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Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

Corneal confocal microscopy (CCM) is emerging as a tool for identifying small fiber neuropathy in both peripheral neuropathies and neurodegenerative disease of the central nervous system (CNS). The value of corneal nerves as biomarkers for efficacy of clinical interventions against small fiber neuropathy and neurodegenerative disease is less clear but may be supported by preclinical studies of investigational agents. We, therefore, used diverse investigational agents to assess concordance of efficacy against corneal nerve loss and peripheral neuropathy in a mouse model of diabetes. Ocular delivery of the peptides ciliary neurotrophic factor (CNTF) or the glucagon-like peptide (GLP) analog exendin-4, both of which prevent diabetic neuropathy when given systemically, restored corneal nerve density within 2 weeks. Similarly, ocular delivery of the muscarinic receptor antagonist cyclopentolate protected corneal nerve density while concurrently reversing indices of systemic peripheral neuropathy. Conversely, systemic delivery of the muscarinic antagonist glycopyrrolate, but not gallamine, prevented multiple indices of systemic peripheral neuropathy and concurrently protected against corneal nerve loss. These data highlight the potential for use of corneal nerve quantification by confocal microscopy as a bridging assay between in vitro and whole animal assays in drug development programs for neuroprotectants and support its use as a biomarker of efficacy against peripheral neuropathy.

Background: Bronchodilators are used to treat asthma symptoms. The administration of this therapy can be given through monotherapy or in combination to achieve the maximum therapeutic effect. Objective: This study aimed to examine the prescribing pattern of bronchodilators in asthmatic outpatients. Methods: A retrospective study was done by reviewing and analyzing medical records of asthmatic outpatients from January 2019 until December 2020. Data analysis was performed descriptively. Results: In this study, bronchodilators were administered by inhalation 97.4% compared to oral routes 2.6%. Combination bronchodilator therapy showed 54.7% compared to monotherapy by 46.3%. The combination ICS/LABA budesonide/formoterol 160/4.5 mcg was the most widely used 45.7%. Conclusion: The use of a bronchodilator was in accordance with the Global Initiative for Asthma guidelines. The route of drug administration through inhalation is more widely used than oral. Combination bronchodilators were more recommended than bronchodilator monotherapy to control asthma symptoms.

Background: Bronchodilators are used to treat asthma symptoms. The administration of this therapy can be given through monotherapy or in combination to achieve the maximum therapeutic effect. Objective: This study aimed to examine the prescribing pattern of bronchodilators in asthmatic outpatients. Methods: A retrospective study was done by reviewing and analyzing medical records of asthmatic outpatients from January 2019 until December 2020. Data analysis was performed descriptively. Results: In this study, bronchodilators were administered by inhalation 97.4% compared to oral routes 2.6%. Combination bronchodilator therapy showed 54.7% compared to monotherapy by 46.3%. The combination ICS/LABA budesonide/formoterol 160/4.5 mcg was the most widely used 45.7%. Conclusion: The use of a bronchodilator was in accordance with the Global Initiative for Asthma guidelines. The route of drug administration through inhalation is more widely used than oral. Combination bronchodilators were more recommended than bronchodilator monotherapy to control asthma symptoms. [ABSTRACT FROM AUTHOR]

Muscarinic receptors (mAChRs) are typical members of the G protein-coupled receptor (GPCR) family and exist in five subtypes from M1 to M5. Muscarinic receptor subtypes do not sufficiently differ in affinity to orthosteric antagonists or agonists; therefore, the analysis of receptor subtypes is complicated, and misinterpretations can occur. Usually, when researchers mainly specialized in CNS and peripheral functions aim to study mAChR involvement in behavior, learning, spinal locomotor networks, biological rhythms, cardiovascular physiology, bronchoconstriction, gastrointestinal tract functions, schizophrenia, and Parkinson's disease, they use orthosteric ligands and they do not use allosteric ligands. Moreover, they usually rely on manufacturers' claims that could be misleading. This review aimed to call the attention of researchers not deeply focused on mAChR pharmacology to this fact. Importantly, limited selective binding is not only a property of mAChRs but is a general attribute of most neurotransmitter receptors. In this review,wewant to give an overview of the most common off-targets for established mAChR ligands. In this context, an important point is a mention the tremendous knowledge gap on off-targets for novel compounds compared to very well-established ligands. Therefore, we will summarize reported affinities and give an outline of strategies to investigate the subtype's function, thereby avoiding ambiguous results. Despite that, the multitargeting nature of drugs acting also on mAChR could be an advantage when treating such diseases as schizophrenia. Antipsychotics are a perfect example of a multitargeting advantage in treatment. A promising strategy is the use of allosteric ligands, although some of these ligands have also been shown to exhibit limited selectivity. Another new direction in the development of muscarinic selective ligands is functionally selective and biased agonists. The possible selective ligands, usually allosteric, will also be listed. To overcome the limited selectivity of orthosteric ligands, the recommended process is to carefully examine the presence of respective subtypes in specific tissues via knockout studies, carefully apply "specific" agonists/antagonists at appropriate concentrations and then calculate the probability of a specific subtype involvement in specific functions. This could help interested researchers aiming to study the central nervous system functions mediated by the muscarinic receptor. [ABSTRACT FROM AUTHOR]

