Search

Introduction: Long-acting muscarinic antagonists (LAMAs), long-acting β2-agonists (LABAs), inhaled corticosteroids (ICS), and their combinations, are recommended for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to determine whether the safety and efficacy of aclidinium bromide differs by baseline maintenance LABA and ICS therapies. Methods: ASCENT-COPD was a phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium 400 μg or placebo twice daily, via a multidose dry-powder inhaler for up to 3 years. Outcomes included time to first major adverse cardiovascular events (MACE), all-cause mortality, change from baseline in trough forced expiratory volume in 1 s (FEV1), and COPD assessment test (CAT) total score over 3 years, and annual moderate-to-severe COPD exacerbation rate in patients receiving aclidinium or placebo with maintenance LABA monotherapy, ICS monotherapy, LABA + ICS (fixed/free), or no maintenance therapy (neither LABA nor ICS) at baseline. Results: A total of 3589 patients were included (LABA, n = 227; ICS, n = 290; LABA + ICS, n = 2058; no maintenance, n = 1130). Aclidinium did not increase the risk of MACE or all-cause mortality versus placebo, regardless of baseline maintenance treatment. Reductions in moderate-to-severe exacerbation rates were observed with aclidinium versus placebo in all subgroups [LABA 43% (P = 0.046); ICS 25% (P = 0.202); LABA + ICS 22% (P = 0.003); no maintenance 18% (P = 0.130)]. Aclidinium improved morning trough FEV1 irrespective of baseline therapy and CAT total scores, except for LABA and ICS subgroups, versus placebo at several time points. Conclusion: In patients with moderate-to-severe COPD and CV risk factors, the addition of aclidinium to maintenance therapy with LABA or LABA + ICS provided further benefit. Trial Registration: ClinicalTrials.gov identifier NCT01966107. [ABSTRACT FROM AUTHOR]

Abstract Background DA-8010 is a novel compound developed for the treatment of overactive bladder (OAB) and urinary incontinence. The aims of this study were to investigate the effects of DA-8010 on OAB in a rat model. Methods Study animals were divided into the following five groups of seven animals each: a sham-operated control group, a control group with partial bladder outlet obstruction (BOO) (OAB group), and three DA-8010 (doses of 0.3 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day, respectively) with partial BOO groups. Oral administration of the drugs was continued for 14 days after 2 weeks of partial BOO. After 4 weeks of partial BOO, cystometrography was performed in all groups. Additionally, pro-inflammatory cytokines, Rho-kinases, and histology of the bladder were analyzed. Results There was a significant increase in the contraction interval and a decrease in contraction pressure in the 3 mg/kg/day DA-8010 group versus those in the OAB group. Rho kinase was also significantly decreased in the DA-8010 3 mg/kg/day dosage treatment group. The increased ratio of collagen to smooth muscle after partial BOO was significantly attenuated in the DA-8010 3 mg/kg/day dosage group. Conclusions Oral administration of DA-8010 at 3 mg/kg/day improved findings in an OAB rat model induced by partial BOO. Our results suggest that the novel muscarinic receptor antagonist DA-8010 may be a promising drug for treating patients with OAB.

Background Catheter-related bladder discomfort (CRBD) is a frequent complaint after awakening from anesthesia in patients receiving perioperative bladder catheterization. Overactive bladder (OAB) and CRBD show similar symptoms; thus, drugs used for the management of OAB influence symptoms of CRBD. Trospium chloride has been found effective in managing resistant cases of OAB. We evaluated the efficacy of oral trospium on CRBD in the postoperative period. Methods Sixty-four male and female adult patients, with planned spinal surgery and requiring urinary bladder catheterization, were randomly divided into two groups of 32 each. Group T patients received 60 mg extended-release oral trospium (extended-release) 1 h before induction of anesthesia and Group C patients received a similar-looking placebo. The anesthetic technique was identical in both groups. The CRBD score was evaluated in the postoperative ward using a 4-point scale (1 = no discomfort, 2 = mild, 3 = moderate, 4 = severe). Readings were recorded on arrival (0 h), and 1 h, 2 h, and 6 h postoperatively. All patients received fentanyl for postoperative pain relief. Results The incidence of CRBD was significantly higher in Group C than in Group T at 0 h (66% vs. 22%, P = 0.001) and 1 h postoperatively (72% vs. 28%, P = 0.001). The incidence of moderate to severe CRBD was higher in Group C at postoperative 2 h (82% vs. 14%, P = 0.004). There was no significant difference in postoperative fentanyl requirements. Conclusions Pretreatment with 60 mg extended release trospium reduced the incidence and severity of CRBD in the early postoperative period.

Purpose: We studied the effect of solifenacin on reducing storage symptoms after photoselective vaporization of the prostate (PVP). Materials and Methods: This study included patients with persistent storage symptoms of urgency and frequency in a 3-day voiding diary, International Prostate Symptom Score (IPSS) storage subscore (IPSS-s) ≥5, overactive bladder symptom score (OABSS) ≥5, and OABSS for question 3 ≥4 at 5 days after urethral catheter removal. The patients were randomly assigned to receive once-daily solifenacin 5 mg or placebo for 4 weeks. Evaluation of the 3-day voiding diary, IPSS, and OABSS was performed at 2 and 4 weeks after treatment. Results: At 2 and 4 weeks after treatment, the urgency and frequency in the 3-day voiding diary, IPSS, IPSS-s, and OABSS were decreased in the solifenacin group. Although the OABSS of the solifenacin group was not significantly different from that of the placebo group, the OABSS of the placebo group increased at 4 weeks compared with that at 2 weeks after treatment. The Benefit, Satisfaction, and Willingness to continue questionnaire showed no significant difference in patient satisfaction between the groups. Although the solifenacin group showed increased post-void residual volume compared with the placebo group, there was no statistically significant difference. Conclusions: Storage symptoms measured using OABSS tended to decrease after medication with solifenacin in the early period after PVP. Therefore, we suggest that anticholinergics have a potential role in improving storage symptoms after PVP.

Chronic obstructive pulmonary disease (COPD) is being increasingly diagnosed in the UKs on the rise, and is expected to continue to rise due to an ageing population with multiple co-morbidities and exposure to risk factors, such as cigarette smoke, noxious gases and air pollutants. The prevalence of this disease is high is areas of socioeconomic deprivation and among high industrial areas. The use of self-management plans in COPD is recommended by the National Institute for Health and Care Excellence (NICE), to enable to patients with this disease to be competent and confident in taking part in managing their own health condition and recognising signs and symptoms of an exacerbation. The aim of this article is to discuss self-management of COPD and the clinical guidance surrounding exacerbation of disease. A follow-up literature review will focus on the effectiveness of self-management plans in COPD. [ABSTRACT FROM AUTHOR]

Purpose: SNRIs (serotonin and norepinephrine reuptake inhibitors) like duloxetine are known to have role in the treatment of anxiety disorder and stress urinary incontinence. According to the correlation of anxiety disorder and overactive bladder, this study aimed to evaluate the clinical efficacy and complications of duloxetine (SNRI) as a medication in the treatment of overactive bladder in the female patients. We were interested to know the probable therapeutic effect and side effects of duloxetine in overactive bladder.Methods and Materials: In this single-blinded interventional randomized clinical trial, 60 female patients with idiopathic overactive bladder (hyperreflexia) referred to the urology clinic, were divided into two groups as pilots. The first group were treated by 10mg/daily solifenacin and the second group received 20mg/daily duloxetine. The patients were evaluated by the ICIQ-OAB Questionnaire before and after one-month follow-up period. The intervention primary outcomes were evaluated by the patient's presentation of the frequency, nocturia, urgency, urge urinary incontinence and the drugs side effects as secondary outcomes were checked.   Results: Sixty women with confirmed overactive bladder disease were evaluated. Solifenacin and duloxetine had the same effect on the treatment of overactive bladder (p value=0.148). The clinical symptoms were obviously relieved in both groups after treatment. Side effects were insignificantly more common in the solifenacin group (p value>0.05). However, the different frequency of blurred vision in the two groups was statistically significant (p value=0.04). The most common complication in solifenacin and duloxetine group was anxiety.Conclusion: The results showed that solifenacin and duloxetine improved overactive bladder symptoms. According to this evaluation, duloxetine can be a suitable alternative option for overactive bladder treatment, due to the acceptable therapeutic effect and side effects. [ABSTRACT FROM AUTHOR]

