Search

Mario Cazzola,1 Paola Rogliani,1 Rossella Laitano,1 Luigino Calzetta,2 Maria Gabriella Matera3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 2Unit of Respiratory Diseases and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: Although pharmacological treatment of COPD is codified in different guidelines and strategy documents, there is abundant evidence of discrepancy between what they suggest and what health professionals prescribe, especially in low-risk groups where there is widespread overprescription of triple therapy. It is therefore necessary to clarify when the use of triple therapy is indicated in COPD patients and when it is preferable to maintain treatment with dual bronchodilation. In this article, we discuss our views based on our experience and what is reported in the literature and try to give answers to these two questions. The evidence generated by pivotal RCTs supports the use of triple therapy in patients who present for the first time and have severe airway obstruction, are symptomatic, have had frequent moderate or severe exacerbations in the previous year, and have peripheral eosinophilia. However, it is difficult to determine whether step-up is useful in all other cases because the available data are quite conflicting. It is likely that the inconsistency in the information generated by the various available studies may explain the prescribing behaviour of many physicians who do not adhere to recommendations of guidelines and strategies. However, it is necessary to establish whether and when the addition of an ICS to the LAMA/LABA combination is effective, to determine whether triple therapy can induce an additional clinical benefit over dual bronchodilation, irrespective of a preventive effect on COPD exacerbations, to establish its value, and to examine whether cost differences can support the use of triple therapy over combined LAMA/LABA therapy in real life.Keywords: dual bronchodilation, triple therapy, ICSs, LABs, LAMAs

OBJECTIVE: To provide an overview of the existing international and Chinese evidence regarding dual bronchodilator inhalation therapy and to make recommendations for the further improvement of chronic obstructive pulmonary disease (COPD) management in clinical practice in China. BACKGROUND: COPD is a progressive lung disease that is characterized by persistent airflow limitation and is a major contributor to the disease burden in China. Symptoms in Chinese patients are relatively more severe. Currently, many Chinese COPD patients are undertreated. Dual bronchodilator therapy consisting of a long-acting muscarinic antagonist (LAMA) and a long-acting β agonist (LABA) is considered a good choice for COPD patients due to the increased bronchodilation without an increase in adverse events; these combinations can fill in the gap in currently available COPD treatments and provide new pharmacotherapy options for Chinese patients. LAMA/LABA fixed-dose combinations (FDCs) have become more important in clinical practice and guidelines in China regarding their therapeutic effects and safety. METHODS: Clinical trials on LAMA/LABA in COPD were retrieved in ClinicalTrials.gov, while important COPD guidelines published in English or Chinese were found in PubMed and Wanfang Database. CONCLUSIONS: We recommend the adoption of a clinical pathway in China that includes an assessment and management algorithm that considers the clinical characteristics in China and classifies the phenotypic characteristics of COPD according to a suitable system. Based on the current information, we can conclude that LAMA/LABA FDCs are a suitable and economically viable choice to reduce symptoms and improve the quality of life (QoL) of patients.

Despite the evidence that the muscarinic agonist arecoline is a drug of abuse throughout Southeast Asia, its stimulus characteristics have not been well studied. The goal of this work was to understand more about the mediation of discriminative stimulus effects of arecoline. Arecoline (1.0 mg/kg s.c.) was trained as a discriminative stimulus in a group of eight rats. Evaluation was made of the ability of various cholinergic agonists and antagonists to mimic or antagonize the discriminative stimulus effects of arecoline and to modify its rate-suppressing effects. A muscarinic antagonist, but neither of two nicotinic antagonists, were able to modify the discriminative stimulus effects of arecoline, suggesting a predominant muscarinic basis of arecoline’s discriminative stimulus effects in this assay. However, both nicotine itself, and two nicotine agonists with selective affinity for the α4β2* receptor (ispronicline and metanicotine) produced full arecoline-like discriminative stimulus effects in these rats. The discriminative stimulus effects of the selective nicotine agonists were blocked by both the general nicotine antagonist mecamylamine, and by the selective α4β2* antagonist, dihydro-beta-erythroidine (DHβE). Surprisingly, only DHβE antagonized the rate-suppressing effects of the selective nicotine agonists. These data indicate a selective α4β2* nicotine receptor component to the behavioral effects of arecoline. Although the nicotinic aspects of arecoline’s behavior effects could suggest that abuse of arecoline-containing material (e.g., betel nut chewing), is mediated through nicotinic rather than muscarinic actions, further research, specifically on the reinforcing effects of arecoline, is necessary before this conclusion can be supported.

