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Objective To evaluate the long-term safety and efficacy of indacaterol/glycopyrronium (IND/GLY) in patients with COPD in a real-world setting in Japan. Methods This 52-week, multicentre, post-marketing surveillance conducted in Japan between December 2013 and August 2019 included patients using IND/GLY for the first time to relieve airway obstructive disorder-related symptoms. Safety outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and serious ADRs during the 52-week period. The incidence of priority variables, including cardiovascular/cerebrovascular (CCV) AEs, β-adrenergic-related or anticholinergic AEs and cough, was also assessed. Safety outcomes were also evaluated in elderly patients. Efficacy outcomes included a physician's global assessment, COPD assessment test (CAT) and lung function test. Results Of the 1,167 patients registered, 1,108 were included in the safety and efficacy analysis. In the safety analysis population, the incidence of AEs was 13.54%, that of SAEs was 4.69%, that of ADR was 3.61%, and that of serious ADRs was 0.36% over 52 weeks. CCV AEs, β-adrenergic-related and anticholinergic AEs and cough were reported as 2.62%, 1.99% and 0.63%, respectively. The physician's global assessment showed that the overall response rate at the last assessment was 74.19%. The mean (95% confidence interval) CAT scores decreased from the start of treatment to Week 52 with IND/GLY (-6.9 [-7.8 to -6.1]). The lung function (FEV1 and FVC) improved over time from the start of IND/GLY to Week 52. Conclusion IND/GLY demonstrated a good long-term safety profile in a real-world setting in Japanese patients with COPD, with beneficial effects in terms of the lung function and symptoms in clinical use.

Overactive bladder is a symptom complex consisting of bothersome storage urinary symptoms that is highly prevalent among both sexes and has a significant impact on quality of life. Various antimuscarinic agents and the beta-3 agonists mirabegron and vibegron are currently available for the treatment of OAB. Each drug has specific pharmacologic properties, dosing schedule and tolerability profile, making it essential to individualize the medical treatment for the patient's characteristics and expectations. In this manuscript, we review the most important factors involved in the contemporary pharmacological treatment of OAB.

Objective To evaluate the efficacy and safety of vibegron in patients with overactive bladder (OAB) in real-world clinical practice in Japan. Methods This multicenter, prospective, non-controlled study consecutively enrolled patients with OAB determined by an OAB symptom score (OABSS) of three points or more and a question 3 (urgency) score of two points or more. A total of 212 patients from 43 institutions were recruited from January 2019 through March 2020. Vibegron, 50 mg, was administrated daily for 8 weeks as first-line monotherapy (first-line group, FL), monotherapy switching from antimuscarinics (post-antimuscarinic group, PA) or mirabegron (post-mirabegron group, PM) and combination therapy with antimuscarinics (add-on group). The OABSS was collected at baseline and every 2 weeks. Adverse events were recorded at every visit. Results Of the 212 patients registered, 188 (male 76, female 112) were eligible for analysis (124 in the FL group, 27 in PA, 29 in PM, and eight in the add-on group). The add-on group was excluded from further analysis due to its small number. The OABSS (mean ± SD) showed significant improvement in all groups (FL; 8.8 ± 2.5, 3.8 ± 2.8, PM; 9.4 ± 2.2, 4.5 ± 4.0, PM; 8.9 ± 2.5, 4.7 ± 3.3 at 0 and 8 weeks, respectively). The overall incidence of adverse events was 25%. No grade 3 or higher adverse events were observed. Conclusions In the real-world clinical setting, vibegron is effective and well-tolerated by OAB patients, including those switching therapy from antimuscarinics and mirabegron.

BACKGROUND AND PURPOSE The ability of the muscarinic cholinergic antagonist atropine to inhibit myopia development in humans and animal models would suggest that cholinergic hyperactivity may underlie myopic growth. To test this, we investigated whether cholinergic agonists accelerate ocular growth rates in chickens. Furthermore, we investigated whether atropine alters ocular growth by downstream modulation of dopamine levels, a mechanism postulated to underlie its antimyopic effects. EXPERIMENTAL APPROACH Muscarinic (muscarine and pilocarpine), nicotinic (nicotine) and non-specific (oxotremorine and carbachol) cholinergic agonists were administered to chicks developing form-deprivation myopia (FDM) or chicks that were otherwise untreated. Vitreal levels of dopamine and its primary metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were examined using mass spectrometry MS in form-deprived chicks treated with atropine (360, 15 or 0.15 nmol). Further, we investigated whether dopamine antagonists block atropine's antimyopic effects. KEY RESULTS Unexpectedly, administration of each cholinergic agonist inhibited FDM but did not affect normal ocular development. Atropine only affected dopamine and DOPAC levels at its highest dose. Dopamine antagonists did not alter the antimyopia effects of atropine. CONCLUSION AND IMPLICATIONS Muscarinic, nicotinic and non-specific cholinergic agonists inhibited FDM development. This indicates that cholinergic hyperactivity does not underlie myopic growth and questions whether atropine inhibits myopia via cholinergic antagonism. This study also demonstrates that changes in retinal dopamine release are not required for atropine's antimyopic effects. Finally, nicotinic agonists may represent a novel and more targeted approach for the cholinergic control of myopia as they are unlikely to cause the anterior segment side effects associated with muscarinic treatment.

Background In the absence of head-to-head trials, we performed an indirect treatment comparison of the β3-adrenergic agonists vibegron and mirabegron in the treatment of overactive bladder (OAB). Methods PubMed, Embase, and Cochrane Library were searched for articles related to phase 3, double-blind, controlled trials of vibegron 75 mg and mirabegron 25/50 mg in patients with OAB. Efficacy outcomes included change from baseline at weeks 4, 12, and 52 in mean daily number of total urinary incontinence episodes and micturitions and mean volume voided/micturition. Effect size was computed as placebo-subtracted change from baseline (weeks 4, 12) or active control (tolterodine)-subtracted change from baseline (week 52) for each treatment group. Adverse events (AEs) are presented descriptively. Results After removal of duplicates, 49 records were identified, and after screening 9 met inclusion criteria for analysis. Vibegron showed significantly greater reduction in mean daily number of total incontinence episodes than mirabegron 25 mg at week 4, mirabegron 50 mg (weeks 4, 52), and tolterodine (weeks 4, 12) (P

Background Combination drug therapy for lower urinary tract symptoms (LUTS) is beneficial to selected patients and recommended by guidelines. Patterns of real-world LUTS drug use, especially combination drug therapy, have not been studied extensively. Moreover, further understanding of the recent landscape is required following the introduction of the beta-3-adrenoceptor agonist mirabegron in the UK in 2013 for overactive bladder (OAB). The objective was to describe mono- and combination drug therapy use for LUTS in patients in UK clinical practice. Methods This was a retrospective, descriptive, observational database study using UK Clinical Practice Research Datalink GOLD and linked databases. Men and women ≥ 18 years with a first prescription for any LUTS drug from 2014 to 2016 with ≥ 12 months continuous enrollment pre- and post-index date were included. Primary endpoints were mono- or combination drug therapy use for LUTS in male and female cohorts. Secondary endpoints were description of treatment prescribed, treatment persistence and patient demographics. Data were analyzed descriptively. Sub-cohorts were defined by drugs prescribed at index date. Results 79,472 patients (61.3% male) were included, based on index treatments. Of all men, 82.5% received any benign prostatic obstruction (BPO) drug, 25.4% any OAB drug, and 7.9% any BPO drug plus any OAB drug. As either mono- or combination drug therapy, 77.1% received an alpha-blocker, 18.9% a 5-alpha reductase inhibitor, 23.9% an antimuscarinic agent, and 2.1% mirabegron. Of all women, 94.5% received any OAB drug, 6.0% duloxetine, and 0.5% any OAB drug plus duloxetine. As either mono- or combination drug therapy, 87.7% received an antimuscarinic, and 9.7% mirabegron. In men or women receiving OAB treatment, approximately 2.5% received combination drug therapy with an antimuscarinic agent and mirabegron. For OAB drug monotherapies, mirabegron had the highest persistence in both male and female cohorts. Conclusions This study provides a better understanding of the recent landscape of LUTS drug use in UK clinical practice. It highlights potential undertreatment of storage symptoms in men with LUTS and the low use of combination OAB treatments.

Summary: Objective: Historical and current view on the therapy of overactive bladder. Methods: This review summarizes the historical approach and current therapy of overactive bladder. The articles were gathered from Pubmed and Scopus databases. Studies published before December 2020 were used for the review. Results and Conclusion: Overactive bladder is a condition that quite a lot reduces the quality of life of our patients. Our therapeutic approach starts with non-pharmacological treatment, such as pelvic floor exercises. The next step is a pharmacological approach. The entry level drug is trospium. If the effect is not sufficient, propiverine, solifenacin, fesoterodine, darifenacin or mirabegron are used. Electrostimulation or botulinum toxin A application is an option only in cases that didn’t respond to pharmacological treatment. It is safe to say, that in the end, there is a way of reducing the severity of overactive bladder symptoms for every patient.

