Muscarinic Antagonist Research Articles

Inhibiting cholinergic signalling in the cerebellar interpositus nucleus impairs motor behaviour.

The role of neuromodulators in the cerebellum is not well understood. In particular, the behavioural significance of the cholinergic system in the cerebellum is unknown. To investigate the importance of cerebellar cholinergic signalling in behaviour, we infused acetylcholine receptor antagonists, scopolamine and mecamylamine, bilaterally into the rat cerebellum (centred on interpositus nucleus) and observed the motor effects through a battery of behavioural tests. These tests included unrewarded behaviour during open field exploration and a horizontal ladder walking task and reward-based beam walking and pellet reaching tasks. Infusion of a mix of the antagonists did not impair motor learning in the horizontal ladder walking or the reaching task but reduced spontaneous movement during open field exploration, impaired coordination during beam walking and ladder walking, led to fewer reaches in the pellet reaching task, slowed goal-directed reaching behaviour and reduced reward pellet consumption in a free access to food task. Infusion of the muscarinic antagonist scopolamine on its own resulted in deficits in motor performance and a reduction in the number of reward pellets consumed in the free access to food task. By contrast, infusion of the nicotinic antagonist mecamylamine on its own had no significant effect on any task, except beam walking traversal time, which was reduced. Together, these data suggest that acetylcholine in the cerebellar interpositus nucleus is important for the execution and coordination of voluntary movements mainly via muscarinic receptor signalling, especially in relation to reward-related behaviour.

The clinical characteristics and treatment response of patients with chronic obstructive pulmonary disease with low body mass index.

Background: This study aimed to analyze the clinical characteristics and treatment response of patients with chronic obstructive pulmonary disease (COPD) with low body mass index (BMI). Methods: In this cross-sectional study, we enrolled patients with stable COPD from the database setup by the Second Xiangya Hospital of Central South University. We classified the patients into three groups based on BMI: low-BMI (<18.5kg/m2), normal-BMI (≥18.5 and <24.0kg/m2), and high-BMI (≥24kg/m2) groups. We defined clinically important deterioration (CID) as a COPD Assessment Test (CAT) score increase of ≥2 and minimum clinically important difference (MCID) as a CAT score decrease of ≥2 during 6months of follow-up. We recorded the number of exacerbations and mortality during 1year of follow-up. Results: A total of 910 COPD patients were included with 144 (15.8%) patients in low-BMI, 475 (52.2%) in normal-BMI, and 291 (32.0%) in high-BMI groups. Patients with low BMI had worse pulmonary function, higher symptom scores, and exacerbations in the past year compared with normal- and high-BMI groups (p < 0.05). Logistic regression analysis revealed that age, Global Initiative for Chronic Obstructive Lung Disease grades 3 and 4, and hospitalizations in the past year were independent risk factors for patients with low BMI (p < 0.05). After 1year of follow-up, patients with low BMI had higher mortality and number of hospitalizations. Patients with low BMI were more likely to attain CID and less likely to attain MCID compared with patients with high BMI (p < 0.05). In addition, patients with low BMI treated with long-acting β2-agonist (LABA)+long-acting muscarinic antagonist (LAMA) and LABA+LAMA+inhaled corticosteroid (ICS) were more likely to attain MCID than those treated with LABA+ICS and LAMA (p < 0.05). Conclusion: COPD patients with low BMI had worse pulmonary function, higher symptom scores, and higher risk of future hospitalizations and mortality and were less likely to attain MCID and more likely to attain CID. It is worth noting that patients with low BMI treated with LABA+LAMA and LABA+LAMA+ICS were more likely to attain MCID than those treated with LABA+ICS and LAMA.

Using the 6-min walk test to assess the clinical response to mepolizumab and conventional therapy in severe eosinophilic asthma.

