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Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE-307, a brain-penetrant, small-molecule antagonist with favorable drug-like properties that selectively targets M1R. We evaluate PIPE-307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2-5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE-307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE-307 for clinical studies.

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

The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut-brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB1Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the SI were quantitated. DIO mice, when compared to those fed a low-fat/no-sucrose diet, displayed increased expression of cFos protein in the dorsal motor nucleus of the vagus, which suggests an increased activity of efferent cholinergic neurotransmission. These mice exhibited elevated levels of 2-AG biosynthesis in the SI, that was reduced to control levels by mAChR antagonists. Moreover, the peripherally restricted mAChR antagonist, methylhomatropine bromide, and the peripherally restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs. These results suggest that hyperactivity at mAChRs in the periphery increases formation of 2-AG in the SI and activates local CB1Rs, which drives hyperphagia in DIO.

Background: It remains unclear how the salivary flow and the fat content of food affect bolus formation during mastication. Objectives: We aimed to clarify: (1) how hyposalivation affects jaw‐closing and hyoid‐elevating muscle activities in bolus formation, and (2) if the effect of hyposalivation on muscle activity depends on the fat content of food. Methods: Eighteen healthy male volunteers were instructed to freely ingest four test foods: Plain, Fat without seasoning, Fat with seasoning, and Soft rice crackers. Masseter and suprahyoid electromyographic activities were recorded before and 30 min after the administration of atropine sulfate, a muscarinic receptor antagonist that induces hyposalivation. Results: Hyposalivation extended the masticatory duration significantly in all the test foods except Fat with seasoning. Masticatory cycle time was significantly longer with vs without hyposalivation for the Soft (p =.011). Suprahyoid activity/cycle was significantly greater with vs without hyposalivation (p =.013). Masticatory cycle time was significantly longer at the late stage with vs without hyposalivation for the Soft (p <.001). Suprahyoid activity/cycle was significantly greater at the middle (p =.045) and late stages (p =.002) with vs without hyposalivation for the Soft and greater at the late stage with vs without hyposalivation for the Plain (p =.043). Changes in masticatory cycle time and suprahyoid activity/cycle for these foods had significantly positive relationship (p <.001). Conclusion: Hyposalivation‐induced changes in masticatory behaviours resulted from the middle and late stage suprahyoid activity. Fat content and seasoning compensate for salivary flow inhibition. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a persistent, chronic inflammatory disease of the lungs. Tiotropium, used in the treatment of COPD, is a muscarinic receptor antagonist that provides long-acting bronchodilation. Our study aimed to investigate the effects of Tiotropium on anterior chamber parameters. Methods: The study was conducted as an observational cross-sectional and prospectively between October 2023 and April 2024. Patients were examined in three groups: Group 1 consisted of untreated COPD patients; Group 2 consisted of healthy volunteers similar age and gender, and Group 3 included COPD patients receiving Tiotropium 18 mcg via HandiHaler. Anterior chamber parameters, intraocular pressure values, and photopic-mesopic pupil diameters were measured at the initial visit for Group 1 and Group 2 patients, and at the third month of treatment for Group 3 patients. Results: Thirty-six patients were included in each group in the study. No significant differences were observed in ocular findings between the patient and control groups. In COPD patients receiving Tiotropium, narrowing of angle parameters, an increase in photopic-mesopic pupil diameters, and intraocular pressure were observed at the third month of treatment. Conclusion: This study is the first research that investigate the effects of Tiotropium on anterior chamber parameters, pupil diameters, and intraocular pressure in COPD treatment. In conclusion, patients with COPD receiving Tiotropium therapy for three months showed narrowing in angle parameters, an increase in intraocular pressure, and photopic-mesopic pupil diameter; however, no patients developed drug-induced acute angle closure glaucoma. Trial registration: An independent ethics committee approved the study (Giresun EAH KEAK 2023/180 and 9.10.2023/02) which was performed in accordance with the Declaration of Helsinki, Guidelines for Good Clinical Practice. The study was conducted as prospectively, observational case–control. The Clinical Trial Number obtained for the study is NCT06525051 and was taken on 2024–07-29. [ABSTRACT FROM AUTHOR]

Background: In recent years, the incorporation of LAMAs into asthma therapy has been expected to enhance symptom control. However, a significant number of patients with asthma continue to experience poorly managed symptoms. There have been limited investigations on LAMA-induced airway alterations in asthma treatment employing IOS. In this study, we administered a LAMA to patients with poorly controlled asthma, evaluated clinical responses and respiratory function, and investigated airway changes facilitated by LAMA treatments using the IOS. Methods: Of a total of 1282 consecutive patients with asthma, 118 exhibited uncontrolled symptoms. Among them, 42 switched their treatment to high-dose fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) (ICS/LABA/LAMA). The patients were then assessed using AHQ-33 or LCQ and ACT. Spirometry parameters (such as FEV1 or MMEF) and IOS parameters (such as R20 or AX) were measured and compared before and after exacerbations and the addition of LAMA. Results: Of the 42 patients, 17 who switched to FF/UMEC/VI caused by dyspnea exhibited decreased pulmonary function between period 1 and baseline, followed by an increase in pulmonary function between baseline and period 2. Significant differences were observed in IOS parameters such as R20, R5-R20, Fres, or AX between period 1 and baseline as well as between baseline and period 2. Among the patients who switched to inhaler due to cough, 25 were classified as responders (n = 17) and nonresponders (n = 8) based on treatment outcomes. Among nonresponders, there were no significant differences in spirometry parameters such as FEV1 or PEF and IOS parameters such as R20 or AX between period 1 and baseline. However, among responders, significant differences were observed in all IOS parameters, though not in most spirometry parameters, between period 1 and baseline. Furthermore, significant differences were noted between baseline and period 2 in terms of FEV1, %MMEF, %PEF, and all IOS parameters. Conclusion: ICS/LABA/LAMA demonstrates superiority over ICS/LABA in improving symptoms and lung function, which is primarily attributed to the addition of LAMA. Additionally, IOS revealed the effectiveness of LAMA across all airway segments, particularly in the periphery. Hence, LAMA can be effective against various asthma phenotypes characterized by airway inflammation, even in real-world cases. [ABSTRACT FROM AUTHOR]

