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PubMed2006

Selective beta-adrenoceptor agonists, calcium antagonists and potassium channel openers as a possible medical treatment of the overactive bladder and urge incontinence.

Urinary incontinence affects millions of people worldwide and also represents a social problem. People of all ages suffer from urinary incontinence. The disease is found in about 30% of women aged 30 to 60 years. There are different types of incontinence. Urge incontinence is the most often pharmacologically treated type. The mainly used substances belong to the class of antimuscarinic drugs. Their use is limited by several side effects. Furthermore, in some patients anticholinergic medication is ineffective and antimuscarinics used as single medication do not lead to a sufficient therapeutic effect. Other possible pharmacological substances for treatment of overactive bladder (detrusor instability) associated with urge and urge incontinence are the selective beta-adrenoceptor-agonists which are mainly responsible for the adrenergic mediated relaxation. It depends on the species, which beta-adrenoceptor-subtype (the beta2- and/or beta3-adrenoceptor) mainly mediates the relaxation. Non selective beta-adrenoceptor-agonists exhibit serious cardiovascular side effects like tachycardia or decrease of blood pressure by stimulating beta1- and beta2-adrenoceptors. These side effects should be decreased when using selective agonists. Additionally, substances whose targets are membrane channels of muscle cells could be interesting for treatment of overactive bladder. This group includes L-type calcium antagonists and potassium channel openers of ATP-sensitive potassium channels or BK channels. Especially the local use of the pharmacologically very potent calcium antagonists could be an interesting therapeutic approach, since systemic cardiovascular side effects were avoided. After chronic oral treatment with different calcium antagonists effects on the detrusor muscle were reduced or could not be detected, possibly due to an upregulation of 1,4-dihydropyridine-sensitive potassium channels. A very interesting approach is the use of potassium channel openers said to be selective for the urinary bladder. If there is a selectivity for the detrusor muscle, cardiovascular side effects were reduced. Possibly, the local use is a useful application form. Selective beta-adrenoceptor agonists, calcium antagonists and potassium channel openers are pharmacological approaches, which are not yet available for clinical use.

Adrenergic beta-Agonists↗
PubMed1993

Subtypes of overactive bladder in old age.

The prevalence of urinary incontinence increases dramatically with age and is mainly related to urge incontinence and bladder overactivity. It is a reasonable hypothesis that bladder overactivity primarily results from a disturbed central neuronal control of the lower urinary tract. Different sites and extents of neurogenic lesions or dysfunctions should result in different functional and urodynamic characteristics. We have recently identified three distinct urodynamic subtypes of bladder overactivity, and we report a retrospective study of the distribution of these subtypes in elderly patients. Eight hundred and fourteen patients aged 65 years or older with symptoms of urgency and/or urge incontinence underwent cystometry and the ice-water test. Two hundred and sixty-seven of them (33%) presented an overactive bladder. The prevalence of overactive bladder was constant up to the age of 65. A marked increase above this age was almost entirely ascribed to an increase of the so-called uninhibited overactive bladder subtype. This dysfunction occurred in 70% of the older patients. Patients with this condition have a coordinated reflex micturition at normal bladder volumes, but an abnormal perception of bladder fullness and lack of voluntary inhibitory control. This constellation of symptoms and signs indicates a suprapontine dysfunction.

Aged↗
PubMed2007

The urgency perception score: validation and test-retest.

PURPOSE: We validate a grading system for urinary urgency. MATERIALS AND METHODS: A total of 225 subjects participated in a validation study of a fixed format question that examined the reasons why an individual usually voids. The response comprised 5 graded categories. The written questionnaire was completed by the subject twice in 3 to 14 days, during which there was no change in symptoms. Subjects included asymptomatic normal volunteers and consecutive patients with lower urinary tract symptoms without urinary urgency and those with overactive bladder with or without other lower urinary tract symptoms. Content validity was established by an expert panel. Discriminant validity was assessed by examining the frequency of responses in the various categories across the 3 groups (chi-square test) and by comparing average scores in each of the 3 groups using 1-way ANOVA, followed by LSD post hoc tests. Test-retest reliability was assessed using the intraclass correlation coefficient and kappa coefficient. RESULTS: A total of 83 normal subjects, 62 patients with lower urinary tract symptoms and 80 patients with overactive bladder were included in the study. Median age was 71 years (range 21 to 97). For test-retest reliability the intraclass correlation coefficient (0.86) and kappa coefficient (0.68) indicated a good level of agreement (p <0.001). The overactive bladder group achieved a significantly higher score than the normal and lower urinary tract symptoms groups (mean +/- SD 2.5 +/- 0.99 vs 1.6 +/- 0.93 and 1.8 +/- 0.93, respectively, each p <0.001). CONCLUSIONS: The urgency perception score appears to be a valid and reliable means of grading urinary urgency. We believe that this method of grading urgency will prove to be more clinically useful than the simple yes/no characterization of urgency as a sudden compelling desire to void and it will be a useful item for questionnaires and diary keeping.