Severe asthma limits exercise to avoid respiratory symptoms. The objective of the present study was to investigate the role of the 6-min walk test (6MWT) in severe asthma. Consecutive patients with severe eosinophilic asthma were enrolled. A 6MWT was performed before and after 12 months. Inhaled therapy dose, oral corticosteroids dose, pulmonary function tests, eosinophil blood count, fractional exhaled nitric oxide (FeNO), Asthma Control Test (ACT) score and responses to the Asthma Quality of Life Questionnaire (AQLQ) were also recorded. Of the 22 patients enrolled, 13 were treated with mepolizumab 100 mg every 4 weeks in addition to conventional therapy and nine with conventional therapy only. The majority of the patients were treated with high-dose inhaled corticosteroids/long-acting β-agonists/long-acting muscarinic receptor antagonists, while approximately half were on continuous oral corticosteroids. After 12 months, the mepolizumab group only showed a significant improvement in pulmonary function tests (percentage forced expiratory volume in 1 s and percentage forced expiratory flow at 25-75% forced vital capacity (FEF25-75%), both p<0.001; percentage forced vital capacity, p<0.01) and clinical laboratory parameters (eosinophil count, FeNO measured at a flow rate of 50 mL·s-1, ACT and AQLQ, p<0.001). No significant changes in the proportion of patients using continuous oral corticosteroids and high-dose inhaled corticosteroids/long-acting β-agonists/long-acting muscarinic receptor antagonists were observed in either group (p>0.05). By paired comparisons, statistically significant improvements of the mean 6-min walk distance (6MWD) were observed in the mepolizumab (p<0.001) and conventional therapy (p<0.01) groups, while no improvement was seen in dyspnoea Borg scale, heart rate, percentage oxygen saturation or systolic and diastolic blood pressure. 6MWD showed significant direct correlations with ACT (r=0.5998, p<0.001), AQLQ (r=0.3978, p=0.009) and FEF25-75% (r=0.3589, p=0.017). The 6MWT could complement severe asthma assessment and be relevant in evaluating the objective response to treatment, including biological therapies like mepolizumab.

Vitamin D Improves Dementia Induced by Scopolamine in Mice: Histological Study

In Dementia, there is a deterioration in cognitive ability, which affect memory, thinking, and the ability to perform daily activities. Vitamin D is a steroid hormone; its deficiency may play an aggressive role in neurodegeneration disorders. Scopolamine is a muscarinic receptor antagonist that induces memory impairment and oxidative stress. The aim of the work is to determine the histological effect of vitamin D on dementia induced by scopolamine in albino mice. Male albino mice were divided into eight groups of six each. Group 1: Administered T80(1%) for one week, Group 2: Administered scopolamine for one week, Group 3: Administered Vitamin D for one week, Group 4: Administered scopolamine plus Vitamin D for one week (prophylactic effect), Group 5: Administered scopolamine for one week, followed by vitamin D administration for another one week (treatment). Group 6: Administered scopolamine for one week, followed by no treatment for another week, Group 7: Administered donepezil as standard to evaluate learning and memory, Group 8: Administered scopolamine plus Donepezil for one week. Drugs were administered by intraperitoneal route, at the volume of 5ml/kg body weight. All drugs were freshly prepared. The transfer latency was measured using plus maze; mice were killed by neck dislocation; the brains were immediately removed, inserted in 10% formalin, and sent to the histology department, for histological study. Vitamin D repairs the histological damage induced by scopolamine; the improvement induced by vitamin D was much better when given with scopolamine as prophylaxis, more than when it is given after dementia is established as treatment. The model of dementia induced by scopolamine is a reversible model.

Open and Closed Triple Inhaler Therapy in Patients with Uncontrolled Asthma.

Long-acting muscarinic antagonists (LAMAs) are a class of inhalers that has recently been included as add-on therapy in the GINA guidelines, either in a single inhaler device with inhaled corticosteroids plus long-acting β2-agonists (ICS + LABA) (closed triple inhaler therapy) or in a separate one (open triple inhaler therapy). This review summarizes the existing evidence on the addition of LAMAs in patients with persistently uncontrolled asthma despite ICS + LABA treatment based on clinical efficacy in the reduction of asthma symptoms and exacerbations, the improvement in lung function, and its safety profile.