Background: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count – focusing on blood EOS count 100 to < 300 cells/mm3 – as a function of exacerbation history and COPD severity. Methods: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12–24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. Results: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. Conclusions: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations. Trial registration: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015). [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of triple inhaled therapy, a combination of inhaled glucocorticoids, long-acting muscarinic antagonists, and long-acting β2 agonists in managing acute exacerbations of chronic obstructive pulmonary disease (COPD). Methods: Medical data of 100 patients with acute exacerbation of COPD admitted to Shaoxing Second Hospital, Shaoxing, China between January 2020 to December 2022 was collected and retrospectively analyzed. The patients were randomized into control (n = 50) and study groups (n = 50). Control group received budesonide/formoterol inhalers while the study group received triple inhaled therapy (budesonide/glycopyrronium/formoterol inhalers). Arterial blood gas, pulmonary function, immune function, adverse effects, and efficacy were evaluated. Results: The study group exhibited significantly higher pH, partial pressure of arterial oxygen (PaO2), and lower partial pressure of carbon dioxide (PaCO2) compared to control group (p < 0.001). Furthermore, the study group showed significantly higher levels of pulmonary function and immune function indices compared to control group (p < 0.001). There was no significant difference in incidence of adverse reactions between the two groups (p > 0.05). The study group was associated with higher clinical efficacy compared to the control group (p < 0.05). Conclusion: Triple inhaled therapy significantly alleviates the clinical symptoms of patients with COPD and enhances pulmonary and immune functions. Future studies should cover a larger and more diverse group of participants for broader validity. [ABSTRACT FROM AUTHOR]

Interictal psychosis is a psychotic symptom that is not temporally related to epileptic seizures. Pregnancy delusion is defined as a person's fixed belief that she is pregnant despite objective evidence that she is not pregnant. In this case report, pregnancy delusion was described in a patient with epilepsy. A 31-year-old woman with epilepsy was admitted to a psychiatric ward. The patient, whose pregnancy test results were never positive, believed that she was pregnant. It was learned that her identical twin had experienced reproductive-sexuality-themed psychotic symptoms 10 years ago. The patient was hospitalized for three weeks and discharged in remission with paliperidone 6 mg/day and biperiden 2 mg/day. Caution should be exercised when using antipsychotics because of their epileptogenic effects. Pregnancy delusion in epilepsy is rare. In addition to this rare condition, it is noteworthy that reproductive-sexual delusions were reported in the patient's twin brother who was diagnosed with epilepsy. [ABSTRACT FROM AUTHOR]

The article focuses on hereditary hyperekplexia (HPX), a rare disorder characterized by exaggerated startle response and generalized muscle stiffness, often presenting in infancy. It discusses the standard treatment with clonazepam and explores the novel use of trihexyphenidyl to alleviate persistent generalized stiffness episodes in patients unresponsive to clonazepam.

Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood–brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia. KarXT, a promising medication for schizophrenia, combines xanomeline, an agonist for muscarinic receptors M1 and M4, with trospium, an antimuscarinic agent. Xanomeline can effectively penetrate the blood–brain barrier (BBB), allowing it to target and stimulate muscarinic receptors in the brain, leading to decline or eliminate of positive and negative symptoms as well as cognitive improvement. On the other hand, trospium lacks the ability to cross the BBB and primarily acts as an antimuscarinic agent in peripheral organs, reducing the potential side effects associated with xanomeline. These findings underscore the potential of KarXT as a viable treatment option for schizophrenia, offering symptom relief while minimizing the adverse effects typically associated with xanomeline as a monotherapy. [ABSTRACT FROM AUTHOR]

The effect of bronchodilators is mainly assessed with forced expiratory volume in 1 s (FEV1) in chronic obstructive pulmonary disease (COPD). Their impact on oxygenation and lung periphery is less known. Our objective was to compare the action of long-acting β2-agonists (LABA-olodaterol) and muscarinic antagonists (LAMA-tiotropium) on tissue oxygenation in COPD, considering their impact on proximal and peripheral ventilation as well as lung perfusion. FEV1, Helium slope (SHe) from a single-breath washout test (SHe decreases reflecting a peripheral ventilation improvement), frequency dependence of resistance (R5-R19), area under reactance (AX), lung capillary blood volume (Vc) from double diffusion (DLNO/DLCO), and transcutaneous oxygenation (TcO2) were measured before and 2 h post-LABA (day 1) and LAMA (day 3) in 30 patients with COPD (FEV1 54 ± 18% pred; GOLD A 31%/B 48%/E 21%) after 5–7 days of washout, respectively. We found that TcO2 increased more (P = 0.03) after LAMA (11 ± 12% from baseline, P < 001) compared with LABA (4 ± 11%, P = 0.06) despite a lower FEV1 increase (P = 0.03) and similar SHe (P = 0.98), AX (P = 0.63), and R5-R19 decreases (P = 0.37). TcO2 and SHe changes were negatively correlated (r = −0.47, P = 0.01) after LABA, not after LAMA (r = 0.10, P = 0.65). DLNO/DLCO decreased and Vc increased after LAMA (P = 0.04; P = 0.01, respectively) but not after LABA (P = 0.53; P = 0.24). In conclusion, LAMA significantly improved tissue oxygenation in patients with COPD, while only a trend was observed with LABA. The mechanisms involved may differ between both drugs: LABA increased peripheral ventilation, whereas LAMA increased lung capillary blood volume. Should oxygenation differences persist over time, LAMA could arguably become the first therapeutic choice in COPD. NEW & NOTEWORTHY: Long-acting muscarinic antagonists (LAMAs) significantly improved tissue oxygenation in patients with COPD, while only a trend was observed with β2-agonists (LABAs). The mechanisms involved may differ between drugs: increased peripheral ventilation for LABA and likely lung capillary blood volume for LAMA. This could argue for LAMA as the first therapeutic choice in COPD. [ABSTRACT FROM AUTHOR]

