Muscarinic Antagonist Research Articles

Comparative effectiveness and safety of escalating to triple therapy versus switching to dual bronchodilators after discontinuing LABA/ICS in patients with COPD: a retrospective cohort study.

The latest guidelines discourage the use of long-acting beta2-agonists/inhaled corticosteroids (LABA/ICS) for chronic obstructive pulmonary disease (COPD). However, there is a lack of evidence regarding the optimal subsequent treatment after discontinuing LABA/ICS. To compare the effectiveness and safety of switching from LABA/ICS to triple therapy (LABA/long-acting muscarinic antagonists (LAMA)/ICS) or to dual bronchodilators (LABA/LAMA) in COPD patients. This was a new-user, active-comparator, and propensity score-matched cohort study analyzing the Taiwanese nationwide healthcare insurance claims. We recruited COPD patients switching from LABA/ICS to triple therapy or to dual bronchodilators from 2015 to 2019. The primary effectiveness outcome was the annual rate of exacerbations, and safety outcomes included severe pneumonia and all-cause mortality. Stratification by prior exacerbations was conducted. After matching, each group comprised 1892 patients, 55% of whom experienced no exacerbations in the prior year. Treatment with LABA/LAMA/ICS versus LABA/LAMA showed comparable annual rate of moderate-to-severe exacerbations (incidence rate ratio, 1.04; 95% confidence interval (CI), 0.91-1.19). However, switching to LABA/LAMA/ICS was associated with increased risks of severe pneumonia (hazard ratio (HR), 1.65; 95% CI, 1.30-2.09) and all-cause death (HR, 1.39; 95% CI, 1.09-1.78). In patients with⩾2 prior exacerbations, LABA/LAMA/ICS versus LABA/LAMA was related to a 21% reduced rate of exacerbations but with a twofold increased pneumonia risk and a 49% elevated risk of all-cause mortality. Switching from LABA/ICS to triple therapy versus dual bronchodilators in COPD patients was associated with similar rates of annual exacerbations but was related to elevated risks of severe pneumonia and all-cause mortality. Among frequent exacerbators, triple therapy was associated with lower rates of exacerbation but was accompanied by increased risks of pneumonia and mortality compared to LABA/LAMA. Careful consideration of the examined safety events is necessary when switching from LABA/ICS to triple therapy in COPD management.

Pharmacologic Treatment of Type 2-High Severe Asthma

Asthma is a common and heterogeneous disease whose treatment has considerably changed over the last decades. While inhaled therapies based on inhaled corticosteroids and long acting β2 agonists are effective in controlling asthma in the majority of patients, about 5% of asthmatics poorly respond to inhaled steroids or inhaled steroids/long acting β2 agonists combinations. These patients are affected by “severe asthma”, which is associated with need of oral corticosteroids, progression of the disease, increased use of healthcare services, deterioration of quality of life, and a significant economic burden on society. Asthma is no longer considered a single disease, but a respiratory syndrome with complex biological network of distinct and interrelating inflammatory and remodeling pathways (endotypes) that are associated with different clinical manifestations (phenotypes) both in the lungs (asthma) and other organs (e.g. nose and skin). Severe asthma endotypes may be broadly regarded as Type 2-high and Type 2-low, a model that has become central to asthma management with the development of novel treatments for the Type 2-high endotypes. The hallmark feature of Type 2-high asthma is eosinophilic inflammation, often associated with increased serum IgE, increased exhaled nitric oxide (FeNO) and blood eosinophilia. The discovery of the main key drivers of Type 2-high inflammation (IgE, cytokines such as interleukin IL-5, -4 and -13) enabled the development of new biological agents directed towards specific molecular targets. These advances have shifted the existing paradigm “one drug fits all” to “patient-tailored” novel therapies. The monoclonal antibodies direct to IgE (omalizumab), IL-5 and IL-5 receptor (mepolizumab, benralizumab, reslizumab), and to the α chain of the IL-4 and IL-13 combined receptor (dupilumab), and more recently, to the thymic stromal lymphopoietin (tezepelumab) have been shown in both clinical trials and real-life studies to control symptoms, reduce asthma exacerbations and improve lung function in severe asthmatics not controlled by full inhalation therapies. More recently, the Single Inhaler Triple Therapy (SITT) containing inhaled steroids, long acting β2 agonists and muscarinic antagonists has been developed, slightly improving the effectiveness/safety of the inhalation therapy. This report aims to review available therapeutic opportunities for patients with severe asthma focusing on patients with Type 2-high severe asthma and how to position these new therapeutic alternatives in clinical practice.