Characterization of Obesity in Severe Asthma in the German Asthma Net

Asthma is increasingly recognized as heterogeneous, characterized by different endotypes, with obesity not only a distinct phenotype but a risk factor for severe asthma. We sought to understand the associations of obesity with relevant parameters of severe asthma, including asthma control, disease burden, and lung function. The German Asthma Net registry is a multicenter international real-life registry capturing long-term follow-up data. This analysis included 2213 patients (52 ± 16 years, 58% female, 29% with obesity [body mass index ≥30 kg/m2], 4.2 ± 4.3 exacerbations/year). The primary analysis assessed relationships between BMI and variables through univariate tests, followed by a multiple regression model. Secondary outcomes regarded clinically relevant variables in relation to weight groups. Patients with obesity were more frequently female, more likely to have depression and gastroesophageal reflux, and suffered from worse asthma control, lower quality of life, reduced static lung volumes, more pronounced hypoxemia, and higher blood neutrophil counts, all statistically significant. Blood eosinophils, exhaled nitric oxide, and total IgE were independent of obesity. In the multiple regression analysis, obesity was significantly associated with more frequent reflux and depression, reduced static lung function values, older age, poor asthma control, and long-acting muscarinic antagonist therapy, and inversely associated with bronchiectasis and nonsmoking status. In this large, well-characterized cohort, we identified the association of obesity with a significantly higher disease burden and a similar portfolio of inflammation type 2 markers in patients with and without obesity; therefore, patients with obesity seem similarly eligible for the treatment with biologics targeting these disease endotypes.

Budget Impact Analysis of Single-Inhaler Fluticasone Furoate/Umeclidinium/Vilanterol in Patients with Asthma in the Dubai Academic Healthcare Corporation.

Asthma is a common, chronic respiratory disorder associated with substantial societal and economic burden globally, despite the availability of different treatment modalities. GSK has developed a once-daily single-inhaler triple therapy (SITT), comprised of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI); a combination of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β2-agonist for patients with uncontrolled asthma. A budget impact analysis was conducted to determine the financial impact of introducing FF/UMEC/VI SITT from the perspective of the Dubai Academic Healthcare Corporation (DAHC). A budget impact model was constructed using an epidemiology-based approach and used to estimate the expected 5-year budget impact of including FF/UMEC/VI for the treatment of eligible patients within the DAHC in the United Arab Emirates (UAE). The model included both pharmacy and efficacy-related costs. The perspective of the DAHC healthcare payer was adopted, thus only direct payer costs were included in the analysis. A one-way sensitivity analysis was conducted to test the robustness of the model structure, assumptions, and input parameters. The total budget impact was estimated to save 1 million United States Dollars (USD) over 5 years, with budget impacts of 0.08 million USD in Year 1; 0.14 million USD in Year 2; 0.22 million USD in Year 3; 0.28 million USD in Year 4; and 0.33 million USD in Year 5. The overall budget impact per patient was estimated to save 12.2 USD over 5 years. In one-way sensitivity analyses, the budget impact was most sensitive to changes in the market uptake of FF/UMEC/VI. Healthcare payers may consider FF/UMEC/VI in the management of uncontrolled asthma which would save costs and reduce healthcare resource use in the UAE.

Bisoprolol versus celiprolol on dynamic hyperinflation, cardiopulmonary exercise and domiciliary safety in COPD: a single-centre, randomised, crossover study

BackgroundChronic obstructive pulmonary disease (COPD) is frequently associated with cardiovascular disease. The utility of beta-blockers for treating patients with COPD may be beneficial, but their safety remains uncertain, including worsening...

Cajanus cajan (L) Millsp. seed extract ameliorates scopolamine-induced amnesia through increase in antioxidant defense mechanisms and cholinergic neurotransmission.

