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PubMed2006

Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder.

PURPOSE: We characterized the binding affinities of several antimuscarinic agents in human muscarinic receptors. MATERIALS AND METHODS: Competitive inhibitory effects of antimuscarinic agents on specific NMS [H] (PerkinElmer Life Sciences, Boston, Massachusetts) binding were examined in human tissue homogenates and in CHO-K1 cell membranes expressing human muscarinic receptor subtypes. RESULTS: Oxybutynin, propiverine, tolterodine, the respective metabolites DEOB, DPr-P-4(N-->O) and 5-HM, and darifenacin inhibited in concentration dependent fashion specific [(3)H]NMS binding in homogenates of the human bladder and parotid gland as well as in membranes of CHO-K1 cell lines expressing human muscarinic M(1) to M(5) receptor subtypes. Based on inhibition constant values the inhibitory effects of tolterodine, 5-HM and DPr-P-4(N-->O) were 1.4 to 1.7 times greater in the bladder than in the parotid gland, whereas the inhibitory effects of oxybutynin, DEOB, propiverine and darifenacin were 2 to 10 times greater in the parotid gland. Consequently tolterodine, 5-HM and DPr-P-4(N-->O) compared with oxybutynin, DEOB, propiverine and darifenacin were found to show 3 to 4 times greater affinity to muscarinic receptors in the human bladder than in the parotid gland. Tolterodine and 5-HM were 2-fold more potent for inhibiting specific [(3)H]NMS binding at cell membranes expressing the M(2) vs the M(3) subtype. Conversely oxybutynin, DEOB, propiverine, DPr-P-4(N-->O) and darifenacin showed 2 to 22 times higher affinity to the M(3) than to the M(2) subtype. CONCLUSIONS: Compared with oxybutynin, tolterodine, 5-HM and DPr-P-4(N-->O) may bind more selectively to muscarinic receptors in the human bladder than in the parotid gland.

Humans↗
PubMed2006

Overactive bladder: a better understanding of pathophysiology, diagnosis and management.

PURPOSE: We reviewed current information regarding the updated definitions, prevalence, etiologies, disease burden, and management of OAB from a number of perspectives, including professional impact and patient quality of life. MATERIALS AND METHODS: Published literature and current treatment concepts were reviewed regarding the understanding and management of OAB. RESULTS: OAB is a symptom syndrome including urinary urgency with or without urinary incontinence, usually with frequency and nocturia. Approximately 17% of the adult population experience OAB. There are evolving theories regarding its pathophysiology and the mechanism of action of the most commonly prescribed pharmacological therapy (antimuscarinic agents). Treatment primarily revolves around improving quality of life. CONCLUSIONS: Behavioral therapy combined with pharmacological therapy often will bring about acceptable outcomes for patients with OAB. Modalities such as botulinum toxin injections, neuromodulation, and various surgical interventions also are showing encouraging results in more refractory patients.

Adult↗
PubMed2006

Predictors of medication adherence and associated health care costs in an older population with overactive bladder syndrome: a longitudinal cohort study.

PURPOSE: We examined the relationship between self-reported health status data, subsequent antimuscarinic medication adherence and health care service use in older adults with OAB syndrome in a managed care setting. MATERIALS AND METHODS: This was a longitudinal cohort study of older adults in the southeastern United States with OAB who completed a health status assessment, used antimuscarinic medications and were enrolled in an HMO continuously for 1 to 3 years. Demographic, clinical and use related economic variables were also retrieved from the administrative claims data of patient HMOs. Prescription refill patterns were used to measure medication adherence. Associations were examined with a sequential, mixed model regression approach. RESULTS: A total of 275 patients were included. The severity of comorbidity (Charlson index), patient perception of quality of life (Short Form-12 scores) and total number of prescribed medications during the year prior to enrollment in a Medicare HMO were independently associated with decreased antimuscarinic MPRs after enrollment. After controlling for other variables increased antimuscarinic MPR remained the strongest predictor of decreased total annual health care costs (5.6% decrease in annual costs with every 10% increase in MPR, p < 0.001). CONCLUSIONS: We found strong associations between decreased antimuscarinic medication adherence and increased health care service use in older adults with OAB in a managed care setting. Health status assessments completed at enrollment had the potential to identify enrollees at higher risk for nonadherent behaviors and poor health related outcomes.