Effect of estradiol with or without micronized progesterone on cholinergic-related cognitive performance in postmenopausal women.

Women are at a higher risk of developing Alzheimer's disease (AD), and the decline in estrogens post-menopause is thought of as a factor increasing this risk. Estradiol (E2) is important in supporting cholinergic neuronal integrity, and cholinergic functioning may be negatively impacted following the loss of E2 post-menopause. The use of exogenous E2 has been observed to enhance cholinergically mediated cognitive performance in healthy post-menopausal women, which indicates a potentially protective mechanism. However, E2 is often co-administered with progestin or progesterone to prevent endometrial proliferation. Progesterone/progestins have previously been shown to have a detrimental effect on E2-mediated biological and cognitive effects mediated by cholinergic systems in preclinical models, therefore the present study aimed to assess whether progesterone would modify the effect of E2 to influence cognition during cholinergic blockade. Twenty participants completed 3-months of oral E2 treatment with micronized progesterone (mPRO) or with placebo (PLC) in a repeated-measures within-subjects crossover design, in which they also completed five anticholinergic challenge days per hormone treatment condition. During the challenge participants were administered low or high doses of the nicotinic cholinergic antagonist mecamylamine, the muscarinic cholinergic antagonist scopolamine, or placebo. Following drug administration participants performed cognitive tests sensitive to cholinergic tone, assessing attention, episodic memory, and working memory. Significant decrements were found on some tasks when participants were taking E2+mPRO compared to E2 alone. Specifically, under more challenging task conditions and larger anticholinergic doses, participants showed poorer performance on the Critical Flicker Fusion task and the Stroop test and responded more conservatively on the N-back working memory task. Other tasks showed no differences between treatments under cholinergic blockade. The findings show that mPRO when taken in concert with E2, was detrimental to effortful cognitive performance, in the presence of cholinergic blockade. These results are important for assessing the impact of combined postmenopausal hormone treatment on cognitive performance that is dependent on cholinergic functioning after menopause.

Donepezil as a new therapeutic potential in KCNQ2- and KCNQ3-related autism.

The KCNQ2/KCNQ3 genes encode the voltage-gated K channel underlying the neuronal M-current, regulating neuronal excitability. Loss-of-function (LoF) variants cause neonatal epilepsy, treatable with the M-current-opener retigabine, which is no longer marketed due to side effects. Gain-of-function (GoF) variants cause developmental encephalopathy and autism that could be amenable to M-current, but such therapies are not clinically available. In this translational project, we investigated whether donepezil, a cholinergic drug used in Alzheimer's, suppresses M currents in vitro and improves cognitive symptoms in patients with GoF variants. (1) The effect of 1 μM donepezil on the amplitude of the M-current was measured in excitatory and inhibitory neurons of mouse primary cultured hippocampal cells. M-current was measured using the standard deactivation protocol (holding at 0 mV and deactivation at -60 mV) in the voltage-clamp configuration of the whole-cell patch clamp technique. The impact of donepezil was also examined on the spontaneous firing activity of hippocampal neurons in the current-clamp configuration. (2) Four children with autism, aged 2.5-8 years, with the following GoF variants were enrolled: KCNQ2 (p. Arg144Gln) and KCNQ 3 (p.Arg227Gln, p.Arg230Cys). Patients were treated off-label with donepezil 2.5-5 mg/d for 12 months and assessed with: clinical Global Impression of Change (CGI-c), Childhood Autism Rating Scale 2 (CARS-2), Adaptive Behavior Assessment System-II (ABAS-II), and Child Development Inventory (CDI). (1) Application of donepezil for at least 6 min produced a significant inhibition of the M-current with an IC50 of 0.4 μM. At 1 μM, donepezil reduced by 67% the M-current density of excitatory neurons (2.4 ± 0.46 vs. 0.89 ± 0.15 pA/pF, p < 0.05*). In inhibitory neurons, application of 1 μM donepezil produced a lesser inhibition of 59% of the M-current density (1.39 ± 0.43 vs. 0.57 ± 0.21, p > 0.05). Donepezil (1 μM) potently increased by 2.6-fold the spontaneous firing frequency, which was prevented by the muscarinic receptor antagonist atropine (10 μM). (2) The CARS-2 decreased by 3.8 ± 4.9 points (p > 0.05), but in two patients with KCNQ3 variants, the improvement was over the 4.5 clinically relevant threshold. The global clinical change was also clinically significant in these patients (CGI-c = 1). The CDI increased by 65% (p < 0.05*), while the ABAS-II remained unchanged. Donepezil should be repurposed as a novel alternative treatment for GoF variants in KCNQ2/KCNQ3 encephalopathy.

