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PubMed2002

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

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

Journal Article↗
PubMed1998

Common urological problems in women.

BACKGROUND: Significant advances in the management of some common urinary problems have occurred in recent years. Problems that are likely to present to the general practitioner include urinary incontinence, voiding dysfunction, recurrent bacterial cystitis and interstitial cystitis. OBJECTIVE: The aim of this article is to highlight the advances that have occurred in the management of these common problems and their management strategy in the primary care setting. DISCUSSION: The management of incontinence, particularly stress urinary incontinence includes an accurate diagnosis and treatment tailored to the condition identified. Urinary incontinence due to the overactive and/or underactive bladder is more difficult to cure but significant improvement can be achieved in the majority of people. While severe incontinence requires an accurate diagnosis, non-operative strategies without a urodynamic diagnosis can be used in the treatment of milder forms. It is important to obtain an accurate diagnosis when the patient is not improving with conservative strategies. The problem of recurrent bacterial infections is common in women of all ages but cure should be possible in the majority of affected women. While the enigmatic entity of interstitial cystitis is increasingly recognised in out patients the exact basis for this condition remains obscure. Symptomatic improvement is achievable to a variable degree in most patients.

Adult↗
PubMed2001

Posterior tibial nerve stimulation as neuromodulative treatment of lower urinary tract dysfunction.

PURPOSE: Recently, intermittent percutaneous posterior tibial nerve stimulation was introduced as a treatment modality filling the gap between conservative and surgical therapies in patients with certain types of lower urinary tract dysfunction. MATERIALS AND METHODS: In a prospective multicenter trial posterior tibial nerve stimulation was evaluated in 37 patients who presented with symptoms of bladder overactivity, that is the urgency and frequency syndrome and/or urge incontinence, and 12 with nonobstructive urinary retention. Results were recorded in voiding diaries and on quality of life questionnaires before and after treatment. Patients were classified as responders, including those in whom therapy was successful and chose to continue treatment after the initial 12 weeks, and nonresponders, those who chose to stop treatment. RESULTS: Overall, a positive response was seen in 60% of all patients. In patients with bladder overactivity a statistically significant decrease was observed in leakage episodes, number of pads used, voiding frequency and nocturia, and an equal increase in mean and smallest volume voided. Improvements were also seen in nonobstructive urinary retention, including number of catheterizations, total and mean volume catheterized, and total and mean volume voided. Disease specific quality of life and some domains of general quality of life improved, especially of bladder overactivity. Only mild side effects were observed. CONCLUSIONS: Posterior tibial nerve stimulation is a minimally invasive and successful treatment option for patients with certain types of lower urinary tract dysfunction.

Adult↗
PubMed1998

Dose-ranging study of tolterodine in patients with detrusor hyperreflexia.

Tolterodine is a potent antimuscarinic agent specifically developed for the treatment of urinary urge incontinence and other symptoms related to the overactive bladder. In order to assess the optimum dosage for use in future clinical studies, a double-blind, randomized, placebo-controlled, parallel-group, multicenter study was performed in 90 patients with detrusor hyperreflexia and symptoms of urinary urgency, frequency, and/or urge incontinence. Urodynamic variables, micturition diary variables, and subjective urinary symptoms were measured before and after 2 weeks' treatment with either placebo or tolterodine 0.5, 1, 2, or 4 mg twice daily (bd). Serum drug concentrations, electrocardiogram recordings, blood pressure, and incidence of adverse events were also assessed. Linear regression analysis showed a significant dose-response relationship for several clinically relevant urodynamic variables, while there was a trend towards an improvement in micturition diary variables and subjective assessment of symptoms with increasing dosages of tolterodine. There were no safety or tolerability concerns regarding any of the dosages of tolterodine investigated, although 2 patients treated with a dosage of 4 mg bd experienced urinary retention that necessitated dosage reduction. The results of this study suggest that tolterodine is well-tolerated and exerts a dose-dependent effect on bladder function in patients with detrusor hyperreflexia. The optimum dosage of tolterodine for use in future studies is 1-2 mg bd.

Adolescent↗
PubMed2003

Pharmacological effects of darifenacin on human isolated urinary bladder.

