Muscarinic Antagonist Research Articles

Ensifentrine in COPD patients taking long-acting bronchodilators: A pooled post-hoc analysis of the ENHANCE-1/2 studies.

The efficacy and safety of ensifentrine, a novel PDE3/PDE4 inhibitor, were previously evaluated in the ENHANCE-1 (NCT04535986) and ENHANCE-2 (NCT04542057) trials. Here, we present a pooled post-hoc subgroup analysis of patients according to background chronic obstructive pulmonary disease (COPD) maintenance medication regimens. This analysis aimed to explore the efficacy and safety of ensifentrine in patients receiving long-acting muscarinic antagonists (LAMA) or long-acting beta-agonists with inhaled corticosteroids (LABA + ICS). Eligible patients had moderate to severe COPD, were aged 40-80years, and were symptomatic at randomization. Patients were randomized 5:3, receiving twice-daily ensifentrine 3mg or placebo via standard jet nebulizer over 24weeks. The pooled post-hoc analysis included 485 LAMA patients and 272 LABA + ICS patients. Ensifentrine showed lung function improvement over placebo at week 12, including average FEV1 AUC0-12h in the LAMA (placebo-corrected least squares mean change from baseline [LSMC], 92mL; 95% CI, 54, 131; p < 0.001) and LABA + ICS subgroups (LSMC, 74mL; 95% CI, 27, 121; p = 0.002). Ensifentrine reduced the rate and risk of exacerbations in both LAMA (48% and 50%, respectively) and LABA + ICS (51% and 56%, respectively) subgroups. Ensifentrine-treated patients reported improvement in symptoms and quality of life over 24weeks. The safety profile of ensifentrine in each subgroup was similar to the profile in the pooled modified intention-to-treat population. Nebulized ensifentrine offers a novel non-steroidal anti-inflammatory and bronchodilator treatment added to existing LAMA or LABA + ICS treatment options in patients with moderate to severe, symptomatic COPD.

Challenges in treating patients with comorbid asthma and bronchiectasis.

The management of patients with overlapping asthma and bronchiectasis requires a tailored approach, starting with a comprehensive assessment of the patient's clinical profile, including the severity of asthma and the extent of bronchiectasis. Inhaled corticosteroids (ICS) are often recommended, but their use should be carefully monitored because of the risk of increased infection. If the asthma is well controlled and the bronchiectasis remains stable, a gradual reduction in the dose of ICS may be considered. Adjunctive therapies such as macrolides, which have anti-inflammatory and antimicrobial effects, or leukotriene receptor antagonists may be beneficial. However, leukotriene receptor antagonists should be used with caution in patients with bronchiectasis. Long-acting muscarinic antagonists (LAMA), especially in combination with ICS and long-acting beta-agonists (LABA), can improve bronchodilation and reduce inflammation. Although triple therapy (ICS/LABA/LAMA) is promising, its efficacy in bronchiectasis has not yet been confirmed by randomised controlled trials (RCTs). Ongoing monitoring is essential to adjust treatment as the patient's condition evolves. Preventive measures, including vaccination and regular sputum cultures, are important to minimize the risk of infection. Further research and RCTs are needed to better understand the role of dual bronchodilators and triple therapy in the management of overlapping asthma-bronchiectasis.

A retrospective study on potential drug‒drug interactions in patients with severe asthma receiving biological therapy: a single-center experience