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Background: Some systematic reviews (SRs) on triple therapy (consisting of long-acting β2-agonist, long-acting muscarinic antagonist, and inhaled corticosteroid, LABA/LAMA/ICS) for chronic obstructive pulmonary disease (COPD) have reported conflicting results. As the number of syntheses increases, the task of identifying and interpreting evidence becomes increasingly complex and demanding. Objectives: To provide a comprehensive overview of the efficacy and safety of triple therapy for COPD. Design: Overview of SRs. Methods: Two independent reviewers conducted comprehensive searches in PubMed, Embase, Web of Science, and the Cochrane Library to identify relevant SRs that compared triple therapy with any non-triple therapy for COPD, from the inception of these databases until 1 June 2023. The AMSTAR 2 and GRADE tools were utilized to assess the quality of the included studies and the evidence for each outcome. Results: Eighteen SRs encompassing 30 original studies and involving 47,340 participants were analyzed. The overall AMSTAR 2 rating revealed that 3 SRs were of low quality, 13 SRs were of critically low quality, and 2 SRs were of high quality. No high-certainty evidence revealed a significant advantage of triple therapy in improving lung function or reducing acute exacerbations. However, all evidence, including one high certainty, supported the benefits of improving quality of life. Regarding all-cause mortality, no significant difference was found when compared to LAMA or ICS/LABA; however, high-certainty evidence confirmed its effectiveness when compared with LABA/LAMA. Notably, high-certainty evidence indicated that triple therapy was associated with a significant increase in the risk of pneumonia compared to LABA/LAMA. Conclusion: Triple therapy demonstrated notable benefits in improving lung function, reducing exacerbations, improving quality of life, and reducing all-cause mortality. However, it is important to note that it may also significantly increase the risk of pneumonia. Trial registration: This overview protocol was prospectively registered with PROSPERO (No. CRD42023431548). [ABSTRACT FROM AUTHOR]

This study aimed to define real-world prescription patterns in Korea and compare the effectiveness of chronic obstructive pulmonary disease (COPD) medications. We used national claims data provided by the Health Insurance Review and Assessment Service in Korea and examined patients who were first diagnosed with COPD and started treatment between May 1, 2017, and April 30, 2018, with no change in drug regimen. Among 30,784 patients with COPD, long-acting β2 agonist (LABA) combined with long-acting muscarinic antagonist (LAMA) (32.7%), inhaled corticosteroid-LABA (ICS–LABA) (25.6%), LAMA (18.3%), ICS (5.8%), or LABA (4.6%) were prescribed as the first-choice inhalers. The use of LABA–LAMA (hazard ratio [HR], 0.248–0.584), LAMA (HR, 0.320–0.641), ICS–LABA (HR, 0.325–0.643), and xanthine (HR, 0.563–0.828) significantly reduced the total and severe exacerbation rates compared with no use of each medication. However, the use of ICS or LABA individually did not yield such effects. The continued use of LABA–LAMA, LAMA, and ICS–LABA showed a significant effect on exacerbation rate, whereas the long-term use of ICS, LABA, and xanthine did not. Moreover, some high doses of ICS–LABA did not show significant effects. This real-world study revealed that LAMA and/or LABA could be the first choice of therapy, as recommended by recent guidelines. However, ICS, xanthine, and high-dose ICS–LABA are still being prescribed frequently as first-line drugs in Korea. [ABSTRACT FROM AUTHOR]

Coccoloba uvifera is a Mayan medicinal plant, and these leaves are used as antidiarrheal and diuretic agents. In the present work, we develop in-vitro, ex-vivo, in-vivo, and in-silico strategies to evaluate several aqueous extracts of C. uvifera leaves. In vitro tests showed that decoction extract (CuDe) presented the best yield and chlorophyll, phenol, and flavonoid content; however, CuDe showed low antioxidant activity (DPPH model). All aqueous extracts exert spasmolytic and vasorelaxant activity in a concentration-dependent manner (ex vivo), and in vivo tests showed that CuDe exerts the best antiperistaltic and diuretic effects. The in-silico analysis suggests that C. uvifera triterpenes act as a ligand of GPCR, and β-sitosterol could act as an antagonist of muscarinic acetylcholine receptor subtype 3 (m3AChR). In the context of aqueous extracts of C. uvifera, β-sitosterol and their heterosides were identified by FTIR and 1H-NMR spectroscopy. The concerted binding of β-sitosterol and other triterpenes within the m3AChR binding site may be relevant for the induction of relaxant effects at the gastrointestinal smooth muscle level. In this context, C. uvifera is a high-value plant species that requires analytical and pharmacological studies to confirm traditional medicinal use. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is one of the top three causes of death throughout the world. Because of the preventable and treatable nature of the disease along with its prevalence, COPD represents a major public health challenge. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report provides a review of the most current evidence for prevention of COPD as well as the assessment, diagnosis, and treatment of people with the disease. The purpose of this article is to provide a summary of the 2024 revised GOLD Report and current best practices in accordance with the evidence. [ABSTRACT FROM AUTHOR]

