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1.
Int J Chron Obstruct Pulmon Dis ; 17: 2745-2755, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36317185

RESUMO

Purpose: The 24-week INTREPID trial demonstrated the clinical benefits of once-daily single-inhaler triple therapy (SITT) with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) versus non-ELLIPTA multiple-inhaler triple therapy (MITT) in patients with symptomatic chronic obstructive pulmonary disease (COPD). This analysis assessed the cost-effectiveness of FF/UMEC/VI versus non-ELLIPTA MITT for the treatment of symptomatic COPD from a United Kingdom (UK) National Health Service (NHS) perspective. Patients and Methods: The analysis was conducted using the validated GALAXY COPD disease progression model. Baseline characteristics, treatment effect parameters (forced expiratory volume in 1 second and St. George's Respiratory Questionnaire score [derived from exploratory COPD Assessment Test score mapping]), and discontinuation data from INTREPID were used to populate the model. UK healthcare resource and drug costs (2020 British pounds) were applied, and costs and outcomes were discounted at 3.5%. Analyses were conducted over a lifetime horizon from a UK NHS perspective. Model outputs included exacerbation rates, total costs, life years (LYs), quality-adjusted LYs (QALYs) and incremental cost-effectiveness ratio per QALY. Sensitivity analyses were conducted to assess the robustness of the results by varying parameter values and assumptions. Results: Over a lifetime horizon, FF/UMEC/VI provided an additional 0.174 (95% confidence interval [CI]: 0.024, 0.344) LYs (approximately 2 months), and 0.253 (95% CI: 0.167, 0.346) QALYs (approximately 3 months), at a cost saving of £1764 (95% CI: -£2600, -£678) per patient, compared with non-ELLIPTA MITT. FF/UMEC/VI remained the dominant treatment option, meaning greater benefits at lower costs, across all scenario and sensitivity analyses. Conclusion: Based on this analysis, in a UK setting, FF/UMEC/VI would improve health outcomes and reduce costs compared with non-ELLIPTA MITT for the treatment of patients with symptomatic COPD. SITT may help to reduce the clinical and economic burden of COPD and should be considered by physicians as a preferred treatment option.


Assuntos
Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica , Humanos , Administração por Inalação , Androstadienos , Álcoois Benzílicos , Broncodilatadores , Clorobenzenos , Análise Custo-Benefício , Método Duplo-Cego , Combinação de Medicamentos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas , Medicina Estatal
2.
Org Lett ; 24(42): 7737-7741, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36239346

RESUMO

N-Trifluoroacetoxyquinuclidinium trifluoroacetate was prepared in situ from quinuclidine N-oxide and (CF3CO)2O. Except for some electron-poor substrates, this reagent allows for the high-yielding oxidative trifluoroacetoxylation of 1°, 2°, and 3° benzylic C-H bonds under photocatalytic conditions. The trifluoroacetoxylation of an ibuprofen methyl ester allowed the selective functionalization of a 2° benzylic C-H bond. For alkylbenzenes, hydrogen-atom transfer from a benzylic C-H bond to a quinuclidine cation radical was proposed to be the reaction-product-determining step.


Assuntos
Quinuclidinas , Sais , Catálise , Oxirredução , Estresse Oxidativo
3.
Ter Arkh ; 94(3): 396-400, 2022 Mar 15.
Artigo em Russo | MEDLINE | ID: mdl-36286904

RESUMO

AIM: To evaluate the effectiveness of a fixed triple combination of vilanterol/umeclidinium bromide/fluticasone furoate in the treatment of chronic obstructive pulmonary disease (COPD) patients with frequent exacerbations. MATERIALS AND METHODS: The study included 46 patients with severe and extremely severe COPD (GOLD 34) with frequent exacerbations. All patients were divided into 2 groups. The 1st group included 22 COPD patients with a content of eosinophils in the peripheral blood of 300 cells/ml, the 2nd group included 24 COPD patients with no signs of eosinophilic inflammation in the peripheral blood. Group 1 patients were recommended therapy with a fixed triple combination of vilanterol/umeclidinium bromide/fluticasone furoate at a dose of 22/55/92 mcg 1 time per day, group 2 patients received vilanterol+umeclidinium bromide at a dose of 22/55 mcg 1 time per day. The duration of follow-up was 12 months. RESULTS: After 12 months of treatment with a fixed triple combination of vilanterol/umeclidinium bromide/fluticasone furoate, a statistically significant decrease in peripheral blood eosinophilia was noted in patients with COPD with frequent exacerbations and peripheral blood eosinophilia (p=0.001), as well as a decrease in shortness of breath on the MMRs scale (p=0.001) and the frequency of exacerbations in patients with COPD with frequent exacerbations and eosinophilia (p=0.001). CONCLUSION: The use of a fixed combination of vilanterol/umeclidinium bromide/fluticasone furoate for 12 months allowed to reduce the impact of the disease, improve respiratory function and quality of life in COPD patients with eosinophilia.


