Outcomes of patients with COPD switching from multiple-inhaler to once-daily single-inhaler triple therapy in a real-world primary care setting in England: a retrospective pre-post cohort study.

BACKGROUND: Compared with multiple-inhaler triple therapy (MITT), single-inhaler triple therapy (SITT) with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) demonstrated improved lung function and meaningful improvements in chronic obstructive pulmonary disease (COPD) Assessment Test score. This real-world study compared the effectiveness of switching patients with COPD in England from MITT to once-daily SITT with FF/UMEC/VI by evaluating rates of COPD exacerbation, healthcare resource use (HCRU) and associated direct medical costs. METHODS: Retrospective cohort pre-post study using linked primary care electronic health record and secondary care administrative datasets. Patients diagnosed with COPD at age ≥35 years, with smoking history, linkage to secondary care data and continuous GP registration for 12 months pre-switch and 6 months post-switch to FF/UMEC/VI were included. Index date was the first initiation of an FF/UMEC/VI prescription immediately following MITT use from 15 November 2017 to 30 September 2019. Baseline was 12 months prior to index, with outcomes assessed 6/12 months pre-switch and post-switch, and stratified by prior COPD exacerbation status. RESULTS: We included 2533 patients (mean [SD] age: 71.1 [9.9] years; 52.1% male). In the 6 months post-switch, there were significant decreases in the proportion of patients experiencing ≥1 moderate-to-severe (36.2%-28.9%), moderate only (24.4%-19.8%) and severe only (15.4%-11.8%) COPD exacerbation (each, p<0.0001) compared with the 6 months pre-switch. As demonstrated by rate ratios, there were significant reductions in exacerbation rates of each severity overall (p<0.01) and among patients with prior exacerbations (p<0.0001). In the same period, there were significant decreases in the rate of each COPD-related HCRU and total COPD-related costs (-24.9%; p<0.0001). CONCLUSION: Patients with COPD switching from MITT to once-daily SITT with FF/UMEC/VI in a primary care setting had significantly fewer moderate and severe exacerbations, and lower COPD-related HCRU and costs, in the 6 months post-switch compared with the 6 months pre-switch.

The effect of inhaler prescription on the development of lung cancer in COPD: a nationwide population-based study.

BACKGROUND: COPD is associated with the development of lung cancer. A protective effect of inhaled corticosteroids (ICS) on lung cancer is still controversial. Hence, this study investigated the development of lung cancer according to inhaler prescription and comorbidties in COPD. METHODS: A retrospective cohort study was conducted based on the Korean Health Insurance Review and Assessment Service database. The development of lung cancer was investigated from the index date to December 31, 2020. This cohort included COPD patients (≥ 40 years) with new prescription of inhalers. Patients with a previous history of any cancer during screening period or a switch of inhaler after the index date were excluded. RESULTS: Of the 63,442 eligible patients, 39,588 patients (62.4%) were in the long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) group, 22,718 (35.8%) in the ICS/LABA group, and 1,136 (1.8%) in the LABA group. Multivariate analysis showed no significant difference in the development of lung cancer according to inhaler prescription. Multivariate analysis, adjusted for age, sex, and significant factors in the univariate analysis, demonstrated that diffuse interstitial lung disease (DILD) (HR = 2.68; 95%CI = 1.86-3.85), a higher Charlson Comorbidity Index score (HR = 1.05; 95%CI = 1.01-1.08), and two or more hospitalizations during screening period (HR = 1.19; 95%CI = 1.01-1.39), along with older age and male sex, were independently associated with the development of lung cancer. CONCLUSION: Our data suggest that the development of lung cancer is not independently associated with inhaler prescription, but with coexisting DILD, a higher Charlson Comorbidity Index score, and frequent hospitalization.

Budesonide/Glycopyrrolate/Formoterol for the Management of COPD in a UK Primary Care Population: Real-World Use and Early Medication Success.

