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Overactive bladder (OAB) is a common and distressing condition which is known to increase with age and to have a significant effect on quality of life (QoL). Whilst OAB is a symptomatic diagnosis, many patients will require basic investigations prior to initiating the appropriate management. This paper will explore the prevalence and pathophysiology of OAB as well as diagnosis and management of the condition. There is increasing evidence that local oestrogen therapy may be beneficial in the management of postmenopausal women with OAB, either when used alone or as combination therapy with an antimuscarinic drug. This paper will review the postulated mechanisms of action as well as exploring the available evidence base supporting efficacy. There is now a substantial evidence base to support the use of local vaginal oestrogen therapy in postmenopausal women with OAB either in isolation or alternatively as an adjunctive therapy when used with antimuscarinic medication. Available evidence supports an improvement in lower urinary tract symptoms as well as a significant improvement in health-related quality of life (HRQoL).

INTRODUCTION The use of antimuscarinic drugs is common in the management of the overactive bladder (OAB). Concerns have been raised over their use in the elderly population in whom the use of these drugs is highly prevalent, consequent to the reported link between these drugs and cognitive impairment and dementia. Areas covered: Recent publications have heightened concerns regarding antimuscarinic drug use in the elderly. In this review, the author discusses the available evidence upon which conclusions have been based and has presented the need for cortical review and need for caution in interpreting the data. The available evidence is inconsistent, differences in pharmacokinetics have not been widely recognized in clinical trials, clinical estimation of antimuscarinic activity has not been standardized, and serum antimuscarinic activity has not been found to correlate with cognitive impairment. Furthermore, the significant heterogeneity within cognitive aging processes raises questions regarding the extent to which various factors, including medication, influences this process. Expert opinion: Whilst caution should indeed be exercised in the use of antimuscarinic medication in the elderly, advocacy of discontinuation of their use may deprive patients of the benefits of improved quality of life from treatment where currently alternative management remain limited or invasive.

The nonselective muscarinic antagonist scopolamine is a rapid-acting antidepressant in limited clinical studies and shares common downstream signaling partners to ketamine, which is much more thoroughly studied both in the clinic and in preclinical models. In psychiatry, a clinically validated pathway is a rare phenomenon that holds particular importance for guiding neuroscientists toward neurobiological targets with the potential of affording more effective medicines for patients: either through reverse translation in search of targets that retain the clinical efficacy but increase the therapeutic window or through formulations that can be tailored to dosing schedules amenable to patients’ ease of use. Scopolamine’s rapid antidepressant profile provides an opportunity to deliver optimized medicines to patients, much like the recent clinical success of S-ketamine that ensued from robust follow-up investigation of ketamine’s clinical profile. This chapter is an attempt to review the clinical and preclinical antidepressant data of scopolamine with a view on illuminating the critical muscarinic receptor subtype(s) that could prove fruitful as a next-generation antimuscarinic drug target for depression.

The aim of this investigation was to characterize and compare the pharmacokinetics (PK) of the antimuscarinic drug solifenacin in pediatric patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) utilizing data from three phase III trials. LION was a placebo‐controlled, 12‐week trial in children (5–

Objectives This network meta-analysis aimed to assess the safety profiles of seven commonly used oral antimuscarinic drugs (darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, and tolterodine) in patients with overactive bladder (OAB). Methods PubMed, Cochrane Library, EMBASE, CNKI, and Wanfang databases were searched for randomized controlled trials (RCTs). Studies comparing one or more antimuscarinic drugs for treating OAB with reported adverse effects (AEs) were eligible. Data were extracted, and a network meta-analysis was performed by two authors independently. Results Forty-five RCTs and 124,587 patients were included. The results demonstrated that tolterodine had better safety outcomes for 7 out of 12 major AEs, including dry mouth, constipation, urinary retention, dizziness, urinary tract infection, dry eyes, and dry skin. Darifenacin, fesoterodine, imidafenacin, oxybutynin, and solifenacin presented comparable safety profiles. Conclusions Tolterodine may be preferable as it showed a reduced association with important AEs. Darifenacin, fesoterodine, imidafenacin, oxybutynin, and solifenacin have similar safety profiles in treating patients with OAB. Taken together, this analysis provides a valuable overview of the therapeutic safety for oral antimuscarinic drugs and is useful for personalized medicine in patients with OAB. Trial registration: This trial was retrospectively registered at INPLASY ( https://inplasy.com/ ) with the registration number 202170095.