Muscarinic receptors (mAChRs) are typical members of the G protein-coupled receptor (GPCR) family and exist in five subtypes from M1 to M5. Muscarinic receptor subtypes do not sufficiently differ in affinity to orthosteric antagonists or agonists; therefore, the analysis of receptor subtypes is complicated, and misinterpretations can occur. Usually, when researchers mainly specialized in CNS and peripheral functions aim to study mAChR involvement in behavior, learning, spinal locomotor networks, biological rhythms, cardiovascular physiology, bronchoconstriction, gastrointestinal tract functions, schizophrenia, and Parkinson’s disease, they use orthosteric ligands and they do not use allosteric ligands. Moreover, they usually rely on manufacturers’ claims that could be misleading. This review aimed to call the attention of researchers not deeply focused on mAChR pharmacology to this fact. Importantly, limited selective binding is not only a property of mAChRs but is a general attribute of most neurotransmitter receptors. In this review, we want to give an overview of the most common off-targets for established mAChR ligands. In this context, an important point is a mention the tremendous knowledge gap on off-targets for novel compounds compared to very well-established ligands. Therefore, we will summarize reported affinities and give an outline of strategies to investigate the subtype’s function, thereby avoiding ambiguous results. Despite that, the multitargeting nature of drugs acting also on mAChR could be an advantage when treating such diseases as schizophrenia. Antipsychotics are a perfect example of a multitargeting advantage in treatment. A promising strategy is the use of allosteric ligands, although some of these ligands have also been shown to exhibit limited selectivity. Another new direction in the development of muscarinic selective ligands is functionally selective and biased agonists. The possible selective ligands, usually allosteric, will also be listed. To overcome the limited selectivity of orthosteric ligands, the recommended process is to carefully examine the presence of respective subtypes in specific tissues via knockout studies, carefully apply “specific” agonists/antagonists at appropriate concentrations and then calculate the probability of a specific subtype involvement in specific functions. This could help interested researchers aiming to study the central nervous system functions mediated by the muscarinic receptor.

Background: Chronic Obstructive Pulmonary Disease (COPD) has several implications on health, lifestyle, and economic burden. Combinational therapy using muscarinic antagonists and beta-2 agonists has long been warranted for use as maintenance therapy. A lack of studies directly comparing Glycopyrrolate/Formoterol (GFF) versus Tiotropium/Formoterol (TFF) was observed which led us to analyze the effectiveness of these combinations. Methods: In this pilot, prospective, randomized, open-label, parallel-arm, 12-week period study, 60 patients with COPD (moderate-severe) were randomized in a 1:1 ratio to receive either GFF or TFF (n = 30 each). The primary outcome was to demonstrate non-inferiority between the two groups concerning FEV1 for 12 weeks. The secondary outcome was the assessment of the ratio of FEV1/FVC and state of health evaluation by St. George's Respiratory Questionnaire (SGRQ). Results: Out of 60 participants, 58 subjects completed the study. At week 12, the mean and standard deviation value of FEV1 between groups were 1.49 ± 0.38 and 1.38 ± 0.30 (p > 0.05) and FEV1/FVC ratio were 0.67 ± 0.09 and 0.74 ± 0.08 (p

