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Background: Hyperhidrosis (HH), characterized by excessive sweating, poses a significant challenge to patients' quality of life. This meta-analysis evaluates the safety and efficacy of topical glycopyrronium bromide (GBP) in treating primary hyperhidrosis, a chronic condition affecting various body regions. Despite its prevalence, primary axillary hyperhidrosis is often undertreated due to a lack of awareness and social stigma., Methods: Following PRISMA guidelines, we conducted a systematic review and meta-analysis of randomized controlled trials comparing GBP to a placebo in primary hyperhidrosis patients. Eligibility criteria included outcomes related to perspiration suppression and symptom improvement., Results: Four RCTs involving 1401 patients were included. GBP significantly increased Hyperhidrosis Disease Severity Scale (HDSS) responders (RR = 2.33, 95% CI [1.99 to 2.74], p < 0.00001) and Axillary Sweating Daily Diary (ASDD/ASDD-C) responders (MD = 3.07, 95% CI [2.32 to 4.06], p < 0.002) without significantly causing adverse events. Dermatology life quality index was also significantly improved in the GBP group (MD = -2.32, 95% CI [-3.09, -1.55], P < 0.00001)., Conclusion: GBP demonstrated effectiveness in reducing sweat production while improving HDSS and DLQI scores. Adverse events included dry mouth and anticholinergic effects. Dry eye and local skin reactions were not significant, which makes GBP promising in managing primary hyperhidrosis, offering improvements in symptoms and quality of life. While adverse events should be considered, further research with larger sample sizes and long-term follow-up is warranted for comprehensive clinical integration., (© 2024. The Author(s).)

Study Objective: To compare the effects of neostigmine/glycopyrrolate (a traditional agent) and sugammadex on bowel motility recovery and the occurrence of digestive system complications after colorectal surgery., Design: Prospective, randomized controlled trial., Setting: A single tertiary center., Patients: 111 patients undergoing laparoscopic colorectal surgery., Interventions: Patients were randomized into two groups based on the block reversal agent: 1) a mixture of 50 μg.kg -1 of neostigmine and 10 μg.kg-1 of glycopyrrolate (neostigmine group) and 2) 2 mg.kg -1 of sugammadex (sugammadex group)., Measurements: The primary outcome was the time from the surgery's completion to the first flatus. The time to the first postoperative defecation, incidences of postoperative nausea or vomiting, ileus, and dry mouth, as well as postoperative length of stay, were also assessed., Main Results: The time to the first flatus was significantly shorter in the sugammadex group than in the neostigmine group (59 [42-79] h vs 69 [53-90] h, P = 0.027). The time to the first defecation and the incidences of postoperative nausea or vomiting and ileus did not differ between the groups, nor did the postoperative length of stay. However, the incidence of postoperative dry mouth was significantly lower in the sugammadex group than in the neostigmine group (7 patients [13%] vs 39 patients [71%], P < 0.001)., Conclusions: The time to the first flatus was shorter using 2 mg.kg -1 sugammadex to reverse the neuromuscular block for laparoscopic colorectal surgery compared to reversal with conventional neostigmine/glycopyrrolate., Competing Interests: Declaration of competing interest No competing interests declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the frequency of medication success among patients with COPD who initiated BGF using real-world data., Patients and Methods: Patients with a recorded diagnostic COPD code who started BGF with ≥2 prescriptions within 90-days were identified in the UK Optimum Patient Care Research Database and followed from first prescription until censoring at the end of follow-up (180-days), death, leaving database or end of data at 24/10/2022. The primary outcome was medication success at 90-days post-BGF initiation, defined as no major cardiac or respiratory event (ie no complicated COPD exacerbation, hospitalization for any respiratory event, myocardial infarction, new/hospitalized heart failure, and death) and no incidence of pneumonia. Medication success was also assessed at 180-days post-BGF initiation. Overall real-life medication success was claimed if the lower 95% confidence interval (CI) for the proportion of patients meeting the primary outcome was ≥70% (defined a priori)., Results: Two hundred eighty-five patients were included. Prior to BGF initiation, these patients often had severe airflow obstruction (mean ppFEV 1 : 54.5%), were highly symptomatic (mMRC ≥2: 77.9% (n = 205/263); mean CAT score: 21.7 (SD 7.8)), with evidence of short-acting β 2 -agonist (SABA) over-use (≥3 inhalers/year: 62.1%, n=179/285), repeat OCS prescriptions (≥2 courses/year: 33.0%, n = 95/285) and multiple primary care consultations (≥2 visits/year: 61.1%, n = 174/285). Overall, 39.6% of patients (n = 113/285) switched from previous triple therapies. Real-life medication success was achieved by 96.5% of patients (n = 275/285 [95% CI: 93.6, 98.3]) during 90-days treatment with BGF and by 91.8% (n = 169/184 [95% CI: 86.9, 95.4]) of patients at 180-days. The prescribed daily dose of SABA remained stable over the study period., Conclusion: The majority of patients initiating BGF experienced real-life medication success reflecting the absence of severe cardiopulmonary events. These benefits were apparent after 90-days of treatment and sustained over 180-days., Competing Interests: Hana Müllerová, Stefan Franzén, Johann Castaneda, and Jonathan Marshall are employees of, and own stock in, AstraZeneca. Jeffrey Shi Kai Chan, Heath Heatley, Victoria Carter, John Townend, and Derek Skinner are employees of Observational and Pragmatic Research Institute. David Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy and lecture fees from Medscape, Inside Practice paid to Observational and Pragmatic Research Institute; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Viatris, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme, Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Teva Pharmaceuticals; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. The authors report no other conflicts of interest in this work., (© 2024 Müllerová et al.)

Purpose: To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany., Patients and Methods: Retrospective cohort study of patients with COPD and ≥1 prescription for single-inhaler triple therapy (SITT; fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or beclomethasone dipropionate/glycopyrronium bromide/formoterol [BDP/GLY/FOR]) or multiple-inhaler triple therapy (MITT), using data from the AOK PLUS German sickness fund (1 January 2015-31 December 2019). The index date was the first date of prescription for FF/UMEC/VI or BDP/GLY/FOR (SITT users), or the first date of overlap of inhaled corticosteroid, long-acting β 2 -agonist, and long-acting muscarinic antagonist (MITT users). Two cohorts were defined: the prevalent cohort included all identified triple therapy users; the incident cohort included patients newly initiating triple therapy for the first time (no prior use of MITT or SITT in the last 2 years). Patient characteristics and treatment patterns were assessed on the index date and during the 24-month pre-index period., Results: In total, 18,630 patients were identified as prevalent triple therapy users (MITT: 17,945; FF/UMEC/VI: 700; BDP/GLY/FOR: 908; non-mutually exclusive) and 2932 patients were identified as incident triple therapy initiators (MITT: 2246; FF/UMEC/VI: 311; BDP/GLY/FOR: 395; non-mutually exclusive). For both the prevalent and incident cohorts, more than two-thirds of patients experienced ≥1 moderate/severe exacerbation in the preceding 24 months; in both cohorts more BDP/GLY/FOR users experienced ≥1 moderate/severe exacerbation, compared with FF/UMEC/VI and MITT users. Overall, 97.9% of prevalent triple therapy users and 86.4% of incident triple therapy initiators received maintenance treatment in the 24-month pre-index period., Conclusion: In a real-world setting in Germany, triple therapy was most frequently used after maintenance therapy in patients with recent exacerbations, in line with current treatment recommendations., Competing Interests: Kai-Michael Beeh is a full-time employee of Insaf Respiratory Research Institute. He has received personal or institutional compensation for services on advisory boards or consulting for AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Chiesi, Elpen, GSK, Mundipharma, Novartis, Pohl Boskamp, Sanofi, sterna, and Zentiva, and compensation for speaker activities in scientific meetings supported by AstraZeneca, Berlin Chemie, Boehringer Ingelheim, ERT, GSK, Novartis, Pfizer, Pohl Boskamp, Sanofi, and Teva, all outside the submitted work. The institution has received compensation for design and performance of clinical trials from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Parexel, Pearl Therapeutics, sterna, and Zentiva. Kieran J Rothnie, Jing Claussen, Chris Compton, and Afisi S Ismaila are employees of and/or hold stocks/shares in GSK. Afisi S Ismaila is also an unpaid part-time member of the McMaster University faculty. Alexandrosz Czira was an employee of GSK at the time of the study and now works for Gedeon Richter PLC. Fränce Hardtstock and Rachel K Knapp participated in this study as employees of Cytel/Ingress-Health. Cytel/Ingress-Health received funding from GSK to conduct the study. Thomas Wilke reports grants from GSK and Cytel/Ingress-Health during the conduct of the study and grants from Apontis, Janssen, and Pfizer outside the submitted work. Thomas Wilke received honoraria and other financial support from Cytel Inc., which does studies with all major pharmaceutical companies. The authors report no other conflicts of interest in this work., (© 2024 Beeh et al.)

Purpose: This study aimed to examine reports of cardiovascular adverse events (CV AEs) observed in the real-world during treatment with aclidinium, tiotropium, glycopyrronium, and umeclidinium alone or in combination with a LABA and, in the context of triple therapy, with the addition of an ICS, and submitted to the food and drug administration adverse event reporting system (FAERS)., Methods: A retrospective disproportionality analysis was conducted utilizing CV AE reports submitted to the FAERS from January 2020 to 30 September 2023. Disproportionality was measured by calculating the reporting odds ratio., Results: Compared with ipratropium, tiotropium was associated with fewer reports of CV AEs. Compared with tiotropium, other LAMAs were more likely to be associated with reports of CV AEs. Combinations of glycopyrronium with indacaterol or formoterol and umeclidinium with vilanterol significantly reduced reports of CV AEs compared with the respective LAMA. The addition of an ICS to these combinations further reduced the risk of CV AE reports., Conclusion: Our study suggests that inhaled LAMAs are not free from cardiac AE risks. This risk may be more evident when the newer LAMAs are used, but it is generally significantly reduced when COPD patients are treated with dual bronchodilators or triple therapy. However, these results do not prove that LAMAs cause CV AEs, as FAERS data alone are not indicative of a drug's safety profile. Given the frequency with which COPD and cardiovascular disease co-exist, a large study in the general population could shed light on this very important issue., (© 2024. The Author(s).)

