Muscarinic Antagonist Research Articles

What happens between first symptoms and first acute exacerbation of COPD - observational study of routine data and patient survey.

Chronic obstructive pulmonary disease affects nearly 400 million worldwide - over a million in the United Kingdom - and is the third leading cause of death. However, there is limited understanding of what prompts a diagnosis, how long this takes from symptom onset and the different approaches to clinical management by primary care professionals. Map out the clinical management and National Health Service contacts from symptom presentation to chronic obstructive pulmonary disease diagnosis and first acute exacerbation of chronic obstructive pulmonary disease in three time periods; construct risk prediction for first acute exacerbation of chronic obstructive pulmonary disease. Retrospective cohort study and cross-sectional survey. Primary care. Patients with incident chronic obstructive pulmonary disease aged > 35 years in England. None. First acute exacerbation of chronic obstructive pulmonary disease. Clinical Practice Research Datalink Aurum; new online survey. Forty thousand five hundred and seventy-seven patients were diagnosed between April 2006 and March 2007 (cohort 1), 48,249 between April 2016 and March 2017 (cohort 2) and 4752 between March and August 2020 (cohort 3). The mean (standard deviation) age was 68.3 years (12.0); 47.3% were female. Around three-quarters were diagnosed in primary care, with a slight fall in cohort 3. Compliance with National Institute for Health and Care Excellence diagnostic guidelines was slightly higher in cohorts 2 and 3 for all patients; 35.8% (10.0% in the year before diagnosis) had all four elements met for all cohorts combined. Multilevel modelling showed considerable between-practice variation in spirometry. The survey on the charity website had 156 responses by chronic obstructive pulmonary disease patients. Many respondents had not heard of the condition, hoped the symptoms would go away and identified various healthcare-related barriers to earlier diagnosis. Clinical Practice Research Datalink analysis showed notable changes in post-diagnosis prescribing from cohort 1 to 2, such as increases in long-acting muscarinic antagonist (21.7-46.3%). Triple therapy rose from 2.9% in cohort 2 to 11.1% in cohort 3. Documented pulmonary rehabilitation rose from just 0.8% in cohort 1 to 13.7% in cohort 2 and 20.9% in cohort 3. For all patients combined, the median time to first acute exacerbation of chronic obstructive pulmonary disease in patients who had one was 1.4 years in cohorts 1 and 2. Acute exacerbation of chronic obstructive pulmonary disease prediction models identified some consistent predictors, such as age, deprivation, severity, comorbidities, post-diagnosis spirometry and annual review. Models without post-diagnosis general practitioner actions had a c-statistic of around 0.70; the highest c-statistic was 0.81, for cohort 2 with post-diagnosis general practitioner actions and 6-month follow-up. All models had good calibration. The three most important predictors in terms of their population attributable risks were being a current smoker and offered smoking cessation advice (32.8%), disease severity (30.6%) and deprivation (15.4%). The highest population attributable risks for variables with adjusted hazard ratios < 1 were chronic obstructive pulmonary disease review (-27.3%) and flu vaccination (-26.6%). Symptom recording and chronic obstructive pulmonary disease diagnosis vary between practice; predicted forced expiratory volume in 1 second had many missing values. There has been some improvement over time in chronic obstructive pulmonary disease diagnosis and management, with large changes in prescribing, though patient and system barriers to further improvement exist. Data available to general practitioners cannot generate risk prediction models with sufficient accuracy. It will be important to expand the COVID-era cohort with longer follow-up and augment general practitioner data for better prediction. This study is registered as Researchregistry.com: researchregistry4762. This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/99/72) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 43. See the NIHR Funding and Awards website for further award information.