Background: Tiotropium bromide, a long‐acting muscarinic antagonist, reduces the frequency of exacerbation in patients with moderate to severe asthma, but its underlying mechanism is not clear. Asthma exacerbations are associated with exposure to external stimuli, and group 2 innate lymphoid cells (ILC2s) are considered to be involved in the pathophysiology of asthma exacerbation. We investigated whether tiotropium modulates airway inflammation through ILC2 functions. Methods: Mice were administered papain intranasally to induce innate‐type airway inflammation with or without tiotropium pretreatment, and bronchoalveolar lavage fluids (BALF) and lung tissues were collected. Lung‐derived ILC2s and bone marrow‐derived basophils were stimulated in vitro with IL‐33 in the presence or absence of tiotropium. Muscarinic M3 receptor (M3R) expression on immune cells was assessed by RNA sequence. Results: Papain induced airway eosinophilic inflammation, and tiotropium reduced the numbers of eosinophils in BALF. The concentrations of IL‐4, IL‐5, and IL‐13, and the numbers of ILC2s in BALF were also reduced by tiotropium treatment. However, tiotropium did not affect IL‐33‐induced IL‐5 and IL‐13 production from ILC2s, suggesting that tiotropium regulates ILC2s indirectly. Gene‐expression analysis showed that basophils predominantly expressed M3R mRNA among murine immune cells. Tiotropium reduced IL‐4 production from basophils derived from mouse bone marrow and human basophils after stimulation with IL‐33. Conclusions: These findings suggest that tiotropium attenuates ILC2‐dependent airway inflammation by suppressing IL‐4 production from basophils and, subsequently, regulating ILC2 activation. The inhibitory effects of long‐acting muscarinic antagonists on the innate response may contribute to reducing asthma exacerbation. [ABSTRACT FROM AUTHOR]

Introduction: 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Reports recommends that patients with clinically significant symptoms and exacerbations of chronic obstructive pulmonary disease (COPD) should escalate to triple therapy, a combined use of inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA) and long-acting b2-agonists (LABA)(ICS/LAMA/LABA). Triple therapy in fixed-dose combinations (FDCs), i.e., combining ICS, LABA with LAMA and administrating by a single inhalation device, has appeared in recent years. This study aims to compare the efficacy of triple therapy in FDCs in treating patients with moderate to severe COPD. Methods and analyses: Literature search will be conducted on PubMed, Embase and Web of science, according to pre-specified and corresponding search strategies, for relevant reports published since the inception dates of the databases. Randomised controlled trials (RCT) which compared the triple therapy in FDCs with other pharmacological therapies will be included. The Cochrane risk of bias assessment tool (RoB 2) will be used to assess the RCT quality. The outcomes will be analyzed as rate ratios and mean differences under a random-effects model in a frequentist network meta-analysis (NMA). Additional statistical analyses including subgroup analysis, sensitivity analysis, and publication bias analysis will be performed to assess the evidential heterogeneity and robustness. The strength of evidence from the NMA will be evaluated with the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) methods. Ethics and dissemination: No ethics approval is required as this systematic review and network meta-analysis do not collect confidential personal data and do not carry out interventions in treating patients. Protocol registration number: CRD42021240823. [ABSTRACT FROM AUTHOR]

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%, p = 0.01) and at the 4th hour of infusion (22% vs 100%, p < 0.001) compared to patients who received lorazepam. There was a significant decrease in agitation scores in the physostigmine arm compared to the lorazepam arm after the initial bolus (89% vs 30%, p = 0.02), but no difference at the 4th hour of infusion (p > 0.99). There were no seizures, bradycardia, bronchorrhea, bronchospasm, intubation, or cardiac dysrhythmias. 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 [ABSTRACT FROM AUTHOR]

Nocturia is a complex symptom that is attributed to a wide range of causes, including advanced age, comorbidities and medications. Non-pharmacological treatments are first-line options in the management of nocturia in frail, elderly patients due to their safety in this vulnerable population. If pharmacotherapy is required, the benefits must be carefully weighed against the potential for adverse effects. Desmopressin, α-antagonists, antimuscarinic drugs and β3‑adrenergic agonists have been identified as potential pharmacological options, though the evidence for their use in frail, elderly patients is limited. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and safety of mirabegron in children and adolescents (aged 3 to <18 years) with neurogenic detrusor overactivity (NDO) using clean intermittent catheterization. Methods: In this open‐label, multicenter, baseline‐controlled, Phase III study (NCT02751931), participants received once‐daily mirabegron at an adult dose equivalent of 25 mg. Dose was increased to 50 mg equivalent unless there were safety/tolerability concerns. The primary efficacy endpoint was change from baseline to Week 24 in maximum cystometric capacity (MCC). Secondary urodynamic assessments, Pediatric Incontinence Questionnaire (PIN‐Q), Patient Global Impression of Severity (PGI‐S), Clinician Global Impression of Change (CGI‐C), and Acceptability questionnaires were included. Results: Overall, 86 participants (55 aged 3 to <12 years, 31 aged 12 to <18 years) received treatment; 68 were included in efficacy assessments. A statistically significant increase in MCC from baseline to Week 24 was observed (87.20 ml, 95% confidence interval: 66.07, 108.33; p <.001); this increase was apparent from Week 4. Significant increases in bladder compliance, bladder volume until first detrusor contraction, average volume per catheterization, maximum daytime catheterized volume and number of dry days per week. Significant decreases in detrusor pressure and number of leakage episodes per day were also observed. Significant improvement in PGI‐S but not PIN‐Q was observed. Most participants reported their condition had either much or very much improved using the CGI‐C. Mirabegron was well tolerated in this population with a profile aligned with that in adults. Conclusions: Mirabegron was effective and well‐tolerated in the treatment of pediatric patients with NDO. [ABSTRACT FROM AUTHOR]

• Anticholinergics are effective to manage PD, but their side effects limit their utility. • Targeting SCIN has antiparkinsonian and antidyskinetic effects, avoiding side effects. • SCIN burst-pause firing can reveal the mechanisms of anticholinergics in PD and LID. • Restoring normal SCIN activity might maximize the therapeutic effects. • Dopamine D5 receptors in SCIN emerge as a promising target to restore SCIN activity. Before the advent of L-DOPA, the gold standard symptomatic therapy for Parkinson's disease (PD), anticholinergic drugs (muscarinic receptor antagonists) were the preferred antiparkinsonian therapy, but their unwanted side effects associated with impaired extrastriatal cholinergic function limited their clinical utility. Since most patients treated with L-DOPA also develop unwanted side effects such as L-DOPA-induced dyskinesia (LID), better therapies are needed. Recent studies in animal models demonstrate that optogenetic and chemogenetic manipulation of striatal cholinergic interneurons (SCIN), the main source of striatal acetylcholine, modulate parkinsonism and LID, suggesting that restoring SCIN function might serve as a therapeutic option that avoids extrastriatal anticholinergics' side effects. However, it is still unclear how the altered SCIN activity in PD and LID affects the striatal circuit, whereas the mechanisms of action of anticholinergic drugs are still not fully understood. Recent animal model studies showing that SCINs undergo profound changes in their tonic discharge pattern after chronic L-DOPA administration call for a reexamination of classical views of how SCINs contribute to PD symptoms and LID. Here, we review the recent advances on the circuit implications of aberrant striatal cholinergic signaling in PD and LID in an effort to provide a comprehensive framework to understand the effects of anticholinergic drugs and with the aim of shedding light into future perspectives of cholinergic circuit-based therapies. [ABSTRACT FROM AUTHOR]