BackgroundPrevalence of potential drug-drug interactions (pDDIs) in adult patients with severe asthma on biological therapy and their clinical significance have not been fully addressed, thus the aim of this study was to investigate them.MethodsIn this retrospective observational study, patients who were diagnosed with severe asthma and to whom biological therapy was prescribed between September 2015 and December 2020, were enrolled. The study was conducted at the Department of Allergic and Obstructive Pulmonary Diseases, Clinic for Lung Diseases Jordanovac, Clinical Hospital Center Zagreb. Data on demographic characteristics as well as concomitant medication were collected. The analysis of pDDIs was conducted via Lexicomp® online software. Interactions of significance levels A and B were only recorded, while those of levels C, D and X were further analysed. The collected data was processed via Microsoft Excel 365 software.Results60 adult patients, 60% female and 40% male, with median age of 56.2 years, were enrolled. The incidence of pDDIs was 86.67%. Total number of pDDIs detected was 518, out of which 43.24%, 45%, 4.44% and 7.3% of clinical significance B, C, D and X. Interactions of level C, D and X were recorded in, as follows: 83.33%, 25% and 33.33% patients with an average of 4.66, 1.53 and 1.9 interactions per patient. Only 13.33% of the patients had none of the potential clinically significant DDI. Most drug pairs contained at least one antiasthmatic drug. Muscarinic receptor antagonists, oral corticosteroids, β2 agonists and methylxanthines showed potential of entering into clinically significant DDIs, while leukotriene antagonists and biologicals showed no potential for the above.ConclusionPrevalence of potential drug-drug interactions in patients with severe asthma on biological therapy is high. The majority of identified interactions have moderate to high level of clinical significance. Their identification, prevention and resolution could contribute to optimizing therapy, maximizing its therapeutic effect and avoiding undesirable adverse events.

Evaluating remyelination compounds for new applications in opioid use disorder management

Opioid use disorder (OUD) is associated with a reduction in brain white matter, affecting critical areas involved in decision-making, impulse control, and reward processing. The FDA has approved several drugs and natural compounds that enhance myelination, targeting oligodendrocyte progenitor cells (OPCs), directly enhancing oligodendrocyte (OL) function, or acting as cofactors for myelin production. This retrospective case study aimed to assess whether current clinical evidence supports the use of myelin-enhancing agents to promote remission in OUD. We evaluated a range of compounds with demonstrated effects on myelination, including muscarinic antagonists, cholesterol and lipid homeostatic agents, anti-aging drugs, immunomodulatory agents, anti-inflammatory medications, and others (25 medications in total), as well as 17 vitamins and supplements. Buprenorphine and methadone were used as positive controls. Sequential analyses were performed to identify individual drugs driving significant changes in remission rates (p ≤ 0.01; N ≥ 3,000) and their effects across age, sex, and Body Mass Index (BMI) categories. Three key findings emerged: (1) melatonin improved remission rates in males but showed no effect in females; (2) ibuprofen significantly increased remission rates, particularly in individuals aged 20–39 and 40–59 years; and (3) thiamin was associated with decreased remission rates in males and individuals with a BMI ranging from normal weight to obese. Additionally, buprenorphine and methadone were confirmed as effective in promoting remission. These findings highlight the importance of personalized medicine in treating OUD and suggest that further research is needed to explore individualized treatment strategies based on sex, age, and BMI.

CHOLINERGIC MODULATION OF CELLULAR RESONANCE IN NON-HUMAN PRIMATE HIPPOCAMPUS.

Acetylcholine modulates the network physiology of the hippocampus, a crucial brain structure that supports cognition and memory formation in mammals 1-3 . In this and adjacent regions, synchronized neuronal activity within theta-band oscillations (4-10Hz) is correlated with attentive processing that leads to successful memory encoding 4-10 . Acetylcholine facilitates the hippocampus entering a theta oscillatory regime and modulates the temporal organization of activity within theta oscillations 11,12 . Unlike rodents that exhibit constant theta oscillations during movement and exploration, primates only manifest theta oscillations in transient bouts during periods of acute attention-despite conserved hippocampal anatomy 13-16 . The phasic nature of primate theta oscillations and their susceptibility to muscarinic antagonists 17 , suggest that acetylcholine afferents acutely modulate local circuitry, resulting in a temporary shift in hippocampal rhythmic dynamics. However, we lack a mechanistic understanding that links cellular physiology to emergent theta-rhythmic network dynamics. We explored the hypothesis that acetylcholine induces a distinct modulation of cellular properties to facilitate synchronization within the theta band in non-human primate neurons. Here we show that non-human primate neurons from the CA1 region of monkey hippocampus are not homogeneous in their voltage response to inputs of varying frequencies, a phenomenon known as cellular resonance 18,19 . We classified these neurons as 'resonant' or 'non-resonant'. Under the influence of carbachol, these two classes of neurons become indistinguishable in their resonance, suggesting that acetylcholine transiently creates a homogeneous susceptibility to inputs within the theta range. This change is mediated by metabotropic acetylcholine receptors that enhance sag potentials, indicating that acetylcholine acts on principal neurons to modulate Hyperpolarization-activated Cyclic Nucleotide-gated channels. Our results reveal a mechanism through which acetylcholine can rapidly modulate intrinsic properties of primate hippocampal neurons to facilitate synchronization within theta-rhythmic circuits, providing insight into the unique features of primate hippocampal physiology.

