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Introduction and hypothesis: This study was aimed at determining the effect of sugammadex versus a combination of glycopyrrolate and neostigmine (GN) for neuromuscular reversal blockage on transient postoperative urinary retention (TPOUR) in patients undergoing a laparoscopic and robot-assisted laparoscopic hysterectomy. Methods: We conducted a retrospective cohort study in patients undergoing a laparoscopic or robotic hysterectomy between February 2017 and December 2021. Patients with and without concomitant procedures were included. Demographics and perioperative data were extracted from the patient's medical record. Before discharge, all patients were required to spontaneously void and have a post-void residual of less than 150 ml. Results: We identified 500 patients and 485 were included in the final analysis. We had 319 subjects who received sugammadex and 166 GN combination. Both groups had overall similar demographics and perioperative characteristics. Most patients had a conventional laparoscopy procedure (391 [82.5%]) compared with robotic (83 [17.5%]). Patients who received GN were significantly more likely to be discharged home with an indwelling catheter (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.09—3.05). After adjusting for perioperative medications and sling implantation during the surgery a logistic regression model continued to demonstrate that patients who received GN had significantly higher odds of being discharged with a catheter (OR, 1.79; 95% CI, 1.03–3.12). Conclusions: Our findings suggest that sugammadex decreases the odds of TPOUR after laparoscopic hysterectomies with and without slings compared with the combination of GN. Additional prospective trials are required to confirm this finding. [ABSTRACT FROM AUTHOR]

Background: Postoperative ileus (POI) is a common complication following colorectal surgery and is mediated in part by the cholinergic anti-inflammatory pathway (CAIP). Neostigmine (acetylcholinesterase inhibitor), co-administered with glycopyrrolate, is frequently given for neuromuscular reversal before tracheal extubation and modulates the CAIP. An alternative reversal agent, sugammadex (selective rocuronium or vecuronium binder), acts independently from the CAIP. The aim of our study was to assess the impact of neuromuscular reversal agents used during anaesthesia on gastrointestinal recovery. Methods: Three hundred thirty-five patients undergoing elective colorectal surgery at the Royal Adelaide Hospital between January 2019 and December 2021 were retrospectively included. The primary outcome was GI-2, a validated composite measure of time to diet tolerance and passage of stool. Demographics, 30-day complications and length of stay were collected. Univariate and multivariate analyses were performed. Results: Two hundred twenty-four (66.9%) patients (129 [57.6%] males and 95 [42.4%] females, median age 64 [19–90] years) received neostigmine/glycopyrrolate and 111 (33.1%) received sugammadex (62 [55.9%] males and 49 [44.1%] females, median age 67 [18–94] years). Sugammadex patients achieved GI-2 sooner after surgery (median 3 (0–10) vs. 3 (0–12) days, p = 0.036), and reduced time to first stool (median 2 (0–10) vs. 3 (0–12) days, p = 0.035). Rates of POI, complications and length of stay were similar. On univariate analysis, POI was associated with smoking history, previous abdominal surgery, colostomy formation, increased opioid use and postoperative hypokalaemia (p < 0.05). POI was associated with increased complications, including anastomotic leak and prolonged hospital stay (p < 0.001). On multivariate analysis, neostigmine, bowel anastomoses and increased postoperative opioid use (p < 0.05) remained predictive of time to GI-2. Conclusions: Patients who received sugammadex had a reduced time to achieving first stool and GI-2. Neostigmine use, bowel anastomoses and postoperative opioid use were associated with delayed time to achieving GI-2. [ABSTRACT FROM AUTHOR]

Background: Topical anticholinergics have been reported to be effective in managing hyperhidrosis (HH) given the recent approval of glycopyrronium tosylate. Objective: This review aimed to examine the effectiveness of emerging topical anticholinergic treatments for HH and their associated adverse effects in comparison to current treatment options. Methods: We conducted a search within the PubMed and Embase databases for current and emerging topical anticholinergic treatments for primary HH. Results: The topical anticholinergics that have been recently investigated for use in HH include glycopyrrolate, oxybutynin, sofpironium bromide, and umeclidinium. The only agent currently FDA approved is glycopyrrolate. Conclusion: Knowledge of topical anticholinergic treatment options is important for patient care when managing HH. This review shows that while available safety data thus far are limited, emerging topical anticholinergics pose minimal known human risks. [ABSTRACT FROM AUTHOR]

Introduction: Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD.Methods: A systematic literature review (October 2015-November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented.Results: The NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV1 versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 μg, glycopyrronium 50 μg, glycopyrronium 18 μg, tiotropium 18 μg and salmeterol 50 μg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation.Conclusion: UMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV1 at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments. [ABSTRACT FROM AUTHOR]

Pharyngocutaneous fistula (PCF) after laryngectomy occurs when there is a failure in the pharyngeal repair resulting in a salivary leak (Dedivitis et al. in Acta Otorhinolaryngol Ital 27(1):2–5, 2007). In the post-operative period this complication is not only a challenge to the surgeon but also distressing to the patient and his family. We conducted a retrospective cum prospective study, to research the effect of starting prophylactic glycopyrrolate intravenous injection in total laryngectomy. Fifty patients underwent total laryngectomy with modified radical neck dissection over a period of 5 years by the trainee otolaryngologists. Of these 25 patients were started on glycopyrrolate for 7 post-operative days. And 25 control patients, who were not given glycopyrrolate. All the patients were observed for evidence of PCF. Of the total 50 patients, only 1 patient in study group and 12 patients in the control group developed PCF. This was statistically significant (p value 0.0039). Tumor stage, site, and gender were found to have no statistically significant correlation with development of PCF. The prophylactic administration of glycopyrrolate was found to reduce the odds of development of PCF in total laryngectomy cases. There was associated blurring of vision and constipation amongst the cases subjects, which was only transient with complete recovery on cessation of drug. [ABSTRACT FROM AUTHOR]

