RESUMO
In this study, covalent organic frameworks (COFs) were grown in situ on magnetic nitrogen-doped graphene foam (MNGF), and the resulting composite of COFs-modified MNGF (MNC) was wrapped by molecularly imprinted polymers (MNC@MIPs) for specifically capturing SAs. A magnetic solid phase extraction (MSPE) method for SAs was established using MNC@MIPs with good magnetic responsiveness. The adsorption performance of MNC@MIPs was superior to that of non-molecularly imprinted polymers (MNC@NIPs), with shorter adsorption/desorption time and higher imprinting factors. A high-efficiency SAs analytical method was developed by fusing HPLC and MNC@MIPs-based MSPE. This approach provides excellent precision, a low detection limit, and wide linearity. By analyzing fish samples, the feasibility of the approach was confirmed, with SAs recoveries and relative standard deviations in spiked samples in the ranges of 77.2-112.7 % and 2.0-7.2 %, respectively. This study demonstrated the potential use of MNC@MIPs-based MSPE for efficient extraction and quantitation of trace hazards in food.
Assuntos
Peixes , Contaminação de Alimentos , Estruturas Metalorgânicas , Polímeros Molecularmente Impressos , Extração em Fase Sólida , Sulfonamidas , Extração em Fase Sólida/métodos , Extração em Fase Sólida/instrumentação , Animais , Polímeros Molecularmente Impressos/química , Adsorção , Contaminação de Alimentos/análise , Estruturas Metalorgânicas/química , Sulfonamidas/isolamento & purificação , Sulfonamidas/química , Sulfonamidas/análise , Impressão Molecular , Polímeros/químicaRESUMO
A green, simple and sensitive spectrofluorometric approach for determining vonoprazan fumarate in bulk and pharmaceutical dosage form by turning off the fluorescence of sodium salicylate is developed. The addition of vonoprazan fumarate reduced linearly the fluorescence intensity of 0.4 mM sodium salicylate at λem 408 nm and at λex 330 nm. The approach was found to be linear in the 50.0-3000.0 ng/mL range. The limits of detection and quantification were 10.97 and 33.23 ng/mL, respectively. The presented method proved its suitability in determination of vonoprazan fumarate in its pure and pharmaceutical dosage form. This method employs water as the exclusive solvent and utilizes safe reagents, evaluated using the Analytical Eco Scale, Green Analytical Procedure Index (GAPI), and carbon footprint. In contrast, previous methods relied on toxic reagents and required extended heating times, resulting in higher environmental impact. The novel method not only enhances analytical efficiency but also aligns with green chemistry principles, offering a sustainable solution for routine pharmaceutical analysis.
Assuntos
Corantes Fluorescentes , Química Verde , Limite de Detecção , Pirróis , Salicilato de Sódio , Espectrometria de Fluorescência , Sulfonamidas , Sulfonamidas/análise , Sulfonamidas/química , Espectrometria de Fluorescência/métodos , Pirróis/química , Química Verde/métodos , Corantes Fluorescentes/química , Salicilato de Sódio/química , Salicilato de Sódio/análise , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Hyperphosphatemia occurs universally in end-stage renal disease(ESRD), and the attainment of target serum phosphate levels remains suboptimal with currently available phosphate binders. This meta-analysis aimed to evaluate the efficacy and safety of tenapanor in end-stage renal disease patients with hyperphosphatemia. METHODS: Data sources included PubMed, Embase, Web of Science, and Cochrane Library. This meta-analysis included randomized controlled trials evaluating both the efficacy of tenapanor in reducing serum phosphate levels and its safety profile. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs. The GRADE system was used to assess the overall certainty of evidence. A meta-analysis was carried out by using fixed effects (I2 values < 50%) or random effects (I2 values ≥ 50%) models to calculate MD with 95% CI for continuous outcome variables and RR with 95% CI for dichotomous variables. Publication bias was evaluated using funnel plots. RESULTS: A total of seven RCTs involving 877 individuals were included. The pooling analysis demonstrates that the reduction in mean serum phosphorus levels in the tenapanor group was significantly greater than that in the placebo group [MD= -1.06 mg/dl, 95% CI (-1.59, -0.53); I2 = 83%, p < 0.0001]. The proportion of patients achieving a serum phosphorus level of < 5.5 mg/dL, along with the incidence of any adverse events (AEs) and gastrointestinal disorders, was higher in the tenapanor group compared to the placebo group. CONCLUSION: Tenapanor has the potential to significantly reduce serum phosphorus levels and enhance the rate of achieving target levels compared to placebo, all while maintaining an acceptable safety and tolerability profile. REGISTRATION: PROSPERO registration number CRD42024544531.