Post Hoc Analysis of Lung Function Improvement and Patient-Reported Outcomes With Revefenacin in Adults With Moderate-to-Very Severe COPD and Comorbid Anxiety or Depression.

Revefenacin, a once-daily, nebulized, long-acting muscarinic antagonist approved in the United States for the maintenance of chronic obstructive pulmonary disease (COPD), significantly improves lung function and quality of life versus placebo in patients with moderate-to-very severe COPD. Comorbid anxiety and/or depression may alter patients' symptom perception and response to bronchodilators. The impact of revefenacin in patients with COPD with comorbid anxiety and/or depression has not been previously investigated. This post hoc subgroup analysis examined data from two 12-week, randomized, phase 3 trials in patients with moderate-to-very severe COPD with the following self-reported subgroups: anxiety only (A), depression only (D), anxiety and depression (+A/+D), and neither anxiety nor depression (-A/-D). We assessed change from baseline in trough forced expiratory volume in 1 second (FEV1) at Day 85 and health status by the St George's Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT). Of 812 patients, 90 (11%), 110 (14%), 141 (17%), and 471 (58%) had A, D, +A/+D, and -A/-D respectively. In revefenacin versus placebo, trough FEV1 significantly improved from baseline at Day 85 across all subgroups as well as the SGRQ and CAT scores in patients with A, +A/+D, and -A/-D. Revefenacin was well tolerated regardless of A/D status, with a minimal incidence of treatment-emergent antimuscarinic adverse events across subgroups. In this analysis, revefenacin versus placebo significantly improved health outcomes in patients with moderate-to-very severe COPD with A, +A/+D, and -A/-D, but not in patients with D. The safety profile of revefenacin was not affected by comorbid anxiety/depression status.

Bronchodilator Responsiveness Measured by Spirometry and Impulse Oscillometry in Patients with Asthma After Short Acting Antimuscarinic and/or Beta-2-Agonists Inhalation.

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. 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. 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. 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.

Experience of clinicians with dual bronchodilator therapy in COPD (EXPAND) in Nepal

Introduction: Combination of bronchodilators, particularly long-acting muscarinic antagonists (LAMAs) and long-acting β2 agonists (LABAs) have become the mainstay of pharmacological therapy for COPD. COPD is now a common non communicable disease in Nepal. Objective: The study evaluated the current perception and experience of the clinicians in Nepal on diagnosis and management of COPD with focus on use of dual bronchodilator therapy. Method: This cross-sectional, observational survey evaluated experiences of clinicians (n=96; pulmonologist-13, physician-57, general practitioner-26) in Nepal on diagnosis, management trends, and current perceptions on the use of dual bronchodilator therapy in COPD management. Result: 93% of clinicians were practising in an urban setting for an average of 10 years and an average of 35% of their patients are of COPD. 61% of clinicians use mMRC with (34%) or without (27%) CAT score. 92% of clinicians perceived that most of their patients had 1 (32%) or &gt;1 (59%) exacerbation/year. 54% of clinicians performed spirometry on all their patients with suspected COPD. 49% of clinicians measured blood EOS in their patients with severe COPD before adding ICS. 93% of clinicians preferred dual therapy (separate inhalers or a combination) for their COPD patients, but 83% of clinicians preferred LABA + LAMA in a single inhaler over inhalers given separately. 57% of clinicians preferred LABA + LAMA and 82% preferred the Tiotropium + Formoterol combination. 81% of clinicians stepped up or stepped down their treatment. 56% of patients were taking LABA + LAMA + ICS and 55% of clinicians co-prescribed ICS + LABA with LABA + LAMA. 80% of clinicians checked the inhalation technique at every visit and an average of 54% of their COPD patients were adherent (&gt;80%) to the prescribed inhalation therapy. 78% of clinicians felt that dryness of mouth was the most common side effect of LABA + LAMA. 94% of clinicians believed that managing COPD better could improve cardiovascular outcomes in their patients with coexistent COPD. Conclusion: In the EXPAND survey, Formoterol + Tiotropium was preferred by most clinicians in Nepal amongst the LABA + LAMA combination. There is a good scope for improvement in the utilization of tools like spirometry, mMRC, CAT, and blood EOS in the daily practice of clinicians in Nepal.