Aim The present study was a comparison of the validity of the Medication Adherence Self-Report Inventory (MASRI) questionnaire with other methods of assessing adherence to antimuscarinic drugs treatment in older patients with urge incontinence. Methods The experiment involved 733 men and women aged >65 years who had noted no less than one urge incontinence episode per day. At the beginning of the experiment, and after 4, 8 and 12 weeks, their adherence to treatment was monitored using the MASRI. Results The construct validity of the tool was confirmed by data on the correlation of the percentage of non-adherent patients according to the MASRI and the percentage of patients having a belief barrier on the Brief Medication Questionnaire screen (r = 0.89, P ≤ 0.01; r = 0.91, P ≤ 0.01; and r = 0.91, P ≤ 0.05 at the 4th, 8th and 12th week of the follow up). The hypothesis of competitive validity was supported by comparing the percentage of non-adherent patients according to the MASRI and the number of missed doses on the Brief Medication Questionnaire screen (r = 0.94, P ≤ 0.01; r = 0.85, P ≤ 0.05; and r = 0.7, P ≤ 0.05), and according to a visual count of pills. The area under the curve at the 4th, 8th, and 12th week was 0.95 ± 0.04, 0.92 ± 0.03 and 0.94 ± 0.04, respectively. Conclusion The MASRI questionnaire has high validity, and is effective for evaluating adherence to treatment among older patients with urge incontinence taking antimuscarinic drugs. Using the MASRI would imply lower costs and greater availability of diagnostics, and it is the tool of choice in clinical practice. Geriatr Gerontol Int 2017; ••: ••–••.

A mild and efficient approach for highly regio- and enantioselective copper-catalyzed hydroboration of 1,1-diaryl substituted alkenes with bis(pinacolato)diboron (B2Pin2) was developed for the first time, providing facile access to a series of valuable β,β-diaryl substituted boronic esters with high enantiomeric purity. Moreover, this approach could also be suitable for hydroboration of α-alkyl styrenes for the synthesis of enantioenriched β,β-arylalkyl substituted boronic esters. Gram-scale reaction, stereospecific derivatizations, and the application of important antimuscarinic drug (R)-tolterodine for concise enantioselective synthesis further highlighted the attractiveness of this new approach.

Background : Overactive Bladder Syndrome(OAB) is not an uncommon problem. Although exact incidence of this disease in our country is not known but a significant number of people suffering from this disease seek treatment at the Urology department of different hospitals. At present two common antimuscarinic drug Solifenacin Succinate and Tolterodine are available in our country for the treatment of OAB.Objective : To compare the efficacy of Solifenacin Succinate and Tolterodine to treat OAB.Methodology : This hospital based randomized control trial was conducted in the Department of Urology, Dhaka Medical College Hospital, Dhaka and a private hospital from January 2009 to December 2010 to compare the efficacy of two new generation antimuscarinics, Solifenacin succinate and Tolterodine at their recommended doses for the treatment of OAB.Results : After 3 months of treatment it has clearly shown that Solifenacin is more effective in reducing OAB symptoms compared with extended release preparation of Tolterodine. This include statistically significant reduction in episodes of frequency, urgency, urge incontinence, nocturia and significant improvement of voided volume.Northern International Medical College Journal Vol.8(2) January 2017: 231-234