The aim of this study is to report cognitive dysfunction with commonly used antimuscarinic overactive bladder medications in patients suffering from overactive bladder disorder with and without baseline neurologic conditions. We conducted an Ovid MEDLINE, Embase, and PsycINFO search from January 1998 to December 2018 using PRISMA guidelines. Eighteen studies met the inclusion criteria, including 5 randomized controlled trials and 13 observational studies. Cognitive decline was reported with oxybutynin use (5 of 8 studies) and tolterodine use (4 of 7 studies) among patients with and without baseline cognitive impairment. Oxybutynin use was linked to functional, mental, and behavioral decline among patients with Alzheimer’s disease (2 studies). No cognitive decline was detected among patients with and without baseline cognitive impairment taking trospium (6 studies), darifenacin (3 studies), imidafenacin (2 studies), and fesoterodine (1 study). Solifenacin was not associated with cognitive decline (2 studies) but was linked to an increased risk of dementia among patients with diabetes (1 study). In this review, cognitive decline was reported with oxybutynin and tolterodine use and should be used with caution in adults over 65 years of age. Solifenacin, fesoterodine, and imidafenacin showed mixed results related to central nervous system effect. Trospium and darifenacin were not associated with cognitive decline among patients with and without baseline cognitive impairment.

Aim This study describes patients with different degrees and combinations of symptom resolution in response to fesoterodine exposure to aid physicians in counselling patients with overactive bladder (OAB) on the likelihood of treatment success. Methods Data came from 12‐week fixed‐dose studies of fesoterodine. The proportions of patients experiencing symptom resolution and change in patient‐reported outcome measures (PROM) at 4, 8, and 12 weeks were calculated. Treatment‐emergent adverse events (TEAE) were reported according to response in urinary urgency episodes (UUE). The relationship between PROM and response was examined. Results Out of 6689 patients, 81.6% female, urgency urinary incontinence (UUI) episodes/24 h were more responsive to fesoterodine than UUE; with roughly 50% of patients reporting a 50% reduction and fewer than 10% reporting absence of UUE at 12 weeks compared to approximately 40%–50% reporting absence of UUI. TEAE was numerically lower in patients with greater response. There was a statistically significant relationship between improvement in urinary urgency and associated change in OAB‐q symptom bother scores, r = 0.54, p

Objectives This analysis from the PERSPECTIVE (a Prospective, Non‐interventional Registry Study of Patients Initiating a Course of Drug Therapy for Overactive Bladder) study evaluated treatment persistence with mirabegron or antimuscarinics over a 12‐month period. Methods Participants were adults diagnosed with overactive bladder (OAB) by their health care provider (HCP), who were initiating mirabegron or antimuscarinic treatment. The HCP made all treatment decisions, and patients were followed for 12 months with no mandatory scheduled visits. Information requests were sent to patients at baseline and months 1, 3, 6, and 12. Patients were nonpersistent if they switched, discontinued, or added OAB medications/therapies to their initial treatment. Reasons for discontinuation and switching patterns were investigated. Results Overall, 1514 patients were included (613 mirabegron and 901 antimuscarinic initiators). Persistence rates decreased steadily over time in both groups. A low proportion of patients added or switched medication at each time point. Unadjusted Kaplan‐Meier analysis showed similar persistence rates for both groups. When the data were adjusted for patient characteristics (age, sex, and OAB treatment status), mirabegron initiators had higher persistence rates. No significant differences were noted in unadjusted median time to end of persistence. However, end of treatment persistence by any cause was longer with mirabegron (median: 9.5 vs 6.7 months for antimuscarinics). HCPs stated that the most common reasons for nonpersistence were no symptomatic improvement and side effect aversion. Conclusions Treatment persistence was longer for mirabegron compared with antimuscarinic initiators after controlling for patient characteristics. End of treatment persistence by any cause was also longer with mirabegron.

The combination of the noradrenergic agent atomoxetine plus the antimuscarinic oxybutynin has recently been shown to improve upper airway physiology and reduce obstructive sleep apnea (OSA) severity. However, the effects of different antimuscarinics when combined with atomoxetine is limited. This study aimed to determine the effects of atomoxetine combined with two different antimuscarinics with varying M-subtype receptor selectivity on OSA severity and upper airway physiology. Ten people with predominantly severe OSA completed a double-blind, randomized, placebo-controlled, cross-over trial. Participants completed three overnight in-laboratory sleep studies after either 80 mg atomoxetine + 5 mg solifenacin succinate (ato-sol) or 80 mg atomoxetine + 2 mg biperiden hydrochloride (ato-bip) or placebo. OSA severity, ventilatory stability (loop gain), respiratory-arousal threshold (via epiglottic manometry), next-day subjective sleepiness [Karolinska Sleepiness Scale (KSS)], and alertness were compared between conditions. Neither drug combination altered the apnea/hypopnea index versus placebo (P = 0.63). Ato-sol caused a shift toward milder respiratory events with reduced frequency of obstructive apneas (13 ± 14 vs. 22 ± 17 events/h; means ± SD, P = 0.04) and increased hypopneas during nonrapid eye movement (NREM) (38 ± 21 vs. 24 ± 18 events/h, P = 0.006) with improved nadir oxygenation versus placebo (83 ± 4 vs. 80 ± 8%, P = 0.03). Both combinations reduced loop gain by ∼10% versus placebo; sleep efficiency and arousal threshold were unaltered. Ato-bip reduced next-day sleepiness versus placebo (KSS = 4.3 ± 2.2 vs. 5.6 ± 1.6, P = 0.03). Atomoxetine + biperiden hydrochloride reduces perceived sleepiness, and atomoxetine + solifenacin modestly improves upper airway function in people with OSA but to a lesser extent versus recently published atomoxetine + oxybutynin (broad M-subtype receptor selectivity) findings. These results provide novel mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA. NEW & NOTEWORTHY In contrast to recent findings of major reductions in OSA severity when atomoxetine is combined with a nonspecific antimuscarinic, oxybutynin (broad M-subtype receptor selectivity), addition of solifenacin succinate (M2 and M3 muscarinic receptor selectivity) or biperiden (M1 muscarinic receptor selectivity) with atomoxetine had modest effects on upper airway function during sleep, which provide mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.

Physostigmine is the preferred treatment for antimuscarinic toxicity. Its use has a clear biological rationale and is supported by extensive clinical use which demonstrated effectiveness and safety.

The cholinergic nervous system has been implicated in mood disorders, evident in the fast-onset antidepressant effects of scopolamine, a potent muscarinic antagonist, in clinical studies. One prominent disadvantage of the use of scopolamine in the treatment of depression is its detrimental effects on cognition, especially as such effects might aggravate cognitive deficits that occur with depression itself. Thus, the identification of antimuscarinic drugs that are free of such detrimental effects may provide an important avenue for the development of novel therapeutics for the management of depression. The present data in rats indicate that a historical muscarinic antagonist, L-687,306, and a muscarinic antagonist of our own design, CJ2100, were as or more effective than scopolamine in antagonizing both the bradycardic effects of the muscarinic agonist arecoline in cardiovascular studies and its discriminative stimulus and rate-decreasing effects in behavioral studies. Additionally, both novel muscarinic antagonists were as effective as scopolamine in decreasing immobility in the forced swim test, a preclinical indicator of potential antidepressant activity. However, at equieffective or even larger doses, they were considerably less disruptive than scopolamine in assays of cognition-related behavior. All three drugs displayed high specificity for the mAChRs with few off-target binding sites, and CJ2100 showed modest affinity across the mAChRs when compared with L-687,306 and scopolamine. These data emphasize the dissimilar pharmacological profiles that are evident across antimuscarinic compounds and the potential utility of novel antagonists for the improved treatment of depression. SIGNIFICANCE STATEMENT: Some clinical studies with the muscarinic antagonist scopolamine document its ability to produce antidepressant effects in patients with mood disorders; however, scopolamine also has well known adverse effects on both autonomic and centrally mediated physiological functions that limit its therapeutic use. This study characterizes the cardiovascular and discriminative stimulus effects of two novel muscarinic antagonists, L-687,306 and CJ2100, that produce antidepressant-like effects in a rodent model (forced swim test) without affecting touchscreen-based cognitive performance (titrating psychomotor vigilance and delayed matching-to-position).

Diphenhydramine is frequently misused and ingested recreationally for its antihistaminergic and antimuscarinic effects and is often involved in both serious and fatal poisonings, either in isolation or in combination with other xenobiotics.This analysis sought to determine which patient and encounter characteristics were associated with severe outcome after diphenhydramine overdose.This is an analysis of the multi-center ToxIC registry (2010-2016). Descriptive analysis of all cases with diphenhydramine listed as the "primary agent" contributing to toxicity were included. Analysis sought to determine which patient and encounter characteristics were associated with severe outcome, defined as occurrence of seizure, ventricular dysrhythmia, or intubation. To determine which patient and encounter characteristics were individually associated with severe outcome, we performed chi-square tests. Fisher's exact tests were used in the case of sparse data. We also performed multivariable logistic regression to further determine independent risk factors for severe outcome in diphenhydramine overdose.Eight hundred and sixty-three cases remained after exclusion with 15.6% (Acidemia, QRS prolongation, and elevated anion gap are associated with severe outcomes in diphenhydramine toxicity. Further research is warranted to determine their predictive characteristics.

To investigate the change and recovery of choroid thickness after short-term application of 1% atropine gel and its influencing factors in 6-7-year-old children.71 right eyes of 71 children were enrolled and divided into myopia and control group. 1% atropine gel was administered twice a day for one week and then stopped. Spherical equivalent (SE), accommodative amplitude (AA), keratometry (K), axial length (AL), and choroidal thickness (CT) were obtained at baseline and 1In both groups, all CTs increased following the change in SE, AA, and AL after administration of 1% atropine for one week. They gradually recovered to baseline levels seven weeks after withdrawal. The change (Δ) in CT at 3 mm superior from the fovea was significantly higher in the myopia group than in the control group. In both groups, ΔCT at subfovea had no significant correlation with SE, AA, and AL, both at baseline and one week. However, ΔCT at subfovea was negatively correlated with ΔAL in the control group.One-week application of 1% atropine gel may increase CT in 6-7-year-old Chinese children. Meanwhile, the recovery process after withdrawal lasts seven weeks. During the recovery process, the changes in structural parameters (AL, CT) and functional parameters (AA, SE) in both groups occurred synchronously. The SE, AA, and AL at baseline may not predict the extent of atropine's effect on CT.