Assuntos
Broncodilatadores , Doença Pulmonar Obstrutiva Crônica , Humanos , Broncodilatadores/uso terapêutico , Qualidade de Vida , Brometos/uso terapêutico , Administração por Inalação , Clorobenzenos/efeitos adversos , Álcoois Benzílicos/uso terapêutico , Quinuclidinas/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Combinação de Medicamentos , Resultado do Tratamento
4.
J Am Chem Soc ; 144(42): 19499-19507, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36223562

RESUMO

Cooperative H-bonding interactions are a feature of supramolecular networks involving alcohols. A family of phenol oligomers, in which the hydroxyl groups form intramolecular H-bonds, was used to investigate this phenomenon. Chains of intramolecular H-bonds were characterized using nuclear magnetic resonance (NMR) spectroscopy in solution and X-ray crystallography in the solid state. The phenol oligomers were used to make quantitative measurements of the effects of the intramolecular interactions on the strengths of intermolecular H-bonding interactions between the H-bond donor on the end of the chain and a series of H-bond acceptors. Intramolecular H-bonding interactions in the chain increase the strength of a single intermolecular H-bond between the terminal phenol and quinuclidine by up to 14 kJ mol-1 in the n-octane solution. Although the magnitude of the effect increases with the length of the H-bonded chain, the first intramolecular H-bond has a much larger effect than subsequent interactions. H-bond cooperativity is dominated by pairwise interactions between nearest neighbors, and longer range effects are negligible. The results were used to develop a simple model for cooperativity in H-bond networks using an empirical parameter κ to quantify the sensitivity of the H-bond properties of a functional group to polarization. The value of κ measured in these systems was 0.33, which means that formation of the first H-bond increases the polarity of the next H-bond donor in the chain by 33%. The cumulative cooperative effect in longer H-bonded chains reaches an asymptotic value, which corresponds to a maximum increase in the polarity of the terminal H-bond donor of 50%.


Assuntos
Álcoois , Fenóis , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Quinuclidinas
5.
BMC Anesthesiol ; 22(1): 317, 2022 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-36241968

RESUMO

BACKGROUD: Postoperative nausea and vomiting (PONV) is one of the most common complications after total thyroidectomy under general anesthesia. Total intravenous anesthesia (TIVA) has been documented to prevent PONV in patients undergoing total thyroidectomy. Penehyclidine, an anticholinergic agent with an elimination half-life of over 10 h, is widely used as premedication to reduce glandular secretion. This study aimed to explore the preventative effects of penehyclidine with propofol-remifentanil-TIVA to single-TIVA on PONV in patients undergoing total thyroidectomy. METHODS: A total of 100 patients scheduled for total thyroidectomy were randomly assigned to either the penehyclidine group (n = 50) or TIVA group (n = 50). Propofol and remifentanil were was used for TIVA in all patients. No patients who received premedication. Patients were administrated with either 5 ml of normal saline or 0.5 mg of penehyclidine soon after anesthesia induction. The incidence of nausea and vomiting, the severity of nausea, the requirement of rescue antiemetics, and adverse effects were investigated during the first 24 h in two time periods (0-2 h and 2-24 h). RESULTS: The overall PONV incidence during the 24 h after surgery was significantly lower in the penehyclidine group compared with the TIVA group (12% vs 36%, P < 0.005). Besides, the incidence of nausea and the incidence of vomiting were significantly lower in the penehyclidine group compared with the TIVA group at 2-24 h after surgery. However, there was no significant difference between the two groups at 0-2 h after surgery. CONCLUSIONS: Administration of penehyclidine under TIVA with propofol-remifentanil is more effective for prevention of PONV than TIVA alone, especially 2-24 h after total thyroidectomy. TRIAL REGISTRATION: https://www.chictr.org.cn/edit.aspx?pid=132463&htm=4 (Ref: ChiCTR2100050278, the full date of first registration: 25/08/2021).