Use of the Oral Sialogogue “Oriza Tablet” in Reducing Drug-Induced Xerostomia in Patients with Overactive Bladder or Neurogenic Bladder: Randomized Clinical Study

Purpose Evaluate the clinical efficacy of “Oriza tablet” (OT) for patients with neurologic bladder or overactive bladder affected by xerostomia due to receiving antimuscarinic drugs. Material and methods This was a randomized clinical trial. Twenty-eight patients (median age = 64 years) with xerostomia were divided into two groups: OT (intervention group) and placebo (control) group. Both groups comprised 14 patients each. Objective We assessed severity using a questionnaire for the subjective evaluation of xerostomia. Objective evaluation was undertaken for the stimulated salivary flow rate (SSFR). Xerostomia evaluation took place before treatment (baseline) as well as 2 weeks and 4 weeks after treatment. Results The xerostomia score decreased significantly ( p &lt; 0.05) in the OT group compared to the placebo group, with scores of 2.75 versus 4.4 at 2 weeks and 2.19 versus 4.13 at 4 weeks, respectively. The SSFR increased significantly ( p &lt; 0.05) in the OT group compared to the placebo group, with SSFR of 2 versus 1.2 at 2 weeks and 1.85 versus 1.1 at 4 weeks, respectively. Throughout the trial, no patient discontinued taking antimuscarinic medications. There were no adverse effects noted. Conclusion Continuous daily use of OT for 4 weeks reduced xerostomia symptoms and increased saliva production in patients suffering from neurologic bladder or overactive bladder who received antimuscarinic medications. Clinical trial registration The study was registered with The Thai Clinical Trials Registry (TCTR). ID: TCTR20240715015.

Implications of the non-neuronal cholinergic system for therapeutic interventions of inflammatory skin diseases.

The pivotal roles of acetylcholine (ACh) in physiological processes encompass both the nervous and non-neuronal cholinergic systems (NNCS). This review delineates the synthesis, release, receptor interactions, and degradation of ACh within the nervous system, and explores the NNCS in depth within skin cells including keratinocytes, endothelial cells, fibroblasts, macrophages, and other immune cells. We highlight the NNCS's essential functions in maintaining epidermal barrier integrity, promoting wound healing, regulating microcirculation, and modulating inflammatory responses. The potential of the NNCS as a therapeutic target for localized ACh regulation in the skin is discussed, though the translation of these findings into clinical practice remains uncertain due to the complexity of cholinergic signalling and the lack of comprehensive human studies. The review progresses to therapeutic modulation strategies of the NNCS, including AChE inhibitors, nicotinic and muscarinic receptor agonists and antagonists, choline uptake enhancers, and botulinum toxin, highlighting their relevance in dermatology. We highlight the impact of the NNCS on prevalent skin diseases such as psoriasis, atopic dermatitis, rosacea, acne, bullous diseases, hyperhidrosis and hypohidrosis, illustrating its significance in disease pathogenesis and therapy. This comprehensive overview aims to enhance understanding of the NNCS's role in skin health and disease, offering a foundation for future research and therapeutic innovation.

Single-inhaler triple versus LABA-ICS therapy for COPD: Comparative safety in real-world clinical practice