Background: Compared to proton pump inhibitors, vonoprazan exerts a greater inhibitory effect on gastric acid secretion and is useful for treating acid-related diseases, such as gastro-esophageal reflux disease. However, there is a problem that vonoprazan causes hypergastrinemia, which confers a risk of carcinoid tumor. A previous report demonstrated that pirenzepine, an M1 muscarinic receptor antagonist, enhances the acid inhibitory effects while suppressing hypergastrinemia induced by omeprazole. Here, we examined whether pirenzepine enhances the gastric acid inhibitory effects of vonoprazan without further increasing serum gastrin levels. Methods: Eleven healthy volunteers were subjected to 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: pirenzepine 75 mg alone, vonoprazan 10 mg alone, and vonoprazan 10 mg plus pirenzepine 75 mg administered in a randomized crossover fashion. Results: Median pH 4 holding time ratios (range) achieved with pirenzepine 75 mg, vonoprazan 10 mg, and vonoprazan 10 mg plus pirenzepine 75 mg were 6.9% (2.4–32.8%), 88.4% (54.6–100%), and 84.2% (40.3–100%), respectively. Respective serum gastrin levels were 79 (75–210) pg/ml, 310 (110–870) pg/ml, and 170 (140–930) pg/ml. In cases with hypergastrinemia (gastrin ≥ 200 pg/ml) induced by vonoprazan 10 mg alone, concomitant treatment with pirenzepine significantly reduced serum gastrin levels from 370 to 180 pg/ml (P = 0.028). Conclusion: Although pirenzepine does not enhance acid inhibition, it does improve hypergastrinemia induced by vonoprazan to some extent. [ABSTRACT FROM AUTHOR]

Involvement of small airways, those of <2 mm in internal diameter, is present in all stages of asthma and contributes substantially to its pathophysiologic expression. Therefore, small airways are a potential target to achieve optimal asthma control. Airway tone, which is increased in asthma, is mainly controlled by the vagus nerve that releases acetylcholine (ACh) and activates muscarinic ACh receptors (mAChRs) post‐synaptically on airway smooth muscle (ASM). In small airways, M3 mAChRs are expressed, but there is no vagal innervation. Non‐neuronal ACh released from the epithelial cells that may express choline acetyltransferase in response to inflammatory stimuli, as well as from other structural cells in the airways, including fibroblasts and mast cells, can activate mAChRs. By antagonizing M3 mAChR, the contraction of the ASM is prevented and, potentially, local inflammation can be reduced and the progression of remodeling may be averted. In fact, ACh also contributes to inflammation and remodeling of the airways and regulates the growth of ASM. Several experimental studies have demonstrated the potential benefit derived from the use of mAChR antagonists, mainly long‐acting mAChR antagonists (LAMAs), on small airways in asthma. However, there are several confounding factors that may cause a wrong estimation of the relationship between LAMAs and small airways in asthma. Further studies are needed to differentiate broncholytic and anti‐inflammatory effects of LAMAs and to better understand the interaction between LAMAs and corticosteroids, also in the context of a triple therapy that includes a β2‐AR agonist, at different levels of the bronchial tree. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Acetylcholinesterase inhibitors (AChEIs) have been associated with an increased risk of starting antimuscarinic treatment to treat overactive bladder (OAB)—an example of a prescribing cascade. Limited comparative data exist regarding the prescribing cascade of antimuscarinics across individual AChEIs in older adults with dementia. Objective: This study examined the association between individual AChEI use and antimuscarinic cascade in older adults with dementia. Methods: We conducted a new user retrospective cohort study from January 2005 to December 2018 using data from the TriNetX electronic medical record database, a federated electronic medical records network in the US. The cohort included patients 65 years or older with a diagnosis of dementia using AChEIs (donepezil, galantamine, or rivastigmine). Individual AChEIs were identified with index dates from 1 January 2006 to 31 June 2018, with a 1-year washout period. The study excluded patients with any antimuscarinic use and OAB diagnosis 1 year before the AChEI index date. The primary outcome of interest was the prescription of antimuscarinics within 6 months of the AChEI index date. A Cox proportional hazard model was used to assess the association between individual incident AChEI use and antimuscarinic prescribing cascade after controlling for several covariates. Results: The study included 47,059 older adults with dementia who were incident users of AChEIs. Most of these patients were initiated with donepezil (83.1%), followed by rivastigmine (12.3%) and galantamine (4.6%). Overall, 8.16% of the study cohort had incident OAB diagnosis or antimuscarinic prescription. Antimuscarinics were initiated by 1725 (3.7%) older adults with dementia within 6 months of AChEI prescription, and cascade varied widely across individual agents—donepezil (3.9%), rivastigmine (2.6%), and galantamine (2.9%). Cox proportional hazard analyses revealed that donepezil users had an increased risk of receiving antimuscarinics (adjusted hazard ratio 1.55, 95% confidence interval 1.31–1.83) compared with rivastigmine. The findings were consistent in sensitivity analyses. Conclusion: This study found that donepezil use is more likely to lead to antimuscarinic cascade than rivastigmine. Future studies are needed to determine the potential consequences of this cascade in dementia. [ABSTRACT FROM AUTHOR]

Purpose This article reviews the efficacy and safety of revefenacin, the first once-daily, long-acting muscarinic antagonist, when delivered via a standard jet nebulizer in patients with chronic obstructive pulmonary disease (COPD). Summary Revefenacin 175 µg is indicated for the maintenance treatment of patients with moderate to very severe COPD. Preclinical studies showed that revefenacin is a potent and selective antagonist with similar affinity for the different subtypes of muscarinic receptors (M1-M5). Furthermore, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose dependent and lasted longer than 24 hours, demonstrating a long duration of action. In phase 2 and 3 trials, treatment with revefenacin was demonstrated to result in statistical improvements in pulmonary function (≥100 mL, P < 0.05) vs placebo, including among patients with markers of more severe disease and those who received concomitant long-acting β-agonists or long-acting β-agonists together with inhaled corticosteroids. Revefenacin was also demonstrated to have efficacy similar to that of tiotropium. The clinical trial findings indicated no significant difference between revefenacin and tiotropium with regard to rates of adverse events. Overall, revefenacin was well tolerated, with COPD worsening/exacerbation, dyspnea, headache, and cough among the most common adverse events noted in the clinical trials. Conclusions Revefenacin treatment delivered via nebulization led to improvements in lung function in patients with COPD. It was also generally well tolerated, with no major safety concerns. Revefenacin provides a viable treatment option for patients with COPD and may be a suitable alternative for those with conditions that may impair proper use of traditional handheld inhalers. [ABSTRACT FROM AUTHOR]

Background and Aim: Xerostomia, is a chronic and common symptom of dry mouth that many patients report when the their doctor or dentist or oral hygienist. As far as Corona virus spreading widely, it is khown as one of the latest etiology complication. Salivary reduction causes serious damages to the oral and pharyngeal mucosa due to dryness, Same as ora pharyngeal mucosa discontinuity. The aim of this study was to evaluate dry mouth and its necessary treatment considera related articles in patients with Covid19, as important and know complicate. Material and Methods: by searching the keywords, COVID-19; Therapeutics; Xerostomia; Salivary glands in data base as pubmed; Google scholar; scopus; SID; net, 40 articles that published between the years 2016-2020, which are conform our inclusive and exclusive factors,were selected. Results: Secondary to taste dysfunction (59.5%), Xerostomia (45.9%) is the most prevalent condition related to corona i 74.5% of corona infected who experience Xerostomia, announced that they have had the signs of Xerostomia before cov diagnosis. Some medications used in the treatment of Covid-19, such as antiviral drugs (Remdesivir and Ritonavir) and antimuscarinic drugs, also causes dry mouth. There is a wide range and different efficiencies of dry mouth treatments. Th emerged therapies have also been effective in treating dry mouth and have shown promising results. Conclusion: The corona virus can affected salivary glands function, directly and indirectly. It cause changes in amount a quality of saliva, the important and significant result of which is dry mouth. It could be secondary to the destructive activ the virus, or secondary to the use of therapeutic drugs. Due to the widespread effects of dry mouth on patients' quality of important to consider concomitant treatment of dry mouth in patients who affected by covid-19 currently or in past. [ABSTRACT FROM AUTHOR]