Objectives: The recent publication of additional data retrieval for patients missing week 52 vital status in the original analyses of the ETHOS study provides the urgent need of updating previous network meta-analyses (NMA) to produce stronger evidence on mortality in patients receiving dual and triple FDCs according with the level of ICS dose. Methods: A NMA was performed to compare the effect of ICS/LABA/LAMA, ICS/LABA, and LABA/LAMA FDCs administered via the same inhaler device in COPD patients. The number need to treat (NNT) was also calculated. Results: When considering on-treatment all-cause of death (analyzed patients: 18,864), MD ICS/LABA/LAMA and MD ICS/LABA FDCs significantly reduced the risk of mortality vs. LABA/LAMA FDC (RR 0.59 95%CrI 0.35–0.97 and 0.61 95%CrI 0.38–0.99 respectively, P

Purpose Macrolides are a recommended treatment option for severe asthma, but data for “difficult-to-treat” asthma, the asthma-COPD “overlap” syndrome, and treatment duration beyond one year are lacking. We present long-term data from community practice experience providing insights for practice and research. Methods We report data from (1) baseline (pre-treatment) chart review of antibiotic-treated asthma patients and (2) follow-up telephone interviews documenting severe exacerbations (NIH criteria), Asthma Control Test (ACT) scores, and asthma controller use at baseline and follow-up, analyzed using a “before-after” model. Results A total of 101 patients (mean age 55.6 years (Sd 16.8), 66 females) were included. None had ever taken high dose inhaled corticosteroids and 79 (78.2%) were severely uncontrolled (ACT score ≤15) before treatment. Coexisting COPD was present in 62 (61.4%) patients. Azithromycin or azithromycin plus doxycycline was primarily prescribed with a median treatment duration of 12 months and median follow-up duration of 22 months. Severe exacerbations in the month before treatment occurred in 50.5% vs 17.8% at follow-up (P, Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/0vF55ewkTVc

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

Acetylcholine (ACh) has distinct functional roles in striatum compared with cortex, and imbalance between these systems may contribute to neuropsychiatric disease. Preclinical studies indicate markedly higher ACh concentrations in the striatum. The goal of this work was to leverage positron emission tomography (PET) imaging estimates of drug occupancy at cholinergic receptors to explore ACh variation across the human brain, because these measures can be influenced by competition with endogenous neurotransmitter. PET scans were analyzed from healthy human volunteers (n = 4) and nonhuman primates (n = 2) scanned with the M1-selective radiotracer [11C]LSN3172176 in the presence of muscarinic antagonist scopolamine, and human volunteers (n = 10) scanned with the α4β2* nicotinic ligand (−)-[18F]flubatine during nicotine challenge. In all cases, occupancy estimates within striatal regions were consistently lower (M1/scopolamine human scans, 31 ± 3.4% occupancy in striatum, 43 ± 2.9% in extrastriatal regions, p = 0.0094; nonhuman primate scans, 42 ± 26% vs. 69 ± 28%, p

Cannabidiol, approved for treatment of pediatric refractory epilepsy, has anti-seizure effects in various animal seizure models. Chemical warfare nerve agents, including soman, are organophosphorus chemicals that can induce seizure and death if untreated or if treatment is delayed. Our objective was to evaluate whether cannabidiol would ameliorate soman-induced toxicity using a mouse model that similar to humans lacks plasma carboxylesterase. In the present study, adult female plasma carboxylesterase knockout (Es1-/-) mice were pre-treated with cannabidiol (20−150 mg/kg) or vehicle 1 h prior to exposure to a seizure-inducing dose of soman and evaluated for survival and seizure activity. The muscarinic antagonist atropine sulfate and the oxime HI-6 were administered at 1 min after exposure, and the benzodiazepine midazolam was administered at 30 min after seizure onset. Cannabidiol (150 mg/kg) pre-treatment led to a robust increase in survival rate and attenuated body weight loss in soman-exposed mice treated with medical countermeasures, compared to mice pre-treated with vehicle. In addition, mice pretreated with cannabidiol (150 mg/kg) had a modest reduction in seizure severity after midazolam treatment compared to vehicle-pretreated. These findings of improved outcome with cannabidiol administration in a severe seizure model of soman exposure provide additional pre-clinical support for the benefits of cannabidiol against exposure to seizure-inducing chemical agents and suggest cannabidiol may augment the anti-seizure effects of midazolam.