Introduction: Lung hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with activity limitation, impaired cardiac output, and mortality. Several studies have demonstrated that long-acting muscarinic antagonists (LAMAs) delivered by dry powder inhalers can promote lung deflation; however, the potential of nebulized LAMAs on improving hyperinflation in COPD is currently unknown. Methods: This single-center, randomized, double-blind, two-way crossover study (NCT04155047) evaluated the efficacy of a single dose of nebulized LAMA [glycopyrrolate (GLY) 25 µg] versus placebo in patients with COPD and lung hyperinflation. Patients with moderate-to-severe COPD and a residual volume (RV) ≥ 130% of predicted normal were included. The primary endpoint was changed from baseline in RV at 6 h post-treatment. Other endpoints included changes from baseline in spirometric and plethysmographic measures up to 6 h post-treatment. Results: A total of 22 patients (mean pre-bronchodilator RV, 153.7% of predicted normal) were included. The primary objective of the study was not met; the placebo-adjusted least squares (LS) mean [95% confidence interval (CI) change from baseline in RV with GLY at 6 h post-treatment was − 0.323 l (− 0.711 to 0.066); p = 0.0987]. A post hoc evaluation of the primary analysis was conducted after excluding a single statistical outlier; substantial improvements in RV with GLY compared with placebo was observed after exclusion of this outlier [placebo-adjusted LS mean change from baseline (95% CI) in RV was − 0.446 l (− 0.741 to − 0.150)]. Improvements from baseline were also observed with GLY compared with placebo in spirometric and plethysmographic measures up to 6 h post-treatment. GLY was generally safe, and no new safety signals were detected. Conclusions: This is the first study to evaluate the effect of nebulized GLY on lung deflation. Nebulized GLY resulted in marked improvements in RV up to 6 h post-treatment, compared with placebo. Improvements were also observed with GLY in spirometric and plethysmographic parameters of lung function. Trial Registration: ClinicalTrials.gov identifier, NCT04155047. [ABSTRACT FROM AUTHOR]

Background and Objective: In asthma, symptom control is a primary goal that is not consistently met with available treatment options. The first commercially available fixed-dose combination in a single inhaler of a long-acting beta-agonist (indacaterol, IND), an inhaled corticosteroid (mometasone furoate, MF) and a long-acting muscarinic antagonist (glycopyrronium, GLY) has shown promising clinical results in phase III trials. The aim of the present study is to evaluate the cost-utility of IND/GLY/MF fixed-dose combination relative to a combination of salmeterol/fluticasone and tiotropium or salmeterol/fluticasone or IND/MF in adult patients with asthma, from the Italian Health Service (NHS) perspective. Methods: A two-state and 4-week cycle Markov model was used to estimate lifetime clinical outcomes and costs. Patients entered the model in stable disease and could experience a non-fatal exacerbation event. The exacerbation rate is dependent upon the therapy a patient is receiving, as per the IND/GLY/MF clinical trials. The impact of each type of exacerbation is accounted by applying a utility decrement, obtained from the literature, and a treatment cost. Utility values were obtained from the EQ-5D questionnaires in the IND/GLY/MF clinical trials. Lifetime costs considered in the analysis were drugs and exacerbation management. Probabilistic sensitivity analyses were carried out, with the aim of evaluating the impact of uncertainty on input parameters. Results: IND/GLY/MF is associated with a higher quality of life [+ 0.25 quality-adjusted life-year (QALY)] than salmeterol/fluticasone plus tiotropium, with an incremental cost of −€3213.90. The incremental cost-utility ratio indicates dominance. At a threshold of €5000 per QALY, IND/GLY/MF has nearly a 100% probability of being cost effective. IND/GLY/MF is associated with a higher quality of life (+ 0.21 QALY) than salmeterol/fluticasone, with an incremental cost of €2547.76. Incremental cost-utility ratio results in €11,897 per QALY. At a threshold of €20,000 per QALY, IND/GLY/MF has nearly a 100% probability of being cost effective. IND/GLY/MF is associated with a higher quality of life (+ 0.34 QALY) than IND/MF, with an incremental cost of €4745.91. Incremental cost-utility ratio results in €14,088 per QALY. At a threshold of €20,000 per QALY, IND/GLY/MF has nearly a 100% probability of being cost effective. Conclusion: The results indicate that IND/GLY/MF is cost effective against the considered comparators in a cohort representative of adult patients with asthma in Italy. [ABSTRACT FROM AUTHOR]