Tiotropium is now delivered via two different inhaler devices: the original Handihaler 18 μg once daily, which uses a powder formulation; and the newer Respimat Soft Mist Inhaler (SMI) 5 μg once daily. It has been questioned whether the two devices can be assumed to have the same safety profile, although the TIOSPIR trial showed that tiotropium when administered via Respimat SMI 5 μg is not less safe than Handihaler 18 μg. Therefore, we have carried out a safety evaluation of tiotropium Handihaler 18 µg versus tiotropium Respimat SMI 5 µg and 2.5 µg, via systematic review and network meta-analysis of the currently available clinical evidence. The results of our meta-analysis with an extremely large number of patients analysed demonstrate that the safety profile of tiotropium HandiHaler is generally superior to that of tiotropium Respimat SMI, although no statistical difference was detected between these two devices. However, the SUCRA analysis favoured tiotropium Respimat SMI with regards to serious adverse events (AEs). We do not believe that using Respimat SMI rather that HandiHaler exposes patients to higher risks of real AEs. Rather, we believe that there may be a different cardiovascular (CV) response to muscarinic receptors blockage in individual patients. Therefore, it will be essential to make all possible efforts to proactively identify patients at increased risk of CV AEs when treated with tiotropium or another antimuscarinic drug.

Many common prescription and over-the-counter medications have antimuscarinic effects. Antimuscarinics are a well recognized cause of dry mouth, with potential to cause other physical and cognitive adverse effects. A comprehensive medication review in a patient presenting with dry mouth can lead to overall health improvements. Scoring systems can be helpful in identifying antimuscarinic drugs and their adverse effects. CPD/Clinical Relevance: Antimuscarinic drug use is prevalent and a common cause of dry mouth. Older people are particularly susceptible to antimuscarinic adverse effects.

What's known on the subject? and What does the study add? Nocturia is a common and bothersome lower urinary tract symptom, particularly in men. Many single drug therapies have limited benefit. For men who have persistent nocturia despite alpha-blocker therapy, the addition of behavioural and exercise therapy is statistically superior to anticholinergic therapy. Objective To compare reductions in nocturia resulting from adding either behavioural treatment or antimuscarinic drug therapy to α-adrenergic antagonist (α-blocker) therapy in men. Patients and Methods Participants were men who had continuing urinary frequency >8 voids/day) and urgency after 4 weeks of α-blocker therapy run-in and who had ≥1 nightly episode of nocturia. Participants received individually titrated drug therapy (extended-release oxybutynin) or multicomponent behavioural treatment (pelvic floor muscle training, delayed voiding and urge suppression techniques). Seven-day bladder diaries were used to calculate reductions in mean nocturia. Results A total of 127 men aged 42–88 years with ≥1 nocturia episode per night were included in the study. There were 76 men who had a mean of ≥2 nocturia episodes. Among those with ≥1 nocturia episode, behavioural treatment reduced nightly nocturia by a mean of 0.97 episodes and was significantly more effective than drug therapy (mean reduction = 0.56 episodes; P = 0.01). Participants with ≥2 episodes nocturia at baseline also showed larger changes with behavioural treatment compared with antimuscarinic therapy (mean reduction = 1.26 vs 0.61; P = 0.008). Conclusions Both behavioural treatment and drug therapy reduced nocturia in men with ≥1 episode of nocturia/night when added to α-blocker therapy. These results were similar even when only those with ≥2 episodes of nocturia were considered. The addition of behavioural treatment was statistically better than bladder-relaxant therapy for nocturia.

The efficacy of antimuscarinic drug therapy in patients who have more severe symptoms of overactive bladder (OAB) at baseline has not been evaluated thoroughly.This analysis determined the effects of solifenacin in patients with severe OAB symptoms at baseline.All randomized, placebo-controlled phase III studies of solifenacin were pooled to determine the effects in patients with severe OAB symptoms at baseline. In these studies, patients were randomized to treatment with placebo or solifenacin 5 or 10 mg once daily. Baseline severity was defined according to the number of incontinence episodes/24 h, number of urgency episodes/24 h, and micturition frequency/24 h. The proportion of patients with restoration of continence, resolution of urgency, and normalization of micturition frequency at endpoint was determined. Mean change from baseline to endpoint in the number of episodes/24 h for incontinence, urgency, and micturition, and in the volume voided/micturition were assessed. Comparisons of change from baseline to endpoint were done with analysis of covariance (ANCOVA), and comparisons of percentage change from baseline to endpoint were based on van Elteren's test.Results from four multinational phase III studies of solifenacin with 2848 patients were pooled. The proportion of patients with restoration of continence, resolution of urgency, and normalization of micturition frequency at endpoint was significantly greater with solifenacin than with placebo among patients with severe OAB at baseline. Solifenacin 5 and 10 mg were significantly (p0.05) more effective than placebo for reductions in the number of episodes of incontinence, urgency, and micturition, and for the increase in volume voided/micturition among most subgroups of patients who were highly symptomatic at baseline (incontinence, urgency, or micturitions).Solifenacin was significantly more effective than placebo for patients with severe symptoms of OAB. The significant and consistent response was observed for all endpoints with solifenacin 10 mg and for most endpoints with solifenacin 5 mg using different definitions of baseline disease severity, and supports the overall effectiveness of solifenacin in highly symptomatic patients.