Biperiden reverses the increase in 50-kHz ultrasonic vocalizations but not the increase in locomotor activity induced by cocaine

Cocaine use disorder (CUD) is a worldwide public health problem, associated with severe psychosocial and economic impacts. Currently, no FDA-approved treatment is available for CUD. However, an emerging body of evidence from clinical and preclinical studies suggests that biperiden, an M1 muscarinic receptor antagonist, presents potential therapeutic use for CUD. These studies have suggested that biperiden may reduce the reinforcing effects of cocaine. It is well established that rodents emit 50-kHz ultrasonic vocalizations (USV) in response to natural rewards and stimulant drugs, including cocaine. Nonetheless, the effects of biperiden on the cocaine-induced increase of 50-kHz USV remains unknown. Here, we hypothesized that biperiden could antagonize the acute effects of cocaine administration on rat 50-kHz USV. To test this hypothesis, adult male Wistar rats were divided into four experimental groups: saline, 5 mg/kg biperiden, 10 mg/kg cocaine, and biperiden/cocaine (5 and 10 mg/kg, i.p., respectively). USV and locomotor activity were recorded in baseline and test sessions. As expected, cocaine administration significantly increased the number of 50-kHz USV. Biperiden administration effectively antagonized the increase in 50-kHz USV induced by cocaine. Cocaine administration also increased the emission of trill and mixed 50 kHz USV subtypes and this effect was antagonized by biperiden. Additionally, we showed that biperiden did not affect the cocaine-induced increase in locomotor activity, although biperiden administration per se increased locomotor activity. In conclusion, our findings indicate that administering biperiden acutely reduces the positive affective effects of cocaine, as demonstrated by its ability to inhibit the increase in 50-kHz USV.

Investigating the Mechanisms Underlying U46619-Induced Contraction on Porcine Lower Esophageal Sphincter.

Gastroesophageal reflux disease (GERD) is associated with an incompetent lower esophageal sphincter (LES), resulting in the reflux of gastric contents into the esophagus. U46619, a thromboxane A2 (TXA2) receptor agonist, induces contractions in various smooth muscles. Therefore, this study aimed to investigate the effects and mechanisms of action of U46619 on the porcine LES. To achieve this, contractions of the clasp and sling strips of the porcine LES, induced by U46619, were measured using isometric transducers. Furthermore, the contractile mechanism of U46619 in the porcine LES was investigated by pretreating the strips with atropine (a muscarinic receptor antagonist), tetrodotoxin (a neuronal sodium channel blocker), nifedipine (a calcium channel blocker), and Ca2+-free Krebs-Henseleit solution. Additionally, reverse transcription polymerase chain reaction (PCR) and immunohistochemistry (IHC) were performed to determine the presence of the TXA2 receptor in porcine LES. The results of this study demonstrated that U46619 caused marked concentration-dependent contractions in both porcine sling and clasp strips. The mechanism of U46619-induced contraction of the porcine LES was found to be related to calcium channels. Furthermore, the reverse transcription PCR analysis and IHC revealed that the TXA2 receptor was expressed in the clasp and sling fibers of porcine LES. Consequently, this study suggests that U46619 mediates the contraction of porcine LES through calcium channels and has potential as a therapeutic approach for treating GERD. SIGNIFICANCE STATEMENT: This study establishes that U46619 induces concentration-dependent contractions in porcine LES, primarily mediated by calcium channels. The presence of the TXA2 receptor in LES clasp and sling fibers is confirmed. These findings highlight U46619's potential as a GERD therapeutic by targeting calcium channels for LES contraction modulation.

Cognitive-Enhancing Effects of Acetylcholine Receptor Agonists in Group-Housed Cynomolgus Monkeys Who Drink Ethanol.