Budesonide/glycopyrronium/formoterol (BREZTRI AEROSPHERE™; TRIXEO AEROSPHERE™) is an inhaled fixed-dose combination of the inhaled corticosteroid (ICS) budesonide, the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide and the long-acting β2-agonist (LABA) formoterol fumarate approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD). It is delivered via a pressurized metered-dose Aerosphere inhaler and is formulated using co-suspension delivery technology. In two pivotal phase III trials of 24–52 weeks' duration, budesonide/glycopyrronium/formoterol reduced the rates of moderate/severe COPD exacerbations and improved lung function to a greater extent than budesonide/formoterol and/or glycopyrronium/formoterol. Budesonide/glycopyrronium/formoterol also demonstrated beneficial effects on dyspnoea, rescue medication requirements and health-related quality of life (HR-QOL), and reduced the risk of all-cause mortality. Budesonide/glycopyrronium/formoterol was generally well tolerated, with the tolerability profile being generally similar to that of the individual components. Budesonide/glycopyrronium/formoterol provides a useful and convenient option for the maintenance treatment of COPD, including for patients whose disease is inadequately controlled with dual ICS/LABA or LAMA/LABA therapy. Plain Language Summary: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease that is characterized by chronic airflow limitation and persistent respiratory symptoms. A step-up treatment approach combining an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA) may provide clinical benefits in patients with COPD whose disease is inadequately controlled by dual therapies (ICS/LABA or LAMA/LABA). Budesonide/glycopyrronium/formoterol (BREZTRI AEROSPHERE™; TRIXEO AEROSPHERE™) is a fixed-dose ICS/LAMA/LABA combination approved for the maintenance treatment of COPD. It is administered twice daily via a single pressurized metered-dose Aerosphere inhaler. Patients with moderate to very severe COPD receiving budesonide/glycopyrronium/formoterol had fewer moderate or severe COPD exacerbations and improved lung function, respiratory symptoms and quality of life compared with patients receiving ICS/LABA or LAMA/LABA therapy. The risk of death was reduced compared with that of patients receiving LAMA/LABA therapy. Budesonide/glycopyrronium/formoterol was generally well tolerated, with similar rates of adverse events to dual therapy. Budesonide/glycopyrronium/formoterol is a useful and convenient option for the maintenance treatment of COPD. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease is a major cause of morbidity and mortality worldwide. Combining an inhaled anticholinergic and a β2-agonist are a convenient way of delivering treatment, obtaining better lung function and improved symptoms. We aimed to develop and validate a reliable HPLC method for the simultaneous determination of the anticholinergics; ipratropium bromide, glycopyrronium bromide and tiotropium bromide in addition to the β2-agonists; bambuterol hydrochloride, formoterol fumarate and indacaterol maleate. The chromatographic separation was achieved on a Phenomenex Luna phenyl-hexyl (250 × 4.6 mm i.d., 5 μm) column and a mobile phase composed of 0.2% phosphoric acid (pH 3.0)/methanol/acetonitrile (66:12:22, v/v/v). The analysis was performed at a flow rate of 1 mL/min with UV detection at 210 nm. Method validation showed that calibration curves were linear within the range from 0.5 to 30.0 μg/mL with a correlation coefficient > 0.998. Intraday and interday precision and accuracy evaluated by relative standard deviation were lower than 2%. The limits of detection were in the ranges of 0.037–0.152 μg/mL. The developed method which is rapid, sensitive and highly efficient was applied for the analysis of the six bronchodilators in single and combined formulations saving money, solvents and chemicals. In addition, the environmental impact of the proposed method was evaluated using a suitable analytical Eco-Scale. [ABSTRACT FROM AUTHOR]

In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 μg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies. [ABSTRACT FROM AUTHOR]

Background: Tecfidera® (dimethyl fumarate [DMF]) is an approved product for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate (MMF) is the only active metabolite of DMF and is responsible for its therapeutic efficacy.Objective: The objective of this study was to determine whether two Bafiertam™ capsules each containing 95 mg of MMF is bioequivalent to one Tecfidera® capsule containing 240 mg of DMF, a prodrug of MMF.Methods: This was a single-dose, open-label, randomized, two-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Fifty healthy subjects were randomized to receive a single dose of the test drug MMF 190 mg as 2 × 95 mg delayed-release capsules or the reference drug DMF 240 mg as a 1 × 240-mg delayed-release capsule. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. The pharmacokinetic parameters of MMF were calculated including maximum observed concentration, time to reach maximum observed concentration, apparent half-life of the drug in plasma, AUC0-t which is the area under the plasma concentration-time curve (AUC) from time zero (dosing time) to the last time point, t, with measurable analyte concentration, and AUC0-inf, which is AUC0-t plus the extrapolated AUC from time t to infinity.Results: The geometric least-squares mean ratios (90% confidence interval) of the test drug MMF vs the reference drug DMF were 96.80% (92.18-101.64), 96.35% (91.81-101.12), and 104.84% (95.54-115.05) for AUC0-t, AUC0-inf, and maximum observed concentration, respectively. Two capsules of Bafiertam™ was safe and generally well tolerated. The most common adverse event for both products was flushing, 60% and 51%, for Bafiertam™ and Tecfidera®, respectively.Conclusions: Based on the statistical analysis results of the pharmacokinetic parameters of MMF, a single oral dose of two Bafiertam™ DR 95 mg capsules is bioequivalent to a single oral dose of one Tecfidera® DR 240 mg capsule.Clinical Trial Registration: This study was retrospectively registered with ClinicalTrials.gov (NCT04570670) on 30 September, 2020. [ABSTRACT FROM AUTHOR]

Background: Glycopyrronium tosylate (GT; Qbrexza® [glycopyrronium] cloth, 2.4%) is a topical anticholinergic approved (USA) for primary axillary hyperhidrosis in patients aged ≥ 9 years. Objective: The objective of this study was to compare the pharmacokinetics and safety of GT to oral glycopyrrolate (phase I study) and assess the relationship between glycopyrronium pharmacokinetics and anticholinergic-related adverse events or efficacy with population pharmacokinetics using data from two phase II studies. Methods: In the phase I study, study staff applied GT to axillae of patients with primary axillary hyperhidrosis (aged 9–65 years) once daily (5 days); oral glycopyrrolate was administered to healthy adults (aged 18–65 years) every 8 hours (15 days). In the phase II studies (NCT02016885 [20 December, 2013], NCT02129660 [2 May, 2014]), adults with primary axillary hyperhidrosis applied topical glycopyrronium (0.8–3.2%) or vehicle to axillae once daily (4 weeks). Pharmacokinetic and adverse event data were collected in all studies. Results: Glycopyrronium pharmacokinetic parameters were similar between adult and pediatric patients treated with GT; there was no evidence of accumulation. Systemic absorption of glycopyrronium was lower with GT vs oral glycopyrrolate. No anticholinergic-related adverse events occurred with GT in the phase I study, while dry mouth and nasal dryness occurred with oral glycopyrrolate; anticholinergic adverse events occurred in the phase II studies. In the population pharmacokinetic analysis, frequency/severity of anticholinergic-related adverse events increased with higher glycopyrronium concentration; no relationship was observed between efficacy and pharmacokinetic measures. Conclusions: These studies indicate limited absorption of GT compared to oral glycopyrrolate and a low risk of anticholinergic adverse events with proper GT administration when following instructions for use (wipe each underarm once with same cloth, wash hands, avoid ocular contact). [ABSTRACT FROM AUTHOR]

