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PubMed2002

Urinary antispasmodic use and the risks of ventricular arrhythmia and sudden death in older patients.

OBJECTIVES: The introduction of new medications to treat overactive bladder has resulted in a significant increase in the number of individuals with this condition who use medications for symptoms. Formal epidemiological studies of the safety of these medications in typical patient populations are lacking, particularly studies of serious events. We sought to determine whether the use of urinary antispasmodics increases the risk of ventricular arrhythmias or sudden death. DESIGN: Retrospective cohort study. SETTING: Retrospective analysis of data of participants in community, hospital or nursing home setting. PARTICIPANTS: Fourteen thousand six hundred thirty-eight subjects with a diagnosis of urinary incontinence made between January 1, 1991, and June 30, 1995; all were aged 65 and older and enrolled in Medicare and Medicaid or the Pharmacy Assistance for the Aged and Disabled programs of New Jersey. MEASUREMENTS: Filled prescriptions for oxybutynin (Ditropan), flavoxate (Urispas), hyoscyamine (Cystospas), and hyoscyamine sulfate (Cystospas-M) were used to define days of exposure to these drugs. We also identified all use of nonsedating antihistamines and cytochrome P450 3A4 inhibitors, and their concurrent use, to serve as a positive control exposure. Two outcomes were then defined: a new diagnosis of ventricular arrhythmia combined with initiation of an antiarrhythmic medication and sudden death. Other covariates, including clinical, demographic, medication use, and healthcare utilization variables, were also assessed. Adjusted risk ratios of ventricular arrhythmia and sudden death were derived from multivariable Cox proportional hazards models. RESULTS: There was no significant association between periods of use of urinary antispasmodics and the development of ventricular arrhythmias (adjusted risk ratio (RR) = 1.23, 95 confidence interval (CI) = 0.87-1.75) or sudden death (adjusted RR = 0.70, 95% CI = 0.28-1.74). A significantly increased risk of ventricular arrhythmia was observed for the positive control regimen, concurrent use of nonsedating antihistamines and cytochrome P450 3A4 inhibitors (adjusted RR = 5.47; 95% CI = 1.34-22.26), but not for use of either drug group alone. Concurrent use of nonsedating antihistamines and cytochrome P450 3A4 inhibitors was also associated with a significant increase in the risk of sudden death (adjusted RR = 21.50, 95% CI = 5.23-88.37). Other variables significantly associated with ventricular arrhythmia included ischemic heart disease and congestive heart failure, whereas nursing home use before the index date was associated with a decreased likelihood of receiving a diagnosis of and treatment for ventricular arrhythmia. Other variables significantly associated with sudden death included male gender, black race, and congestive heart failure. CONCLUSIONS: Antimuscarinic urinary antispasmodics available before 1996 were not associated with an increased risk of ventricular arrhythmias and sudden death. Additional study will be required to confirm these results, exclude the possibility of unmeasured confounders contributing to any lack of an observed relationship, and extend these findings to newer agents such as tolterodine.

Aged↗

PubMed2000

Drug therapy for urinary incontinence.

Drugs used for treatment of urinary incontinence may act on the central nervous system (CNS) or peripherally. Few drugs with a defined CNS site of action are available for treatment of urine storage disorders; most of those currently used have a peripheral site of action. To treat bladder overactivity associated with urgency and urge incontinence, antimuscarinic drugs, alpha-adrenoceptor antagonists, beta-adrenoceptor agonists, prostaglandin synthesis inhibitors, and several other agents most often developed for non-urological indications, are employed. Current treatment is based on the use of antimuscarinic drugs, and oxybutynin is, despite a high incidence of side-effects, the gold standard. Pharmacological treatment of stress incontinence has had limited success, and only alpha-adrenoceptor agonists, with and without combination with oestrogens have had a documented effect. New drugs, specifically directed at treatment of urine storage disorders, are desirable.

Female↗

PubMed2002

Effect of tolterodine on the anticoagulant actions and pharmacokinetics of single-dose warfarin in healthy volunteers.