The cognitive impairments that are often observed in patients with alcohol use disorder (AUD) partially contribute to the extremely low rates of treatment initiation and adherence. Brain acetylcholine receptors (AChR) mediate and modulate cognitive and reward-related behavior, and their distribution can be altered by long-term heavy drinking. Therefore, AChRs are promising pharmacotherapeutic targets for treating the cognitive symptoms of AUD. In the present study, the procognitive efficacy of two AChR agonists, xanomeline and varenicline, were evaluated in group-housed monkeys who self-administered ethanol for more than 1 year. The muscarinic AChR antagonist scopolamine was used to disrupt performance of a serial stimulus discrimination and reversal (SDR) task designed to probe cognitive flexibility, defined as the ability to modify a previously learned behavior in response to a change in reinforcement contingencies. The ability of xanomeline and varenicline to remediate the disruptive effects of scopolamine was compared between socially dominant and subordinate monkeys, with lighter and heavier drinking histories, respectively. We hypothesized that subordinate monkeys would be more sensitive to all three drugs. Scopolamine dose-dependently impaired performance on the serial SDR task in all monkeys at doses lower than those that produced nonspecific impairments (e.g., sedation); its potency did not differ between dominant and subordinate monkeys. However, both AChR agonists were effective in remediating the scopolamine-induced deficit in subordinate monkeys but not in dominant monkeys. These findings suggest xanomeline and varenicline may be effective for enhancing cognitive flexibility in individuals with a history of heavy drinking. SIGNIFICANCE STATEMENT: Procognitive effects of two acetylcholine (ACh) receptor agonists were assessed in group-housed monkeys who had several years' experience drinking ethanol. The muscarinic ACh receptor agonist xanomeline and the nicotinic ACh receptor agonist varenicline reversed a cognitive deficit induced by the muscarinic ACh receptor antagonist scopolamine. However, this effect was observed only in lower-ranking (subordinate) monkeys and not higher-ranking (dominant monkeys). Results suggest that ACh agonists may effectively remediate alcohol-induced cognitive deficits in a subpopulation of those with alcohol use disorder.

Deoxycholic Acid, a Secondary Bile Acid, Increases Cardiac Output and Blood Pressure in Rats.

Deoxycholic acid (DCA) is a secondary bile acid produced by gut bacteria. Elevated serum concentrations of DCA are observed in cardiovascular disease (CVD). We hypothesized that DCA might influence hemodynamic parameters in rats. The concentration of DCA in systemic blood was measured with liquid chromatography coupled with mass spectrometry. Arterial blood pressure (BP), heart rate (HR) and echocardiographic parameters were evaluated in anesthetized, male, 3-4-month-old Sprague-Dawley rats administered intravenously (IV) or intracerebroventricularly (ICV) with investigated compounds. Mesenteric artery (MA) reactivity was tested ex vivo. The baseline plasma concentration of DCA was 0.24 ± 0.03 mg/L. The oral antibiotic treatment produced a large decrease in the concentration. Administered IV, the compound increased BP and HR in a dose-dependent manner. DCA also increased heart contractility and cardiac output. None of the tested compounds-prazosin (an alpha-blocker), propranolol (beta-adrenolytic), atropine (muscarinic receptor antagonist), glibenclamide (K-ATP inhibitor) or DY 268 (FXR antagonist), glycyrrhetinic acid (11HSD2 inhibitor)-significantly diminished the DCA-induced pressor effect. ICV infusion did not exert significant HR or BP changes. DCA relaxed MAs. Systemic vascular resistance did not change significantly. DCA elevates BP primarily by augmenting cardiac output. As a metabolite derived from gut bacteria, DCA potentially serves as a mediator in the interaction between the gut microbiota and the host's circulatory system.

Delphi Consensus on Clinical Applications of GOLD 2023 Recommendations in COPD Management: How Aligned are Recommendations with Clinical Practice?