Urgency is the cornerstone symptom of overactive bladder (OAB) syndrome. It affects millions of people worldwide and has considerable effects on society. Most previous studies concentrated on urinary incontinence and it wasn’t until 2002, when the new definition of OAB was published, that interest in this condition began to increase. Unfortunately, the cause of OAB is not clearly established, thus all available treatments are aimed at alleviating symptoms rather than cure. Management is based on making an accurate diagnosis by excluding other pathologies and treating the symptoms conservatively and/or pharmacologically. Treatments are based on the assumption that OAB is due to involuntary detrusor contractions typical of detrusor overactivity. Antimuscarinic agents form the mainstay of medical therapy. There have been many recent developments in antimuscarinic drug therapy for OAB, which have gained more interest, particularly with the introduction of the term ‘bladder selectivity’, and it is hoped that t...

The aim was to further develop a method for studying the active and passive tissue properties in the human oesophagus. An impedance planimetric probe with a bag for distension was placed in the distal oesophagus in 14 healthy volunteers. Distension was done at an infusion rate of 25 mL min(-1) with and without the administration of the antimuscarinic drug butylscopolamine. The flow was reversed when moderate pain was experienced by the subject. The total and the passive tension showed an exponential behaviour as function of the change in radius. The active tensions increased until they reached a maximum point. The active tension decreased after the maximum until the distension was stopped shortly after due to the pain. The change in tension during distension-induced contractions (the afterload) was plotted as function of the precontraction radius (the preload). The human oesophagus behaves in a manner known from in vitro studies on muscle strips and exhibits a muscle diagram similar to that in the heart, i.e. the larger the initial muscle length during distension (within limits), the greater the contraction force.

KRP-197, 4-(2-methylimidazol-l-yl)-2,2-diphenylbutyramide, is a newly synthesized antimuscarinic drug, developed for the treatment for overactive bladder. For evaluation of pharmacological characteristics of KRP-197, we investigated whether it influenced both prejunctional and postjunctional muscarinic receptors on the isolated human detrusor smooth muscles as compared with the effects of atropine, oxybutynin, and propiverine. Using the muscle bath technique, we investigated the effects of various antimuscarinic drugs on the contractions induced by carbachol, KCl, CaCl2, and electrical field stimulation. Furthermore, using high-performance liquid chromatography with a microdialysis technique, we measured the acetylcholine release from the muscle strips during electrical field stimulation. The effects of various antimuscarinic drugs on acetylcholine releases were also evaluated. Pretreatment with various antimuscarinic drugs caused parallel shifts to the right in carbachol-induced concentration-response curves. The rank order of pA2 values was KRP-197 ≧ atropine > oxybutynin > propiverine. Atropine and KRP-197 did not cause significant inhibition of KCl- and CaCl2-induced contractions. All drugs caused concentration-dependent inhibitions in electrical field stimulation-induced contractions. Pretreatment with atropine and propiverine did not cause significant changes in electrical field stimulation-induced acetylcholine release. However, KRP-197, and oxybutynin caused significant decreases in acetylcholine release. The present study demonstrates that KRP-197 has an inhibitory effect on postjunctional muscarinic receptors as well as on prejunctional muscarinic receptors to modulate acetylcholine release in human detrusor smooth muscles. The findings suggest the usefulness of KRP-197 as a therapeutic drug for an overactive bladder with symptoms of frequency, urgency, and urge incontinence.