Introduction Anticholinergic medications block cholinergic transmission. The central effects of anticholinergic drugs can be particularly marked in patients with dementia. Furthermore, anticholinergics antagonise the effects of cholinesterase inhibitors, the main dementia treatment. Objectives This study aimed to assess anticholinergic drug prescribing among dementia patients before and after admission to UK acute hospitals. Methods 352 patients with dementia were included from 17 hospitals in the UK. All were admitted to surgical, medical or Care of the Elderly wards in 2019. Information about patients’ prescriptions were recorded on a standardised form. An evidence-based online calculator was used to calculate the anticholinergic drug burden of each patient. The correlation between two subgroups upon admission and discharge was tested with Spearman’s Rank Correlation. Results Table 1 shows patient demographics. On admission, 37.8% of patients had an anticholinergic burden score ≥1 and 5.68% ≥3. At discharge, 43.2% of patients had an anticholinergic burden score ≥1 and 9.1% ≥3. The increase was statistically significant (rho 0.688; p=2.2x10-16). The most common group of anticholinergic medications prescribed at discharge were psychotropics (see Figure 1). Among patients prescribed cholinesterase inhibitors, 44.9% were also taking anticholinergic medications. Conclusions This multicentre cross-sectional study found that people with dementia are frequently prescribed anticholinergic drugs, even if also taking cholinesterase inhibitors, and are significantly more likely to be discharged with a higher anticholinergic drug burden than on admission to hospital. Conflict of interest This project was planned and executed by the authors on behalf of SPARC (Student Psychiatry Audit and Research Collaborative). We thank the National Student Association of Medical Research for allowing us use of the Enketo platform. Judith Harrison was su

Importance: The benefits and harms of adding long-acting muscarinic antagonists (LAMAs) to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) for moderate to severe asthma remain unclear.Objective: To systematically synthesize the outcomes and adverse events associated with triple therapy (ICS, LABA, and LAMA) vs dual therapy (ICS plus LABA) in children and adults with persistent uncontrolled asthma.Data Sources: MEDLINE, Embase, CENTRAL, ICTRP, FDA, and EMA databases from November 2017, to December 8, 2020, without language restriction.Study Selection: Two investigators independently selected randomized clinical trials (RCTs) comparing triple vs dual therapy in patients with moderate to severe asthma.Data Extraction and Synthesis: Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses, including individual patient-level exacerbation data, were used. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach was used to assess certainty (quality) of the evidence.Main Outcomes and Measures: Severe exacerbations, asthma control (measured using the Asthma Control Questionnaire [ACQ-7], a 7-item list with each item ranging from 0 [totally controlled] to 6 [severely uncontrolled]; minimal important difference, 0.5), quality of life (measured using the Asthma-related Quality of Life [AQLQ] tool; score range, 1 [severely impaired] to 7 [no impairment]; minimal important difference, 0.5), mortality, and adverse events.Results: Twenty RCTs using 3 LAMA types that enrolled 11 894 children and adults (mean age, 52 years [range, 9-71 years]; 57.7% female) were included. High-certainty evidence showed that triple therapy vs dual therapy was significantly associated with a reduction in severe exacerbation risk (9 trials [9932 patients]; 22.7% vs 27.4%; risk ratio, 0.83 [95% CI, 0.77 to 0.90]) and an improvement in asthma control (14 trials [11 230 patients]; standardized mean difference [SMD], -0.06 [95% CI, -0.10 to -0.02]; mean difference in ACQ-7 scale, -0.04 [95% CI, -0.07 to -0.01]). There were no significant differences in asthma-related quality of life (7 trials [5247 patients]; SMD, 0.05 [95% CI, -0.03 to 0.13]; mean difference in AQLQ score, 0.05 [95% CI, -0.03 to 0.13]; moderate-certainty evidence) or mortality (17 trials [11 595 patients]; 0.12% vs 0.12%; risk ratio, 0.96 [95% CI, 0.33 to 2.75]; high-certainty evidence) between dual and triple therapy. Triple therapy was significantly associated with increased dry mouth and dysphonia (10 trials [7395 patients]; 3.0% vs 1.8%; risk ratio, 1.65 [95% CI, 1.14 to 2.38]; high-certainty evidence), but treatment-related and serious adverse events were not significantly different between groups (moderate-certainty evidence).Conclusions and Relevance: Among children (aged 6 to 18 years) and adults with moderate to severe asthma, triple therapy, compared with dual therapy, was significantly associated with fewer severe asthma exacerbations and modest improvements in asthma control without significant differences in quality of life or mortality. [ABSTRACT FROM AUTHOR]

Purpose: To analyze effect of pharmacist-conducted medication reconciliation on 30-day readmission rates in chronic obstructive pulmonary disease (COPD) and identify common medication errors among patient with readmissions. Methods: Pharmacists were educated on discharge medication reconciliation for patients with COPD. A retrospective chart review was conducted on patients who underwent pharmacist-conducted discharge medication reconciliation to determine 30-day readmissions. Medication errors analyzed included medication omissions and dose or frequency errors. Previously collected internal research without pharmacist-conducted medication reconciliation served as the control. Results: There were 65 patients in the control group and 50 in the intervention group. About 25% of patients in the control group and 26% of patients in the intervention group had any cause readmissions within 30 days of discharge (P =.87). Both the control and the intervention group had similar COPD-related readmissions of 12.3% and 12.6%, respectively. Medication dose or frequency errors consisted of 68.9% and 46.7% of total errors in the control and the intervention groups, respectively. Long-acting muscarinic antagonist (LAMA) or long-acting beta 2-agonist (LABA) were the most common drug classes to be incorrectly dosed or omitted at discharge. In the intervention group, 30 errors were identified. Due to inability to coordinate discharges, pharmacists intervened on 13 errors, 7 of which were accepted by the prescriber. Conclusion: Pharmacist-conducted medication reconciliation at discharge did not affect 30-day readmission rates of patients with COPD. Confounding factors included a small sample size, passive pharmacist education, and discharge issues. The most common medication errors at discharge were dosing or frequency errors of LABAs or LAMAs. [ABSTRACT FROM AUTHOR]

Tiotropium bromide is a long-acting muscarinic antagonist (LAMA) and is the only LAMA licensed for management for patients' ≥6 years old with severe asthma who have experienced one or more severe asthma exacerbations in the preceding year. Recent clinical trials have demonstrated that once-daily tiotropium is safe and efficacious in 6-17 year-olds with symptomatic asthma despite treatment with inhaled corticosteroids (ICSs), with or without additional controllers. In this paper, we review the evidence of the safety and efficacy of tiotropium add-on maintenance treatment in children and adolescents with symptomatic moderate and severe asthma. [ABSTRACT FROM AUTHOR]

In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 μg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies. [ABSTRACT FROM AUTHOR]

Aqueous extract of Moringa oleifera leaves (MOE) is a potent inducer of endothelium-dependent relaxation of mesenteric resistance arteries of rats induced to be hypertensive using Nω-nitro-L-arginine methyl ester (L-NAME). Hydrogen sulfide (H2S) has been shown to participate in endothelium-dependent relaxation of small resistance arteries. Therefore, this study aimed to investigate whether endothelial H2S-dependent signaling plays a role in the vasorelaxation in response to MOE. Mesenteric arterial beds isolated from L-NAME hypertensive rats were set up in an ex vivo perfusion system for measurement of vasoreactivity. All experiments were performed in the presence of the nitric oxide synthase inhibitor, L-NAME (100 µM) and the cyclooxygenase inhibitor, indomethacin (10 µM) to prevent the formation of nitric oxide and prostanoids, respectively. In the presence of the nitric oxide synthase inhibitor, L-NAME and the cyclooxygenase inhibitor, indomethacin, the endothelium-dependent vasorelaxation induced by MOE (0.001–3 mg) was completely inhibited by DL-propargylglycine (100 µM), which inhibits the H2Sgenerating enzyme, cystathionine γ-lyase. This H2Sdependent response was reduced by the KATP channel blocker; glibenclamide (10 µM), the KCa channel blocker; tetraethylammonium (1 µM), and the myo-endothelial gap-junctional uncoupler; 18α-glycyrrhetinic acid (10 µM). In contrast, the muscarinic receptor antagonist, atropine (100 µM), did not affect the response to MOE. The results may suggest that H2S is the likely mediator of endothelium-dependent relaxation in response to MOE in mesenteric arterial beds of L-NAME-induced hypertensive rats. MOE-induced H2S-dependent vasorelaxation involves activation of KATP and KCa channels and requires myo-endothelial gap-junctional communication. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Stand-alone prescription drug plans (S-PDPs) and Medicare Advantage prescription drug (MAPD) plans are incentivized to cover outpatient medications differently. This could affect the coverage of inhalers that prevent costly exacerbations of chronic obstructive pulmonary disease (COPD), with impacts for the Medicare program and its beneficiaries. This study compared the coverage of guideline-recommended COPD inhalers between S-PDPs and MA-PD plans. STUDY DESIGN: A cross-sectional analysis of the formularies for all 689 S-PDPs and 2578 MA-PD plans offered in 2017. METHODS: We assessed each prescription drug plan's coverage of inhalers in 6 therapeutic categories recommended by the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report and compared the use of prior authorization, step therapy, and coinsurance between S-PDPs and MA-PD plans. RESULTS: In 2017, all S-PDPs and MA-PD plans covered at least 1 inhaler from each GOLD therapeutic category, except for long-acting β agonist/long-acting muscarinic antagonist combination inhalers. S-PDPs were more likely to require coinsurance for inhalers across all therapeutic categories, whereas MA-PD plans required prior authorization more frequently for 3 of the 6 therapeutic categories. S-PDPs required coinsurance more frequently than MA-PD plans for inhalers that treat mild (20.8% vs 11.4%; P < .001), moderate (40.0 vs 13.2%; P < .001), and severe (45.4% vs 11.0%; P < .001) disease. CONCLUSIONS: Medicare Part D S-PDPs are more likely than MA-PD plans to require coinsurance for outpatient COPD inhalers, especially for severe disease. This likely reflects their different financial incentives and is an important consideration for providers and policy makers aiming to improve outpatient COPD management. [ABSTRACT FROM AUTHOR]