Adult↗
PubMed2006

Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder.

PURPOSE: NGF and PGs in the bladder can be affected by pathological changes in the bladder and these changes can be detected in urine. We investigated changes in urinary NGF and PGs in women with OAB. MATERIALS AND METHODS: The study groups included 65 women with OAB and 20 without bladder symptoms who served as controls. Evaluation included patient history, urinalysis, a voiding diary and urodynamic studies. Urine samples were collected. NGF, PGE2, PGF2alpha and PGI2 were measured using enzyme-linked immunosorbent assay and compared between the groups. In addition, correlations between urinary NGF and PG, and urodynamic parameters in patients with OAB were examined. RESULTS: Urinary NGF, PGE2 and PGF2alpha were significantly increased in patients with OAB compared with controls (p <0.05). However, urinary PGI2 was not different between controls and patients with OAB. In patients with OAB urinary PGE2 positively correlated with volume at first desire to void and maximum cystometric capacity (p <0.05). Urinary NGF, PGF2alpha and PGI2 did not correlate with urodynamic parameters in patients with OAB. CONCLUSIONS: NGF and PGs have important roles in the development of OAB symptoms in female patients. Urinary levels of these factors may be used as markers to evaluate OAB symptoms.

Adult↗
PubMed2000

Behavioral therapy for overactive bladder.

What is behavioral therapy? On the one hand there is no consensus in the literature as to the definition of the treatment or the optimal mode of delivery. On the other hand, it is possibly the "best" single treatment for urinary incontinence when viewed from a risk:benefit analysis. There is general agreement that within this framework wide variations exist in intensity of treatment, expertise required to deliver the treatment, and the subsequent cost of therapy. A definition of behavioral therapy should include at least the following techniques: first, education and explanation of normal lower urinary tract function; second, micturition charts and diaries; and finally, timed voiding/bladder training regimens. All of the behavioral methods are demonstrably effective, with improvement rates in incontinence episodes uniformly in excess of 50%. Our challenge is to define the critical parts of behavioral therapy and develop algorithms that can be delivered to the incontinent population in the most cost-effective manner.

Behavior Therapy↗
PubMed2000

Biofeedback in overactive bladder.

Biofeedback is a form of learning or re-education in which the participant is retrained within a closed feedback loop. Information about one or more of the patient's normally unconscious physiologic processes is made available to the patient as a visual, auditory, or tactile signal. Objective responses are recorded on a polygraph trace so that they can be easily observed. Subjective responses are more difficult to monitor and it is often difficult to separate these effects of biofeedback from the placebo effect. Biofeedback has been successfully employed in cases of urinary incontinence due to detrusor instability. Indeed, a recent report has shown that biofeedback-assisted behavioral treatment is more effective than either oxybutynin or placebo in the treatment of urge and mixed urinary incontinence in older, community-dwelling women. Patients embarking on biofeedback need to be well motivated and intelligent enough to understand what is expected of them. The treatment is time consuming for both the patient and the operator, but the benefits of successful treatment include a reduction in morbidity and side effects associated with other therapies. Biofeedback can be employed as an adjunct to other forms of treatment, such as drug therapy, and is particularly useful in children.

Biofeedback, Psychology↗
PubMed2003

The discovery of a new class of large-conductance Ca2+-activated K+ channel opener targeted for overactive bladder: synthesis and structure-activity relationships of 2-amino-4-azaindoles.

2-Amino-4-azaindoles have been identified as a structurally novel class of BK(Ca) channel openers. Their synthesis from 2-chloro-3-nitropyridine is described together with their in vitro properties assessed by 86Rb(+) efflux and whole-cell patch-clamp assays using HEK293 cells stably transfected with the BK(Ca) alpha subunit. In vitro functional characterization of BK(Ca) channel opening activity was also assessed by measurement of relaxation of smooth muscle tissue strips obtained from Landrace pig bladders. The preliminary SAR data indicate the importance of steric bulk around the 2-amino substituent.

Amines↗