Purpose: Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the frequency of medication success among patients with COPD who initiated BGF using real-world data. Patients and Methods: Patients with a recorded diagnostic COPD code who started BGF with ≥2 prescriptions within 90-days were identified in the UK Optimum Patient Care Research Database and followed from first prescription until censoring at the end of follow-up (180-days), death, leaving database or end of data at 24/10/2022. The primary outcome was medication success at 90-days post-BGF initiation, defined as no major cardiac or respiratory event (ie no complicated COPD exacerbation, hospitalization for any respiratory event, myocardial infarction, new/hospitalized heart failure, and death) and no incidence of pneumonia. Medication success was also assessed at 180-days post-BGF initiation. Overall real-life medication success was claimed if the lower 95% confidence interval (CI) for the proportion of patients meeting the primary outcome was ≥70% (defined a priori). Results: Two hundred eighty-five patients were included. Prior to BGF initiation, these patients often had severe airflow obstruction (mean ppFEV1: 54.5%), were highly symptomatic (mMRC ≥2: 77.9% (n = 205/263); mean CAT score: 21.7 (SD 7.8)), with evidence of short-acting ß2-agonist (SABA) over-use (≥3 inhalers/year: 62.1%, n=179/285), repeat OCS prescriptions (≥2 courses/year: 33.0%, n = 95/285) and multiple primary care consultations (≥2 visits/year: 61.1%, n = 174/285). Overall, 39.6% of patients (n = 113/285) switched from previous triple therapies. Real-life medication success was achieved by 96.5% of patients (n = 275/285 [95% CI: 93.6, 98.3]) during 90-days treatment with BGF and by 91.8% (n = 169/184 [95% CI: 86.9, 95.4]) of patients at 180-days. The prescribed daily dose of SABA remained stable over the study period. Conclusion: The majority of patients initiating BGF experienced real-life medication success reflecting the absence of severe cardiopulmonary events. These benefits were apparent after 90-days of treatment and sustained over 180-days.

Characteristics of Users and New Initiators of Single- and Multiple-Inhaler Triple Therapy for Chronic Obstructive Pulmonary Disease in Germany.

Purpose: To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany. Patients and Methods: Retrospective cohort study of patients with COPD and ≥1 prescription for single-inhaler triple therapy (SITT; fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or beclomethasone dipropionate/glycopyrronium bromide/formoterol [BDP/GLY/FOR]) or multiple-inhaler triple therapy (MITT), using data from the AOK PLUS German sickness fund (1 January 2015-31 December 2019). The index date was the first date of prescription for FF/UMEC/VI or BDP/GLY/FOR (SITT users), or the first date of overlap of inhaled corticosteroid, long-acting ß2-agonist, and long-acting muscarinic antagonist (MITT users). Two cohorts were defined: the prevalent cohort included all identified triple therapy users; the incident cohort included patients newly initiating triple therapy for the first time (no prior use of MITT or SITT in the last 2 years). Patient characteristics and treatment patterns were assessed on the index date and during the 24-month pre-index period. Results: In total, 18,630 patients were identified as prevalent triple therapy users (MITT: 17,945; FF/UMEC/VI: 700; BDP/GLY/FOR: 908; non-mutually exclusive) and 2932 patients were identified as incident triple therapy initiators (MITT: 2246; FF/UMEC/VI: 311; BDP/GLY/FOR: 395; non-mutually exclusive). For both the prevalent and incident cohorts, more than two-thirds of patients experienced ≥1 moderate/severe exacerbation in the preceding 24 months; in both cohorts more BDP/GLY/FOR users experienced ≥1 moderate/severe exacerbation, compared with FF/UMEC/VI and MITT users. Overall, 97.9% of prevalent triple therapy users and 86.4% of incident triple therapy initiators received maintenance treatment in the 24-month pre-index period. Conclusion: In a real-world setting in Germany, triple therapy was most frequently used after maintenance therapy in patients with recent exacerbations, in line with current treatment recommendations.

