Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.611
Filtrar
1.
BMJ Open ; 14(7): e082404, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39002963

RESUMO

INTRODUCTION: The efficacy of multitarget neuroprotective drug DL-3-n-butylphthalide (NBP) in improving cognitive function has been confirmed in patients with vascular cognitive impairment without dementia. However, its efficacy in patients with symptomatic predementia phase of Alzheimer's disease remains uncertain. This study aims to evaluate the efficacy and safety of NBP in improving cognitive function in patients with mild cognitive impairment (MCI) through a clinical randomised controlled trail. METHODS AND ANALYSIS: This study is a 12-month, randomised, double-blind, placebo-controlled, multicentric trial, involving 270 patients with MCI. Subjects are randomly assigned to receive either NBP soft capsule (200 mg, three times per day) or placebo with an allocation ratio of 1:1. The efficacy and safety of NBP are assessed by comparing the results of neuropsychological, neuroimaging and laboratory tests between the two groups. The primary endpoint is the change in Alzheimer's Disease Assessment Scale-Cognitive Subscale after 12 months. All patients will be monitored for adverse events. ETHICS AND DISSEMINATION: This study involving human participants has been reviewed and approved by Ethics Committee of Xuan Wu Hospital (No.2017058). The participants provide their written informed consent to participate in this study. Results will be published in peer-reviewed medical journals and disseminated to healthcare professionals at local and international conferences. PROTOCOL VERSION: V 3.0, 3 September 2022. TRIAL REGISTRATION NUMBER: ChiCTR1800018362.


Assuntos
Benzofuranos , Disfunção Cognitiva , Fármacos Neuroprotetores , Humanos , Benzofuranos/uso terapêutico , Benzofuranos/efeitos adversos , Disfunção Cognitiva/tratamento farmacológico , Método Duplo-Cego , Masculino , Idoso , Feminino , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/efeitos adversos , Pessoa de Meia-Idade , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Testes Neuropsicológicos , Cognição/efeitos dos fármacos , Estudos Multicêntricos como Assunto
2.
Cancer Med ; 13(13): e7438, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38967496

RESUMO

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of fruquintinib-based therapy as a salvage therapy for patients with advanced or metastatic sarcoma, including soft tissue sarcoma (STS) and bone sarcoma. METHODS: Patients with advanced or metastatic sarcoma were divided into two groups. One group received fruquintinib monotherapy, while the other received fruquintinib combined therapy. Safety and efficacy of fruquintinib-based therapy were recorded and reviewed retrospectively, including progression-free survival (PFS), overall response rate (ORR), and adverse events (AEs). RESULTS: Between August 2021 and December 2022, 38 sarcoma patients were retrospectively included. A total of 14 patients received fruquintinib alone (including 6 STS and 8 bone sarcoma), while 24 were treated with fruquintinib combined therapy (including 2 STS and 22 bone sarcoma). The median follow-up was 10.2 months (95% CI, 6.4-11.5). For the entire population, the median PFS was 8.0 months (95% CI, 5.5-13.0). The ORR was 13.1%, while the disease control rate (DCR) was 86.8%. The univariate analysis showed that radiotherapy history (HR, 4.56; 95% CI, 1.70-12.24; p = 0.003), bone sarcoma (HR, 0.34; 95% CI, 0.14-0.87; p = 0.024), and treatment method of fruquintinib (HR, 0.36; 95% CI, 0.15-0.85; p = 0.021) were significantly associated with PFS. The multivariate analysis showed that patients without radiotherapy history were associated with a better PFS (HR, 3.71; 95% CI: 1.31-10.55; p = 0.014) than patients with radiotherapy history. Patients in combination group reported pneumothorax (8.3%), leukopenia (33.3%), thrombocytopenia (12.5%), diarrhea (4.2%), and anemia (4.2%) as the most frequent grade 3 or higher treatment-emergent AEs (TEAEs), while there was no severe TEAEs occurred in the monotherapy group. CONCLUSIONS: Fruquintinib-based therapy displayed an optimal tumor control and an acceptable safety profile in patients with advanced or metastatic sarcoma.