Darifenacin [(S)-2--2,2-diphenylacetamide] is a novel antimuscarinic drug currently undergoing phase III trials for the treatment of overactive bladder. We investigated the functional antagonist potency of darifenacin, and the antimuscarinic drugs propiverine, oxybutynin and atropine, on human detrusor smooth muscle. Urinary bladder specimens were obtained from 20 patients who underwent total cystectomy for malignant bladder tumor. Using an organ-bath technique, the effects of the compounds on carbachol-, KCl-, CaCl(2)- or electrical field stimulation (EFS)-induced contractions of the tissues were evaluated. The order of antagonist potency (pA(2 )values) at the muscarinic M(3) receptors was: darifenacin (9.34) > atropine (9.26) > oxybutynin (7.74) > propiverine (7.68). Darifenacin and atropine, at concentrations up to 10(-6) mol/l, did not inhibit the KCl- and CaCl(2)-induced contractions (concentrations 80 and 5 mmol/l, respectively), while propiverine and oxybutynin (10(-5) mol/l) significantly inhibited these contractions. Pretreatment with darifenacin (10(-9)-10(-6) mol/l), propiverine (10(-8)- 10(-5) mol/l), oxybutynin (10(-8)-10(-5) mol/l) and atropine (10(-9)-10(-6) mol/l) significantly inhibited maximum EFS-induced contractions. Darifenacin inhibited contractions of human detrusor smooth muscle only through its antimuscarinic action, while propiverine and oxybutynin had both antimuscarinic and Ca(2+) channel antagonist actions. These findings indicate that darifenacin is a potent antagonist at the M(3) receptor and support its use as a treatment for overactive bladder.

Aged↗
PubMed1998

Testosterone-induced prostatic growth in the rat causes bladder overactivity unrelated to detrusor hypertrophy.

BACKGROUND: Testosterone treatment of rats produces prostatic hypertrophy and detrusor overactivity. Whether or not the detrusor overactivity can be related to an increase in the responsiveness of lower urinary tract smooth muscles is not known. METHODS: Male Sprague-Dawley rats were given daily injections of testosterone propionate for 2 weeks. Effects on cystometric parameters and on the responsiveness of isolated detrusor, urethral, and prostate smooth muscle preparations to drugs and electrical field stimulation were investigated. RESULTS: Testosterone treatment increased prostatic weight twofold (controls, 768 mg; testosterone-treated, 1,478 mg), but not bladder weight (103 mg vs. 116 mg). Micturition pressure (77%), bladder capacity (75%), residual volume (56%), and micturition volume (83%) increased significantly in treated animals, and bladder overactivity developed. No effect of intraarterial doxazosin on these changes was observed. The differences in urodynamic parameters between control and testosterone-treated rats could not be correlated with changes in bladder, urethral, or prostate excitatory innervation, as revealed by responses to electrical field stimulation, or by smooth muscle responses to different contractant drugs. CONCLUSIONS: Some of the urodynamic effects seen after testosterone treatment seem to be caused by the mechanical obstruction of the enlarged prostate. Since there were no changes in smooth muscle responsiveness, it is suggested that the bladder overactivity observed can partly be related to testosterone-induced changes of the micturition reflex at the lower urinary tract, spinal, and/or supraspinal levels.

Animals↗
PubMed2003

Role of 5-HT receptors in treatment of overactive bladder.

Normal bladder function requires coordinated detrusor relaxation and urethral sphincter contraction during the filling phase and the reverse during micturition. This is achieved by the integration of excitatory, inhibitory, and sensory nerve activity in control centers in the spinal cord, pons, and forebrain. It is possible that much of bladder pathology is related to disturbances in the vesical ganglia, sensory reflex loops, and central control of micturition. Experimental studies in animals have revealed that spinal reflex circuits involved in voiding function exhibit a dense serotonergic innervation, multiple 5-HT receptors, and sensitivity to 5-HT receptor agonists and antagonists, and 5-HT reuptake inhibitors. Activity in the serotonergic pathway generally enhances urine storage by facilitating the vesical sympathetic reflex pathway and inhibiting the parasympathetic voiding pathway. Thus, 5-HT receptor antagonists and reuptake inhibitors represent important targets for the development of new treatments of detrusor overactivity and urinary incontinence. Among the drugs modulating the bladder function through 5HT receptor, duloxetine, a potent and selective inhibitor of 5-HT and NE reuptake, is presently undergoing clinical trials for stress urinary incontinence after being shown to be effective in animal models of this condition.