Assuntos
Antieméticos , Propofol , Anestesia Geral/efeitos adversos , Anestesia Intravenosa , Anestésicos Intravenosos/efeitos adversos , Antieméticos/uso terapêutico , Antagonistas Colinérgicos , Humanos , Piperidinas/efeitos adversos , Náusea e Vômito Pós-Operatórios/induzido quimicamente , Náusea e Vômito Pós-Operatórios/epidemiologia , Náusea e Vômito Pós-Operatórios/prevenção & controle , Propofol/efeitos adversos , Quinuclidinas , Remifentanil , Solução Salina , Tireoidectomia/efeitos adversos
6.
Can Respir J ; 2022: 2878648, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060827

RESUMO

Background: Both long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs) are widely used in the treatment of chronic obstructive pulmonary disease (COPD). A novel LAMA/LABA combination of umeclidinium/vilanterol (UMEC/VI; 62.5 µg/25 µg) is approved for chronic obstructive pulmonary disease (COPD) treatment. Objective: This study aimed to assess the efficacy and cost-effectiveness of UMEC/VI versus tiotropium (TIO) 18 µg in symptomatic patients with COPD from the perspective of the Chinese National Healthcare System. Methods: A simple analysis included three studies in the meta-analysis that compared UMEC/VI with TIO. A Markov model was developed to estimate the cost-effectiveness of UMEC/VI compared with TIO treatment in symptomatic patients with COPD. First, utilities, clinical efficacy, and adverse events obtained from the literature were utilized as model inputs. Costs were from Chinese average data, including local data. Costs were expressed in dollars based on 2020 prices. Then, the model outputs including drug costs, other medical costs, and total costs, and quality-adjusted life years (QALYs) were estimated. Costs and outcomes were discounted at a 5% annual rate. Furthermore, incremental cost-effective ratios (ICERs) were analyzed. Finally, the influences of changing parameters on the uncertainty of the results were assessed by means of one-way and probabilistic sensitivity analyses. Results: This study revealed that UMEC/VI treatment had a higher rate of clinical efficacy in comparison with TIO, and the differences in the rate of adverse events between the two treatments were not significant. The results indicated that UMEC/VI was superior to TIO, which provided an increase in QALYs (0.002) and a total cost savings of $765.67 per patient over 3 years. In the base case, the ICER of UMEC/VI is -$397468.04/QALY compared with TIO, suggesting that UMEC/VI may be considered a dominant option over TIO. According to the Chinese medical system, the probability of UMEC/VI being cost-effective was 61.6% at a willingness-to-pay (WTP) of $31554/QALY. Sensitivity analyses confirmed that the results were robust. Conclusion: UMEC/VI could be considered a cost-effective treatment compared with TIO in symptomatic COPD patients from the Chinese National Healthcare System perspective. These results may help decision-makers in China when making judgements on which treatments to administer.


Assuntos
Broncodilatadores , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Álcoois Benzílicos , Broncodilatadores/uso terapêutico , Clorobenzenos , Análise Custo-Benefício , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Quinuclidinas , Brometo de Tiotrópio/uso terapêutico , Resultado do Tratamento
7.
J Clin Invest ; 132(18)2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36106631

RESUMO

In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.


Assuntos
Inibidores de Checkpoint Imunológico , Macrófagos Associados a Tumor , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos , Quinuclidinas , Microambiente Tumoral , Proteína Supressora de Tumor p53/genética
8.
Int J Chron Obstruct Pulmon Dis ; 17: 2043-2052, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072608

RESUMO

Background: In the FULFIL trial, once-daily single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) resulted in reduced moderate/severe exacerbation rates and conferred significant improvements in lung function and health status in patients with chronic obstructive pulmonary disease (COPD) versus twice-daily budesonide/formoterol (BUD/FOR) dual therapy. Methods: FULFIL was a Phase III, randomized, double-blind, double-dummy, parallel-group study. Patients ≥40 years of age with symptomatic COPD were randomized 1:1 to FF/UMEC/VI 100/62.5/25 mcg or BUD/FOR 400/12 mcg. In this post hoc analysis, patients were categorized by exacerbation history in the year prior to study entry (≥1 moderate/severe exacerbation [recent exacerbation] versus no recent exacerbation). Endpoints included annual rate of on-treatment moderate/severe exacerbations up to Week 24, annual rate of on-treatment severe exacerbations up to Week 24, change from baseline in trough forced expiratory volume in 1 second at Week 24, and change from baseline in health status as measured by St George's respiratory questionnaire total score at Week 24. Results: Of the 1810 patients in the intent-to-treat population, 1180 (65%) had one or more moderate/severe exacerbation in the year prior to entry, while 630 (35%) patients did not. FF/UMEC/VI versus BUD/FOR significantly reduced moderate/severe exacerbation rates in the recent exacerbation subgroup (mean annualized rate: 0.19 vs 0.29; rate ratio [95% confidence interval [CI]]: 0.64: [0.45, 0.91]; p=0.014) and numerically reduced moderate/severe exacerbation rates in the no recent exacerbation subgroup (mean annualized rate: 0.29 vs 0.43; rate ratio [95% CI]: 0.67 [0.43, 1.04]; p=0.073). Severe exacerbation rates were numerically reduced with FF/UMEC/VI versus BUD/FOR treatment across both subgroups. FF/UMEC/VI conferred significant improvements in lung function and health status versus BUD/FOR, regardless of recent exacerbation history. Conclusion: FF/UMEC/VI reduced moderate/severe and severe exacerbation rates and improved lung function and health status versus BUD/FOR in patients with symptomatic COPD, regardless of recent exacerbation history.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Androstadienos , Álcoois Benzílicos , Broncodilatadores/efeitos adversos , Combinação Budesonida e Fumarato de Formoterol/uso terapêutico , Clorobenzenos , Fluticasona/uso terapêutico , Humanos , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas
9.
ESMO Open ; 7(5): 100573, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36084396