According to Global Initiative for Asthma (GINA) guidelines, long-acting muscarinic antagonists (LAMAs) should be considered as add-on therapy in patients with asthma that remains uncontrolled, despite treatment with medium-dose (MD) or high-dose (HD) inhaled corticosteroids (ICS)/long-acting β2-agonist (LABA) combinations. In patients ≥ 18 years, LAMA may be added in triple combination with an ICS and a LABA. To date, the precise efficacy of triple ICS/LABA/LAMA combination remains uncertain concerning the impact on exacerbation risk in patients with uncontrolled asthma. Therefore, an umbrella review was performed to systematically summarize available data on the effect of triple ICS/LABA/LAMA combination on the risk of asthma exacerbation. An umbrella review has been performed according to the PRIOR statement. The overall results obtained from 5 systematic reviews and meta-analyses suggest that triple ICS/LABA/LAMA combination reduces the risk of asthma exacerbation. HD-ICS showed a greater effect particularly in reducing severe asthma exacerbation, especially in patients with evidence of type 2 inflammation biomarkers. The findings of this umbrella review suggest an optimization of ICS dose in triple ICS/LABA/LAMA combination, based on the severity of exacerbation and type 2 biomarkers expression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this review is to summarize the management of asthma in children and to highlight different guideline-based approaches. This review also discusses literature regarding the use of corticosteroids, both inhaled and systemic, as well as biologic agents, in asthma management. Summary Asthma is a common chronic respiratory condition in the pediatric population and has evolved into a highly patient-specific disease. Of the 2 main asthma guidelines, one developed by the National Asthma Education and Prevention Program was recently published as a focused update in 2020. The other, from the Global Initiative for Asthma, focuses on a global strategy for management and prevention, with the most recent update in 2023. Both reports discuss diagnosis, assessment, and treatment of asthma in adults and children. Treatment is designed as a stepwise approach in both reports, although there are key differences. This article focuses on gaps in these guidelines, including the use of bronchodilators and inhaled corticosteroids with single maintenance and reliever therapy and long-acting muscarinic antagonists in children. It also reviews treatment in children under 5 years of age, although recommendations are limited due to a lack of evidence in this age group. Finally, this review discusses considerations for emerging treatments, including biologics, for patients who are difficult to treat. Conclusion New treatment strategies and agents have emerged in the treatment of pediatric asthma. Pharmacists play a key role in providing education about, dispensing, and recommending the newest evidence-based treatment options for children. [ABSTRACT FROM AUTHOR]

Many people around the world suffer from neurodegenerative diseases associated with cognitive impairment. As life expectancy increases, this number is steadily rising. Therefore, it is extremely important to search for new treatment strategies and to discover new substances with potential neuroprotective and/or cognition-enhancing effects. This study focuses on investigating the potential of astragaloside IV (AIV), a triterpenoid saponin with proven acetylcholinesterase (AChE)-inhibiting activity naturally occurring in the root of Astragalus mongholicus, to attenuate memory impairment. Scopolamine (SCOP), an antagonist of muscarinic cholinergic receptors, and lipopolysaccharide (LPS), a trigger of neuroinflammation, were used to impair memory processes in the passive avoidance (PA) test in mice. This memory impairment in SCOP-treated mice was attenuated by prior intraperitoneal (ip) administration of AIV at a dose of 25 mg/kg. The attenuation of memory impairment by LPS was not observed. It can therefore be assumed that AIV does not reverse memory impairment by anti-inflammatory mechanisms, although this needs to be further verified. All doses of AIV tested did not affect baseline locomotor activity in mice. In the post mortem analysis by mass spectrometry of the body tissue of the mice, the highest content of AIV was found in the kidneys, then in the spleen and liver, and the lowest in the brain. [ABSTRACT FROM AUTHOR]

A drug that combines the muscarinic receptor agonist xanomeline and the muscarinic receptor antagonist trospium reduced positive and negative symptoms of schizophrenia in a Phase 3 placebo‐controlled trial. The study's investigators wrote that the results suggest the drug, known as KarXT, could represent a new class of antipsychotic medications. Results were published online Dec. 14, 2023, in The Lancet. [ABSTRACT FROM AUTHOR]

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

Neurogenic lower urinary tract dysfunction (NLUTD) encompasses a broad spectrum of neurological conditions affecting the lower urinary tract. Managing NLUTD requires a tailored approach focused on preserving kidney function and enhancing patients' quality of life. Clinical guidelines provide valuable guidance for healthcare professionals, but discrepancies in recommendations arise among other factors due to limited high-quality clinical evidence. Prominent guidelines from organisations like the International Consultation of Incontinence, the European Association of Urology, the American Urological Association, and the National Institute for Health and Care Excellence offer varying recommendations for NLUTD management. This study reviews and summarizes the recommendations for conservative, pharmacological, and surgical management options across these guidelines. [ABSTRACT FROM AUTHOR]