Adult↗
PubMed2005

Is it possible to make cross-study comparisons of urinary continence rates in patients with overactive bladder?

Several antimuscarinic agents are available for the treatment of overactive bladder but there are few head-to-head studies to guide physicians in choosing one over another. Here we propose ways in which logical adjustments can be made to account for differences in disease severity and placebo effects when considering continence data to allow estimation of relative effectiveness across studies.

Cholinergic Agents↗
PubMed1997

A neurologic basis for the overactive bladder.

OBJECTIVES: The functions of the lower urinary tract (LUT) to store and periodically release urine are dependent on neural circuits in the brain and spinal cord. This paper reviews the central neural control of micturition and how disruption of this control can lead to bladder overactivity and incontinence. METHODS: Neuroanatomic, electrophysiologic, and pharmacologic techniques have provided information about the neural circuitry and the neurotransmitters involved in the central nervous control of voiding. Experimental models of neural injury, including spinal cord transection, cerebral infarction, and localized brain lesions, have been studied to identify the mechanisms contributing to the neurogenic overactive bladder. RESULTS: Normal storage of urine is dependent on 1) spinal reflex mechanisms that activate sympathetic and somatic pathways to the urethral outlet and 2) tonic inhibitory systems in the brain that suppress the parasympathetic excitatory outflow to the urinary bladder. Voiding is mediated by inhibition of sympathetic-somatic pathways and activation of a spinobulbospinal parasympathetic reflex pathway passing through a micturition center in the rostral pons. Damage to the brain can induce bladder overactivity by reducing suprapontine inhibition. Damage to axonal pathways in the spinal cord leads to the emergence of primitive spinal bladder reflexes triggered by C-fiber bladder afferent neurons. The C-fiber afferent neurotoxin capsaicin, administered intravesically, has been useful in treating certain types of neurogenic bladder overactivity. CONCLUSIONS: The central nervous mechanisms controlling the LUT are organized in the brain and spinal cord as simple on-off switching circuits that are under voluntary control. Damage to central inhibitory pathways or sensitization of peripheral afferent terminals in the bladder can unmask primitive voiding reflexes that trigger bladder overactivity.

Animals↗
PubMed2005

["Pathophysiology and treatment of the overactive bladder"].

The International Continence Society (ICS) recently derived a consensus symptomatic definition of overactive bladder (OAB) as urinary urgency, with or without urge incontinence, usually with frequency and nocturia. These symptom combinations are suggestive of urodynamically demonstrable detrusor overactivity. The etiology of OAB falls into two broad categories: neurogenic and nonneurogenic. It is not easy to confirm the etiology of OAB in patients with bladder outlet obstruction and neurological disease. This debate has attempted to examine the pathophysiology of OAB and to determine the optimal treatment strategy in a patient with two diseases possibly causing OAB. A 75-year-old man visited our hospital due to symptoms of OAB (urgency, nocturia, and urge incontinence) occurring after cerebrovascular accidents. Urge incontinence worsened concomitantly with the appearance of turbid urine. Urinary tract infection was accompanied by 84 ml of post-void residual. The prostate volume and PSA value were 28 ml and 1.2 ng/ml, respectively. The total International Prostate Symptom Score (IPSS) and Quality of Life (QOL) Index were 23 and 5, respectively. IPSS for storage symptoms was higher than that for obstructive symptoms. The maximum flow rate, measured after treatment for UTI, was 9.4 ml/s. Two debaters discuss the treament modality, TURP, or pharmacotherapy.

Aged↗
PubMed2003

A review of the overactive bladder in women and men.