Factors Influencing the Prescription of Add-on Long-Acting Muscarinic Antagonists in Real-World Asthma Management: Insights from a National Registry

Current guidelines recommend adding long-acting muscarinic antagonists (LAMAs) in patients with uncontrolled asthma, despite the use of moderate to high doses of inhaled steroid-long-acting beta agonists (ICS/LABA). This study aims to analyze the factors related to the prescription of add-on LAMA in clinical practice for asthma patients, shedding light on physicians’ preferences.This study included adult asthma patients on add-on LAMA and ICS/LABA monitored for at least one year in a national registry comprising 2053 asthmatics. Patients’ characteristics and disease profiles were analyzed to identify factors associated with the prescription of add-on LAMA across the entire cohort. A comparative analysis was performed among three groups: MART (ICS/formoterol as a maintenance and reliever therapy) plus LAMA, Conventional (ICS/LABA as a maintenance and short-acting beta agonist as reliever) plus LAMA and Triple (ICS/LABA/LAMA single inhaler).LAMAs were added to ICS/LABA in 11.7% of patients in the national registry. Logistic regression analysis revealed that older age, low FEV1 (%), Asthma Control Test (ACT) scores less than 20, and severe exacerbation were the main factors influencing the initiation of LAMA in our registry. However, demographic characteristics of asthma, control status, pulmonary function test results were similar among the three groups of LAMA users (p>0.05). Physicians used LAMAs without phenotyping based on allergic status or eosinophil levels (p>0.05). Mepolizumab was added after LAMA in all patients, while omalizumab was initiated before LAMA in 16.9% of the patients receiving LAMA along with biologics.Add-on LAMAs were predominantly prescribed for older, uncontrolled, and exacerbated asthma patients with low FEV1.

Efficacy and safety of long-acting muscarinic antagonists in COPD: a meta-analysis and meta-regression with a focus on aging.

The increasing global elderly population, projected to reach 20% of individuals aged 65 and over by 2030, faces significant pulmonary challenges, including chronic obstructive pulmonary disease (COPD). Aging is associated with a natural decline in lung function and structural changes that exacerbate respiratory issues. COPD, characterized by chronic respiratory symptoms and airflow obstruction, presents a unique challenge in older patients due to the accelerated decline in lung function. Acetylcholine plays a pivotal role in airway dynamics through muscarinic acetylcholine receptors, particularly M3 subtype, which mediates bronchoconstriction. The efficacy of long-acting muscarinic antagonists (LAMA) may differ in older adults, with evidence suggesting that these patients can respond favorably to LAMA treatment. This study utilized meta-analysis and meta-regression to explore the efficacy and safety of LAMA in treating COPD, while considering aging as a potential modifier. A meta-analysis of Phase III randomized controlled trials highlighted significant improvements in trough forced expiratory volume in the 1st second when LAMA were compared to placebo (PCB). Furthermore, the meta-regression revealed a trend suggesting older adults may experience enhanced benefits from LAMA therapy, particularly with once-daily regimens. Safety outcomes, including serious adverse events (SAE), cardiovascular SAE, and mortality, were not modulated by age when comparing LABA to PCB. Overall, these findings support the use of LAMA in elderly COPD patients and underscore the need for tailored treatment strategies to improve clinical outcomes in this vulnerable population.

Prevalence and Clinical Outcomes of Eosinophilic COPD in a Saudi Population: A Retrospective Study