Assuntos
Hiperfosfatemia , Isoquinolinas , Falência Renal Crônica , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas , Humanos , Hiperfosfatemia/tratamento farmacológico , Hiperfosfatemia/etiologia , Hiperfosfatemia/sangue , Falência Renal Crônica/terapia , Falência Renal Crônica/complicações , Falência Renal Crônica/sangue , Sulfonamidas/uso terapêutico , Isoquinolinas/uso terapêutico , Isoquinolinas/efeitos adversos , Fósforo/sangue , Resultado do Tratamento , Fosfatos/sangue , Diálise Renal/efeitos adversosRESUMO
INTRODUCTION: It remains uncertain whether Descemet membrane endothelial keratoplasty (DMEK) or Descemet stripping only (DSO) yields better outcomes in patients with symptomatic Fuchs endothelial corneal dystrophy (FECD). This paper presents the protocol for the Descemet Endothelial Thickness Comparison Trial II (DETECT II), a multicentre, outcome-masked, randomised, placebo-controlled, clinical trial comparing DMEK to DSO with ripasudil (DSO-R) for this patient population. METHODS AND ANALYSIS: A total of 60 patients with endothelial dysfunction due to symptomatic FECD will be enrolled from seven participating sites in the USA. The patients will be randomly assigned in a 1:1 ratio to one of the following treatment groups: group 1-DMEK plus topical placebo and group 2-DSO plus topical ripasudil 0.4%. The enrolment period is 24 months. The primary outcome is best spectacle-corrected visual acuity at 12 months. Secondary outcomes include peripheral and central endothelial cell density, visual acuity, vision-related quality of life and Pentacam Scheimpflug tomography. Study outcomes will be analysed using mixed effects linear regression. Adverse events, including rebubble procedures, endothelial failure and graft rejection, will be documented and analysed using appropriate statistical methods. DETECT II aims to provide evidence on the comparative effectiveness of DMEK and DSO-R. The results of this trial will contribute to optimising the treatment of FECD, while also exploring the cost-effectiveness of these interventions. Dissemination of findings through peer-reviewed publications and national/international meetings will facilitate knowledge translation and guide clinical practice in the field of corneal transplantation. ETHICS AND DISSEMINATION: A data and safety monitoring committee has been empanelled by the National Eye Institute. All study protocols will be subject to review and approval by WCG IRB as the single IRB of record. This study will comply with the National Institute of Health (NIH) Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Data from the trial will be made available on reasonable request. TRIAL REGISTRATION NUMBER: NCT05275972.
Assuntos
Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior , Distrofia Endotelial de Fuchs , Isoquinolinas , Sulfonamidas , Acuidade Visual , Humanos , Distrofia Endotelial de Fuchs/cirurgia , Distrofia Endotelial de Fuchs/tratamento farmacológico , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/métodos , Acuidade Visual/efeitos dos fármacos , Masculino , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Feminino , Isoquinolinas/uso terapêutico , Isoquinolinas/administração & dosagem , Endotélio Corneano/patologia , Lâmina Limitante Posterior/cirurgia , Resultado do Tratamento , Pessoa de Meia-Idade , Idoso , Soluções Oftálmicas/uso terapêutico , Estudos Multicêntricos como AssuntoRESUMO
Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad-spectrum anti-inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART-648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an in vitro whole-blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART-648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide-induced TNFα release in ex vivo whole-blood assay. In the single rising dose study, ART-648 was safe and well tolerated with a dose-proportional increase in exposures up to 4 mg. Single doses of ART-648 demonstrated dose-dependent PD response, indicating target engagement at 2-8 mg doses. In the multiple rising dose study, doses up to 4 mg BID after careful titration were well tolerated, while doses up to 6 mg BID were tolerated not in all but the majority of subjects. In conclusion, ART-648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.
