[Safety of umeclidinium/vilanterol in Chinese patients in a real-world setting: a prospective, multicenter, single-arm, observational study].

Objective: To evaluate the safety of umeclidinium/vilanterol in Chinese participants in a real-world setting. Methods: This was a 24-week, prospective, multicenter, single-arm, observational study that enrolled participants treated with umeclidinium/vilanterol in real-world settings from 14 sites in China from 14 December 2020 to 30 January 2022. The primary outcomes were the incidence of adverse events (AEs) and serious adverse events (SAEs) at week 24. Results: A total of 887 participants on umeclidinium/vilanterol were enrolled. The mean (±SD) age of these participants was 67.5 (±9.6) years, with more men (77.7%) enrolled. The majority of the participants (98.1%) had been diagnosed with chronic obstructive pulmonary disease, and 67.6% of them reported comorbidities. More than half of the participants (52.8%) were taking concomitant medication in addition to the study treatment. AEs were reported in 59 (6.7%) participants and were predominantly mild to moderate in severity. SAEs were reported in 21 (2.4%) participants, including 9 fatal SAEs, 10 reported non-fatal SAEs, and 2 reported both non-fatal and fatal SAEs. None of the SAEs, including the fatal events, were considered by the investigators to be related to umeclidinium/vilanterol. Adverse drug reactions (ADRs) were reported in 6 (0.7%) participants with 4 preferred terms (PTs), all of which were considered mild in severity. Of these PTs, 2 were known ADRs of umeclidinium/vilanterol. Three participants (0.3%) reported AEs that were part of serious identified/potential hazards, all of which were considered by the investigators to be unrelated to umeclidinium/vilanterol. Conclusion: The results of this study showed that umeclidinium/vilanterol was well tolerated in Chinese participants in a real-world setting and no new drug-related safety signals were observed.

APR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy.

Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (224Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using 224Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.

ZBP1-mediated PANoptosis: A possible novel mechanism underlying the therapeutic effects of penehyclidine hydrochloride on myocardial ischemia-reperfusion injury.

Although penehyclidine hydrochloride (PHC) has been identified to alleviate myocardial injury induced by ischemia/reperfusion (I/R), the regulatory molecules and related mechanisms are unknown. In this study, bioinformatics, molecular biology, and biochemistry methods were used to explore the molecular mechanisms and targets of PHC. In the myocardial ischemia-reperfusion injury (MIRI)-induced rat model, PHC pretreatment significantly improved cardiac function (p < 0.01). Multiple differentially expressed genes, including Z-DNA binding protein 1 (ZBP1), were identified through mRNA sequencing analysis of myocardial ischemic penumbra tissue in MIRI rats. The transduction of the ZBP1 adenovirus vector (Ad-Zbp1) in PHC-pretreated rats exhibited a reversible augmentation in myocardial infarct size (p < 0.01), pronounced pathological damage to the myocardial tissue, as well as a significant elevation of serum myocardial enzymes (p < 0.05). The interaction among ZBP1, fas-associating via death domain (FADD), and receptor-interacting serine/threonine-protein kinase 3 (RIPK3) leads to a remarkable up-regulation of cleaved-Caspase-1 (Cl-Casp-1), N-terminal gasdermin D (N-GSDMD), phospho-mixed lineage kinase domain-like Ser358 (p-MLKLS358), and other regulatory proteins, thereby triggering pyroptosis, apoptosis, and necroptosis (PANoptosis) in cardiomyocytes of MIRI rats. Moreover, the transduction of Ad-Zbp1 in the oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced H9c2 cell model also dramatically augmented the number of cell deaths. However, the intervention of PHC considerably enhanced cell viability (p < 0.01), effectively mitigated the release of myocardial enzymes (p < 0.05), and markedly attenuated the expression levels of PANoptosis regulatory proteins through restraint of ZBP1 expression. Therefore, the therapeutic efficacy of PHC in improving MIRI might be attributed to targeting ZBP1-mediated PANoptosis.