The objective of this Delphi study was to understand and assess the level of consensus among respiratory experts on the clinical application of GOLD 2023 recommendations in management of patients with chronic obstructive pulmonary disease (COPD). The study comprised two online surveys and a participant meeting with 34 respiratory experts from 16 countries. Responses of 73 questions were recorded using a Likert scale ranging from 0 (disagreement) to 9 (agreement). The consensus threshold was 75%. Survey 1 and survey 2 had 34 and 32 participants, respectively; and 25 attended the participant meeting. Consensus was reached on survey 1: 28/42; survey 2: 18/30 close-ended questions. A consensus was reached on the clinical relevance of most updates in definitions and diagnosis of COPD. Mixed results for the treatment recommendations by GOLD were noted: 74% agreed with the recommendation to initiate treatment with dual bronchodilators for group E patients; 63% agreed for including inhaled corticosteroids (ICS)/long-acting β2 agonist(LABA)/ Long-acting muscarinic receptor antagonists (LAMA) as a treatment option for GOLD B patients. Also, consensus lacked on removing ICS + LABA as an initial therapeutic option, in countries with challenges in access to other treatment option;. 88% agreed that they use GOLD recommendations in their daily clinical practice. This Delphi study demonstrated a high level of consensus regarding key concepts of GOLD 2023 report, with most participants favoring recent updates in definitions, diagnosis, management, and prevention of COPD. More evidence on the etiotype based management and treatment options for group B and E are required which could further strengthen clinical application of the GOLD report.

Solifenacin promotes remyelination in cuprizone mouse model by inhibiting the Wnt/β-catenin signaling pathway

Demyelinating diseases are a type of neurological disorder characterized by the damage to the myelin sheath in the central nervous system. Promoting the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) is crucial for treatment. Non-selective muscarinic receptor (MR) antagonists have been shown to improve remyelination in rodent models, although the mechanisms are still unclear. In this study, we treated cuprizone (CPZ)-induced demyelination mouse model with different concentrations of Solifenacin (Sol), a selective M3 receptor antagonist, to determine the optimal concentration for promoting remyelination. Behavioral tests and Luxol fast blue (LFB) staining were used to observe the extent of remyelination, while immunofluorescence was used to measure the expression levels of myelin-related proteins, including myelin basic protein (MBP) and platelet-derived growth factor receptor alpha (PDGFR-α). Western blot analysis was employed to analyze the expression levels of molecules associated with the Wnt/β-catenin signaling pathway. The results showed that Sol treatment significantly promoted myelin regeneration and OPCs differentiation in CPZ-induced demyelination mouse model. Additionally, Sol treatment inhibited the Wnt/β-catenin signaling pathway and reversed the effects of CPZ on OPCs differentiation. In conclusion, Sol may promote the differentiation of OPCs by inhibiting the Wnt/β-catenin signaling pathway, making it a potential therapeutic option for central nervous system demyelinating diseases.

Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial

New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis. EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161). From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]). In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia. Karuna Therapeutics.

Cost-effectiveness of triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate compared with dual therapy for the treatment of chronic obstructive pulmonary disease (COPD) in Canada

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with significant economic and societal burden in Canada. For patients whose symptoms remain uncontrolled with dual therapies including long-acting muscarinic antagonists (LAMA)/long-acting beta2-adrenergic agonists (LABA) or inhaled corticosteroids (ICS)/LABA, step-up to triple-therapy with ICS/LAMA/LABA is recommended. Budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) is an ICS/LAMA/LABA therapy with demonstrated efficacy compared to dual therapies in pivotal phase 3 trials (ETHOS and KRONOS). OBJECTIVES The objectives of this study were to conduct a cost-utility analysis to compare BGF with dual therapies (ICS/LABA and LAMA/LABA) for patients with COPD requiring escalation to triple therapy. METHODS A Markov cohort-based cost-utility analysis was conducted over a 30-year time horizon from a public payer perspective, to compare costs and outcomes in patients with COPD requiring escalation from dual therapy to triple therapy. The analysis was based on data from the ETHOS trial, Canadian administrative data, and published sources. Health states were characterized by forced expiratory volume (FEV1) severity and exacerbations (none, moderate, severe). RESULTS Over a 30-year time horizon in probabilistic analysis across several scenario analyses, BGF was associated with modest but consistent benefits to overall costs ($40,406 total for BGF, $40,685 for LAMA/LABAs and $43,261 for ICS/LABAs), as well as life years and quality-adjusted life year (QALYs) gained compared to dual therapies (8.7 total QALYs for BGF triple therapy, 8.5 for LAMA/LABAs and 8.4 for ICS/LABAs). CONCLUSIONS From a Canadian public healthcare perspective, BGF is associated with both cost-savings and improved health benefits compared with dual therapies for maintenance treatment of COPD patients at risk of exacerbations. These results may help to inform optimal decision-making.

A Developmental Switch in Cholinergic Mechanisms of Modulation in the Medial Nucleus of the Trapezoid Body.