Decline in cholinergic function and oxidative/nitrosative stress play a central role in Alzheimer's disease (AD). Previous quantitative HPLC profiling analysis has revealed the presence of Pinostrobin, formononetin, vitexin and other neuroprotective flavonoids in Cajanus cajan seed extract. This study was designed to investigate the protective action of Cajanus cajan ethanol seed extract (CC) on learning and memory functions using scopolamine mouse model of amnesia. Materials and methods: Adult mice were pretreated with CC (50, 100, or 200mg/kg, p.o) or vehicle (10ml/kg, p.o) for 16 days consecutively. Scopolamine, a competitive muscarinic cholinergic receptor antagonist (1mg/kg, i.p.) was given an hour after CC pretreatment from days 3 to 16. The mice were subjected to behavioural tests from day 11 (open field test (OFT)/ Y-maze test (YMT) and Morris water maze task (MWM) from days 12-16. Animals were euthanized 1h after behavioral test on day 16 and discrete brain regions isolated for markers of oxidative stress and cholinergic signaling. Molecular docking analysis was undertaken to predict the possible mechanism(s) of CC-induced anti-amnesic action. pre-administration of CC significantly reversed working memory and learning deficits caused by scopolamine in YMT and MWM tests, respectively. Moreover, CC prevented scopolamine-induced oxidative and nitrosative stress radicals in the hippocampus evidenced in significant increase in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities with a marked decrease in malondialdehyde (MDA) production, as well as significant inhibition of hippocampal scopolamine-induced increase in acetylcholinesterase activity by CC. The molecular docking analysis showed that out of the 19 compounds, the following had the highest binding affinity; Pinostrobin (-8.7 Kcal/mol), friedeline (-7.5kCal/mol), and lupeol (-8.2 Kcal/mol), respectively, to neuronal muscarinic M1 acetylcholine receptor, α7 nicotinic acetylcholine receptor and amyloid beta peptide binding pockets, which further supports the ability of CC to enhance neuronal cholinergic signaling and possible inhibition of amyloid beta aggregation. This study showed that Cajanus cajan seeds extract improved working memory and learning through enhancement of cholinergic signaling, antioxidant capacity and reduction in amyloidogenesis.

Might It Be Appropriate to Anticipate the Use of Long-Acting Muscarinic Antagonists in Asthma?

A growing number of clinical trials are documenting that adding a long-acting muscarinic antagonist (LAMA) to established asthma treatment with an inhaled corticosteroid (ICS) and a long-acting β2-agonist (LABA) is a treatment option that improves the health of patients with uncontrolled severe asthma even when therapy is optimized. These favorable results are the reasonwhy the leading guidelines recommend triple therapy with ICS + LABA + LAMA in patients with asthma uncontrolled by medium- to high-dose ICS-LABA. However, we suggest adding LAMAs to ICS-LABAs at an earlier clinical stage. Such action could positively influence airflow limitation, exacerbations, and eosinophilic inflammation, conditions that are associated with acetylcholine (ACh) activity. It could also interrupt the vicious cycle related to a continuous release of ACh leading to the progressive expansion of neuronal plasticity resulting in small airway dysfunction. The utility of an earlier use of triple therapy in asthma should, in any case, be confirmed by statistically powered trials.

