1+/-5.7%, p<0.01) or in strips with urothelium. In contrast, rolipram (10(-9) to 10(-4)mol/l) drastically inhibited phasic contractile activity: The developed tension, the area under the curve, and the amplitude of phasic activity were reduced to 64.8+/-3.6, 91.2+/-5.3, and 82.3+/-7.3%, respectively, versus 23.6+/-9.5, 34.7+/-18.8, and 18.0+/-16.2% for vehicle, respectively (p<0.05). Frequency of phasic activity was 0.96+/-0.45 contractions per minute versus 2.6+/-0.18 for vehicle (p<0.001). In strips with urothelium, the inhibitory effect of rolipram on phasic contractile activity was similar. CONCLUSIONS: PDE4 isoenzymes are strongly involved in the regulation of phasic myogenic activity of human bladder strips. Because an increase of this phasic activity may play a role in the pathophysiology of detrusor overactivity, PDE4 inhibitors might represent an attractive strategy for the treatment of OAB.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2001

Detection and inhibition of hyperreflexia-like bladder contractions in the cat by sacral nerve root recording and electrical stimulation.

Detection of bladder volume and hyperreflexive bladder contractions would be useful in individuals with overactive bladders. We sought to determine whether bladder filling and/or reflex bladder contractions could be detected by electrical recording from the sacral nerve roots, and whether bladder contractions could be inhibited by stimulation of sacral afferents. Six male cats were anesthetized with alpha-chloralose and bipolar cuff electrodes were used to measure sacral nerve root electroneurograms (ENG) during slow bladder filling, during rapid injections of fluid into the bladder, and during hyperreflexia-like bladder contractions. The rectified and time-averaged activity of the S1 extradural root increased by 0-5 % above the baseline during bladder filling. Rapid injections caused a sudden increase in bladder pressure, and a 3-36 % increase over baseline in the S1 nerve activity. Withdrawal of the same volume caused a reduction in pressure and a decrease in recorded activity (4-14 %). At the onset of a bladder contraction, there was a 7-38 % increase over baseline in the S1 nerve activity. This activity increase was sustained for the duration of the contraction and decreased during bladder relaxation. The onset and duration of bladder contractions could be detected consistently from these nerve activity changes. Recording only afferent activity showed that the increased nerve activity was due to S1 sensory rather than motor fibers. In two cats, it was demonstrated that an ongoing bladder contraction could be inhibited by rectal distension. In one cat, the contractions could be terminated by electrical stimulation of the S1 dorsal root. The results demonstrate that afferent sacral root nerve activity can be used to detect hyperreflexive bladder contractions at low bladder pressures. Such a signal might be used to trigger bladder inhibition via electrical stimulation of specific sacral afferents.

Animals↗

PubMed2007

BXL-628, a vitamin D receptor agonist effective in benign prostatic hyperplasia treatment, prevents RhoA activation and inhibits RhoA/Rho kinase signaling in rat and human bladder.

BACKGROUND: BXL-628 is a calcitriol analog shown to decrease prostate growth in preclinical and clinical studies. BPH symptoms are generated not only by prostate overgrowth but also by bladder overactivity, resulting from an increased RhoA/Rho-kinase signaling. Because bladder smooth muscle cells express VDR, we studied effects of BXL-628 on this pathway. METHODS: RhoA and Rho-kinase gene expression and functional activity were studied in rat and human bladder smooth muscle by real-time RT-PCR, immuno-kinase assays, western blot analysis, confocal microscopy, in vitro contractility, and cell migration. RESULTS: In bladder smooth muscle, carbachol responsiveness was delayed and Rho-kinase activity reduced by BXL-628 treatment because of impaired RhoA membrane translocation and activation. Accordingly, RhoA-mediated biological functions, such as cell migration and cytoskeleton remodeling were also inhibited by BXL-628. CONCLUSIONS: BXL-628 inhibits RhoA/Rho-kinase signaling, a calcium sensitizing pathway, suggesting its possible clinical use in the treatment of altered bladder contractility often associated with BPH-induced lower urinary tract symptoms.

Animals↗

PubMed2004

Childhood nocturnal enuresis: developing a conceptual framework.

Nocturnal enuresis has been described as the most prevalent and chronic of all childhood problems. The experience, particularly for the older child, can be extremely distressing and limiting. It is now thought that psychological distress (emotional, behavioural, and self-esteem) arises as a consequence of bedwetting, and reaches clinical importance in only a minority who are vulnerable. Many aetiological theories have been proposed with the cause of nocturnal enuresis now regarded as heterogeneous. Based on empirical findings, a new model, termed 'the three systems,' has facilitated a greater clinical understanding of the problem and identification of the appropriate intervention. The model proposes bedwetting results from excessive nocturnal urine production and/or nocturnal bladder overactivity coupled with an inability to arouse to bladder sensations. Effective treatment arises from identification of the child's particular need and application of the appropriate psychological and pharmacological approach. Treatment methods are reviewed in terms of the new model, the mode of action, effectiveness, and application in combination.