Urinary incontinence is a major medical problem that affects people worldwide. More than 17 million people in the United States are affected by the disorder, with billions of dollars in annual costs. The overactive bladder is a major cause of incontinence. The symptoms of frequent urination, pain, and leakage of urine range in severity and debilitation. Overactive bladder produces significant social and physical ramifications that if left untreated result in a dismal quality of life. Newer medications that have been developed allow simple oral treatment. Most patients can now be treated successfully and compassionately.

Activities of Daily Living↗
PubMed2006

[Female sexual function before and after treatment of urinary incontinence].

The prevalence of urinary incontinence is around 20% of healthy middle-aged women. Incontinence causes a negative impact on the quality of life and sexuality. From August 2002 to January 2004, 30 patients (mean age 43 years) with stress urinary incontinence (59%), overactive bladder (15%) and mixed incontinence (26%) answered the ICIQ-SF(International Consultation on Incontinence Questionnarie-Short Form) and FSFI (Female Sexual Function Index) questionnaires before and after treatment for urinary incontinence. The follow-up ranged from 12 to 53 months. Mean ICIQ score was 17 and 7 before and after treatment respectivelly (p<0,001). Overactive bladder showed the worst scores in all domains. The patients who underwent surgery increased their scores of desire (p=0,02), satisfaction (p=0,05) and total score (p=0,02). Thirteen patients which ICIQ was zero increased: desire (p<0,01), satisfaction (p=0,05) and total score (p=0,01). Urinary incontinence significantly affects the quality of life. Therefore sexual evaluation in incontinence patients is recommended.

Adult↗
PubMed2006

Late-stage clinical development in lower urogenital targets: sexual dysfunction.

In recent years, late-stage clinical drug development that primarily focuses on urogenital targets has centered around four areas of medical need (both unmet need and aiming to improve on existing therapies). These include male sexual dysfunction (MSD), female sexual dysfunction (FSD), prostatic pathology (neoplastic, pre-neoplastic, and non-neoplastic), and improvement in lower urinary tract symptoms. Despite the regulatory approval of compounds to treat erectile dysfunction (ED), benign prostatic hyperplasia, a number of treatments for overactive bladder, and stress urinary incontinence, there remains a deficiency in addressing a number of conditions that arise out of pathophysiological dysfunction resulting in lower urogenital tract sexual conditions. In terms of late-stage clinical development, significant progress has most recently been made in MSD development, especially in understanding further a common and complex sexual dysfunction--that of premature ejaculation. The search also continues for compounds that improve ED in terms of better efficacy and superior safety profile compared to the currently marketed phosphodiesterase-5-inhibitors. Whilst there are no approved medications to treat the subtypes of FSD, there has been significant progress in attempting to better understand how to appropriately assess treatment benefit in clinical trial settings for this difficult to diagnose and treat condition. This review will focus on late-stage human clinical development pertaining to MSD and FSD.

Alprostadil↗
PubMed1999

Control of the unstable urinary bladder by graded thermoelectric cooling of the spinal cord.

OBJECTIVE: To evaluate local lumbosacral spinal-cord cooling (a novel technique for neuromodulating urinary bladder reflexes) for its feasibility in possible clinical use, by determining the efficacy and the optimum temperature for suppressing reflex urinary incontinence in two rat models of neurogenic urinary bladder instability. MATERIALS AND METHODS: Overactivity of the detrusor muscle was induced by inflammation of the urinary bladder in a group of rats. A second group of rats was examined 6 weeks after complete midthoracic spinal cord transection, when all animals had developed neurogenic bladder hyper-reflexia. The intravesical pressure, urethral pressure and electromyographic (EMG) activity of the external urethral sphincter (EUS) were recorded simultaneously during repetitive local cooling and re-warming of the dorsal L6/S1 spinal cord segments, using a thermoelectric cooling device. RESULTS: Spinal cord cooling at L6/S1 had no influence on the recorded values at >26 degrees C, but markedly suppressed detrusor contraction frequency at 21- 25 degrees C. Cooling to <20 degrees C completely and reversibly eliminated inflammation-induced bladder contractions in rats with an intact neural axis and significantly reduced the contraction amplitudes (mean reduction 61%) and duration of contractions in spinally transected rats. Cooling simultaneously increased tonic EUS EMG activity and urethral perfusion pressure in both experimental groups, indicating closure of the urethral outlet. Cooling of adjacent spinal cord segments had no influence on bladder and urethral functions. CONCLUSION: Cooling the dorsal spinal cord at the origin of the parasympathetic innervation of the bladder can be used to reversibly suppress bladder instability with simultaneous closure of the urethral outlet. Therefore, local spinal cord cooling, e.g. as an implantable thermoelectric device, may offer a suitable method to treat detrusor overactivity and restore continence.