The medial nucleus of the trapezoid body (MNTB) has been intensively investigated as a primary source of inhibition in brainstem auditory circuitry. MNTB-derived inhibition plays a critical role in the computation of sound location, as temporal features of sounds are precisely conveyed through the calyx of Held/MNTB synapse. In adult gerbils, cholinergic signaling influences sound-evoked responses of MNTB neurons via nicotinic acetylcholine receptors (nAChRs; Zhang et al., 2021) establishing a modulatory role for cholinergic input to this nucleus. However, the cellular mechanisms through which acetylcholine (ACh) mediates this modulation in the MNTB remain obscure. To investigate these mechanisms, we used whole-cell current and voltage-clamp recordings to examine cholinergic physiology in MNTB neurons from Mongolian gerbils (Meriones unguiculatus) of both sexes. Membrane excitability was assessed in brain slices, in pre-hearing (postnatal days 9-13) and post-hearing onset (P18-20) MNTB neurons during bath application of agonists and antagonists of nicotinic (nAChRs) and muscarinic receptors (mAChRs). Muscarinic activation induced a potent increase in excitability most prominently prior to hearing onset with nAChR modulation emerging at later time points. Pharmacological manipulations further demonstrated that the voltage-gated K+ channel KCNQ (Kv7) is the downstream effector of mAChR activation that impacts excitability early in development. Cholinergic modulation of Kv7 reduces outward K+ conductance and depolarizes resting membrane potential. Immunolabeling revealed expression of Kv7 channels as well as mAChRs containing M1 and M3 subunits. Together, our results suggest that mAChR modulation is prominent but transient in the developing MNTB and that cholinergic modulation functions to shape auditory circuit development.

Design of ADEPT‐2, a phase 3, parallel group study to evaluate KarXT [xanomeline‐trospium] as a treatment for psychosis associated with Alzheimer’s disease

AbstractBackgroundPsychosis represents a major unmet medical need in patients with Alzheimer’s disease (AD) dementia. With no approved medications for AD dementia psychosis (ADP), current treatment relies on off‐label uses of antipsychotics with limited efficacy and significant safety concerns. Xanomeline is an M1/M4 preferring muscarinic receptor agonist that has previously been shown to have antipsychotic effects in subjects with AD (Bodick et al., 1997). While xanomeline had promising efficacy for potentially treating psychosis in AD, cholinergic adverse events limited further clinical development of xanomeline. KarXT is an investigational treatment that combines xanomeline with trospium, an FDA‐approved non‐specific muscarinic receptor antagonist. Unlike xanomeline, trospium does not measurably cross the blood‐brain barrier, providing a mechanism to mitigate peripheral cholinergic effects of xanomeline while maintaining its muscarinic receptor agonist activities in the brain.MethodsADEPT‐2 trial is a phase 3, randomized, double‐blind, placebo‐controlled, parallel group study to evaluate the safety and efficacy of KarXT for the treatment of ADP. Subjects aged 55‐90 years with moderate to severe psychosis associated with mild to severe AD dementia will be enrolled into the study. Eligible subjects will be randomized to receive either KarXT or placebo in a double‐blinded manner for 14 weeks and subjects who complete the study will be eligible to participate in a one‐year, open‐label safety extension study.ResultsThe primary efficacy endpoint of the study is change from Randomization to End of Treatment in the Neuropsychiatric Inventory‐Clinical (NPI‐C): Hallucinations and Delusions (H+D) score and the key secondary efficacy endpoint is change from Randomization to End of Treatment in the Cohen‐Mansfield Agitation Inventory (CMAI). The safety endpoints include the evaluation of safety and tolerability of KarXT compared with placebo in subjects with ADP. The study is planned to start in 2023 and will enroll approximately 360 subjects with psychosis associated with AD dementia.ConclusionADEPT‐2 is designed to assess the safety and efficacy of KarXT for the treatment of psychosis in patients with AD dementia. If ADEPT‐2 is successful, KarXT has the potential to be the first in a new class of pharmacologic treatment for AD psychosis based on muscarinic receptor agonism.

Inhaled medications for chronic obstructive pulmonary disease predict surgical complications and survival in stage I non-small cell lung cancer.