Objective To evaluate the implementation of a nursing home urinary incontinence management program. Design A prospective field trial of the program incorporating practice guidelines and principles of continuous quality improvement. Setting Five nursing homes in New York, Virginia, and Georgia Participants One hundred fifty-one residents identified as being incontinent of urine and who met inclusion criteria for ongoing participation in the program. Intervention Key multidisciplinary staff from the five nursing homes were trained in the program and assumed responsibility for implementing it in their facilities. The program consisted of a clinical assessment, toileting protocols, and the addition of the antimuscarinic drug tolterodine in selected residents who did not respond well to toileting alone. Data on dryness rates during the 60-day toileting protocols, collected by nursing home staff, were analyzed on a weekly basis by an overall project coordinator who sent data back to the nursing homes in an easy-to-read graphical format. Measures (1) The dryness rate, defined as the number of times the resident was dry divided by the number of times the resident was checked (every 2 hours from 7 a.m. to 7 p.m.); and (2) adverse events (eg, dry mouth, increased confusion, need for dosage reduction). Results Of 645 residents in the 5 nursing homes, 377 (58%) were identified as incontinent of urine, of whom 151 (40%) were placed on an ongoing toileting program. Of these 151 residents, 48 (32%) were prescribed tolterodine, and 117 (78%) completed the 60-day trial. The initial dryness rate was 57%, and for the group as a whole remained essentially unchanged (increase in dryness 1%, P = 0.50). Among 50 clinically stable residents on a toileting program alone, the increase in the dryness rate was 16% (P = 0.001), and for 31 clinically stable residents prescribed tolterodine, the increase in the dryness rate was 29% (P = 0.012). Two residents had their dosage of tolterodine reduced because of dry mouth and nausea, and one resident was taken off the drug because of increased pain in the back and legs and increased confusion. Conclusions Overall, this program resulted in significant increases in dryness rates for clinically stable incontinent nursing home residents. These residents represented 22% of the total number of residents identified as incontinent in the five participating nursing homes. Tolterodine was prescribed for approximately one-third of incontinent residents as a supplement to a toileting program, and was well tolerated. Nursing homes should be encouraged to implement similar urinary incontinence programs, target toileting protocols to the most responsive residents, and maintain the program using principles of continuous quality improvement.

Antimuscarinic drug treatment is known to have side effects and, consequently, poor adherence in therapeutic regimens. In this systematic review we study the long-term (greater than 6 months) adherence to antimuscarinic drugs in daily clinical practice, and identify factors contributing to poor adherence and persistence.This systematic review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A literature search was performed using PubMed® and Embase™ using synonyms for incontinence, overactive bladder and antimuscarinics combined with synonyms for medication adherence. We chose to include only pharmaceutical database studies (using prescription/insurance claim data) and patient self-report studies, using established pharmacoepidemiological parameters such as persistence rate and medication possession rate.A total of 1,245 titles were screened, of which 102 abstracts were assessed. Fourteen studies were ultimately included, comprising 190,279 unique patients (mean age 69.5 years). Regardless of which specific antimuscarinic drug is studied, persistence rates are usually poor. Considering all drugs together, median persistence rates were 12.0% to 39.4% (with an outlier of 75.5%) at 12 months, 8.0% to 15.0% at 18 months and 6.0% to 12.0% at 24 months. At 36 months persistence rates ranged from 0.0% (darifenacin) to 16.0% (trospium). Mean reported medication possession rates were also low, with a mean of 0.37 at 12 months. Risk factors for discontinuation were identified, with the most important being younger age group, use of oxybutynin and use of immediate release formulations.Improvement in adherence and persistence with antimuscarinic medication should be an important goal in the development of new drugs for overactive bladder and urinary incontinence.