Evaluation of Efficacy of Adding Aprepitant to Palonosetron and Dexamethasone in Carboplatin and Etoposide Therapy.

Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in addition to a 5-hydroxytryptamine type 3 receptor antagonist with dexamethasone (DEX) for CBDCA-containing chemotherapy because of its higher emetogenic risk. However, the additional efficacy of aprepitant (APR) in CBDCA-containing treatment remains controversial, and data on multiple-day treatments are limited. Etoposide (ETP) was administered on days 1-3 in the CBDCA + ETP regimen, and it is important to evaluate suitable antiemetic therapy for the regimen. Therefore, we evaluated the efficacy of additional APR in CBDCA + ETP. Patients were divided into two groups and retrospectively evaluated. One was the control group, which was prophylactically administered palonosetron (PALO) and DEX, and the other was the APR group, which received APR orally with PALO and DEX. The primary endpoint was complete response (CR) between the groups. The overall CR rates were 75.0 and 76.4% in the control and APR groups, respectively, with no significant difference (p = 1.00). In the acute phase, it was 88.9 and 97.2%, respectively, and 86.1 and 79.2% in the delayed phase, respectively, without significant differences (p = 0.10 and 0.38, respectively). The incidence and severity of nausea, vomiting, and anorexia were not significantly different between the two groups in the acute and delayed phases. Our findings suggest that combining APR with PALO and DEX does not improve the CR rate in CBDCA + ETP therapy.

Efficacy and safety of netupitant/palonosetron in preventing nausea and vomiting in diffuse large B cell lymphoma patients undergoing R-CHOP chemotherapy.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma, for which cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab(R-CHOP) is one of the standard regimens. Given that R-CHOP is highly emetogenic, chemotherapy-induced nausea and vomiting (CINV) prevention is clinically important. However, there is a paucity of studies focusing on these patients. This study aimed to ascertain the effectiveness of an oral fixed-dose combination of netupitant and palonosetron (NEPA) in preventing CINV in patients with DLBCL undergoing first-line R-CHOP chemotherapy. Seventy patients were enrolled in this single-center prospective non-comparative study conducted between November 2020 and May 2023 in South Korea. NEPA was administered 1 h prior to chemotherapy initiation on day 1. The primary endpoint of the study was the complete response rate (no emesis, and no rescue medication) during the acute, delayed, and overall phases, which were assessed over a period of 120 h post-chemotherapy. The complete response rates for NEPA were 90.0% [95% CI 80.5, 95.9] for the acute phase, 85.7% [95% CI 75.3, 92.9] for the delayed phase, and 84.3% [95% CI 73.6, 91.9] for the overall phase, with no-emesis rates (acute: 97.1% [95% CI 97.1, 99.7], delayed: 95.7% [95% CI 88.0, 99.1], overall: 92.9% [95% CI 84.1, 97.6]). NEPA was well tolerated with no severe treatment-emergent adverse events. NEPA exhibited substantial efficacy in mitigating CINV in DLBCL patients undergoing R-CHOP chemotherapy, demonstrating high CR and no-emesis rates, and favorable safety profiles.

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.

Effect of cevimeline and different concentration of gum arabic on parotid salivary gland function in methotrexate-induced xerostomia: a comparative study.