This randomized, double-blind, crossover study investigated the potential effects of tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5), an antimuscarinic agent for the treatment of the overactive bladder, on the anticoagulant actions and pharmacokinetics of single-dose warfarin (CAS 81-81-2) in 20 healthy male volunteers. In terms of study design, volunteers randomly received oral tolterodine L-tartrate (2 mg twice daily) or matching placebo for 7 days, with a single oral dose of warfarin (25 mg) administered on day 4 of each treatment period. R-(+)- and S-(-)-warfarin pharmacokinetics were estimated from plasma levels measured up to 96 h post-dose, in conjunction with assessment of prothrombin time and factor VII activity. Pharmacokinetics of tolterodine and its active 5-hydroxymethyl metabolite ((R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethyl-phenyl)-3-phenylpropanamine; 5-HM), in the presence and absence of warfarin, were also determined. Relative to placebo, tolterodine had no discernible effect on the anticoagulant actions of warfarin. Point estimates of the tolterodine: placebo ratios for prothrombin time and factor VII activity were 1.00 (90% confidence interval [CI]: 0.91-1.10) and 0.91 (90% CI: 0.83-0.99), respectively, consistent with equivalence. No clinically significant changes in the pharmacokinetics of R-(+)- and S-(-)-warfarin were noted. Serum concentration-time profiles and the pharmacokinetics of tolterodine and 5-HM were similar in the presence and absence of warfarin. There were no safety concerns. These findings indicate that co-administration of tolterodine and warfarin is safe and well tolerated, with no clinically significant pharmacodynamic or kinetic interaction in healthy volunteers.

Adult↗

PubMed2001

Tissue distribution of tolterodine, a muscarinic receptor antagonist, and transfer into fetus and milk in mice.

Tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5) is an antimuscarinic agent developed specifically for the treatment of the overactive bladder. In this study, the extent and profile of tissue distribution of 14C-tolterodine, after single and repeat oral dosing, was investigated in the mouse. Overall, distribution of radioactivity in tissues was rapid, and there were no gender-specific differences. The concentration of radioactivity in most tissues was similar to, or exceeded, that in blood. Highest concentrations were measured in gall bladder, urinary bladder, liver, kidneys and lungs, while the lowest concentration (10-times lower than in plasma) was seen in the brain. The distribution pattern after repeat oral dosing was similar to that after a single dose, although the decline in tissue concentrations was slower. Studies in pregnant mice showed that the distribution of radioactivity differed between dams and fetuses. Radioactivity was low and showed homogeneous distribution in the fetus, while a heterogeneous pattern was seen in the dam. Highest concentrations were seen in the fetal liver, brain and spinal cord. Some accumulation was observed in the choroid plexus. Placental concentrations of radioactivity were generally higher than those in the fetus, with some accumulation in the yolk sac. Studies in suckling mouse pups showed low levels of exposure to drug-related radioactivity (around 0.2% of the dose); the milk:plasma concentration ratio was 0.0-0.7. In conclusion, tolterodine and its metabolites are rapidly distributed into tissues following oral administration of radiolabelled drug in the mouse, with many tissues (including the fetus) reaching similar concentrations to that observed in blood. In other tissues, especially the eliminating organs, radioactivity levels were much higher than in blood. Penetration of the central nervous system was low, suggesting that the risk of deleterious effects on cognitive function may be lower with tolterodine than with more lipophilic antimuscarinic drugs.

Animals↗

PubMed2001

Pharmacokinetics of tolterodine, a muscarinic receptor antagonist, in mouse, rat and dog. Interspecies relationship comparing with human pharmacokinetics.

Tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5) is an antimuscarinic agent developed specifically for the treatment of the overactive bladder. In this study, the pharmacokinetics of tolterodine were investigated in the mouse, rat and dog, following which allometric scaling was performed to predict oral pharmacokinetics in man. The intestinal absorption of tolterodine after oral dosing was almost complete in all three species, with peak serum concentrations observed within 1 hour post-dose. Bioavailability varied between 2-20% in rodents and 58-63% in the dog. A high volume of distribution in all three species was consistent with extravascular distribution. Tolterodine was extensively metabolised in all the animal models, but the profile of metabolism differed in the rat compared to the mouse and dog, the latter having similar metabolism routes as man. Limitation of metabolism capacity caused a non-linear increase of tolterodine concentrations with dose (repeat-dose study in the mouse), and changed the relative metabolite concentration pattern. The results suggest that the hydroxylation of tolterodine is a high affinity, low capacity pathway, while N-dealkylation follows a low affinity, high capacity pathway. The elimination of tolterodine from serum was rapid, with a half-life of less than 2 h in all species. A very high clearance in the mouse and rat (10-15 l/h.kg), and in the dog (1.4 l/h.kg), indicated additional non-metabolic clearance mechanisms for tolterodine (shown to be attributed to biliary excretion). Urinary excretion of compound-related radioactive substance was around 15%, 45% and 50%, respectively, in the rat, mouse and dog. Allometric scaling allowed a good prediction of clearance and volume of distribution to be extrapolated for comparison with tolterodine pharmacokinetics in man. In conclusion, the pharmacokinetics of tolterodine are similar in the mouse and dog, and correlate with that in man. Although the rat has a different metabolic profile, clearance fits into the allometric relationship between species, enabling prediction of total clearance of tolterodine in man from preclinical data.

Animals↗

PubMed2006

[Use of permanent electrodes in the peripheral nerve evaluation test (PNE-Test) in comparison to conventional wire electrodes].

PURPOSE: Prior to implantation of a chronic sacral neurostimulator, it is important to establish which patients might profit from this kind of therapy in order to ensure, by means of a PNE (peripheral nerve evaluation) test, that the implantation of a permanent stimulating device is effective. In this study we compared the two different techniques used in our department (implantation of the permanent neurostimulation electrodes, the so-called "two-stage-implantation" vs. conventional PNE). MATERIALS AND METHODS: We performed a sacral nerve stimulation in 53 patients (mean age: 49.7 years, range: 14 - 75 years) over a minimum of 5 days. In 42 patients we performed a conventional PNE, 11 patients underwent "two-stage implantation" with implantation of the permanent electrodes. RESULTS: 52 of 53 patients received bilateral test stimulation (9 % at S2, 91 % at S3). One patient underwent unilateral PNE (S3) because of an anatomic deformity of the os sacrum. In 20 cases the conventional PNE-test (cPNE) was successful according to standard criteria (47.6 % of all cPNE). The response rate of "two-stage implantation" with implantation of the permanent electrodes was 81.8 % (9 of 11 patients). CONCLUSIONS: The success rate of implantation of permanent neurostimulation electrodes in selecting patients for the permanent implant is significantly higher than the conventional PNE. In this group patients with neurogenic and overactive bladder dysfunctions showed the highest response rates to sacral nerve stimulation and are the most likely to benefit from sacral neuromodulation.

Adolescent↗

PubMed2002

Efferent control of different visceral pelvic organs by spinal and supraspinal centres.

A growing number of patients with pelvic organ dysfunction and failing response to standard treatment concepts are referred to special neuro-urology services. New therapeutic options are available, such as unilateral and bilateral sacral nerve stimulation, and the use of different neurotoxins for the overactive bladder. However, a lack of knowledge and understanding in central innervation and modulation of pelvic organ function prevents a striking progress in this clinical area. A concept of efferent innervation of pelvic organs based on experimental animal studies, using the retrograde, transneuronal and self-amplifying tracer Pseudorabiesvirus, is discussed in a clinical context.

Animals↗

PubMed2005

A peripheric neuromodulation technique for curing detrusor overactivity: Stoller afferent neurostimulation.