Purpose: The TRITRIAL study assessed the effects of beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) fixed combination in patients with chronic obstructive pulmonary disease (COPD) in a real-world setting, focusing on patient's experience and perspective through the use of patients reported outcomes., Patients and Methods: TRITRIAL was a multicenter, prospective, observational study conducted on patients with moderate-severe COPD treated with BDP/FF/G fixed therapy for 12 months. The main objective was to evaluate the impact of BDP/FF/G on health status through the COPD Assessment Test (CAT) score. Additional assessments included adherence and satisfaction, measured by the TAI-10/12 questionnaire and a specifically designed eight-item questionnaire, quality of life through the EQ-5D-5L test, sleep quality through the COPD and Asthma Sleep Impact Scale (CASIS), as well as safety and disease-related outcomes., Results: Data from 655 patients were analyzed in the study. The mean total CAT score significantly improved (from 22.8 at baseline to 18.1 at 6 months and 16.5 at 12 months; p < 0.0001), as well as all the eight CAT sub-items, which decreased on average by 0.5-0.9 points during the study. Adherence and usability of the inhaler also improved during the study, with a decrease in poor compliance (from 30.1% to 18.3%) and an increase in good compliance (from 51.8% to 58.3%) according to the TAI score. Patients also benefited from significantly improved quality of life (EQ Index from 0.70 to 0.80; EQ-5D VAS score from 55.1 to 63.1) and sleep quality (CASIS score from 41.1 to 31.8). Finally, patients reported a significant reduction in exacerbation during the study., Conclusion: TRITRIAL showed that the BDP/FF/G fixed combination is effective and safe in patients with moderate-severe COPD and poorly controlled disease, improving patients' HRQoL, sleep quality, adherence and inhaler usability and reducing COPD symptoms and the risk of exacerbation in a real-life setting., Competing Interests: LR has received grants/research support from Roche and Boehringer Ingelheim; he has received honoraria or consultation fees from Boehringer Ingelheim, Promedior, Biogen, FibroGen, Sanofi-Aventis, Promedior, RespiVant, Roche, Celgene, Nitto, and Veracyte. GC reports personal fees from Astra Zeneca, Sanofi, and GSK, outside the submitted work. AP, USA and EI are employees of Chiesi Italia, Parma, Italy. The other authors report no conflicts of interest in this work., (© 2024 Richeldi et al.)

Background: The extrafine single inhaler triple therapy (efSITT) containing beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 μg has proved to be efficacious in patients with chronic obstructive pulmonary disease (COPD) in randomized control trials., Objective: TRIWIN study evaluated the effectiveness of efSITT delivering beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 μg in COPD patients previously treated with multiple-inhaler triple therapy (MITT) in a real-world study in Greece., Design: Prospective, multicenter, observational, non-interventional study was conducted over 24 weeks., Methods: A total of 475 eligible patients had moderate-to-severe COPD, an indication for treatment with efSITT, and were symptomatic despite receiving MITT. COPD Assessment Test (CAT) score, pulmonary function parameters, use of rescue medication, and adherence to inhaler use were recorded at baseline (Visit 1), 3 (Visit 2), and 6 months (Visit 3) after treatment., Results: Mean CAT score decreased from 21.4 points at Visit 1, to 16.6 at Visit 2 and 15.1 at Visit 3 ( p  < 0.001 for all pair comparisons). At Visit 3, 79.8% of patients reached a CAT improvement exceeding minimal clinically important difference (⩾2), compared to baseline. Mean forced expiratory volume in 1 s (%pred.) increased from 55.4% at Visit 1 to 63.5% at the end of study period ( p  < 0.001), while mean forced vital capacity (%pred.) increased from 71.1% at Visit 1, to 76.7% at Visit 3 ( p  < 0.001). The mean Test of Adherence to Inhalers score increased from 42.5 to 45.3 and 46.3 points, for the three visits, respectively ( p  < 0.001 comparing Visits 1/2 and Visits 1/3; p  = 0.006 comparing Visits 2/3). The percentage of patients showing good adherence rose from 33.7% at baseline to 58.3% at Visit 3. The percentage of patients using rescue medication during the last month dropped from 16.2% to 7.4% at the end of study period ( p  < 0.001). Pulmonary function parameters also improved., Conclusion: The TRIWIN results suggest that extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium is effective in improving health status, pulmonary function, and adherence and in reducing rescue medication use in COPD patients previously treated with MITT, in a real-world setting in Greece.

Purpose: Triple therapy to prevent exacerbations from chronic obstructive pulmonary disease (COPD) is associated with improved health compared to single and dual-agent therapy in some populations. This study assessed the benefits of prompt administration of budesonide/glycopyrrolate/formoterol fumarate (BGF) following a COPD exacerbation., Patients and Methods: EROS was a retrospective analysis of people with COPD using the MORE 2 Registry ® . Inclusion required ≥1 severe, ≥2 moderate, or ≥1 moderate exacerbation while on other maintenance treatment. Within 12 months following the index exacerbation, ≥1 pharmacy claim for BGF was required. Primary outcomes were the rate of COPD exacerbations and healthcare costs for those that received BGF promptly (within 30 days of index exacerbation) versus delayed (31-180 days) and very delayed (181-365 days). The effect of each 30-day delay in initiation of BGF was estimated using a multivariable negative binomial regression model., Results: 2409 patients were identified: 434 prompt, 1187 delayed, and 788 very delayed. The rate (95% CI) of total exacerbations post-index increased as time to BGF initiation increased: prompt 1.52 (1.39-1.66); delayed 2.00 (1.92-2.09); and very delayed 2.30 (2.20-2.40). Adjusting for patient characteristics, each 30-day delay in receiving BGF was associated with a 5% increase in the average number of subsequent exacerbations (rate ratio, 95% CI: 1.05, 1.01-1.08; p <0.05). Prompt initiation of BGF was also associated with lower post-index annualized COPD-related costs ($5002 for prompt vs $7639 and $8724 for the delayed and very delayed groups, respectively)., Conclusion: Following a COPD exacerbation, promptly initiating BGF was associated with a reduction in subsequent exacerbations and reduced healthcare utilization and costs., Competing Interests: SS, SP, DE, NF, and MP are employees of AstraZeneca and hold AstraZeneca stock. JT, JS, BL, and BA are employees of Inovalon, who received funding from AstraZeneca to conduct this study. DRT, EP, and CS are paid consultants of AstraZeneca. DRT reports personal fees from Stage Analytics, eMax Health, Horizon Pharmaceuticals, Monument Analytics; grants from Takeda Pharmaceuticals, outside the submitted work. CS reports personal fees from AlphaNet, Adverum, CSL Behring, Morair, UpToDate, GlaxoSmithKline; grants from Arrowhead, OCI, Pandorum, Pulmanage, Takeda, Vertex, NuVaira, CSA Medical, Grifols, Pulmonx, and AstraZeneca, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Strange et al.)

Purpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with significant morbidity and mortality and increased economic healthcare burden for patients with COPD. Long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) dual therapy is recommended for patients receiving mono-bronchodilator therapy who experience exacerbations or ongoing breathlessness. This study compared two single-inhaler LAMA/LABA dual therapies, umeclidinium/vilanterol (UMEC/VI) and indacaterol/glycopyrronium (IND/GLY), on moderate-to-severe exacerbation rates in patients with COPD in England., Patients and Methods: This retrospective cohort study used linked primary care electronic health record data (Clinical Practice Research Datalink-Aurum) and secondary care data (Hospital Episode Statistics) to assess outcomes for patients with COPD who had a first prescription for single-inhaler UMEC/VI or IND/GLY (index date) between 1 January 2015 and 30 September 2019 (indexing period). Analyses compared UMEC/VI and IND/GLY on moderate-to-severe, moderate, and severe exacerbations, healthcare resource utilization (HCRU), and direct costs at 6, 12, 18, and 24 months, and time-to-first on-treatment exacerbation up to 24 months post-index date. Following inverse probability of treatment weighting (IPTW), non-inferiority and superiority of UMEC/VI versus IND/GLY were assessed., Results: In total, 12,031 patients were included, of whom 8753 (72.8%) were prescribed UMEC/VI and 3278 (27.2%) IND/GLY. After IPTW, for moderate-to-severe exacerbations, weighted rate ratios were <1 at 6, 12, and 18 months and equal to 1 at 24 months for UMEC/VI; around the null value for moderate exacerbations and <1 at all timepoints for severe exacerbations. UMEC/VI showed lower HCRU incidence rates than IND/GLY for all-cause Accident and Emergency visits and COPD-related inpatient stays and associated all-cause costs at 6 months post-indexing. Time-to-triple therapy was similar for both treatments., Conclusion: UMEC/VI demonstrated non-inferiority to IND/GLY in moderate-to-severe exacerbation reduction at 6, 12 and 18 months. These results support previous findings demonstrating similarity between UMEC/VI and IND/GLY on reduction of moderate-to-severe exacerbations., Competing Interests: GR, CCo, KJR, and ASI are employees of GSK and hold stocks and shares at GSK. ASI also holds an unpaid faculty position at McMaster University. AC was an employee of GSK and held stocks and shares at GSK at the time of the study. FJFH is an employee of the Translational Lung Research Center Heidelberg, part of the Germany lung research Foundation (DZL). JKQ holds a position at Imperial College London and has received grants or contracts paid to this institution outside the scope of the submitted work from the Medical Research Council, Health Data Research UK, GSK, Boehringer Ingelheim, Asthma + Lung UK, and AstraZeneca. JKQ has also received payment for advisory board participation, teaching or lectures from GSK, AstraZeneca, and Insmed. CCa, TT, RWo, and RWi are employees of Adelphi Real World. VB and JY were employees of Adelphi Real World at the time of the study. Adelphi Real World is a business that provides consulting and other research services to pharmaceutical, device, government, and non-government organizations which received funding from GSK to conduct the study. Adelphi Real World employees work with a variety of companies and organizations and are expressly prohibited from receiving any payment or honoraria directly from these organizations for services rendered. The authors report no other conflicts of interest in this work., (© 2023 Requena et al.)