Purpose: The purpose of this scoping review was to identify existing clinical and basic science knowledge surrounding the effect of muscarinic receptor antagonism on allergen-induced airway responses to inform future clinical research in this area.Methods: Multiple advanced searches were performed using the National Library of Medicine PubMed search engine. Each search began with two terms; for example, "atropine and asthma" or "tiotropium and airway inflammation". Results were then further refined to include terms such as "allergen" or "ovalbumin (OVA)". Abstracts of refined searches were reviewed for relevance to allergic asthma and allergen-induced airway responses including the early and late asthmatic responses, airway inflammation and tissue remodelling. There was no restriction regarding publication date. Reference lists of selected papers were also reviewed for relevant publications.Results: Nine human clinical trial publications and fourteen animal model publications were identified. In humans, single dose atropine (n=4), ipratropium (n=4) or oxitropium (n=1) administered pre-challenge produced equivocal effects on allergen-induced early asthmatic responses as reported but favored inhibition in eight of nine studies after re-analyses. Animal model investigations (n=14) showed mostly favorable results, especially with respect to airway inflammation and tissue remodelling, although two studies were negative, and one study showed a worsening in allergen induced airway inflammation following muscarinic receptor antagonism.Conclusion: Existing human and animal model data suggest muscarinic receptor antagonism may be beneficial in preventing allergen induced airway responses in those with allergic asthma. Additional human research utilizing current standardized methodologies is required. [ABSTRACT FROM AUTHOR]

The urethral catheter is used in various clinical situations such as diagnosing urologic disease, urine drainage in patients after surgery, and for patients who cannot urinate voluntarily. However, catheters can cause numerous adverse effects, such as catheter-associated infection, obstruction, bladder stones, urethral injury, and catheter-related bladder discomfort (CRBD). CRBD symptoms vary among patients from burning sensation and pain in the suprapubic and penile areas to urinary urgency. CRBD significantly reduces patient quality of life and can lead to several complications. CRBD is caused by catheter-induced bladder irritation due to muscarinic receptor-mediated involuntary contractions of bladder smooth muscle and also can be caused by mechanical stimulus of the urethral catheter. Various pharmacologic studies for managing CRBD, including antimuscarinic and antiepileptic agents and botulinum toxin injections have been reported. If urologists can reduce patients’ CRBD, their quality of life and recovery can improve.

Abstract Introduction In pediatric patients with asthma, measurements of forced expiratory volume in 1 s (FEV1) may be normal or may not correlate with symptom severity. Forced expiratory flow at 25–75% of the vital capacity (FEF25–75%) is a potentially more sensitive parameter for assessing peripheral airway function. This post hoc analysis compared FEF25–75% with FEV1 as an endpoint to assess bronchodilator responsiveness in children with asthma. Methods Change from baseline in trough FEF25–75% and trough FEV1 following treatment with either tiotropium (5 µg or 2.5 µg) or placebo Respimat® was analyzed in four phase III trials in children (aged 6–11 years) and adolescents (aged 12–17 years) with symptomatic moderate (VivaTinA-asthma® and PensieTinA-asthma®) and mild (CanoTinA-asthma® and RubaTinA-asthma®) asthma. Data from all treatment arms were pooled and correlations between FEF25–75% and FEV1 were calculated and analyzed. Results A total of 1590 patients were included in the analysis. Tiotropium Respimat® consistently improved FEF25–75% and FEV1 versus placebo, although in adolescents with severe asthma, the observed improvements were not statistically significant. Improvements in FEF25–75% response with tiotropium versus placebo were largely more pronounced than improvements in FEV1. Statistical assessment of the correlation of FEV1 and FEF25–75% showed moderate-to-high correlations (Pearson’s correlation coefficients 0.73–0.80). Conclusions In pediatric patients, FEF25–75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than FEV1 and should be evaluated as an additional lung function measurement.