Triple therapy (a combination of three different respiratory inhaled medications) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience repeated short-term symptom flare-ups when taking dual therapy (a combination of two different respiratory medications). Previously, patients had to take triple therapy using two or three separate inhalers. More recently, single-inhaler triple therapies have been developed, meaning patients can take all three different medications at the same time via one single inhaler. This study assessed the characteristics of patients who were already receiving triple therapy, or who started triple therapy (either via multiple inhalers or a single inhaler), in Germany between January 2015 and December 2019. In total, 18,630 patients who were already receiving triple therapy during the study period, and 2932 patients who newly started using triple therapy were included. The study reported that more than two-thirds of included patients had experienced at least one flare-up of COPD symptoms in the 2 years before starting triple therapy. Most patients had also received another therapy for COPD before starting triple therapy. A small proportion of patients started taking triple therapy after receiving no other therapy for COPD in the previous 2 years. The results of the study suggest that triple therapy for COPD in Germany is most often used in accordance with recommendations (patients already receiving therapy and experiencing repeated symptom flare-ups).

Baseline Characteristics and ICS/LAMA/LABA Response in Asthma: Analyses From the CAPTAIN Study.

BACKGROUND: Findings from CAPTAIN (NCT02924688) suggest that treatment response to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) differs according to baseline type 2 inflammation markers in patients with moderate to severe asthma. Understanding how other patient physiologic and clinical characteristics affect response to inhaled therapies may guide physicians toward a personalized approach for asthma management. OBJECTIVE: To investigate, using CAPTAIN data, the predictive value of key demographic and baseline physiologic variables in patients with asthma (lung function, bronchodilator reversibility, age, age at asthma onset) on response to addition of the long-acting muscarinic antagonist UMEC to inhaled corticosteroid/long-acting ß2-agonist combination FF/VI, or doubling the FF dose. METHODS: Prespecified and post hoc analyses of CAPTAIN data were performed using categorical and continuous variables of key baseline characteristics to understand their influence on treatment outcomes (lung function [trough FEV1], annualized rate of moderate/severe exacerbations, and asthma control [Asthma Control Questionnaire]) following addition of UMEC to FF/VI or doubling the FF dose in FF/VI or FF/UMEC/VI. RESULTS: Adding UMEC to FF/VI led to greater improvements in trough FEV1 versus doubling the FF dose across all baseline characteristics assessed. Doubling the FF dose was generally associated with numerically greater reductions in the annualized rate of moderate/severe exacerbations compared with adding UMEC, independent of baseline characteristics. Adding UMEC and/or doubling the FF dose generally led to improvements in Asthma Control Questionnaire scores irrespective of baseline characteristics. CONCLUSIONS: Unlike previous findings with type 2 biomarkers, lung function, bronchodilator reversibility, age and age at asthma onset do not appear to predict response to inhaled therapy.

Long-acting B-2 agonists (LABA) or long-acting muscarinic antagonists (LAMA): which one may be the first option in group A COPD patients?

INTRODUCTION: Long-acting muscarinic antagonists (LAMA) or beta-2 agonists (LABA) have been recommended for symptom control in group A COPD patients as a first-line bronchodilator treatment in GOLD guidelines. However, there is no mention of priority/superiority between the two treatment options. We aimed to compare the effectiveness of these treatments in this group. METHODS: The study cohort was formed of all subjects from six pulmonology clinics with an initial diagnosis of COPD who were new users of a LAMA or LABA from January 2020 to December 2021. Seventy-six group A COPD patients, in whom LABA or LAMA therapy had been started in the last 1 month as a first-line treatment, were included in our study. Participants were evaluated with spirometry, COPD Assessment Test (CAT), mMRC scale, and St. George Respiratory Questionnaire (SGRQ) for three times (baseline, 6-12th months). RESULTS: There were 76 group A COPD patients with LAMA (67.1%) and LABA (32.9%). The number of patients who improved in CAT score at the end of the first year was significantly higher in patients using LAMA than those using LABA (p = 0.022); the improvement at minimum clinically important difference (MCID) in CAT score of LAMA group at 1st year was also significant (p = 0.044). SGRQ total and impact scores were found to be statistically lower at 1st year compared to baseline in patients using LAMA (p = 0.010 and 0.006, respectively). Significant improvement was detected in CAT and SGRQ scores at the 6th month visit in the LAMA group having emphysema (p = 0.032 and 0.002, respectively). CONCLUSION: According to significant improvements in CAT and SGRQ score, LAMA may be preferred over LABA as a bronchodilator agent in group A COPD patients, especially in emphysema-dominant phenotype.