Development and validation of LC-MS/MS methods for the quantification of 101BHG-D01, a novel, long-acting and selective muscarinic receptor antagonist, and its main metabolite M6 in human plasma, urine and feces: Application to a clinical study in healthy Chinese subjects

101BHG-D01 is a novel, long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD) and rhinorrhea in rhinitis. To support its clinical study, several liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the quantification of 101BHG-D01 and its main metabolite M6 in human plasma, urine and feces were developed. The plasma samples were prepared by protein precipitation, and the urine and fecal homogenate samples were pretreated by direct dilution, respectively. The chromatographic separation was performed on an Agilent InfinityLab Poroshell 120 C18 column with 0.1% formic acid and 10.0 mM ammonium acetate buffer solution in water and methanol as the mobile phase. The MS/MS analysis was performed by using multiple reaction monitoring (MRM) under a positive ion electrospray ionization mode. The methods were validated with regards to selectivity, linearity, lower limit of quantitation (LLOQ), accuracy and precision, matrix effect, extraction recovery, dilution integrity, batch size, carryover and stability. The calibration ranges were as follows: 1.00–800 pg/mL for 101BHG-D01 and 1.00–20.0 pg/mL for M6 in plasma; 0.0500–20.0 ng/mL for 101BHG-D01 and M6 in urine; 0.400–400 ng/mL for 101BHG-D01 and 0.100–100 ng/mL for M6 in feces. There was no endogenous or cross interference observed at the retention time of the analytes and internal standard in various biological matrices. Across these matrices, for the lower limit of quantitation quality control (LLOQ QC) samples, the intra- and inter-batch coefficients of variation were within 15.7%. For other QC samples, the intra- and inter-batch coefficients of variation were within 8.9%. The intra- and inter-batch accuracy deviations for all QC samples were within the range of − 6.2–12.0%. No significant matrix effect was observed from the matrices. The extraction recoveries of these methods at different concentrations were consistent and reproducible. The analytes were stable in different matrices under various storage conditions. The other bioanalytical parameters were also fully validated and met the criteria given in the FDA guidance. These methods were successfully applied to a clinical study in healthy Chinese subjects after a single dose administration of 101BHG-D01 inhalation aerosol. After inhalation, 101BHG-D01 was absorbed into plasma rapidly with the time to reach the maximum drug concentration (Tmax) of 5 min and eliminated slowly with a half-life time about 30 h. The cumulative urinary and fecal excretion rates revealed 101BHG-D01 was mainly excreted in feces, rather than urine. The pharmacokinetic results of the study drug laid a foundation for its further clinical development.

EE538 Cost-Utility Analysis of Revefenacin, Long-Acting Muscarinic Antagonist, Vs. Tiotropium, in the Treatment and Management of COPD

COPD is a chronic respiratory disease that is costly to the United States. For instance, the CDC estimated direct costs of COPD in 2010 to be $32 billion dollars. Accounting for indirect costs, such as lost days of work, costs rose to $52.4 billion dollars (Guarascio, 2013). Per 2010 data, 51% of these costs were paid by Medicare, 25% were paid by Medicaid, and 18% were covered by private insurance (CDC, 2022). As such, a cost-utility analysis was conducted to appropriately understand and contextualize the most effective ways to control COPD-related symptoms as well as accrued costs.

Progressive electrophysiological changes in a mouse prion model of terminal neurodegenerative disease

AbstractBackgroundIntracerebral injection of prion brain homogenate into mice recapitulates several features of Alzheimer’s disease, including memory deficits, progressive neuronal loss and terminal disease. Pharmacological interventions can preserve species‐specific behaviour and extend survival, but whether treatment can modulate cognition‐related brain activity is unclear. The purpose of this study is to define electrophysiological changes in the murine prion model, and inform future studies of the effects of interventions on neural activity.MethodMice inoculated with either Rocky Mountain Laboratories prion (n = 5) or control brain homogenate (n = 3) underwent surgery to implant seven skull screw recording electrodes (Figure 1). From 4 weeks post‐inoculation, weekly recordings were made by attaching a wireless transmitter to the implant. Prion mice were humanely killed 9‐12 weeks post‐inoculation once they exhibited clinical signs of disease. Brains were retained for histological analysis.Decibel power spectra were generated from recordings using a 2.5 s sliding window with 50% overlap. Theta peak frequency and area under the curve measures were extracted (Figure 2). Effects of prion and week post‐inoculation on these features were determined using mixed effects analyses.ResultPrion mice exhibited a progressive reduction in peak theta frequency, which differed from control mice at 8‐ and 9‐weeks post‐inoculation. The mean ± 95% confidence interval for control mice at 8 weeks post‐inoculation was 8.9±0.4 Hz, compared to 7.0±0.7 Hz for prion mice (Figure 2). The extent of slowing at 9 weeks post‐inoculation correlated with survival outcomes: clinical signs occurred 10‐25 days earlier in mice with a peak theta frequency &lt;6.5 Hz. Delta power showed a week by inoculation interaction, declining in control mice up to 6 weeks post‐inoculation and increasing in the latter weeks of prion infection.ConclusionWe have shown that slowing of electrical activity, a common feature of progressive neurodegenerative diseases, occurs in the murine prion model and correlates with survival. This further validates using the prion model to investigate interventions aimed at treating Alzheimer’s disease and related dementias. Elevated delta power is associated with neurodegenerative disease and muscarinic receptor antagonism, further demonstrating the suitability of the prion model to test pro‐muscarinic interventions in neurodegenerative disease.