Purpose: Glycopyrronium, also known as glycopyrrolate, is an antimuscarinic competitive inhibitor of acetylcholine widely utilized topically for its anticholinergic properties in dermatology. A single topical glycopyrronium tosylate (GT) formulation is available on the market, and prescription of this medication has become increasingly popular among dermatologists. This medication has a relatively notable adverse effect profile and carries risks that patients need to be counseled on before initiation., Summary: A 22-year-old female presented to our emergency department (ED) with a chief complaint of difficulty urinating for 48 hours and blurred vision for 2 weeks. Over the course of a week, she visited the ED once and urgent care multiple times due to complications associated with combination use of GT and cetirizine. Although these clinical effects were reversible, the patient impact in our case was profound given the time, cost, and invasive nature of these visits., Conclusion: The notable adverse effects of GT should be considered when prescribing this agent., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Severe sialorrhoea is a common, distressing problem in children/adolescents with neurodisabilities, which has adverse health and social consequences. The SALIVA trial is designed to evaluate the efficacy and safety of a paediatric-specific oral solution of glycopyrronium along with its impact on quality-of-life (QoL), which has been lacking from previous trials of sialorrhoea treatments., Methods and Analysis: A double-blind, placebo-controlled, randomised phase IV trial is ongoing in several centres across France. Eighty children aged 3-17 years with severe sialorrhoea (≥6 on the modified Teachers Drooling Scale) related to chronic neurological disorders in whom non-pharmacological standard of care has already been implemented or has failed, will be recruited. Patients will be randomised 1:1 to receive a 2 mg/5 mL solution of glycopyrronium bromide (Sialanar 320 µg/mL glycopyrronium) or placebo three times daily during a 3-month blinded period. After Day 84, participants will be invited into a 6-month, open-label study extension period, where they will all receive glycopyrronium. The primary endpoint of the double-blind period will be the change from baseline to Day 84 in the Drooling Impact Scale (DIS), a validated measure to assess sialorrhoea. A series of secondary efficacy endpoints involving change in total DIS, specific DIS items and response (DIS improvement ≥13.6 points) will be analysed in a prespecified hierarchy. QoL data will be collected from parents, caregivers and patients where possible using specific DIS questions and DISABKIDS questionnaires. Safety endpoints, including adverse events, will be assessed throughout the trial periods., Ethics and Dissemination: In total, 87 children have been recruited and recruitment is now complete. Final results are expected by the end of 2023. Findings will be presented at conferences and published in peer-reviewed journals., Trial Registration Number: EudraCT 2020-005534-15., Competing Interests: Competing interests: PF receives fees from Merz Pharma for providing training sessions. SA has served as consultant or given lectures for Angelini, Biocodex, Eisai, Encoded, Grintherapeutics, Jazz Pharmaceuticals, Neuraxpharm, Orion, Nutricia, Proveca, UCB Pharma, Vitaflo, Xenon and Zogenix. SA has been an investigator for clinical trials for Eisai, Marinus, Proveca, Takeda, UCB Pharma and Zogenix. MD and DP report no competing interests. HS, NP and FV are employees of Proveca Ltd. NT is an employee of the contract research organisation, Kappa Santé., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Air trapping is one of the main determinants of dyspnea in patients with chronic obstructive pulmonary disease (COPD). An increase in air trapping leads to a change in the normal diaphragmatic configuration with associated functional impairment. Said deterioration improves with bronchodilator therapy. Chest ultrasound (CU) has been used to assess changes in diaphragmatic motility after short-acting bronchodilator therapy, but there are no previous studies on these changes after long-acting bronchodilator treatment., Material and Methods: Interventional prospective study. Patients with COPD and moderate to very severe ventilatory obstruction were included in the study. Diaphragm motion and thickness were assessed by CU before and after 3 months of treatment with indacaterol/glycopirronium 85/43 mcg., Results: Thirty patients were included (56.6% men, mean age: 69.4 ± 6.2 years). Pre- and post-treatment diaphragmatic mobility measured during resting breathing, deep breathing, and nasal sniffing were 19.9 ± 7.1 mm and 26.4 ± 8.7 mm (p < 0.0001); 42.5 ± 14.1 mm and 64.5 ± 25.9 mm (p < 0.0001); and 36.5 ± 17.4 mm and 46.7 ± 18.5 mm (p = 0.012), respectively. A significant improvement was also found in the minimum and maximum diaphragm thickness (p < 0.05), but there were no significant changes in the diaphragmatic shortening fraction after treatment (p = 0.341)., Conclusions: Treatment with indacaterol/glycopyrronium 85/43 mcg every 24 hours for 3 months improved diaphragmatic mobility in patients with COPD with moderate to very severe airway obstruction. CU may be useful for assessing the response to treatment in these patients., (Copyright © 2023 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Background: Rocuronium is an intermediate-acting non-depolarizing neuromuscular blocking agent frequently used in the emergency department for rapid sequence intubation. The prolonged effects of rocuronium may prevent the ability to conduct a meaningful neurological examination, thereby delaying appropriate diagnosis and treatment. Sugammadex and neostigmine are pharmacologic agents commonly used to reverse rocuronium. The safety of sugammadex versus neostigmine with glycopyrrolate for the reversal of rocuronium in the emergency department has not been well described. Objective: Evaluate the occurrence of hemodynamic instability post-administration of sugammadex versus neostigmine with glycopyrrolate in the emergency department for the reversal of rocuronium. Methods: A retrospective cohort study conducted among adult patients that received sugammadex or neostigmine with glycopyrrolate in the emergency department for the reversal of rocuronium. The primary outcome was occurrence of hemodynamic instability that required escalation of treatment. Secondary outcomes included occurrence of hypotensive, bradycardic, or cardiac arrest events. Results: A total of 37 patients met inclusion criteria (n = 10, sugammadex; n = 27, neostigmine). There was no difference between the two groups in regard to hemodynamic instability that required escalation of treatment within 30 minutes after receiving either sugammadex or neostigmine with glycopyrrolate ( P = .557). Conclusion: There was no difference between the two groups in regard to occurrence of hemodynamic instability that required escalation of treatment. Given the small sample size, future studies are warranted to further delineate the safety of sugammadex and neostigmine with glycopyrrolate for the reversal of rocuronium in the emergency department.

Background: Primary axillary hyperhidrosis (PAHH) strongly affects the patient's quality of life. To date, topical treatment options are limited. One percent glycopyrronium bromide (GPB) showed promising efficacy and safety in a pivotal 4-week Phase 3a study., Objectives: To assess efficacy and safety of topical 1% GPB cream in patients with severe PAHH in a long-term study of 72 weeks versus baseline., Methods: This was a long-term, open-label, Phase 3b trial for 72 weeks including 518 patients with severe PAHH. Patients were treated with 1% GPB cream once daily for 4 weeks, followed by a flexible dosing scheme (min. twice per week, max. once daily). Primary endpoint was the absolute change in sweat production from baseline to week 12. Further study endpoints included assessment of the severity of PAHH and the impact on quality of life., Results: Total median sweat production decreased by 119.30 mg (-65.6%, both median) until week 12. Absolute change in sweat production from baseline to week 12 in logarithmic values was statistically significant (p < 0.0001). Patients' quality of life was improved at all study time points compared to baseline, as assessed by Hyperhidrosis Quality of Life Index and Dermatology Life Quality Index (p < 0.0001). Treatment was safe and locally well-tolerated with only few mild to moderate adverse drug reactions (ADRs). Dry mouth and application site erythema were the most common reported ADRs., Conclusions: Treatment with 1% GPB cream over 72 weeks significantly reduces sweat production and improves quality of life in patients with severe PAHH. One percent GPB cream is well-tolerated and provides an effective treatment option for long-term use in patients with severe PAHH., (© 2023 Dr. August Wolff GmbH & Co. KG Arzneimittel. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: The small airway disease has been recognized as a central feature of chronic obstructive pulmonary disease (COPD). Triple fixed combination beclomethasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) is provided as a pressurized single-dose inhaler based on an extra-fine formulation, which has been approved for patients with COPD experiencing frequent disease exacerbations., Methods: The aim of our real-life single-center observational study was to investigate, in 22 patients with COPD, the effects of BDP/FF/G on lung function, respiratory symptoms, health status, and exacerbation rate. Several clinical and lung functional parameters were evaluated at baseline and after 12 months of treatment with combined inhaled triple therapy., Results: With respect to baseline, after 12 months of treatment with BDP/FF/G, significant changes were recorded with regard to forced expiratory flow at 75% of forced vital capacity (FVC) ( p  < 0.01), forced expiratory flow at 50% of FVC ( p  < 0.01), forced expiratory flow at 25% of FVC ( p  < 0.05), and forced mid-expiratory flow between 25% and 75% of FVC ( p  < 0.01). Moreover, we observed reductions of total resistance ( p  < 0.01), effective resistance ( p  < 0.01), and effective specific resistance ( p  < 0.01). In the same period, residual volume diminished ( p  < 0.01) and forced expiratory volume in 1 s increased ( p  < 0.01). Moreover, in a subgroup of 16 patients, an enhancement of diffusion lung capacity ( p  < 0.01) was also detected. These functional results were paralleled by concomitant clinical effects, as evidenced by the improvements of modified British Medical Research Council (mMRC) dyspnea scale ( p  < 0.001), COPD Assessment Test (CAT) score ( p  < 0.0001), and COPD exacerbations ( p  < 0.0001)., Conclusion: In conclusion, the valuable findings of our observational study consist in the corroboration in a real-life context of the therapeutic effects evidenced by randomized controlled trials with regard to the use of the triple inhaled BDP/FF/G therapy in patients with COPD.