Animals↗
PubMed2005

Characterization of prejunctional serotonin receptors modulating [3H]acetylcholine release in the human detrusor.

Bladder overactivity (OAB) is a chronic and debilitating lower urinary tract (LUT) disorder that affects millions of individuals worldwide. LUT symptoms associated with OAB, such as urgency and urinary incontinence, cause a hygienic and social concern to patients, but their current pharmacological treatment is largely inadequate due to the lack of uroselectivity. Although OAB etiology remains multifactorial and poorly understood, increasing evidence indicates that serotonin [5-hydroxytryptamine (5-HT)] is an endogenous substance involved in the control of micturition at central and peripheral sites. In this study, we demonstrated the presence of three distinct 5-HT receptors localized at parasympathetic nerve terminals of the human bladder by measuring electrically evoked tritiated acetylcholine release in isolated detrusor strips. These prejunctional receptors, involved in both positive and negative feedback mechanisms regulating cholinergic transmission, have been characterized by means of three highly selective 5-HT antagonists for 5-HT(4), 5-HT(7), and 5-HT(1A) receptors, namely GR113808A ([1-[2-[(-methylsulphonyl) amino] ethyl]4-piperinidyl]methyl1-methyl-1H-indole-3-carboxylate succinate), SB269970 [(R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl)phenol hydrochloride], and WAY100635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexane-carboxamide trichloride]. Under these conditions, we confirmed the facilitatory role of 5-HT(4) heteroreceptors on acetylcholine release and revealed for the first time the occurrence of 5-HT(7) and 5-HT(1A) heteroreceptors with a facilitatory and an inhibitory action, respectively. Our findings strengthen the novel concept for the use of recently patented selective 5-HT agonists and antagonists for the control of OAB dysfunctions associated with inflammatory conditions, although their therapeutic efficacy needs to be explored in the clinical setting.

Acetylcholine↗
PubMed2006

The functional effects of a c-kit tyrosine inhibitor on guinea-pig and human detrusor.

OBJECTIVE: To describe the effect of a specific c-kit receptor inhibitor (imatinib mesylate) on human detrusor strips in vitro and guinea-pig cystometry in vivo, and to show histological data suggesting differences in the distribution of interstitial cells of Cajal (ICC)-like cells in 'normal' and overactive human detrusor, as these cells have been identified as possible mediators of spontaneous activity and excitability in bladder smooth muscle. MATERIALS AND METHODS: Specimens of human detrusor were stained immunohistochemically with a c-kit antibody. Human detrusor strips were mounted in a superfused organ-bath apparatus, and smooth muscle contraction was evoked with carbachol and electrical field stimulation in the presence and absence of imatinib mesylate. Also, guinea-pig urodynamic studies were conducted before and after i.v. administration of imatinib mesylate, and changes in bladder variables and spontaneous activity were recorded. RESULTS: Imatinib mesylate (10(-6)M) inhibited evoked smooth muscle contraction and spontaneous activity in overactive human detrusor, with less effect on normal human tissue. Imatinib mesylate (10(-5)M) improved bladder capacity, compliance, voided volumes, urinary frequency, and reduced contraction thresholds and spontaneous activity during guinea-pig cystometry. c-kit labelling showed significantly more ICC-like cells in overactive human detrusor than in normal specimens. CONCLUSION: c-kit receptor blockers have inhibitory effects on guinea-pig and overactive human detrusor, possibly via c-kit receptors on bladder ICC-like cells. This and the possibility that there are more ICC-like cells in overactive bladder suggest that the c-kit receptor may provide a novel target for treating detrusor overactivity.

Animals↗
PubMed2005

Detrusor overactivity induced by intravesical application of adenosine 5'-triphosphate under different delivery conditions in rats.