Muscarinic acetylcholine receptor antagonism attenuates sensitivity to learned values in value-based decision making

Muscarinic acetylcholine receptor antagonism attenuates sensitivity to learned values in value-based decision making

Clinical Efficacy of Long-Acting β2 Agonists and Long-Acting Muscarinic Antagonist for Moderate to Severe Chronic Obstructive Pulmonary Disease

Clinical Efficacy of Long-Acting β2 Agonists and Long-Acting Muscarinic Antagonist for Moderate to Severe Chronic Obstructive Pulmonary Disease

EE187 Umeclidinium/Vilanterol Versus Tiotropium/Olodaterol in the Treatment of Severe to Very Severe Chronic Obstructive Pulmonary Disease (COPD) from the Brazilian Public Healthcare System Perspective: A Budget Impact Analysis

Umeclidinium/vilanterol (UMEC/VIL) and tiotropium/olodaterol (TIO/OLO), both combinations of long-acting muscarinic antagonist and long-acting beta2-adrenergic (LAMA/LABA) with similar efficacy and safety, are reimbursed for COPD treatment in Brazilian Public Healthcare System (SUS) since 2020. In 2021/2022, according to the Brazilian Government Price Panel (PP), TIO/OLO public sales volume were four times higher compared to UMEC/VIL. Our aim was to estimate the budget impact analysis (BIA) of switching TIO/OLO to UMEC/VIL for severe to very severe COPD treatment in SUS.

Vertigoheel promotes rodent cognitive performance in multiple memory tests.

Cognitive impairment associated with old age or various brain disorders may be very disabling for affected individuals, placing their carers and public health services under considerable stress. The standard-of-care drugs produce only transient improvement of cognitive impairment in older people, so the search for novel, safe and effective therapeutics that would help to reverse or delay cognitive impairment is warranted. Repurposing pharmacological therapies with well-established safety record for additional indications is a promising recent trend in drug development. Vertigoheel (VH-04), a multicomponent drug made of Ambra grisea, Anamirta cocculus L., Conium maculatum, and Petroleum rectificatum, has been successfully used for several decades in the treatment of vertigo. Here, we investigated effects of VH-04 on cognitive performance in standard behavioral tests assessing different types of memory and explored cellular and molecular underpinnings of VH-04's biological activity. In the majority of behavioral experiments, namely in the spontaneous and rewarded alternation tests, passive avoidance test, contextual/cued fear conditioning, and social transmission of food preference, we examined the ability of single and repeated intraperitoneal administrations of VH-04 to improve cognitive parameters of mice and rats disrupted by the application of the muscarinic antagonist scopolamine. In addition, we also assessed how VH-04 affected novel object recognition and influenced performance of aged animals in Morris water maze. Furthermore, we also studied the effects of VH-04 on primary hippocampal neurons in vitro and mRNA expression of synaptophysin in the hippocampus. Administration of VH-04 positively influenced visual recognition memory in the novel object recognition test and alleviated the impairments in spatial working memory and olfactory memory caused by the muscarinic antagonist scopolamine in the spontaneous alternation and social transmission of food preference tests. In addition, VH-04 improved retention of the spatial orientation memory of old rats in the Morris water maze. In contrast, VH-04 did not have significant effects on scopolamine-induced impairments in tests of fear-aggravated memory or rewarded alternation. Experiments in vitro showed that VH-04 stimulated neurite growth and possibly reversed the age-dependent decrease in hippocampal synaptophysin mRNA expression, which implies that VH-04 may preserve synaptic integrity in the aging brain. Our findings allow a cautious conclusion that in addition to its ability to alleviate manifestations of vertigo, VH-04 may be also used as a cognitive enhancer.

