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International Journal of Chronic... 2024Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the... (Observational Study)
Observational Study
PURPOSE
Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the frequency of medication success among patients with COPD who initiated BGF using real-world data.
PATIENTS AND METHODS
Patients with a recorded diagnostic COPD code who started BGF with ≥2 prescriptions within 90-days were identified in the UK Optimum Patient Care Research Database and followed from first prescription until censoring at the end of follow-up (180-days), death, leaving database or end of data at 24/10/2022. The primary outcome was medication success at 90-days post-BGF initiation, defined as no major cardiac or respiratory event (ie no complicated COPD exacerbation, hospitalization for any respiratory event, myocardial infarction, new/hospitalized heart failure, and death) and no incidence of pneumonia. Medication success was also assessed at 180-days post-BGF initiation. Overall real-life medication success was claimed if the lower 95% confidence interval (CI) for the proportion of patients meeting the primary outcome was ≥70% (defined a priori).
RESULTS
Two hundred eighty-five patients were included. Prior to BGF initiation, these patients often had severe airflow obstruction (mean ppFEV: 54.5%), were highly symptomatic (mMRC ≥2: 77.9% (n = 205/263); mean CAT score: 21.7 (SD 7.8)), with evidence of short-acting β-agonist (SABA) over-use (≥3 inhalers/year: 62.1%, n=179/285), repeat OCS prescriptions (≥2 courses/year: 33.0%, n = 95/285) and multiple primary care consultations (≥2 visits/year: 61.1%, n = 174/285). Overall, 39.6% of patients (n = 113/285) switched from previous triple therapies. Real-life medication success was achieved by 96.5% of patients (n = 275/285 [95% CI: 93.6, 98.3]) during 90-days treatment with BGF and by 91.8% (n = 169/184 [95% CI: 86.9, 95.4]) of patients at 180-days. The prescribed daily dose of SABA remained stable over the study period.
CONCLUSION
The majority of patients initiating BGF experienced real-life medication success reflecting the absence of severe cardiopulmonary events. These benefits were apparent after 90-days of treatment and sustained over 180-days.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Male; Female; Aged; Primary Health Care; Treatment Outcome; Bronchodilator Agents; Middle Aged; Time Factors; Adrenergic beta-2 Receptor Agonists; United Kingdom; Glycopyrrolate; Databases, Factual; Budesonide, Formoterol Fumarate Drug Combination; Lung; Muscarinic Antagonists; Drug Combinations; Retrospective Studies; Glucocorticoids; Aged, 80 and over
PubMed: 38813078
DOI: 10.2147/COPD.S452624 -
Ethiopian Journal of Health Sciences Jul 2023Enuresis, defined as involuntary nocturnal urination without any underlying organic disorder in a child expected to control urination, poses a common problem. This study... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
BACKGROUND
Enuresis, defined as involuntary nocturnal urination without any underlying organic disorder in a child expected to control urination, poses a common problem. This study evaluated the effectiveness of Tolterodine and Oxybutynin in children presenting with primary desmopressin-resistant enuresis.
MATERIALS AND METHODS
A randomized clinical trial was undertaken involving 68 participants aged between 5 and 16 years, all suffering from primary enuresis. These patients were randomly assigned to one of two treatment groups for a three-month period: Group 1, treated with Oxybutynin and Desmopressin, and Group 2, treated with Tolterodine and Desmopressin. Data on demographics, clinical and laboratory findings, and subjective responses to treatment were gathered. The response was measured based on the frequency of wetting incidents per night and week and compared with pre-treatment data.
RESULTS
Patients were divided into two groups (30 patients in Group 1 and 38 patients in Group 2). The mean age of the patients was 88.97±27.09 months. In the first treatment group, 6 out of 30 patients (20%) experienced a complete treatment response, as did 5 out of 38 patients (13.2%) in the second treatment group. This difference between the groups was not statistically significant. Seven patients (23%) in the Oxybutynin group and 13 patients (34%) in the Tolterodine group reported a lack of response to treatment, a difference that also lacked statistical significance.
CONCLUSION
For patients resistant to Desmopressin, the addition of anticholinergic drugs elicited a significant response in over half of the patients. However, no benefit was observed in using either Oxybutynin or Tolterodine in the treatment of Desmopressin-resistant enuresis.