OBJECTIVE: This study assessed the effect of cevimeline and different concentrations of gum arabic on the parotid gland of rats being given xerostomia-inducing methotrexate. METHODS: One hundred twenty-five rats were divided into five equal groups of twenty-five each. The rats in Group I received basic diets, while those in Groups II, III, IV, and V received 20 mg/kg MTX as a single intraperitoneal dose on day one. Group III received 10 mg/kg CVM dissolved in saline orally and daily, and the other two groups received a 10% W/V aqueous suspension of GA. Therefore, Group IV received 2 ml/kg suspension orally and daily, while Group V received 3 ml/kg suspension orally and daily. After 9 days, the parotid glands were dissected carefully and prepared for hematoxylin and eosin (H&E) staining as a routine histological stain and caspase-3 and Ki67 immunohistochemical staining. Quantitative data from α-Caspase-3 staining and Ki67 staining were statistically analysed using one-way ANOVA followed by Tukey's multiple comparisons post hoc test. RESULTS: Regarding caspase-3 and Ki67 immunohistochemical staining, one-way ANOVA revealed a significant difference among the five groups. For Caspase-3, the highest mean value was for group II (54.21 ± 6.90), and the lowest mean value was for group I (15.75 ± 3.67). The other three groups had mean values of 31.09 ± 5.90, 30.76 ± 5.82, and 20.65 ± 3.47 for groups III, IV, and V, respectively. For Ki67, the highest mean value was for group I (61.70 ± 6.58), and the lowest value was for group II (18.14a ± 5.16). The other three groups had mean values of 34.4 ± 9.27, 48.03 ± 8.40, and 50.63 ± 8.27 for groups III, IV, and V, respectively. CONCLUSION: GA, rather than the normally used drug CVM, had a desirable effect on the salivary glands of patients with xerostomia.

Penehyclidine hydrochloride improves cognitive function of rats with brain injury via CAMP/CREB signaling pathway.

This study explored the impact of penehyclidine hydrochloride on cognitive function in rats with brain injury. Sprague-Dawley rats (n=36) were randomly assigned to sham-operation, model, and penehyclidine hydrochloride groups. Rats in the sham-operation group underwent craniotomy, while the model and penehyclidine hydrochloride groups received brain injury models and interventions with normal saline and penehyclidine hydrochloride, respectively. Specimens were obtained two weeks post-intervention. Neurological deficits were evaluated using Zea-Longa scores, and memory was assessed with the Morris water maze test. ELISA determined brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) content. mRNA expressions of BDNF and NGF were assessed via qPCR, and phosphorylated CREB (p-CREB) protein expression was measured by Western blotting. Compared to the sham-operation group, both model and penehyclidine hydrochloride groups showed increased Zea-Longa scores. Escape latencies were longer and platform crossings were fewer in model and penehyclidine hydrochloride groups compared to the sham-operation group, but penehyclidine hydrochloride demonstrated a shorter latency and more platform crossings than the model group. BDNF and NGF content decreased in model and penehyclidine hydrochloride groups compared to the sham-operation group, with an increase in the penehyclidine hydrochloride group compared to the model group. mRNA expression levels declined in model and penehyclidine hydrochloride groups but were higher in the latter. p-CREB protein expression was lower in model and penehyclidine hydrochloride groups compared to the sham-operation group but higher in the penehyclidine hydrochloride group than the model group. Penehyclidine hydrochloride exhibited neuroprotective effects by upregulating the cAMP/CREB signaling pathway, improving cognitive function in rats with brain injury.

Real-world characteristics of patients with asthma initiating fluticasone furoate/umeclidinium/vilanterol single-inhaler triple therapy in Japan.

BACKGROUND: Real-world data assessing characteristics of patients with asthma initiating inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) triple therapy in Japan are limited. METHODS: Descriptive, observational study of patients with asthma aged ≥15 years newly initiating single- or multiple-inhaler triple therapy (SITT: fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI], SITT: indacaterol/glycopyrronium bromide/mometasone furoate [IND/GLY/MF] or MITT) or ICS/LABA using JMDC/Medical Data Vision (MDV) health insurance databases from February 2021-February 2022 (first prescription date: index date). Patients were assigned to three non-mutually exclusive cohorts: A) new FF/UMEC/VI initiators; B) new FF/UMEC/VI, IND/GLY/MF, or MITT initiators; C) new FF/UMEC/VI, IND/GLY/MF, MITT or ICS/LABA initiators as initial maintenance therapy (IMT). Patient characteristics were assessed descriptively for 12-months pre-treatment initiation (baseline period). RESULTS: Cohort A: among new FF/UMEC/VI initiators, 12.8% and 0.1% (JMDC) and 21.7% and 0.9% (MDV) of patients had ≥1 moderate and severe exacerbation; 52.0% (JMDC) and 79.2% (MDV) had ICS/LABA use. Cohort B: most patients initiated FF/UMEC/VI and IND/GLY/MF over MITT (JMDC: 91.3% vs 8.7%; MDV: 67.8% vs 32.2%), with fewer exacerbations and lower rescue medication use. Cohort C: a greater proportion of FF/UMEC/VI initiators as IMT experienced a moderate exacerbation at index versus ICS/LABA initiators as IMT (JMDC: 17.8% vs 10.7%; MDV: 8.0% vs 5.1%). CONCLUSIONS: Patient characteristics were generally similar between treatment groups; SITT initiators had fewer exacerbations and lower rescue medication use than MITT initiators, represented by the greater proportion of IMT among SITT versus MITT initiators. Physicians may have prescribed triple over dual therapy as IMT in response to an exacerbation.