Assuntos
Relação Dose-Resposta a Droga , Voluntários Saudáveis , Inibidores da Fosfodiesterase 4 , Humanos , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/administração & dosagem , Inibidores da Fosfodiesterase 4/efeitos adversos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Método Duplo-Cego , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Lipopolissacarídeos/administração & dosagem , Administração Oral , Sulfonamidas , para-AminobenzoatosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Linfocítica Crônica de Células B , Sulfonamidas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Resultado do TratamentoAssuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Combinação de Medicamentos , Hospitalização , Hospedeiro Imunocomprometido , Ritonavir , Humanos , Ritonavir/uso terapêutico , Ritonavir/administração & dosagem , Hospitalização/estatística & dados numéricos , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Citidina/análogos & derivados , Citidina/uso terapêutico , Hidroxilaminas/uso terapêutico , Leucina/análogos & derivados , Leucina/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , COVID-19/prevenção & controle , Lactamas , NitrilasRESUMO
OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety of the nine most widely studied Vonoprazan (VPZ)-based treatment regimens along with traditional Proton pump inhibitor (PPI)-based treatment regimens in eradicating Helicobacter pylori (H. pylori) infection. DESIGN: Through searching PubMed, Embase, Cochrane Library, Web of Science, we exclusively included randomized controlled trials (RCTs) to investigate the efficacy of VPZ-based and PPI-based therapies for H. pylori infection. The included studies were evaluated for methodological quality using the Cochrane bias risk assessment tool, and the data analysis software was used to analyze the data accordingly. RESULTS: The RCTs were collected from the earliest available date up to August 2023. Twenty-one RCTs were included, with a total sample size of 5481. The results of the network meta-analysis showed that the eradication rate of the VPZ-based quadruple 14-day (VPZ-Q14) treatment regimen in Intention-to-treat (ITT) analysis was the highest (SUCRA: 0.874); The eradication rate of the VPZ-based quadruple 10-day (VPZ-Q10) treatment plan in Per-protocol (PP) analysis was the highest (SUCRA: 0.849). All regimens were well tolerated without significant differences. According to the probability ranking of safety, high-dose VPZ-based dual 14-day therapy (H-VPZ-D14) ranked first in SUCRA, reaching 0.952. This indicates that H-VPZ-D14 treatment is the safest with a relatively low incidence of adverse effect. Therefore, VPZ-based therapies not only have a higher eradication rate, but also possess satisfactory safety. CONCLUSION: Compared with traditional PPI-based therapies, VPZ-based therapies have shown superior eradication effects. Based on the Ranking Plot of the Network, the VPZ-Q14 or VPZ-Q10 treatment regimen for H. pylori has a higher eradication rate and acceptable differences compared to other treatment regimens. In addition, for regions with high antibiotic resistance rates, we recommend a 14-day quadruple therapy with bismuth based on VPZ.
Assuntos
Quimioterapia Combinada , Infecções por Helicobacter , Helicobacter pylori , Metanálise em Rede , Inibidores da Bomba de Prótons , Pirróis , Sulfonamidas , Humanos , Infecções por Helicobacter/tratamento farmacológico , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Pirróis/uso terapêutico , Pirróis/efeitos adversos , Pirróis/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Helicobacter pylori/efeitos dos fármacos , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Sulfonamide (SA) residues in food of animal origin possess a potential threat to human health and environment. However, due to the polar and ionic characteristics and trace level of SAs and the complexity of food matrices, direct measurement of SAs in these samples is still very difficult. Development of efficient sample pretreatment method for sensitive and selective extraction of trace SAs is of great significance and urgently desired. Therefore, rational design and synthesizing advanced and selective extractants is quite important. RESULTS: In this work, a novel phenazine-based microporous organic network (MON) named TEPM-DP is reasonably synthesized and employed as a packing material for selective solid phase extraction (SPE) and sensitive determination of four typical SAs in milk samples. Phenazine-based monomer with aromatic and heteroaromatic ring and numerous N atoms is chosen to construct TEPM-DP adsorbent to provide π-π, hydrogen bonding, hydrophobic, and electrostatic extraction sites for SAs. The proposed method owns wide linear ranges, low limits of detection, high enrichment factors, and good precisions and recoveries for SAs in complex milk samples. The recoveries of SAs on TEPM-DP are much higher than those of commercial C18 and activated carbon. The extraction mechanisms are also elucidated via FT-IR, XPS, and comparative experiments. SIGNIFICANCE: This work reports the first example of design and synthesizing phenazine-based MON in SPE via a simple and rapid solvothermal method. The results reveal the great prospects of TEPM-DP for enriching polar and ionic SAs in complex samples and uncover the potency of phenazine-based MON in sample pretreatment, which will promote the development of MON.