Here, we report a case of unilateral ocular mydriasis in a pediatric patient with longstanding hyperhidrosis, as well as similar findings in her cat. The patient had been undergoing treatment of her hyperhidrosis with topical glycopyrrolate. This case highlights the potential side effect profile of topical antimuscarinics and the importance of counseling patients on proper precautions., (© 2022 Wiley Periodicals LLC.)

Background: In the 52-week ETHOS study (NCT02465567), fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) reduced moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations versus fixed-dose long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) or inhaled corticosteroid (ICS)/LABA dual therapies. Here, ETHOS data were used to estimate the long-term cost-effectiveness of BGF versus LAMA/LABA and ICS/LABA dual therapies in the United Kingdom., Methods: Costs, exacerbations, quality-adjusted life-years (QALYs), and LYs were extrapolated using a Markov model that considered disease severity progression, risk of moderate and severe exacerbations, adverse events, and treatment discontinuation in patients with moderate-to-very severe COPD receiving BGF 320/14.4/10 µg, the LAMA/LABA glycopyrronium/formoterol fumarate dihydrate 14.4/10 µg (GFF), or the ICS/LABA budesonide/formoterol fumarate dihydrate 320/10 µg (BFF). Utilities for COPD severity states were estimated using EuroQol 5-dimension 5-level data from ETHOS. Exacerbation disutilities were sourced from published literature. Healthcare resource utilization was based on ETHOS data, published literature, key external experts' input, and informed assumptions. Unit costs came from the UK National Health Service Schedule of Reference Costs, Unit Costs of Health and Social Care from the Personal Social Services Research Unit, and published literature. A lifetime horizon was considered, with costs, QALYs, and LYs discounted at 3.5% per annum., Results: The incremental cost-utility ratio (ICUR; per QALY gained) was £9901 for BGF versus GFF and £2164 for BGF versus BFF. The probability of treatments being cost-effective at the conventional UK-adopted willingness-to-pay threshold of ICUR <£20,000 was 85.1% for BGF, 14.3% for GFF, and 0.6% for BFF., Conclusion: Based on ETHOS data, BGF was demonstrated to be cost-effective versus LAMA/LABA and ICS/LABA dual therapies at the conventional UK-adopted willingness-to-pay threshold (ICUR <£20,000). The main cost-effectiveness driver for BGF versus LAMA/LABA and ICS/LABA therapies was reduction in rate of exacerbations, which reduced costs and preserved quality of life., Competing Interests: Enrico de Nigris is a former employee of AstraZeneca and previously held stock and/or stock options in the company. Catrin Treharne and Nick Brighton are former employees of Parexel International. Ulf Holmgren is an employee of AstraZeneca and holds stock and/or stock options in the company. Andrew Walker is the Director of Salus Alba, was funded for this work by AstraZeneca, and has earned consultancy income in the last 3 years from AbbVie, Aesara, Akcea, Albireo, Alexion, Allergan, Almirall, Amarin, Arena, Apsara, Astellas, AstraZeneca, Autolus, Avexis, Bayer, BioCryst, Biogen, BioMarin, Bristol-Myers Squibb, Boehringer Ingelheim, Calico, Celgene, Chiesi, Daiichi-Sankyo, Deciphera, Diurnal, Eisai, Eli Lilly, Ferring, Galapagos, Gedeon Richter, Gilead, GlaxoSmithKline, GW Pharma, Intercept, Idorsia, Incyte, Ionis, Ipsen, Janssen, Jazz, Jcyte, Kite, LEK, LEO, Les Laboratoires Servier, Lundbeck, Merck Serono, Miltenyi, Mundi Biopharma, Mylan, Myovant, Norgine, Novartis, Novo Nordisk, Orchard, Paion, Pfizer, Pierre Fabre, PTC, RegenXBio, Rhythm, Sarepta, Sanofi, Santen, Seagen, Shionogi, Sigmatec, SOBI, Takeda, Tanaya, UCB, and Vertex. John Haughney has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Circassia, and Teva, unrelated to the conduct of the study. The authors report no other conflicts of interest in this work., (© 2022 de Nigris et al.)

Background: Goldenhar syndrome (GS) is a rare congenital disease characterized by impaired development of different facial structures and deformations of the teeth structures. Sialorrhea, which can cause difficulties in breathing and language impairment, is very common in GS and often difficult to treat. This case report highlights the short- and long-term importance of the therapeutic choice - glycopyrronium in oral solution - for the treatment of sialorrhea in children with poly-malformative syndrome, complicated by outcomes of post-hemorrhagic hydrocephalus., Case Presentation: We report the case of a 6-year-old child with GS, carrying a percutaneous endoscopic gastrostomy after tracheostomy. The child also presented developmental dysfunction of oral motor skills of feeding, complicated by severe sialorrhea, related to the maxillo-facial dysmorphism. Sialorrhea caused several respiratory tract infections and led to an increase in the care burden. Both the inoculations of botulinum toxin and the treatment with scopolamine transdermal patch have shown mild and transient efficacy. The therapeutic choice of glycopyrronium in oral solution was the most suitable for this patient, leading to long-term sialorrhea control., Conclusions: This clinical experience represents the first long-term efficacy and tolerability evaluation in using glycopyrrolate oral solution in treating drooling in children with GS. The reduction of drooling over time and the lack of clinically relevant adverse events have contributed to the decrease of respiratory tract infections, the development of oral motor skills, and determining a positive psycho-social impact on the patient's quality of life and her family., (© 2022. The Author(s).)

Objective: Chronic obstructive pulmonary disease (COPD) is a major and difficult disease of the chronic respiratory system that is common and frequent, with a huge disease burden. The aim of this study was to investigate the efficacy and safety of budesonide/glyburide/formoterol fumarate (BGF) in the treatment of COPD., Methods: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. The basic features of the seven pieces of literature were identified using the search strategy. The sample size range was 130∼1264., Results: The effects of BGF increased FEV1 in patients with COPD (mean difference = 2.86, 95%CI: 2.71-3.01, p < 0.00001). The effects of BGF improved in patients with ≥1 TEAE in patients with COPD, and was not statistically significant after treatment (Odds rate = 1.00, 95%CI: 0.85-1.17, p =0.97). The effects of BGF increased in patients with TEAEs related a to study treatment in patients with COPD (odds rate = 1.27, 95% CI: 1.03-1.57, p =0.02). The effects of BGF in decreased patients with serious TEAEs in patients with COPD (odds rate = -0.02, 95% CI: -0.03--0.00, p =0.04). The effects of BGF decreased the death rate in patients with COPD, and were not statistically significant after treatment (odds rate = 0.77, 95% CI: 0.31-1.97, p =0.59). The effects of BGF decreased the hypertension rate in patients with COPD (odds rate = 0.92, 95% CI: 0.44-1.89, p =0.81), and was not statistically significant after treatment. The effects of BGF increased pneumonia in patients with COPD (odds rate = 1.55, 95% CI: 0.81-2.97, p =0.19), and were not statistically significant after treatment. The effects of BGF increased FEV1, increased patients with TEAEs related a to study treatment, and decreased patients with serious TEAEs in patients with COPD., Conclusion: This study elucidates the efficacy and safety of BGF in the treatment of COPD with a view to providing a clinical reference., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Min Guo et al.)

Background: An extrafine formulation triple therapy combination of beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) has been developed for the maintenance treatment of asthma and chronic obstructive pulmonary disease. This study used gamma scintigraphy to evaluate the intrapulmonary and extrapulmonary in vivo deposition of BDP/FF/GB, and the intrapulmonary regional distribution of the deposited formulation. Methods: This open-label uncontrolled nonrandomized single-dose study recruited 10 healthy volunteers and 9 patients with asthma. After a krypton-81m ( 81m Kr) ventilation scan was conducted, subjects inhaled study drug (four inhalations of BDP/FF/GB 100/6/12.5 μg radiolabeled using technetium-99 m [ 99m Tc]) through pressurized metered-dose inhaler, and a series of scintigraphic images were taken. The primary objective was to evaluate intrapulmonary drug deposition of BDP/FF/GB, determined as the percentage of nominal (i.e., metered) dose. Secondary endpoints included central/peripheral deposition ratio (C/P), and the standardized central/peripheral ratio (sC/P; 99m Tc aerosol C/P/ 81m Kr gas C/P). Results: All participants completed the study, with all scintigraphy procedures performed at one site. In patients with asthma, mean ± standard deviation intrapulmonary deposition was 25.50% ± 6.81%, not significantly different to that in healthy volunteers (22.74% ± 9.19%; p  = 0.4715). Approximately half of the lung dose was deposited in the peripheral region of the lung (fraction deposited 0.52 ± 0.07 and 0.49 ± 0.06 in healthy volunteers and patients with asthma, respectively), resulting in C/P ratios of 0.94 ± 0.25 and 1.06 ± 0.25, respectively, with sC/P ratios of 1.80 ± 0.40 and 1.94 ± 0.38. Deposition patterns were similar in the two populations. BDP/FF/GB was well tolerated. Conclusions: This study confirmed that the extrafine particles delivered by BDP/FF/GB penetrate the peripheral areas of the lungs, with a similar proportion of particles deposited in the central and peripheral regions. Importantly, the deposition patterns were similar in healthy volunteers and patients with asthma, suggesting that disease characteristics are unlikely to impact drug deposition. Clinical Trial Registration number: NCT03795350.