RESUMO

BACKGROUND: We conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938). PATIENTS AND METHODS: For dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with previous anti-PD-1/PD-L1 therapy. Patients received eprenetapopt 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle. Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and recommended phase II dose (RP2D) of eprenetapopt. RESULTS: Forty patients were enrolled (median age 66 years; range 27-85) and 37 received eprenetapopt plus pembrolizumab. No DLTs were reported and the RP2D for eprenetapopt in combination was 4.5 g/day IV on days 1-4. The most common eprenetapopt-related AEs were dizziness (35.1%), nausea (32.4%), and vomiting (29.7%). AEs leading to eprenetapopt discontinuation occurred in 2/37 patients (5.4%). In efficacy-assessable patients (n = 29), one achieved complete response (urothelial cancer), two achieved partial responses (NSCLC, urothelial cancer), and six patients had stable disease. CONCLUSIONS: The eprenetapopt plus pembrolizumab combination was well tolerated with an acceptable safety profile and showed clinical activity in patients with solid tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quinuclidinas/uso terapêutico
10.
J Med Chem ; 65(18): 12334-12345, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36074125

RESUMO

Venglustat is a known allosteric inhibitor for ceramide glycosyltransferase, investigated in diseases caused by lysosomal dysfunction. Here, we identified venglustat as a potent inhibitor (IC50 = 0.42 µM) of protein N-terminal methyltransferase 1 (NTMT1) by screening 58,130 compounds. Furthermore, venglustat exhibited selectivity for NTMT1 over 36 other methyltransferases. The crystal structure of NTMT1-venglustat and inhibition mechanism revealed that venglustat competitively binds at the peptide substrate site. Meanwhile, venglustat potently inhibited protein N-terminal methylation levels in cells (IC50 = 0.5 µM). Preliminary structure-activity relationships indicated that the quinuclidine and fluorophenyl parts of venglustat are important for NTMT1 inhibition. In summary, we confirmed that venglustat is a bona fide NTMT1 inhibitor, which would advance the study on the biological roles of NTMT1. Additionally, this is the first disclosure of NTMT1 as a new molecular target of venglustat, which would cast light on its mechanism of action to guide the clinical investigations.


Assuntos
Carbamatos/farmacologia , Inibidores Enzimáticos , Metiltransferases , Quinuclidinas/farmacologia , Carbamatos/química , Ceramidas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicosiltransferases/metabolismo , Metilação , Quinuclidinas/química
11.
Support Care Cancer ; 30(11): 9307-9315, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36074186

RESUMO

PURPOSE: The aim of this study was to assess the cost-effectiveness of NEPA, a fixed-dose combination of oral netupitant (300 mg) and palonosetron (0.5 mg), compared to available treatments in Spain after aprepitant generic introduction in the market, and to discuss results in previously performed analyses in different wordwide settings. METHODS: A Markov model including three health states, complete protection, complete response at best and incomplete response, was used to evaluate the cost-effectiveness of NEPA versus common treatment options in Spain during 5 days after chemotherapy. Incremental costs including treatment costs and treatment failure management cost as well as incremental effects including quality adjusted life days (QALDs) and emesis-free days were compared between NEPA and the comparator arms. The primary outcomes were cost per avoided emetic event and cost per QALDs gained. RESULTS: NEPA was dominant (more effective and less costly) against aprepitant combined with palonosetron, and fosaprepitant combined with granisetron, while, compared to generic aprepitant plus ondansetron, NEPA showed an incremental cost per avoided emetic event of €33 and cost per QALD gained of €125. CONCLUSION: By most evaluations, NEPA is a dominant or cost-effective treatment alternative to current antiemetic standards of care in Spain during the first 5 days of chemotherapy treatment in cancer patients, despite the introduction of generics. These results are in line with previously reported analyses throughout different international settings.


