The effect of tolterodine 4 and 8mg on the heart rate variability in healthy subjects

Purpose: To investigate the potential effect of tolterodine on the human heart rate variability (HRV). Oral antimuscarinic treatment for overactive bladder might significantly alter HRV, which is an important predictor for cardiac and all-cause mortality. Yet, little information exists regarding the influence of oral antimuscarinics on the HRV. Methods: Healthy female volunteers were randomly assigned to either placebo, tolterodine extended release (ER) 4 or 8mg. Before and 4h post treatment, a 10min electrocardiogram (ECG) was recorded in supine position. Frequency domain and time domain analysis of both ECG measurements resulted in very low frequency (VLF), low frequency (LF), and high frequency (HF) data, the root mean square of differences of successive NN (=normal to normal, i.e. interval between two R-peaks) intervals (RMSSD), and the standard deviation of the NN intervals (SDNN). Results: Thirty subjects (mean age: 23.7±2.3years) were investigated. Placebo caused no significant HRV changes. Tolterodine 4mg significantly increased heart rate (HR) and significantly decreased VLF. Tolterodine 8mg significantly decreased HF, VLF, RMSSD and SDNN and significantly increased HR and LF/HF ratio. The changes observed with 4mg were not significantly different versus placebo, but 8mg significantly increased LF/HF as compared to placebo. Conclusions: A single dose of 8mg tolterodine ER, but not 4mg seems to reduce resting HRV versus placebo in young healthy subjects. This might be particular relevant for patients with pre-existing cardiac conditions on daily overactive bladder drug treatment and should be further investigated in larger trial

Can the ice-water test predict the outcome of intradetrusor injections of botulinum toxin in patients with neurogenic bladder dysfunction?

The aim of this project was to evaluate the ice-water test as a predictor of the response to intradetrusor botulinum toxin injection in patients with neurogenic detrusor overactivity. We retrospectively evaluated the urodynamic parameters in 22 patients with neurogenic bladder dysfunction and positive ice-water test. Maximum cystometric capacity (MCC), reflex volume (RV), maximum detrusor pressure during voiding (MVP) and bladder compliance (BC) were compared before and after intradetrusor injection of 300units botulinum toxin and calculated as a quotient. The ice-water test was performed before the injection, and the maximum pressure rise and the time to maximum pressure were measured. Furthermore, the ratio between maximum pressure and time to reach maximum pressure was calculated as the velocity of pressure rise. Correlations between the ice-water test criteria and the quotients of the cystometric data before and after injection were determined by the Spearmen's Rho coefficient. The increase in MCC and RV after botulinum toxin A injection showed a small positive, but insignificant correlation of 0.25 and 0.2 to the velocity of pressure rise of the ice-water test. A small negative, but insignificant correlation was found in change of BC and MVP with −0.17 and −0.2, respectively. Based on our population the ice-water test cannot predict the efficacy of intradetrusor botulinum toxin injections in patients with neurogenic detrusor overactivit

The facilitatory effect of duloxetine combined with pelvic floor muscle training on the excitability of urethral sphincter motor neurons

Introduction and hypothesis: Aim of this study was to investigate the excitability of sphincter motor neurons under the influence of pelvic floor muscle training (PFMT) and duloxetine. Due to their mechanisms of action, there might be a synergistic effect of duloxetine and PFMT in regard to the facilitation of spinal reflexes controlling urethral sphincter contractions and hence continence. Methods: In ten healthy female subjects, clitoral electric stimulation (CES) and transcranial magnetic stimulation (TMS) were used to determine individual motor thresholds for external urethral sphincter (EUS) contractions before and after PFMT, duloxetine, and PFMT + duloxetine. Results: PFMT and duloxetine alone significantly decreased the motor thresholds for EUS contractions during CES and TMS. However, the combined treatment reduced the motor threshold for EUS contractions significantly stronger compared to PFMT or duloxetine alone. Conclusions: The results are suggestive for a synergistic facilitatory effect of PFMT and duloxetine on sphincter motor neuron activatio

A morphological evaluation of botulinum neurotoxin A injections into the detrusor muscle using magnetic resonance imaging

Objectives: Although botulinum neurotoxin type A (BoNT/A) intradetrusor injections are a recommended therapy for neurogenic detrusor overactivity (NDO), refractory to antimuscarinic drugs, a standardisation of injection technique is missing. Furthermore, some basic questions are still unanswered, as where the toxin solution exactly spreads after injection. Therefore, we investigated the distribution of the toxin solution after injection into the bladder wall, using magnet resonance imaging (MRI). Methods: Six patients with NDO were recruited. Three of six patients received 300U of BoNT/A+contrast agent distributed over 30 injection sites (group 1). The other three patients received 300U of BoNT/A+contrast agent distributed over 10 injection sites (group 2). Immediately after injection, MRI of the pelvis was performed. The volume of the detrusor and the total volume of contrast medium inside and outside the bladder wall were calculated. Results: In all patients, a small volume (mean 17.6%) was found at the lateral aspects of the bladder dome in the extraperitoneal fat tissue, whereas 82.4% of the injected volume reached the target area (detrusor). In both groups there was a similar distribution of the contrast medium in the target area. A mean of 33.3 and 25.3% of the total detrusor volume was covered in group 1 and 2, respectively. Six weeks after injection, five of six patients were continent and showed no detrusor overactivity in the urodynamic follow-up. No systemic side effects were observed. Conclusions: Our results provide morphological arguments that the currently used injection techniques are appropriate and saf