Background: Airway epithelial cells (AECs) are a major component of local airway immune responses. Direct effects of type 2 cytokines on AECs are implicated in type 2 asthma, which is driven by epithelial-derived cytokines and leads to airway obstruction. However, evidence suggests that restoring epithelial health may attenuate asthmatic features. Methods: We investigated the effects of passive sensitisation on IL-5, NF-κB, HDAC-2, ACh, and ChAT in human bronchial epithelial cells (HBEpCs) and the effects of fluticasone furoate (FF) and umeclidinium (UME) alone and in combination on these responses. Results: IL-5 and NF-κB levels were increased, and that of HDAC-2 reduced in sensitised HEBpCs. Pretreatment with FF reversed the effects of passive sensitisation by concentration-dependent reduction of IL-5, resulting in decreased NF-κB levels and restored HDAC-2 activity. Addition of UME enhanced these effects. Sensitized HEBpCs also exhibited higher ACh and ChAT levels. Pretreatment with UME significantly reduced ACh levels, and addition of FF caused a further small reduction. Conclusion: This study confirmed that passive sensitisation of AECs results in an inflammatory response with increased levels of IL-5 and NF-κB, reduced levels of HDAC-2, and higher levels of ACh and ChAT compared to normal cells. Combining FF and UME was found to be more effective in reducing IL-5, NF-κB, and ACh and restoring HDAC-2 compared to the individual components. This finding supports adding a LAMA to established ICS/LABA treatment in asthma and suggests the possibility of using an ICS/LAMA combination when needed. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effectiveness and safety of fixed-dose combination (FDC) inhaled corticosteroids/long-acting β2-agonists (ICS/LABA) in bronchiectasis. A retrospective cohort study analyzed electronic medical records of bronchiectasis patients initiating ICS/LABA FDC or LAMA between 2007 and 2021. All bronchiectasis diagnoses were made by radiologists using high-resolution computed tomography. Of the 1,736 patients, 1,281 took ICS/LABA FDC and 455 LAMA. Among the 694 propensity score matched patients, ICS/LABA FDC had comparable outcomes to LAMA, with HRs of 1.22 (95% CI 0.81–1.83) for hospitalized respiratory infection, 1.06 (95% CI 0.84–1.33) for acute exacerbation, and 1.06 (95% CI 0.66–1.02) for all-cause hospitalization. Beclomethasone/formoterol (BEC/FOR) or budesonide/formoterol (BUD/FOR) led to a lower risk of acute exacerbation compared to fluticasone/salmeterol (FLU/SAL) (BEC/FOR HR 0.59, 95% CI 0.43–0.81; BUD/FOR HR 0.68, 95% CI 0.50–0.93). BEC/FOR resulted in lower risks of hospitalized respiratory infection (HR 0.48, 95% 0.26–0.86) and all-cause hospitalization (HR 0.55, 95% 0.37–0.80) compared to FLU/SAL. Our findings provide important evidence on the effectiveness and safety of ICS/LABA FDC compared with LAMA for bronchiectasis. BEC/FOR and BUD/FOR were associated with better outcomes than FLU/SAL. [ABSTRACT FROM AUTHOR]

Background and objectives: Few studies have reported which inhaled combination therapy, either bronchodilators and/or inhaled corticosteroids (ICSs), is beneficial in patients with bronchiectasis and airflow obstruction. Our study compared the efficacy and safety among different inhaled combination therapies in patients with bronchiectasis and airflow obstruction. Methods: Our retrospective study analyzed the patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity < 0.7 and radiologically confirmed bronchiectasis in chest computed tomography between January 2005 and December 2021. The eligible patients underwent baseline and follow-up spirometric assessments. The primary endpoint was the development of a moderate-to-severe exacerbation. The secondary endpoints were the change in the annual FEV1 and the adverse events. Subgroup analyses were performed according to the blood eosinophil count (BEC). Results: Among 179 patients, the ICS/long-acting beta-agonist (LABA)/long-acting muscarinic antagonist (LAMA), ICS/LABA, and LABA/LAMA groups were comprised of 58 (32.4%), 52 (29.1%), and 69 (38.5%) patients, respectively. ICS/LABA/LAMA group had a higher severity of bronchiectasis and airflow obstruction, than other groups. In the subgroup with BEC ≥ 300/uL, the risk of moderate-to-severe exacerbation was lower in the ICS/LABA/LAMA group (adjusted HR = 0.137 [95% CI = 0.034–0.553]) and the ICS/LABA group (adjusted HR = 0.196 [95% CI = 0.045–0.861]) compared with the LABA/LAMA group. The annual FEV1 decline rate was significantly worsened in the ICS/LABA group compared to the LABA/LAMA group (adjusted β-coefficient=-197 [95% CI=-307–-87]) in the subgroup with BEC < 200/uL. Conclusion: In patients with bronchiectasis and airflow obstruction, the use of ICS/LABA/LAMA and ICS/LABA demonstrated a reduced risk of exacerbation compared to LABA/LAMA therapy in those with BEC ≥ 300/uL. Conversely, for those with BEC < 200/uL, the use of ICS/LABA was associated with an accelerated decline in FEV1 in comparison to LABA/LAMA therapy. Further assessment of BEC is necessary as a potential biomarker for the use of ICS in patients with bronchiectasis and airflow obstruction. [ABSTRACT FROM AUTHOR]

The letter to the editor discusses the association between psychological health and asthma control in African American young adults. The authors of the letter agree with a previous study that found a high rate of psychological disorders in young adults with poorly controlled asthma. They suggest that the relationship between psychological health and asthma control may be bidirectional and propose that the parasympathetic system may play a role in triggering bronchial obstruction in asthmatic individuals. The authors also recommend considering the use of long-acting muscarinic antagonists (LAMAs) in patients with increased basal cholinergic activity. They conclude by emphasizing the need for further research to better understand the complex relationship between anxiety and asthma. [Extracted from the article]

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes. [ABSTRACT FROM AUTHOR]