Background/Aim. Infantile hypertrophic pyloric stenosis (IHPS) is the most common cause of surgery in newborns and young infants. Conservative treatment of IHPS is of great importance because it spares the newborn from stress caused by surgery and general anesthesia. The aim of this study was to evaluate the impact of various oral administration regimens of atropine on its efficacy in treating IHPS. Methods. The study included 45 patients with IHPS, conservatively treated by atropine sulfate in the period from 2006 to 2016. Clinical examination, laboratory analysis, and ultrasonography were performed on all patients on admission. The efficacy of treatment with different oral dosage regimens was analyzed and potential predictive factors of the negative outcome were defined. The evaluation of the success of the treatment was statistically analyzed by the method of the multivariate logistic regression model. Results. Out of 45 patients, 36 (80%) were successfully cured (p = 0.0008, without the need for surgery and without any complications. Gender prevalence, age, birth weight, body weight on admission, duration of symptoms, pyloric muscle thickness, and length had no statistically significant individual effect on the success of the atropine treatment. Patients who received a progressively increased dose of atropine had an 18 times higher risk of surgery, patients with hypochloremic alkalosis (HCA) had a 15 times higher risk, while others, with more than 5 vomitings within the first three days of the therapy, were 9 times more likely to be surgically treated. Conclusion. High success rate and no side effects represent an orally administered atropine treatment as a valid alternative choice for non-operative management of IHPS. Administration of initially high doses was shown to be more effective in relation to gradually increased oral doses of atropine sulfate. HCA and continued vomiting are considered as potential predictive factors of negative outcomes of the atropine treatment.

Luca Richeldi,1 Alessio Piraino,2 Francesco Macagno,1 Gianluigi Micarelli,2 Eleonora Ingrassia2 1Unità Operativa Complessa di Pneumologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico A, Gemelli, Rome; 2Chiesi Italia S.p.a., Parma, ItalyCorrespondence: Gianluigi MicarelliChiesi Italia S.p.a., Via Giacomo Chiesi 1, Parma 43122, ItalyTel +39 345 6350692Fax +39 0521 279592Email g.micarelli@chiesi.comBackground: The fixed triple combination Beclometasone dipropionate/Formoterol fumarate/Glycopyrronium (BDP/FF/G, Trimbow®), an extrafine formulation in a unique pressurized metered dose inhaler, is indicated for the maintenance treatment in adult patients with moderate to severe COPD, not adequately treated by ICS/LABA or LABA/LAMA. Besides the evidence from three randomized controlled trials, the impact of fixed triple therapy has not been extensively evaluated in a real-world population of COPD patients. TRITRIAL (TRIple Therapy in Real life: Impact on Adherence and HeaLth status) is a non-interventional study to assess the effect of BDP/FF/G in a real world setting in Italy.Design: TRITRIAL is a 12-month, multicenter, cohort, prospective, longitudinal observational study. Two follow-up visits will be performed at 6 and 12 months, respectively. The study includes the collection of anamnestic clinical and functional data before the start of BDP/FF/G. The study is built for digital conduction, from signature of the informed consent on a dedicated web platform, to the collection of questionnaires and clinical data on the eCRF.Population: A total of 800 patients with COPD ranging from Global Initiative for Obstructive Lung Disease (GOLD) stages 2 to 4, receiving therapy with BDP/FF/G according to the Summary of Product Characteristics and local clinical practice, will be recruited. All concomitant therapies will be permitted for the duration of the study.Evaluations: The primary endpoint is the change of CAT score at 12 months versus baseline. Secondary endpoints are adherence, health-related quality of life, sleep quality, disease-related outcomes (lung function and COPD exacerbations), device usability, economic resources consumption, and safety.Conclusion: TRITRIAL study is expected to give relevant information about effectiveness of BDP/FF/G fixed triple therapy in a real-life setting of patients with COPD, where adherence, usability of inhalers and patient’s preference of the device are crucial factors for the success of the therapy.Keywords: COPD, symptoms, health status, adherence, LAMA, LABA, ICS

Background: Various combinations of inhaled corticosteroid (ICS), long-acting muscarinic antagonist (LAMA), and long-acting beta-agonist (LABA) have been used as triple therapy for stable chronic obstructive pulmonary disease (COPD). Objective: Our study was conducted to answer whether there were significant differences among various combinations in efficacy, for reducing exacerbation or mortality, and in safety, for increasing cardiovascular events or pneumonia. Method: We searched parallel-group randomized controlled trials (RCTs) comparing ICS/LAMA/LABA with other inhaled drugs in patients with stable COPD for at least 12 weeks in PubMed, EMBASE, the Cochrane Library, and clinical trial registries from inception to December 31, 2019. We conducted a network meta-analysis with Bayesian statistics using a random-effects model with heterogeneous variance structure (PROSPERO, CRD42019126757). Results: Nine different combinations of ICS/LAMA/LABA were identified in 21 RCTs containing 29,892 patients with moderate to very severe COPD. We could not find any significant evidence suggesting a better treatment for reducing total exacerbations or all-cause mortality among ICS/LAMA/LABA combinations. There were also no significant differences in moderate to severe exacerbation, COPD-related mortality, or cardiovascular disease-related mortality among ICS/LAMA/LABA combinations, and the risk of major adverse cardiovascular events was not different. A significantly lower risk of pneumonia was found in fluticasone propionate (FP)/glycopyrrolate/salmeterol (SAL) than FP/tiotropium/SAL {median odds ratio [OR] (95% credible interval [CrI]) = 0 [0–0.72]} and FP/umeclidinium/SAL {median OR (95% Crl) = 0 [0–0.97]}. Conclusion: There were no significant differences in clinical outcomes, including acute exacerbation and all-cause mortality among various ICS/LAMA/LABA combinations in patients with moderate to very severe COPD.

Toxicity from antimuscarinic agents precipitates a constellation of signs and symptoms; two of the most significant are agitation and delirium. Benzodiazepines are commonly used for treatment; physostigmine is also effective but is underutilized due to concerns for safety and short duration of action. The objective of this study was to compare lorazepam to physostigmine for the treatment of antimuscarinic delirium and agitation.This was a blinded, randomized clinical trial in patients presenting for antimuscarinic toxidrome. Inclusion criteria were: ≥10-18 years old, at least one central and two peripheral antimuscarinic symptoms, delirium and moderate agitation. Subjects were randomized to either (1) lorazepam bolus (0.05 mg/kg) followed by a 4-h normal saline infusion, or (2) physostigmine 0.02 mg/kg bolus followed by a 4-h physostigmine infusion (0.02 mg/kg/h). Primary outcomes were the control of delirium and agitation after bolus and during the infusion.Ten (53%) subjects were enrolled in the lorazepam arm, 9 (47%) in the physostigmine arm. Diphenhydramine was the most common agent ingested (16, 84%). Fewer patients receiving physostigmine had delirium after the initial bolus (44% vs 100%,Physostigmine was superior to lorazepam in controlling antimuscarinic delirium and agitation after bolus dosing, and control of delirium after a 4-h infusion. There were no serious adverse events in either treatment arm. Physostigmine bolus and infusion should be considered in adolescent patients with significant delirium and agitation from antimuscarinic agents.

Wen-Chien Cheng,1– 6 Biing-Ru Wu,1,3,5,6 Wei-Chih Liao,1,2,4,7 Chih-Yu Chen,1 Wei-Chun Chen,1,3– 6 Te-Chun Hsia,1,4,8 Chih-Yen Tu,1– 3 Chia-Hung Chen,1,2,7 Wu-Huei Hsu1 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 2School of Medicine, China Medical University, Taichung, Taiwan; 3Department of Life Science, National Chung Hsing University, Taichung, Taiwan; 4Department of Internal Medicine, Hyperbaric Oxygen Therapy Center, China Medical University Hospital, Taichung, Taiwan; 5Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 6Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; 8Department of Respiratory Therapy, China Medical University, Taichung, TaiwanCorrespondence: Chia-Hung Chen; Chih-Yu ChenDepartment of Internal Medicine, China Medical University Hospital, No. 2, Yude Road, Taichung, TaiwanEmail hsnu758@gmail.com; cychen0808@gmail.comPurpose: Triple therapy versus dual therapy for chronic pulmonary obstructive disease (COPD) can reduce symptoms, limit the risk of acute exacerbations (AEs) as well as improve lung function. Currently, studies that feature clinically important deterioration (CID) as a composite endpoint to assess the need for treatment intensification for patients maintained on dual therapy remained to be scarce.Patients and Methods: This study is a retrospective analysis (January 2014 to January 2018) of COPD patients that presented with moderate to severe AEs during the previous year with blood eosinophil counts ≥ 100 cells/μL. The first line of therapy included a combination of inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA). Composite CID was used in assessing the response to treatment after 24 weeks of therapy.Results: This study included 110 patients, of which 49 patients reportedly experienced CID. The most common events of CID include a decline in forced expiratory volume in 1 second (FEV1) ≥  100 mL from baseline (25/49, 51%) and an increase in COPD Assessment Test (CAT) scores ≥ 2 (13/49, 26.5%); many of these patients respond to the addition of a long-acting muscarinic antagonist (LAMA). Seven patients (7/110, 6.3%) experienced moderate to severe exacerbations while undergoing treatment with ICS/LABA. Univariate and multivariate analyses have identified low baseline FEV1 (OR = 0.81, p = 0.004), high CAT score (OR = 1.89, p = 0.004), and the frequency of AE (OR = 19.86, p = 0.021) as independent predictors of CID. A baseline FEV1 of ≤ 42%, an initial CAT score ≥ 18, and AE ≥ 2 last year were considered the optimal cut-off values, which were identified via receiver operating characteristics (ROC) curve analysis.Conclusion: Triple therapy (ICS/LABAs/LAMAs) may be considered as first-line treatment in patients experiencing more than 2 times moderate to severe AEs of COPD in the previous year and who have blood eosinophil counts ≥ 100 cells/μL, reduced lung function (FEV1 ≤ 42%), and more symptoms (CAT score ≥ 18).Keywords: inhaled corticosteroid, ICS, long-acting muscarinic antagonist, LAMA, long-acting β2 agonist, LABA, triple therapy, chronic pulmonary obstructive disease, COPD, clinically important deterioration, CID