Assuntos
Leite , Fenazinas , Extração em Fase Sólida , Sulfonamidas , Fenazinas/química , Leite/química , Animais , Sulfonamidas/análise , Sulfonamidas/isolamento & purificação , Extração em Fase Sólida/métodos , Porosidade , Limite de Detecção , Adsorção , Contaminação de Alimentos/análiseRESUMO
BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts. METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage. RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts. CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.
Assuntos
Neoplasias do Endométrio , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Humanos , Animais , Camundongos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/genética , Linhagem Celular Tumoral , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Sequenciamento do Exoma , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Gradação de Tumores , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/antagonistas & inibidores , Oxazepinas , Sulfonamidas , Pirazinas , Benzamidas , ImidazóisRESUMO
New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.
Assuntos
Antibacterianos , Benzamidas , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Relação Estrutura-Atividade , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Estrutura Molecular , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Relação Dose-Resposta a Droga , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Modelos MolecularesRESUMO
Background: Diabetic foot ulcers (DFUs) pose a substantial healthcare challenge due to their high rates of morbidity, recurrence, disability, and mortality. Current DFU therapeutics continue to grapple with multiple limitations. Senescent cells (SnCs) have been found to have a beneficial effect on acute wound healing, however, their roles in chronic wounds, such as DFU, remain unclear. Methods and results: We collected skin, fat, and muscle samples from clinical patients with DFU and lower limb fractures. RNA-sequencing combined with qPCR analyses on these samples demonstrate a significant accumulation of SnCs at DFU, as indicated by higher senescence markers (e.g., p16 and p21) and a senescence-associated secretory phenotype (SASP). We constructed a type 2 diabetic model of db/db mice, fed with a high-fat diet (Db-HFD), which were wounded using a 6 mm punch to the dorsal skin. HFD slightly affected wound healing in wild-type (WT) mice, but high glucose significantly delayed wound healing in the Db-HFD mice. We injected the mice with a previously developed fluorescent probe (XZ1208), which allows the detection of SnCs in vivo, and observed a strong senescence signal at the wound site of the Db-HFD mice. Contrary to the beneficial effects of SnCs in acute wound healing, our results demonstrated that clearance of SnCs using the senolytic compound ABT263 significantly accelerated wound healing in Db-HFD mice. Conclusion: Collectively, these findings suggest that SnCs critically accumulate at wound sites, delaying the healing process in DFUs. Thus, targeting SnCs with senolytic therapy represents a promising approach for DFU treatment, potentially improving the quality of life for patients with DFUs.
Assuntos
Senescência Celular , Diabetes Mellitus Tipo 2 , Pé Diabético , Pele , Cicatrização , Animais , Camundongos , Senescência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Humanos , Pé Diabético/terapia , Pé Diabético/metabolismo , Masculino , Pele/patologia , Pele/metabolismo , Dieta Hiperlipídica/efeitos adversos , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Diabetes Mellitus Experimental , Fenótipo Secretor Associado à Senescência , Feminino , SulfonamidasRESUMO
To determine the efficacy and safety of selinexor combined with venetoclax (VEN) and azactitidine (AZA) for patients with relapsed and/or refractory acute myeloid leukemia (R/R AML) . Twelve patients with R/R AML treated with selinexor plus VEN and AZA in the Affiliated Cancer Hospital of Zhengzhou University from May 2022 to May 2023 were included. Their clinical data were retrospectively analyzed. Among the 12 R/R AML patients, 5 (41.7%) achieved complete remission (CR) , 1 (8.3%) achieved CR with incomplete hematological recovery, and 5 (41.7%) achieved partial remission. The median time to reach CR was 28 (16-59) days. The median PFS was 61 (15-300) days. The main adverse event of the regimen was hematological toxicity. No chemotherapy-related deaths were observed. The combination of selinexor plus VEN and AZA is an effective treatment for R/R AML patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Hidrazinas , Leucemia Mieloide Aguda , Sulfonamidas , Triazóis , Humanos , Triazóis/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Hidrazinas/administração & dosagem , Hidrazinas/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Masculino , Feminino , Quimioterapia de Indução/métodos , Pessoa de Meia-Idade , AdultoRESUMO