Animals↗
PubMed2006

Detrusor underactivity: Clinical features and pathogenesis of an underdiagnosed geriatric condition.

Urinary incontinence and other lower urinary tract symptoms exert a major influence on the health and independence of frail older people. Detrusor underactivity (DU) is defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span. DU may influence the clinical presentation and impede the therapy of disorders as common and as disparate as detrusor overactivity, urinary retention, and benign prostatic hyperplasia. Urodynamically, nearly two-thirds of incontinent nursing home residents exhibit DU. The clinical diagnosis of DU when present alone or in association with other bladder conditions such as detrusor overactivity (detrusor hyperactivity with impaired contractility (DHIC)) is challenging, because symptoms lack adequate precision. A catheterized and increasingly noninvasive ultrasound-based postvoid residual assessment allows a bedside diagnosis of retention and may suggest the presence of DU in individuals (mostly women) with a low likelihood of bladder outlet obstruction (BOO). Nevertheless, it cannot differentiate primary DU from retention secondary to BOO. The management of individuals with DHIC remains unsatisfactory, because antispasmodic anticholinergic medications may worsen retention, whereas bethanechol does not improve bladder emptying. Human detrusor biopsies reveal axonal degeneration, muscle loss, and fibrosis in DU. Animal studies suggest that multiple risk factors, including retention itself, lack of estrogen, infection, inflammation, and aging, may contribute to DU. Priority areas for future research include efforts to facilitate clinical nonurodynamic diagnosis of probable DU plus translational research designed to address the pathogenesis of this complex multifactorial geriatric syndrome.

Aged↗
PubMed1999

Advances in the pharmacological control of the bladder.

To effectively control bladder activity, and to treat urinary incontinence caused by bladder overactivity, identification of suitable targets for pharmacological intervention is necessary. Such targets may be found in the central nervous system (CNS) or peripherally. The causes of bladder overactivity are not known, but theoretically increased afferent activity, decreased inhibitory control in the CNS and/or peripheral ganglia, and increased sensitivity of the detrusor to efferent stimulation may be involved. Several CNS transmitters may modulate voiding, but few drugs with a defined CNS site of action have been developed for treatment of voiding disorders. Potentially, drugs affecting GABA, opioid, 5-HT, noradrenaline, dopamine, or glutamatergic receptors and mechanisms can be developed, but a selective action on the lower urinary tract may be difficult to obtain. Traditionally, drugs used for treatment of bladder overactivity have had a peripheral site of action, mainly the efferent neurotransmission or the detrusor muscle itself. Antimuscarinic drugs, beta-adrenoceptor agonists, alpha-adrenoceptor antagonists, drugs affecting membrane channels, prostaglandin synthetase inhibitors and several other agents have been used. However, none of them has been developed specifically for treatment of bladder disorders, and their efficacy, as judged from controlled clinical trials (where performed), is often limited. Recent information on the alpha-adrenoceptor, beta-adrenoceptor (beta 3), and muscarinic receptor subtypes of the human detrusor and outflow region can be the basis for the development of compounds with effect on bladder overactivity and with improved tolerance. New ways of decreasing acetylcholine release may represent a promising way of controlling bladder contraction. Potassium channel (KATP) openers are theoretically attractive, but the drugs available so far have targeted vascular rather than bladder smooth muscle, which has limited their clinical use. However, new drugs belonging to these groups with an interesting profile of action have been developed. Drugs decreasing afferent activity represent an attractive therapeutic approach and transmitters of afferent nerves and their receptors are possible targets for pharmacological interventions. Tachykinins, such as substance P, neurokinins A and B, and other neuropeptides have been demonstrated in nerves of the lower urinary tract and have been shown to influence bladder function. Agents affecting these nerves by causing release of tachykinins, such as capsaicin and resiniferatoxin, given intravesically can be effective in some cases of bladder overactivity, and agents antagonizing tachykinin receptors may also be of therapeutic interest. New drugs specifically directed for control of bladder activity are under development and will hopefully lead to improved treatment of urinary incontinence.