Background The effects of triple therapy on gas trapping in COPD are not fully understood. We evaluated the effects of the long acting bronchodilator components of the extrafine single inhaler triple therapy beclometasone dipropionate/formoterol/glycopyrronium (BDP/F/G) pMDI on gas trapping. Methods This open-label, randomised, single centre, 2-way cross-over study recruited 23 COPD patients taking inhaled corticosteroid combination treatments and with residual volume (RV) > 120% predicted at screening. Inhaled BDP was taken during run-in and washout periods. Baseline lung function (spirometry, lung volumes, oscillometry) was measured over 12 h prior to randomisation to BDP/F/G or BDP/F for 5 days followed by washout and crossover. Lung function was measured prior to dosing on day 1 and for 12 h post-dose on day 5. Results Co-primary endpoint analysis: BDP/F/G had a greater effect than BDP/F on FEV1 area under the curve over 12 h (AUC0–12) (mean difference 104 mls, p = 0.0071) and RV AUC0–12 (mean difference − 163 mls, p = 0.0028). Oscillometry measurements showed a greater effect of BDP/F/G on the difference between resistance at 5 and 20 Hz (R5–R20) AUC0–12, which measures small airway resistance (mean difference − 0.045 kPa/L/s, p = 0.0002). Comparison of BDP/F with the baseline measurements (BDP alone) showed that F increased FEV1 AUC0–12 (mean difference 227 mls) and improved RV AUC0–12 (mean difference − 558 mls) and R5–R20 AUC0–12 (mean difference − 0.117 kPa/L/s), all p Conclusions In COPD patients with hyperinflation, the G and F components of extrafine BDP/F/G improved FEV1, RV and small airway function. These long acting bronchodilators target small airway function, thereby improving gas trapping and airflow. Trial registration The study was retrospectively registered at ClinicalTrials.gov on 15th February 2019 (No.: NCT03842904, https://clinicaltrials.gov/ct2/show/NCT03842904).

The Global Initiative for Asthma recommends a stepwise approach to adjust asthma treatment to the needs of individual patients; inhaled corticosteroids (ICS) remain the core pharmacological treatment. However, many patients remain poorly controlled, and evidence-based algorithms to decide on the best order and rationale for add-on therapies are lacking. We explore the challenges of asthma management in primary care and review outcomes from randomised controlled trials and meta-analyses comparing the long-acting muscarinic antagonist (LAMA) tiotropium with long-acting β2-agonists (LABAs) or leukotriene receptor antagonists (LTRAs) as add-on to ICS in patients with asthma. In adults, LAMAs and LABAs provide a greater improvement in lung function than LTRAs as add-on to ICS. In children, results were positive and comparable between therapies, but data are scarce. This information could aid decision-making in primary care, supporting the use of add-on therapy to ICS to help improve lung function, control asthma symptoms and prevent exacerbations.

While human eccrine sweat glands respond to adrenergic agonists, there remains a paucity of information on the factors modulating this response. Thus, we assessed the relative contribution of α- and β-adrenergic sweating during a heat exposure and as a function of individual factors of sex and training status. α- and β-adrenergic sweating was assessed in forty-eight healthy young men (n = 35) and women (n = 13) including endurance-trained (n = 12) and untrained men (n = 12) under non-heat exposure (temperate, 25°C; n = 17) and heat exposure (hot, 35°C; n = 48) conditions using transdermal iontophoresis of phenylephrine (α-adrenergic agonist) and salbutamol (β-adrenergic agonist) on the ventral forearm, respectively. Adrenergic sweating was also measured after iontophoretic administration of atropine (muscarinic receptor antagonist) or saline (control) to evaluate how changes in muscarinic receptor activity modulate the adrenergic response to a heat exposure (n = 12). α- and β-adrenergic sweating was augmented in hot compared with temperate conditions (both P ≤ .014), albeit the relative increase was greater in β (~5.4-fold)- as compared to α (~1.5-fold)-adrenergic-mediated sweating response. However, both α- and β-adrenergic sweating was abolished by atropinization (P = .001). Endurance-trained men showed an augmentation in α- (P = .043) but not β (P = .960)-adrenergic sweating as compared to untrained men. Finally, a greater α- and β-adrenergic sweating response (both P ≤ .001) was measured in habitually active men than in women. We show that heat exposure augments α-and β-adrenergic sweating differently via mechanisms associated with altered muscarinic receptor activity. Sex and training status modulate this response.

Background: Patients with asthma who are inadequately controlled on inhaled corticosteroid–long-acting β2-adrenoceptor agonist (ICS–LABA) combinations might benefit from the addition of a long-acting muscarinic receptor antagonist. The aim of the IRIDIUM study was to assess the efficacy and safety of a once-daily, single-inhaler combination of mometasone furoate, indacaterol acetate, and glycopyrronium bromide (MF–IND–GLY) versus ICS–LABA in patients with inadequately controlled asthma. Methods: In this 52-week, double-blind, double-dummy, parallel-group, active-controlled phase 3 study, patients were recruited from 415 sites across 41 countries. Patients aged 18 to 75 years with symptomatic asthma despite treatment with medium-dose or high-dose ICS–LABA, at least one exacerbation in the previous year, and a percentage of predicted FEV1 of less than 80% were included. Enrolled patients were randomly assigned (1:1:1:1:1) via interactive response technology to receive medium-dose or high-dose MF–IND–GLY (80 μg, 150 μg, 50 μg; 160 μg, 150 μg, 50 μg) or MF–IND (160 μg, 150 μg; 320 μg, 150 μg) once daily via Breezhaler, or high-dose fluticasone–salmeterol (FLU–SAL; 500 μg, 50 μg) twice daily via Diskus. The primary outcome was change from baseline in trough FEV1 with MF–IND–GLY versus MF–IND at week 26 in patients in the full analysis set, analysed by means of a mixed model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02571777, and is completed. Findings: Between Dec 8, 2015, and Jun 14, 2019, 3092 of 4851 patients screened were randomly assigned (medium-dose MF–IND–GLY, n=620; high-dose MF–IND–GLY, n=619; medium-dose MF–IND, n=617; high-dose MF–IND, n=618; high-dose FLU–SAL, n=618). 2747 (88·8%) patients completed the 52-week treatment and 321 (10·4%) started but discontinued study treatment prematurely. Medium-dose MF–IND–GLY (treatment difference [Δ] 76 mL [95% CI 41–111]; p1 versus corresponding doses of MF–IND at week 26. Improvements in trough FEV1 were greater for both medium-dose MF–IND–GLY (99 mL [64–133]; p

Chad Moretz,1 Beth Hahn,1 John White,2 Alyssa Goolsby Hunter,2 Breanna Essoi,2 Caitlin Elliott,2 Riju Ray3 1US Value Evidence & Outcomes, GlaxoSmithKline, Research Triangle Park, NC, USA; 2Optum, Eden Prairie, MN, USA; 3US Medical Affairs, GlaxoSmithKline, Research Triangle Park, NCCorrespondence: Beth HahnGSK, 5 Moore Drive, Research Triangle Park, Durham, NC, USATel +1 919 274 0660Email beth.a.hahn@gsk.comBackground: Long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) provide greater improvements in lung function and symptoms than inhaled corticosteroid (ICS)/LABA in patients with chronic obstructive pulmonary disease (COPD). This study evaluated symptom burden and Global Initiative for Obstructive Lung Disease (GOLD) categorization among patients who recently initiated umeclidinium/vilanterol (UMEC/VI; LAMA/LABA) or fluticasone propionate/salmeterol (FP/SAL; ICS/LABA) single-inhaler dual therapy.Methods: COPD-diagnosed Medicare Advantage enrollees aged ≥ 65 years were identified from the Optum Research Database (ORD). Eligible patients had ≥ 1 pharmacy claim for UMEC/VI or FP/SAL in the 6-month period before sample identification, with no evidence of triple therapy (ICS/LAMA/LABA), asthma, or lung cancer. Symptom burden was assessed via cross-sectional surveys using the COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnea scale. Patients were classified into GOLD categories using patient-reported symptoms and claims-based exacerbation history. Treatment groups were balanced on potential confounders using inverse probability of treatment weighting (IPTW). CAT and mMRC scores were analyzed with generalized linear regression models using IPTW propensity scores.Results: The final analytic sample included 789 respondents (UMEC/VI: N=392; FP/SAL: N=397). Approximately 66% patients were classified as GOLD B when assessing symptoms with CAT and mMRC together, or CAT alone; more patients were classified as GOLD A (∼ 40%) than GOLD B (∼ 36%) using mMRC alone. Proportions of patients in each GOLD group were similar between treatment cohorts. Post-IPTW multivariable modeling showed similar symptom burden between treatment groups.Conclusion: After controlling for baseline characteristics, symptom burden was similar between patients receiving UMEC/VI or FP/SAL. GOLD classification using mMRC produced more conservative results compared with CAT, potentially underestimating patient symptoms. Many patients receiving FP/SAL were classified as GOLD A or B, despite GOLD recommending non-ICS-containing therapy in these patients. These findings support the need for routine assessment of symptoms in patients with COPD.Keywords: COPD, fluticasone propionate/salmeterol, umeclidinium/vilanterol, CAT, mMRC, GOLD group