OBJECTIVE: To perform Stoller afferent neurostimulation (SANS) with and without a low-dose anticholinergic (oxybutynin hydrochloride) in patients with detrusor overactivity and compare the results obtained with the two therapeutic approaches. MATERIAL AND METHODS: A total of 43 patients with symptoms of detrusor overactivity (frequency, urgency, urge incontinence) underwent urodynamic studies (UDS). Those in whom UDS revealed phasic detrusor overactivity were evaluated using a quality of life questionnaire and voiding diaries. Patients were randomized into two groups: Group 1 received SANS alone; Group 2 received SANS combined with a low-dose anticholinergic (5 mg of oral oxybutynin hydrochloride). Both groups were re-evaluated following 8 weeks of therapy. RESULTS: There were 21 patients in Group 1 and 22 in Group 2. The treatment response rate was 61.6% and 83.2% in Groups 1 and 2, respectively. In both groups, the best symptomatic improvements were obtained in patients with urge incontinence. The percentage decreases in the mean number of symptoms of frequency and urgency were 36.7% and 46.1%, respectively in Group 1 and 44.2% and 61.1%, respectively in Group 2. However, there were no statistically significant differences in the effects on frequency and urgency between the two groups. The anticholinergic drug was well tolerated by all patients in Group 2. One patient reported local tenderness, and a small hematoma developed in another following SANS therapy. CONCLUSION: SANS is an easy and inexpensive therapeutic method with low morbidity in patients with an overactive bladder. Combination with a low-dose anticholinergic increases the success rate without causing any significant side-effects.

Administration, Oral↗

PubMed2005

Urinary storage symptoms and comorbidities: a prospective population cohort study in middle-aged and older women.

OBJECTIVE: to identify predictive morbidities for urinary storage syndromes including indicators for neurological, musculoskeletal, cardiovascular, immune, lower bowel and psychological systems. This is the first study to test prior hypotheses, based on a literature review. DESIGN: this was a prospective cohort study involving 12,570 female respondents aged 40 or more registered with general practitioners and living at home in Leicestershire. Postal questionnaires were used at baseline and 1-year follow-up (response rates 65 and 79%, respectively). MEASURES: pure stress urinary incontinence (SUI) and overactive bladder syndrome (OAB) were defined using standardised symptom indicators. Specific morbidities included reported medical diagnoses, standardised symptoms and general health indicators. Associations were identified using logistic regression, adjusting for age and physical impairment, with separate models for general and specific morbidities. RESULTS: multivariate morbidities consistently associated (i.e. both longitudinally and cross-sectionally) were SUI-cystitis and obesity; and OAB-bowel urgency, osteoporosis, imbalance, ankle swelling, cystitis, poor health and old age. Other independent predictors were SUI-multiple sclerosis and joint pain; and OAB-deep vein thrombosis and diabetes. Consistent univariate indicators supported neurological, musculoskeletal, cardiovascular, immunological and psychological connections with both types of storage disorder plus an association with lower bowel problems for OAB. CONCLUSIONS: abnormal urinary storage symptoms were predicted by obesity and poor general health, involving a range of systems of the body. OAB showed more extensive links than SUI with specific morbidities, including more medically diagnosed as opposed to symptom-based conditions. These findings were independent of problems with physical impairment.

Adult↗

PubMed2005

Evaluating the educational content of direct-to-consumer fulfillment materials.

PURPOSE: The educational content of direct-to-consumer (DTC) fulfillment materials was evaluated. METHODS: A list of prescription drug products advertised to consumers via broadcast media from August 1997 through April 20, 2002, was obtained from the Food and Drug Administration (FDA). The prescription products were categorized by disease state on the basis of their FDA-approved indications. Eight disease states were selected for analysis purposes and included acne, allergic rhinitis, depression, diabetes, hypercholesterolemia, migraine, overactive bladder, and osteoporosis. A total of 31 products were advertised directly to consumers for the eight targeted disease states, 26 of which met the inclusion criteria. The educational content of the advertisements for these 26 products was assessed by analyzing the materials' consistency, instructiveness, and consumer orientation. RESULTS: Two of the 26 materials analyzed contained claims that potentially broadened a drug's indication from that listed in the FDA-approved labeling. The majority of materials listed the condition name (92%), symptom information (77%), the drug's mechanism of action (65%), the drug's time to onset of action (54%), and supportive behaviors (62%). Twenty of 24 DTC fulfillment materials (83%) were not written at the reading level of eighth grade or lower. Fifteen of the 26 mailings contained educational diagrams, 52% of which met the criteria for necessity, and a greater percentage met the criteria for suitability (90%), familiarity (86%), overall layout (88%), single concept (86%), and lack of distracting elements (100%). CONCLUSION: DTC fulfillment materials appear to have more educational content than DTC print advertisements but are still overwhelmingly deficient in meeting the recommended sixth to eighth-grade reading level.