Abstract Objective: This study assessed the prevalence of eosinophilic chronic obstructive pulmonary disease (COPD) among a selected Saudi population and examined its correlation with baseline characteristics, clinical outcomes, exacerbation risk, and current management. Materials and Methods: This retrospective single-center study was conducted over a 2-year period. The patients were divided into two groups based on the blood eosinophil count at the time of diagnosis: eosinophilic COPD (≥300 cells/μl) and non-eosinophilic COPD (&lt;300 cells/μl) groups. Results: Overall, 156 patients were included, of which 76 (48.7%) and 80 (51.3%) patients belonged to the eosinophilic and non-eosinophilic COPD groups, respectively. There were no significant differences between both groups regarding age, gender, smoking status, coexisting morbidities, FEV1, FEV1/FVC, and COPD severity (for all, P &gt;0.05). Besides, there were no significant differences between both groups regarding the frequency and numbers of exacerbations, emergency room visits, in-patient hospitalizations, and intensive care unit admissions (for all, P &gt;0.05). Among patients with eosinophilic COPD, 64 patients (84.2%) were correctly receiving the triple therapy of long-acting β2 agonists + long-acting muscarinic antagonist + inhaled corticosteroids, whereas 4 patients (5.26%) were incorrectly receiving the dual therapy of long-acting β2 agonists + inhaled corticosteroids. Univariate regression analyses revealed that heart failure, GOLD 3 severity, use of triple therapy, and use of non-invasive ventilation were significantly correlated with a higher risk of COPD exacerbation. Conversely, higher FEV1 was significantly correlated with lower risk of COPD exacerbation. The eosinophilic COPD phenotype was not found to be a significant independent variable of COPD exacerbation. Conclusion: This study found that among Saudi patients with COPD, there was no clinically important relationship between baseline blood eosinophil count and the rate of exacerbation.

Scopolamine affects fear learning and social recognition in adult zebrafish.

Scopolamine is the secondary metabolite of the Datura stramonium and act as a muscarinic receptor antagonist. Previous studies showed that scopolamine caused attention and memory deficit. However, the effects of scopolamine on specific cognitive functions, such as fear learning and social recognition, remain poorly understood. Here, we demonstrate the effects of scopolamine on fear learning, social memory, and neural activity in zebrafish, providing a novel perspective on its impact on cognitive and social behaviors. Here, we used equal number of male and female zebrafish as an animal model and performed a series of behavioral tests after treatment with scopolamine (100µM and 200µM) for 1h to evaluate social and cognitive functions. Treatment with scopolamine increased locomotion activity, reduced the level of anxiety in the novel tank diving test, and impaired memory retrieval in the active avoidance test. Scopolamine also increased the preference for newly introduced fish in the social recognition test. In situ hybridization of c-fos mRNA showed that scopolamine decreased the neural activity of the telencephalic regions that are crucial for social, cognitive, and memory functions. Our results demonstrate the effects of scopolamine on fear learning and social recognition in adult zebrafish.

Utilization patterns of drugs used in the treatment of chronic obstructive pulmonary disease in a tertiary hospital

Background: Chronic obstructive pulmonary disease (COPD) is a disease where there is a limitation of airflow that comes in and out of the lungs due to some abnormalities of the lung`s airway. COPD affects 10% of the global population and is associated with significant morbidity and mortality. The treatment aims to control the symptoms and achieve a good quality of life. The aim of this study is to identify the utilization patterns of different drugs used in the treatment of COPD in Sultan Qaboos University Hospital (SQUH). Methods: This was a retrospective study that included 170 patients who received treatment for COPD. Patients’ data and drugs’ data were collected through accessing the TrackCare system at SQUH. Results: The results show that 139 (81.8%) of patients were prescribed with muscarinic receptor antagonists followed by 131 (77.1%) patients who were prescribed with beta 2 receptor agonists. Salbutamol and tiotropium were the most specific drugs prescribed for 103 (60.6%) and 102 (60.0%) patients respectively. 24.7% of the patients received only one drug. There is evidence of a significant association between muscarinic receptor antagonist usage and gender. Conclusion: This study shows the utilization patterns of drugs that were used in the treatment of COPD in a tertiary hospital.

Preclinical Identification of Poorly Controlled COPD: Patients with a Single Moderate Exacerbation Matter Too.