Background: Facial hyperhidrosis (HH), a common problem with both cosmetic and psychological impact, interferes with quality of life. Wide range of treatment options is available for HH. Finding the most effective and yet a safe, tolerable option is the main target., Objective: To evaluate and compare clinical efficacy, safety, and tolerability of topical 2% glycopyrrolate versus intradermal Botulinum toxin A injection in facial HH treatment., Materials and Methods: Twenty-four patients with primary facial HH were randomly divided into 2 equal groups: Group A included patients treated by intradermal Botulinum toxin A injection and Group B included patients treated by topical glycopyrrolate gel 2%. Starch iodine test was performed before and after treatment to assess response, along with Hyperhidrosis Disease Severity Scale, Dermatology Life Quality Index (DLQI), and patient satisfaction., Results: Both modalities showed complete response in 75% of cases with a longer duration of action in botulinum toxin group up to 6 months. Side effects were minor and temporary. Both Hyperhidrosis Disease Severity Scale and DLQI showed statistically significant improvement after treatment., Conclusion: Topical glycopyrrolate 2% showed comparable results to Botulinum toxin A in facial HH treatment with faster onset but shorter duration of action., (Copyright © 2022 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The single-inhaler extrafine formulation triple combination beclometasone dipropionate (BDP), formoterol fumarate (FF) plus glycopyrronium bromide (GB) is available for asthma management in adults. Its use in adolescents has not yet been evaluated. This study investigated the pharmacokinetic profile of BDP/FF/GB in adults and adolescents, with the aim of ruling out higher plasma exposure in adolescents compared to adults. In this open-label, non-randomized study, patients with asthma aged 12-17 (adolescents) and 18-64 years (adults) self-administered a single dose of BDP/FF/GB 400/24/50 μg via pressurized metered-dose inhaler (pMDI). The primary objective was to rule out higher systemic exposure to beclometasone 17-monopropionate (B17MP; active metabolite of BDP), formoterol, and GB in terms of the area under the plasma concentration-time curve from 0 to the last quantifiable concentration (AUC 0-t ) in adolescents versus adults. A total of 40 adolescents and 40 adults entered the study (mean age of 14.8 and 43.6 years, respectively). The primary objective (AUC 0-t ) was met, with the upper 90% confidence interval of the geometric mean ratio between adolescents and adults <125% for B17MP (point estimate 79.28 [90% CI 71.19; 88.29]), formoterol (88.68 [77.71; 101.20]) and GB (85.49 [72.96; 100.16]). All secondary pharmacokinetic endpoints supported the primary, with pharmacodynamic (safety) and tolerability results similar in the two populations. In conclusion, systemic exposure to extrafine BDP/FF/GB pMDI in adolescents was not higher than that in adults. Furthermore, there were no safety or tolerability signals to warrant a reduction in the dose of BDP/FF/GB for adolescents with asthma., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Objective: To evaluate the efficacy and safety of three doses of glycopyrrolate metered dose inhaler (GP MDI) in patients with uncontrolled asthma despite treatment with inhaled corticosteroid/long-acting β 2 -agonists (ICS/LABA) with or without tiotropium, to characterize the benefit of triple therapy., Method: This phase II/III, double-blind study randomized patients to 24 weeks' treatment with twice-daily GP MDI 36 µg, 18 µg, 9 µg, or placebo MDI (all delivered via Aerosphere inhalers), or once-daily open-label tiotropium 2.5 µg. Patients continued their own ICS/LABA regimen throughout the study. The primary endpoint was change from baseline in forced expiratory volume in 1 s (FEV 1 ) area under the curve from 0 - 4 h (AUC 0 - 4 ) at Week 24. Secondary endpoints included patient questionnaires to measure asthma control or symptoms. Safety was also assessed., Results: The primary analysis (modified intent-to-treat) population included 1066 patients. The primary study endpoint was not met (changes from baseline in FEV 1 AUC 0 - 4 at Week 24 were 294 mL, 284 mL, 308 mL, 240 mL, and 347 mL for GP MDI 36 µg, GP MDI 18 µg, GP MDI 9 µg, placebo, and open-label tiotropium, respectively). There were no significant differences between treatment and placebo in secondary endpoints at Week 24. Post-hoc analyses using post-bronchodilator FEV 1 as the baseline measurement, or averaging values across multiple baseline visits, showed a dose-related response to GP MDI. The incidence of adverse events was low and similar across treatments., Conclusion: Although this study did not meet its primary endpoint, post hoc analyses identified a dose-related response to GP MDI when alternative definitions of baseline FEV 1 were used in the analyses.

Background: Hyperhidrosis of the palms has a significant negative impact on quality of life. There is no FDA-approved treatment; however, clinicians often use glycopyrronium cloth off-label for this indication despite the lack of published guidance on optimal method of application for treatment of palms., Objective: To compare the safety and efficacy of 4 different methods of application of glycopyrronium cloth to give clinicians guidance when treating palmar hyperhidrosis., Study Design: This study, conducted completely virtually using live interactive telemedicine, compared application times of 15 minutes, 30 minutes, and overnight without occlusion and 30 minutes under occlusion. The primary endpoint was a decrease in the mean of the Hand Severity Score (HHS) after 4 weeks of once-daily application. Safety data, including local skin reactions and other adverse events, were tabulated by cohort., Results: Of the application times and methods tested, 30 minutes without occlusion produced the greatest decrease in the HHS with an acceptable safety profile. The most common adverse event was unilateral mydriasis, which presumably occurred from inadvertent introduction of study drug into the eye despite multiple warnings to the subjects to avoid eye contact. A few subjects had adverse events presumably due to systemic absorption of the drug similar to those seen in the pivotal trials for treatment of axillary hyperhidrosis., Conclusion: Glycopyrronium cloth can be used successfully to treat palmar hyperhidrosis. Occlusion for 30 minutes had the poorest response presumably due to the increased sweating causing dilution of the study drug., Clinicaltrials: gov: NCT04906655 J Drugs Dermatol. 2022;21(5):488-494. doi:10.36849/JDD.6688.

Background: Pediatric sedation is a clinical activity with potential for serious but rare airway adverse events, particularly laryngospasm. Anticholinergic drugs, atropine and glycopyrrolate, are frequently used with the intention to improve sedation safety by virtue of their antisialagogue effects., Aims: The objective of this study is to describe the current practice of anticholinergic use in pediatric sedation and to compare the frequency of serious sedation-related adverse events in patients who received anticholinergics to those who did not., Methods: We examined prospectively collected data from the Pediatric Sedation Research Consortium database. Patient characteristics, procedure type, sedation provider, sedatives, location of sedation, anticholinergic administered, adverse events, and airway interventions were reported. Propensity score matching and multivariable logistic regression were used to test whether any association exists between anticholinergic use and serious sedation-related adverse events., Results: Anticholinergics were administered in 7.1% (n = 18 707) of all cases (n = 263 883) reported between November 2011 and October 2017. When anticholinergics were used, atropine was used in 22% (n = 4111) and glycopyrrolate in 78.1% (n = 14 601) of sedations. Use of anticholinergics was more common in patients with well-described risk factors for airway adverse events: active/history of upper respiratory infection, history of reactive airway disease/asthma, and exposure to smoke. However, infants and ASA 3 patients were not associated with higher rate of anticholinergic use. Anticholinergic use was independently associated with an increase in the odds of serious adverse events, OR 1.8 (95% CI 1.6-2.1), especially airway adverse events., Conclusions: In this large Pediatric Sedation Research Consortium study, we found the use of anticholinergic adjuvants independently associated with greater odds of serious adverse events, especially airway adverse events, after adjusting for well-known sedation risk factors using propensity score matching and multivariate analysis., (© 2022 John Wiley & Sons Ltd.)

Background: Long-acting beta-agonists (LABA) and long-acting muscarinic antagonists (LAMA) combination therapy improved lung function and health-related quality-of-life and reduced exacerbation rates and dyspnea in symptomatic chronic obstructive pulmonary disease (COPD) patients. We compared the real-world effects of three fixed-dose LABA/LAMA combinations for COPD in Taiwan., Methods: This multicenter, retrospective study evaluated 1-year outcomes after LABA/LAMA combination therapy in patients with symptomatic COPD. Exacerbations and symptoms of COPD, lung functions, and therapy escalation were compared among patients using tiotropium/olodaterol, umeclidinium/vilanterol and indacaterol/glycopyrronium. Propensity score matching (PSM) was applied to balance the baseline characteristics., Results: Data of 1,617 patients were collected. After PSM, time to first moderate-to-severe COPD exacerbation was comparable among three groups, while the annualized rates of the exacerbation (episodes/patient/year) in patients receiving tiotropium/olodaterol (0.19) or umeclidinium/vilanterol (0.17) were significantly lower than those receiving indacaterol/glycopyrronium (0.38). COPD-related symptoms were stable over the treatment period, and there was no significant difference in the changes of symptom scores including CAT and mMRC among three groups at the end of the study period., Conclusion: This study presented valuable real-world outcome in terms of exacerbation and treatment response of COPD patients treated with fixed-dose LABA/LAMA regimens in Taiwan. The annualized rates of moderate-to-severe exacerbation in patients receiving tiotropium/olodaterol or umeclidinium/vilanterol were significantly lower than those receiving indacaterol/glycopyrronium, though the time to first moderate-to-severe exacerbation was similar among different fixed-dose LABA/LAMA combinations., Competing Interests: The authors declare no conflicts of interest for this work. The authors did not receive payment related to the development of the manuscript and publication., (© 2022 Hsieh et al.)