Glycopyrronium 320 µg/mL in children and adolescents with severe sialorrhoea and neurodisabilities: A randomized, double-blind, placebo-controlled trial.

AIM: To investigate the efficacy, safety, and impact on quality of life (QoL) of an oral formulation of 320 µg/mL glycopyrronium designed for children. METHOD: A double-blind, placebo-controlled SALIVA (Sialanar plus orAl rehabiLitation against placebo plus oral rehabilitation for chIldren and adolescents with seVere sialorrhoeA and neurodisabilities) trial was conducted. Children (3-17 years) with neurodisabilities and severe sialorrhoea (modified Teachers Drooling Scale ≥6) were randomized to 320 µg/mL glycopyrronium or placebo, in addition to non-pharmacological standard care. RESULTS: Of 87 participants, 44 were aged 10 years or under and 43 had cerebral palsy. The primary endpoint, change in total Drooling Impact Scale (DIS) score from baseline to day 84, was significantly greater (improved) with 320 µg/mL glycopyrronium versus placebo (median [quartile 1, quartile 3] -29.5 [-44.5, 0] vs -1 [-16, 5]; p < 0.001), an effect also observed at day 28 (median - 25 vs -2; p < 0.01). Significant reduction in bibs/clothes used per day was seen with glycopyrronium versus placebo at day 84 (median - 2 vs 0; p < 0.01). Glycopyrronium significantly improved DIS items 9 and 10 related to the extent that drooling affects the child's and family's life (p ≤ 0.03). Adverse events were reported by 77.3% and 69.8% of children with glycopyrronium and placebo respectively; the most common treatment-related adverse event was constipation (20.5% and 16.3%). INTERPRETATION: The formulation of 320 µg/mL glycopyrronium significantly improved drooling and reduced its impact on QoL, with good tolerability in children with neurodisabilities. WHAT THIS PAPER ADDS: The formulation of 320 µg/mL glycopyrronium significantly improved Drooling Impact Scale score versus placebo at day 84. The formulation reduced the impact of drooling on the child's and family's quality of life. There were no safety or tolerability concerns with this specific formulation.

The Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide 400 µg Administered by Inhalation as Single and Multiple (Twice Daily) Doses in Healthy Chinese Participants.