Topics: Humans; Tolterodine Tartrate; Child; Mandelic Acids; Male; Female; Deamino Arginine Vasopressin; Adolescent; Treatment Outcome; Child, Preschool; Nocturnal Enuresis; Muscarinic Antagonists; Antidiuretic Agents; Urological Agents; Enuresis; Drug Resistance
PubMed: 38784212
DOI: 10.4314/ejhs.v33i4.7 -
Frontiers in Medicine 2024The prevalence of bronchiectasis among adult Aboriginal Australians is higher than that of non-Aboriginal Australians. However, despite evidence to suggest higher...
BACKGROUND
The prevalence of bronchiectasis among adult Aboriginal Australians is higher than that of non-Aboriginal Australians. However, despite evidence to suggest higher prevalence of bronchiectasis among Aboriginal people in Australia, there is sparce evidence in the literature assessing clinical parameters that may predict survival or mortality in this population.
METHODS
Aboriginal Australians residing in the Top End Health Service region of the Northern Territory of Australia aged >18 years with chest computed tomography (CT) confirmed bronchiectasis between 2011 and 2020 were included. Demographics, body mass index (BMI), medical co-morbidities, lung function data, sputum microbiology, chest CT scan results, hospital admissions restricted to respiratory conditions and all-cause mortality were assessed.
RESULTS
A total of 459 patients were included, of whom 146 were recorded deceased (median age at death 59 years). Among the deceased cohort, patients were older (median age 52 vs. 45 years, = 0.023), had a higher prevalence of chronic obstructive pulmonary disease (91 vs. 79%, = 0.126), lower lung function parameters (median percentage predicted forced expiratory volume in 1 s 29 vs. 40%, = 0.149), a significantly greater proportion cultured non- fungi (65 vs. 46%, = 0.007) and (46 vs. 28%, = 0.007) on sputum microbiology and demonstrated bilateral involvement on radiology. In multivariate models advancing age, prior culture and Intensive care unit (ICU) visits were associated with increased odds of mortality. Higher BMI, better lung function on spirometry, prior positive sputum microbiology for and use of inhaled long-acting beta antagonist/muscarinic agents may have a favourable effect.
CONCLUSION
The results of this study may be of use to stratify high risk adult Aboriginal patients with bronchiectasis and to develop strategies to prevent future mortality.
PubMed: 38774399
DOI: 10.3389/fmed.2024.1366037 -
BMJ Open Respiratory Research May 2024Compared with multiple-inhaler triple therapy (MITT), single-inhaler triple therapy (SITT) with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) demonstrated...
Outcomes of patients with COPD switching from multiple-inhaler to once-daily single-inhaler triple therapy in a real-world primary care setting in England: a retrospective pre-post cohort study.
BACKGROUND
Compared with multiple-inhaler triple therapy (MITT), single-inhaler triple therapy (SITT) with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) demonstrated improved lung function and meaningful improvements in chronic obstructive pulmonary disease (COPD) Assessment Test score. This real-world study compared the effectiveness of switching patients with COPD in England from MITT to once-daily SITT with FF/UMEC/VI by evaluating rates of COPD exacerbation, healthcare resource use (HCRU) and associated direct medical costs.
METHODS
Retrospective cohort pre-post study using linked primary care electronic health record and secondary care administrative datasets. Patients diagnosed with COPD at age ≥35 years, with smoking history, linkage to secondary care data and continuous GP registration for 12 months pre-switch and 6 months post-switch to FF/UMEC/VI were included. Index date was the first initiation of an FF/UMEC/VI prescription immediately following MITT use from 15 November 2017 to 30 September 2019. Baseline was 12 months prior to index, with outcomes assessed 6/12 months pre-switch and post-switch, and stratified by prior COPD exacerbation status.
RESULTS
We included 2533 patients (mean [SD] age: 71.1 [9.9] years; 52.1% male). In the 6 months post-switch, there were significant decreases in the proportion of patients experiencing ≥1 moderate-to-severe (36.2%-28.9%), moderate only (24.4%-19.8%) and severe only (15.4%-11.8%) COPD exacerbation (each, p<0.0001) compared with the 6 months pre-switch. As demonstrated by rate ratios, there were significant reductions in exacerbation rates of each severity overall (p<0.01) and among patients with prior exacerbations (p<0.0001). In the same period, there were significant decreases in the rate of each COPD-related HCRU and total COPD-related costs (-24.9%; p<0.0001).