Objective To evaluate the long-term safety and efficacy of indacaterol/glycopyrronium (IND/GLY) in patients with chronic obstructive pulmorary disease (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 (FEV 1 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.

Glycopyrronium tosylate cloth, an anticholinergic drug, has been approved for the topical treatment of primary axillary hyperhidrosis in the USA, but its effects in Japanese patients have not been previously investigated. This 4-week, randomized, double-blind, vehicle-controlled, multicenter study was conducted to evaluate the efficacy and safety of glycopyrronium tosylate cloth for primary axillary hyperhidrosis patients in Japan. Eligible patients, who were ≥9 years of age and had primary axillary hyperhidrosis ≥6 months, with gravimetrically-measured sweat production ≥50 mg/5 min, and Hyperhidrosis Disease Severity Scale ≥3 (moderate) were randomized 1:1:1 to once daily topical glycopyrronium tosylate 3.75%, 2.5%, or vehicle. Overall, 497 patients (163 in the glycopyrronium tosylate 3.75% group, 168 in the glycopyrronium tosylate 2.5% group, and 166 in the vehicle group, hereinafter in this order) were randomized. Statistically higher proportions of patients in the glycopyrronium tosylate groups achieved ≥2-point improvement in Hyperhidrosis Disease Severity Scale and ≥50% reduction in sweat production from baseline versus vehicle at week 4 (51.6%, 41.1%, and 16.4%, respectively; p < 0.001 in both cases). Higher responder rates in the glycopyrronium tosylate groups compared with the vehicle group occurred as early as week 1. The most common treatment-emergent adverse events in patients treated with glycopyrronium tosylate were photophobia, mydriasis, thirst, and dysuria. Most treatment-emergent adverse events were mild as determined by the investigators. The incidence of treatment-emergent adverse events leading to treatment modification was low in the three groups. The 4-week use of topical glycopyrronium tosylate improved the patient-reported outcome measure Hyperhidrosis Disease Severity Scale and objectively-evaluated sweat production with a favorable benefit/risk profile., (© 2021 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Introduction: Fixed-dose long-acting beta2-agonist (LABA)/inhaled corticosteroid (ICS) combinations and add-on therapies as needed are the mainstay for maintenance therapy in asthma. However, more than 40% of patients have an inadequately controlled disease. The development of triple fixed-dose combinations consisting of long-acting muscarinic antagonist (LAMA)/LABA/ICS has paved the way for a new approach to reach therapeutic goals of an optimal control of symptoms and an effective prevention of future exacerbations., Areas Covered: A search was conducted on PubMed (MEDLINE), using the MeSH terms [asthma] + [indacaterol] + [glycopyrronium] +[mometasone furoate] + [treatment], until October 2021. Original data from clinical trials, prospective and retrospective studies and reviews were selected. Clinical studies with IND/MF/GLY (Enerzair Breezhaler) are summarized, and its place in current asthma therapy is examined., Expert Opinion: Triple therapy has been shown to be an effective and safe therapeutic option for asthma patients who remain uncontrolled despite ICS/LABA combination. The recently approved single-inhaler indacaterol/glycopyrronium/mometasone fixed dose combination has demonstrated to significantly reduce exacerbations, improve FEV 1 , symptoms and quality of life compared to ICS/LABA, including, salmeterol/fluticasone combination. Moreover, once-daily dosing may improve adherence.

Background: The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest., Methods: Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias., Results: Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m 2 , age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study., Conclusions: Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants., Trial Registration: ClinicalTrials.gov Identifier: NCT03346057 ., (© 2021. The Author(s).)

Background: Effective topical treatment options for patients with primary axillary hyperhidrosis (PAHH) are limited. A phase I trial showed promising results regarding the efficacy and safety of a topical cream containing glycopyrronium bromide (GPB)., Objectives: To assess the efficacy, safety and tolerability of a 4-week topical treatment of GPB 1% cream in patients with PAHH vs. placebo., Methods: In total, 171 patients (84 receiving placebo; 87 receiving GPB 1%) with PAHH were included in the 4-week, multicentre, randomized, double-blind, placebo-controlled phase IIIa part of the pivotal study. Sweat production was measured by gravimetry. Patients rated the impact of disease with the Hyperhidrosis Disease Severity Scale (HDSS) and Hyperhidrosis Quality of Life Index (HidroQoL © )., Results: Absolute change in sweat production from baseline to day 29 in logarithmic values was significantly larger in the GPB 1% group compared with the placebo group (P = 0·004). The improvement in HidroQoL exceeded the minimal clinically important difference of 4. The proportion of responders was twofold higher for sweat reduction (-197·08 mg GPB 1% vs. -83·49 mg placebo), HDSS (23% GPB 1% vs. 12% placebo) and HidroQoL (60% GPB 1% vs. 26% placebo). Treatment was safe: most treatment-emergent adverse effects were mild or moderate, and transient. Local tolerability was very good, with 9% of patients having only mild or moderate application-site reactions. The most reported adverse drug reaction was dry mouth (16%), an expected anticholinergic effect of the treatment., Conclusions: GPB 1% cream may provide an effective new treatment option exhibiting a good safety profile for patients with PAHH. The long-term open-label part (phase IIIb) is ongoing., (© 2021 Dr August Wolff GmbH und Co KG Arzneimittel. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Bronchodilators are the cornerstone for treating patients with chronic obstructive pulmonary diseases (COPD), although some studies have shown that dual bronchodilators may exacerbate incidence of adverse cardiovascular events. Here, we evaluated the cardiopulmonary safety of indacaterol/glycopyrronium (IND/GLY) using a meta-analysis., Methods: We searched PubMed, OVID, Cochrane Library and Web of Science databases, using "indacaterol/glycopyrronium", "indacaterol/glycopyrrolate", "IND/GLY", "QVA149", "chronic obstructive pulmonary diseases", "COPD", "chronic obstructive airway disease", "chronic obstructive lung disease" as key words. Acute exacerbation of COPD and FEV 1 as indicators of pulmonary function and occurrence of hypertension, atrial fibrillation, myocardial infarction and heart failure as indicators of cardiovascular safety., Results: A total of 23 articles, comprising 21,238 participants, were included in the analysis. FEV 1 values were significantly different compared to IND/GLY and single bronchodilator therapy (LABA or LAMA), with the MD 0.11 L (95%CI: 0.10-0.13, P<0.01). Hypertension was more frequent in the IND/GLY, than the single bronchodilator therapy group, although this difference was insignificant (IND/GLY vs LABA, RR=1.88, P = 0.09; IND/GLY vs LAMA, RR=1.42, P = 0.08; IND/GLY vs LABA+ICS, RR=1.85, P = 0.23). In addition, IND/GLY did not significantly increase the risk of myocardial infarction (IND/GLY vs LAMA or double therapy, total RR: 1.49, 95%CI: 0.72-3.08, P = 0.28), atrial fibrillation (IND/GLY vs LAMA, RR: 1.62, 95%CI: 0.64-4.10, P = 0.31) and heart failure (IND/GLY vs LAMA, RR: 0.40, 95%CI: 0.07-2.33, P = 0.31) in COPD patients., Conclusions: IND/GLY significantly reduced incidence of acute COPD exacerbations, and slowed down the decline of FEV 1 . Adequate safety measures are needed to control incidence of adverse cardiovascular events., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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 β 2 -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.

Background: Glycopyrronium tosylate (GT; Qbrexza ® [glycopyrronium] cloth, 2.4%) is a topical anticholinergic approved (USA) for primary axillary hyperhidrosis in patients aged ≥ 9 years., Objective: The objective of this study was to compare the pharmacokinetics and safety of GT to oral glycopyrrolate (phase I study) and assess the relationship between glycopyrronium pharmacokinetics and anticholinergic-related adverse events or efficacy with population pharmacokinetics using data from two phase II studies., Methods: In the phase I study, study staff applied GT to axillae of patients with primary axillary hyperhidrosis (aged 9-65 years) once daily (5 days); oral glycopyrrolate was administered to healthy adults (aged 18-65 years) every 8 hours (15 days). In the phase II studies (NCT02016885 [20 December, 2013], NCT02129660 [2 May, 2014]), adults with primary axillary hyperhidrosis applied topical glycopyrronium (0.8-3.2%) or vehicle to axillae once daily (4 weeks). Pharmacokinetic and adverse event data were collected in all studies., Results: Glycopyrronium pharmacokinetic parameters were similar between adult and pediatric patients treated with GT; there was no evidence of accumulation. Systemic absorption of glycopyrronium was lower with GT vs oral glycopyrrolate. No anticholinergic-related adverse events occurred with GT in the phase I study, while dry mouth and nasal dryness occurred with oral glycopyrrolate; anticholinergic adverse events occurred in the phase II studies. In the population pharmacokinetic analysis, frequency/severity of anticholinergic-related adverse events increased with higher glycopyrronium concentration; no relationship was observed between efficacy and pharmacokinetic measures., Conclusions: These studies indicate limited absorption of GT compared to oral glycopyrrolate and a low risk of anticholinergic adverse events with proper GT administration when following instructions for use (wipe each underarm once with same cloth, wash hands, avoid ocular contact).