Chronic Obstructive Pulmonary Disease Exacerbations and Pneumonia Hospitalizations Among New Users of Combination Maintenance Inhalers

Clinical guidelines on chronic obstructive pulmonary disease (COPD) recommend inhalers containing long-acting muscarinic antagonists (LAMAs) and long-acting β-agonists (LABAs) over inhalers containing inhaled corticosteroids (ICSs) and LABAs. However, data from randomized clinical trials comparing these combination inhalers (LAMA-LABAs vs ICS-LABAs) have been conflicting and raised concerns of generalizability. To assess whether LAMA-LABA therapy is associated with reduced COPD exacerbations and pneumonia hospitalizations compared with ICS-LABA therapy in routine clinical practice. This was a 1:1 propensity score-matched cohort study using Optum's Clinformatics Data Mart, a large commercial insurance-claims database. Patients must have had a diagnosis of COPD and filled a new prescription for a combination LAMA-LABA or ICS-LABA inhaler between January 1, 2014, and December 31, 2019. Patients younger than 40 years were excluded, as were those with a prior diagnosis of asthma. The current analysis was performed from February 2021 to March 2023. Combination LAMA-LABA inhalers (aclidinium-formoterol, glycopyrronium-formoterol, glycopyrronium-indacaterol, tiotropium-olodaterol, or umeclidinium-vilanterol) and combination ICS-LABA inhalers (budesonide-formoterol, fluticasone-salmeterol, fluticasone-vilanterol, or mometasone-formoterol). The primary effectiveness outcome was first moderate or severe COPD exacerbation, and the primary safety outcome was first pneumonia hospitalization. Propensity score matching was used to control for confounding between the 2 groups. Logistic regression analysis was used to estimate propensity scores. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models stratified on matched pairs. Among 137 833 patients (mean [SD] age, 70.2 [9.9] years; 69 530 [50.4%] female) (107 004 new ICS-LABA users and 30 829 new LAMA-LABA users), 30 216 matched pairs were identified for the primary analysis. Compared with ICS-LABA use, LAMA-LABA use was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation (HR, 0.92; 95% CI, 0.89-0.96) and a 20% reduction in the rate of first pneumonia hospitalization (HR, 0.80; 95% CI, 0.75-0.86). These findings were robust across a range of prespecified subgroup and sensitivity analyses. In this cohort study, LAMA-LABA therapy was associated with improved clinical outcomes compared with ICS-LABA therapy, suggesting that LAMA-LABA therapy should be preferred for patients with COPD.