Recent treatment guidelines for chronic obstructive pulmonary disease (COPD) have replaced the long-acting beta2-agonist and inhaled corticosteroid (LABA-ICS) combination with single-inhaler triple therapy that adds a long-acting muscarinic antagonist (LAMA-LABA-ICS). Yet, the corresponding trials reported numerically higher incidences of cardiovascular adverse events with triple therapy compared with LABA-ICS. Does single-inhaler triple therapy increase the incidence of major adverse cardiovascular events, compared with LABA-ICS, in a real-world clinical practice setting? We identified a cohort of COPD patients, 40 years or older, treated during 2017-2021, from the United Kingdom's Clinical Practice Research Datalink. Among LAMA-naïve patients, initiators of single-inhaler triple therapy were matched 1:1 to LABA-ICS users on time-conditional propensity scores. They were compared on the incidence of major adverse cardiovascular events (MACE), defined as hospitalization for myocardial infarction or stroke, or all-cause-mortality, over one year. The cohort included 10,255 initiators of triple therapy and 10,255 matched users of LABA-ICS. The incidence rate of MACE was 11.3 per 100 per year with triple therapy compared with 8.7 per 100 per year for LABA-ICS. The corresponding adjusted hazard ratio (HR) of MACE with triple therapy was 1.28 (95% CI: 1.05-1.55), relative to LABA-ICS, though the increase was mainly in the first four months (HR 1.41; 95%CI: 1.14-1.74). The HR of all-cause death was 1.31 (95% CI: 1.06-1.62), while for acute myocardial infarction and stroke hospitalization it was 1.00 (95% CI: 0.56-1.79) and 1.06 (95% CI: 0.48-2.36), respectively, with triple therapy, relative to LABA-ICS. In a real-world setting of COPD treatment, patients who initiated single-inhaler triple therapy had an increased incidence of MACE compared with similar patients treated with a LABA-ICS inhaler. This small increase was due to the all-cause mortality component, occurring mainly in the first four months after treatment initiation.

Clinical Effectiveness and Safety of Dupilumab in Chronic Obstructive Pulmonary Disease Patients: A 7-Year Population-based Cohort Study

BackgroundPrevious randomized controlled trials had established the efficacy of dupilumab among patients with chronic obstructive pulmonary disease (COPD) treated with triple therapy over 52 weeks of follow-up. ObjectiveThis population-based cohort study aimed to explore the long-term clinical effectiveness of dupilumab in COPD patients. MethodsThis population-based cohort study included U.S. patients with COPD between April 2017 and August 2024. Patients initiating dupilumab and therapies that incorporated long-acting β2-agonists (LABA) inhalers were included. Patients with asthma or lung cancer were excluded. The risk of outcomes after the initiation of dupilumab versus LABA-containing therapies was measured. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org. ResultsA total of 1,521 dupilumab initiators and 1,521 propensity score-matched patients receiving LABA-based therapies were included. Dupilumab recipients were associated with lower all-cause mortality (HR:0.53, 95% CI:0.43-0.65), emergency visits (HR:0.78, 95% CI:0.69-0.89), and acute exacerbation (AE) rates (HR:0.59, 95% CI:0.53-0.65). Dupilumab was also associated with reductions in the requirement of short-acting β2-agonists (HR:0.48, 95% CI:0.43-0.52), short-acting muscarinic antagonists (HR:0.43, 95% CI:0.37-0.49) for symptoms control. Additionally, dupilumab decreased subsequent pneumonia (HR:0.65, 95% CI:0.50-0.86), and COPD-relevant comorbidities including new-onset heart failure (HR:0.69, 95% CI:0.53-0.90) and new-onset anxiety (HR:0.70, 95% CI:0.53-0.93). ConclusionsDupilumab was associated with a lower rate of mortality, emergency visits, reduced risk of AEs, respiratory symptoms, and respiratory infections in COPD patients. More studies are required to validate the effectiveness of dupilumab among patients with COPD across various severities.

Serum levels of prostate specific antigen, free PSA, [-2]proPSA, fPSA/tPSA ratio, Prostate Health Index, and glycosylation patterns of free PSA in patients with benign prostatic hyperplasia pharmacotherapy.

