Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the ß(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction.

UNLABELLED: Experimental urethral obstruction in rats alters micturition patterns with non-voiding activity (NVA) during filling cystometry, showing similarity to that observed in human detrusor overactivity. Several drug classes with therapeutic potential in overactive bladder in humans have been tested in this model in rats, rabbits or guinea pigs, but no detailed analysis of drug effects on cystometric patterns has been published. The present study uses a rat model of overactivity with partial bladder outflow obstruction (BOO) in combination with the procedures to analyse NVA to study the effects of the anticholinergic drug tolterodine and the novel ß(3)-adrenoceptor agonist mirabegron. The current data for the first time show that NVA in rats with BOO is sensitive to both the muscarinergic antagonist tolterodine and the ß(3)-adrenoceptor agonist mirabegron, but with clear differences between the two drugs: during progression of bladder filling, tolterodine affected both the amplitude and frequency of NVA whereas mirabegron affected primarily the frequency. In addition, tolterodine dose-dependently reduced voiding contractions, while mirabegron did not. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism which is sensitive to cholinergic excitatory and beta-adrenergic inhibitory inputs. Such concepts could provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs. OBJECTIVE: To investigate the hypothesis that tolterodine and the ß(3)-adrenoceptor agonist mirabegron exert their actions on the motor component of the motor/sensory system in the bladder wall: non-voiding activity (NVA). MATERIALS AND METHODS: The present study used standard cystometric techniques and a conscious rat model of partial bladder outflow obstruction (BOO). A single dose of either tolterodine (0.01, 0.1 0.3 or 1.0 mg/kg) or mirabegron (0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg) was given i.v. to each animal. RESULTS: In the dose ranges used, tolterodine reduced the voiding contraction amplitude, whereas mirabegron did not. Non-voiding activity consisted of small (<0.6 mmHg) and large (>0.6 mmHg) transients. As a fill progressed, both tolterodine and mirabegron reduced the cumulative activity of the large non-voiding contractions, but had little effect on the small transients. Tolterodine affected both the amplitude and frequency of NVA, whereas mirabegron affected primarily the frequency. CONCLUSIONS: Non-voiding activity is sensitive to muscarinergic antagonists and ß(3)-adrenoceptor agonists, but there are clear differences between the two drugs. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism with cholinergic excitatory and adrenergic inhibitory inputs. Such concepts may provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs.

Impact of a multi-faceted training intervention on the improvement of hand hygiene and gloving practices in four healthcare settings including nursing homes, acute-care geriatric wards and physical rehabilitation units.

AIMS: To assess the impact of a multi-faceted training program on the compliance with hand hygiene and gloving practices. BACKGROUND: Hand hygiene is considered as the cornerstone of the prevention of hospital-acquired infections. Several studies have enhanced the poor effectiveness of training programs in improving hand hygiene compliance. DESIGN: A before-after evaluation study. METHODS: The study was conducted in four healthcare settings before and after an intervention program which included the performance feedback of the first evaluation phase, three six-h training sessions, the assessment of hand hygiene performance with teaching boxes and the organisation of one full-day session devoted to institutional communication around hand hygiene in each setting. Hand hygiene compliance and quality of hand rubbing were evaluated. Hand hygiene opportunities were differentiated into extra-series opportunities (before or after a single contact and before the first contact or after the last contact of a series of consecutive contacts) and intra-series opportunities (from the opportunity following the first contact to the opportunity preceding the last in the same series). RESULTS: Overall, 969 contacts corresponding to 1,470 hand hygiene opportunities (760 during the first phase and 710 during the second) were observed. A significant improvement of observed practices was recorded for the hand hygiene compliance in intra-series opportunities (39·0% vs. 19·0%; p < 10(-5) ), the proportion of gloves worn if indicated (71·4% vs. 52·0%; p < 0·001) and the quality of hand rubbing (85·0% vs. 71·9%; p < 10(-5) ). CONCLUSIONS: Some of the performances measured for both hand hygiene and gloving practices were improved. We plan to extend this investigation by performing a qualitative study with experts in behavioural sciences to try improving practices for which adherence was still weak after the training program such as hand hygiene in intra-series opportunities. RELEVANCE TO CLINICAL PRACTICE: This study underscored the usefulness of implementing contextualised training programs, while more traditional courses have shown little impact.