International audience; Rodent models of depression are useful for the investigation of cellular and neuronal mechanisms of antidepressant drugs and for the discovery of potential new targets. In this study, we examined the antidepressant-like effect of scopolamine, a non-selective muscarinic antagonist, in a genetic mouse model of depression obtained through a selective breeding strategy and called H/Rouen. In this model, we observed that scopolamine was active both in males and females at a lower dose (0.03 mg/kg) in the tail suspension test, 30 min following its administration, than observed in CD-1 mice. In addition, we showed this antidepressant-like effect was partly inhibited by an injection of 10 mg/kg of the AMPA receptor antagonist NBQX in both males and females, suggesting the anti-depressant like effect of scopolamine was mainly driven by AMPA receptors in the H/Rouen mouse line. Altogether, our results showed the high sensitivity of the H/Rouen mouse model of depression to study the antidepressant-like effects of pharmacological compounds.

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

Introduction Bronchodilators are the cornerstone of chronic obstructive pulmonary disease (COPD) therapy and long-acting muscarinic antagonists (LAMAs) as a mono or combination treatment play a pivotal role. Several LAMAs are already available on the market in different formulations, but developing a new compound with a higher M3 receptor selectivity and a lower affinity to M2 receptors to increase the therapeutic effect and minimize the adverse effects is still a goal. Moreover, new formulations could improve adherence to therapy. Areas covered This systematic review assesses investigational long-acting muscarinic antagonist in Phase I and II clinical trials over the last decade. It offers insights on whether LAMAs and/or their new formulations in clinical development can become effective treatments for COPD in the future. Expert opinion Research on LAMA seems to have come to a standstill, the few new molecules under study do not show distinctive characteristics compared to the previous ones. Muscarinic antagonist/β2-agonist (MABAs) appear to be the major innovation currently under investigation, and they could theoretically open new research frontiers on the effect between adrenergic and muscarinic interaction in the same cell.

The aim of this study was to review clinical evidence supporting the use of fixed-dose combination of tiotropium and olodaterol, a long-acting muscarinic antagonist (LAMA) and a long-acting βFor this narrative review, the available literature was searched to identify studies including patients with COPD receiving tiotropium and olodaterol as either monotherapy or combination therapy and studies including patients with COPD receiving inhaled corticosteroids (ICS) in addition to long-acting bronchodilators. Relevant studies were included in the review.Patients with COPD are often prescribed ICS therapy, which, when used over a long term, can be associated with local and systemic adverse effects. The GOLD 2020 report recommends dual bronchodilator therapy as both an initial and follow-up treatment option. A LABA + LAMA combination is mechanistically synergistic, and cumulative evidence surrounding the efficacy and safety of fixed-dose combination of tiotropium and olodaterol supports therapeutic advantages over monotherapy in most patients with COPD.The early stages of COPD may represent a "window of therapeutic opportunity" during which initiation of tiotropium and olodaterol dual bronchodilator therapy may improve lung function and quality of life and reduce exacerbations in patients with COPD.

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

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.

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

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

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

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.

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

Aim: To compare health plan-paid costs, exacerbations and pneumonia outcomes for patients with chronic obstructive pulmonary disease (COPD) initiating combination tiotropium olodaterol (TIO + OLO) versus triple therapy (TT: long-acting muscarinic antagonist + long-acting β 2 agonists + inhaled corticosteroid). Patients & methods: COPD patients initiating TIO + OLO or TT between 1 January 2014 and 30 June 2016 were identified from a managed care Medicare database and balanced for baseline characteristics using inverse probability of treatment weighting before assessment of outcomes. Results: Annual COPD-related and all-cause costs were US$4118 (35%) and US$5384 (23%) lower for TIO + OLO versus TT (both p ≤ 0.001). TIO + OLO patients had nearly half the severe exacerbations (8.3 vs 15.5%; p = 0.014) and pneumonia was also less common (18.9 vs 30.9%; p Conclusion: TIO + OLO was associated with improved economic and COPD health outcomes versus TT.

Background: Increasing evidence has implicated the cholinergic system as a modulator of mood episodes, with possible involvement of nicotinic and/or muscarinic receptors. A number of randomized controlled trials (RCTs) have demonstrated a putative rapid antidepressant effect of the muscarinic antagonist scopolamine. Here, we review the clinical evidence regarding the three principal muscarinic-modulating agents administered in studies involving mood disorders: scopolamine, biperiden and physostigmine. We conduct a meta-analysis on RCTs where these agents were administered to participants experiencing a depressive episode. Methods: A systematic bibliographic search of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies utilizing the above agents was conducted between January 1970 and December 2020. A meta-analysis was subsequently performed on 9 studies which satisfied inclusion criteria, including 322 participants. Results: Administration of scopolamine significantly reduced depressive symptoms compared to placebo, as measured by objective mood rating scales with SMD of -0.95 (95% CI -1.49, -0.42, p = 0.0005). This effect increased to -1.13 (95% CI -1.61, -0.66, p