CONCLUSION
Patients with COPD switching from MITT to once-daily SITT with FF/UMEC/VI in a primary care setting had significantly fewer moderate and severe exacerbations, and lower COPD-related HCRU and costs, in the 6 months post-switch compared with the 6 months pre-switch.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Male; Retrospective Studies; Female; Aged; Primary Health Care; Middle Aged; Benzyl Alcohols; Chlorobenzenes; England; Drug Combinations; Administration, Inhalation; Nebulizers and Vaporizers; Bronchodilator Agents; Quinuclidines; Treatment Outcome; Muscarinic Antagonists; Androstadienes
PubMed: 38772900
DOI: 10.1136/bmjresp-2023-001890 -
Medicine May 2024This study was aimed to analyze ocular biometric changes following cycloplegia in pediatric patients with strabismus and amblyopia. Cycloplegia is routinely used to... (Observational Study)
Observational Study
This study was aimed to analyze ocular biometric changes following cycloplegia in pediatric patients with strabismus and amblyopia. Cycloplegia is routinely used to measure refractive error accurately by paralyzing accommodation. However, effects on axial length (AL), anterior chamber depth (ACD), keratometry (Km), and white-to-white distance (WTW) are not well studied in this population. This retrospective study examined 797 patients (1566 eyes) undergoing cycloplegic refraction at a Samsung Kangbuk hospital pediatric ophthalmology clinic from 2010 to 2023. Ocular biometry was measured before and after instilling 1% cyclopentolate and 0.5% phenylephrine/0.5% tropicamide. Patients were categorized by strabismus diagnosis, age, refractive error and amblyopia status. Differences in AL, ACD, Km, WTW, and refractive error pre- and post-cycloplegia were analyzed using paired t tests. ACD (3.44 ± 0.33 vs 3.58 ± 0.29 mm, P < .05) and WTW (12.09 ± 0.42 vs 12.30 ± 0.60 mm, P < .05) increased significantly after cycloplegia in all groups except other strabismus subgroup (Cs) in both parameters and youngest subgroup (G1) in ACD. Refractive error demonstrated a hyperopic shift from -0.48 ± 3.00 D to -0.06 ± 3.32 D (P < .05) in overall and a myopic shift from -6.97 ± 4.27 to -8.10 ± 2.26 in high myopia (HM). Also, AL and Km did not change significantly. In conclusion, cycloplegia impacts ocular biometrics in children with strabismus and amblyopia, significantly increasing ACD and WTW. Refractive error shifts hyperopically in esotropia subgroup (ET) and myopically in high myopia subgroup (HM), eldest subgroup (G3) relating more to anterior segment changes than AL/Km. Understanding cycloplegic effects on biometry is important for optimizing refractive correction in these patients.
Topics: Humans; Amblyopia; Strabismus; Retrospective Studies; Male; Female; Child; Biometry; Mydriatics; Child, Preschool; Refraction, Ocular; Cyclopentolate; Refractive Errors; Adolescent; Anterior Chamber; Axial Length, Eye
PubMed: 38758890
DOI: 10.1097/MD.0000000000038143 -
Molecules (Basel, Switzerland) May 2024The participation of butyrylcholinesterase (BChE) in the degradation of atropine has been recurrently addressed for more than 70 years. However, no conclusive answer has...