Summary: Intraoperative bradycardia is not an uncommon complication in anaesthetised horses and it has been recommended that severe bradycardia (defined as heart rate (HR) <25 beats/min) during general anaesthesia, when associated with hypotension (mean arterial pressure (MAP) <70 mmHg) and other signs of inadequate tissue perfusion, should be treated with anticholinergics. Muscarinic antagonists, such as atropine and glycopyrrolate, cause positive chronotropism and dromotropism (improved atrioventricular conduction) by competitively blocking the effects of acetylcholine at muscarinic receptors in the heart. However, in horses, prolonged intestinal hypomotility and colic have been associated with the use of atropine and glycopyrrolate which has led to the investigation of the use of hyoscine N‐butylbromide (hyoscine NBB) to treat alpha 2 agonist‐induced bradycardia in horses. This report describes the successful use of hyoscine NBB to treat symptomatic intraoperative bradycardia in three isoflurane‐anaesthetised horses. [ABSTRACT FROM AUTHOR]

Objective: To compare nerve growth factor (NGF) levels in patients who received antimuscarinic, versus onabotulinum toxin-A (onaBoNT-A) injection, as well as to investigate whether there is a correlation between NGF levels, and 8-item overactive bladder questionnaire(OAB-V8), urogenital distress inventory (UDI)-6, and incontinence impact questionnaire (IIQ)-7 forms. Material and methods: Forty adult patients with OAB were enrolled in this prospective study. An antimuscarinic was prescribed to 20 naive patients, and onaBoNT-A injection was administered to 20 patients, who were refractory to antimuscarinics. Urine samples were obtained before, and after 3rd and 6th months of treatment, and NGF levels were measured. Symptom scores of OAB-V8, UDI-6,and IIQ-7 were recorded. Results: There was no significant difference between groups in terms of the initial OAB-V8, IIQ-7, and UDI-6 scores, whereas NGF values showed no significant difference over time in onaBoNT-A group (p=0.069, p=0.069). NGF levels were significantly lower in 3rd and 6th months, in patients receiving antimuscarinic (p=0.003, p=0.007); a strong correlation was found in 3rd month between the NGF levels, OAB-V8 scores (r=0.704, p=0.001), and IIQ-7 scores (r=0.676, p=0.001), and a moderate correlation between NGF levels, and UDI-6 scores (r=0.583, p=0.007). In the 6th months, a very strong correlation was found between NGF levels, and OAB-V8 scores (r=0.811, p=0.004), and a strong correlation was found between NGF levels, and IIQ-7 scores (r=0.671, p=0.001). In onaBoNT-A group, there was no significant correlation between NGF levels, and other variables. Conclusion: NGF level might be a good marker to evaluate effectiveness of treatment in patients receiving antimuscarinics, owing to correlation of urinary NGF levels with symptom scores. Lack of correlation in patients receiving onaBoNT-A injection could be a result of differences in the mechanism of action. [ABSTRACT FROM AUTHOR]

Background: Overactive bladder (OAB) is a common disease. However, the patients who stop taking medicines after clinical improvement are at risk for symptom recurrence. Objective: To determine the disease recurrence rates and evaluate the potential predictive factors for recurrent OAB symptoms after discontinuation of an antimuscarinic drug. Materials and Methods: The OAB patients who discontinued antimuscarinic drugs after symptom improvement were studied prospectively. The OAB symptoms were evaluated by the International Consultation on Incontinence Questionnaire Overactive Bladder (ICIQ-OAB) questionnaire. The symptom scores were evaluated at the time of recruitment and at 1, 3, 6, and 12 months after drug discontinuation. The curve of time to symptom recurrence was plotted. The factors associated with symptom recurrence were analyzed and compared. Results: Eighty-two patients including 40 (48.78%) males and 42 (51.22%) females, were included in the present study. Forty-one (50.0%) patients experienced recurrent symptoms within 12 months. The median time to symptom recurrence was 3.01 months (interquartile range [IQR] 1.0, 6.0). The mean symptom scores in the recurrent group at 1, 3, and 6 months were significantly higher than those in the non-recurrent group (10.75Â7.39 versus 22.76Â13.10, p<0.001; 10.89Â8.93 versus 16.41Â11.70, p=0.040; and 10.51Â8.03 versus 22.33Â14.59, p=0.001, respectively). The results of the univariate analyses indicated that other factors were not associated with recurrence. Conclusion: Symptom recurrence after antimuscarinic discontinuation is common in OAB patients. The high ICIQ-OAB score might be the predictive factor for recurrence. Most of the cases of symptom recurrence were observed within three months. [ABSTRACT FROM AUTHOR]

Introduction: In patients with chronic obstructive pulmonary disease (COPD), treatment with long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination therapy significantly improves lung function versus LABA/inhaled corticosteroid (ICS). To investigate whether LAMA/LABA could provide better clinical outcomes than LABA/ICS, this non-interventional database study assessed the risk of COPD exacerbations, pneumonia, and escalation to triple therapy in patients with COPD initiating maintenance therapy with tiotropium/olodaterol versus any LABA/ICS combination.Methods: Administrative healthcare claims and laboratory results data from the US HealthCore Integrated Research Databasesm were evaluated for patients with COPD initiating tiotropium/olodaterol versus LABA/ICS treatment (January 2013-March 2019). Patients were aged at least 40 years with a diagnosis of COPD (but not asthma) at cohort entry. A Cox proportional hazard regression model was used (as-treated analysis) to assess risk of COPD exacerbation, community-acquired pneumonia, and escalation to triple therapy, both individually and as a combined risk of any one of these events. Potential imbalance of confounding factors between cohorts was handled using fine stratification, reweighting, and trimming by exposure propensity score (high-dimensional); subgroup analyses were conducted on the basis of blood eosinophil levels and exacerbation history.Results: The total population consisted of 61,985 patients (tiotropium/olodaterol n = 2684; LABA/ICS n = 59,301); after reweighting, the total was 42,953 patients (tiotropium/olodaterol n = 2600; LABA/ICS n = 40,353; mean age 65 years; female 54.5%). Patients treated with tiotropium/olodaterol versus LABA/ICS experienced a reduction in the risk of COPD exacerbations (adjusted hazard ratio 0.76 [95% confidence interval 0.68, 0.85]), pneumonia (0.74 [0.57, 0.97]), escalation to triple therapy (0.22 [0.19, 0.26]), and any one of these events (0.45 [0.41, 0.49]); the combined risk was similar irrespective of baseline eosinophils and exacerbation history.Conclusions: In patients with COPD, tiotropium/olodaterol was associated with a lower risk of COPD exacerbations, pneumonia, and escalation to triple therapy versus LABA/ICS, both individually and in combination; the combined risk was reduced irrespective of baseline eosinophils or exacerbation history.Trial Registration: ClinicalTrials.gov identifier, NCT04138758 (registered 23 October 2019). [ABSTRACT FROM AUTHOR]