Bo Ding,1 Lee Kallenbach,2 Lukas Slipski,2 Alan Wilk,2 Dan O’Brien,2 Deniz Guranlioglu3 1AstraZeneca, Gothenburg, Sweden; 2Practice Fusion, San Francisco, CA, USA; 3AstraZeneca, Cambridge, UKCorrespondence: Bo DingAstraZeneca, Pepparedsleden 1, Gothenburg SE 431 83, Mölndal, SwedenTel +46 31 776 2406Email Bo.Ding@astrazeneca.comIntroduction: This retrospective, observational cohort study utilized an integrated dataset from an electronic health records system and a claims database to describe demographic and clinical characteristics, healthcare resource utilization (HCRU), and treatment patterns in COPD patients initiating long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combination (FDC) treatment in the USA.Methods: Patients were aged ≥ 40 years and had a COPD diagnosis (Practice Fusion system) and ≥ 1 prescription of LAMA/LABA FDC therapy, with an index date (first prescription) 1 May 2014– 31 December 2017. For the HCRU analysis, patients had ≥ 2 claims from the Symphony Health database within 12 months before index. All analyses of outcomes relating to demographic and clinical characteristics, HCRU, and treatment patterns were descriptive.Results: Patients initiating LAMA/LABA FDCs (n=8224) had a mean age of 67.9 years, 52.8% were female, and mean BMI was 29.2 kg/m2. The most common comorbidities were cardiovascular disease (74.3%), hypertension (64.0%), and hyperlipidemia (45.6%). In the 12 months prior to index, 53.1% of patients had used inhaled therapy: 23.4% short-acting therapy only, 16.7% short-acting and maintenance therapy, and 13.1% maintenance therapy only. Amongst users of inhaled therapies, the pMDI was the most frequently used device (64.3%, n=2812/4370). Of 7050 patients included in the HCRU analysis, 79.8% had COPD-related costs; mean cost/patient was $4174. Mean COPD-related costs per patient for moderate and severe exacerbations were $910 and $23,208, respectively. Per-patient costs included $23,032 for inpatient visits, $2358 for emergency visits, $4432 for outpatient visits, and $1989 for pharmacy claims.Conclusion: This observational study is the first to describe the real-world demographic and clinical characteristics and HCRU of patients initiating LAMA/LABA FDC treatment in the USA. Patients were generally elderly and overweight, with comorbidities of CVD, hypertension, and hyperlipidemia. Inpatient visits were the largest contributor to COPD-related costs per patient in the year prior to initiation of LAMA/LABA FDCs.Keywords: muscarinic antagonist, β2-agonist, demographic characteristics, disease characteristics, cost

Plain Language Summary Asthma is characterised by problems with the way that the lungs work, particularly narrowing of the airways. Doctors can measure the effect of asthma on someone’s breathing in different ways. We looked to see whether these different methods work for different people with asthma, and whether treatment affects all measurements in a similar way. Lung function was measured after treatment with a drug that opens the airways (tiotropium), and comparisons were made between adults and adolescents with asthma. We also looked at people with severe asthma and those whose asthma was less severe. Tiotropium improved all the measures of lung function in both age groups and across severities. One measure improved more in adults than in adolescents. This may be because adolescents had better lung function at the start and thus less room for improvement, or because the adolescents had not had asthma for as long, and so may have had less long-term damage to their airways than adults. Trial Registration Numbers: NCT00772538, NCT00776984, NCT01172808, NCT01172821, NCT01316380, NCT01257230.

Fernando J Martinez,1 Klaus F Rabe,2 Brian J Lipworth,3 Samir Arora,4 Martin Jenkins,5 Ubaldo J Martin,6 Colin Reisner6,7 1Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA; 2Department of Pneumonology, LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 3Division of Molecular and Clinical Medicine, Scottish Centre for Respiratory Research, Ninewells Hospital, University of Dundee, Dundee, Scotland, UK; 4Aventiv Research Inc., Columbus, OH, USA; 5Global Medicines Development, AstraZeneca, Cambridge, UK; 6Research and Development, AstraZeneca, Gaithersburg, MD, USA; 7R&D Biopharmaceuticals, AstraZeneca, Morristown, NJ, USACorrespondence: Fernando J MartinezJoan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th Street, Room M-522, Box 130, New York, NY 10065, USATel +1646 962 2748Email fjm2003@med.cornell.eduBackground: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a short-acting bronchodilator or single long-acting bronchodilator as an initial pharmacological treatment for GOLD category A patients with COPD. We pooled data from the PINNACLE-1, -2, and -4 studies to evaluate the efficacy and safety of the dual bronchodilator fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, in GOLD category A patients with moderate-to-very severe COPD.Materials and Methods: PINNACLE-1, -2, and -4 were Phase III, randomized, double-blind, parallel-group, multicenter studies (NCT01854645, NCT01854658, and NCT02343458). Patients received 24 weeks’ treatment with GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI twice daily. GOLD category A patients were identified based on a COPD Assessment Test score of 1), peak change from baseline in FEV1 within 2 hrs post-dose, and adverse events (AEs).Results: The pooled intent-to-treat population comprised 729 GOLD category A patients. GFF MDI significantly improved morning pre-dose trough FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences 54 mL, 62 mL, and 188 mL, respectively; all p≤0.0053), and peak FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (LSM differences 124 mL, 104 mL, and 307 mL, respectively; all p