The participation of butyrylcholinesterase (BChE) in the degradation of atropine has been recurrently addressed for more than 70 years. However, no conclusive answer has been provided for the human enzyme so far. In the present work, a steady-state kinetic analysis performed by spectrophotometry showed that highly purified human plasma BChE tetramer slowly hydrolyzes atropine at pH 7.0 and 25 °C. The affinity of atropine for the enzyme is weak, and the observed kinetic rates versus the atropine concentration was of the first order: the maximum atropine concentration in essays was much less than . Thus, the bimolecular rate constant was found to be / = 7.7 × 10 M min. Rough estimates of catalytic parameters provided slow < 40 min and high = 0.3-3.3 mM. Then, using a specific organophosphoryl agent, echothiophate, the time-dependent irreversible inhibition profiles of BChE for hydrolysis of atropine and the standard substrate butyrylthiocholine (BTC) were investigated. This established that both substrates are hydrolyzed at the same site, i.e., S198, as for all substrates of this enzyme. Lastly, molecular docking provided evidence that both atropine isomers bind to the active center of BChE. However, free energy perturbations yielded by the Bennett Acceptance Ratio method suggest that the L-atropine isomer is the most reactive enantiomer. In conclusion, the results provided evidence that plasma BChE slowly hydrolyzes atropine but should have no significant role in its metabolism under current conditions of medical use and even under administration of the highest possible doses of this antimuscarinic drug.
Topics: Butyrylcholinesterase; Atropine; Humans; Kinetics; Hydrolysis; Molecular Docking Simulation; Models, Molecular
PubMed: 38731631
DOI: 10.3390/molecules29092140 -
BMC Chemistry May 2024In the investigation of active ingredients from natural products, current technologies relying on drug-target affinity recognition analysis face significant challenges....
In the investigation of active ingredients from natural products, current technologies relying on drug-target affinity recognition analysis face significant challenges. This is primarily due to their limited specificity and inability to provide downstream pharmacodynamic information, such as agonistic or antagonistic activity. In this study, a two-point method was developed by immobilizing M3 acetylcholine receptor (M3R) through the combination of the conformation-specific peptide BJ-PRO-13a and the HaloTag trap system. We systematically assessed the specificity of the immobilized M3R using known M3R antagonists (pirenzepine and atropine) and agonists (cevimeline and pilocarpine). By frontal analysis and nonlinear chromatography, the performance of immobilized M3R was evaluated in terms of binding kinetics and thermodynamics of four drugs to the immobilized M3R. Additionally, we successfully identified two M3R antagonists within an extract from Daturae Flos (DF), specifically hyoscyamine and scopolamine. Our findings demonstrate that this immobilization method effectively captures receptor-ligand binding interactions and can discern receptor agonists from antagonists. This innovation enhances the efficiency of receptor chromatography to determine binding-affinity in the development of new drugs, offering promise for the screening and characterization of active compounds, particularly within complex natural products.
PubMed: 38702791
DOI: 10.1186/s13065-024-01198-z -
PloS One 2024We conducted a systematic evaluation of the therapeutic efficacy and complications of tolterodine and α-adrenergic receptor blockers in alleviating ureteral... (Meta-Analysis)
Meta-Analysis Comparative Study
Comparison of the efficacy and complications of tolterodine and α-adrenergic receptor blockers in improving ureteral stent-related symptoms: A systematic review and meta-analysis.
OBJECTIVE
We conducted a systematic evaluation of the therapeutic efficacy and complications of tolterodine and α-adrenergic receptor blockers in alleviating ureteral stent-related symptoms.
METHODS
Until August 2023, we conducted a comprehensive literature search on PubMed, Embase, Web of Science, and Cochrane Library to identify randomized controlled trials evaluating the efficacy and complications of tolterodine and α-adrenergic receptor blockers in treating ureteral stent-related symptoms. Two reviewers independently screened studies and extracted data. The scores from various domains of the Ureteral Stent Symptom Questionnaire (USSQ) were summarized and compared, and statistical analysis was performed using RevMan 5.4.0 software.
RESULTS
A total of 8 studies met the inclusion criteria for our analysis. These studies were conducted at different centers. All studies were randomized controlled trials, involving a total of 487 patients, with 244 patients receiving α-adrenergic receptor blockers and 243 patients receiving tolterodine. The results showed that tolterodine demonstrated significantly better improvement in body pain (MD, 1.56; 95% CI [0.46, 2.66]; p = 0.005) (MD, 0.46; 95% CI [0.12, 0.80]; p = 0.008) (MD, 3.21; 95% CI [1.89, 4.52]; p = 0.00001) among patients after ureteral stent placement compared to α-adrenergic receptor blockers at different time points. Additionally, at 4 weeks, tolterodine showed superior improvement in general health (MD, 0.15; 95% CI [0.03, 0.27]; p = 0.01) and urinary symptoms (MD, 1.62; 95% CI [0.59, 2.66]; p = 0.002) compared to α-adrenergic receptor blockers, while at 6 weeks, tolterodine showed better improvement in work performance (MD, -1.60; 95% CI [-2.73, -0.48]; p = 0.005) compared to α-adrenergic receptor blockers. Additionally, the incidence of dry mouth (RR, 4.21; 95% CI [1.38, 12.87]; p = 0.01) is higher with the use of tolterodine compared to α-adrenergic receptor blockers. However, there were no significant statistical differences between the two drugs in other outcomes.