Animals↗
PubMed1990

Effect of intravesical instillation of varying doses of verapamil (20 mg, 40 mg, 80 mg) upon urinary bladder function in chronic traumatic paraplegics with overactive detrusor function.

The effect of intravesical instillation of verapamil was studied in eight chronic, traumatic paraplegics. Cystometry was performed before and 2 h after intravesical instillation of 20 mg of verapamil. After a gap of 10 days, the study was performed with 40 mg of verapamil and after an interval of another 10 days, the effect of intravesical instillation of 80 mg of verapamil was studied. No side-effects were observed after the intravesical administration of 20 mg, 40 mg or 80 mg of verapamil. The intravesical volume at detrusor reflex activity or at first uninhibited detrusor contraction (IV-DR) showed no significant change after intravesical instillation of 20 mg; but IV-DR increased from 90 +/- 22 ml to 131 +/- 21 ml (p less than 0.001) after intravesical instillation of 40 mg of verapamil. There was a significant increase in IV-DR from 96 +/- 23 ml to 242 +/- 35 ml after intravesical instillation of 80 mg of verapamil (p less than 0.001). There was no significant change in detrusor pressure at detrusor reflex activity or at first uninhibited detrusor contraction after intravesical instillation of 20 mg, 40 mg or 80 mg of verapamil. The frequency of voiding recorded before and one day after intravesical instillation of either 20 mg or 40 mg of verapamil showed no significant change. But the frequency of voiding recorded before and one day after intravesical instillation of 80 mg of verapamil showed a significant decrease from 19 +/- 2 to 8 +/- 1 (p less than 0.001).

Administration, Intravesical↗
PubMedDate not supplied

Urinary incontinence in women.

NICE guidance has been issued to help health professionals diagnose and manage urinary incontinence in women. The problem is common but under-reported as women are often too embarrassed to seek help. This report outlines assessment, diagnosis and treatment options for women with stress, urge or mixed urinary incontinence and overactive bladder syndrome.

Exercise Therapy↗
PubMed2004

Cost-effectiveness analysis of extended-release formulations of oxybutynin and tolterodine for the management of urge incontinence.

INTRODUCTION: Oxybutynin and tolterodine are two drugs widely used for the management of overactive bladder and urge urinary incontinence. The once-daily, extended-release formulations benefit from being well tolerated and efficacious. However, their costs, compared with generic immediate-release (IR) oxybutynin, are significantly greater. This study compared the cost effectiveness of oxybutynin extended-release (Oxy-XL), tolterodine extended-release (Tol-ER), tolterodine immediate-release (Tol-IR) and oxybutynin immediate-release (Oxy-IR). STUDY DESIGN: A cost-effectiveness model. METHODS: A systematic review that identified appropriate randomised clinical trials provided evidence on efficacy. Empirical models of drug effects (number of incontinent-free weeks) and persistence (proportion of patients still on therapy) were constructed in order to determine clinical effectiveness which was combined with cost data (direct medical costs to the UK NHS, year 2001 values) to calculate the drugs' cost-effectiveness from the perspective of the NHS. Univariate sensitivity analyses were conducted to test the robustness of the results. PATIENTS: Hypothetical cohort of patients with urge incontinence associated with overactive bladder. MAIN OUTCOME MEASURES AND RESULTS: The incremental cost per incontinent-free week for Oxy-IR (versus no treatment) ranged from pound sterling 2.58 to pound sterling 16.59. Oxy-XL and Tol-ER were more effective than Oxy-IR but at additional costs per incontinent-free week. Tol-IR did not appear to be a cost-effective option as it was less effective and more costly than the extended-release formulations. Uncertainty surrounding the health and cost consequences of early discontinuation affected these results, although the model results were robust to parameter uncertainty. CONCLUSION: Oxy-IR, Oxy-XL and Tol-ER appear to be cost-effective options for the management of urge incontinence from the NHS perspective. A decision among the treatments depends on the acceptable cost per additional incontinent-free week.

Adult↗
PubMed2006

Management of incontinence for family practice physicians.

Family practice physicians are likely to encounter urinary incontinence and overactive bladder (OAB) in their patients. An informed family practice physician can generally accurately diagnose the cause and type of incontinence in patients with a properly focused physical examination and, if necessary, auxiliary testing. Accurate diagnosis can lead to effective treatment when physicians are familiar with available treatment options, including pharmacologic, surgical, behavioral therapies, and catheterization.

Family Practice↗