The medication used to treat benign prostate hyperplasia (BPH), a common condition in men over 50 years of age, can alter the levels of biomarkers used in prostate cancer detection. Commonly used medications for BPH include alpha-blockers, 5-alpha reductase inhibitors (5-ARIs), and muscarinic antagonists. We studied the impact of these drugs on total prostate-specific antigen (tPSA), free PSA (fPSA), [-2]proPSA, fPSA/tPSA ratio, and the Prostate Health Index (PHI), as well as novel potential biomarkers in the form of glycan composition of fPSA. Serum samples were collected from 564 males with BPH, with a mean age of 68.5 years. The samples were used to measure levels of tPSA, fPSA, and [-2]proPSA. The fPSA/tPSA and PHI were then calculated. The glycan composition of fPSA was analyzed using lectin-based glycoprofiling. Pharmacotherapy data was collected from the patients' medical records. Alpha-blocker monotherapy was associated with higher fPSA and fPSA/tPSA ratio, and decreased PHI. Levels of tPSA were not impacted. Alpha-blocker and 5-ARI dual therapy was associated with reduced levels of fPSA, [-2]proPSA, and PHI. Therapy combining alpha-blockers and antimuscarinic agents did not significantly influence biomarker levels apart from an increase in a Maackia amurensis lectin-recognized glycan originating in fPSA. BPH pharmacotherapy notably affects prostate cancer biomarkers. Recognizing the impact of pharmacotherapy is crucial for achieving an accurate diagnosis of prostate cancer and for planning treatment.

An Improved and Efficient Practical Process for the Synthesis of Enantiomerically Pure Solifenacin Succinate as an Antimuscarinic Agent

Background: Solifenacin succinate is an active pharmaceutical drug molecule that is extremely effective in treating overactive bladder symptoms, such as urine incontinence, urgency, and frequent urination. The free base is yellow oil, and the salt solifenacin succinate forms yellowish crystals that are extremely stable and effective. Solifenacin is a very active antagonist due to its potent muscarinic M3 receptor antagonist characteristics. Furthermore, solifenacin is effective in the treatment of bowel syndrome (IBS) by blocking M3 receptors and a broad spectrum of bowel dysfunction. Objective: The objective of this study was to develop a practical and highly efficient scalable synthesis of enantiomerically pure solifenacin as an antimuscarinic agent. Methods: In this work, the Zn(OTf)2 catalyst was used to develop a novel, environmentally benign, high-yielding, and robust protocol for the synthesis of enantiomerically pure solifenacin succinate. Results: The synthesis of enantiomerically pure solifenacin succinate was achieved in seven steps using commercially available phenylethylamine and benzoyl chloride as the starting materials. We carried out the reaction optimization by treatment of (S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)- carbonyl chloride and (R)-(-)-3-Quinuclidinolin in the presence of Zn(OTf)2 catalyst. Furthermore, the solifenacin-free base was treated with succinic acid to afford its corresponding salt. The highlight of this protocol is the use of 20 mol% Zn(OTf)2 catalyst for the first time. The readily available starting materials, robustness, easy operation, high yield, and low cost make the approach more attractive and highly applicable. Conclusion: In summary, we developed a novel Zn(OTf)2-catalysed environmentally benign, highyielding, and robust protocol for the synthesis of enantiomerically pure solifenacin succinate. The proposed strategy is highly cost-effective and avoids the use of hazardous and unsafe sensitive, strong bases as well as tedious work-up procedures. Effective synthesis was achieved using readily available starting materials and reagents. Thus, the protocol is highly efficient, compatible, and commercially viable for the synthesis of important solifenacin products.

Preclinical Evaluation of Electronic Health Records (EHRs) to Predict Poor Control of Chronic Respiratory Diseases in Primary Care: A Novel Approach to Focus Our Efforts.

Background/Objectives: Managing chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) within the Spanish Sistema Nacional de Salud (SNS) presents significant challenges, particularly due to their high prevalence and poor disease control rates-approximately 45.1% for asthma and 63.2% for COPD. This study aims to develop a novel predictive model using electronic health records (EHRs) to estimate the likelihood of poor disease control in these patients, thereby enabling more efficient management in primary care settings. Methods: The Seleida project employed a bioinformatics approach to identify significant clinical variables from EHR data in primary care centers in Seville and Valencia. Statistically significant variables were incorporated into a logistic regression model to predict poor disease control in patients with asthma and COPD patients. Key variables included the number of short-acting β-agonist (SABA) and short-acting muscarinic antagonist (SAMA) canisters, prednisone courses, and antibiotic courses over the past year. Results: The developed model demonstrated high accuracy, sensitivity, and specificity in predicting poorly controlled disease in both asthma and COPD patients. These findings suggest that the model could serve as a valuable tool for the early identification of at-risk patients, allowing healthcare providers to prioritize and optimize resource allocation in primary care settings. Conclusions: Integrating this predictive model into primary care practice could enhance the proactive management of asthma and COPD, potentially improving patient outcomes and reducing the burden on healthcare systems. Further validation in diverse clinical settings is warranted to confirm the model's efficacy and generalizability.