Background The role of inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) is unclear. Hence, this study aimed to evaluate the efficacy of ICS as an add-on to long-acting muscarinic antagonist (LAMA)/long-acting beta 2 agonist (LABA), which was assessed using the impulse oscillation system (IOS), in patients with COPD. Methodology We included patients with COPD whose treatment was changed from LAMA/LABA (≥four weeks) to ICS/LAMA/LABA between April 2019 and March 2021. To gain insight into the effect and safety of ICS-containing triple therapy for COPD, pulmonary function; Short-Form 36, St. George’s Respiratory Questionnaire, COPD Assessment Test, and modified Medical Research Council scores; and airway resistance assessed using the IOS from one week before LAMA/LABA was switched to ICS/LAMA/LABA therapy until more than eight but less than twelve weeks after switching were evaluated. Results In total, 46 patients with COPD (mean age: 72.28 ± 7.81 years) were included in the study. None of the pulmonary function test parameters significantly changed from baseline values (mean difference in forced expiratory volume in one second [FEV1.0]: +0.032, P = 0.12; percentage FEV1.0 [FEV1.0%]/forced vital capacity [FVC]: −0.58, P = 0.42; and FVC: +0.087, P = 0.058). Meanwhile, the IOS showed that resonant frequency (mean difference from baseline: −2.12, P < 0.0001) and bodily pain scores in the St. George’s Respiratory Questionnaire (mean difference: −7.03, P = 0.031) significantly decreased. Conclusions Switching from LAMA/LABA to ICS/LAMA/LABA therapy reduces airway elasticity-to-inertial resistance ratios, which may lead to structural airway improvements in patients with COPD.

Iki šiol nebuvo atlikta tyrimų, vertinusių trijų vaistų derinio viename inhaliatoriuje veiksmingumą gydant sergančiuosius astma. Šiame straipsnyje pristatomi du nauji klinikiniai tyrimai, kurie pirmą kartą įvertino itin smulkių dalelių beklometazono dipropionato (BDP), formaterolio fumarato (FF) ir glikopironio (G) derinio viename inhaliatoriuje veiksmingumą, lyginant su BDP ir FF deriniu, gydant sergančiuosius nekontroliuojama astma. Tyrimų rezultatai parodė, kad sergantiesiems nekontroliuojama astma ir gydomiems įkvepiamaisiais gliukokortikoidais bei ilgo veikimo β2 agonistais, pridėjus ilgo veikimo muskarino antagonistą, pagėrėja plaučių funkcija bei sumažėjo paūmėjimų dažnis.

Functional autoantibodies directed to the M2 muscarinic acetylcholine receptor (M2R) could affect the heart rate directly by altering cardiac M2R activity and/or indirectly by changing vagal-mediated cardiac M2R activity. We measured M2R autoantibody activity in sera from 10 subjects with postural tachycardia syndrome (POTS) and 5 healthy control subjects using a cell-based bioassay. Half of the POTS subjects demonstrated presence of elevated M2R autoantibody activity, while no significant M2R autoantibody activity was found in the healthy subjects. Serum-derived immunoglobulin G (IgG) from antibody-positive POTS patients induced a dose-dependent activation of M2R, which was blocked by the muscarinic antagonist atropine. Moreover, antibody-positive POTS IgG decreased the responsiveness to oxotremorine, an orthosteric muscarinic agonist, indicating an indirect inhibitory effect. These data suggest that M2R autoantibodies may contribute to the pathophysiology of POTS by increasing the normal vagal withdrawal during upright posture through its negative allosteric modulation of M2R activity. M2 muscarinic receptor-activating autoantibodies are present in a subgroup of patients with POTS and act as a negative allosteric modulator of the orthosteric ligand response.

Graphical abstract, Highlights • Cypermethrin poisoning can present as a medical emergency with neurological, gastrointestinal or cardiac manifestations. • Prolonged bradycardia following acute oral intoxication with cypermethrin is a rare entity. • In view of the absence of antidote, conservative management has been found effective in prolonged bradycardia induced by cypermethrin toxicity., Pyrethrins and their synthetic derivatives known as pyrethroids are highly effective insecticides used worldwide in the agricultural fields and households. Cypermethrin is a type II pyrethroid which acts primarily by delaying the closure of voltage-sensitive sodium channels at higher concentrations. Its toxicity in humans occur due to accidental or intentional exposure through inhalation, skin contact or via ingestion. Acute oral intoxication of cypermethrin commonly manifests with neurotoxic and gastrointestinal effects in humans. Cardiotoxic effects following ingestion of this compound have occurred in a few cases but underreported to date. This case highlights a case of intentional cypermethrin poisoning with acute effects in the form of prolonged bradycardia symptomatically managed with a muscarinic antagonist like atropine sulphate.