Objective: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY)., Methods: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison., Results: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%)., Conclusions: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Anxiety and depression (A/D) are common in patients with chronic obstructive pulmonary disease (COPD) and are often associated with lower adherence to treatment and worse patient-related outcomes. However, studies on the impact of comorbid A/D on responses to bronchodilators are limited., Methods: This post hoc analysis of pooled data (N=861) from the GOLDEN 3 and 4 studies compared the efficacy and safety of nebulized glycopyrrolate (GLY) 25 µg in patients with moderate-to-very-severe COPD, grouped by self-reported A/D. Changes in forced expiratory volume in 1 second (FEV 1 ) and health-related quality of life determined by St George's Respiratory Questionnaire (SGRQ) scores in patients with or without comorbid A/D (A/D [+] or A/D [-]) were examined following 12 weeks of GLY 25 µg twice-daily (BID) or placebo treatment., Results: A/D (+) patients were predominantly female, younger, included a higher proportion of current smokers, and had higher baseline SGRQ scores compared with the A/D (-) group. At 12 weeks, GLY resulted in placebo-adjusted improvements from baseline in FEV 1 of 46.9 mL (p=0.19; not significant) and 106.7 mL (p<0.0001), in the A/D (+) and A/D (-) groups, respectively. Improvements were observed with GLY compared to placebo in SGRQ scores, regardless of baseline A/D status; the placebo-adjusted least squares mean change from baseline in SGRQ total scores was -3.16 (p>0.05) and -3.34 (p<0.001), for the A/D (+) and A/D (-) groups, respectively. Despite numerical improvements in SGRQ scores with GLY in the A/D (+) group, a higher response to placebo was observed. GLY was generally well tolerated throughout 12 weeks of treatment; incidence of adverse events was higher in the A/D (+) group compared with the A/D (-) group in both treatment arms., Conclusion: GLY 25 µg BID resulted in numerical improvements in FEV 1 , SGRQ total scores and SGRQ responder rates in patients with moderate-to-very-severe COPD, regardless of A/D status at baseline; significant improvements were noted only in the A/D (+) group. The results emphasize the importance of considering underlying comorbidities including A/D when evaluating the efficacy of COPD treatments., Competing Interests: NAH received honoraria for serving as a consultant or advisory boards for GlaxoSmithKline, Sanofi, Regeneron, Genentech, Novartis, Boehringer Ingelheim, Astra Zeneca, Teva, Amgen, and Mylan Pharmaceuticals. His institution receives research grant support from GlaxoSmithKline, Sanofi, Genentech, Gossamer Bio, Boehringer Ingelheim, Novartis, and AstraZeneca. AMY received an honorarium for consultation fees from AstraZeneca. AOG was an employee of Sunovion Pharmaceuticals Inc. at the time of the study and is currently an employee of Alexion Pharmaceuticals. MT, TG, SSh, and SSa are employees of Sunovion Pharmaceuticals Inc. The authors report no other conflicts of interest in this work., (© 2021 Hanania et al.)

Background: A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan., Methods: TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) < 50% predicted, ≥ 1 exacerbation in the previous 12 months, and receiving inhaled maintenance medication. Patients received either extrafine BDP/FF/G 100/6/10 µg via pressurised metered-dose inhaler, or non-extrafine budesonide/formoterol (BUD/FF) 160/4.5 µg via dry-powder inhaler, both administered as two puffs twice-daily for 24 weeks. The co-primary objectives (analysed in the overall population) were to demonstrate superiority of BDP/FF/G over BUD/FF for change from baseline in pre-dose morning and 2-h post-dose FEV 1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint., Results: Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV 1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p < 0.001]. The annualised moderate/severe exacerbation rate was 43% lower with BDP/FF/G [rate ratio 0.57 (95% CI 0.42, 0.77); p < 0.001]. Adverse events were reported by 61.1% and 67.0% patients with BDP/FF/G and BUD/FF. Results were similar in the China subgroup., Conclusions: In patients with COPD, FEV 1  < 50% and an exacerbation history despite maintenance therapy, treatment with extrafine BDP/FF/G improved bronchodilation, and was more effective at preventing moderate/severe COPD exacerbations than BUD/FF. Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html ).

Background: Indacaterol/glycopyrronium (IND/GLY) is a once-daily dual bronchodilator for long-term treatment of patients with chronic obstructive pulmonary disease (COPD). The efficacy and safety of IND/GLY have been proved before, but the cost-effectiveness is unknown in China., Purpose: This study assessed cost-effectiveness of IND/GLY comparing with salmeterol/fluticasone (SAL/FLU) and tiotropium., Methods: A patient-level simulation model was established from Chinese payer perspective. Patient parameters were randomly simulated through resampling from parameter distributions based on clinical trials and China-specific cost data to represent individual level health state and health state transitions in the model. We simulated patient-level health state, costs, life years (LYs) and quality-adjusted life years (QALYs) of whole life horizon to evaluate the cost-effectiveness of IND/GLY comparing with SAL/FLU and tiotropium respectively., Results: Comparing with SAL/FLU, IND/GLY resulted in 0.384 LYs and 0.255 QALYs gained. The incremental cost-effectiveness ratio (ICER) is -35,822 CNY/LY and the incremental cost-utility ratio (ICUR) is -53,834 CNY/QALY for IND/GLY versus SAL/FLU. Comparing with tiotropium, IND/GLY resulted in 0.232 LYs and 0.146 QALYs gained. The ICER is 39,729 CNY/LY and the ICUR is 63,246 CNY/QALY for IND/GLY versus tiotropium., Conclusion: This study found that dual bronchodilator IND/GLY is cost-effective for stable COPD treatment in China from Chinese payer's perspective., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Gong et al.)

Purpose: In the Phase III, 24-week KRONOS study (NCT02497001), triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) reduced exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and no requirement for a history of exacerbations. We report a post hoc analysis investigating whether the benefits observed were driven by patients with ≥1 exacerbation in the 12 months prior to the study., Patients and Methods: Patients received BGF MDI 320/18/9.6 µg, GFF MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 µg twice-daily. Post hoc analyses were conducted on exacerbation and lung function results from patients with and without a documented exacerbation in the 12 months prior to the study., Results: Overall, 74% (1411/1896) of the modified-intent-to-treat (mITT) population had no moderate/severe exacerbations in the 12 months prior to the study. BGF MDI reduced exacerbation rates versus GFF MDI in the prior (58%; unadjusted p =0.0003) and no prior (48%; unadjusted p =0.0001) exacerbations subgroups. The magnitude of reduction in exacerbation rates was generally similar within subgroups for BGF MDI versus BFF MDI and BUD/FORM DPI. In the prior exacerbations subgroup, risk during treatment for time to first exacerbation was lower with BGF MDI versus GFF MDI ( p =0.0022) and BFF MDI ( p =0.0110); excluding the first 30 days of data yielded similar results. The magnitude of reduction in exacerbation rates for BGF MDI compared with GFF MDI increased with eosinophil count., Conclusion: In patients with or without a history of exacerbations in the 12 months prior to the study, BGF MDI reduced exacerbation rates versus GFF MDI, suggesting results observed in the overall population were not driven by the small subgroup with a prior history of exacerbations., Competing Interests: FJM reports grants from AstraZeneca during the conduct of the study; personal fees and non-financial support from AbbVie, Afferent Pharmaceuticals Inc/Merck, Bayer, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, DevPro, Gala, Genentech, Gilead, GlaxoSmithKline, IQVIA, Nitto, Novartis, Promedior/Roche, ProterrixBio, Raziel, Patara/Respivant, Sanofi/Regeneron, Sunovion, Teva, TwoXAR, Veracyte, Verona, Zambon; and grants from National Institutes of Health, outside of the submitted work. GTF reports grants, personal fees, and non-financial support from AstraZeneca during the conduct of the study; grants, personal fees, and non-financial support from AstraZeneca, Boehringer Ingelheim, Novartis, and Sunovion; grants and personal fees from Theravance; and personal fees from Circassia, Galderma, GlaxoSmithKline, Innoviva, Mylan, Orpheris, Sanofi, Teva, and Verona, grants from Altavant and Knopp, outside of the submitted work. PDa, MA, and PDo are employees of AstraZeneca and hold stock and/or stock options in the company. SB is a former employee of AstraZeneca. EB and CR are former employees of AstraZeneca and hold stock and/or stock options in the company. The authors report no other conflicts of interest in this work., (© 2021 Martinez et al.)

Background: 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., Competing Interests: LR has received grants/research supports from Roche and Boehringer Ingelheim; he has received honoraria or consultation fees from Boehringer Ingelheim, Promedior, Biogen, FibroGen, Sanofi-Aventis, Promedior, RespiVant, Roche, Celgene, Nitto, and Veracyte. FM declares no conflict of interests. AP, EI and GM are employees of Chiesi Italia, Parma, Italy. The authors report no other conflicts of interest in this work., (© 2021 Richeldi et al.)