Advertising↗

PubMed2004

(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel ATP-sensitive potassium channel opener: hemodynamic comparison to ZD-6169, WAY-133537, and nifedipine in the anesthetized canine.

The therapeutic utility of KATP channel opening agents (KCOs) in the treatment of overactive bladder may be limited by hypotension as a result of insufficient selectivity in vivo for bladder versus vasculature smooth muscle. Recently, we demonstrated that the putative uroselective KCOs, A-278637, ZD-6169, and WAY-133537 suppress unstable bladder contraction in an in vivo pre-clinical pig model of detrusor instability secondary to partial outlet obstruction. In the present study in the anesthetized dog we targeted plasma concentrations 3-, 10-, and 30-fold above a common index of in vivo efficacy (EC35) for suppression of unstable bladder contraction in pigs, to provide a comprehensive cardiovascular profile of these compounds. When compared at similar multiples of efficacy, dose-dependent reductions in SVR were greater in ZD-6169 and WAY-133537-treated animals versus A-278637. A-278637, unlike ZD-6169 or WAY-133537, produced no effect on MAP at concentrations 10-fold above the EC35. At concentrations 30-fold above the EC35, MAP in A-278637-treated animals was reduced -11% from baseline versus -24% and -42% for ZD-6169 and WAY-133537. Accordingly, at plasma concentrations approximately 30-fold above the EC35 reflex-mediated increases in HR were modest for A-278637-treated animals (15% above baseline) versus ZD-6169 (22%) or WAY-133537 (35%). Increases in both dP/dt and cardiac output occurred at lower therapeutic multiples and were greater in magnitude for animals treated with WAY-133537 (66% and 64% above baseline, respectively, 60 minutes into compound infusion) and ZD-6169 (10% and 13%) versus A-278637 (-2% and 6%). Thus, A-278637 exerted lesser effects on cardiovascular function at equivalent multiples of the EC35 than either ZD-6169 or WAY-133537. These data suggest that A-278637 possesses a greater functional selectivity for urinary bladder versus vascular smooth muscle in vivo and that A-278637 may exhibit a more favorable therapeutic index than either ZD-6169 or WAY-133537.

Adenosine Triphosphate↗

PubMed1998

Use of intravesical capsaicin for urge urinary incontinence and irritative voiding syndromes.

Intravesical capsaicin has been used in the management of selected patients with urge urinary incontinence throughout this decade, but the past 12 months has seen considerable interest in this and related compounds. It is no coincidence that during the same period the capsaicin receptor was cloned and named the vanilloid receptor subtype 1 and the European dual centre study of intravesical capsaicin reported that overall 80% of patients derived some clinical benefit. In spite of this, ultrapotent capsaicin analogues such as resiniferatoxin, which also interact with the vanilloid receptor subtype 1, are being studied. Preliminary reports of the potential advantages of intravesical resiniferatoxin are beginning to emerge, and in the future drugs that manipulate the vanilloid receptor may become universally important in the management of neurogenic overactive bladders.

Journal Article↗

PubMed2004

Voiding dysfunction in x-linked adrenoleukodystrophy: symptom score and urodynamic findings.

PURPOSE: Adrenoleukodystrophy is an x-linked genetic disorder characterized by the breakdown of the myelin sheath surrounding nerve cells in the brain and progressive dysfunction of the adrenal gland with 6 possible phenotypes. Lower urinary tract symptoms affect the quality of life of these patients but only sporadic cases have been previously studied by urodynamics. We report to our knowledge the first series in the literature looking at the prevalent pattern. MATERIALS AND METHODS: A total of 14 children and adults 8 to 53 years old (average age 30) with different phenotypes were referred for evaluation. Of the patients 6 had adrenomyeloneuropathy without cerebral involvement (C-) 3 had the adult cerebral form, 3 had the childhood cerebral form, 1 had cerebral involvement (C+) and 1 was asymptomatic. All patients were submitted to a screening protocol, consisting of the self-administered short form questionnaire International Conference on Incontinence Questionnaire-Short Form (ICIQ-SF) and a 3-day voiding diary. Patients were divided in group 1-no urinary symptoms, ICIQ-SF score 0 and no further investigation (3); group 2-frequency/urgency, ICIQ-SF score 1 to 5, uroflowmetry and post-voiding residual urine (4); and group 3-voiding symptoms and incontinence, ICIQ-SF score greater than 5, standard urodynamic examination (7). RESULTS: A neurogenic overactive bladder was the prevalent urodynamic finding (6 of 7 patients), while hypocontractility was found in 1 case. CONCLUSIONS: Vesicosphincteric dysfunction can be explained by spinal and/or cerebral involvement in the different neurological forms of adrenoleukodystrophy. Attempts at treatment with anticholinergics and neuromodulation in 4 of our patients provided temporary benefit with clear subjective amelioration of symptoms and improved quality of life.