Child↗

PubMed2001

The efficacy of bladder distention therapy in the treatment of frequency and urgency.

BACKGROUND: The aim of this retrospective study was to evaluate whether bladder distention therapy is effective in relieving the symptoms of patients experiencing urinary frequency and urgency. MATERIALS AND METHODS: Twenty-six female patients with a history of frequency and urgency who underwent multi-channel urodynamic assessment, were treated with bladder distention therapy for symptomatic relief of their symptoms. Their mean age was 51 years of age (range from 28 to 75 years old). No patient had detrusor-urethral sphincter dyssynergia. Bladder distention therapy was performed in the operating theatre under epidural anesthesia. Statistical analysis was performed with the Student's t-test. RESULTS: The treatment was successful in 9 out of 26 patients after the first attempt (34.6%) and in 10 out of 26 patients after the second attempt (38%) at 1 month follow-up (FLU) and in 4 out of 28 patients at 9 months FLU (15%). Only one out of four patients who had this treatment twice showed improvement of her symptoms. CONCLUSION: Bladder distention therapy in patients with symptoms of overactive bladder dysfunction has a very small success rate (15%) and therefore, has no place in the modern treatment of bladder dysfunction.

Adult↗

PubMed2004

Functional constipation in children.

PURPOSE: Constipation in children increases the likelihood of urinary incontinence, bladder overactivity, dyscoordinated voiding, a large capacity, poorly emptying bladder, recurrent urinary tract infection and deterioration of vesicoureteral reflux. We present a consensus related to the assessment, diagnosis and treatment of children with bowel dysfunction coexisting with a known disorder of urinary continence or voiding coordination. MATERIALS AND METHODS: A panel of international multidisciplinary clinicians working on pediatric continence care was invited to participate in the First International Children's Continence Society Bowel Dysfunction Workshop. The seminar sought to address the interrelationship of bowel dysfunction with disorders of urinary continence or voiding mechanics. RESULTS: Constipation is an end point defined by a constellation of symptoms, including infrequent passage of stool, difficulty passing stool, feces that are either large and hard or in small pieces, abdominal pain, palpable stool in the abdomen, stool in the rectal vault, loading on x-ray or fecal soiling. Assessment was done to identify potential organic causes of constipation, clarify symptoms, and identify altered motor behavior and abdomino/pelvic floor muscle incoordination. Whether the underlying problem was one of stool consistency, poor cognition, motivation or fear on the part of the child, or whether it related to gut motility, rectal sensation, stool retention or disordered emptying mechanics, the definitive therapy begins with rectal emptying of impacted stool followed by maintenance of regular soft stools to eliminate fear of pain with defecation. CONCLUSIONS: Constipation is a challenge to the clinician but with comprehensive assessment and systematic intervention children can achieve independent bowel emptying, which positively impacts bladder function.

Child↗

PubMed2004

Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging.

Numerous studies have detailed age-related changes in the structure and function of the bladder that may contribute to the high prevalence of overactive bladder (OAB) in the elderly population, but the relation of these changes to OAB symptoms remains unclear. Physiologic and neurochemical studies have been conducted in human detrusor strips obtained from people of different ages, focusing on potential changes in cholinergic and purinergic neurotransmission, as well as the release and actions of acetylcholine (ACh) from nonneuronal bladder cells. Results from physiologic and microdialysis experiments indicate that purinergic transmission increases with age, whereas cholinergic transmission decreases. These effects are most likely because of decreased release of ACh and increased release of adenosine triphosphate (ATP) from postganglionic parasympathetic axons innervating the bladder. Immunohistochemical experiments showed that choline acetyltransferase in the human detrusor is contained not only in parasympathetic axons, but also in cells of the urothelium. The release of nonneuronal ACh increases with age and detrusor stretch. The age-related increase in purinergic transmission in the detrusor and other data indicating that responses to ATP are increased in detrusor overactivity suggest that purinergic receptor antagonists may provide a useful complement to muscarinic receptor antagonists in the treatment of older patients with OAB. Nonneuronal ACh release may play a key role in the storage phase of the micturition reflex, and this may explain, at least in part, the effectiveness of antimuscarinic agents for the treatment of OAB.

Acetylcholine↗