Antimuscarinic drug prescribing scoring systems might better identify patients at risk of adverse drug reactions. The recently developed Anticholinergic Risk Scale (ARS) score is significantly associated with the number of antimuscarinic side effects in older outpatients. We sought to identify the clinical and demographic patient-level correlates of the ARS, including a modified version adjusted for daily dose, in elderly hospitalized patients.Clinical and demographic patient characteristics known to be associated with antimuscarinic prescribing, ARS and dose-adjusted ARS scores, and full medication exposure on admission were recorded in 362 consecutive patients (aged 83.6 ± 6.6 years) admitted to 2 geriatric units (NHS Grampian, Aberdeen, Scotland, UK) between February 1, 2010 and June 30, 2010.Each year of increasing age was associated with reduced number of antimuscarinic drugs (incidence rate ratio [IRR], 0.963; 95% confidence interval [CI], 0.948-0.980; P0.001), non-antimuscarinic drugs (IRR, 0.991; 95% CI, 0.985-0.997; P = 0.006), and total number of drugs (IRR, 0.988; 95% CI, 0.983-0.994; P0.001). Multivariate Poisson regression showed that increasing age and history of dementia were negatively associated with the ARS score (IRR, 0.97; 95% CI, 0.94-0.99; P = 0.001 and IRR, 0.62; 95% CI, 0.41-0.92; P = 0.019, respectively). By contrast, institutionalization (IRR, 1.32; 95% CI, 1.00-1.74; P = 0.050), Charlson comorbidity index (IRR, 1.06; 95% CI, 1.01-1.11; P = 0.015), and total number of non-antimuscarinic drugs (IRR, 1.13; 95% CI, 1.08-1.18; P0.001) were all positively associated with the ARS score. Similar results were observed for the dose-adjusted ARS score.Institutionalization, comorbidities, and non-antimuscarinic polypharmacy show independent positive associations with the ARS and dose-adjusted ARS scores in older hospitalized patients. Increasing age and dementia are negatively associated with the ARS score.

Purpose To review current pharmacological options for myopia control and explore future options. The underlying cause of both myopia and associated retinal complications is excessive ocular growth, which is a logical target for pharmacological intervention. Methods This presentation will review relevant research using animal models for myopia as well as clinical myopia research. Results The first attempts to control human myopia with drugs date back to the middle of the 19th century and involved topical atropine, an antimuscarinic drug. Possible reasons for why it remains the only drug in wide-spread use for myopia control today, despite its significant adverse ocular side-effects, will be considered along with general and drug-specific clinical issues associated with long-term use of topical ophthalmic formulations. Other plausible pharmacological treatment options will also be explored. Conclusion Progress in developing acceptable drug treatments for myopia control has been disappointing, especially given the near epidemic levels of myopia in some countries. However, the increased attention paid to the translation value of biomedical research may help to change this situation.

To investigate the effects of solifenacin on human detrusor smooth muscles, we evaluate the effects of solifenacin on the contractions induced by carbachol, KCl, CaCl2 and electrical field stimulation (EFS), and the EFS-induced acetylcholine release from detrusor smooth muscle strips by using the muscle bath and microdialysis technique. The effects of solifenacin were also compared with effects of other antimuscarinic agents (atropine, oxybutynin and propiverine). Pretreatment with various antimuscarinic agents caused parallel shifts to the right of the concentration-response curves to carbachol. The pA2 value of the Schild plots for solifenacin was similar to that for oxybutynin. Atropine did not inhibit the KCl- and CaCl2-induced contractions, while solifenacin, oxybutynin and propiverine significantly inhibited these contractions. EFS-induced contractions were inhibited by various antimuscarinic drugs in a concentration-dependent manner. In the presence of atropine, solifenacin tended to inhibit the residual atropine-resistant contractions induced by EFS, but it was not significant. However, oxybutynin and propiverine inhibited them under the same conditions. Although pretreatment with atropine and propiverine did not cause significant changes in EFS-induced acetylcholine release, solifenacin and oxybutynin caused significant decreases in acetylcholine release. The present results suggest that solifenacin inhibits contractions of human detrusor smooth muscles mainly by the antimuscarinic action and that the high concentration of solifenacin has Ca2+ channel antagonist action. Moreover, solifenacin may block not only postjunctional receptors, but also prejunctional receptors to modulate acetylcholine releases in cholinergic nerve endings in human detrusor smooth muscles. The findings support that muscarinic-receptor-inhibitory actions in human bladder mainly contribute to the usefulness of solifenacin as a therapeutic drug for overactive bladder.