Adolescent↗

PubMed2004

Predictive value of maximum urethral closure pressure, urethral hypermobility and urethral incompetence in the diagnosis of clinically significant female genuine stress incontinence.

PURPOSE: We determined the value of urethral hypermobility, maximum urethral closure pressure (MUCP) and urethral incompetence in the diagnosis of stress urinary incontinence (SUI). MATERIALS AND METHODS: In this study 369 women with clinical symptoms suggestive of SUI without symptoms of bladder overactivity were evaluated in regard to urethral incompetence, urethral hypermobility and mean MUCP. The cohort was divided into 2 groups according to continence/incontinence status. ROC curves were used to test the performance of the various predicting factors. These factors were combined in forward stepwise logistic regression to find the cutoff point that simultaneously optimized sensitivity and specificity. RESULTS: Continent and incontinent patients differed with regards to urethral incompetence and hypermobility (each p <0.0001). Incontinent patients had a greater probability of a higher grade of each factor. Even after adjusting for the older age of incontinent patients by ANCOVA. MUCP was significantly lower in the incontinent group (p <0.001). The best univariate optimized cutoff point for discriminating continence from incontinence was obtained with urethral incompetence greater than grade I. CONCLUSIONS: The best single predictor of clinically significant SUI is urethral incompetence, followed by urethral hypermobility and MUCP. When combining several factors, namely grade II urethral incompetence with grade III hypermobility, grade III urethral incompetence with grades I to III hypermobility and grade IV urethral incompetence with or without urethral hypermobility, all indicated more than a 90% probability of clinically significant SUI.

Adult↗

PubMed2005

Increased warning time with darifenacin: a new concept in the management of urinary urgency.

PURPOSE: We assessed the effect of darifenacin, an M3 selective receptor antagonist, on the warning time associated with urinary urgency. MATERIALS AND METHODS: In this multicenter, double-blind study subjects with urinary urgency for 6 months or greater and episodes of urgency 4 times or greater daily were randomized to darifenacin controlled release tablets (30 mg once daily) or placebo. Warning time was defined as the time from the first sensation of urgency to voluntary micturition or incontinence. Data were collected using electronic event recorders during 6-hour clinic visits or 3 urge-void cycles, if shorter, at baseline and at treatment end. RESULTS: A total of 72 subjects entered the study and 67 were included in the primary efficacy analysis (darifenacin in 32 and placebo in 35). Darifenacin treatment resulted in a significant increase in mean warning time with a median increase of 4.3 minutes compared with placebo (p = 0.003). Overall 47% of darifenacin treated subjects compared with 20% receiving placebo achieved a 30% increase or greater in mean warning time (OR 5.6, p = 0.009). Median and minimum warning times were also significantly increased following darifenacin treatment vs placebo (p = 0.004 and 0.017, respectively). The median difference in minimum warning time was 1.9 minutes in favor of darifenacin vs placebo. CONCLUSIONS: To our knowledge this is the first study to evaluate change in warning time, which is potentially important to individuals with symptoms associated with overactive bladder. Darifenacin increases mean, median and minimum warning time compared with placebo, allowing subjects more time to reach a toilet and potentially avoiding the embarrassing experience of incontinence.

Adult↗

PubMed2005

A critical review on magnetic stimulation: what is its role in the management of pelvic floor disorders?