Purpose: Japanese guidelines recommend that patients with uncontrolled asthma be referred by non-specialists to specialists (allergists and/or pulmonologists). This study investigated the reality of clinical practice in asthma patients referred to specialists in Japan.Patients and Methods: This was a retrospective, observational cohort study of asthma patients in a health insurance claim database (Cross Fact) referred from facilities with non-specialists to those with specialists from January 2016 to December 2018. The referred asthma patients were defined as patients with ≥ 4 inhaled corticosteroid (ICS)-containing prescriptions during a 1-year baseline period, with an asthma diagnosis, and who had visited a facility with specialists. Asthma exacerbation, maintenance treatment, laboratory tests, and medical procedures before and after referral were analyzed.Results: Data for 2135 patients were extracted, of which 420 with referral codes were analyzed. The proportion of patients with asthma exacerbations was 50.2% (95% confidence interval [CI]: 45.4– 55.1%) before referral and 37.4% (95% CI: 32.7– 42.2%) after, a significant decrease (P< 0.001; McNemar test). The proportions of patients prescribed ICS alone, long-acting beta-agonists (LABA), and ICS/LABA were lower after referral than before, but the proportions of patients prescribed long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, and biologics increased after referral. More asthma-related laboratory tests were performed after referral, and spirometry incidence increased from 16.4% before referral to 51.4% after referral.Conclusion: This study shows a decrease in asthma exacerbations, change in asthma treatments, and increase in laboratory tests after referral to a specialist, suggesting that referrals to specialists lead to better management of asthma. [ABSTRACT FROM AUTHOR]

Background: Bronchodilator responsiveness (BDR) in asthma involves both the central and peripheral airways but is primarily relieved with beta-2-agonists and evaluated by spirometry. To date, antimuscarinics can be added as a reliever medication in more severe asthma. We hypothesize that combining both short-acting beta-2 agonist (SABA) and short-acting muscarinic antagonist (SAMA) could also improve the responsiveness in mild-moderate asthma. Therefore, we aimed to compare the direct effects of inhaling SABA alone, SAMA alone or combining both SABA and SAMA on the central and peripheral airways in asthma.Methods: Twenty-three patients with mild-moderate BDR in asthma performed dynamic spirometry and impulse oscillometry before (baseline) and multiple timepoints within an hour after inhalation of SABA (salbutamol), SAMA (ipratropium bromide), or both SABA and SAMA at three different visits.Results: The use of SAMA alone did not show any improvement compared to the use of SABA alone. Inhalation of SABA+SAMA, however, averaged either similar or better BDR than SABA alone in FEV1, MMEF, FVC, R5, R20 and R5-R20. Inhaling SABA+SAMA reached a stable BDR in more patients within 0– 10 minutes and also reached the FEV1 (Δ%)> 12% faster (3.5 minutes) than inhaling SABA alone (5.1 minutes). Inhaling SABA+SAMA was significantly better than SAMA alone in FEV1 (p = 0.015), MMEF (p = 0.0059) and R20 (p = 0.0049). Using these three variables highlighted a subgroup (30%, including more males) of patients that were more responsive to inhaling SABA+SAMA than SABA alone.Conclusion: Overall, combining SAMA with SABA was faster and more consistent at increasing the lung function than SABA alone or SAMA alone, and the additive effect was best captured by incorporating peripheral-related variables. Therefore, SAMA should be considered as an add-on reliever for mild-moderate patients with BDR in asthma. [ABSTRACT FROM AUTHOR]

Severe asthma affects approximately 5%–10% of patients with asthma. Herein, we describe a case of non‐type 2 asthma that progressively worsened over the years. An 80‐year‐old woman was diagnosed with asthma 11 years back. She experienced repeated exacerbations requiring treatment with systemic corticosteroid despite therapy with medications including high‐dose inhaled corticosteroids/long‐acting beta‐agonists plus long‐acting muscarinic antagonist. The patient presented with non‐eosinophilic asthma. Therefore, the patient was initially treated with bronchial thermoplasty, which was effective for 1 year only. Treatment with bronchial thermoplasty, benralizumab, dupilumab, and mepolizumab was ineffective. The fourth treatment, which included tezepelumab, was initiated. The patient's symptoms and quality of life improved significantly. This is the first case of a patient who did not respond to sequential bronchial thermoplasty, benralizumab, dupilumab, and mepolizumab but who presented with good clinical response to tezepelumab. Therefore, tezepelumab may be useful for patients with non‐type 2 asthma. [ABSTRACT FROM AUTHOR]

A 5‐week trial has found that the combination of the muscarinic receptor agonist xanomeline and the peripheral muscarinic antagonist trospium significantly reduced symptoms of schizophrenia in adults. The xanomeline‐trospium combination was well‐tolerated, with no significant difference from placebo in extrapyramidal symptoms or weight gain. [ABSTRACT FROM AUTHOR]

[Display omitted] Muscarinic receptors are G protein-coupled receptors (GPCRs) that play a role in various physiological functions. Previous studies have shown that these receptors, along with other GPCRs, are voltage-sensitive; both their affinity toward agonists and their activation are regulated by membrane potential. To our knowledge, whether the effect of antagonists on these receptors is voltage-dependent has not yet been studied. In this study, we used Xenopus oocytes expressing the M2 muscarinic receptor (M2R) to investigate this question. Our results indicate that the potencies of two M2R antagonists, atropine and scopolamine, are voltage-dependent; they are more effective at resting potential than under depolarization. In contrast, the M2R antagonist AF-DX 386 did not exhibit voltage-dependent potency.Furthermore, we discovered that the voltage dependence of M2R activation by acetylcholine remains unchanged in the presence of two allosteric modulators, the negative modulator gallamine and the positive modulator LY2119620. These findings enhance our understanding of GPCRs' voltage dependence and may have pharmacological implications. [ABSTRACT FROM AUTHOR]

The article focuses on the long-awaited draft joint BTS/SIGN/NICE asthma guideline, highlighting its significant improvements over previous recommendations. It celebrates the introduction of a more pragmatic approach to asthma management, particularly the use of a single inhaler that combines reliever and preventer functions, which could potentially improve asthma outcomes in the UK.