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 80mg 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. [ABSTRACT FROM AUTHOR]

This Phase II, randomized, parallel group study was conducted as part of US regulatory requirements to identify the most appropriate dose of the long-acting muscarinic antagonist glycopyrronium bromide (GB) for use in a single-inhaler triple-therapy combination with the inhaled corticosteroid beclomethasone dipropionate plus the long-acting β2-agonist formoterol fumarate. Eligible subjects were adults with COPD and post-bronchodilator forced expiratory volume in 1 s (FEV1) 40–80% predicted. Subjects were randomized to receive inhaled double-blind GB 6.25, 12.5, 25 or 50 µg or placebo, all twice daily (BID), or open-label tiotropium 18 µg once daily for six weeks. The primary objective was to evaluate the efficacy of GB versus placebo in terms of FEV1 area under the curve between 0 and 12 h at Week 6. Of 733 subjects randomized, 682 (93.0%) completed the study. For the primary endpoint, all GB doses were superior to placebo (p < 0.05), with a dose-response up to 25 µg BID, and 25 and 50 µg BID both superior to 6.25 µg BID (p < 0.05). Results for the secondary spirometry endpoints were consistent with the primary endpoint. Overall, the efficacy of GB 25 and 50 µg BID was broadly consistent with that of tiotropium. The incidence of adverse events, both overall and for the most common preferred terms, was low and similar in all treatment groups, including placebo (overall, 22.3–29.3%). Based on the totality of the efficacy and safety data, the optimal GB dose is 25 µg BID. [ABSTRACT FROM AUTHOR]

Reward-seeking actions can be guided by external cues that signal reward availability. For instance, when confronted with a stimulus that signals sugar, rats will prefer an action that produces sugar over a second action that produces grain pellets. Action selection is also sensitive to changes in the incentive value of potential rewards. Thus, rats that have been prefed a large meal of sucrose will prefer a grain-seeking action to a sucrose-seeking action. The current study investigated the dependence of these different aspects of action selection on cholinergic transmission. Hungry rats were given differential training with two unique stimulus-outcome (S1-O1 and S2-O2) and action-outcome (A1-O1 and A2-O2) contingencies during separate training phases. Rats were then given a series of Pavlovian-to-instrumental transfer tests, an assay of cue-triggered responding. Before each test, rats were injected with scopolamine (0, 0.03, or 0.1 mg/kg, intraperitoneally), a muscarinic receptor antagonist, or mecamylamine (0, 0.75, or 2.25 mg/kg, intraperitoneally), a nicotinic receptor antagonist. Although the reward-paired cues were capable of biasing action selection when rats were tested off-drug, both anticholinergic treatments were effective in disrupting this effect. During a subsequent round of outcome devaluation testing-used to assess the sensitivity of action selection to a change in reward value--we found no effect of either scopolamine or mecamylamine. These results reveal that cholinergic signaling at both muscarinic and nicotinic receptors mediates action selection based on Pavlovian reward expectations, but is not critical for flexibly selecting actions using current reward values.

Objective To evaluate the long-term efficacy of mirabegron add-on therapy in patients with spinal cord injury (SCI) based on an urodynamic study. Methods This retrospective study involved a chart audit of individuals with SCI who underwent two consecutive urodynamic studies between April 1, 2015 and April 1, 2018. After adding 50 mg of mirabegron once a day to the pre-existing antimuscarinic therapy for a period of, at least 6 months, the following variables were analyzed: change in cystometric capacity, change in bladder compliance, change in maximal detrusor pressure, change in reflex volume, and presence of significant leakage during filling cystometry. Results A total of 31 participants with a mean age of 41±15 years were included in the analysis. A significant increase in cystometric capacity (mean, 362 to 424 mL; p=0.03), reflex volume (mean, 251 to 329 mL; p=0.02), and bladder compliance (median, 12 to 18 mL/cmH2O; p=0.04) was observed. The presence of leakage during filling cystometry was significantly reduced (29% to 10%; p=0.03). Likewise, a non-significant decrease in the change in maximal detrusor pressure was observed (mean, 31 to 27 cmH2O; p=0.39). Conclusion Adding mirabegron to conventional antimuscarinics further improved urodynamic parameters in patients with chronic SCI, and sustained efficacy was observed in long-term use.

Attentional dysfunction in schizophrenia (SZ) is a core deficit that contributes to multiple cognitive deficits and the resulting functional disability. However, developing procognitive therapeutics for neuropsychiatric disorders have been limited by a 'translational gap'--a lack of cognitive paradigms having cross-species translational validity and relevance. The present study was designed to perform an initial validation of the cross-species homology of the 5-choice Continuous Performance Test (5C-CPT) in healthy nonpsychiatric comparison subjects (NCS), SZ patients and mice under pharmacologic challenge. The 5C-CPT performance in SZ patients (n=20) was compared with age-matched NCS (n=23). The effects of the general muscarinic receptor antagonist scopolamine on mice (n=21) performing the 5C-CPT were also assessed. SZ subjects exhibited significantly impaired attention in the 5C-CPT, driven by reduced target detection over time and nonsignificantly increased impulsive responding. Similarly, scopolamine significantly impaired attention in mice, driven by reduced target detection and nonsignificantly increased impulsive responding. Scopolamine also negatively affected accuracy and speed of responding in mice, although these measures failed to differentiate SZ vs. NCS. Thus, mice treated with scopolamine exhibited similar impairments in vigilance as seen in SZ, although the differences between the behavioral profiles warrant further study. The availability of rodent and human versions of this paradigm provides an opportunity to: (1) investigate the neuroanatomic, neurochemical and genomic architecture of abnormalities in attention observed in clinical populations such as SZ; (2) develop and refine animal models of cognitive impairments; and (3) improve cross-species translational testing for the development of treatments for these impairments.

Lowie Vanfleteren,1–3 Leonardo M Fabbri,1,4 Alberto Papi,4 Stefano Petruzzelli,5 Bartolome Celli6 1COPD Center, Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden; 2CIRO, Horn, the Netherlands; 3Department of Respiratory Medicine, Maastricht University Medical Hospital, Maastricht, the Netherlands; 4Section of Cardiorespiratory and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 5Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy; 6Division of Pulmonary and Critical Care, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Abstract: Recently, two “fixed triple” single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting β2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) have become available for patients with COPD. This review presents the clinical evidence that led to the approval of these triple therapies, discusses the role of ICS in patients with COPD, and presents data on the relative efficacy of “fixed triple” (ICS/LAMA/LABA) therapy vs LAMA, ICS/LABA, and LAMA/LABA combinations, and summarizes studies in which ICS/LABAs were combined with LAMAs to form “open triple” combinations. Of the five main fixed triple studies completed so far, three evaluated the efficacy and safety of an extrafine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium; the other two studies evaluated fluticasone furoate, vilanterol, and umeclidinium. Overall, compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio. Furthermore, triple therapy showed a promising signal in terms of improved survival. The evidence suggests that triple therapy is the most effective treatment in moderate/severe symptomatic patients with COPD at risk of exacerbations, with marginal if any risk of side effects including pneumonia. Ongoing studies are examining the role of triple therapy in less severe symptomatic patients with COPD and asthma–COPD overlap. Keywords: muscarinic antagonists, adrenergic β2 receptor agonists, glucocorticoids, pulmonary disease, chronic obstructive, review, exacerbations, safety