Triple Therapy and Clinical Control in B+ COPD Patients: A Pragmatic, Prospective, Randomized Trial.

INTRODUCTION: Treatment with LABA/LAMA is recommended in GOLD B patients. We hypothesized that triple therapy (LABA/LAMA/ICS) will be superior to LABA/LAMA in achieving and maintaining clinical control (CC), a composite outcome that considers both impact and disease stability in a subgroup of GOLD B patients (here termed GOLD B+ patients) characterized by: (1) remaining symptomatic (CAT≥10) despite regular LABA/LAMA therapy; (2) having suffered one moderate exacerbation in the previous year; and (3) having blood eosinophil counts (BEC) ≥150cells/µL. METHODS: The ANTES B+ study is a prospective, multicenter, open label, randomized, pragmatic, controlled trial designed to test this hypothesis. It will randomize 1028 B+ patients to continue with their usual LABA/LAMA combination prescribed by their attending physician or to begin fluticasone furoate (FF) 92µg/umeclidinium (UMEC) 55µg/vilanterol (VI) 22µg in a single inhaler q.d. for 12 months. The primary efficacy outcome will be the level of CC achieved. Secondary outcomes include the clinical important deterioration index (CID), annual rate of exacerbations, and FEV1. Exploratory objectives include the interaction of BEC and smoking status, all-cause mortality and proportion of patients on LABA/LAMA arm that switch therapy arms. Safety analysis include adverse events and incidence of pneumonia. RESULTS: The first patient was recruited on February 29, 2024; results are expected in the first quarter of 2026. CONCLUSIONS: The ANTES B+ study is the first to: (1) explore the efficacy and safety of triple therapy in a population of B+ COPD patients and (2) use a composite index (CC) as the primary result of a COPD trial.

Quinuclidine N-Oxygenation Mediated by Flavin-Containing Monooxygenases 1 and 3 in Kidney and Liver Microsomes from Humans, Monkeys, Dogs, and Pigs.

Flavin-containing monooxygenases (FMOs) are a family of enzymes that are involved in the oxygenation of heteroatom-containing molecules. In humans, FMO3 is the major hepatic form, whereas FMO1 is predominant in the kidneys. FMO1 and FMO3 have also been identified in monkeys, dogs, and pigs. The predicted contribution of human FMO3 to drug candidate N-oxygenation could be estimated using the classic base dissociation constants of the N-containing moiety. A basic quinuclidine moiety was found in natural quinine and medicinal products. Consequently, N-oxygenation of quinuclidine was evaluated using liver and kidney microsomes from humans, monkeys, dogs, and pigs as well as recombinant FMO1, FMO3, and FMO5 enzymes. Experiments using simple reversed-phase liquid chromatography with fluorescence monitoring revealed that recombinant FMO1 mediated quinuclidine N-oxygenation with a high capacity in humans. Moreover, recombinant FMO1, FMO3, and/or FMO5 in monkeys, dogs, and pigs exhibited relatively broad substrate specificity toward quinuclidine N-oxygenation. Kinetic analysis showed that human FMO1 efficiently, and pig FMO1 moderately, mediated quinuclidine N-oxygenation with high capacity, which is consistent with the reported findings for larger substrates readily accepted by pig FMO1 but excluded by human FMO1. In contrast, human FMO3-mediated quinuclidine N-oxygenation was slower than that of the typical FMO3 substrate trimethylamine. These results suggest that some species differences exist in terms of FMO-mediated quinuclidine N-oxygenation in humans and some animal models (monkeys, dogs, and minipigs); however, the potential for quinuclidine, which has a simple chemical structure, to be inhibited clinically by co-administered drugs should be relatively low, especially in human livers. SIGNIFICANCE STATEMENT: The high capacity of human flavin-containing monooxygenase (FMO) 1 to mediate quinuclidine N-oxygenation, a basic moiety in natural products and medicines, was demonstrated by simple reversed-phase liquid chromatography using fluorescence monitoring. The substrate specificity of FMO1 and FMO3 toward quinuclidine N-oxygenation in monkeys, dogs, and pigs was suggested to be relatively broad. Human FMO3-mediated quinuclidine N-oxygenation was slower than trimethylamine N-oxygenation. The likelihood of quinuclidine, with its simple chemical structure, being clinically inhibited by co-administered drugs is relatively low.