Purpose: To date, aclidinium pharmacokinetic (PK) studies have focused on Caucasian populations, and no data are available for Chinese populations. We aimed to characterize the PK and safety profile of aclidinium and its metabolites (LAS34823 and LAS34850) following single and multiple (twice-daily; BID) dosing in healthy Chinese participants, and to compare PK data between Chinese and Caucasian populations. Materials and methods: In this Phase I, open-label study (NCT03276052), healthy participants from a single site in China received aclidinium bromide 400 µg via a dry powder inhaler. The Day 1 single dose was followed by a washout period of 96 hours. On Days 5 through 8, participants received BID doses. Results: Twenty healthy Chinese participants, aged 18-45 years, were enrolled. Aclidinium absorption was rapid (median time to maximum concentration [tmax] 0.08 hours post-dose following single/multiple doses). LAS34823 had a similar median tmax of 0.08 hours, whereas LAS34850 tmax occurred later (median 2.50-3.00 hours). Aclidinium, LAS34823, and LAS34850 concentrations declined in a bi-phasic manner; geometric mean half-life was 13.5 hours (single dosing) and 21.4 hours (multiple dosing), while steady state was generally achieved after 5 days' continuous dosing. Area under the concentration-time curve during a dosage interval (AUCτ) metabolite to parent ratios for LAS34823 were 2.6 (Day 1) and 2.9 (Day 9), while LAS34850 had ratios of 136.0 and 94.8, respectively. Aclidinium accumulation occurred after 5 days of BID dosing (LS mean accumulation ratio for AUCτ Day 9/Day 1: 214.1% [90% CI, 176.5, 259.6]); LAS34823 accumulation was similar, while LAS34850 accumulation was lower. Between-participant exposure variability was moderate to high for aclidinium and LAS34823, and low for LAS34850. Conclusion: Single and multiple doses of aclidinium were well tolerated in healthy Chinese participants. The safety profile of and exposure to aclidinium was consistent with previous studies conducted in Caucasian populations.

Prescription Patterns of New Use of Fixed-Dose Combination Inhalers in Patients with Chronic Obstructive Pulmonary Disease: Long-Acting ß2 Agonists Plus Long-Acting Muscarinic Antagonists versus Long-Acting ß2 Agonists Plus Inhaled Corticosteroids.

Background: The clinical guideline recommends use of long-acting ß2 agonists/long-acting muscarinic antagonists (LABA/LAMA) or long-acting ß2 agonists/inhaled corticosteroids (LABA/ICS) combination therapies for patients with severe chronic obstructive pulmonary disease (COPD). The fixed-dose combination (FDC) inhalers of LABA/LAMA and LABA/ICS were reimbursed in Taiwan in 2015 and in 2002, respectively. This study aimed to examine prescription patterns of new use of either FDC therapy in real-world practice. Methods: We identified COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC between 2015 and 2018 from a population-based Taiwanese database with 2 million, randomly sampled beneficiaries enrolled in a single-payer health insurance system. We compared number of LABA/LAMA FDC and LABA/ICS FDC initiators in each calendar year, from different hospital accreditation levels, and cared for by different physician specialties. We also compared baseline patient characteristics between LABA/LAMA FDC and LABA/ICS FDC initiators. Results: A total of 12,455 COPD patients who initiated LABA/LAMA FDC (n=4019) or LABA/ICS FDC (n=8436) were included. Number of LABA/LAMA FDC initiators increased apparently (n=336 in 2015 versus n=1436 in 2018), but number of LABA/ICS FDC initiators decreased obviously (n=2416 in 2015 versus n=1793 in 2018) over time. The preference of use of LABA/LAMA FDC varied across clinical environments. The proportions of LABA/LAMA FDC initiators were more than 30% in the setting of non-primary care clinics (eg, medical centers) and in the services of chest physicians; but were only less than 10% in primary care clinics and non-chest physicians' services (eg, family medicine physicians). LABA/LAMA FDC initiators appeared to be older, male, to have more comorbidities, and to utilize resources more frequently compared to LABA/ICS FDC initiators. Conclusion: This real-world study found evident temporal trends, variations in healthcare provider, and differences in patient characteristics among COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC.

Riesgos, fenotipos y comparación de tratamiento de EPOC en atención primaria según guías GOLD y GesEPOC / Risks, phenotypes and comparison between treatments according to guidelines GOLD and GesEPOC in primary care