Study Design: This study is a randomized, investigator-blinded, controlled trial with a non-inferiority design., Objective: To investigate the effectiveness of neuromodulation by transcutaneous electrical stimulation of the somatic afferent nerves of the foot in neurogenic detrusor overactivity (NDO) in persons with spinal cord injury (SCI) and compare its effectiveness with oral oxybutynin., Setting: The study was conducted in a rehabilitation in-patient ward of a tertiary care hospital., Methods: Twenty-nine persons with SCI with NDO, either sex, aged 18 years and above were randomized into two groups, one group receiving oral oxybutynin (5 mg thrice a day for two weeks) and the other transcutaneous electrical stimulation (5 Hz, 200 µs pulse, biphasic, amplitude up to 60 mA, 30 min/day for two weeks). Bladder capacity was evaluated by clinical bladder evaluation (i.e. bladder capacity measured by adding leak volume, voiding volume if any, and post-void residue using a catheter) and cystometric bladder capacity by one-channel cystometry. Maximum cystometric pressure was evaluated by one-channel water cystometry. Data were analyzed with Fisher's Exact, t-test, and Wilcoxon rank sum tests., Results: Bladder capacity improved significantly in the oxybutynin and neuromodulation groups as measured by one-channel water cystometry (136 ml vs. 120.57 ml) and clinical evaluation (138.93 ml vs. 112 ml). The increase in the neuromodulation group achieved the pre-decided non-inferiority margin of 30 ml over the oxybutynin group when measured by one-channel water cystometry but not by clinical evaluation. Maximum cystometric pressure did not significantly improve in either group when compared with the baseline., Conclusion: Transcutaneous neuromodulation and oxybutynin effectively increased bladder capacity in persons with SCI with NDO. Neuromodulation by once-a-day transcutaneous electrical stimulation was non-inferior to thrice-a-day oxybutynin when evaluated by one-channel water cystometry. Trial registration: Clinical Trials Registry India identifier: CTRI/2018/05/013735.

Charlie Strange,1 Valery Walker,2 Michael DePietro,3 Junliang Tong,2 Jonathan Kurlander,2 Maureen Carlyle,2 Lauren A Millette,3 Eric Wittbrodt41Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA; 2Health Economics and Outcomes Research, Optum, Inc., Eden Prairie, MN, USA; 3US Medical Affairs, AstraZeneca, Wilmington, DE, USA; 4Health Economics and Outcomes Research, AstraZeneca, Wilmington, DE, USABackground: This study compared real-world patient-reported outcomes (PROs) measured by the Clinical COPD Questionnaire (CCQ), the London Chest Activities of Daily Living (LCADL) scale, and the Work Productivity and Activity Impairment (WPAI) questionnaire between individuals with COPD initiating LAMA/LABA fixed-dose combination (FDC) dual therapy versus either long-acting muscarinic antagonist (LAMA) or long-acting beta2-agonist (LABA) monotherapy.Methods: Individuals with COPD aged ≥40 years initiating a LAMA/LABA FDC dual therapy or a LAMA or LABA monotherapy (index date = first prescription date) between January 1, 2016 and December 31, 2016 were identified from a large US administrative claims database. Individuals were excluded if they were prescribed an inhaled corticosteroid (ICS) or ICS/LABA two months prior to the index date or were diagnosed with cystic fibrosis, idiopathic pulmonary fibrosis, or asthma. The cohorts were propensity score matched (PSM) 1:1 for COPD severity using baseline measures. Each participant completed a survey.Results: Surveys were completed by 399 participants in the dual therapy cohort, and 718 participants in the monotherapy cohort. Following PSM, 379 participants remained in each cohort for analysis (monotherapy: 369 LAMA and 10 LABA). The dual therapy cohort reported fewer COPD-related symptoms (CCQ symptom score 2.75 vs 2.97, respectively, P=0.023), and, fewer limitations in leisure activities (LCADL leisure score 4.78 vs 5.17, respectively, P=0.021) versus the monotherapy cohort. No significant differences were found in the WPAI. A greater percentage of participants in the dual therapy cohort stayed on index therapy (63.1%) when compared with the monotherapy cohort (30.3%, P