Mohamed Ismail Abdul Aziz,1,* Ling Eng Tan,1,* David Bin-Chia Wu,1 Fiona Pearce,1 Gerald Seng Wee Chua,2 Liang Lin,1 Ping-Tee Tan,1 Kwong Ng1 1Agency for Care Effectiveness, Ministry of Health, Singapore; 2Division of Medicine, Ng Teng Fong General Hospital, Singapore *These authors contributed equally to this work Purpose: To assess the comparative efficacy of short-acting muscarinic antagonists (SAMAs), long-acting muscarinic antagonists (LAMAs), LAMA in combination with long-acting beta-agonists (LABAs; LAMA/LABAs) and inhaled corticosteroids (ICS) in combination with LABA (ICS/LABAs) for the maintenance treatment of COPD.Materials and methods: We systematically reviewed 74 randomized controlled trials (74,832 participants) published up to 15 November 2017, which compared any of the interventions (SAMA [ipratropium], LAMA [aclidinium, glycopyrronium, tiotropium, umeclidinium], LAMA/LABA [aclidinium/formoterol, indacaterol/glycopyrronium, tiotropium/olodaterol, umeclidinium/vilanterol] and ICS/LABA [fluticasone/vilanterol, budesonide/formoterol, salmeterol/fluticasone]) with each other or with placebo. A random-effects network meta-analysis combining direct and indirect evidence was conducted to examine the change from baseline in trough FEV1, transition dyspnea index, St George’s Respiratory Questionnaire and frequency of adverse events at weeks 12 and 24.Results: Inconsistency models were not statistically significant for all outcomes. LAMAs, LAMA/LABAs and ICS/LABAs led to a significantly greater improvement in trough FEV1 compared with placebo and SAMA monotherapy at weeks 12 and 24. All LAMA/LABAs, except aclidinium/formoterol, were statistically significantly better than LAMA monotherapy and ICS/LABAs in improving trough FEV1. Among the LAMAs, umeclidinium showed statistically significant improvement in trough FEV1 at week 12 compared to tiotropium and glycopyrronium, but the results were not clinically significant. LAMA/LABAs had the highest probabilities of being ranked the best agents in FEV1 improvement. Similar trends were observed for the transition dyspnea index and St George’s Respiratory Questionnaire outcomes. There were no significant differences in the incidences of adverse events among all treatment options.Conclusion: LAMA/LABA showed the greatest improvement in trough FEV1 at weeks 12 and 24 compared with the other inhaled drug classes, while SAMA showed the least improvement. There were no significant differences among the LAMAs and LAMA/LABAs within their respective classes. Keywords: anticholinergics, muscarinic antagonists, frequentist meta-analysis, mixed treatment comparison, indirect treatment comparison, chronic obstructive pulmonary disease

• LAMAs, originally developed for COPD, have been shown to be effective in asthma • LAMAs are an effective add-on treatment for asthma uncontrolled by ICS/LABA • The add-on effect to ICS on lung function of LAMA is at least as good as of LABA • LAMAs are now available in single-inhaler ICS/LABA/LAMA triple therapy for asthma Long-acting muscarinic antagonists (LAMAs) have a recognised role in the management of chronic obstructive pulmonary disease. In asthma, muscarinic antagonists (both short- and long-acting) were historically considered less effective than β 2 -agonists; only relatively recently have studies been conducted to evaluate the efficacy of LAMAs, as add-on to either inhaled corticosteroid (ICS) monotherapy or ICS/long-acting β 2 -agonist (LABA) combinations. These studies led to the approval of the first LAMA, tiotropium, as an add-on therapy in patients with poorly controlled asthma. Subsequently, a number of single-inhaler ICS/LABA/LAMA triple therapies have been approved or are in clinical development for the management of asthma. There is now substantial evidence of the efficacy and safety of LAMAs in asthma that is uncontrolled despite treatment with an ICS/LABA combination. This regimen is recommended by GINA as an optimisation step for patients with severe asthma before any biologic or systemic corticosteroid treatment is initiated. This narrative review summarises the potential mechanisms of action of LAMAs in asthma, together with the initial clinical evidence supporting this use. We also discuss the studies that led to the approval of tiotropium for asthma and the data evaluating the efficacy and safety of the various triple therapies, before considering other potential uses for triple therapy. [ABSTRACT FROM AUTHOR]

Background: Patients admitted to the hospital with COPD are commonly managed with inhaled short-acting bronchodilators, sometimes in lieu of the long-acting bronchodilators they take as outpatients. If held on admission, these long-acting inhalers should be re-initiated upon discharge; however, health-care transitions sometimes result in unintentional discontinuation.Research Question: What is the risk of unintentional discontinuation of long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist and inhaled corticosteroid (LABA-ICS) combination medications following hospital discharge in older adults with COPD?Study Design and Methods: A retrospective cohort study was conducted by using health administrative data from 2004 to 2016 from Ontario, Canada. Adults with COPD aged ≥ 66 years who had filled prescriptions for a LAMA or LABA-ICS continuously for ≥ 1 year were included. Log-binomial regression models were used to determine risk of medication discontinuation following hospitalization in each medication cohort.Results: Of the 27,613 hospitalization discharges included in this study, medications were discontinued 1,466 times. Among 78,953 patients with COPD continuously taking a LAMA or LABA-ICS, those hospitalized had a higher risk of having medications being discontinued than those who remained in the community (adjusted risk ratios of 1.50 [95% CI, 1.34-1.67; P < .001] and 1.62 [95% CI, 1.39, 1.90; P < .001] for LAMA and LABA-ICS, respectively). Crude rates of discontinuation for people taking LAMAs were 5.2% in the hospitalization group and 3.3% in the community group; for people taking LABA-ICS, these rates were 5.5% in the hospitalization group and 3.1% in the community group.Interpretation: In an observational study of highly compliant patients with COPD, hospitalization was associated with an increased risk of long-acting inhaler discontinuation. These Results suggest a likely larger discontinuation problem among less adherent patients and should be confirmed and quantified in a prospective cohort of patients with COPD and average compliance. Quality improvement efforts should focus on safe transitions and patient medication reconciliation following discharge. [ABSTRACT FROM AUTHOR]

The association between bladder antimuscarinic use and dementia development is unclear. We used data from the Taiwan National Health Insurance Research Database to determine the association between the exposure dose and duration of bladder antimuscarinics and the subsequent dementia risk. We enrolled participants aged 55 years or more and defined a dementia cohort (International Classification of Diseases, Ninth Revision, Clinical Modification codes 290, 294.1, and 331.0). We used a propensity score matching method, and randomly enrolled two controls without dementia. We evaluated dementia risk with respect to the exposure dose and duration of treatment with seven bladder antimuscarinics (oxybutynin, propiverine, tolterodine, solifenacin, trospium, darifenacin, and fesoterodine) used for at least 1 year before the index date, after adjusting for age, sex, comorbidities, and medications. The dementia risk was 2.46-fold (95% confidence interval: 2.22–2.73) higher in Taiwanese patients who used bladder antimuscarinics for ≥ 1 year than in those who were not exposed to this treatment. The risk proportionally increased with increasing doses of antimuscarinics for less than 4 years. Taiwanese patients aged 55 years or more on bladder antimuscarinics exhibited a higher risk of dementia. Additional studies in other countries are required to determine whether this result is valid worldwide. [ABSTRACT FROM AUTHOR]

Background and Objectives: Revefenacin is a lung-selective, long-acting muscarinic antagonist indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. The objectives of this analysis were to evaluate the pharmacokinetics of revefenacin and its major metabolite (THRX-195518) in patients with chronic obstructive pulmonary disease, and identify significant covariates affecting revefenacin disposition using a population pharmacokinetic approach based on plasma concentration–time data obtained after single- and repeated-dose once-daily administration in three phase II and two phase III studies. Methods: Plasma concentrations of revefenacin and THRX-195518 following once-daily administration via nebulization at a dose levels ranging from 22–700 μg in 935 patients (488 men, 447 women; age 41–88 years) were analyzed using nonlinear mixed-effects modeling. Results: Plasma revefenacin pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. Pharmacokinetic parameters for THRX-195518 were estimated using a sequential approach, where the concentration–time profiles were fit to a combined model. The formation of the metabolite in each subject was estimated to be a fixed fraction of the individually estimated (post-hoc) clearance rate of revefenacin. Four statistically significant covariates were identified: for revefenacin, age on apparent clearance and body weight on apparent intercompartment clearance, for THRX-195518, age on apparent clearance and body weight on the fraction of revefenacin apparent clearance that was metabolized to THRX-195518. Conclusions: None of the identified statistically significant covariates were associated with a clinically meaningful effect on revefenacin or THRX-195518 exposure in patients with chronic obstructive pulmonary disease. Registration: ClinicalTrials.gov identifier number NCT03064113, NCT01704404, NCT02040792, NCT02459080, and NCT02512510 [ABSTRACT FROM AUTHOR]