“Muscarinic Receptor Antagonists: From Pharmacology to Folklore: Discovering Medications that Effectively Treat COPD and Asthma”

Acetylcholine is released into M3 muscarinic receptors by parasympathetic neurons, which give them dominating control over the smooth muscle of the airways in the lungs. Anticholinergic medications that inhibit muscarinic receptors have been used to treat respiratory disorders for more than 2,000 years. Clinical outcomes for antimuscarinic medications in asthma were inconsistent, despite pharmacologic data suggesting that they should be quite effective. As a result, the use of muscarinic antagonists decreased after β-adrenergic receptor agonists were found to be effective. Numerous reasons, such as undesirable side effects (which might range from dry mouth to coma) and the identification of other muscarinic receptor subtypes in the lungs that occasionally have conflicting effects, contribute to the lack of efficacy of muscarinic antagonists. Possibly the most significant issue is inefficient dosing as a result of poorly understood variations in administration routes is no reliable method for determining if antagonists block receptors that acetylcholine stimulates physically. Asthma and chronic obstructive pulmonary disease seem to respond well to the development of newer muscarinic receptor antagonists that address the issues of side effects and receptor specificity.

The Biochemical Effects of Hydroalcoholic Extract of Quercus brantii Fruit on Morphine-Induced Amnesia in the Presence and Absence of Cholinergic Muscarinic Receptors in Adult Male Mice

Background: In our previous study, we demonstrated that oak hydroalcoholic extract improves memory impairment in a postpartum depression model due to its antioxidant properties. The purpose of this study is to further investigate the effect of oak on another amnesia model and explore the mediating role of cholinergic muscarinic receptors. Objectives: This study investigated the effect of hydroalcoholic extract of oak fruit on amnesia induced by morphine in the presence and absence of cholinergic muscarinic receptors, as well as changes in serum biochemical factors. Methods: In this experimental study, adult male mice were divided into groups: Control and morphine-receiving (5 and 7.5 mg/kg) groups to induce amnesia after training. In the groups receiving 7.5 mg/kg morphine, oak extract (1 and 10 mg/kg) was administered one day after training and continued for one week. Atropine (0.1 and 1 mg/kg) was injected only on the first day after training and before the oak extract injection. Passive avoidance memory was evaluated 1, 3, and 7 days after training using a step-down device. Motor activity was assessed using the open field test. Blood biochemical factors, including triglycerides, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total antioxidant capacity (TAC), were measured after one week of injections. Results: Morphine (7.5 mg/kg) impaired memory on days 1 and 7 (P &lt; 0.05), while oak extract (1 and 10 mg/kg) improved memory (P &lt; 0.001). Additionally, the oak extract maintained its enhancing effect even in the presence of atropine, a cholinergic muscarinic system antagonist. Oak extract significantly increased HDL and TAC levels but did not affect LDL, cholesterol, and triglyceride levels. Conclusions: These findings suggest that oak extract can improve morphine-induced amnesia due to its antioxidant effect, without involving the cholinergic system. Additionally, oak extract can increase beneficial lipids without affecting harmful lipids.

Association analysis of ADRB3:rs4994 with urodynamic outcome, six months after a single intra-detrusor injection of botulinum toxin, in women with overactive bladder.