Background and Objectives: Chronic obstructive pulmonary disease (COPD) remains a critical global health challenge, characterized by high morbidity, mortality, and healthcare costs. Current guidelines may overlook patients who present with only one moderate exacerbation or with frequent short-acting beta-agonist (SABA) use. Building on findings from the Seleida study, this research refines the criteria for poor COPD control to include these patients, aiming to improve early identification of high-risk cases in primary care. Methods: A retrospectiveand multicenter study is conducted using data from 110 COPD patients in Spain. Poor control is redefined as having at least one moderate exacerbation or as using three or more SABA inhalers annually. Key predictors, such as SABA/short-acting muscarinic antagonist (SAMA) inhalers and antibiotic prescriptions, are identified using logistic regression and LASSO regularization to enhance predictive accuracy. Results: The model achieves a good predictive performance, with an AUC-ROC of 0.978, sensitivity of 92.86%, and specificity of 87.50%. Key predictors reliably identify high-risk patients, enabling timely interventions. This study demonstrates a statistically significant association between once-daily inhaler therapies and better COPD control compared to multiple daily doses, supported by chi-square analysis (p = 0.008) and binary logistic regression (p = 0.018). Nevertheless, the variable 'daily inhalation frequency' (1 vs. >1 inhalation/day) was excluded from the final model to prevent overfitting. Conclusions: By refining the criteria for COPD control to include patients with at least one moderate exacerbation or frequent SABA use, this model provides a practical tool for early risk stratification in primary care, particularly in resource-limited settings. Early identification of high-risk patients can reduce hospitalizations and healthcare costs, supporting a proactive approach to COPD management. Further validation in larger cohorts is essential to confirm its broader applicability.

Evaluation of the anti-spasmodic activity of essential oils of Ammodaucus leucotrichus fruits and its main chemical component “perillaldehyde” on intestinal smooth muscle contractions of rodents: ex vivo and in silico approaches

Ethnopharmacological relevanceIn Moroccan traditional medicine, plants from the Apiaceae family are widely utilized in folk medicine to treat various diseases associated with the digestive system. Ammodaucus leucotrichus plays an important role as an antispasmodic that has been traditionally used, especially to treat digestive tract diseases in children.Aim of the studyThe aim of this research was to verify the traditional use by assessing the relaxant and spasmolytic activities of A. leucotrichus essential oil (ALEO) and then comparing them to the effects and potency of the major constituent of ALEO, which is perillaldehyde.Materials and methodsThe in vitro evaluation of ALEO’s relaxant and spasmolytic effects was carried out on isolated rats and rabbit jejunum in an organ bath setup. Intestinal contractility was recorded using an isotonic transducer connected to an amplifier. GC/MS analysis was conducted to identify components within ALEO. Subsequently, these compounds underwent in silico absorption, toxicity, and molecular docking studies.ResultsGC/MS analysis of this essential oil studied revealed seven compounds, which account for 98.67% of the oil, with the dominance of two compounds, namely, perillaldehyde (91.12%) and limonene (6.33%). ALEO and its main compound, perillaldehyde, reversibly relaxed the basal tone of rabbit jejunum, with the IC50 values 158.68 ± 13.89 and 95.03 ± 0.93 μg/mL, respectively. Moreover, ALEO caused a dose-dependent spasmolytic effect on Carbachol (CCh) and KCl provoked jejunum contraction in rats. Furthermore, the decrease in contractions of pre-contracted jejunum by CCh was more pronounced for perillaldehyde compared to ALEO, with an IC50 value of 68.59 ± 6.57 μg/mL, which was half compared to that of ALEO. The pre-treatment of the tissue with concentrations ranging from 30 to 100 μg/mL caused a rightward and downward shift in the concentration–response curves for CaCl2 and CCh. These results suggest that the spasmolytic effect of ALEO is mediated possibly through a non-competitive antagonist of calcium channel or muscarinic receptors. Our results are confirmed by the fact that perillaldehyde exhibited the highest docking scores on muscarinic acetylcholine receptors (M2 and M3) and voltage-gated calcium channels, with D-limonene showing lower binding energies in comparison. These remarks confirm that the activity of ALEO is attributed to the presence of perillaldehyde. In addition, perillaldehyde exhibits a low degree of in silico acute toxicity and high percent of intestinal absorption.ConclusionIn summary, ALEO exhibits myorelaxant and antispasmodic effects by inhibiting muscarinic receptors and calcium channels, which can be attributed to the presence of perillaldehyde. This provides a scientific foundation for the traditional use of A. leucotrichus in treating gastrointestinal disorders and opens up possibilities for developing a more effective and less toxic drug-utilizing perillaldehyde.

Cholinergic regulation of decision making under risk of punishment.