Characteristics of Users and New Initiators of Single- and Multiple-Inhaler Triple Therapy for Chronic Obstructive Pulmonary Disease in Germany.

Purpose: To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany. Patients and Methods: Retrospective cohort study of patients with COPD and ≥1 prescription for single-inhaler triple therapy (SITT; fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or beclomethasone dipropionate/glycopyrronium bromide/formoterol [BDP/GLY/FOR]) or multiple-inhaler triple therapy (MITT), using data from the AOK PLUS German sickness fund (1 January 2015-31 December 2019). The index date was the first date of prescription for FF/UMEC/VI or BDP/GLY/FOR (SITT users), or the first date of overlap of inhaled corticosteroid, long-acting ß2-agonist, and long-acting muscarinic antagonist (MITT users). Two cohorts were defined: the prevalent cohort included all identified triple therapy users; the incident cohort included patients newly initiating triple therapy for the first time (no prior use of MITT or SITT in the last 2 years). Patient characteristics and treatment patterns were assessed on the index date and during the 24-month pre-index period. Results: In total, 18,630 patients were identified as prevalent triple therapy users (MITT: 17,945; FF/UMEC/VI: 700; BDP/GLY/FOR: 908; non-mutually exclusive) and 2932 patients were identified as incident triple therapy initiators (MITT: 2246; FF/UMEC/VI: 311; BDP/GLY/FOR: 395; non-mutually exclusive). For both the prevalent and incident cohorts, more than two-thirds of patients experienced ≥1 moderate/severe exacerbation in the preceding 24 months; in both cohorts more BDP/GLY/FOR users experienced ≥1 moderate/severe exacerbation, compared with FF/UMEC/VI and MITT users. Overall, 97.9% of prevalent triple therapy users and 86.4% of incident triple therapy initiators received maintenance treatment in the 24-month pre-index period. Conclusion: In a real-world setting in Germany, triple therapy was most frequently used after maintenance therapy in patients with recent exacerbations, in line with current treatment recommendations.

Triple therapy (a combination of three different respiratory inhaled medications) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience repeated short-term symptom flare-ups when taking dual therapy (a combination of two different respiratory medications). Previously, patients had to take triple therapy using two or three separate inhalers. More recently, single-inhaler triple therapies have been developed, meaning patients can take all three different medications at the same time via one single inhaler. This study assessed the characteristics of patients who were already receiving triple therapy, or who started triple therapy (either via multiple inhalers or a single inhaler), in Germany between January 2015 and December 2019. In total, 18,630 patients who were already receiving triple therapy during the study period, and 2932 patients who newly started using triple therapy were included. The study reported that more than two-thirds of included patients had experienced at least one flare-up of COPD symptoms in the 2 years before starting triple therapy. Most patients had also received another therapy for COPD before starting triple therapy. A small proportion of patients started taking triple therapy after receiving no other therapy for COPD in the previous 2 years. The results of the study suggest that triple therapy for COPD in Germany is most often used in accordance with recommendations (patients already receiving therapy and experiencing repeated symptom flare-ups).