OBJECTIVES: To investigate the effects of intravesical application of adenosine 5'-triphosphate (ATP) on bladder activity to elucidate the role of urothelial barrier function and ecto-ATPase activity in the ATP-mediated mechanism inducing detrusor overactivity. METHODS: Continuous cystometry by an intravesical catheter inserted from the bladder dome was performed in conscious female rats. RESULTS: ATP solutions adjusted to pH 6.0 did not elicit significant detrusor overactivity at a concentration of 60 mM. However, in bladders pretreated with protamine sulfate (10 mg/mL) to increase urothelial permeability, ATP solution (pH 6.0) induced detrusor overactivity by decreasing the intercontraction intervals. These irritant effects of ATP after protamine treatment were antagonized by P2X receptor antagonists, such as pyridoxal-5-phosphate-6-azophenyl-2',4'-disulfonic acid (70 micromol/kg) and 2',3'-O-(2,4,6, trinitrophenyl) ATP (30 micromol/kg). These were also suppressed in rats pretreated with systemic capsaicin (125 mg/kg subcutaneously). Alpha,beta-methylene ATP (5 mM, pH 6.0) or ATP (60 mM, pH6) after intravesical infusion of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (5 mM, pH 6.0), an ecto-ATPase inhibitor, induced detrusor overactivity without protamine pretreatment, but the reduction in intercontraction intervals was smaller compared with that with ATP after protamine treatment. CONCLUSIONS: Low permeability of bladder epithelium and ecto-ATPase activity can prevent ATP activation of subepithelial P2X receptors to induce bladder overactivity. Thus, enhanced penetration of endogenous ATP owing to urothelial damage may contribute to urinary frequency and bladder pain in hypersensitive bladder disorders such as interstitial cystitis.

Adenosine Triphosphatases↗
PubMed2001

Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder.

OBJECTIVES: To determine the presence, distribution and molecular forms of the vanilloid receptor VR1, and confirm the presence and distribution of the ATP-gated ion channel P2X3 in the human urinary bladder. Materials and methods Normal urinary bladder tissues were obtained at postmortem from four subjects. Eight urinary bladder biopsies were also taken from patients with detrusor hyper-reflexia treated with intravesical resiniferatoxin. The specimens were studied using affinity-purified specific antibodies to VR1 and P2X3 by Western blotting and immunocytochemistry, and compared with immunostaining using antibodies to the pan-neuronal marker PGP 9.5 and Schwann cell marker S-100. RESULTS: VR1- and P2X3-immunoreactive fine nerve fibres were scattered throughout the suburothelium of the normal bladder and cystoscopic biopsies, and traversed the muscle layer. They had a similar distribution to PGP 9.5-immunoreactive fibres, but there were fewer, suggesting localization in subsets of axons. Western blot studies showed an expected 100-kDa VR1 protein and a P2X3-immunoreactive 66-kDa protein. Conclusion VR1 and P2X3 are present in the human urinary bladder and may contribute to distinct pathophysiological states of bladder overactivity, in accord with their differential expression in sensory neurones. Intravesical vanilloids act via VR1 and are effective in the treatment of detrusor hyper-reflexia. P2X3 may represent a selective therapeutic target for other causes of overactive bladder.

Adenosine Triphosphate↗
PubMed1992

[Clinical significance of urinary flow pattern--based on combined uroflowmetry and external sphincter electromyography].

We performed combined uroflowmetry and external sphincter electromyography in 108 patients (87 males and 21 females); 16 serving as normal controls, 49 with benign prostatic hyperplasia, 16 with overactive type of neurogenic bladder, 27 with underactive type of neurogenic bladder. Urinary flow pattern was classified into 5 categories. All of urinary flow patterns of normal controls showed pattern A which had the form of a bell. EMG showed complete suppression during micturition followed by a few intermittent increases in amplitude. Urinary flow patterns of BPH patients were distributed widely from pattern A to E. Intermittent increases in EMG amplitude during a late phase of micturition were characteristic in patients with BPH. We must pay attention to sex differences to evaluate urinary flow pattern because it could be influenced by abdominal pressure such as stressing or Créde maneuver in female patients with an underactive type of neurogenic bladder.

Adult↗