Background: A shorter treatment duration potentially offers the advantage of reducing adverse events (AEs) and enhancing patient compliance for Helicobacter pylori eradication. However, the difference in eradication rates between short-duration vonoprazan-based regimens and fourteen-day proton pump inhibitor (PPI)-based therapy remained unknown. Objective: This meta-analysis aimed to compare the efficacy and safety of ten-day vonoprazan-based regimens with fourteen-day conventional PPI-based therapy for H. pylori eradication. Methods: We performed a comprehensive literature search up to November 28, 2023, using PubMed. A random-effects model was applied to conduct a meta-analysis to determine the pooled Odds Ratio (OR) with 95% confidence intervals (CIs). Results: This meta-analysis included four randomized controlled clinical trials with 1560 patients. The H. pylori eradication rate of ten-day vonoprazan-based regimens was comparable to that of fourteen-day PPI-based therapy (88.7% vs 82.9%, OR 1.53, 95% CI [0.85-2.75], p = .16) in ITT analysis. The incidence of AEs in ten-day vonoprazan-based therapy was also similar to the control group (11.2% vs 17.6%, OR 0.66, 95% CI [0.33-1.31], p = .24). Conclusion: Current evidence suggests that the ten-day vonoprazan-based regimen is as effective as fourteen-day PPI-based therapy in eradicating H. pylori, with comparable AEs. However, additional research is required for confirmation.
Assuntos
Infecções por Helicobacter , Inibidores da Bomba de Prótons , Pirróis , Sulfonamidas , Humanos , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Antibacterianos/administração & dosagem , China/epidemiologia , Esquema de Medicação , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/uso terapêutico , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAFV600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients. METHODS: In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C). RESULTS: Brain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases-free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76). CONCLUSIONS: In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases-free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.).
Assuntos
Neoplasias Encefálicas , Carbamatos , Inibidores de Checkpoint Imunológico , Melanoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Melanoma/tratamento farmacológico , Melanoma/secundário , Melanoma/patologia , Melanoma/genética , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Feminino , Masculino , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Pessoa de Meia-Idade , Carbamatos/uso terapêutico , Carbamatos/farmacologia , Carbamatos/administração & dosagem , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/administração & dosagem , Benzimidazóis/uso terapêutico , Benzimidazóis/farmacologia , Benzimidazóis/administração & dosagem , Nivolumabe/uso terapêutico , Nivolumabe/farmacologia , Nivolumabe/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/administração & dosagem , Idoso , Ipilimumab/uso terapêutico , Ipilimumab/farmacologia , Ipilimumab/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaRESUMO
BACKGROUND: Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. METHODS: Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b+, CD68+, and CD11b+/CD68+ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. RESULTS: Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1+/CD68+ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b+, CD68+, and CD11b+/CD68+ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1ß, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. CONCLUSION: Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma.