INTRODUCTION Asthma symptoms can be relieved through a maintenance treatment combining long-acting β2-agonist and inhaled corticosteroids (LABA/ICS). However, for patients with inadequately controlled asthma, the LABA/ICS combination might not be sufficient. Under these conditions, clinical guidelines recommend the administration of inhaled long-acting muscarinic antagonists (LAMA) as an add-on therapy to LABA/ICS to better control asthma and improve lung function. For nearly two decades, the only LAMA to be approved on the market has been tiotropium. AREAS COVERED We reviewed recent clinical studies evaluating the safety and efficacy of LABA/LAMA/ICS fixed dose combinations by searching PubMed database. Molecular mechanisms and clinical data support the use of a once-daily, single-inhaler fixed dose combination of the LABA/LAMA/ICS indacaterol/glycopyrronium/mometasone (IND/GLY/MF), the first therapy combining three agents in a fixed dose approved in Europe for the treatment of uncontrolled asthma. EXPERT OPINION IND/GLY/MF was superior to both IND/MF and salmeterol/fluticasone (SAL/FLU), a well-established LABA/ICS combination improving lung function in uncontrolled asthma. Moreover, IND/GLY/MF, delivered through the Breezhaler inhaler in a single inhalation, is the first inhaled therapy prescribed alongside a digital companion, a sensor and the Propeller app, allowing for improved treatment adherence, reduced rescue inhaler usage and hospitalizations, increased patient satisfaction and asthma control.

Repeated high-frequency pulse-burst stimulations of the rat perforant pathway elicited positive BOLD responses in the right hippocampus, septum and prefrontal cortex. However, when the first stimulation period also triggered neuronal afterdischarges in the hippocampus, then a delayed negative BOLD response in the prefrontal cortex was generated. While neuronal activity and cerebral blood volume (CBV) increased in the hippocampus during the period of hippocampal neuronal afterdischarges (h-nAD), CBV decreased in the prefrontal cortex, although neuronal activity did not decrease. Only after termination of h-nAD did CBV in the prefrontal cortex increase again. Thus, h-nAD triggered neuronal activity in the prefrontal cortex that counteracted the usual neuronal activity-related functional hyperemia. This process was significantly enhanced by pilocarpine, a mACh receptor agonist, and completely blocked when pilocarpine was co-administered with scopolamine, a mACh receptor antagonist. Scopolamine did not prevent the formation of the negative BOLD response, thus mACh receptors modulate the strength of the negative BOLD response.

PURPOSE: We aimed to explore the pathways followed by patients with overactive bladder (OAB) from referral to the urologist to final treatment.METHODS: This was a single-center, retrospective cohort study of female patients diagnosed with OAB in a large Dutch nonacademic teaching hospital. The number, sequence, and duration of treatment steps offered were analyzed, and the effectiveness, reasons for discontinuation, and possible case-mix variables influencing OAB treatment were studied.RESULTS: In total, 120 patients were enrolled and required a median of 2 steps (range, 1-6) of treatment over a median total duration of 28 weeks (range, 5-256). Treatment typically started with drug therapy, including antimuscarinics (38%; 95% CI, 30%-47%), antimuscarinics plus pelvic floor muscle therapy (21%; 95% CI, 15%-29%), or mirabegron (11%; 95% CI, 6%-18%). However, 52% of patients required further treatment, with botulinum toxin A (BoNT-A) injections being most effective (67%; 95% CI, 42%-85%), followed by antimuscarinics plus percutaneous tibial nerve stimulation (50%; 95% CI, 25%-75%), and antimuscarinics plus pelvic floor muscle therapy (36%; 95% CI, 21%-54%). Other therapies showed lower effectiveness. Common reasons for discontinuation were insufficient response and side effects. Overall, 22 patients were lost to follow-up.CONCLUSION: Most patients try at least two treatments before they experience satisfactory symptom relief, with treatment evaluations requiring time because therapeutic onsets differ by patient and treatment. Our data can help to manage expectations among urologists and patients when seeking treatment for OAB.

Cumulative exposure to one or more anticholinergic medications (“anticholinergic burden”) is associated with an increased risk of adverse outcomes, particularly among older individuals. Mirabegron, an oral selective β3-adrenergic receptor agonist, has demonstrated efficacy in managing the symptoms of overactive bladder without contributing to anticholinergic burden. However, it is not known whether the favorable safety profile of mirabegron relative to antimuscarinics varies with increasing age among a patient population who may have a high anticholinergic burden. The primary objective of this study was to indirectly compare the safety and efficacy profile of mirabegron relative to antimuscarinics in older adults with overactive bladder. A systematic literature review was conducted to identify randomized controlled trials that reported safety and efficacy endpoints among patients aged ≥ 65 years. Identified randomized controlled trials were subsequently synthesized via a network meta-analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines in designing, performing, and reporting the literature review were followed. In line with current best practices, the network meta-analysis was conducted using a Bayesian approach and according to the overall general guidance for evidence synthesis developed by the National Institute for Health and Care Excellence decision support unit. Estimates of relative safety were assessed via the odds ratio and estimates of relative efficacy were assessed via means and credible intervals. A total of 3078 abstracts, 300 of which underwent full-text screening, were identified using the search criteria. Twenty articles reporting on 21 randomized controlled trials were eligible for data extraction and synthesis. Following review, five safety and five efficacy endpoints were considered for inclusion in the network meta-analysis. Regarding findings typical of anticholinergic exposure in older adults, mirabegron was not associated with an increased odds of dry mouth (odds ratio 95% credible interval 0.76 [0.26–2.37]) or constipation (1.08 [0.39–3.02]) relative to placebo, whereas antimuscarinics were strongly associated with these events (odds ratio range 3.78–7.85 and 2.12–4.66, respectively). In this older population, mirabegron was associated with a similar odds of experiencing adverse event-related treatment discontinuations relative to placebo (0.99 [0.57–1.70]), while the odds of experiencing an adverse event-related treatment discontinuation for antimuscarinics had a range of 1.14–3.03 (in most cases, the association was mild). No increased odds of experiencing overall treatment-emergent adverse events was observed for mirabegron or antimuscarinics (odds ratio range 1.25–1.55), apart from fesoterodine (2.23 [1.37–3.37]). Finally, a similar treatment effect was observed across all efficacy endpoints between mirabegron and antimuscarinics in this older population. This study indicates that the safety and efficacy profile of mirabegron remains favorable compared with antimuscarinics among older adults. This includes safety outcomes typically associated with anticholinergic burden, which were less frequently observed in patients treated with mirabegron.

PURPOSE To explore patterns of antimuscarinic medication as a risk factor for type 2 diabetes mellitus (T2DM). METHODS This is a retrospective cohort study of females 18 years or older within the Military Health System from 2006 to 2016. Administrative and claims data were used to select patients who initiated therapy with tolterodine, fesoterodine, oxybutynin, darifenacin, solifenacin, or trospium. Patients with no documented history of T2DM were followed for the occurrence of T2DM, the end of the study or loss of eligibility. Rates of T2DM were calculated for the overall population, by duration of therapy and by individual drugs. Crude and adjusted Cox proportional hazards were calculated to assess differences by duration of use and specific muscarinic antagonist. RESULTS Over 2.6 million antimuscarinic prescriptions were dispensed to 241 829 females (mean age/SD, 62 ± 18 years). Patients exposed to M3 selective antagonists had highest risk of developing T2DM compared to those exposed to nonselective antagonists. Using oxybutynin, a nonselective antagonist as a comparator, adjusted rate ratios of T2DM were 57% (HR 1.57, 95%CI 1.48-1.67) and 29% (HR 1.29, 95%CI 1.24-1.35) significantly higher for darifenacin and solifenacin, respectively (both M3 selective). CONCLUSIONS We found exposure to M3 selective antagonists darifenacin and solifenacin had the highest risk of developing T2DM compared to nonselective antagonist oxybutynin. This is supported by well described physiologic mechanisms and may allow for more informed prescribing decisions, particularly if minimizing risk of T2DM is a priority.