Spherulites are the most common crystalline morphology and thus the visual expression of crystal structures for polymers. The diversified patterns have provided intuitive morphology probes for various crystallization behaviors, while the correlations between them are still needed to be enriched. In this work, the complicated spherulitic morphology of poly(propylene fumarate) (PPF), which is sensitive to crystallization temperature, is investigated. PPF melt, respectively, crystallizes into rough spherulites, regularly banded spherulites, and spherulites containing both two kinds of morphology at low, high, and mediate temperatures. By systematically assaying, it is clear that the growth axis along the radial direction changes from a-axis to b-axis as the crystallization temperature increases, which leads to the formation of unique crystallization-temperature-dependent spherulites. Based on detailed characterization of Fourier transform infrared spectroscopy, the packing state of the specific hydrogen bonds of "C=C-H⋯O=C-C=C" in PPF crystal lattices is determined, and furthermore, the mechanism for temperature-dependent selection of growth axes for PPF spherulites in melt is reasonably speculated. [ABSTRACT FROM AUTHOR]

Background: Chronic cerebral hypoperfusion (CCH) induced oxidative stress and inflammation is known to be implicated in the pathogenesis of vascular dementia. The nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a potential therapeutic target for neuroprotection. In the present study, we investigated the beneficial effects of dimethyl fumarate (DMF), an Nrf2 activator in an experimental model of vascular dementia. Methods: Permanent occlusion of the bilateral common carotid arteries (2-VO) was performed to induce CCH in adult male Sprague–Dawley rats. DMF (15, 30, and 60 mg/kg) was administered for 4 weeks. Cognitive performance was assessed using the Morris water maze (MWM) and novel object (NOR) tests. After behavior tests, various oxidative and inflammatory markers were assessed in the hippocampus. Results: The obtained results indicate that treatment with DMF significantly improved 2 VO-induced cognitive deficits. DMF decreased MDA (p < 0.001), protein carbonyl (PCO) contents (p < 0.001), and acetylcholinesterase (p < 0.01) activities, and inhibited inflammatory markers (TNF-α, IL-1β, NF-κβ, and COX-2) levels. Furthermore, our results showed that DMF augmented GSH (p < 0.001) levels and SOD (p < 0.05), CAT, and GSH-Px (p < 0.001) activities in the hippocampus. Nrf2 (p < 0.05) and its downstream targets HO-1 levels (p < 0.01) and NQO1 (p < 0.05) levels were also up-regulated after DMF treatment. Conclusion: Taken together, the results demonstrate that DMF could serve as a promising neuroprotective agent for treating vascular dementia. [ABSTRACT FROM AUTHOR]

Rationale: Salivary glands are highly perfused and express the prostate-specific membrane antigen (PSMA) receptor as well as the sodium—iodide symporter. As a consequence, treatment with 177Lu/225Ac-PSMA for prostate cancer or 131I for thyroid cancer leads to a high radiation dose in the salivary glands, and patients can be confronted with persistent xerostomia and reduced quality of life. Salivation can be inhibited using an antimuscarinic pharmaceutical, such as glycopyrronium bromide (GPB), which may also reduce perfusion. The primary objective of this work was to determine if inhibition with GPB could provide a considerable (> 30%) reduction in the accumulation of administered 123I or 68Ga-PSMA-11 in salivary glands. Methods: Ten patients who already received a whole-body 68Ga-PSMA-11 PET/CT scan for (re)staging of prostate cancer underwent a repeat PET/CT scan with tracer administration at 90 min after intravenous injection of 0.2 mg GPB. Four patients in follow-up after thyroid cancer, who had been treated with one round of ablative 131I therapy with curative intent and had no signs of recurrence, received 123I planar scintigraphy at 4 h after tracer administration without GPB and a repeated scan at least one week later, with tracer administration at 30 min after intramuscular injection of 0.4 mg GPB. Tracer uptake in the salivary glands was quantified on PET and scintigraphy, respectively, and values with and without GPB were compared. Results: No significant difference in PSMA uptake in the salivary glands was seen without or with GPB (Mean SULmean parotid glands control 5.57, intervention 5.72, p = 0.50. Mean SULmean submandibular glands control 6.25, intervention 5.89, p = 0.12). Three out of 4 patients showed increased 123I uptake in the salivary glands after GPB (Mean counts per pixel control 8.60, intervention 11.46). Conclusion: Muscarinic inhibition of salivation with GPB did not significantly reduce the uptake of PSMA-ligands or radioiodine in salivary glands, and can be dismissed as a potential strategy to reduce toxicity from radionuclide therapies. [ABSTRACT FROM AUTHOR]

Background: Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited. Objective: The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting. Methods: We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated. Results: Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6–41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy. Conclusions: Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies. [ABSTRACT FROM AUTHOR]

Introduction: Personalized therapy for patients with COPD requires appropriate choice of drug and delivery device. Inhalers and nebulizers vary in their drug delivery characteristics, particularly the need for passive or active patient inhalation for appropriate drug dispersal and delivery. In this in vitro analysis, we assessed the aerosol performance and drug delivery of two long-acting muscarinic antagonists, glycopyrrolate (GLY; 25 µg solution; 1 ml) and tiotropium (TIO; 18 µg powder) through their respective delivery systems: the eFlow® Closed System (CS) vibrating membrane nebulizer and the HandiHaler® dry-powder inhaler (DPI). Methods: The aerosol performances of the eFlow® CS nebulizer and the HandiHaler® were determined using the Next Generation cascade Impactor. The delivered dose of GLY and TIO was determined using different breathing patterns, which varied in tidal volume and peak inspiratory flow rate, respectively, to simulate breathing conditions ranging from normal to severe obstruction. Results: Aerodynamic particle analysis showed generally similar mass median aerodynamic diameter (MMAD, range, 3.6–4.6 µm) and fine particle fraction (FPF, range, 48.2%–63.7%) with GLY delivered using the eFlow® CS nebulizer under all breathing patterns tested. TIO, delivered via the HandiHaler®, showed variations in MMAD (range, 3.8–5.8 µm) and FPF (range, 16.1%–32.4%) under different inspiratory flow rates. The majority of GLY was deposited in stages 2–5 of the impactor, which corresponds with particle sizes in the respirable range (< 5 µm), whereas a large proportion of TIO was deposited in the throat/mouthpiece pre-separator, irrespective of test conditions. The median residual dose of GLY with eFlow® CS was notably lower compared to that of TIO with HandiHaler® (2.4%–4.4% vs. 40%–67%, respectively). Conclusions: These simulation results highlight the different deposition patterns generated by a DPI device and a vibrating membrane nebulizer, which may help inform device selection and treatment decision in COPD management. [ABSTRACT FROM AUTHOR]