Visceral perception and secondary peristalsis evoked by distension of the duodenum were studied in 10 healthy volunteers. An impedance planimetric probe for cross-sectional area (CSA) measurements inside a balloon and with three pressure channels was used. Balloon distensions were performed in the fed state with or without the administration of the antimuscarinic drug butylscopolamine. A modified questionnaire was used to assess the nonpainful and painful sensations. The total tension (T(total)) and the passive tension (T(passive)) were determined from the distensions without and with the administration of butylscopolamine, respectively. The active tension (T(active)) was T(total) - T(passive). The stepwise balloon distensions induced the first sensation at a volume of 33 +/- 3 mL. After administration of butylscopolamine the first sensation appeared at 42 +/- 1 mL. The perception score (PS) revealed an approximately linear increase as function of volume, CSA, pressure and tension after the first sensation. Butylscopolamine resulted in significant changes in PS score as function of volume, CSA and strain, but not as a function of pressure and tension. The frequency of the secondary peristalsis increased to the highest value (8.2 +/- 0.8 contractions min(-1)) at a volume of 21 mL. Butylscopolamine almost abolished the distension-evoked motility. T(total) and T(passive) increased nonlinearly as a function of volume, whereas T(active) increased up to a distension volume of 33 mL and then decreased at higher volumes. Hence, the conventional length-tension diagrams as known from studies of smooth muscle strips in vitro can be reproduced in the human duodenum in vivo. This new way of studying intestinal sensation and motility may prove to have both basic and clinical importance as both passive tissue structures and the sensorimotor function are tested.

Tone, motility and secretion of the colon are under the control of the autonomic nervous system. Under the stimulation of the parasympathetic system, a marked increase in tone and motility is recorded, together with an increase in secretion and sphincter relaxation. Conversely, under the stimulation of the sympathetic system, tone and motility are slightly reduced, with secretion inhibition and sphincter contraction. Parasympathetic innervation becomes particularly important in DCBE, for the greater control it exerts on the above mentioned colon functions, which may significantly affect the results of the examination, and also because these effects can be easily inhibited with appropriate drugs.

Mirabegron, a novel, non-antimuscarinic drug for the overactive bladder: An up-to-dated review

Overactive bladder (OAB) is a common problem whose prevalence increases with advancing age and compromises health-related quality of life. Tolterodine was the first antimuscarinic drug specifically designed to treat OAB. Through MEDLINE, we reviewed articles, standardization reports and meeting abstracts, published between 2001 and 2011, on the efficacy and tolerability of Tolterodine extended release (ER). Our search terms included Tolterodine, extended release, overactive bladder, therapeutic use, efficacy, tolerance, and adverse events. Tolterodine ER, via steady drug release during the daytime, gives the benefit of constant serum concentration and thus better efficacy and tolerability in comparison to Tolterodine immediate release, even in elderly patients with co-morbid conditions.

The pharmacokinetics of tritiated hexahydrosila- difenidol ([\(^3\)H]-HHSiD) were examined in rats. Furthermore, the distribution of radioactivity was studied by means of whole body autoradiography. After i. v. administration of 2.9 mg/kg HHSiD plus [\(^3\)H]-HHSiD to anaesthetized rats bearing a catheter implanted in the ductus choledochus and receiving a mannitol infusion, HHSiD was rapidly distributed and metabolized. Only 5% ofthe radioactivity was recovered in blood after 23 s and 0.4% after 2.5 h. 64% of the plasma radioactivity could be extracted with hexane from the samples taken 23 s after administration. 52% of the radioactivity was eliminated within 2.5 h, 13% by urinary and 39% by biliary excretion. Following oral administration of 8.6 mg/kg HHSiD plus [\(^3\)H]-HHSiD there was an absorption of approximately one fourth of the administered radioactivity within 4 h. By means of whole body autoradiography (i. v. injection) as well as by tissue distribution measurement the highest Ievels of radioactivity were found in bile, urine, lung, kidney, adrenals, liver and .pancreas. Thus, after i. v. administration to rats HHSiD is rather quickly distributed, metabolized and excreted. This explains its low antimuscarinic potency in vivo.