CONCLUSION
This meta-analysis suggests that tolterodine is superior to α-adrenergic receptor blockers in improving physical pain symptoms after ureteral stent placement, while α-adrenergic receptor blockers are more effective than tolterodine in enhancing work performance. Additionally, the incidence of dry mouth is higher with the use of tolterodine compared to α-adrenergic receptor blockers. However, higher-quality randomized controlled trials are needed to further investigate this issue.
Topics: Tolterodine Tartrate; Humans; Stents; Adrenergic alpha-Antagonists; Ureter; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 38701097
DOI: 10.1371/journal.pone.0302716 -
American Journal of Physiology. Heart... May 2024Activation of the vagus nerve mediates cardioprotection and attenuates myocardial ischemia/reperfusion (I/R) injury. In response to vagal activation, acetylcholine (ACh)...
BACKGROUND
Activation of the vagus nerve mediates cardioprotection and attenuates myocardial ischemia/reperfusion (I/R) injury. In response to vagal activation, acetylcholine (ACh) is released from the intracardiac nervous system (ICNS) and activates intracellular cardioprotective signaling cascades. Recently, however, a non-neuronal cholinergic cardiac system (NNCCS) in cardiomyocytes has been described as an additional source of ACh.
AIM
To investigate whether the NNCCS mediates cardioprotection in absence of vagal and ICNS activation. For that, we used a reductionist approach of isolated adult rat ventricular cardiomyocytes in absence of neuronal cells with hypoxic preconditioning (HPC) as protective stimulus.
METHODS
Adult rat ventricular cardiomyocytes were isolated, absence of neuronal cells was confirmed, HPC was induced by 10/20 min hypoxia/reoxygenation (H/R) before subjection to 30/5 min H/R to simulate I/R injury. Cardiomyocyte viability was assessed by trypan blue staining. Intra- and extracellular ACh was quantified using liquid chromatography-coupled mass spectrometry at baseline, after HPC, after hypoxia, and after reoxygenation, respectively. In a subset of experiments, muscarinic/nicotinic ACh receptor (mAChR/nAChR) antagonists were added during HPC or during H/R.
RESULTS
Cardiomyocyte viability at baseline (69±4%) was reduced by H/R (10±3%). With HPC cardiomyocyte viability was preserved after H/R (25±6%). Intra- and extracellular ACh increased during hypoxia, HPC further increased both intra- and extracellular ACh (from 0.9±0.7 to 1.5±1.0 nmol/mg; from 0.7±0.6 to 1.1±0.7 nmol/mg). Addition of mAChR and nAChR antagonists during HPC had no impact on HPC´s protection, however protection was abrogated when antagonists were added during H/R (cardiomyocyte viability after H/R: 23±5%; 13±4%).
CONCLUSION
Activation of the NNCCS is involved in cardiomyocyte protection: HPC increases intra- and extracellular ACh during H/R, and m-/nAChRs are causally involved in HPC´s cardiomyocyte protection during H/R. The interplay between upstream ICNS activation and the NNCCS activation to myocardial cholinergic metabolism and cardioprotection needs to be investigated in future studies.
PubMed: 38700468
DOI: 10.1152/ajpheart.00211.2024 -
JAMA Psychiatry May 2024A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents....
IMPORTANCE
A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia.
OBJECTIVE
To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia.
DESIGN, SETTING, AND PARTICIPANTS
EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023.
INTERVENTIONS
Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks.
MAIN OUTCOMES AND MEASURES
The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated.
RESULTS
A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups.
CONCLUSIONS AND RELEVANCE
Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04738123.
PubMed: 38691387
DOI: 10.1001/jamapsychiatry.2024.0785