Introduction: Triple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual LAMA/LABA or ICS/LABA therapy. The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 µg (BGF MDI) in COPD was compared with other ICS/LAMA/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA).Methods: A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV1), post-dose peak FEV1, and St. George's Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score. Change from baseline in rescue medication use over weeks 12-24 was also analyzed. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies.Results: Eighteen studies (n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario.Conclusion: This NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available. [ABSTRACT FROM AUTHOR]

Rosemary is a restorative plant that has numerous utilizations in traditional medicine. In this investigation, rosemary leaf extracts were examined for their antimicrobial and antioxidant activities. The antimicrobial activity was tested against 8 bacterial strains. The antioxidant feature of rosemary extract on rat testicular tissue after exposure to the electromagnetic field. Sixty adult male albino rats weighing 180–200 g (aged 2 months) were divided into six groups: control group, rosemary group (receiving rosemary extract at a dose of 5 mg/kg b.wt), EMF (2 h) group (exposed to 50 Hz and 5.4 kV per meter of magnetic field for 2 h), EMF (4 h) group (exposed to 50 Hz and 5.4 kV per meter of magnetic field for 4 h), EMF (2 h) + rosemary group (receiving both magnetic field for 2 h and extract), and EMF (4 h) + rosemary group (receiving both magnetic field for 4 h and extract). After 30 days, the rats were sacrificed, and some estimates were determined. Results exhibited that the ethanolic extract of rosemary leaves was active against pathogenic bacteria. Results also demonstrated that exposure to EMF diminished level of male hormones (e.g., follicle stimulating hormone (FSH), testosterone, and luteinizing hormone (LH)) in serum and catalase (CAT) activity remarkably and increased the malondialdehyde (MDA) levels in comparison to the control group. Signs of improvement in the male hormones, CAT activity, and MDA levels were noticed during the treatments with rosemary. Histological results showed that the rosemary extract inhibited the destructive effect of electromagnetic fields on testicular tissue. This research reveals that the ethanolic extract of rosemary has many beneficial effects that can be compelling in supporting individuals living with EMF ecological contamination. [ABSTRACT FROM AUTHOR]

Introduction: This pre-specified subgroup analysis evaluated the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) triple therapy versus corresponding dual therapies in the China subgroup of the phase III, double-blind KRONOS study in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).Methods: Patients were randomized 2:2:1:1 to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice daily for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over weeks 12-24. Secondary endpoints included symptoms, health-related quality of life, and safety. Rate of moderate/severe COPD exacerbations was an additional efficacy endpoint.Results: In the China subgroup (n = 432; 22.7% of the KRONOS population), BGF MDI demonstrated nominally significant improvements in the primary endpoint versus BFF MDI (least squares mean (LSM) difference 68 mL; P = 0.0035) and BUD/FORM DPI (LSM difference 78 mL; P = 0.0010) but not GFF MDI (LSM difference - 4 mL; P = 0.8316). BGF MDI demonstrated at least numerical improvements versus comparators in secondary lung function and symptom endpoints. BGF MDI reduced the rate of moderate/severe COPD exacerbations versus GFF MDI (rate ratio 0.41; P = 0.0030), with numerical benefits versus BFF MDI and BUD/FORM DPI. All treatments were well tolerated.Conclusions: Results demonstrated that BGF MDI showed benefits on lung function (vs inhaled corticosteroid/long-acting β2-agonist), as well as symptoms and exacerbations relative to dual therapies. Findings support BGF MDI use in Chinese patients with moderate to very severe COPD.Clinical Trial Registration: ClinicalTrials.gov NCT02497001. [ABSTRACT FROM AUTHOR]

Background: Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile.Objectives: The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing-remitting multiple sclerosis.Methods: EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing-remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability.Results: DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39-0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%).Conclusions: DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events.Clinical Trials Registration: ClinicalTrials.gov (NCT03093324). [ABSTRACT FROM AUTHOR]

The present work described the first voltammetric sensor for the estimation of indacaterol (IND) in the presence of its co-formulated drug glycopyrronium bromide. Indacaterol (IND) is used to treat chronic obstructive pulmonary disease, which is a major cause of morbidity and mortality worldwide so the quick analysis of minor concentrations of this drug is very important. Titanium(IV) oxide nanoparticles (TiO2-NPs) and the ionic liquid (IL) n-hexyl-3-methylimidazolium hexafluorophosphate were used for the new formulated carbon paste electrode. Other factors, such as the pH of the solution, the TiO2-NP concentration and the scan rate, were also optimized using cyclic voltammetry. Scanning electron microscopy, chronoamperometry and electrochemical impedance spectroscopy were utilized for determination of the character of the electrochemical sensor. Moreover, the electrochemical redox mechanism of IND at the proposed sensor was studied. Under the optimum conditions, the proposed TiO2-NP–IL–MCPE showed good linearity over a concentration range of 2.00 nM–200.00 mM using square wave voltammetry. The LOD was found to be 500 pM, indicating excellent sensitivity. Satisfactory recoveries of IND from pharmaceutical formulations, content uniformity tests and human plasma and urine were achieved, clearly revealing that the new sensor can be used in the clinical analysis of IND and in quality control laboratories. [ABSTRACT FROM AUTHOR]