Intra-detrusor injection of botulinum neurotoxin type A (BoNT/A) is recommended as a possible treatment for patients with overactive bladder (OAB) in whom first-line therapies have failed. The c.190T > C (rs4994) polymorphism in the gene encoding the beta-3 adrenergic receptor (ADRB3) has been suggested to be associated with predisposition to OAB or with response to OAB treatment via a cholinergic muscarinic receptor antagonist. This prospective study aimed to use a urodynamic parameter-based assessment of response, six months after a single intra-detrusor injection of BoNT/A in female OAB patients, to elucidate possible association with the ADRB3 polymorphism. The study group consisted of 138 consecutive, Polish, adult, female OAB patients. Urodynamic parameters were recorded before injection of BoNT/A and at six months after administration. ADRB3:rs4994 variants were identified by the sequencing of genomic DNA extracted from buccal swabs. Apart from baseline, and relative, increase in Maximum Cystometric Capacity (MCC) six months after BoNT/A injection, no significant differences were found in urodynamic parameters between reference TT homozygotes and women with at least one C allele. Our results do not exclude that ADRB3:rs4994 variants are associated with a positive urodynamic test-based response to intra-detrusor injection of BoNT/A in females with OAB.

Antinociceptive in vivo activity and chemical profiling by UHPLC-MS/MS of stem bark and leaves extracts of Ficus maxima Mill. (Moraceae)

Ethnopharmacological relevanceFicus maxima is a medicinal plant extensively used in traditional medicine by Indigenous peoples across Central and South America. It is a member of the family Moraceae, subgenus Pharmacosycea, employed in treating various conditions, including intestinal parasites, gingivitis, internal inflammations, and snake bites. Despite its significant pharmacological potential, the species remains underrepresented in scientific literature. Aim of the studyThis study aimed to evaluate the in vivo antinociceptive properties of leaf (ELFM) and stem bark (EBFM) extracts from Ficus maxima. Additionally, the chemical composition of these extracts was determined using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Materials and methodsPlant material was collected in Abaetetuba, Pará, Brazil, in October 2013 and subjected to static maceration to obtain crude ELFM and EBFM. Bio-guided fractionation was performed by sequential liquid-liquid partitioning with hexane (Hex), dichloromethane (DCM), and ethyl acetate (EtOAc), yielding the following fractions: ELFM-Hex and EBFM-Hex, ELFM-DCM and EBFM-DCM, and ELFM-EtOAc and EBFM-EtOAc. The biological activity of EBFM, ELFM, and their respective fractions were evaluated using the formalin-induced pain test and the hot plate test, followed by an assessment of their mechanisms of action. The UHPLC-MS/MS analysis was conducted using electrospray ionization (ESI) in both positive and negative modes. Metabolite annotation was facilitated by MS/MS libraries and molecular networks constructed on the GNPS platform. ResultsThe reactivity time to formalin in the neurogenic phase was reduced from 84.7 ± 7.6 s (100%) to 37.3 ± 4.7 s (44%), 33.1 ± 6.3 s (39%), 40.7 ± 7.4 s (48%), 57.2 ± 2.6 s (77%), 49.7 ± 4.1 s (58%), 46.8 ± 8.1 s (55%), and 52.4 ± 5.3 s (61%) after treatment with ASA, morphine, EBFM, ELFM, ELFM-Hex, ELFM-DCM, and ELFM-EtOAc at doses of 30 mg/kg, respectively. In the inflammatory phase, the reactivity time to formalin was reduced from 124.3 ± 25.9 s (100%) to 49.7 ± 4.7 s (40%), 9.8 ± 4.3 s (8%), 32.5 ± 8.5 s (26%), 59.8 ± 16.8 s (48%), and 54.4 ± 7.3 s (44%) after treatment with ASA, morphine, EBFM, ELFM, and ELFM-Hex at doses of 30 mg/kg, respectively. A reversal of the antinociceptive action of EBFM and ELFM was observed in the inflammatory phase after treatment with atropine, a muscarinic antagonist, and naloxone, an opioid antagonist, respectively. In the hot plate test, EBFM showed Antinociceptive Activity (AA) of 62.6 ± 9.2% after 90 min; however, there was a reversal of AA to 8.6 ± 2.8% when naloxone was used. The UHPLC-MS/MS metabolite analysis revealed the presence of loliolide (3), luteolin (13), lupeol (14), gallic acid (15), chlorogenic acid (16), pygenic acid A (17), and other metabolites from the alkaloids and fatty acids classes.