Assuntos
Antieméticos , Antineoplásicos , Humanos , Palonossetrom/uso terapêutico , Análise Custo-Benefício , Aprepitanto/uso terapêutico , Eméticos/efeitos adversos , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Vômito/prevenção & controle , Antineoplásicos/efeitos adversos , Náusea/induzido quimicamente , Náusea/prevenção & controle , Náusea/tratamento farmacológico , Internacionalidade , Quinuclidinas
12.
BMC Cancer ; 22(1): 915, 2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-35999527

RESUMO

BACKGROUND: The non-inferiority of dexamethasone (DEX) on day 1, with or without low-dose DEX on days 2 and 3, combined with oral NEPA (netupitant/palonosetron), compared with the guideline-consistent use of DEX was demonstrated in cisplatin. Here, we complete the analysis by assessing the impact of emesis on daily lives of patients receiving DEX-sparing regimens using the Functional Living Index-Emesis (FLIE). METHODS: Chemotherapy-naïve patients undergoing cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized to receive either 1) no further DEX (DEX1), 2) oral DEX (4 mg daily) on days 2-3 (DEX3), or 3) DEX (4 mg twice daily) on days 2-4 (DEX4; control). Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included the FLIE nausea domain, vomiting domain, and overall combined domain scores, as well as the proportion of patients with no impact on daily life (NIDL; overall score > 108). This was a protocol-planned analysis. RESULTS: In the DEX1 group, no significant differences were observed in the FLIE nausea score (48.9 [±1.8; SE] vs. 53.7 [±1.5]), vomiting score (56.6 [±1.4] vs. 58.7 [±0.8]) and overall score (105.6 [±2.8] vs.112.4 [±1.9]) versus DEX4 control; similar results were observed in the DEX3 group for nausea score (49.6 [±1.7]), vomiting score (58.2 [±1]) and overall score (107.8 [±2.4]) versus control. There were no significant between-group differences in the proportion of patients reporting NIDL. CONCLUSION: Reducing DEX, when administered with NEPA, does not seem to adversely impact the daily functioning in patients undergoing cisplatin. TRIAL REGISTRATION: ClinicalTrials.gov NCT04201769 . Registration date: 17/12/2019 - Retrospectively registered.


Assuntos
Antieméticos , Antineoplásicos , Antineoplásicos/efeitos adversos , Benzenoacetamidas , Cisplatino/efeitos adversos , Dexametasona , Humanos , Náusea/induzido quimicamente , Palonossetrom/uso terapêutico , Piperazinas , Piridinas , Quinuclidinas , Vômito/induzido quimicamente , Vômito/tratamento farmacológico
13.
Int J Chron Obstruct Pulmon Dis ; 17: 1633-1642, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35915738

RESUMO

Objectives: In the IMPACT trial (NCT02164513), triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) showed clinical benefit compared with dual therapy with either FF/VI or UMEC/VI in the treatment of chronic obstructive pulmonary disease (COPD). We used data from IMPACT to determine whether this translated into differences in COPD-related healthcare resource utilization (HRU) costs in a United Kingdom (UK) setting. Methods: In a within-trial analysis, individual patient data from the IMPACT intention-to-treat (ITT) population were analyzed to estimate rates of COPD-related HRU with FF/UMEC/VI, FF/VI, or UMEC/VI. A Bayesian approach was applied to address issues typically encountered with this kind of data, namely data missing due to early study withdrawal, subjects with zero reported HRU, and skewness. Rates of HRU were estimated under alternate assumptions of data being missing at random (MAR) or missing not at random (MNAR). UK-specific unit costs were then applied to estimated HRU rates to calculate treatment-specific costs. Results: Under each MNAR scenario, per patient per year (PPPY) rates of COPD-related HRU were lowest amongst those patients who received treatment with FF/UMEC/VI compared with those receiving either FF/VI or UMEC/VI. Although absolute HRU rates and costs were typically higher for all treatment groups under MNAR scenarios versus MAR, final economic conclusions were robust to patient withdrawals. Conclusions: PPPY rates were typically lower with FF/UMEC/VI versus FF/VI or UMEC/VI.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Androstadienos/efeitos adversos , Teorema de Bayes , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Atenção à Saúde , Método Duplo-Cego , Combinação de Medicamentos , Fluticasona/uso terapêutico , Humanos , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/efeitos adversos
14.
Future Oncol ; 18(30): 3389-3397, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36017782

RESUMO

Aim: To further evaluate the antiemetic efficacy of single-dose versus multiple-dose dexamethasone (DEX) against nausea and vomiting caused by cisplatin. Materials & methods: Two similar non-inferiority studies were pooled. Patients were randomized to single-day DEX or multiple-day DEX plus palonosetron and neurokinin-1 receptor-antagonists (NK-1RAs). The primary endpoint was complete response (CR; no vomiting and no rescue medication) during the overall phase. Results: The combined analysis included 242 patients. The absolute risk difference between single day versus multi-day DEX for CR was -2% (95% CI, -14 to 9%). Conclusion: Administration of single-dose DEX offers comparable antiemetic control to multiple-day DEX when combined with palonosetron and an NK-1RA in the setting of single-day cisplatin.