Supraspinal Control of Urine Storage and Micturition in Men—An fMRI Study

Despite the crucial role of the brain in the control of the human lower urinary tract, little is known about the supraspinal mechanisms regulating micturition. To investigate the central regulatory mechanisms activated during micturition initiation and actual micturition, we used an alternating sequence of micturition imitation/imagination, micturition initiation, and actual micturition in 22 healthy males undergoing functional magnetic resonance imaging. Subjects able to micturate (voiders) showed the most prominent supraspinal activity during the final phase of micturition initiation whereas actual micturition was associated with significantly less such activity. Initiation of micturition in voiders induced significant activity in the brainstem (periaqueductal gray, pons), insula, thalamus, prefrontal cortex, parietal operculum and cingulate cortex with significant functional connectivity between the forebrain and parietal operculum. Subjects unable to micturate (nonvoiders) showed less robust activation during initiation of micturition, with activity in the forebrain and brainstem particularly lacking. Our findings suggest that micturition is controlled by a specific supraspinal network which is essential for the voluntary initiation of micturition. Once this network triggers the bulbospinal micturition reflex via brainstem centers, micturition continues automatically without further supraspinal input. Unsuccessful micturition is characterized by a failure to activate the periaqueductal gray and pons during initiatio

Botulinum toxin and detrusor overactivity

L'incontinence urinaire due à l'hyperactivité vésicale est un problème fréquent. Elle a des répercussions significatives sur la qualité de vie des patients, aussi bien que sur leur bien être physique et social. Chez les patients neurologiques, la perte de l'inhibition des centres suparaspinaux conduit à une contraction détrusorienne anormale, nommée hyperréfléxie détrusorienne, ou plus récemment hyperactivité détrusorienne neurogène. En plus de leur incontinence les patients présentent un risque élevé de reflux vésico-rénal et d'atteinte de la fonction rénale. Dans la pratique courante, les traitements pharmacologiques aux anticholinergiques sont utilisés pour réduire la contractilité vésicale. Cependant, leurs effets secondaires fréquents tels que sécheresse buccale, constipation, vision trouble et somnolence, peuvent affecter la compliance des patients, ce qui limite l'efficacité de ces traitements. Lorsque les traitements anticholinergiques se révèlent inefficaces, il n'y a actuellement pas de traitement conservateur alternatif valable et la dernière option thérapeutique reste la chirurgie. Les injections intra-détrusoriennes de toxine botulique de type A pour traiter l'hyperactivité vésicale ont été évaluées dans plusieurs études cliniques de hautes qualités et semblent être une alternative valable et sûre aux traitements anticholinergiques, du moins en ce qui concerne l'hyperactivité détrusorienne neurogène

The effect of botulinum toxin type a on overactive bladder symptoms in patients with multiple sclerosis: a pilot study

PURPOSE: Patients with multiple sclerosis often experience overactive bladder symptoms. High dose intradetrusor botulinum toxin A treatment is effective but often results in urinary retention and urinary diversion via a catheter. In this pilot study we evaluated whether only 100 U botulinum toxin A would significantly decrease overactive bladder symptoms in patients with multiple sclerosis without impairing pretreatment voluntary voiding. MATERIALS AND METHODS: Included in our study were 12 patients with multiple sclerosis who had overactive bladder symptoms such as urgency, frequency and/or urgency incontinence. The treatment effect was evaluated using data on 3 consecutive visits, that is before, and a mean +/- SD of 46.2 +/- 11.9 and 101 +/- 21 days after intradetrusor injection of 100 U Botox, including the results of cystometry and uroflowmetry at visits 1 and 2, and uroflowmetry alone at visit 3. Patients completed a 3-day voiding diary for all 3 visits. RESULTS: Maximum bladder capacity significantly increased and maximum detrusor pressure decreased. Daytime and nighttime frequency, urgency and pad use significantly decreased. Post-void residual volume significantly increased initially but decreased until 12 weeks. Median time to re-injection due to recurrent overactive bladder symptoms was 8 months. CONCLUSIONS: Overactive bladder treatment in patients with multiple sclerosis using 100 U Botox intradetrusor injections seems to be effective and safe. Despite slightly impaired detrusor contractility most patients still voided voluntarily without symptoms. Thus, 100 U Botox may be a reasonable treatment option for overactive bladder symptoms in patients with multiple sclerosis who still void voluntarily