Purpose Bladder antimuscarinic (BAM) drug use is associated with increased risk of Alzheimer's disease and related dementias (ADRD). It is hypothesized that BAMs with non-selective receptor binding may increase ADRD risk more than M3-selective BAMs. This study compared ADRD risk for users of non-selective and M3-selective BAMs and examines ADRD risk associated with overall BAM use. Methods Retrospective cohort study of Medicare claims for 71 688 individuals who used BAM drugs during 2007-2009 without an ADRD diagnosis. We compared ADRD incidence (2011-2016) between non-selective BAM users (fesoterodine, flavoxate, oxybutynin, tolterodine, trospium) and M3-selective BAM users (darifenacin, solifenacin). Logistic regressions compared individuals using target drugs in the same category of total standardized daily doses (TSDD) as a standardized measure of drug exposure, and adjusted for age, sex, race/ethnicity, healthcare utilization, other medication use, socioeconomic status, and comorbidities. Secondary analyses compared ADRD risk associated with different doses of BAMs overall. Results Non-selective BAM use (compared to M3-selective) was not significantly associated with ADRD incidence. Odds ratios for non-selective use were 0.97 (CI: 0.89-1.04) for 1-364 TSDD, 0.94 (CI: 0.83-1.06) for 365-729, 1.00 (CI: 0.87-1.16) for 730-1094, and 1.03 (CI: 0.88-1.20) for >1094. Higher TSDD of BAMs overall (combining both non-selective and M3-selective BAMs), when compared to 1-364 TSDD, were associated with increased ADRD incidence (OR = 1.05 (CI: 0.99-1.10) for 365-729, OR = 1.11 (CI: 1.05-1.17) for 730-1094, and OR = 1.10 (CI: 1.04-1.15) for >1094). Conclusions Non-selective and M3-selective BAM users had similar odds of ADRD incidence, and BAM use overall was significantly associated with ADRD incidence.

Reviews assessing mirabegron's safety and efficacy, synthesize data from both genders, without providing specific details for female patients with OAB. The aim of this study is to qualitatively and quantitatively synthesize data evaluating mirabegron's use on female patients with OAB. PubMed/Scopus/Cochrane library/Web of Knowledge were searched for full texted, published in English-language and in peer-reviewed journals, up to November 2019, using the keyword "mirabegron".Jadad score modified by adding allocation concealment, MINORS and RoB were used for the Methodological quality and risk of bias assessment. Twenty-one studies were included in this review;7 RCTs, 3 non-RCTs and 11 observational studies. Controlled trials were of unclear (75%), high (12.5%) or serious risk (12.5%) of bias. Twelve weeks of mirabegron use resulted in significant decrease of urgency, frequency, nocturia and UUI by 1.3-2.2,2.04-2.33,0.42-0.5 and 0.9-1.04 episodes/24 h, respectively. Quality of life and sexual health was improved significantly. Sexual dysfunction decreased from 98% (84/85) at baseline, to 60% (51/85) after 12-weeks of mirabegron (p-value 0.001). Mirabegron had the same efficacy as anticholinergics in improving all OAB symptoms but with fewer adverse events. Hypertension and antimuscarinics' effects (i.e dry mouth, constipation) had an incidence of 2% (28/1221) and 1.9% (23/1221) when mirabegron was administered, respectively. Mirabegron is a safe and effective alternative therapy for females with OAB. However, there is a paucity of high-quality RCTs, with large sample sizes, long-term follow-up focusing on mirabegron's comparison to other therapies, quality of life and sexual health of female patients with OAB.

Introduction Although antimuscarinics form the first-line therapy in overactive bladder (OAB), little is known regarding antimuscarinic discontinuation among OAB patients in nursing homes. This study examined treatment patterns and predictors of antimuscarinic discontinuation among long-term nursing home (LTNH) residents with OAB. Methods The study cohort included LTNH residents (defined as residents staying ≥ 101 consecutive days) from the Minimum Data Set linked 2013–2015 Medicare claims data. Patients with OAB were defined by OAB-related claims and medication codes. Treatment patterns and discontinuation (medication gap ≥ 30 days) were characterized by examining OAB-specific antimuscarinics prescribed during LTNH stays. The Andersen Behavioral Model was used to identify predisposing, enabling and need factors that predict discontinuation. Kaplan-Meier curves and multivariable Cox proportional hazards regression model were used to assess the unadjusted and adjusted times to discontinuation, respectively, among different antimuscarinics. Results The mean age of the study cohort (n = 11,012) was 81.6 years (± 8.5), 74.6% were female, and 89.8% were non-Hispanic White. The mean duration of nursing home stay was 530.1 (± 268.4) days. The most commonly prescribed OAB-specific antimuscarinic was oxybutynin (69.8%). Overall, 66.5% of the study cohort discontinued the index antimuscarinic. Multivariable Cox PH regression analysis revealed that compared to LTNH residents who initiated treatment with oxybutynin, treatment discontinuation was lower with solifenacin or fesoterodin and discontinuation was more frequent when treatment was initiated with tolterodine, darifenacin or trospium compared with oxybutynin. In addition, several need factors (comorbidities, medication use and anticholinergic burden, etc.) were associated with antimuscarinic discontinuation. Conclusion About two-thirds of LTNH residents with OAB discontinued their index antimuscarinic during their nursing home stay. There was significant variation in discontinuation based on the index antimuscarinic agent with lowest risk of discontiuation with solifenacin and fesoterodin. Concerted efforts to optimize antimuscarinic use are needed to improve the management of OAB in nursing homes. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01412-z) contains supplementary material, which is available to authorized users.

Background Overactive bladder is defined as “urgency, with or without urge incontinence, usually with frequency and nocturia”. Electroacupuncture may be a safe and an effective alternative therapy for overactive bladder, but the evidence is limited. Methods We will conduct a three-arm, non-inferiority, multi-centre randomized controlled clinical trial. A total of 420 patients with moderate and severe overactive bladder will be randomly assigned to one of three groups: the electroacupuncture group (N = 140), sham electroacupuncture group (N = 140), and solifenacin group (N = 140). The primary outcome will be the change in the overactive bladder symptom score from baseline to the end of the 12-week treatment. The secondary outcomes will include the proportion of participants with a decrease in the overactive bladder symptom score ≥ 3 at weeks 4, 8, 12, 20, and 32; the change in average 24 h values of urination, nocturnal urination, urgency incontinence and urgency episodes from baseline to weeks 4, 8, 12, 20 and 32, and so forth. The adverse events will be recorded. Statistical analysis will include covariance analysis, nonparametric tests and descriptive statistics. Discussion This study will answer the question of whether electroacupuncture is effective and non-inferior to solifenacin for improving the symptoms of overactive bladder patients. Trial registration Chinese clinical trial registry (ChiCTR1800019928).

Purpose of review This review aims to update the studies involving the treatment of lower urinary tract symptoms (LUTS) in neurogenic patients, published in the last two years. Recent findings Treatment of neurogenic LUTS (NLUTS) patients with β3 adrenoreceptor agonists was investigated in real-life conditions. A randomized controlled trial compared the efficacy of antimuscarinics versus onabotulinum toxin A in neurogenic patients. The use of desmopressin to treat nocturia in multiple sclerosis patients is also reported. The long-term treatment with BontA efficacy, its discontinuation, and possible strategies to maintain patients on treatment were also evaluated. Sacral neuromodulation and tibial nerve stimulation are continuously being evaluated in neurogenic patients, especially in the last years. Summary The management of urinary tract infections and vesical lithiasis, two common complications in NLUTS patients, and the management of both these patients was assessed in clinical trials.A trial evaluating the use of the anti-Nogo-A antibody after a spinal cord injury to facilitate neuronal rewiring and prevent or improve NLUTS was reported for the first time.

Scopolamine as a drug is often used to treat motion sickness. Derivatives of scopolamine have also found applications as antispasmodic drugs among others. In neuroscience-related research, it is often used to induce cognitive disorders in experimental models as it readily permeates the bloodbrain barrier. In the context of Alzheimer’s disease, its effects include causing cholinergic dysfunction and increasing amyloid-β deposition, both of which are hallmarks of the disease. Hence, the application of scopolamine in Alzheimer’s disease research is proven pivotal but seldom discussed. In this review, the relationship between scopolamine and Alzheimer’s disease will be delineated through an overall effect of scopolamine administration and its specific mechanisms of action, discussing mainly its influences on cholinergic function and amyloid cascade. The validity of scopolamine as a model of cognitive impairment or neurotoxin model will also be discussed in terms of advantages and limitations with future insights.

Racemic 3-quinuclidinyl-α-methoxydiphenylacetate (MB266) was synthesised. Its activity at muscarinic acetylcholine receptors (mAChRs), and muscle and neuronal nicotinic acetylcholine receptors (nAChRs), was compared to that of atropine and racemic 3-quinucidinyl benzilate (QNB) using a functional assay based on agonist-induced elevation of intracellular calcium ion concentration in CN21, Chinese Hamster Ovary (CHO) and SHSY5Y human cell lines. MB266 acted as an antagonist at acetylcholine receptors, displaying 18-fold selectivity for mAChR versus nAChR (compared to the 15,200-fold selectivity observed for QNB). Thus O-methylation of QNB reduced the affinity for mAChR antagonism and increased the relative potency at both muscle and neuronal nAChRs. Despite MB266 having a pharmacological profile potentially useful for the treatment of anticholinesterase poisoning, its administration did not improve the neuromuscular function in a soman-poisoned guinea-pig diaphragm preparation pretreated with the organophosphorus nerve agent soman. Consideration should be given to exploring the potential of MB266 for possible anticonvulsant action in vitro as part of a multi-targeted ligand approach.