The ability to choose between options that differ in their risks and rewards depends on brain regions within the mesocorticolimbic circuit and regulation of their activity by neurotransmitter systems. Dopamine neurotransmission in particular plays a critical role in modulating such risk-taking behavior; however, the contribution of other major modulatory neurotransmitters, such as acetylcholine, is not as well-defined, especially for decision making in which the risk associated with more rewarding outcomes involves adverse consequences. Consequently, the goal of the current experiments was to examine how cholinergic signaling influences decision making involving risk of explicit punishment. Male and female rats were trained in a decision-making task in which they chose between a small safe food reward and a larger food reward accompanied by a risk of footshock punishment. After training in this task, the effects of nicotinic and muscarinic agonists and antagonists on risk-taking performance were evaluated. Neither nicotine, a nicotinic receptor agonist, nor mecamylamine, a nicotinic receptor antagonist, affected preference for the risky lever, although mecamylamine did alter latencies to press the risky lever and the percentage of omissions. The muscarinic receptor agonist oxotremorine decreased preference for the large, risky lever; similar effects on behavior were observed with the administration of the muscarinic receptor antagonist scopolamine. Control experiments were therefore conducted in which these same muscarinic receptor ligands were administered prior to testing in a reward discrimination task. These experiments revealed that the effects of oxotremorine and scopolamine on risk taking may be due to altered motivational processes rather than to changes in sensitivity to risk of punishment. Importantly, there were no sex differences in the effects of cholinergic manipulations on preference for the large, risky lever. Collectively, these findings suggest that in both males and females, cholinergic signaling via muscarinic receptors is involved in decision making involving risk of explicit punishment, with a specific role in modulating sensitivity to differences in reward magnitude. Future studies will expand upon this work by exploring whether targeting cholinergic receptors has therapeutic potential for psychiatric conditions in which risk taking is pathologically altered.

Minimising inhaled corticosteroids for COPD.

This Therapeutic Letter considers the evidence for inhaled corticosteroids (ICS) as a treatment for Chronic Obstructive Pulmonary Disease (COPD). Drug therapy aims to alleviate symptoms, enhance functional capacity and prevent exacerbations, but has not consistently shown to reduce mortality or improve quality of life based on randomised trials.Inhaled corticosteroids have shown limited benefits for COPD symptoms and exacerbations but increased risks of serious harms. Guidelines recommend limiting ICS to severe COPD and only for repeated exacerbations. Studies show withdrawing ICS can be done safely for stable COPD patients with infrequent exacerbations, especially those with lower eosinophil counts. Provincial, national and international guidelines now recommend limiting ICS prescriptions to severe COPD stages. Long-term ICS use may lead to serious side effects, including pneumonia and fractures. Initial COPD therapy should focus on short-acting bronchodilators, not ICS. Adding long-acting bronchodilators is recommended before considering ICS because of limited benefits and risks of serious harms. For persistent symptoms, long-acting muscarinic antagonists (LAMA) or long-acting beta2 agonists (LABA) are recommended, with the addition of ICS reserved for those with repeated exacerbations and severe COPD. Deprescribing ICS can be considered in clinically stable patients, particularly for those with infrequent exacerbations and mild COPD. When applicable, tapering ICS over several months is advised for patients with elevated eosinophil counts. Overall, the risks of serious harms from ICS typically outweigh their limited benefits for mild COPD patients in primary care.

Non-surgical management of BPH: An updated review of current literature and state of the art on natural compounds and medical therapy.

Benign prostatic hyperplasia (BPH) is a common urological disease that is strongly associated with the aging process and can lead to lower urinary tract symptoms (LUTS). LUTS due to BPH can significantly affect the quality of life of many patients. Among the treatments available for BPH to improve symptoms and functional outcomes, drug therapy and surgical therapy are the options of choice. However, for most patients with symptomatic BPH, medical management remains the cornerstone of treatment. Pharmacologic interventions are often preferred as a first approach, being less invasive compared to surgery. Although the medical treatment of BPH is currently defined by the algorithms of international guidelines, the need for a more personalized approach is increasingly recognized given the wide and heterogeneous range of therapeutic options available. A review of medical therapy for BPH was conducted using relevant articles in PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. In this review, all drug treatments currently available on the international market whose efficacy is scientifically proven are reviewed and described (phytotherapy, alpha-blockers, muscarinic receptor antagonists, 5-alpha-reductase inhibitors, combination therapies, etc.). A total of 17 randomized clinical trials were selected for review. Further, 75 studies were included for analysis and discussion. As the treatment landscape continues to evolve, tailoring therapy to individual patient needs and preferences is likely to become increasingly important to ensure that treatment strategies are both effective and meet patient expectations.