Assuntos
Fármacos Neuroprotetores , Piridinas , Células Ganglionares da Retina , Quinases Associadas a rho , Animais , Piridinas/farmacologia , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Ratos , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Retina/efeitos dos fármacos , Retina/patologia , Retina/metabolismo , Amidas/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Ratos Sprague-Dawley , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Inibidores de Proteínas Quinases/farmacologia , Masculino , Traumatismos do Nervo Óptico/tratamento farmacológico , Traumatismos do Nervo Óptico/patologia , Traumatismos do Nervo Óptico/metabolismo , Isoquinolinas , SulfonamidasAssuntos
Antirreumáticos , Artrite Reumatoide , Azetidinas , Purinas , Pirazóis , Sulfonamidas , Humanos , Artrite Reumatoide/tratamento farmacológico , Feminino , Purinas/efeitos adversos , Purinas/uso terapêutico , Purinas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Azetidinas/uso terapêutico , Azetidinas/efeitos adversos , Azetidinas/administração & dosagem , Pessoa de Meia-Idade , Adulto , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Masculino , Estudos de Coortes , Adulto Jovem , Adolescente , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos , Gravidez , Países Escandinavos e Nórdicos/epidemiologia , Sistema de Registros , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/epidemiologia , IdosoRESUMO
Diabetes Mellitus (DM) is linked to various factors causing cardiovascular diseases, with uncontrolled postprandial hyperglycemia being a direct contributor. α-Glucosidase inhibitors (AGIs) aid in reducing postprandial hyperglycemia, potentially mitigating cardiovascular risks. In order to synthesize novel chemical scaffolds with possible α-glucosidase inhibition activity, a series of novel soritin sulfonamide derivatives were synthesized. The soritin hydrazide was treated with various aryl sulfonyl chlorides to obtain targeted compounds (1-16). Findings suggested that all compounds have better α-glucosidase inhibition compared to standard drugs, acarbose (2187.00 ± 1.25 µM) and 1-deoxynojirimycin (334.90 ± 1.10 µM), with IC50 values ranging from 3.81 ± 1.67 µM to 265.40 ± 1.58 µM. The most potent analog was Compound 13, a trichloro phenyl substituted compound, with IC50 value of 3.81 ± 1.67 µM. Structure-activity relationship (SAR) showed that introducing an additional chlorine group into the parent nucleus increases the potency. The docking studies validated that Compound 13 established hydrogen bonds with the active site residues Asp214, Glu276, and Asp349, while being further stabilized by hydrophobic interactions, providing an explanation for its high potency.
Assuntos
Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , Sulfonamidas , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo , Humanos , Domínio Catalítico , Ligação de HidrogênioRESUMO
Antibiotics usually induce the hormetic effects on bacteria, featured by low-dose stimulation and high-dose inhibition, which challenges the central belief in toxicity assessment and environmental risk assessment of antibiotics. However, there are currently no ideal parameters to quantitatively characterize hormesis. In this study, an effective area in hormesis (AH) was developed to quantify the biphasic dose-responses of single antibiotics (sulfonamides (SAs), sulfonamides potentiators (SAPs), and tetracyclines (TCs)) and binary mixtures (SAs-SAPs, SAs-TCs, and SAs-SAs) to the bioluminescence of Aliivibrio fischeri. Using Ebind (the lowest interaction energy between antibiotic and target protein) and Kow (octanol-water partition coefficient) as the structural descriptors, the reliable quantitative structure-activity relationship (QSAR) models were constructed for the AH values of test antibiotics and mixtures. Furthermore, a novel method based on AH was established to judge the joint toxic actions of binary antibiotics, which mainly exhibited synergism. The results also indicated that SAPs (or TCs) contributed more than SAs in the hormetic effects of antibiotic mixtures. This study proposes a new quantitative parameter for characterizing and predicting antibiotic hormesis, and considers hormesis as an integrated whole to reveal the combined effects of antibiotics, which will promote the development of risk evaluation for antibiotics and their mixtures.
Assuntos
Aliivibrio fischeri , Antibacterianos , Hormese , Relação Quantitativa Estrutura-Atividade , Antibacterianos/toxicidade , Antibacterianos/química , Antibacterianos/farmacologia , Hormese/efeitos dos fármacos , Aliivibrio fischeri/efeitos dos fármacos , Sulfonamidas/toxicidade , Sulfonamidas/química , Tetraciclinas/toxicidade , Tetraciclinas/química , Relação Dose-Resposta a DrogaRESUMO
The purpose of this paper was to study in vitro atomization properties of the self-developed sodium sivelestat for inhalation, evaluate the feasibility of this preparation as an aerosol inhalation, and provide the guidance for the following animal administration experiment. Firstly, in order to ensure accurate, uniform and stable doses of the self-developed product after administration, its atomization performance was analyzed through the testing of fine particle mass and the total emitted dose, and the results of its atomization parameters meet the requirement of inhalation. Next, Atomization characteristics of two commonly used nebulizers, air compressed nebulizer and mesh nebulizer, were studied and compared. The results showed that mesh atomizers have a smaller and more uniform particle size distribution. And then, the experiment of acute lung injury induced by aerosol inhalation of lipopolysaccharide in mice was used to test the therapeutic effect of our self-developed formulation, and compared with the positive control (sodium sivelestat for injection). The results showed that inhalation had a lower concentration and was equally effective than injection of sodium sivelestat. All the results support that the self-developed sodium sivelestat can be used as an aerosol inhaled drug.