This study aimed to use central and peripheral assays to compare the effects of the muscarinic antagonist scopolamine with those of a novel muscarinic antagonist, L-687,306 [(3R,4R)-3-(3-cyclopropyl-1,2,4,oxadiazol[5-yl]-1-azabicyclo[2.2.1]heptane. Groups of rats were trained to discriminate the stimulus effects of the muscarinic agonist, arecoline (1.0 mg/kg); concomitant measures of response rate were recorded. Separate groups were prepared with telemetery devices for recording bradycardia induced by arecoline (10 mg/kg). Methyl arecoline and arecoline were nearly equally potent in producing a brief but profound bradycardia, indicative of an equivalent effect in the heart. L-687,306 and scopolamine were both able to block this peripheral effect of arecoline. L-687,306 produced a surmountable antagonism of both the discriminative and rate-suppressing effects of arecoline. Scopolamine, however, was unable to antagonize the rate-reducing effects of arecoline in the discrimination assay. This limited the number of rats that could respond to the discriminative stimulus effects of arecoline, as well as the amount of arecoline stimulus effects they were able to report. The data suggest that L-687,306 may be a more generally effective muscarinic antagonist than scopolamine and support earlier reports that this antagonist has less direct effect on behavior.

Context The nonspecific storage symptom complex overactive bladder (OAB) is an important clinical condition in functional urology. Until recently, pharmacological therapy comprised antimuscarinic drugs, but more recently beta 3 agonists have added to the available agents. Traditional reporting of efficacy and safety of these agents relies upon regulatory placebo-controlled studies. There remains no head-to-head comparison of existing agents in the contemporary literature. Contemporary conclusions on comparative efficacy and safety drawn from the use of these agents are based on systematic reviews of the literature and associated meta-analyses. Objective In this study, we used the analytical model of multicriteria decision analysis (MCDA) to compare contemporary pharmacotherapy for OAB. Evidence acquisition Efficacy and safety data from published, randomised, placebo-controlled trials of antimuscarinic antagonists, the beta 3 agonist, and the combination of an antimuscarinic and beta 3 agonist were used to populate the MCDA model. Evidence synthesis Experts assessed weights of the relative importance of favourable and unfavourable effects, which provided a common measure of benefits and safety that were combined in the MCDA model to give an overall ranking of the OAB drugs. Results When benefits are judged as more important than safety, fesoterodine 4 or 8 mg used in a flexible dosing pattern provides the most favourable therapeutic option, over a wide sensitivity analysis relating to benefits and harms. Conclusions In our analysis using an MCDA model, in both the flexible dosing pattern of fesoterodine and the solifenacin combination with mirabegron, the benefit-safety balance is better in terms of benefits and/or safety than any of the other available OAB drugs. Caution in interpretation of the data has to be expressed as the fesoterodine data are based on a flexible dosing regimen, which adds an additional dimension of personalising therapy. Patient summary Overactive bladder (OAB) is a common condition with a significant impact on the quality of life. Possible symptoms include the following: (1) urgency—a compelling desire to urinate, which is difficult to defer; (2) urgency urinary incontinence—urgency leading to incontinence episodes; (3) frequency—increased frequency of wanting to pass urine; and (4) nocturia—increase in instances of getting up at night to urinate. To date, the mainstay of therapy for OAB has been antimuscarinic drugs and, more recently, the beta 3 agonist mirabegron. Ten international experts in urology, obstetrics, gynaecology, healthy ageing, and data analysis compared the benefit-risk balance of 14 OAB drugs licensed in Europe. The experts considered the importance of a favourable effect on the above four symptoms and also potential for side effects, but only three of these side effects, constipation, dry mouth, and dizziness, showed clinically relevant differences among the six drugs they considered. The observations recorded here suggest interesting differences between drugs across a wide range of possible trade-offs between benefit and safety. The different recruitment criteria used for each study may influence the results seen, so they need to be treated with caution. Comparison of flexibly dosed fesoterodine studies with fixed-dose fesoterodine studies introduces an additional potential bias; definitive conclusions can be drawn only if enough comparable placebo-controlled flexible dosing studies with other drugs were available.

We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old patient, followed by psychiatrists for depression and behavioral disorders, received a diagnosis of dementia with Lewy bodies (DLB) at another Center due to auditory hallucinations, gait impairment, and tendency to fall. He was then admitted to our Memory Clinic Unit for behavioral disturbances, such as delusional thinking, auditory hallucinations, and memory complaints. At that time, the patient's therapy included Lorazepam, Quetiapine, Promazine, and Biperiden. The latter was immediately suspended for the absence of extrapyramidal signs and to avoid the anticholinergic cognitive side effects. A 18F-FDG PET showed a derangement of cortical metabolism with diffusely reduced activity, and limited areas of hyperactivity involving lateral frontal and lateral temporal inferior regions bilaterally. The patient underwent a series of exams, including neuropsychological tests, 123I-MIBG scintigraphy, cerebrospinal fluid examination, and genetic analysis. A second 18F-FDG PET showed an extensive remodulation of metabolic activity: relative higher concentration of the tracer in the prefrontal and inferior temporal cortex was no more detectable. Similarly, the diffuse reduced metabolic activity could not be traced anymore. Nonetheless, the metabolic activity still appeared reduced in the frontal lobe, in the anterior cingulate bilaterally, and in the anterior part of the hemispheric fissure. Taken together, clinical and neuroimaging features would point to a FTLD-like form. Furthermore, the diagnostic work-up was likely confounded by the anticholinergic drug on 18F-FDG PET, highlighting the importance of carefully checking the patient's pharmacology during the diagnostic process.

Background Hyperhidrosis (HH) is characterized by exaggerated sweating in a specific region due to hyperfunction of the sweat glands. In the late 2000s, we started treating patients with an anticholinergic, oxybutynin, that was not being used until then. Objectives To present, after 12 years of utilizing this medication in our service, the substantial experience obtained with the use of oxybutynin as an initial treatment of HH in a large series of 1,658 patients. Methods We analyzed 1,658 patients treated with oxybutynin for HH from May 2006 to June 2018. The patients were divided into four groups according to the main site of HH: the plantar group, the axillary group, the facial group, and the palmar group. To measure the degree of satisfaction, a quality of life (QoL) questionnaire was used. Results Pre-treatment QoL was poor or very poor in more than 94% of the cases, and the palmar group had the worst quality of life. After treatment, we observed an improvement in the quality of life in 77% of patients. More than 70% of the patients in all groups present moderate or optimal subjective clinical improvement in sweating after treatment. The group with the best result was the facial group. Intense dry mouth was reported in 24.9% of all patients in all groups. Conclusions This study included a large number of patients followed for a long period and demonstrated the good effectiveness of treatment with oxybutynin for hyperhidrosis in the main sites of sweating.

OBJECTIVE The aims of this study are to determine how long it takes female patients with overactive bladder (OAB) to receive third-line treatment after starting OAB medications and identify factors associated with increased time. METHODS This was a retrospective observational cohort study of adult female patients with OAB who received third-line treatment between 2013 and 2015 using insurance claims databases. Primary outcome was time between first OAB medication and first third-line treatment. Additional variables were patient demographics, diagnostic tests, and medical comorbidities. RESULTS Of 3232 patients included in this study, 48.8% underwent sacral neuromodulation, 31.6% percutaneous tibial nerve stimulation, and 23% intradetrusor onabotulinumtoxin A injections. Twenty-one percent of patients filled medication prescriptions for 3 or more antimuscarinic medications, 30.4% took mirabegron, and 32.3% had advanced diagnostic tests suggestive of a specialist evaluation prior to starting medications. Median time to third-line treatment was 37.7 (interquartile range, 14.9, 16.3) months. Adjusted linear regression model revealed 2 predominant predictors of time to third-line treatments: each antimuscarinic medication trial was associated with 5.3 (95% confidence interval, 4.4-6.3) more months before third-line treatment (P < 0.001), and advanced diagnostic evaluations prior to starting medications were associated with 28.2 (95% confidence interval, 21-35) fewer months before third-line treatment (P < 0.001). CONCLUSIONS Women with OAB who undergo third-line therapy do so on average more than 3 years after starting medications. Time to third-line treatment is largely driven by the number of antimuscarinic medications tried and timing of diagnostic evaluation by a specialist. Based on these results, we suggest providers consider limiting antimuscarinic trials to 2 medications prior to moving on to other treatment options.

Background: Catheter-related bladder discomfort (CRBD) has been observed in many patients undergoing a urethral catheterization. CRBD may be so severe that the patients require additional analgesics. Muscarinic receptors are involved in the mechanism of CRBD. The aim of this study is to determine the effects of the antimuscarinic properties of atropine, which is frequently used in current practice on CRBD, by comparing it with sugammadex which has no antimuscarinic effects. Methods: Sixty patients selected for transurethral resection due to bladder tumors were randomized into 2 groups: an atropine group and a sugammadex group, with no antimuscarinic effect. The patients were given rocuronium (0.6 mg/kg) as a neuromuscular-blocker. In addition to the frequency and severity of CRBD postoperatively at 0, 1, 6, 12, and 24 hours, postoperative numeric rating scale (NRS) scores, and postoperative nausea and vomiting were examined. Results: The incidence of CRBD was significantly lower in the atropine group in all postoperative measurements. The score was found to be significantly lower in the atropine group when NRS measurements were performed at all time periods (P < 0.01). There was no difference between the groups in terms of nausea and vomiting (P > 0.05). Conclusions: Atropine is a cheap, easy-to-access, safe-to-use drug for reducing CRBD symptoms, without any observed adverse effects. Since it not only reduces CRBD symptoms but also has a positive effect on postoperative pain, it can be used safely to increase patient comfort in patients receiving general anesthesia and a urinary catheter. WOS:000522786000010 2-s2.0-85089625537 PubMed: 32235018

This post hoc Poisson regression analysis investigated the relationship between mean volume voided and incontinence episodes/24 h after fixed frequency adjustment in children with overactive bladder from the LION study, a phase 3, double-blind, randomised, placebo-controlled, sequential, dose-titration solifenacin trial. Patients were aged 5–P = 0.0014 and P = 0.0317, respectively). The model was a good fit to the data in both analyses with a Pearson’s chi-square goodness-of-fit criteria of 0.8.Conclusion: Increase in mean volume voided was significantly correlated to reduction in incontinence episodes/24 h in children with overactive bladder treated with solifenacin.This study is registered atClinicalTrials.gov: NCT01565707. What is known:• Mean volume voided per micturition is used as an indicator of treatment efficacy, with increases noted as number of incontinence episodes (and micturition frequency) decrease.• The relationship between mean volume voided and incontinence episodes is not clearly understood.What is new:• Increase in mean volume voided significantly correlated to reduction in incontinence in solifenacin-treated children with overactive bladder (Poisson regression model analysis).• Compared with placebo, solifenacin-treated children had a lower predicted number of incontinence episodes/24 h.