Penehyclidine hydrochloride alleviates lung ischemia-reperfusion injury by inhibiting pyroptosis.

OBJECTIVE: The aim of this research was to examine how penehyclidine hydrochloride (PHC) impacts the occurrence of pyroptosis in lung tissue cells within a rat model of lung ischemia-reperfusion injury. METHODS: Twenty-four Sprague Dawley (SD) rats, weighing 250 g to 270 g, were randomly distributed into three distinct groups as outlined below: a sham operation group (S group), a control group (C group), and a test group (PHC group). Rats in the PHC group received a preliminary intravenous injection of PHC at a dose of 3 mg/kg. At the conclusion of the experiment, lung tissue and blood samples were collected and properly stored for subsequent analysis. The levels of malondialdehyde, superoxide dismutase, and myeloperoxidase in the lung tissue, as well as IL-18 and IL-1ß in the blood serum, were assessed using an Elisa kit. Pyroptosis-related proteins, including Caspase1 p20, GSDMD-N, and NLRP3, were detected through the western blot method. Additionally, the dry-to-wet ratio (D/W) of the lung tissue and the findings from the blood gas analysis were also documented. RESULTS: In contrast to the control group, the PHC group showed enhancements in oxygenation metrics, reductions in oxidative stress and inflammatory reactions, and a decrease in lung injury. Additionally, the PHC group exhibited lowered levels of pyroptosis-associated proteins, including the N-terminal segment of gasdermin D (GSDMD-N), caspase-1p20, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3). CONCLUSION: Pre-administration of PHC has the potential to mitigate lung ischemia-reperfusion injuries by suppressing the pyroptosis of lung tissue cells, diminishing inflammatory reactions, and enhancing lung function. The primary mechanism behind anti-pyroptotic effect of PHC appears to involve the inhibition of oxidative stress.

Cost-effectiveness analysis of fluticasone furoate/umeclidinium bromide/vilanterol and umeclidinium bromide/vilanterol in the management of moderate and severe COPD in China.

OBJECTIVE: A study has analyzed the long-term cost-effectiveness of fluticasone furoate/umeclidinium bromide/vilanterol combination therapy (FF/UMEC/VI) versus umeclidinium bromide/vilanterol dual therapy (UMEC/VI) in the treatment of moderate or severe chronic obstructive pulmonary disease (COPD), providing evidence for decision-making in COPD treatment. METHODS: From the perspective of the whole society, a Markov model based on the severity of COPD was established, consisting of four states: moderate, severe, very severe, and death. The cycle of the model is three months, and the time frame of the study is 20 years. Data such as initial states, transition probabilities, costs, and utilities were collected from published literature, the National Institute for Health and Care Excellence (NICE) COPD economic report, Yaozh database, and the National Statistics Office. The discount rate is 5 %, and the willingness to pay threshold is set at three times the per capita GDP of China in 2022. TreeAge Pro 2011 was used to obtain the results of multiplication analyses, and one-way factor analysis and probability sensitivity analysis were conducted. RESULTS: The study findings demonstrate that for patients treated with FF/UMEC/VI and UMEC/VI, the 20-year treatment costs amount to $10,126.46 and $10,685.74, respectively. Similarly, the effectiveness is 32.94 quality-adjusted life years (QALYs) and 32.19 QALYs, respectively. The incremental cost-effectiveness ratio is $-745.70/QALY, which is lower than the willingness to pay threshold. The tornado plot from one-way factor analysis indicates that the first two factors impacting the results are the utility values for severe COPD of UMEC/VI and FF/UMEC/VI. Probability sensitivity analysis indicates that FF/UMEC/VI compared to UMEC/VI can be considered a more cost-effective treatment at the willingness to pay threshold of $35,806.96. CONCLUSION: The triple therapy (FF/UMEC/VI) is more affordable than dual therapy (UMEC/VI) when compared to China's three times GDP per capita criterion.