Introduction : Sugammadex has been shown to be associated with prolongation of prothrombin time and activated partial thromboplastin time. However, it is not known whether it could be associated with enhancing postoperative hypocoagulation. The objective of this study was to analyze the effect of 4 mg/kg of sugammadex on thromboelastography (TEG) parameters in surgical patients. Methods: After Institutional Review Board approval, a prospective double-blinded randomized controlled study was conducted between September 2016 and April 2017. Sixty adult patients scheduled for laparoscopic abdominal surgery were randomly allocated to receive either sugammadex 4 mg/kg (sugammadex group) or pyridostigmine 0.15 mg/kg in combination with glycopyrrolate 0.4 mg (control group) to reverse rocuronium-induced neuromuscular blockade at the completion of surgery. Blood samples were collected three time points; After the final suture of surgery (baseline) (T1), and at 10 min (T2) and 1 h (T3) after administration of the study drug. Whole blood was analyzed by TEG using TEG 5000 (Hemonetics Corp, Braintree, MA, USA). The primary endpoints were comparison of coagulation time (K, time to 20 mm clot amplitude), R (reaction time), alpha angle, and maximal amplitude (MA) between two groups. Results: Coagulation time was significantly prolonged in sugammadex group after 10 min of the study drug administration compared to control group (mean value 1.3 ± 0.4 vs. 1.5 ± 0.4, P = 0.03). However, R, alpha angle and MA value were not different between two groups. Conclusions: Sugammadex 4 mg/kg showed an increase in coagulation time in surgical patients. Physician should aware the potential enhancement of hypocoagulation by sugammadex in the setting of high risk of postoperative bleeding., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Study Design: The study is designed as a retrospective cohort study., Objective: The aim of this study was to identify modifiable and nonmodifiable risk factors of postoperative urinary retention in spine surgery patients., Summary of Background Data: Postoperative urinary retention is a common complication in patients undergoing operative procedures requiring anesthesia. Current studies have shown significant risk factors for postoperative urinary retention, but most are nonmodifiable and subsequently of limited usefulness in preventing this complication. Several new studies have shown possible modifiable risk factors, but current data are inconsistent in terms of their statistical significance., Methods: A total of 814 consecutive patients who underwent open posterior lumbar laminectomy and fusion were included in the retrospective cohort study. Pre, intra-, and postoperative characteristics were collected in all patients to identify risk factors for postoperative urinary retention., Results: Glycopyrrolate use (odds ratio [OR] 2.60; P = 0.001), decreased body mass index (OR 0.96; P = 0.018), previous diagnosis of benign prostate hyperplasia (OR 3.34; P ≤ 0.001), and postoperative urinary tract infection (OR 5.60, P = 0.005) were associated with postoperative urinary retention. Previous history of lumbar spine surgery (OR 0.55; P = 0.019) was associated with decreased rates of postoperative urinary retention., Conclusion: Glycopyrrolate use, benign prostate hyperplasia, and postoperative urinary tract infection were independent risk factors for postoperative urinary retention. The use of glycopyrrolate is a potentially modifiable risk factor for postoperative urinary retention.Level of Evidence: 3., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Three 52-week studies in COPD have assessed the efficacy and safety of single-inhaler extrafine formulation triple therapy combining beclomethasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) delivered via pressurized metered-dose inhaler (pMDI). BDP/FF/G is now being developed for delivery via multi-dose dry-powder inhaler (DPI; NEXThaler). This study aimed to demonstrate non-inferiority of BDP/FF/G DPI vs pMDI for lung function., Methods: Multicenter, randomized, double-blind, double-dummy, active-controlled, three-way cross-over study in patients with COPD and post-bronchodilator forced expiratory volume in 1 second (FEV 1 ) 30-80% predicted. Patients received BDP/FF/G 100/6/10µg via DPI and pMDI, and BDP/FF 100/6µg via pMDI, all two inhalations twice daily for four weeks, with treatments separated by two-week washout. The two co-primary objectives were to demonstrate non-inferiority between the two BDP/FF/G formulations for FEV 1 area under the curve between 0 and 12 hours post-dose (AUC 0-12h ) normalized by time and trough FEV 1 at 24 hours, both on Day 28. EudraCT 2017-004405-41., Results: Of 449 patients screened, 366 were randomized, with 342 (93.4%) completing all three treatment periods. The primary objectives were met, with changes from baseline in FEV 1 AUC 0-12h and trough FEV 1 on Day 28 similar for the two BDP/FF/G formulations, and the confidence intervals for the difference lying entirely within the pre-specified non-inferiority criterion (-50mL): -20 (-35, -6) mL and 3 (-15, 20) mL for AUC 0-12h and trough FEV 1 , respectively. BDP/FF/G pMDI and DPI were statistically superior to BDP/FF for these endpoints (p<0.001). A similar proportion of patients experienced adverse events with each treatment (15.5%, 18.7% and 15.4% with BDP/FF/G DPI and pMDI, and BDP/FF, respectively); the majority were mild or moderate, with few related to treatment., Conclusion: Extrafine BDP/FF/G DPI and pMDI demonstrated similar efficacy and safety in patients with COPD, supporting the DPI formulation as a valid alternative., Competing Interests: KMB is a full time employee of insaf Respiratory Research Institute. He has received personal or institutional compensations for services on advisory boards or consulting for AstraZeneca, Berlin Chemie, Boehringer, Chiesi, Elpen, GSK, Mundipharma, Novartis, Pohl Boskamp, Sanofi, sterna and Zentiva, and compensations for speaker activities in scientific meetings supported by AstraZeneca, Berlin Chemie, Boehringer, ERT, GSK, Novartis, Pfizer, Pohl Boskamp, Sanofi and Teva, all outside the submitted work. The institution has received compensations for design and performance of clinical trials from AstraZeneca, Boehringer, Chiesi, GSK, Novartis, Parexel, Pearl Therapeutics, sterna, and Zentiva. PK reports personal fees from Chiesi, Novartis, AstraZeneca, Boehringer Ingelheim, Berlin Chemie Menarini, Adamed, Polpharma and Lekam, all outside the submitted work and reports lectures for Novartis, GSK, Teva, AstraZeneca, Polpharma, and Lekam, outside the submitted work. MC received grants and honoraria for lectures from Chiesi Farmaceutici SpA, outside the submitted work. IV, AG and GG are employees of Chiesi Farmaceutici SpA, the sponsor of the study. The authors report no other potential conflicts of interest for this work., (© 2021 Beeh et al.)

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 FEV 1 area under the curve over 12 h (AUC 0-12 ) (mean difference 104 mls, p = 0.0071) and RV AUC 0-12 (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) AUC 0-12 , 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 FEV 1 AUC 0-12 (mean difference 227 mls) and improved RV AUC 0-12 (mean difference - 558 mls) and R5-R20 AUC 0-12 (mean difference - 0.117 kPa/L/s), all p < 0.0001., Conclusions: In COPD patients with hyperinflation, the G and F components of extrafine BDP/F/G improved FEV 1 , 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 ).

Primary focal hyperhidrosis is a common reason for dermatology outpatient visit and has significant impact on patient's social and professional activities. The study describes the clinical profile of those patients and response with aluminum chloride hexahydrate lotion (ACH 20%) and oral glycopyrrolate (OGP). A retrospective study was carried out at a tertiary care center between the year 2016 and 2018. Details of history, baseline assessment, treatment response recorded in specially designed proformas were analyzed. Initially, the patients received topical ACH daily at night. Non-responders were advised OGP 1 mg BD and increased to 2 mg BD if they did not respond. Response was measured according to patient global assessment and objective evaluation of sweating. Among total 69 patients 57 had onset <10 years of age. There was male preponderance and most common trigger was situations causing anxiety (n = 15). Around 15.3% patients got adequate response with ACH lotion. The cumulative response increased to 45.8% by addition of OGP 1 mg BD and to 55.9% by increasing the dose to 2 mg BD. Addition of OGP to topical ACH increases the treatment efficacy in patients with primary focal hyperhidrosis. Increasing the glycopyrrolate dose augments the response further. However, the current medical treatment options are able to give moderate response., (© 2020 Wiley Periodicals LLC.)

Oral anticholinergics such as oxybutynin (OOx) and glycopyrrolate (OGly) are frequently used in the management of hyperhidrosis. Although OOx is considered currently the anticholinergic drug of first choice, OGly is a safe and effective alternative if OOx fails. The aim of this study was to identify the main variables associated with treatment adherence by patients receiving OGly, for whom previous treatment with OOx had failed. A prospective study was conducted of patients with hyperhidrosis receiving treatment with OGly in the period 2012 to 2019. Epidemiological variables, treatment details, effectiveness and adverse effects were recorded. A total of 58 patients (41 women), with a mean age of 35.9 years, were included in the study. The median follow-up period was 32 months. At 3 months, 70.7% of the patients had responded to treatment (excellent response: 75.6%), and adverse effects were reported by 70.7%. At 12 months, 53.4% had responded (excellent response: 74.2%), with adverse effects in 70.9%. The variables associated with poorer adherence were affected areas: palms of the hands, soles of the feet and armpits. The only variable associated with greater adherence was the generalized presence of hyperhidrosis. Our results provide valuable insights into the outcomes achieved when OGly is used to treat hyperhidrosis., (© 2020 Wiley Periodicals LLC.)

The condition of most patients with hyperhidrosis (HH) is known to worsen with increased temperature. However, most prior studies of oral glycopyrrolate (OGly) for the treatment of HH have assumed a stable treatment protocol, without taking into account seasonal variations in temperature. The main aim of this study is to evaluate the outcomes derived from performing a seasonal adjustment of the dose of OGly for patients with HH. A prospective study of patients who began OGly for HH, and maintained treatment for at least 1 year, was performed. All patients had experienced treatment failure with oral oxybutynin. All were recommended to vary the dose of medication according to the time of year. Of the 35 patients included in the study, 20 (57.14%) varied the dose. Those with palmar and plantar HH had a greater propensity to do so. The patients who varied the dose according to the time of year were significantly more likely to report an "Excellent" response after 12 months of treatment. The frequency of adverse effects was 71.4% with no significant differences among the study groups. However, there was a significantly higher proportion of adverse effects other than oral xerosis in the group that did not vary the dose., (© 2020 Wiley Periodicals LLC.)