Comparison of pneumonia incidence between long-acting muscarinic antagonist and inhaled corticosteroid plus long-acting beta agonist in patients with COPD

Few studies have directly compared the incidence of pneumonia in patients on common chronic obstructive pulmonary disease (COPD) treatments such as long-acting muscarinic antagonists (LAMA) with those on inhaled corticosteroids and long-acting β2-agonist (ICS/LABA). Moreover, risk factors for pneumonia in COPD are still unclear. We aimed to compare the incidence of pneumonia in COPD patients on LAMA and those on ICS/LABA and explored the risk factors associated with pneumonia. This nationwide cohort study used Korean National Health Insurance claim data from January 2002 to April 2016. Patients who received COPD medication, either LAMA or ICS/LABA, with the COPD diagnostic code, were selected. We enrolled patients with good compliance (medication possession ratio ≥ 80%). The primary outcome was pneumonia in COPD patients initiating LAMA or ICS/LABA. We investigated the risk factors associated with pneumonia, including the sub-types of ICS treatments. After propensity score matching, the incidence rate per 1000 person-years of pneumonia was 93.96 for LAMA (n = 1003) and 136.42 for ICS/LABA (n = 1003) patients (p < 0.001). The adjusted hazard ratio (HR) for pneumonia in patients on fluticasone/LABA was 1.496 (95% confidence interval [CI] 1.204–1.859) compared with LAMA (p < 0.001). In multivariable analysis, a history of pneumonia was a risk factor associated with pneumonia (HR 2.123; 95% CI 1.580–2.852; p < 0.001). The incidence of pneumonia was higher in COPD patients on ICS/LABA compared with those on LAMA. It is recommended that ICS use be avoided in COPD patients with high pneumonia risk.

508 Retrospective Review of Early Pulmonary Mechanics After Inhalation Injury

Abstract Introduction Management of inhalation injury is largely supportive and consists primarily of mechanical ventilation, bronchodilators, muscarinic receptor antagonists, and inhaled mucolytics and anticoagulants. The purpose of this study is to examine the early changes in pulmonary mechanics after inhalation injury and see if the use of NT affects lung function. Methods Retrospective study was done on Inhalation injury patients over a 12 years period from 01/2009 to 01/2021. Patients’ data collected from their medical records, included patient demographics and outcomes, percentage Total Body Surface Area (TBSA), Carboxyhemoglobin level upon admission, Respiratory Treatments (bronchodilator, Mucolytic and Heparin), Tobramycin treatment, Oxygen requirement, Lung compliance (peak airway pressure &amp; Mean airway Pressure), Mode of Ventilation, total Ventilator Day, and number of Hospital Days. Patients with inhalation injury from 2009-2019 were retrospectively reviewed for treatment of inhalation injury. Univariate analysis and multiple logistic regression were performed using Excel and Stata. Results Of 90 patients with inhalation injury, median age was 53.5 (IQR:31-65) with 30% (n=28) women and median TBSA of 15%(IQR:2-38%). The median length of stay was 21 days (IQR:6-47). Median ventilator days was (8.5, IQR:3-21) and median ICU days was 12 (IQR:3-28). After adjusting for grade of inhalation injury, patients who did not receive NT were 2.7 times as likely to get pneumonia compared to patients who received NT (p=0.037). Initial median carboxyhemoglobin was 3.9 (IQR: 2-9.1). Overall mortality was 21%, but the incidence of death increased with grade of injury The Median Mean Airway Pressures were Day 1: 9.5mmHg, Day 2: 11mmHg, Day 3: 13mmHg, Day 4: 12mmHg The median peak pressures were Day 1; 20mmHg, Day 2: 21mmHg; Day 3: 22.5mmHg; Day 4: 21mmHg Conclusions Patients with inhalation injury are susceptible to Acute Respiratory Distress Syndrome, indicated by a decrease in lung compliance and increase in the patient’s oxygenation support. The lung compliance of these patients being to change resulting in an increase in their Peak Airway Pressure and Mean Airway Pressure within the first 72 hours. Moderate hypoxemia is present in these patients with the progress of the smoke inhalation injury. The usage of NT did not have a direct benefit to the pulmonary mechanics for inhalation injury when used as a prophylactic strategy. Additional research and clinical trials are needed to better understand the effect of inhalation injury on pulmonary mechanics. Applicability of Research to Practice Analysis of pulmonary mechanics in patients with inhalation injury can allow clinicians to better tailor ventilator settings to improve clinical outcomes.