Breathing for Two: Asthma Management, Treatment, and Safety of Pharmacological Therapy during Pregnancy.

The primary objectives of asthma management during pregnancy are to achieve adequate symptom control, reduce the risk of acute exacerbations, and maintain normal pulmonary function, all of which contribute to ensuring the health and well-being of both the mother and the baby. The Global Initiative for Asthma (GINA) recommends that pregnant women with asthma continue using asthma medications throughout pregnancy, as the benefits of well-controlled asthma for both the mother and fetus outweigh the potential risks of medication side effects, poorly controlled asthma, and exacerbations. The classification of asthma medications by the US Food and Drug Administration (FDA) into categories A, B, C, D, and X is no longer applied. Instead, the potential benefits and risks of each medication during pregnancy and lactation are considered individually. The use of medications to achieve good asthma control and prevent exacerbations during pregnancy is justified, encompassing inhaled corticosteroids (ICS), some leukotriene receptor antagonists (LTRA), short-acting beta-2 agonists (SABA), long-acting beta-2 agonists (LABA), short-acting muscarinic antagonists (SAMA), long-acting muscarinic antagonists (LAMA), and, recently, biological therapies, even in the absence of definitive safety data during pregnancy.

Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC. Docking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin's effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin's effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients' cohort. In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI50 of 26 and 13.6 µM in BxPC-3 and PANC-1 cells, respectively. These results were confirmed in primary PDAC-3 cells, while darifenacin showed no cytotoxicity against HPNE cells. Importantly, darifenacin sensitized PDAC cells to standard chemotherapies, reverted CHI3L1-induced PDAC cellular resistance to therapy, and decreased Akt phosphorylation. Additionally, high CHMR3 expression was associated with low therapeutic response to gemcitabine. This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.

An Updated Structure of Oxybutynin Hydrochloride.

Oxybutynin (Ditropan), a widely distributed muscarinic antagonist for treating the overactive bladder, has been awaiting a definitive crystal structure for ≈50 years due to the sample and technique limitations. Past reports used powder X-ray diffraction (PXRD) to shed light on the possible packing of the molecule however their model showed some inconsistencies when compared with the 2D chemical structure. These are largely attributed to X-ray-induced photoreduction. Here microcrystal electron diffraction (MicroED) is used to successfully unveil the experimental 3D structure of oxybutynin hydrochloride showing marked improvement over the reported PXRD structure. Using the improved model, molecular docking is applied to investigate the binding mechanism between M3 muscarinic receptor (M3R) and (R)-oxybutynin, revealing essential contacts/residues and conformational changes within the protein pocket. A possible universal conformation is proposed for M3R antagonists, which is valuable for future drug development and optimization. This study underscores the immense potential of MicroED as a complementary technique for elucidating unknown pharmaceutical structures, as well as for protein-drug interactions.

Impact of salivary flow inhibition on masticatory behaviours in healthy individuals.

It remains unclear how the salivary flow and the fat content of food affect bolus formation during mastication. 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. 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. 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). Hyposalivation-induced changes in masticatory behaviours resulted from the middle and late stage suprahyoid activity. Fat content and seasoning compensate for salivary flow inhibition.

Effect of Tiotropium on eye findings in the treatment of chronic obstructive pulmonary disease

BackgroundChronic 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.MethodsThe 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.ResultsThirty-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.ConclusionThis 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 registrationAn 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.