Introducción La enfermedad pulmonar obstructiva crónica (EPOC) es una patología infradiagnosticada, con una elevada morbimortalidad. El diagnóstico y el seguimiento se realizan en gran parte en atención primaria (AP). El objetivo de nuestro estudio es clasificar los pacientes EPOC de acuerdo con GOLD 2019 y GesEPOC 2017. Como objetivos secundarios, analizar el tipo de riesgo, describir y comparar el tratamiento pautado con el recomendado por las guías. Material y métodos Estudio observacional transversal multicéntrico realizado en siete equipos de AP. Se incluyeron 637 pacientes EPOC entre 35 y 85años. Resultado La edad media fue de 70,3años, el 84,6% tenían comorbilidades y el 43,5% eran fumadores activos. El FEV1 post-broncodilatador medio fue del 61,92% (DE: 17,42). Predominaron los pacientes con mMRC=1 (43,8%), 57,8% CAT<10. Índice BODEx leve (75,7%). GoldA fue mayoritario (47,7%). El fenotipo más frecuente fue el no agudizador (61,1%). El 25% fueron ACO. El 56,2% eran pacientes de bajo riesgo. El 20,6% no tenían prescrito ningún tratamiento, LABA +LAMA +CI (19,6%), LAMA +LABA (16,5%) y LAMA (16,3%). Si comparamos los tratamientos que tienen pautados los pacientes con lo que recomienda la GOLD, obtenemos que el 61% coinciden con una concordancia moderada, mientras que si los comparamos con la GesEPOC, el 53,8% coinciden con concordancia débil. El 73,4% de los tratamientos coinciden entre ambos documentos (concordancia moderada). Conclusiones Los pacientes EPOC atendidos en AP son de bajo riesgo, leves y no agudizadores. Si comparamos los tratamientos que tienen pautados los pacientes con lo que recomiendan la GOLD y la GesEPOC, encontramos una concordancia moderada y débil, respectivamente (AU)

Introduction Chronic obstructive pulmonary disease (COPD) is an underdiagnosed pathology with a high morbidity and mortality. Diagnosis and follow-up are mostly carried out in primary care (PC). The objective of our study is to classify COPD patients according to GOLD 2019 and GesEPOC 2017 guidelines. As secondary objectives, to analyze the type of risk and to describe and compare the prescribed treatment with that recommended by the guidelines. Material and methods Multicenter cross-sectional observational study in seven Health Care centers. 637 COPD patients between 35 and 85years old were included. Results The mean age was 70.3years old, 84.6% had comorbidities and 43.5% were active smokers. The mean post-bronchodilator FEV1 was 61.92% (SD: 17.42). Most are patients with mMRC=1 (43.8%), 57.8% CAT<10. Mild BODEx index (75.7%). GoldA was the majority (47.7%). The most frequent phenotype was non-exacerbator (61.1%). 25% were ACOs. 56.2% were low-risk patients. 20.6% had not been prescribed any treatment, LABA +LAMA +CI (19.6%), LAMA +LABA (16.5%) and LAMA (16.3%). If we compare the treatments that the patients have prescribed, with the one is recommended by GOLD, we obtain that 61% coincide with moderate concordance, while if we compare with GesEPOC, 53.8% coincide with weak concordance. 73.4% of the treatments coincide between both documents (moderate agreement). Conclusions COPD patients treated in PC are low risk, mild and non-exacerbators. If we compare the treatments that the patients have prescribed, with what is recommended by GOLD and GesEPOC, we find a moderate and weak concordance, respectively (AU)

Revisión narrativa de la terapia inhalatoria en la EPOC / COPD inhaled therapy narrative review

La terapia inhalada con broncodilatadores de acción larga es la base del tratamiento farmacológico de la EPOC. Con el fin conocer los que ofrecen un mejor control, se realizó una búsqueda en Medline (Pubmed). Se analizaron los estudios comparativos de terapia inhaladora en pacientes con EPOC. Tras la comparación entre la combinación fija LABA/LAMA frente LABA/CI en pacientes no exacerbadores, se concluye que hay un mejor control con LABA/LAMA. Dentro de las combinaciones LABA/CI, la combinación budesonida/formoterol ofreció un mejor control. En la terapia LAMA no hay grandes diferencias, pero comparada con LABA ofreció un mayor control. La triple terapia en un único dispositivo se muestra superior a la doble terapia y a la triple terapia en dos dispositivos, no habiendo diferencias relevantes entre las combinaciones disponibles (AU)