The antimuscarinic drug atropine caused a marked fall in plasma pepsinogen values of sheep with burdens of Ostertagia circumcincta and this response was greater in animals which had higher plasma pepsinogen values before administration of the drug. The response was shown to occur whether the elevated plasma pepsinogen values were a consequence of a larval infection in previously naive or exposed animals or of adult parasites directly transplanted into the abomasum of naive lambs.

The relationship between accommodative fluctuations and perimetric sensitivity was investigated in a group of 10 clinically normal emmetropic subjects using the Dicon AP3000 computer-assisted perimeter at a bowl luminance of 10 asb. Accommodative microfluctuations were attenuated with the antimuscarinic drug cyclopentolate HCl 1% and the concomitant mydriasis was matched on a separate trial using the sympathomimetic phenylephrine HCl 10%. Saline 0.9% was used as the control. Accommodative microfluctuations were found to play a minor role in determining the magnitude of sensitivity out to an eccentricity of 5 degrees; between 5 degrees and 27.5 degrees, the effect of microfluctuations was masked by the mydriasis produced by the drugs used in the study. The range of sensitivity values at a given location were reduced when accommodative fluctuations were minimized.

Acetylcholine (ACh) in brain is thought to play a role in a large array of centrally mediated physiological functions. We have been examining central cholinergic involvement in two processes: regulation of blood pressure and schedule-controlled behavior.

Thirty-one adult male rats were trained on a two component (FR10-extinction) operant task. After establishment of an atropine sulfate dose effect curve (vehicle, 1.0, 1.8, 3.2, 5.6 or 10.0 mg/kg), all rats were injected SC with 35.0 micrograms/kg soman three times per week for four weeks. One, twenty-eight and fifty-six days after the last soman injection, additional atropine tests were given. Atropine produced significant dose related decreases in FR10 responding at 3.2, 5.6 and 10.0 mg/kg during the initial dose effect curve with no effect on extinction responding. Although four rats died during the soman exposure period, the remaining rats exhibited neither signs of organophosphate toxicity nor significant disruptions in FR responding. However, a significant increase in extinction component responding was seen on soman injection days. The atropine dose effect curve for FR10 responding showed a significant shift to the left on the day after the last dose of soman. However, the dose effect curves at 4 and 8 weeks were the same as the initial curve. These results provide behavioral evidence that chronic soman exposure results in a supersensitivity to the antimuscarinic drug, atropine, possibly due to a down-regulation in the number of muscarinic receptors.

Neostigmine methylsulfate, a muscarinic drug, is frequently employed to reverse the paralytic effect of curare at the conclusion of surgical procedures. The experiments reported document the potent muscarinic effect of neostigmine on the large bowel, causing intraluminal colonic pressure to rise 15 times above base line. This is accompanied by severe spasm, associated with foreshortening and hypersegmentation of the bowel. The prior administration of atropine sulfate, an antimuscarinic drug, in the dose customarily employed during anesthesia, does not ameliorate or abolish the muscarinic effect of neostigmine on the canine colon. The muscarinic effects of neostigmine did not result in the disruption of an anastomosis fashioned in the canine colon.

• Drugs with antimuscarinic activity are used for a wide variety of medical conditions. Unfortunately, side effects that develop as a result of muscarinic blockade are common and their frequency and clinical significance appear to increase with advanced age. Nevertheless, such drugs are frequently prescribed to elderly persons, particularly to those living in nursing homes. This review details the prevalence of antimuscarinic drug use in the elderly, the classes of drugs that exhibit antimuscarinic activity, organ-specific effects of muscarinic blockade, side effects identified in elderly individuals, and strategies to prevent or treat complications of antimuscarinic therapy, including recent advances in the development of drugs with selective activity for specific subclasses of muscarinic receptors. (Arch Intern Med. 1989;149:2414-2420)