Very recently, we have reported a new glucagon-like peptide-1 (GLP-1) receptor agonist, SKL-18287, (EC50: 1.2 and 0.13 nM for mouse and human, respectively) with extended in vivo half-life (T1/2: 5.8 h in rats), which is a medium-sized oligopeptide comprised of only natural l-amino acids. SKL-18287 is believed to exist in oligomeric form in vivo with a molecular weight of approximately 40,000 Da, which accounts for its extended in vivo half-life. This unique property may set SKL-18287 apart from other marketed GLP-1-based drugs. In this study, we report the pharmacological effects of SKL-18287 on type 2 diabetes mellitus (T2DM) and gastric emptying (GE) in several animal models. In intraperitoneal glucose tolerance tests, SKL-18287 lowered blood glucose level in a dose-dependent manner. Significant differences were observed between the control- and SKL-18287-treated groups at 0–1 h after the 1st and 2nd glucose loading. SKL-18287 glucose-lowering effect was virtually the same for both glucose loadings. In non-obese type 2 diabetic Goto-Kakizaki (GK) rats, SKL-18287, given a range of 6–12 nmol/kg/daily, produced a robust beneficial effect on glycohemoglobin (GHb). As for liraglutide, the 8 nmol/kg/daily dose failed to produce any significant effect on GHb. SKL-18287 had more potent therapeutic effects than liraglutide in GK rats, while it had marginal effect on GE. These results suggested that SKL-18287 was more pancreas-selective than liraglutide and would mitigate gastrointestinal adverse effects such as nausea and vomiting. SKL-18287 might be useful for non-obese patients with T2DM. [ABSTRACT FROM AUTHOR]

Background and Objective: Despite integrase strand transfer inhibitor (INSTI)-containing regimens now being considered a preferred option for both initial therapy and switching strategies in virologically suppressed patients, their effects on lymphocyte phenotypes and functions in the course of effective combination antiretroviral therapy (cART) are still unclear. Thus, we investigated the effect of a 24-week elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/c/FTC/TDF) regimen on the T cell compartment and HIV reservoirs in HIV-infected patients switching from a suppressive protease inhibitor-based regimen. Methods: Thirty HIV-positive patients receiving suppressive tenofovir disoproxil fumarate/emtricitabine (TDF + FTC) (for a median of 5 years) in association with either darunavir/ritonavir (DVR/r) (47%) or atazanavir/ritonavir (ATV/r) (53%) were followed up for 24 weeks after switching to EVG/c/FTC/TDF. At baseline (week 0 [W0]) and after 12 (W12) and 24 (W24) weeks we analyzed HLA-DR (human leukocyte antigen–DR isotype)/CD38/Ki67/CCR7 (C-C chemokine receptor type 7)/CD45RA/CD127/PD-1 (programmed cell death-1) on CD4/CD8, interferon (IFN)-γ/interleukin (IL)-2 after HIV/Staphylococcal enterotoxin B (SEB) exposure (flow cytometry); total, integrated, and unintegrated HIV-DNA; and residual low-level HIV viremia (quantitative polymerase chain reaction [qPCR]). Results: While EVG/c/FTC/TDF introduction resulted in a stable CD4+ and CD8+ count, residual low-level HIV-RNA viremia, and HIV reservoirs, we observed a significant reduction in both activated CD4+ (p = 0.016) and CD8+ (p = 0.048) T cells, coupled with an increase in IL-2 and IFN-γ release by CD4+ and CD8+ effector memory T cells, and a decrease in cytokine production by terminally differentiated CD8+ T cells following SEB exposure. Furthermore, the magnitude of the reduction of activated HLA-DR + CD38 + CD8+ T cells (r = − 0.63, p = 0.014) inversely correlates with the amount of total HIV-DNA at W24. Conclusions: Our data show a favorable effect of EVG/c/FTC/TDF switch to preserve immune activation-driven damage to T cell homeostasis, restore the multifunctional properties of effector T cells, and possibly contain cell-associated HIV viral burden in already virologically suppressed patients. [ABSTRACT FROM AUTHOR]

Glycopyrronium/formoterol (Bevespi Aerosphere®) is a fixed-dose combination of the long-acting muscarinic antagonist glycopyrronium bromide and the long-acting β2-agonist formoterol fumarate delivered via a pressurized metered dose inhaler (pMDI) and formulated using co-suspension delivery technology. It is approved in the USA and EU for use as maintenance treatment in patients with chronic obstructive pulmonary disease (COPD) and in Japan to relieve symptoms in patients with COPD. In the PINNACLE trials in patients with moderate to very severe COPD, glycopyrronium/formoterol was associated with significantly greater improvements in lung function than its monocomponents and placebo at 24 weeks and its monocomponents and open-label tiotropium over 52 weeks. In the AERISTO trial, glycopyrronium/formoterol was non-inferior to umeclidinium/vilanterol dry powder inhaler for peak change in forced expiratory volume in 1 s (FEV1) within 2 h postdose, but not for the change in morning predose trough FEV1, over 24 weeks. Glycopyrronium/formoterol was generally well tolerated in patients with moderate to very severe COPD, with most adverse events (AEs) being of mild or moderate severity. Thus, glycopyrronium/formoterol pMDI formulated using co-suspension delivery technology is a useful new addition that extends treatment options for patients with COPD. [ABSTRACT FROM AUTHOR]