The Bronchodilator and Anti-Inflammatory Effect of Long-Acting Muscarinic Antagonists in Asthma: An EAACI Position Paper.

As cholinergic innervation is a major contributor to increased vagal tone and mucus secretion, inhaled long-acting muscarinic antagonists (LAMA) are a pillar for the treatment of chronic obstructive pulmonary disease and asthma. By blocking the muscarinic receptors expressed in the lung, LAMA improve lung function and reduce exacerbations in asthma patients who remained poorly controlled despite treatment with inhaled corticosteroids and long-acting β2 agonists. Asthma guidelines recommend LAMA as a third controller to be added on before the initiation of biologicals. In addition to bronchodilation, LAMA also exert anti-inflammatory and anti-fibrotic effects by inhibiting muscarinic receptors present in neutrophils, macrophages, fibroblasts and airway smooth muscle cells. Thus, besides bronchodilation, LAMA might provide additional therapeutic effects, thereby supporting an endotype-driven approach to asthma management. The Position Paper, developed by the Asthma Section of the European Academy of Allergy and Clinical Immunology, discusses the main cholinergic pathways in the lung, reviews the findings of significant clinical trials and real-life studies on LAMA use in asthma, examines the placement of these drugs in asthma clinical guidelines, and considers the potential for personalised medicine with LAMA in both adult and paediatric asthma patients.

Maternal Low-Protein Diet During Nursing Leads to Glucose-Insulin Dyshomeostasis and Pancreatic-Islet Dysfunction by Disrupting Glucocorticoid Responsiveness in Male Rats.

Both perinatal malnutrition and elevated glucocorticoids are pivotal triggers of the growing global pandemic of metabolic diseases. Here, we studied the effects of metabolic stress responsiveness on glucose-insulin homeostasis and pancreatic-islet function in male Wistar offspring whose mothers underwent protein restriction during lactation. During the first two weeks after delivery, lactating dams were fed a low-protein (4% protein, LP group) or normal-protein diet (22.5% protein, NP group). At 90 days of age, male rat offspring were challenged with food deprivation (72 h of fasting), intracerebroventricular (icv) injection of dexamethasone (2 µL, 2.115 mmol/L) or chronic intraperitoneal injection of dexamethasone (1 mg/kg body weight/5 days). Body weight, food intake, intravenous glucose tolerance test (ivGTT) results, insulin secretion and biochemical parameters were assessed. LP rats did not display significant metabolic changes after long-term starvation (p > 0.05) or under the central effect of dexamethasone (p = 0.999). Chronic dexamethasone induced rapid hyperglycemia (~1.2-fold, p < 0.001) and hyperinsulinemia (NP: 65%; LP: 216%; p < 0.001), decreased insulin sensitivity (NP: ~2-fold; LP: ~4-fold; p < 0.001), reduced insulinemia (20%) and increased glycemia (35%) only in NP rats under ivGTT conditions (p < 0.001). Glucose and acetylcholine insulinotropic effects, as well as the muscarinic receptor antagonist response, were reduced by chronic dexamethasone only in pancreatic islets from NP rats (p < 0.05). The direct effect of dexamethasone on pancreatic islets reduced insulin secretion (NP: 60.2%, p < 0.001; LP: 33.8%, p < 0.001). Peripheral glucose-insulin dyshomeostasis and functional failure of pancreatic islets in LP rats, as evidenced by an impaired acute and chronic response to metabolic stress, may be due to excessive corticosterone action as a long-term consequence.