Taisuke Jo,1,2 Nobuaki Michihata,1 Hayato Yamana,1 Yusuke Sasabuchi,3 Hiroki Matsui,4 Hirokazu Urushiyama,2 Akihisa Mitani,2 Yasuhiro Yamauchi,2 Kiyohide Fushimi,5 Takahide Nagase,2 Hideo Yasunaga4 1Department of Health Services Research, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 2Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 3Data Science Center, Jichi Medical University, Tochigi, Japan; 4Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan; 5Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan Purpose: Patients with symptomatic COPD are recommended to use inhaled bronchodilators containing long-acting muscarinic receptor antagonists (LAMAs). However, bronchodilators may cause gastrointestinal adverse effects due to anticholinergic reactions, especially in advanced-age patients with COPD. Dai-kenchu-to (TU-100, Da Jian Zhong Tang in Chinese) is the most frequently prescribed Japanese herbal Kampo medicine and is often prescribed to control abdominal bloating and constipation. The purpose of this study was to evaluate the role of Dai-kenchu-to as a supportive therapy in advanced-age patients with COPD. Patients and methods: We used the Japanese Diagnosis Procedure Combination inpatient database and identified patients aged ≥75 years who were hospitalized for COPD exacerbation. We then compared the risk of re-hospitalization for COPD exacerbation or death between patients with and without Dai-kenchu-to using 1-to-4 propensity score matching. A Cox proportional hazards model was used to compare the two groups. We performed subgroup analyses for patients with and without LAMA therapy. Results: Patients treated with Dai-kenchu-to had a significantly lower risk of re-hospitalization or death after discharge; the HR was 0.82 (95% CI, 0.67–0.99) in 1-to-4 propensity score matching. Subgroup analysis of LAMA users showed a significant difference in re-hospitalization or death, while subgroup analysis of LAMA non-users showed no significant difference. Conclusion: Our findings indicate that Dai-kenchu-to may have improved the tolerability of LAMA in advanced-age patients with COPD and, therefore, reduced the risk of re-hospitalization or death from COPD exacerbation. Dai-kenchu-to may be recommended as a useful supportive therapy for advanced-age patients with COPD. Keywords: TU-100, herbal medicine, muscarinic receptor antagonists, propensity score, survival analysis

Introduction: In pediatric patients with asthma, measurements of forced expiratory volume in 1 s (FEV1) may be normal or may not correlate with symptom severity. Forced expiratory flow at 25–75% of the vital capacity (FEF25–75%) is a potentially more sensitive parameter for assessing peripheral airway function. This post hoc analysis compared FEF25–75% with FEV1 as an endpoint to assess bronchodilator responsiveness in children with asthma. Methods: Change from baseline in trough FEF25–75% and trough FEV1 following treatment with either tiotropium (5 µg or 2.5 µg) or placebo Respimat® was analyzed in four phase III trials in children (aged 6–11 years) and adolescents (aged 12–17 years) with symptomatic moderate (VivaTinA-asthma® and PensieTinA-asthma®) and mild (CanoTinA-asthma® and RubaTinA-asthma®) asthma. Data from all treatment arms were pooled and correlations between FEF25–75% and FEV1 were calculated and analyzed. Results: A total of 1590 patients were included in the analysis. Tiotropium Respimat® consistently improved FEF25–75% and FEV1 versus placebo, although in adolescents with severe asthma, the observed improvements were not statistically significant. Improvements in FEF25–75% response with tiotropium versus placebo were largely more pronounced than improvements in FEV1. Statistical assessment of the correlation of FEV1 and FEF25–75% showed moderate-to-high correlations (Pearson's correlation coefficients 0.73–0.80). Conclusions: In pediatric patients, FEF25–75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than FEV1 and should be evaluated as an additional lung function measurement. [ABSTRACT FROM AUTHOR]