Lung function is routinely assessed prior to surgical resection for non-small cell lung cancer (NSCLC). Further assessment of chronic obstructive pulmonary disease (COPD) using inhaled COPD medications to determine disease severity, a readily available metric of disease burden, may predict postoperative outcomes and overall survival (OS) in lung cancer patients undergoing surgery. We retrospectively evaluated clinical stage I NSCLC patients receiving surgical treatment within the Veterans Health Administration from 2006-2016 to determine the relationship between number and type of inhaled COPD medications (short- and long-acting beta2-agonists, muscarinic antagonists, or corticosteroids prescribed within 1 year before surgery) and postoperative outcomes including OS using multivariable models. We also assessed the relationship between inhaled COPD medications, disease severity [measured by forced expiratory volume in 1 second (FEV1)], and diagnosis of COPD. Among 9,741 veterans undergoing surgery for clinical stage I NSCLC, patients with COPD were more likely to be prescribed inhaled medications than those without COPD [odds ratio (OR) =5.367, 95% confidence interval (CI): 4.886-5.896]. Increased severity of COPD was associated with increased number of prescribed inhaled COPD medications (P<0.0001). The number of inhaled COPD medications was associated with prolonged hospital stay [adjusted OR (aOR) =1.119, 95% CI: 1.076-1.165), more major complications (aOR =1.117, 95% CI: 1.074-1.163), increased 90-day mortality (aOR =1.088, 95% CI: 1.013-1.170), and decreased OS [adjusted hazard ratio (aHR) =1.061, 95% CI: 1.042-1.080]. In patients with FEV1 ≥80% predicted, greater number of prescribed inhaled COPD medications was associated with increased 30-day mortality (aOR =1.265, 95% CI: 1.062-1.505), prolonged hospital stay (aOR =1.130, 95% CI: 1.051-1.216), more major complications (aOR =1.147, 95% CI: 1.064-1.235), and decreased OS (aHR =1.058, 95% CI: 1.022-1.095). When adjusting for other drug classes and covariables, short-acting beta2-agonists were associated with increased 90-day mortality (aOR =1.527, 95% CI: 1.120-2.083) and decreased OS (aHR =1.087, 95% CI: 1.005-1.177). In patients with early-stage NSCLC, inhaled COPD medications prescribed prior to surgery were associated with both short- and long-term outcomes, including in patients with FEV1 ≥80% predicted. Routine assessment of COPD medications may be a simple method to quantify operative risk in early-stage NSCLC patients.

Medication use of Canadians with chronic obstructive pulmonary disease: a cohort study

ObjectivesThe objectives of this study were to describe medication use, treatment patterns and adherence, as well as acute exacerbations of chronic obstructive pulmonary disease (AECOPD) among adults living with COPD.MethodsA...

COPD after “Tabouna” Exposure: A Distinct Phenotype in Tunisian Women?

Background: COPD due to exposure to combustible biomass is an increasingly recognized phenotype, particularly among women who use traditional ovens, known as ‘Tabouna’, for baking bread. This paper aims to investigate the clinical and functional characteristics of COPD in Tunisian female patients attributed to the use of ‘Tabouna’. Methods: A retrospective single-center cohort study was conducted on patients recruited from the Department of Respiratory Disease at A. Mami Hospital, who were diagnosed with COPD between January 2014 and December 2022. The diagnosis of COPD adhered to the standards defined in GOLD 2022. Results: Out of the 95 women included in the study, 48 (50.5%) were exposed to tobacco smoke, while 47 (49.5%) were exposed to the ‘Tabouna’. The median age was 70.4 ± 11.5 years, ranging from 40 to 95 years. Patients exposed to biomass were notably older, with a median age of 75.4 compared to 64.6 (p = 0.04). A significant association was observed between COPD and biomass smoke exposure, both in women residing in rural and urban areas (p = 0.006). The frequency of patients exposed to biomass with comorbidities was higher than in the group exposed to tobacco, but only hypertension showed statistically significant results (p = 0.01). Tobacco smoke induced more impairment in lung function than biomass in the group with FEV1 ≤ 30% (p = 0.04). Long-acting muscarinic antagonists were more commonly prescribed to smokers (p = 0.04). Serious complications such as chronic respiratory failure and intensive care admissions were similar in both groups (p = 0.8 and 0.4). Conclusions: COPD in women after exposure to the ‘Tabouna’ was observed in older patients and characterized by delayed diagnosis. Despite these clinical differences, poor COPD outcomes were similar in both groups.