PURPOSE OF REVIEW: This review looks at the acute effects of magnetic stimulation on urodynamic parameters and reviews the data on its use in the management of urinary incontinence. RECENT FINDINGS: Reported cure rates for stress incontinence immediately after a course of perineal magnetic stimulation range from 12.5 to 52.9% with good improvement occurring in 32% to 41%. However the effect seems temporary and dependent on the number of sessions. Sacral and pelvic floor magnetic stimulation have also been shown to increase cystometric capacity, inhibit detrusor overactivity and resolve overactive bladder symptoms acutely. Persistence of this effect with symptomatic improvement one week after sacral magnetic stimulation has been demonstrated. How magnetic stimulation suppresses detrusor contraction is not known. Prospective trials with the Neocontrol chair (Neotonus Inc, Marietta, Georgia, USA) also showed symptomatic improvement in 71 to 87% in the short term. However, the longer term data appear mixed. SUMMARY: Overall, the data available vary too much in terms of treatment protocols, patient mix and symptom severity to determine which group of patients might benefit most and what the optimal stimulation parameters are for each condition. Mean reductions in leak parameters, although statistically significant, may not always be clinically satisfactory. The beneficial effects also appear to be temporary and continuous treatment will probably be required. Further trials are needed to determine the optimum stimulation protocols for different situations and to compare magnetic stimulation with other forms of conservative pelvic floor therapy.

Electric Stimulation Therapy↗

PubMed2006

Current opinion on the working mechanisms of neuromodulation in the treatment of lower urinary tract dysfunction.

PURPOSE OF REVIEW: Neuromodulation is a successful treatment for patients with refractory lower urinary tract dysfunction. In the recent years, more applications of various types and ways have been developed and put into clinical practice. It is important, therefore, for urologists to know the existing theories on the working mechanisms that explain the effect. Although much research has been devoted to this subject for the past 35 years, the working mechanism is still unknown. This review presents an overview of the different theories and research into the physiological background of neuromodulation during the past 3 decades with emphasis on recent developments. RECENT FINDINGS: Specific receptors in the spinal cord have been identified, which are involved in the working mechanism of neuromodulation. The maximal effect of neuromodulation is not directly reached, indicating that neuromodulation induces learning changes (i.e. neural plasticity). The carry-over effect could be caused by negative modulation of excitatory synapses in the central micturition reflex pathway. SUMMARY: Neuromodulation in the treatment of stress incontinence probably induces physiological changes in the sphincter muscles and pelvic floor. In the treatment of overactive bladder syndrome, nonobstructive voiding dysfunction and chronic pelvic pain, the mechanism of action seems to be more complicated. Most likely, it is a combination of the different suggested modes of action, involving the neuroaxis at different levels.

Animals↗

PubMed2006

Multiple doses of the antimuscarinic agent solifenacin do not affect the pharmacodynamics or pharmacokinetics of warfarin or the steady-state pharmacokinetics of digoxin in healthy subjects.

AIMS: Solifenacin succinate is used for the treatment of overactive bladder (OAB). The potential for pharmacokinetic and/or pharmacodynamic interactions between solifenacin and warfarin or digoxin was investigated. METHODS: The solifenacin-warfarin study was a two-period crossover trial conducted in healthy males. Subjects received warfarin on the 10th day of 16 days of dosing with either solifenacin or placebo. The solifenacin-digoxin study was an one-sequence crossover trial conducted in healthy males and females. Following a phase-in period for digoxin, solifenacin was administered concomitantly with the drug on days 9-18. RESULTS: The AUC(PT; 0-168 h) following a single dose of warfarin was unchanged in the presence of solifenacin [point estimate = 1.005; 90% confidence interval (CI) 0.98, 1.02)]. The AUC(0-infinity) values for both warfarin enantiomers were also unchanged. A small increase in the C(max) of digoxin was observed during treatment with solifenacin, but for AUC(ss,tau) and C(max) the 90% CI fell within the prespecified interval of 0.80-1.25. Combined administration of solifenacin and warfarin or digoxin was well tolerated. CONCLUSIONS: Since the pharmacokinetics and pharmacodynamics of a single dose of warfarin and the steady-state pharmacokinetics of digoxin were not affected by coadministration of solifenacin in healthy subjects, the need for dosing adjustments for digoxin and/or warfarin does not seem warranted.

Administration, Oral↗