Background: Glycopyrronium tosylate is a topical anticholinergic approved in the USA for primary axillary hyperhidrosis in patients aged ≥ 9 years (Qbrexza™ [glycopyrronium] cloth, 2.4%). Objective: This 44-week open-label extension study assessed glycopyrronium tosylate safety and descriptive efficacy in patients completing one of two, phase III, double-blind, vehicle-controlled, 4-week trials (NCT02530281; NCT02530294). Methods: Patients aged ≥ 9 years with primary axillary hyperhidrosis were randomized 2:1 (glycopyrronium tosylate: vehicle, once daily) in the double-blind trials. Completers could receive open-label glycopyrronium tosylate for up to an additional 44 weeks. Treatment-emergent adverse events and local skin reactions were assessed. Descriptive efficacy assessments were gravimetrically measured sweat production, Hyperhidrosis Disease Severity Scale responder rate (≥ 2 grade improvement), and Dermatology Life Quality Index/children's Dermatology Life Quality Index. Results: Of 651 patients completing the double-blind trials, 564 (86.6%) entered the open-label extension; 550 were analyzed. Most patients experiencing treatment-emergent adverse events had mild or moderate events (> 90%). Discontinuation because of treatment-emergent adverse events remained low and relatively stable, with a cumulative rate of 8.0% (44/550) over 44 weeks. Common treatment-emergent adverse events (> 5%) were dry mouth (16.9%), vision blurred (6.7%), application-site pain (6.4%), nasopharyngitis (5.8%), and mydriasis (5.3%). Most patients (67.5%) had no local skin reactions; those occurring were predominantly mild/moderate. Glycopyrronium tosylate efficacy was maintained throughout the trial; at week 44, the Hyperhidrosis Disease Severity Scale responder rate was 63.2%, and improvements from baseline (double blind) in sweat production were − 71.3% and 8.7 ± 6.2/6.2 ± 4.9 for Dermatology Life Quality Index/children's Dermatology Life Quality Index. Conclusions: Daily long-term application of glycopyrronium tosylate for up to 48 weeks (double blind plus open label) was generally well tolerated and efficacy was maintained. No new safety signals emerged. Trial Registry: Clinicaltrials.gov NCT02553798. [ABSTRACT FROM AUTHOR]

Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This update presents recent changes and innovation in the treatment of hypersalivation. Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, saliva aspiration, and oro-motor deficiencies. Clinical screening tools and diagnostics such as fiberoptic endoscopic evaluation of swallowing generate important data on therapy selection and control. Many cases profit from swallowing therapy programmes to activate compensation mechanisms as long compliances are given. In children with hypotonic oral muscles, oral stimulation plates can induce a relevant symptom release because of the improved lip closure. The pharmacologic treatment improved for pediatric cases as glycopyrrolate fluid solution (Sialanar®) is now indicated for hypersalivation within the EU. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long-lasting saliva reduction. Here, a phase III trial is completed for incobotulinum toxin A and, in the US, is indicated for the treatment of adult patients with chronic hypersalivation. Surgical treatment should be reserved for isolated cases. External radiation is judged as a safe and effective therapy when using modern 3D techniques to minimize tissue damage. Therapy effects and symptom severity have to be followed, especially in cases with underlying neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Dimethyl fumarate (DMF) is an oral, disease-modifying agent for the treatment of relapsing–remitting multiple sclerosis (RRMS). However, details regarding its mode of action are still emerging. It is believed that the mode of action of DMF involves both nuclear factor erythroid-derived 2-related factor (Nrf2)–dependent and independent pathways, which lead to an anti-inflammatory immune response due to type II myeloid cell and Th2 cell differentiation and neuroprotection. In this review, we will focus on the molecular and signaling effects of DMF that lead to changes in peripheral immune cell composition and function, alteration in CNS cell-specific functions, and effect on the blood-brain barrier. [ABSTRACT FROM AUTHOR]

Bisoprolol fumarate is a beta blocker-type drug substance which has been well known for several decades. However, no relevant data can be found in the literature about its crystal polymorphism. The purpose of this paper was to present two anhydrous forms (Form I and Form II) and a hydrate of bisoprolol fumarate substance. Crystalline forms were studied by various solid-state analytical methods: Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS) and thermoanalytical methods (thermogravimetry and differential scanning calorimetry). Thermodynamic stability and solubility of the presented polymorphs were also investigated. Both FT-IR and XRPD methods were found to be suitable for the characterization of the different crystal structures. Thermoanalytical measurements showed that (1) Form I and Form II own clearly different melting points and (2) both Form II and hydrate forms can transform into Form I at higher temperature values. Results of the DVS measurements prove that both Form I and Form II became metastable under extremely humid conditions (> 80% RH) and converted into the hydrate. Thermodynamic stability studies showed that Form I and Form II polymorphs are in enantiotropic relationship with an enantiotropic point at about 40-45 °C. Solubility studies indicated that all of the prepared forms are highly soluble, and no difference was found between them. Considering the recommendations of the corresponding International Conference of Harmonization guideline, it can be stated that no specification is required for crystal polymorphism in case of this substance. [ABSTRACT FROM AUTHOR]