Overactive bladder (OAB) is a common urological disease with a high prevalence in older adult populations. Antimuscarinic drugs have been the most common treatment for OAB for more than a decade, but their anticholinergic side-effects and potential impact on cognitive function among older patients are usually underestimated. This consensus aimed to provide practical recommendations concerning OAB management, with a particular emphasis on older patients. A joint consensus panel was formed by representatives of the Hong Kong Urological Association and the Hong Kong Geriatrics Society. Literature searches regarding OAB and its management were performed in PubMed and Ovid. Several working meetings were held to present and discuss available evidence, develop consensus statements, and vote for the statements. A modified Delphi method was used in this consensus process. To address questions regarding various aspects of OAB, 29 consensus statements were proposed covering the following areas: diagnosis, initial assessment, non-pharmacological treatments, considerations before administration of pharmacological treatments, various pharmacological treatments, combination therapy, and surgical treatment. Twenty-five consensus statements were accepted., Competing Interests: All authors have disclosed no conflicts of interest.

Introduction: Climacturia is an emerging type of urinary incontinence which occurs immediately following orgasm. Both men and women may suffer from climacturia in equivocal rates. This phenomenon is becoming more problematic as it impacts physiological and psychosexual aspect of well-being and quality of life. While awareness of climacturia becomes evident, studies are inadequate to support evidenced-based management in primary and urologic care settings. Objective: This study aimed to conduct a systematic review and prevalence meta-analysis of climacturia and investigate its risk factors and evidenced-based management. Methods: A systematic review of 24 articles were conducted following PRISMA 2020 guidelines. The PubMed, CINAHL, and Cochrane Library database were searched using the word "climacturia" and phrase "orgasm associated urinary incontinence" respectively. Search limiters applied included literature written in English from year of inception to 2022. Title and abstract reviews were conducted on 78 articles. Articles which did not discuss climacturia, duplicates, and previous systematic reviews were excluded after full article review. Results: The review accounts a total of N = 7798 subjects which are composed of N = 7629 (97.83%) males and N = 169 (2.17%) females with age range of 18 to 80 years old. A total of N = 2, 039 (26%) participants are with climacturia, N = 87 or 4.26% are females and N = 1, 931 or 95.74% are males. The risk factors associated with climacturia include sexually active male, history of prostate cancer after prostatectomy within 12 months of surgery or radiation therapy, increased Body Mass Index (BMI), erectile dysfunction (ED), increased urethral width, presence of urinary incontinence, pain-associated orgasm and loss of penile length after pelvic surgery, use of aides to obtain an erection, and increased incontinence scores for men. For women, the risk factors are high scores of female sexual function index (FSFI) and detrusor overactivity. The management for females is limited to pharmacologic therapy with use of antimuscarinic agents. While, behavioral therapy, pharmacologic regimen, pelvic floor muscle training (PFMT), surgery (sling procedure) are the management options for affected men. Conclusions: Climacturia affects males more than females, however, the evidence to support the efficacy of treatment options for both sexes are equally inadequate. Primary care and Advanced Practice Providers in primary and urologic care settings are at best position to query patients for the presence of and manage climacturia in timely manner. Further research is needed to increase evidence supporting effective management of climacturia for both men and women. Disclosure: No. [ABSTRACT FROM AUTHOR]

Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a. The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 μg [medium-strength BDP]; Study 2: 200/6/12.5 μg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (C max) and area under the plasma concentration–time curve between time zero and the last quantifiable timepoint (AUC 0–t) for the analytes were between 80 and 125 %. In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB C max in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for C max and 127.34 % for AUC 0–t). In Study 1, GB AUC 0–t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for C max and 129.12 % for AUC 0–t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC 0–t , although not for C max. Both formulations were similarly well tolerated in all three studies. Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/ FF /GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential. • Use of propellants with high global warming potential (such as HFA-134a) inpMDIs is being phased down. • The combination of BDP/FF/GB is now being reformulated using the low global warming potential propellant HFA-152a. • These three studies compared BDP/FF/GB pharmacokinetics when delivered via pMDI using HFA-152a vs HFA-134a as propellant. • Overall, these data suggest therapeutic equivalence of the new formulation and the existing BDP/FF/GB pMDI formulation. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials described beneficial effects of inhaled triple therapy (LABA/LAMA/ICS) in patients with chronic obstructive pulmonary disease (COPD) and high risk of exacerbations. We studied whether such effects were also detectable under continuous treatment in a retrospective observational setting., Methods: Data from baseline and 18-month follow-up of the COPD cohort COSYCONET were used, including patients categorized as GOLD groups C/D at both visits (n = 258). Therapy groups were defined as triple therapy at both visits (triple always, TA) versus its complement (triple not always, TNA). Comparisons were performed via multiple regression analysis, propensity score matching and inverse probability weighting to adjust for differences between groups. For this purpose, variables were divided into predictors of therapy and outcomes., Results: In total, 258 patients were eligible (TA: n = 162, TNA: n = 96). Without adjustments, TA patients showed significant (p < 0.05) impairments regarding lung function, quality of life and symptom burden. After adjustments, most differences in outcomes were no more significant. Total direct health care costs were reduced but still elevated, with inpatient costs much reduced, while costs of total and respiratory medication only slightly changed., Conclusion: Without statistical adjustment, patients with triple therapy showed multiple impairments as well as elevated treatment costs. After adjusting for differences between treatment groups, differences were reduced. These findings are compatible with beneficial effects of triple therapy under continuous, long-term treatment, but also demonstrate the limitations encountered in the comparison of controlled intervention studies with observational studies in patients with severe COPD using different types of devices and compounds., (© 2024. The Author(s).)