Peripheral neural lesion-induced stress urinary incontinence in anaesthetized female cats.

OBJECTIVES: To characterize the effect of acute unilateral and bilateral lesion of the pelvic and pudendal nerves, and nerves innervating the iliococcygeous and pubococcygeous muscles during sneezing in anaesthetized female cats, on intravesical pressure (IVP), urethral pressure (UPs) and external urethral sphincter (EUS) activity. MATERIALS AND METHODS: In seven anaesthetized female cats UPs along the urethra (UPs1-4) and IVPs were recorded in the emptied bladder during sneezing before and after unilateral and then bilateral peripheral neural lesions. UPs were measured using microtip transducer catheters with UP4 positioned in the distal urethra where the EUS is located. Urine leakage was also noted, after urethral catheter removal and bladder filling. RESULTS: During sneezing, in intact cats, the magnitude of UP4 was larger than those of IVP and UPs1-3. The area under the curve of both anal sphincter and EUS electromyography was increased. There was no urine leakage. After unilateral neural lesions, the mean magnitude of response was similar all along the urethra and in the bladder. The distal UP response was significantly lower than that recorded in intact cats. In addition, there was urine leakage in six of the seven cats. Bilateral neural lesions caused permanent urine leakage and significant decreases in all the UP responses. CONCLUSION: In female cats, during sneezing, neurally driven reflex contractions of EUS leading to an increase in distal UP contribute to active urethral closure mechanisms and ensure urinary continence.

Netupitant, a Potent and Highly Selective NK1 Receptor Antagonist, Alleviates Acetic Acid-Induced Bladder Overactivity in Anesthetized Guinea-Pigs.

Introduction. Tachykinins potently contract the isolated urinary bladder from a number of animal species and play an important role in the regulation of the micturition reflex. On the guinea-pig isolated urinary bladder we examined the effects of a new potent and selective NK1 receptor antagonist (netupitant) on the contractions induced by a selective NK1 receptor agonist, SP-methylester (SP-OMe). Moreover, the effects of netupitant and another selective NK1 antagonist (L-733,060) were studied in anesthetized guinea-pigs using two experimental models, the isovolumetric bladder contractions and a model of bladder overactivity induced by intravesical administration of acetic acid (AA). Methods and Results. Detrusor muscle strips were mounted in 5 mL organ baths and isometric contractions to cumulative concentrations of SP-OME were recorded before and after incubation with increasing concentrations of netupitant. In anesthetized female guinea-pigs, reflex bladder activity was examined under isovolumetric conditions with the bladder distended with saline or during cystometry using intravesical infusion of AA. After a 30 min stabilization period, netupitant (0.1-3 mg/kg, i.v.) or L-733,060 (3-10 mg/kg, i.v.) were administered. In the detrusor muscle, netupitant produced a concentration-dependent inhibition (mean pKB = 9.24) of the responses to SP-OMe. Under isovolumetric conditions, netupitant or L-733,060 reduced bladder contraction frequency in a dose-dependent manner, but neither drug changed bladder contraction amplitude. In the AA model, netupitant dose-dependently increased intercontraction interval (ICI) but had no effect on the amplitude of micturition (AM). L-733,060 dose-dependently increased ICI also but this effect was paralleled by a significant reduction of AM. Conclusion. Netupitant decreases the frequency of reflex bladder contractions without altering their amplitude, suggesting that this drug targets the afferent limb of the micturition reflex circuit and therefore may be useful clinically in treating bladder overactivity symptoms.

Impact of improving glove usage on the hand hygiene compliance.

We assessed the impact of improving glove using on the hand hygiene (HH) compliance in a multicenter study including 9 chronic care settings. If gloves had been used correctly during the evaluation, the overall compliance with HH measured after contacts with patients or environment would have only increased from 66.3% to 68.7%. This weak impact suggests that improving glove usage is not in itself an alternative strategy to improve HH compliance.

Measurement of hand hygiene compliance and gloving practices in different settings for the elderly considering the location of hand hygiene opportunities during patient care.

We monitored hand hygiene and gloving practices by direct observation in 8 health care settings for elderly persons in western France. Compliance with hand hygiene was better than that reported by previous studies, was better for single contacts and before or after a series of successive contacts than inside series, and was closely related to gloving practices. Practices differed among the settings.