The development of a multistep continuous-flow process, consisting of a direct α-lithiation stage and subsequent hydroxylation by aerobic oxidation, is reported. The protocol is applied to the synthesis of cyclopentylmandelic acid (CPMA), the main building block for the anticholinergic glycopyrronium bromide (glycopyrrolate). We demonstrate the safe utilization of organolithium reagents and molecular oxygen in combination by using a continuous-flow protocol. The first stage involves the formation of a di-lithium enolate intermediate, which was either pre-formed in batch or formed in flow by using n-hexyllithium as a cost-effective and industrially safe base. The subsequent hydroxylation stage utilized molecular oxygen under homogeneous and mild conditions (atmospheric pressure and room temperature) to give the desired product. A diluted form of oxygen gas, consisting of less than 10% O2 in N2 ("synthetic air"), is used in pharmaceutical batch manufacturing to effectively address safety concerns when handling molecular oxygen. The telescoped flow process afforded the target intermediate in 65% solution NMR yield (50% isolated yield after re-crystallization). The continuous-flow process opens up new opportunities for the manufacture of CPMA, with a protocol which can safely handle pure O2, and compares favorably with existing Grignard-based batch processes.ᅟ [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacy and safety of two long-acting dual bronchodilator combinations: indacaterol/glycopyrrolate (IND/GLY) versus umeclidinium/vilanterol (UMEC/VI). Methods: Studies A2349 and A2350 were replicate, randomized, double-blind, double-dummy, active-controlled, cross-over studies in patients with moderate-to-severe COPD. Patients were randomized to sequential 12-week treatments of twice-daily IND/GLY 27.5/15.6 μg and once-daily UMEC/VI 62.5/25 μg, each separated by a 3-week washout. The primary objective was to demonstrate non-inferiority of IND/GLY compared with UMEC/VI in terms of the 24-h forced expiratory volume in 1 s profile at week 12 (FEV AUC). Rescue medication use, symptom control, and safety were assessed throughout. Results: Both treatments delivered substantial bronchodilation over 12 weeks, with improvements in FEV AUC at week 12 of 232 and 185 mL for IND/GLY, and 244 and 203 mL with UMEC/VI in Studies A2349 and A2350, respectively. The primary efficacy objective of non-inferiority of IND/GLY relative to UMEC/VI was not met as the lower bound of the confidence interval for the LS treatment comparison was below the pre-specified non-inferiority margin of −20 mL in both studies: −26.9 and −34.2 mL, respectively (LS mean between-treatment differences: −11.5 and −18.2 mL). Both drugs were well tolerated, with AE profiles consistent with their respective prescribing information. Conclusions: IND/GLY and UMEC/VI provided clinically meaningful and comparable bronchodilation. Non-inferiority of IND/GLY to UMEC/VI could not be declared although between-treatment differences were not clinically relevant. The data support the use of IND/GLY as an efficacious and well tolerated treatment option in patients with COPD. (ClinicalTrials.gov NCT02487446 and NCT02487498) [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. A combination of indacaterol maleate with glycopyrronium bromide has recently been approved as a once-daily maintenance therapy in patients with COPD. The very low dose (µg level/capsule) renders the analysis of such products challenges. This study reports for the first time about HPLC method for the quality control of such combination and it is a stability indicating at the same time. Results: A rapid, simple, precise and reproducible HPLC method was developed and validated for simultaneous determination of indacaterol maleate and glycopyrronium bromide using tenoxicam as an internal standard. The chromatographic separation was achieved on an onyx monolithic C18 column (100 x 4.6 mm) using a mobile phase consisting of acetonitrile and 30 mM phosphate buffer (pH 3.5) (30:70, v/v), run at a flow rate of 2 mL/min with UV detection at 210 nm. The total analysis time was less than 3 min. The HPLC method was validated for linearity, limits of detection and quantitation, precision, accuracy, system suitability and robustness. Calibration curves were obtained in the concentration ranges of 1-44 µg/mL for indacaterol maleate and 0.5-20 µg/mL for glycopyrronium bromide. Stability tests were done through exposure of the analyte solution for different stress conditions and the results indicate no interference of degradants with HPLC method. Conclusions: The method was successfully applied for the quantitative analysis of indacaterol maleate and glycopyrronium bromide both individually and in a combined pharmaceutical inhaler capsules to support the quality control and to assure the therapeutic efficacy of the two drugs. The simple procedure involved in sample preparation and the short run-time added the important property of high throughput to the method. [ABSTRACT FROM AUTHOR]

Asthma is a complex disease where many patients remain symptomatic despite guideline-directed therapy. This suggests an unmet need for alternative treatment approaches. Understanding the physiological role of muscarinic receptors and the parasympathetic nervous system in the respiratory tract will provide a foundation of alternative therapeutics in asthma. Currently, several long-acting muscarinic antagonists (LAMAs) are on the market for the treatment of respiratory diseases. Many studies have shown the effectiveness of tiotropium, a LAMA, as add-on therapy in uncontrolled asthma. These studies led to FDA approval for tiotropium use in asthma. In this review, we discuss how the neurotransmitter acetylcholine itself contributes to inflammation, bronchoconstriction, and remodeling in asthma. We further describe the current clinical studies evaluating LAMAs in adult and adolescent patients with asthma, providing a comprehensive review of the current known physiological benefits of LAMAs in respiratory disease. [ABSTRACT FROM AUTHOR]

Background: Muscarinic receptors are involved in the mechanism of postoperative catheter-related bladder discomfort (CRBD). Glycopyrrolate and atropine as adjuncts to reversal of neuromuscular blockers have differential inhibitory effects on muscarinic receptors. This study was conducted to compare the effect of glycopyrrolate versus atropine on postoperative CRBD in patients undergoing transurethral resection of a bladder tumor (TURBT). Methods: Seventy-four patients undergoing TURBT were randomly allocated to receive either glycopyrrolate 10 μg/kg (glycopyrrolate group, n = 37) or atropine 15 μg/kg (atropine group, n = 37) in combination with neostigmine 25 μg/kg at the end of surgery for reversal of neuromuscular blockade. The incidence and severity (mild/moderate/severe) of CRBD were assessed at 0, 1, 6, and 24 h postoperatively. Tramadol 50-100 mg was administered intravenously if the patients complained of moderate or severe CRBD. Results: The incidence of CRBD was significantly lower in the glycopyrrolate group than in the atropine group at 0 h (65 % vs. 89 %, p = 0.025) and 1 h (54 % vs. 89 %, p = 0.002) postoperatively. The severity of postoperative CRBD was less severe in the glycopyrrolate group than in the atropine group at 0 h ( p = 0.013) and 1 h ( p = 0.006). Fewer patients required tramadol in the glycopyrrolate group than in the atropine group (3 % vs. 12 %, p = 0.024). Conclusions: Glycopyrrolate as an adjunct to reversal of neuromuscular blockers decreased the incidence of early postoperative CRBD and postoperative tramadol requirements in patients undergoing TURBT when compared to atropine. [ABSTRACT FROM AUTHOR]