Purpose The triple combination therapy budesonide/glycopyrrolate/formoterol fumarate in a metered dose inhaler (BGF MDI), formulated by using innovative co-suspension delivery technology, is a new inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination for the maintenance treatment of COPD. For some patients, the use of an MDI may be optimized with a spacer. This Phase I study assessed the effect of a spacer on lung exposure, total systemic exposure, and safety of BGF MDI 320/36/9.6 μg in healthy subjects. Methods : This randomized, open-label, crossover study assessed the pharmacokinetic and safety profiles of BGF MDI in healthy adult subjects who received a single dose of BGF MDI 320/36/9.6 μg (administered as 2 inhalations with 160/18/4.8 μg per actuation) in 4 regimens: without spacer and no charcoal; with spacer and no charcoal; without spacer and with charcoal; and with spacer and with charcoal. Primary objectives were to assess total systemic exposure (without charcoal) and lung exposure (with charcoal) of budesonide, glycopyrronium, and formoterol administered as BGF MDI with and without a spacer. Safety was also assessed. Findings In total, 56 subjects were randomized (mean age, 29.9 years; 60.7% male, 17.9% former smokers). For systemic exposure (without charcoal), the spacer/without spacer ratio, expressed as a percentage (intrasubject %CV) of Cmax and AUC0–tlast, respectively, was 152.0 (47.5) and 132.8 (43.6) for budesonide, 240.6 (80.2) and 154.7 (73.4) for glycopyrronium, and 165.6 (50.7) and 98.6 (53.8) for formoterol. For lung exposure (with charcoal), the spacer/without spacer ratio percentage (%CV) of Cmax and AUC0–tlast, respectively, was 183.6 (65.9) and 198.4 (71.5) for budesonide, 262.0 (91.8) and 373.9 (120.7) for glycopyrronium, and 222.9 (56.3) and 385.2 (147.0) for formoterol. Subjects who were judged to have suboptimal inhalation technique without a spacer (those in the lowest drug exposure quartile based on AUC0–tlast) had the greatest increase in both total systemic and lung exposure when a spacer was used versus no spacer. Subjects in the highest quartile had a minimal change in both total systemic and lung exposure when the spacer was used. Treatment-emergent adverse events (TEAEs) (all mild/moderate) reported by >1 subject per regimen were headache, cough, and dizziness. One subject withdrew because of TEAEs of headache and presyncope (neither considered treatment-related). Implications Drug delivery can be improved for subjects with suboptimal MDI inhalation technique when using a spacer device with BGF MDI triple therapy. ClinicalTrials.gov identifier: NCT03311373 .

Background Acetylcholinesterase inhibitors (e.g., pyridostigmine bromide) are used for neuromuscular blockade (NMB) reversal in patients undergoing surgery under general anesthesia (GA). Concurrent use of anticholinergic agents (e.g., glycopyrrolate) decreases cholinergic side effects but can impede bowel movements. Sugammadex has no cholinergic effects; its use modifies recovery of gastrointestinal (GI) motility following laparoscopic cholecystectomy compared to pyridostigmine/glycopyrrolate. This study evaluated the contribution of sugammadex to the recovery of GI motility compared with pyridostigmine and glycopyrrolate. Methods We conducted a prospective study of patients who underwent laparoscopic cholecystectomy. Patients were randomly allocated to the experimental group (sugammadex, Group S) or control group (pyridostigmine-glycopyrrolate, Group P). After anesthesia (propofol and rocuronium, and 2% sevoflurane), recovery was induced by injection of sugammadex or a pyridostigmine-glycopyrrolate mixture. As a primary outcome, patients recorded the time of their first passage of flatus (‘gas-out time’) and defecation. The secondary outcome was stool types. Results One-hundred and two patients participated (Group S [n = 49], Group P [n = 53]). Mean time from injection of NMB reversal agents to gas-out time was 15.03 (6.36–20.25) h in Group S and 20.85 (16.34–25.86) h in Group P (P = 0.001). Inter-group differences were significant. Time until the first defecation as well as types of stools was not significantly different. Conclusions Sugammadex after laparoscopic cholecystectomy under GA resulted in an earlier first postoperative passage of flatus compared with the use of a mixture of pyridostigmine and glycopyrrolate. These findings suggest that the use of sugammadex has positive effects on the recovery of GI motility.

Mitochondrial dysfunction is implicated in a variety of neurodegenerative diseases of the nervous system. Peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) is a regulator of mitochondrial function in multiple cell types. In sensory neurons, AMP-activated protein kinase (AMPK) augments PGC-1α activity and this pathway is depressed in diabetes leading to mitochondrial dysfunction and neurodegeneration. Antimuscarinic drugs targeting the muscarinic acetylcholine type 1 receptor (M1R) prevent/reverse neurodegeneration by inducing nerve regeneration in rodent models of diabetes and chemotherapy-induced peripheral neuropathy (CIPN). Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) is an upstream regulator of AMPK activity. We hypothesized that antimuscarinic drugs modulate CaMKKβ to enhance activity of AMPK, and PGC-1α, increase mitochondrial function and thus protect from neurodegeneration. We used the specific M1R antagonist muscarinic toxin 7 (MT7) to manipulate muscarinic signaling in the dorsal root ganglia (DRG) neurons of normal rats or rats with streptozotocin-induced diabetes. DRG neurons treated with MT7 (100 nM) or a selective muscarinic antagonist, pirenzepine (1 μM), for 24 h showed increased neurite outgrowth that was blocked by the CaMKK inhibitor STO-609 (1 μM) or short hairpin RNA to CaMKKβ. MT7 enhanced AMPK phosphorylation which was blocked by STO-609 (1 μM). PGC-1α reporter activity was augmented up to 2-fold (p p p 1R-modulated, CaMKKβ-dependent pathway in neurons that represents a therapeutic target to enhance nerve repair in two of the most common forms of peripheral neuropathy.

Objective To evaluate the effects of solifenacin, darifenacin, and propiverine on nasal-, subfoveal-, temporal choroidal thicknesses (NCT, SFCT, TCT), intraocular pressure (IOP) and pupil diameter (PD). Materials and Methods Patients with overactive bladder (OAB) diagnosed according to The International Continence Society were administered with solifenacin, darifenacin or propiverine on a daily basis between November 2017 and May 2018. NCT, SFCT, TCT, IOP, and PD of these patients were measured and compared as initial, fourth and twelfth weeks. Results A total of 165 patients (330 eyes) with OAB were evaluated. Solifenacin (n=140) significantly reduced IOP from 17.30±2.72 mmHg to 16.67±2.56 mmHg (p=0.006) and 16.57±2.41 mmHg (p=0.002), at the fourth and twelfth weeks, respectively. Darifenacin (n=110) significantly reduced NCT from 258.70±23.96 μm to 257.51±22.66 μm (p=0.002) and 255.36±19.69 μm (p=0.038), at the fourth and twelfth weeks, respectively. Propiverine (n=80) significantly increased PD from 4.04±0.48 mm to 4.08±0.44 mm (p=0.009) and 4.09±0.45 mm (p=0.001), at the fourth and twelfth weeks, respectively. Conclusion These findings can help to decide appropriate anticholinergic drug choice in OAB patients. We finally suggest further well-designed randomized prospective studies with a larger population to evaluate the anticholinergic-related complications in eyes.

BACKGROUND: Selective antimuscarinics may offer a favorable safety profile over non-selective antimuscarinics for the management of overactive bladder (OAB) in patients with dementia. OBJECTIVE: To test the hypothesis that non-selective antimuscarinics are associated with increased risk of mortality compared to selective antimuscarinics in older adults with dementia and OAB. DESIGN: Propensity score-matched retrospective new-user cohort design among Medicare beneficiaries in community settings. PATIENTS: Older adults with dementia and OAB with incident antimuscarinic use. MAIN MEASURES: The primary exposure was antimuscarinic medications classified as non-selective (oxybutynin, tolterodine, trospium, fesoterodine) and selective (solifenacin, darifenacin) agents. All-cause mortality within 180 days of incident antimuscarinic use formed the outcome measure. New users of non-selective and selective antimuscarinics were matched on propensity scores using the Greedy 5 → 1 matching technique. Cox proportional-hazards model stratified on matched pairs was used to evaluate the risk of mortality associated with the use of non-selective versus selective antimuscarinics in the sample. KEY RESULTS: The study identified 16,955 (77.6%) non-selective antimuscarinic users and 4893 (22.4%) selective antimuscarinic users. Propensity score matching yielded 4862 patients in each group. The unadjusted mortality rate at 180 days was 2.6% (126) for non-selective and 1.6% (78) for selective antimuscarinic users in the matched cohort (p value