Brian J Lipworth,1 David J Collier,2 Yasuhiro Gon,3 Nanshan Zhong,4 Koichi Nishi,5 Rongchang Chen,4 Samir Arora,6 Andrea Maes,7 Shahid Siddiqui,8 Colin Reisner,7,8 Ubaldo J Martin8 1Scottish Centre for Respiratory Research, Ninewells Hospital, University of Dundee, Dundee, Scotland, UK; 2William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 3Itabashi Hospital, Nihon University School of Medicine, Itabashi, Tokyo, Japan; 4Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Diseases, National Clinical Research Center of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa, Japan; 6Aventiv Research Inc., Columbus, OH, USA; 7Pearl – a member of the AstraZeneca group, Morristown, NJ, USA; 8AstraZeneca, Gaithersburg, MD, USA Background: COPD is a major global cause of mortality and morbidity. PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to-very severe COPD. Methods: In this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed. Results: Of the 1,756 patients randomized, 1,740 patients were included in the intent-to-treat population (mean age 64.2 years, 74.1% male, and 40.2% Asian). GFF MDI significantly improved morning predose trough FEV1 at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72 mL, respectively; all P

Introduction: Airway obstruction is usually assessed by measuring forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF). This post hoc study investigated comparative responses of lung function measurements in adults and adolescents (full analysis set, N = 3873) following treatment with tiotropium Respimat®. Methods: Lung function outcomes were analysed from five phase III trials in adults (≥ 18 years) with symptomatic severe, moderate and mild asthma (PrimoTinA-asthma®, MezzoTinA-asthma® and GraziaTinA-asthma®, respectively), and one phase III trial in adolescents (12–17 years) with symptomatic moderate asthma (RubaTinA-asthma®). Changes from baseline versus placebo in FEV1, FVC, PEF and FEV1/FVC ratio with tiotropium 5 µg or 2.5 µg added to at least stable inhaled corticosteroids at week 24 (week 12 in GraziaTinA-asthma) were analysed. Results: All lung function measures improved in all studies with tiotropium 5 µg (mean change from baseline versus placebo), including peak FEV1 (110–185 mL), peak FVC (57–95 mL) and morning PEF (15.8–25.6 L/min). Changes in adolescents were smaller than those in adults, and were statistically significant primarily for FEV1 and PEF, but not for FVC. Conclusion: Consistent improvements were seen across all lung function measures with the addition of tiotropium to other asthma treatments in adults across all severities, whereas the improvements with tiotropium in adolescents primarily impacted measures of flow rather than lung volume. This may reflect less pronounced airway remodelling and air trapping in adolescents with asthma versus adults. Plain Language Summary: Asthma is characterised by problems with the way that the lungs work, particularly narrowing of the airways. Doctors can measure the effect of asthma on someone's breathing in different ways. We looked to see whether these different methods work for different people with asthma, and whether treatment affects all measurements in a similar way. Lung function was measured after treatment with a drug that opens the airways (tiotropium), and comparisons were made between adults and adolescents with asthma. We also looked at people with severe asthma and those whose asthma was less severe. Tiotropium improved all the measures of lung function in both age groups and across severities. One measure improved more in adults than in adolescents. This may be because adolescents had better lung function at the start and thus less room for improvement, or because the adolescents had not had asthma for as long, and so may have had less long-term damage to their airways than adults. Trial Registration Numbers: NCT00772538, NCT00776984, NCT01172808, NCT01172821, NCT01316380, NCT01257230. [ABSTRACT FROM AUTHOR]