Inhaled therapy with long-acting bronchodilators is the base of pharmacological treatment in COPD. In order to find out those that offer better control, a search was carried out in Medline (Pubmed). Comparative studies of inhaler therapy in COPD patients were analyzed. The comparison between the fixed combination LABA/LAMA versus LABA/CI in non-exacerbating patients, revealed a better control with LABA/LAMA. Within the LABA/CI combinations, budesonide/formoterol combination offered better control. LAMA inhalers revealed no great differences, but when compared to LABA, it offered a better control. Regarding triple therapy in a single device, was superior to double therapy and to triple therapy in two devices, with no relevant differences among the available combinations(AU)

Balanced modulation of neuromuscular synaptic transmission via M1 and M2 muscarinic receptors during inhibition of cholinesterases.

Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 µM). However, neither pirenzepine (0.1 µM) nor atropine (1 µM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 µmol/kg, i.p.) and atropine (50 µmol/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD50 dose of paraoxon.

Intra-dorsal striatal acetylcholine M1 but not dopaminergic D1 or glutamatergic NMDA receptor antagonists inhibit consolidation of duration memory in interval timing.

The striatal beat frequency model assumes that striatal medium spiny neurons encode duration via synaptic plasticity. Muscarinic 1 (M1) cholinergic receptors as well as dopamine and glutamate receptors are important for neural plasticity in the dorsal striatum. Therefore, we investigated the effect of inhibiting these receptors on the formation of duration memory. After sufficient training in a peak interval (PI)-20-s procedure, rats were administered a single or mixed infusion of a selective antagonist for the dopamine D1 receptor (SCH23390, 0.5 µg per side), N-methyl-D-aspartic acid (NMDA)-type glutamate receptor (D-AP5, 3 µg), or M1 receptor (pirenzepine, 10 µg) bilaterally in the dorsal striatum, immediately before initiating a PI-40 s session (shift session). The next day, the rats were tested for new duration memory (40 s) in a session in which no lever presses were reinforced (test session). In the shift session, the performance was comparable irrespective of the drug injected. However, in the test session, the mean peak time (an index of duration memory) of the M1 + NMDA co-blockade group, but not of the D1 + NMDA co-blockade group, was lower than that of the control group (Experiments 1 and 2). In Experiment 3, the effect of the co-blockade of M1 and NMDA receptors was replicated. Moreover, sole blockade of M1 receptors induced the same effect as M1 and NMDA blockade. These results suggest that in the dorsal striatum, the M1 receptor, but not the D1 or NMDA receptors, is involved in the consolidation of duration memory.

Stable Atropine Loaded Film As a Potential Ocular Delivery System For Treatment Of Myopia.

PURPOSE: The objective of the present study was to prepare stable and high bioavailability ocular atropine loaded films (ATR-films) as potential ocular drug delivery systems for the treatment of myopia. METHODS: ATR-films were prepared by the solvent casting method and the physical properties of films were evaluated including thickness, water content, light transparency, disintegration time, and mechanical properties. FT-IR, DSC, XRD, TGA, AFM, and Raman spectroscopy were performed to characterize the film. The stability test was conducted under different conditions, such as high humidity, high temperature, and strong light. The pharmacokinetic study and irritation assessment were conducted in rabbits. The efficacy of ATR-films was evaluated by refraction and ocular biometry in myopia guinea pigs. RESULT: After optimizing the formulation, the resulting ATR-film was flexible and transparent with lower water content (8.43% ± 1.25). As expected, the ATR-film was stable and hydrolysate was not detected, while the content of hydrolysate in ATR eye drops can reach up to 8.1867% (limit: < 0.2%) in the stability study. The safety assessment both in vitro and in vivo confirmed that the ATR-film was biocompatible. Moreover, the bioavailability (conjunctiva 3.21-fold, cornea 2.87-fold, retina 1.35-fold, sclera 2.05-fold) was greatly improved compared with the ATR eye drops in vivo pharmacokinetic study. The pharmacodynamic study results showed that the ATR-film can slow the progress of form-deprivation myopia (~ 100 ± 0.81D), indicating that it has a certain therapeutic effect on form-deprivation myopia. CONCLUSION: The ATR-film with good stability and high bioavailability will have great potential for the treatment of myopia.