Alpha 7 Nicotinic Acetylcholine Receptor Agonist PHA 568487 Reduces Acute Inflammation but Does Not Affect Cardiac Function or Myocardial Infarct Size in the Permanent Occlusion Model.

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematologic parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h or at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.

Gastrointestinal adverse effects associated with the use of intravenous oliceridine compared with intravenous hydromorphone or fentanyl in acute pain management utilizing adjusted indirect treatment comparison methods.

Background: In the absence of head-to-head comparative data from randomized controlled trials, indirect treatment comparisons (ITCs) may be used to compare the relative effects of treatments versus a common comparator (either placebo or active treatment). For acute pain management, the effects of oliceridine have been compared in clinical trials to morphine but not to fentanyl or hydromorphone. Aim: To assess the comparative safety (specifically differences in the incidence of nausea, vomiting and opioid-induced respiratory depression [OIRD]) between oliceridine and relevant comparators (fentanyl and hydromorphone) through ITC analysis. Methods: A systematic literature review identified randomized clinical trials with oliceridine versus morphine and morphine versus fentanyl or hydromorphone. The ITC utilized the common active comparator, morphine, for the analysis. Results: A total of six randomized controlled trials (oliceridine - 2; hydromorphone - 3; fentanyl - 1) were identified for data to be used in the ITC analyses. The oliceridine data were reported in two studies (plastic surgery and orthopedic surgery) and were also reported in a pooled analysis. The ITC focused on nausea and vomiting due to limited data for OIRD. When oliceridine was compared with hydromorphone in the ITC analysis, oliceridine significantly reduced the incidence of nausea and/or vomiting requiring antiemetics compared with hydromorphone (both orthopedic surgery and pooled data), while results in plastic surgery were not statistically significant. When oliceridine was compared with hydromorphone utilizing data from Hong, the ITC only showed a trend toward reduced risk of nausea and vomiting with oliceridine that was not statistically significant across all three comparisons (orthopedic surgery, plastic surgery and combined). An ITC comparing oliceridine with a study of fentanyl utilizing the oliceridine orthopedic surgery data and combined orthopedic and plastic surgery data showed a trend toward reduced risk that was not statistically significant. Conclusion: In ITC analyses, oliceridine significantly reduced the incidence of nausea and/or vomiting or the need for antiemetics in orthopedic surgery compared with hydromorphone and a non-significant trend toward reduced risk versus fentanyl.

Post-treatment with maropitant reduces oxidative stress, endoplasmic reticulum stress and neuroinflammation on peripheral nerve injury in rats.

OBJECTIVE: To determine the effective dose and therapeutic potential of maropitant using through expression of mediators of oxidative stress, inflammatory and of the unfolded protein response (UPR) (bio) markers on spinal cord using a model of neuropathic pain induced through chronic constriction injury (CCI) in rats. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: 98 male Wistar rats. METHODS: Rats were anesthetized with sevoflurane and after CCI, they were randomly assigned to the following groups that received: vehicle, 3, 6, 15, 30 e 50 mg/kg/24q of maropitant. The effect on inflammatory mediators (IL10, TNFα), oxidative stress (GPx, CAT, SOD), microglial (IBA-1) and neuronal (NeuN, TACR1) markers was evaluated though immunohistochemistry and expression levels of markers of hypoxia (HIF1α, Nrf2), antioxidant enzymes (Catalse, Sod1 and GPx1), and endoplasmic reticulum stress mediators (GRP78, CHOP and PERK) through qRT-PCR. RESULTS: Intraperitoneal injection (IP) of maropitant inhibited nociception with ID50 values of 4,1 mg/kg (5,85-19,36) in a neuropathic pain model through CCI. A dose of 30 mg/kg/24q was significantly effective in reducing mechanical allodynia 1 to 4h after treatment with nociception inhibition (145,83%). A reduction in the expression of hypoxia factors (HIF1α, Nrf2) was observed, along with an increase in antioxidant activity (CAT, SOD and GPX). Additionally, there was a reduction in inflammatory markes (IL10, TNFα), microglial (IBA-1), and neuronal markers (NeuN, TACR1). CONCLUSION AND CLINICAL RELEVANCE: These findings demonstrate that the determined dose, administered daily for seven days, had an antinociceptive effect, as well as anti-inflammatory and antioxidant activity.