Rationale: In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses.Objectives: To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.Methods: Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 μg of BGF (BGF 320), 160/18/9.6 μg of BGF (BGF 160), 18/9.6 μg of GFF, or 320/9.6 μg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint.Measurements and Main Results: In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33-0.80; unadjusted P = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44-1.16; P = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively.Conclusions: Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: The aim was to investigate the effectiveness and safety of electroacupuncture (EA) in women with balanced mixed urinary incontinence (MUI) compared with PFMT plus solifenacin. Methods: This is a secondary analysis of a randomized non-inferiority clinical trial. Seventy-nine patients with balanced MUI were randomly assigned to receive either 12-week EA with 24-week follow-up or 36-week PFMT and solifenacin. Primary outcome was the proportion of participants with ≥50% reduction of mean 24-h incontinence episode frequency (IFE) through weeks 1–12 from baseline. Analysis was performed in an intention-to-treat population using a generalized linear model with a binomial distribution, adjusted for imbalances in baseline variables, and a two-sided p value of less than 0.05 was considered significant. Results: A total of 34 participants in the EA group and 45 participants in the PFMT plus solifenacin group were included in the intention-to-treat analysis of primary outcome. Through weeks 1–12, the proportion of participants with ≥50% reduction of mean 24-h IEF was 32.4% in the EA group, and 37.2% in the PFMT plus solifenacin group, with a mean difference of −2.82% (95%CI: −23.88 to 18.23, p=0.79), revealing non-inferiority. No significant difference held true for all the secondary outcomes. Six adverse events occurred in the EA group and 22 in the PEMT plus solifenacin group. Conclusions: The effect of EA is similar to PFMT plus solifenacin in relieving the symptoms of both SUI and UUI and increasing participants' quality of life but with better safety. The effects of EA may sustain 24 weeks after treatment. [ABSTRACT FROM AUTHOR]

Background: Triple therapy consisting of a drug association including an inhaled corticosteroid, a long-acting muscarinic receptor antagonist and a long-acting β2-adrenergic agonist, delivered via a single device, can be a valuable treatment for chronic obstructive pulmonary disease (COPD) patients experiencing frequent disease exacerbations. Objectives: The aim of this real-life, single-center, observational study was to evaluate, in 44 COPD patients with recurrent exacerbations, the effects of the triple inhaled therapy combining fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI). Methods: Within such a therapeutic context, several clinical and lung functional parameters were considered at baseline and after 24 weeks of treatment with combined inhaled triple therapy. Results: With respect to baseline, after 24 weeks of treatment with FF/UMEC/VI, significant changes were recorded with regard to Modified British Medical Research Council (p < 0.0001) and COPD Assessment Test (p < 0.0001) scores, COPD exacerbations (p < 0.001), forced expiratory volume in the first second (p < 0.001), residual volume (p < 0.01), forced mid-expiratory flow between 25 and 75% of FVC (p < 0.0001), inspiratory capacity (p < 0.01), forced vital capacity (p < 0.05), and peak expiratory flow (p < 0.0001). Moreover, in a subgroup of 28 patients, a significant increase of diffusion lung capacity (p < 0.01) was also detected. Conclusions: In conclusion, our real-life results suggest that triple inhaled therapy with FF/UMEC/VI, when given to COPD patients with frequent exacerbations, is able to positively impact on dyspnea and global health status as well as to significantly decrease COPD exacerbations and improve airflow limitation and lung hyperinflation. [ABSTRACT FROM AUTHOR]

This review discusses the available evidence in the current evaluation and treatment of nocturia in frail older adults. No evidence specifically evaluates the use of behavioral interventions in the treatment of the frail older adult with nocturia, but their use is supported in other cohorts. Behavioral modifications and optimal management of comorbidities remain the first-line treatment for all age groups and should be emphasized in the frail due to their favorable safety profile. No studies specific to the frail older adult support the use of pharmacotherapy. Some evidence exists for the efficacy of several agents in the older adult; however, this is difficult to extrapolate to the frail, and safety concerns abound. Desmopressin may be effective in the older adult, but a high risk of hyponatremia raises concerns for its safety, and therefore it is not recommended in the frail. α-Antagonists may have limited efficacy in men with known benign prostatic hyperplasia (BPH); they are relatively well tolerated, although the risk of orthostatic hypotension in the frail should be considered. β3-agonist trials suggest limited clinical utility. Antimuscarinics are not found to be useful in this cohort and are contraindicated in the frail older adult given the ability of antimuscarinics to cause cognitive impairment, delirium, and falls. No data examine the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the frail older adult. Additionally, the American Geriatrics Society Beers Criteria recommends against the use of muscarinics in those over the age of 75 years and therefore their use is not supported. [ABSTRACT FROM AUTHOR]

The aim of this study was to review clinical evidence supporting the use of fixed-dose combination of tiotropium and olodaterol, a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA), respectively, as the initial and follow-up treatment choice in patients with chronic obstructive pulmonary disease (COPD) as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 recommendations—the impact of this treatment strategy on the reduction in the risk of exacerbations—and the importance of early therapeutic interventions. For this narrative review, the available literature was searched to identify studies including patients with COPD receiving tiotropium and olodaterol as either monotherapy or combination therapy and studies including patients with COPD receiving inhaled corticosteroids (ICS) in addition to long-acting bronchodilators. Relevant studies were included in the review. Patients with COPD are often prescribed ICS therapy, which, when used over a long term, can be associated with local and systemic adverse effects. The GOLD 2020 report recommends dual bronchodilator therapy as both an initial and follow-up treatment option. A LABA + LAMA combination is mechanistically synergistic, and cumulative evidence surrounding the efficacy and safety of fixed-dose combination of tiotropium and olodaterol supports therapeutic advantages over monotherapy in most patients with COPD. The early stages of COPD may represent a "window of therapeutic opportunity" during which initiation of tiotropium and olodaterol dual bronchodilator therapy may improve lung function and quality of life and reduce exacerbations in patients with COPD. Impact of T+O therapy on COPD. Please see the online full text version to access Video 1, or the video can be accessed via the supplemental material tab . [ABSTRACT FROM AUTHOR]

Background: In chronic obstructive pulmonary disease (COPD) patients, combination treatment with long-acting muscarinic antagonist (LAMA) and long-acting β2 agonist (LABA) increases forced expiratory volume in one second and reduces symptoms compared to monotherapy. In Japan, three different once-daily fixed-dose combinations (FDCs) have been prescribed since 2015, although a direct comparison of these FDCs has never been performed. The objective of the present study was to compare the effectiveness, preference, and safety of three LAMA/LABA FDCs-glycopyrronium/indacaterol (Gly/Ind), umeclidinium/vilanterol (Ume/Vil), and tiotropium/olodaterol (Tio/Olo)-in patients with COPD.Methods: We enrolled 75 COPD outpatients (male:female ratio, 69:6; 77.4 ± 6.9 years). A prospective, randomized, crossover study was conducted on three groups using three FDCs: Gly/Ind; Ume/Vil; and Tio/Olo. Each medication was administered for 4 weeks before crossover (total 12 weeks). After each FDC administration, a respiratory function test and questionnaire survey were conducted. A comparative questionnaire survey of all three LAMA/LABA FDCs was conducted after 12 weeks (following administration of final FDC).Results: No significant differences in COPD Assessment Test or modified Medical Research Council dyspnea questionnaire were reported in the surveys completed after each FDC administration; no significant differences in spirometric items were observed. In the final comparative questionnaire survey, patients reported better actual feeling of being able to inhale following Gly/Ind administration compared with Tio/Olo, although no significant differences in adverse events or other evaluations were reported.Conclusions: The three LAMA/LABA FDCs administered to COPD patients show similar effects and safety, although some minor individual preference was reported. Trial registration This study retrospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000041342, registered on August 6, 2020). [ABSTRACT FROM AUTHOR]

The article offers information on several psychiatric drugs that are in clinical development in the U.S. in 2021. These include the product candidate Kar-XT that combines xanomeline and trospium, the combination of olanzapine and samidorphan called ALKS 3831, hydroxynorketamine, and the sestrin modulator NV-5138. INSET: A Quick Primer on the Serendipity of Psychopharmacological Develo.