Introduction: Treatment options for COPD have evolved rapidly in the last decade and inhaled bronchodilators have largely supplanted the use of oral bronchodilators because of their increased efficacy and excellent safety with topical delivery to the lung. Recently added to the therapeutic armamentarium are fixed-dose combinations (FDC) of two long acting bronchodilators. LAMAs (long acting muscarinic antagonists) and LABAs (long acting beta agonists) are the main classes available and use different pathways to effectively produce bronchial smooth muscle relaxation. Areas covered: The most recent inhaled FDC LAMA/LABA to come to market is Aclidinium Bromide and Formoterol Fumarate. We searched databases of PubMed, Cochrane Library, and manufacturers' websites and retrieved all the randomized-controlled trials (RCTs) conducted with these drugs up to September 2019. Expert opinion: It is likely that FDCs will become the core of our COPD pharmacotherapy for all but the mildest COPD patients. These individual drugs have excellent efficacy and safety records for the maintenance treatment of COPD. Studies have demonstrated that twice daily treatment with aclidinium/formoterol resulted in significant improvement in lung function and an improved exercise tolerance when compared to placebo. Adverse effects are within the range of what is seen with other LAMA/LABA combinations. [ABSTRACT FROM AUTHOR]

The purpose of this study was the development and validation of an LC-MS/MS method, for the determination of solifenacin from human plasma. The sample workup involved a simple protein precipitation procedure. A core/shell type analytical column (50x2,1 mm, 2.6 Å) was used with C18 stationary phase. The mobile phase consisting of 65% acetonitril and 35% water provided good peak shape, accuracy and precision. The mass spectrometer was operated in positive electrospray ionization mode for analyte and internal standard. The following parameters were evaluated for validation purpose: Selectivity, sensitivity, matrix effect, anticoagulant effect, linearity, precision and accuracy, recovery, short and long term analyte/IS stability in solvent/matrix and carryover. The validated calibration range was 0.71-71.28 ng/ml. The correlation coefficient R² was at least 0.99 in all validation batches. The validated method has been successfully used for the evaluation of bioequivalence of generic solifenacin 10 mg formulations. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate long-term antimuscarinic drug persistence and its associated characteristics in patients with overactive bladder (OAB) treated with antimuscarinic agents. We also assessed the efficacy and safety of switching from solifenacin to mirabegron in patients refractory to antimuscarinic therapy.Methods: In this prospective, open-label, 48-month study, 416 patients (mean age, 70.6 ± 12.4 years) were enrolled. All patients completed the overactive bladder symptom score and urgency severity score questionnaires, along with initial and follow-up uroflowmetry. All patients received antimuscarinic solifenacin 5 mg daily. Mirabegron (25 mg daily) was suggested in patients that were refractory to antimuscarinic therapy or had intolerable side effects.Results: The mean solifenacin persistence was 6.6 ± 8.1 months (range, 0.5-48 months). Only 81 (19.5%) patients had drug persistence of ≥12 months. Male sex, age, cerebral vascular accident, maximum flow rate, and post-void residual were associated with solifenacin persistence in the univariate analysis. Age (odds ratio [OR], 0.14; 95% CI, 0.08-0.21) was the only independent predictor in the multivariate logistic regression. Of the 416 patients, 171 (60.8%) changed from solifenacin to mirabegron for due to the persistence of OAB symptoms. The switch resulted in a significantly longer period of actual OAB pharmacotherapy (9.3 ± 9.2 vs 13.3 ± 9.3 months, p < 0.001).Conclusion: Long-term drug persistence of solifenacin was low during the 2-year follow-up. Age was an independent factor associated with longer drug persistence. Switching from solifenacin to mirabegron was an effective and safe alternative for OAB patients that were refractory to solifenacin treatment. [ABSTRACT FROM AUTHOR]

Standardization of the methacholine inhalation challenge, the most common direct bronchoprovocation test, is important. One aspect of standardization is the appropriate washout period for pharmacologic agents which affect the response. This review summarizes the available data on pharmacologic inhibition of the methacholine response. Specific (anti-muscarinic) agents demonstrate marked bronchoprotection (up to 7 days for the long-acting drugs) which lasts longer than the duration of bronchodilation. The functional antagonist (beta 2 agonist class of medications) shows marked, but less, bronchoprotection which is relatively short lived and is similar to the duration of bronchodilator efficacy. Tolerance develops quickly, especially to the long-acting agents. Single doses of controller medications, such as inhaled corticosteroids (ICS) and leukotriene receptor antagonists, have no effect on the methacholine test, while regular use, at least for ICS, has a modest protective effect whose duration is uncertain and likely variable. Theophylline has a small effect and H1 blockers (all generations) have a negligible effect. [ABSTRACT FROM AUTHOR]