We aimed at further evaluating how well the corticosteroid, dexamethasone (DEX), works as measured in two similar clinical studies of single-day versus multiple-day DEX for the prevention of nausea and vomiting caused by cisplatin, a cell-killing drug, which has high potential of triggering nausea and vomiting. In both studies, cancer patients were randomly assigned to 1-day DEX or multiple-day DEX (3­4 days) in combination with palonosetron (this antagonist attaches to a specific receptor for serotonin without triggering nausea and vomiting), and neurokinin-1 receptor-antagonists (NK-1RAs; they attach to the NK-1 receptor without triggering nausea and vomiting). The combined analysis of the two studies, which includes 242 patients, showed that a single dose of DEX is as effective as multiple-day DEX in terms of the number of patients achieving complete response (defined as no vomiting and no 'as-needed' use of antiemetics) during the 5 days after cisplatin administration. Therefore, administration of single-dose DEX offers comparable antiemetic control to multiple-day DEX when combined with palonosetron and an NK-1RA in patients undergoing single-day cisplatin.


Assuntos
Antieméticos , Antineoplásicos , Humanos , Palonossetrom , Antieméticos/uso terapêutico , Cisplatino/efeitos adversos , Quinuclidinas/uso terapêutico , Isoquinolinas/uso terapêutico , Dexametasona/uso terapêutico , Antineoplásicos/efeitos adversos , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Vômito/prevenção & controle
15.
Acc Chem Res ; 55(18): 2708-2727, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36043467

RESUMO

ConspectusAsymmetric organocatalysis has been considered to be an efficient and reliable strategy for the stereoselective preparation of optically active chemicals. In particular, chiral tertiary amines as Lewis base organocatalysts bearing core structures including quinuclidine, dimethylaminopyridine (DMAP), N-methylimidazole (NMI), amidine, etc. have provided new and powerful tools for various chemical transformations. However, due to the limitations in structural complexity, synthetic difficulty, low catalytic efficiency, and high cost, the industrial application of such catalysts is still far from being widely adopted. Therefore, the development of new chiral tertiary amine catalysts with higher activity and selectivity is greatly desired.In order to address the contradiction between activity and selectivity caused by the ortho group, a bicyclic imidazole structure bearing a relatively large bond angle ∠θ was designed as the skeleton of our new catalysts. 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole (abbreviated as DPI) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (abbreviated as TIP) are two of the utilized skeletons. In addition to obtaining satisfactory catalytic activity, excellent enantioselectivity would also be expected because the stereocontrol R group is neither far nor close to the catalytic active site (sp2-N atom) and is adjustable. Based on this skeleton, a family of chiral bicyclic imidazole catalysts were easily prepared and successfully applied in several enantioselective reactions for the synthesis of a variety of valuable chiral compounds.6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole (abbreviated as DPI) is the predominantly utilized skeleton. First, HO-DPI, the key intermediate of the designed chiral bicyclic imidazole catalysts, could be efficiently synthesized from imidazole and acrolein, then separated by kinetic resolution or optical resolution. Second, Alkoxy-DPI, the alkyloxy-substituted chiral bicyclic imidazole catalysts, were synthesized by a one-step alkylation from HO-DPI. This type of catalyst has been successfully applied in asymmetric Steglich rearrangement (C-acylation rearrangement of O-acylated azlactones), asymmetric phosphorylation of lactams, and a sequential four-step acylation reaction. Third, Acyloxy-DPI, the acyloxy-substituted chiral bicyclic imidazole catalysts, were synthesized with a one-step acetylative kinetic resolution from racemic HO-DPI or acylation from enantiopure HO-DPI. The catalyst AcO-DPI has been successfully applied in enantioselective Black rearrangement and in direct enantioselective C-acylation of 3-substituted benzofuran-2(3H)-ones and 2-oxindoles. Fourth, Alkyl-DPI was synthesized via a two-step reaction from racemic HO-DPI and separated easily by resolution. The catalyst Cy-DPI has been successfully applied in dynamic kinetic resolution of 3-hydroxyphthalides through enantioselective O-acylation. Cy-PDPI was synthesized through a Cu-catalyzed amidation from Cy-DPI and successfully applied in the kinetic resolution of secondary alcohols with good to excellent enantioselectivities. Finally, the carbamate type chiral bicyclic imidazole catalysts, Carbamate-DPI, were readily synthesized from HO-DPI, and the catalyst Ad-DPI bearing a bulky adamantyl group was successfully applied in the synthesis of the anti-COVID-19 drug remdesivir via asymmetric phosphorylation. Alongside our initial work, this Account also introduces four elegant studies by other groups concerning asymmetric phosphorylation utilizing chiral bicyclic imidazole catalysts.In summary, this Account focuses on the chiral bicyclic imidazole catalysts developed in our group and provides an overview on their design, synthesis, and application that will serve as inspiration for the exploration of new organocatalysts and related reactions.