Objectives: Chronic obstructive pulmonary disease (COPD) is a significant cause of mortality, with its prevalence projected to rise in Asia. The primary objective of this study was to describe clinical characteristics, maintenance treatment, and healthcare resource utilization (HCRU) among patients with COPD in Hong Kong. Secondary objectives were to assess patient demographics and clinical characteristics by eosinophil (EOS) levels, and compare the demographics, clinical characteristics, and treatment patterns of patients on multiple-inhaler triple therapy (MITT)., Methods: This study analyzed a cohort of patients with COPD who had entered a previously initiated prospective cohort study involving patients with COPD and/or asthma at the Prince of Wales Hospital between 2017 and 2019., Results: Patients with COPD were enrolled (N = 220, mean age 74.3 years, 97 % male). Twelve months prior to baseline assessment, 66 % of patients were on MITT, 17 % on long-acting muscarinic antagonists (LAMAs)/long-acting beta-agonists (LABAs), and 7 % on inhaled corticosteroids (ICS)/LABA. Compared with ICS/LABA or LAMA/LABA, more patients on MITT experienced ≥1 exacerbation (26.7 %, 10.5 %, 39.7 %, respectively). Patients on MITT also had a higher mean (SD) COPD Assessment Test score (9.4 [5.9]) and modified Medical Research Council Dyspnea Scale score (1.7 [0.7]) and incurred the most COPD-related and total HCRU costs. Compared with patients with EOS ≤300 cells/μL, those with EOS >300 cells/μL had a higher number of exacerbations., Conclusions: Patients with COPD in Hong Kong treated with MITT presented more severe disease profiles and incurred higher costs. These data can be used for decision making in patients with moderate-to-severe COPD in Hong Kong., Competing Interests: Declaration of competing interest FWSK conducted clinical research on asthma and COPD with funding from AstraZeneca, Boehringer Ingelheim, GSK, and Novartis, with all fees paid direct to her institution. XX is an employee of GSK. CC is an employee of GSK. AN is an employee of GSK and owns shares in GSK. DSCH has no conflicts of interest. DM is an employee of GSK and owns shares in GSK., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aclidinium bromide (ACL) is a long-acting muscarinic receptor antagonist used for the long-term treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the degradation of aclidinium bromide under stress and stability testing conditions, for which we developed and validated the first stability-indicating, specific, precise, accurate, and robust assay and related substances HPLC methods. Nine of the compounds used as reference standards were synthesized and fully characterized by 1 H and 13 C NMR, MS, and FTIR techniques. Two of these molecules, namely ACL-dimer and ACL-desphenyl, are novel compounds and reported herein for the first time. Hydrolysis of aclidinium resulted in major degradation via the formation of ACL-desDTG and DTGA metabolites. ACL-desphenyl and phenol were observed only under oxidative conditions at very low levels (< 0.10%), while ACL-hydroxy, known as a metabolite of aclidinium and confirmed by LC/QDa and LC/Q-TOF m/z data, formed under oxidative stress-testing conditions, UV light, and daylight. The identification of two impurities formed only when aclidinium bromide was treated with hydrogen peroxide was done by LC/QDa and LC/Q-TOF studies and the novel structures were proposed as ACL-bromophenoxy and ACL-bromothiophenyl formed via bromination of the phenyl and thiophene ring on the aclidinium, respectively. The stress and photostability testing studies showed that the aclidinium bromide drug substance is not sensitive to elevated temperature (105 °C, 10 days), slightly sensitive to daylight and UV-radiation, and it showed significant degradation under all hydrolysis and oxidizing conditions. The related substances HPLC method reported herein is also capable to monitor the potential genotoxic impurity 3-bromopropoxybenzene (3-BPB), a class 2 impurity according to ICH M7, and ensures that the impurity remains below the threshold of toxicological concern (TTC) limit, making it safe for patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: We investigated the efficacy and safety of high-dose vitamin D supplementation (VDS) plus standard urotherapy (SU) in managing overactive bladder dry in children., Materials and Methods: A 3-arm, randomized clinical trial was performed at an academic center in China between January 2023 and June 2023. Eligible patients (n=303) were randomized to receive 8 weeks of high-dose VDS (vitamin D3 drops encapsulated as soft capsules, 2400 IU/d) plus SU (VDS + SU group; n=100), solifenacin (5-10 mg/d) plus SU (SOL + SU group; n=102), or SU alone (SU group; n=101). Reduction in voiding frequency was the primary outcome. Secondary outcomes encompassed improvement in urgency, nocturia, quality of life score, pediatric lower urinary tract symptom score, and participant satisfaction. Treatment-emergent adverse events were recorded within each group., Results: Participants had a median age of 82.0 months and their baseline mean vitamin D level was 22.64 ng/mL. The VDS + SU group showed greater improvements in voids/d than the SOL + SU group (median difference 3.0; 95% CI, 2.0 to 3.5; P < .001) and the SU group (median difference 4.0; 95% CI, 3.0 to 5.0; P < .001) after intervention. The VDS + SU group also showed the greatest improvement in quality of life and pediatric lower urinary tract symptom scores. Patient satisfaction was similar between the SOL + SU and SU groups. The VDS + SU group did not exhibit a heightened risk of treatment-emergent adverse events compared to the other groups., Conclusions: High-dose VDS plus SU was effective and well-tolerated in managing overactive bladder dry in children, suggesting its potential as a novel therapeutic option for this population.