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease.

BACKGROUND: Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting ß2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 µg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. METHODS: This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 µg per actuation) radiolabeled with technetium­99­pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. RESULTS: The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). CONCLUSIONS: Radiolabeled BGF 320/18/9.6 µg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045.

Tiotropium Bromide Attenuates Mucus Hypersecretion in Patients with Stable Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with stable chronic obstructive pulmonary disease (COPD) have been observed to benefit from tiotropium bromide. However, there are few studies of tiotropium bromide on sputum and sputum viscosity. To evaluate the effect of tiotropium bromide on mucus hypersecretion, a randomized, double-blind controlled trial was performed. METHODS: 120 cases of patients with pulmonary function grade II were divided into two groups, which include the treatment group given tiotropium bromide powder inhalation (18 µg, inhalation, QD) and the control group given formoterol fumarate powder inhalation (12 µg, inhalation, BID) plus ambroxol hydrochloride tablets (60 mg, oral, TID). After 3 months of treatment, the pulmonary function and α 1-acid glycoprotein (α 1-AGP) in sputum were detected, and the changes of glycoprotein and Ca2+ content were evaluated by Miller classification. RESULTS: Three patients (2 cases in the treatment group and 1 case in the control group) were dropped due to loss of follow-up, and 117 cases of patients were enrolled in this study. After 3 months of treatment, the sputum character score, α1-acid glycoprotein, Ca2+ content, and lung function of the two groups were significantly improved; group comparison analyses revealed that there was no significant difference in the content of α 1-AGP, Ca2+ in sputum, and lung function between the two groups (P > 0.05), but the improvement of sputum properties was significant (P < 0.05), and the treatment group was better than the control group (t = -2.77; P = 0.007). CONCLUSIONS: Inhaled tiotropium bromide can effectively inhibit the mucus hypersecretion in stable COPD patients, improve the sputum properties and lung function of patients, and improve the quality of life of patients.

Impact of long-acting muscarinic antagonists on small airways in asthma and COPD: A systematic review.

Small airway disease is recognized as a cardinal pathological process of chronic obstructive pulmonary disease (COPD), and recently small airways have been recognized as a major site of airflow obstruction also in asthmatic patients. The transversal involvement of small airways in COPD and asthma has warranted research efforts to identify therapeutic strategies able to unlock the small airway compartment. The mainstay of COPD treatment is represented by long-acting ß2-adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). In asthma, the efficacy of LAMAs administered add-on to inhaled corticosteroids (ICSs) or ICS/LABA combinations has been investigated only in recent years. The aim of this systematic review was to examine the current literature concerning the impact of LAMAs on small airways and their lung deposition in both COPD and asthma. LAMAs administered either alone or in combination induced an effective bronchorelaxant effect of small airways, however the effectiveness of respiratory medications not only relies on the selected drug, but also on the employed inhalation device and patient's adherence. Tiotropium delivered via Respimat® SMI achieved a superior drug deposition in the peripheral lung compared to HandiHaler® dry powder inhaler and metered-dose inhalers (MDIs). The use of co-suspension™ delivery technology for MDIs and the introduction of the eFlow® nebulizer to deliver glycopyrronium improved aerosol drug delivery to the peripheral lung, by achieving uniform distribution of drug particles. This systematic review provides a synthesis of current literature concerning the impact of LAMAs on small airways and an insight on LAMAs distribution within the lung.