Assuntos
Benzofuranos , Bases de Lewis , Acroleína , Amidinas , Aminas , Carbamatos , Catálise , Imidazóis/química , Lactamas/química , Oxindóis , Piridinas , Quinuclidinas , Estereoisomerismo
16.
Adv Ther ; 39(9): 3957-3978, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35849317

RESUMO

INTRODUCTION: Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting ß2-agonist [LABA], and long-acting muscarinic antagonist [LAMA]) for the treatment of chronic obstructive pulmonary disease (COPD) are limited. This network meta-analysis (NMA) investigated the comparative efficacy of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus any triple (ICS/LABA/LAMA) combinations and dual therapies in patients with COPD. METHODS: This NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEV1), annualized rate of combined moderate and severe exacerbations, St George's Respiratory Questionnaire (SGRQ) total score and SGRQ responders, transition dyspnea index focal score, and rescue medication use (RMU). Analyses were conducted at 24 weeks (primary endpoint), and 12 and 52 weeks (if feasible). RESULTS: The NMA was informed by five trials reporting FEV1 at 24 weeks. FF/UMEC/VI was statistically significantly more effective at increasing trough FEV1 (based on change from baseline) than all triple comparators in the network apart from UMEC + FF/VI. The NMA was informed by 17 trials reporting moderate or severe exacerbation endpoints. FF/UMEC/VI demonstrated statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus single-inhaler budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR). At 24 weeks, the NMA was informed by five trials. FF/UMEC/VI showed statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus UMEC + FF/VI and BUD/GLY/FOR. FF/UMEC/VI also demonstrated improvements in mean SGRQ score versus other triple therapy comparators at 24 weeks, and a significant reduction in RMU compared with BUD/GLY/FOR (160/18/9.6). CONCLUSION: The findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available.


Assuntos
Clorobenzenos , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Corticosteroides/uso terapêutico , Adulto , Androstadienos , Álcoois Benzílicos/uso terapêutico , Broncodilatadores/uso terapêutico , Combinação Budesonida e Fumarato de Formoterol/uso terapêutico , Clorobenzenos/uso terapêutico , Combinação de Medicamentos , Fluticasona/uso terapêutico , Humanos , Antagonistas Muscarínicos/uso terapêutico , Metanálise em Rede , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/uso terapêutico
17.
Leukemia ; 36(9): 2269-2280, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35835991

RESUMO

TP53 mutations correlate with inferior survival in many cancers. APR-246 is a compound to shift mutant p53 and exhibits anti-cancer effects. Among its effects, APR-246 facilitates the binding of restored p53 mutants to target genes and their transcription. A set of 2464 DLBCL cases from multiple cohorts including our center, was integrated to identify the type and localization of TP53 mutations and clinical impacts. APR-246 was applied in TP53-mutated DLBCL cells and xenograft mouse models to explore the anti-tumor effect. TP53 mutations frequency was 16% and TP53 mutations correlated with poor overall survival (OS) and progression-free survival (PFS) in all cases, especially in germinal center B-cell-like (GCB) and unclassified (UNC) subtypes. Notably, TP53 single mutations in the DNA binding domain (DBD) led to poor OS and PFS. Specifically, mutations in exon 7 correlated with poorer OS, while mutations in exons 5 and 6 associated with inferior PFS. APR-246 induces p53-dependent ferritinophagy of DLBCL cells with TP53 missense mutation on exon 7 and ferroptosis of DLBCL cells harboring wild-type TP53 and other TP53 mutations. TP53 mutations on exons 5, 6 and 7 are predictors of progression and survival. Targeting mutant p53 by APR-246 is a promising therapeutic approach for DLBCL patients.