De-escalation of therapy in a patient with chronic obstructive pulmonary disease: A clinical observation

Current clinical guidelines for chronic obstructive pulmonary disease assign a significant role to the combination of a long-acting muscarinic antagonist / a long-acting β2-agonist (LAMA / LABA). The combined use of LAMA / LABA improves symptoms, quality of life, reduces the frequency of exacerbations, hospitalizations and mortality. Despite the existence of various guide-lines for the pharmacological treatment of COPD, there is a significant discrepancy between the recommendations and the actual practice of prescribing inhaled corticosteroids (ICS), especially in low-risk groups, where triple therapy is often overly prescribed. The purpose of this clinical observation is to demonstrate the de-escalation of triple therapy (ICS / LAMA / LABA) to a dual bronchodilation (LAMA / LABA) in a patient with COPD. Based on the dynamics of clinical, instrumental and laboratory parameters of the patient, the absence of indications for the appointment of ICS has been proven. The appointment of combined double therapy indacaterol / glycopyrronium bromide 110/50 mcg inhalation 1 time/day is justified. The positive effect dual bronchodilation therapy (indacatero / glycopyrronium bromide) has been demonstrated the symptoms and quality of life of the patient. The absence of adverse events against the background of taking indacaterol / glycopyrronium bromide and the convenience of using the Breezhaler® inhaler were established. Based on the above, conclusions are drawn: a thorough assessment of the indications for the appointment of ICS in stable patients with chronic obstructive pulmonary disease is necessary; the use of a combination of indacaterol / glycopyrronium bromide in one device 1 time per day provides better adherence to treatment; the inhaler Breezhaler® ensures optimal delivery of a dose of the drug to the lungs.

Veratridine Induces Vasorelaxation in Mouse Cecocolic Mesenteric Arteries.

The vegetal alkaloid toxin veratridine (VTD) is a selective voltage-gated Na+ (NaV) channel activator, widely used as a pharmacological tool in vascular physiology. We have previously shown that NaV channels, expressed in arteries, contribute to vascular tone in mouse mesenteric arteries (MAs). Here, we aimed to better characterize the mechanisms of action of VTD using mouse cecocolic arteries (CAs), a model of resistance artery. Using wire myography, we found that VTD induced vasorelaxation in mouse CAs. This VTD-induced relaxation was insensitive to prazosin, an α1-adrenergic receptor antagonist, but abolished by atropine, a muscarinic receptor antagonist. Indeed, VTD-vasorelaxant effect was totally inhibited by the NaV channel blocker tetrodotoxin (0.3 µM), the NO synthase inhibitor L-NNA (20 µM), and low extracellular Na+ concentration (14.9 mM) and was partially blocked by the NCX1 antagonist SEA0400 (45.4% at 1 µM). Thus, we assumed that the VTD-induced vasorelaxation in CAs was due to acetylcholine release by parasympathetic neurons, which induced NO synthase activation mediated by the NCX1-Ca2+ entry mode in endothelial cells (ECs). We demonstrated NCX1 expression in ECs by RT-qPCR and immunohisto- and western immunolabelling. VTD did not induce an increase in intracellular Ca2+ ([Ca2+]i), while SEA0400 partially blocked acetylcholine-triggered [Ca2+]i elevations in Mile Sven 1 ECs. Altogether, these results illustrate that VTD activates NaV channels in parasympathetic neurons and then vasorelaxation in resistance arteries, which could explain arterial hypotension after VTD intoxication.

Functional Dyspepsia and Gastroesophageal Reflux Disease: From Pathogenesis to Current Treatment Strategies

Aim: to present a modern view on the combination of functional dyspepsia (FD) and gastroesophageal reflux disease (GERD) and to evaluate the effectiveness of acotiamide in patients with FD and GERD.Key points. The high frequency of the combination of FD and GERD is caused by common pathogenetic mechanisms and presents an urgent problem in clinical practice. The concurrent occurrence of these diseases alters the clinical picture, complicates differential diagnostics, and leads to inadequate prescription of drugs. Medical treatment for patients with FD and GERD includes the use of proton pump inhibitors (PPIs) and prokinetics. Currently, acotiamide is recognized as an effective drug that affects the motility of the upper gastrointestinal tract. Acotiamide is an antagonist of muscarinic M1 and M2 receptors and a reversible inhibitor of acetylcholinesterase. The clinical efficacy of this drug has been demonstrated not only in patients with FD but also in those with a combination of FD and GERD.Conclusion. Administration of acotiamide is pathogenetically justified in patients with the combination of GERD and FD.