Characterization of a novel 3-quinuclidinone reductase possessing remarkable thermostability.

The 3-quinuclidinone reductase plays an irreplaceable role in the biopreparation of (R)-3-quinuclidinol, an intermediate vital for synthesis of various pharmaceuticals. Thermal robustness is a critical factor for enzymatic synthesis in industrial applications. This study characterized a new 3-quinuclidinone reductase, named SaQR, with significant thermal stability. The SaQR was overexpressed in a GST-fused state, and substrate and cofactor screening were conducted. Additionally, three-dimensional structure prediction using AlphaFold and analysis were performed, along with relevant thermostability tests, and the evaluation of factors influencing enzyme activity. The findings highlight the remarkable thermostability of SaQR, retaining over 90% of its activity after 72 h at 50°C, with an optimal operational temperature of 85°C. SaQR showed typical structural traits of the SDR superfamily, with its cofactor-determining residue being aspartic acid, conferring nicotinamide adenine dinucleotide (NAD(H)) preference. Moreover, K+ and Na+, at a concentration of 400 mM, could significantly enhance the activity, while Mg2+ and Mn2+ only display inhibitory effects within the tested concentration range. The findings of molecular dynamics simulations suggest that high temperatures may disrupt the binding of enzyme to substrate by increasing the flexibility of residues 205-215. In conclusion, this study reports a novel 3-quinuclidinone reductase with remarkable thermostability.

Penehyclidine for Prevention of Postoperative Nausea and Vomiting in Patients Undergoing Gynecological Laparoscopic Surgery Under Combined Intravenous and Inhalation Anesthesia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: We designed this study to investigate the effect of intravenous use of penehyclidine on postoperative nausea and vomiting (PONV) after gynecological laparoscopic surgery. Patients and Methods: Ninety-two Women Patients (Aged ≥ 18) Scheduled for Elective Gynecologic Laparoscopy Were Enrolled in the Current Study. Patients Were Equally Randomized Assigned Into Penehyclidine group (PHC group: received a bolus of penehyclidine 10 µg/kg during the induction of anesthesia, then followed by a continuous infusion of 10 µg/kg penehyclidine at a fixed rate of 2.0 mL/h in postoperative intravenous analgesia pump over 48h, 0.5 mg upper limit respectively) or Control group (received 0.9% saline in replace of penehyclidine at the same time points). The primary outcome measure was the incidence of postoperative nausea and vomiting in the postanesthesia care unit and ward area. Quality of Recovery-15 (QoR-15) scores and general comfort questionnaire (GCQ) scores were assessed on postoperative day (POD) 1, 2. Results: Patients between two groups had comparable baseline characteristics. Compared with the Control group, the incidence and severity of PONV, postoperative nausea (PON), and postoperative vomiting (POV) were significantly lower in the PHC group at 2h (PONV: P = 0.002, P = 0.004, respectively; PON: P = 0.018, P = 0.038, respectively; POV: P = 0.011, P = 0.072, respectively), 24h (PONV: P = 0.003, P = 0.001, respectively; PON: P = 0.010, P = 0.032, respectively; POV: P = 0.006, P = 0.044, respectively), and 48h (PONV: P = 0.003, P = 0.002, respectively; PON: P = 0.007, P = 0.019, respectively; POV: P = 0.002, P = 0.013, respectively) after surgery. The QoR-15 and GCQ scores of the PHC group were significantly higher than those of the Control group at POD 1, 2 (P < 0.001; P < 0.001, respectively). Conclusion: Our findings suggest that perioperative intravenous application of penehyclidine can effectively prevent postoperative nausea and vomiting in gynecological laparoscopic surgery patients and improve postoperative recovery.