Assuntos
Ferroptose , Linfoma Difuso de Grandes Células B , Quinuclidinas , Animais , Ferroptose/efeitos dos fármacos , Humanos , Ferro/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Camundongos , Mutação , Prognóstico , Quinuclidinas/farmacologia , Proteína Supressora de Tumor p53
18.
Pol J Vet Sci ; 25(2): 357-359, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35861987

RESUMO

The aim of this research was to determine the embryotoxic and teratogenic effects and lethal dose (LD50) of maropitant in ovo, using fertile chicken eggs. The study was designed in two stages, CHEST-I and CHEST-II. For CHEST-I, 210 fertile eggs were divided into seven equal groups; control, saline solution and 5 different doses of maropitant (10, 5, 2.5, 1.25, 0.625 mg/kg) injected groups. For CHEST-II, 150 fertile eggs were divided into five equal groups; control, saline solution and 3 different doses of maropitant (8, 6, 4 mg/kg)-injected groups. Eggs were opened on day 21 of incubation. Maropitant did not cause teratogenicity at any dose, while higher embryonic death rates were observed at doses above 4 mg/kg. The LD50 dose of maropitant was determined as 7.24 mg/kg. In conclusion, maropitant should only be used after full consideration of risks and benefits in pregnancy.


Assuntos
Quinuclidinas , Solução Salina , Animais , Galinhas , Injeções/veterinária
19.
Adv Ther ; 39(11): 4961-5010, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35857184

RESUMO

INTRODUCTION: Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting ß2-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.


Bronchodilators are medicines that open the airways, allowing patients with chronic obstructive pulmonary disease (COPD) to breathe more easily. There are two different types of bronchodilators, namely long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs), which can be used on their own or combined (LAMA/LABAs). Only a few clinical trials have compared different LAMA/LABA combinations with each other, so it is unclear which LAMA/LABA combination provides the greatest benefits for patients.In this study, we used network meta-analysis to compare a LAMA/LABA combination medicine called umeclidinium and vilanterol (UMEC/VI) with other LAMAs and LABAs used alone or in combination to treat patients with COPD. Network meta-analysis is a way of comparing two or more medicines by analysing data from many studies. We systematically searched for evidence from clinical trials in adult patients with COPD that were at least 8 weeks long and that compared LAMA/LABA combinations with a LAMA, a LABA, or another LAMA/LABA combination. We analysed data from 49 clinical trials that met these criteria.We found that patients treated with UMEC/VI had better lung function than patients treated with alternative LAMA/LABA combinations or bronchodilators used on their own. Patients treated with UMEC/VI had better quality of life than those receiving some other treatments, but not all. All the medicines we compared had similar side effects.Our results suggest that treating patients with COPD with UMEC/VI might improve their lung function and quality of life more than alternative bronchodilators.


Assuntos
Broncodilatadores , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2 , Adulto , Álcoois Benzílicos , Clorobenzenos , Combinação de Medicamentos , Dispneia/tratamento farmacológico , Volume Expiratório Forçado , Glicopirrolato/uso terapêutico , Humanos , Antagonistas Muscarínicos , Metanálise em Rede , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas , Xinafoato de Salmeterol/farmacologia , Xinafoato de Salmeterol/uso terapêutico , Brometo de Tiotrópio , Resultado do Tratamento
20.
Respir Med ; 200: 106918, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35803172

RESUMO

Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a large, multicentre, multi-national, randomised, double-blind, 24-week trial. EMAX evaluated the efficacy and safety of dual bronchodilator therapy with umeclidinium bromide (UMEC)/vilanterol (VI) versus monotherapy with either UMEC or salmeterol (SAL) in symptomatic patients with chronic obstructive pulmonary disease (COPD) at low exacerbation risk who were not taking concomitant inhaled corticosteroid (ICS). EMAX generated evidence covering a wide range of patient-centred endpoints in COPD in addition to measures of lung function, clinical deterioration and safety. In addition, prospective and post hoc secondary analyses have generated clinically valuable information regarding the effects of baseline patient characteristics on treatment outcomes. Importantly, as concomitant ICS use was not permitted in this study, EMAX compared dual long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy with LAMA or LABA monotherapy without potential confounding due to concurrent ICS use or withdrawal. EMAX demonstrated beneficial treatment effects of UMEC/VI over UMEC or SAL monotherapy as maintenance treatment across a range of different patient characteristics, with no forfeit in safety. Thus, the trial provided novel insights into the role of LAMA/LABA versus LABA and LAMA monotherapies as maintenance therapy for patients with symptomatic COPD at low risk of exacerbations. This article will explore the clinical implications of the main findings to date of the EMAX trial and consider the key learnings this trial offers for future trial design in COPD.


Assuntos
Broncodilatadores , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2 , Clorobenzenos , Combinação de Medicamentos , Combinação Fluticasona-Salmeterol , Humanos , Estudos Multicêntricos como Assunto , Antagonistas Muscarínicos , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Xinafoato de Salmeterol/uso terapêutico , Resultado do Tratamento
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