DElaying disease Progression In COPD with early escalation to Triple therapy – A Modelling Study (DEPICT-2)

IntroductionIn patients with chronic obstructive pulmonary disease (COPD), dual bronchodilator (long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA)) and triple therapy (inhaled corticosteroid (ICS)/LAMA/LABA) reduce risk of exacerbations and lung function decline in short-mid-term, but their long-term impact is unknown. This modelling study explores long-term impact of these therapies on lung function decline, quality of life (QoL) and all-cause mortality.MethodsThis modelling approach used a longitudinal non-parametric superposition model using published data regarding exacerbations, QoL (assessed by St. George's Respiratory Questionnaire (SGRQ)), and mortality. The model simulated disease progression from 40 to 75 years of age and assessed the impact of initiating dual bronchodilator at age 45 years (“LAMA/LABA only” group) and escalation to triple therapy at age 50 years (“Escalation to triple” group) on forced expiratory volume in 1 s (FEV1) decline, QoL, and mortality.ResultsModel simulation predicted that by 75 years of age: “LAMA/LABA only” preserves 159.1 mL of FEV1versusno treatment, “Escalation to triple” preserves an additional 376.5 mL and 217.3 mL of FEV1versusno pharmacotherapy and “LAMA/LABA only”, respectively. In “LAMA/LABA only”, SGRQ score reduces (−3.2)versusno treatment, which further reduces to −7.5 therapy in “Escalation to triple”. In “LAMA/LABA only”, mortality reduces by 5.4% by 75 yearsversusno treatment, while the “Escalation to triple” shows further decrease in mortality by 12.0%.ConclusionEarly pharmacotherapy initiation and escalation from dual bronchodilator to triple therapy could slow disease progression by preserving lung function and improving QoL and survival in patients with COPD.

The Responsiveness of Exercise Tests in COPD: A Randomized Controlled Trial

BackgroundChronic obstructive pulmonary disease (COPD) is characterised by reduced exercise tolerance and improving physical performance is an important therapeutic goal. A variety of exercise tests are commonly used to assess exercise tolerance, including laboratory and field-based tests. The responsiveness of these tests to common COPD interventions is yet to be compared, but may inform test selection in clinical and research settings. Research QuestionWhat exercise test possesses the greatest sensitivity to change pre- to post-intervention in patients with COPD? Study Design and Methods154 patients with symptomatic COPD were recruited and randomised (2:1:1) to six weeks of long-acting muscarinic antagonist (LAMA), pulmonary rehabilitation (PR), or usual care (UC). Pre- and post-intervention, participants performed a ramp-incremental and constant work rate cycle ergometer exercise test (ICET and CWRCT), incremental and endurance shuttle walk test (ISWT and ESWT), six-minute walk test (6MWT), and a four metre gait speed test (4MGS). Results103 participants (67 ± 8 y; 75 [73%] males; FEV1: 50.6 ± 16.8 % predicted) completed the study. Significant improvements in the ICET, CWRCT, ISWT, ESWT, and 6MWT were observed following PR (p<0.05), with the greatest improvements seen in the constant work rate protocols (% change: CWRCT: 42%; ESWT: 41%). InterpretationThe ESWT and CWRCT appeared to be the most responsive exercise test protocols to LAMA and PR. The magnitude of change was much greater after a programme of rehabilitation compared to bronchodilator therapy.

For people with uncontrolled asthma, how does adding long-acting beta2 agonists (LABA) or long-acting muscarinic antagonists (LAMA) to different doses of inhaled corticosteroids (ICS) or doubling the dose of ICS compare with medium-dose ICS?

For people with uncontrolled asthma, how does adding long-acting beta2 agonists (LABA) or long-acting muscarinic antagonists (LAMA) to different doses of inhaled corticosteroids (ICS) or doubling the dose of ICS compare with medium-dose ICS?