Assuntos
Benzofuranos , Neoplasias Ósseas , Quinazolinas , Sarcoma , Humanos , Feminino , Sarcoma/tratamento farmacológico , Sarcoma/mortalidade , Sarcoma/patologia , Masculino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Quinazolinas/uso terapêutico , Quinazolinas/efeitos adversos , Idoso , Benzofuranos/uso terapêutico , Benzofuranos/efeitos adversos , Neoplasias Ósseas/secundário , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Adulto Jovem , Terapia de Salvação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Progressão , Adolescente , Resultado do Tratamento
3.
J Comp Eff Res ; 13(8): e240084, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38976346

RESUMO

Aim: The objective of this study was to compare adverse event (AE) management costs for fruquintinib, regorafenib, trifluridine/tipiracil (T/T) and trifluridine/tipiracil+bevacizumab (T/T+bev) for patients with metastatic colorectal cancer (mCRC) previously treated with at least two prior lines of therapy from the US commercial and Medicare payer perspectives. Materials & methods: A cost-consequence model was developed to calculate the per-patient and per-patient-per-month (PPPM) AE costs using rates of grade 3/4 AEs with incidence ≥5% in clinical trials, event-specific management costs and duration treatment. Anchored comparisons of AE costs were calculated using a difference-in-differences approach with best supportive care (BSC) as a common reference. AE rates and treatment duration were obtained from clinical trials: FRESCO and FRESCO-2 (fruquintinib), RECOURSE (T/T), CORRECT (regorafenib) and SUNLIGHT (T/T, T/T+bev). AE management costs for the commercial and Medicare perspectives were obtained from publicly available sources. Results: From the commercial perspective, the AE costs (presented as per-patient, PPPM) were: $4015, $1091 for fruquintinib (FRESCO); $4253, $1390 for fruquintinib (FRESCO-2); $17,110, $11,104 for T/T (RECOURSE); $9851, $4691 for T/T (SUNLIGHT); $8199, $4823 for regorafenib; and $11,620, $2324 for T/T+bev. These results were consistent in anchored comparisons: the difference-in-difference for fruquintinib based on FRESCO was -$1929 versus regorafenib and -$11,427 versus T/T; for fruquintinib based on FRESCO-2 was -$2257 versus regorafenib and -$11,756 versus T/T. Across all analyses, results were consistent from the Medicare perspective. Conclusion: Fruquintinib was associated with lower AE management costs compared with regorafenib, T/T and T/T+bev for patients with previously treated mCRC. This evidence has direct implications for treatment, formulary and pathways decision-making in this patient population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzofuranos , Bevacizumab , Neoplasias Colorretais , Compostos de Fenilureia , Piridinas , Timina , Trifluridina , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/economia , Estados Unidos , Piridinas/economia , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Timina/uso terapêutico , Trifluridina/uso terapêutico , Trifluridina/economia , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/economia , Bevacizumab/uso terapêutico , Bevacizumab/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/economia , Compostos de Fenilureia/efeitos adversos , Benzofuranos/economia , Benzofuranos/uso terapêutico , Benzofuranos/efeitos adversos , Irinotecano/uso terapêutico , Irinotecano/economia , Combinação de Medicamentos , Pirrolidinas/uso terapêutico , Pirrolidinas/economia , Oxaliplatina/economia , Oxaliplatina/uso terapêutico , Oxaliplatina/efeitos adversos , Medicare/economia , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/economia , Camptotecina/efeitos adversos , Quinazolinas/economia , Quinazolinas/uso terapêutico , Quinazolinas/efeitos adversos , Compostos Organoplatínicos/economia , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/efeitos adversos , Uracila/análogos & derivados , Uracila/uso terapêutico , Uracila/economia , Uracila/efeitos adversos , Fluoruracila/uso terapêutico , Fluoruracila/economia , Fluoruracila/efeitos adversos , Modelos Econômicos , Produtos Biológicos/economia
4.
Cancer Immunol Immunother ; 73(8): 137, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38833034

RESUMO

Tumor-infiltrating lymphocyte (TIL) deficiency is the most conspicuous obstacle to limit the cancer immunotherapy. Immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibody, have achieved great success in clinical practice. However, due to the limitation of response rates of ICIs, some patients fail to benefit from monotherapy. Thus, novel combination therapy that could improve the response rates emerges as new strategies for cancer treatment. Here, we reported that the natural product rocaglamide (RocA) increased tumor-infiltrating T cells and promoted Th17 differentiation of CD4+ TILs. Despite RocA monotherapy upregulated PD-1 expression of TILs, which was considered as the consequence of T cell activation, combining RocA with anti-PD-1 antibody significantly downregulated the expression of PD-1 and promoted proliferation of TILs. Taken together, these findings demonstrated that RocA could fuel the T cell anti-tumor immunity and revealed the remarkable potential of RocA as a therapeutic candidate when combining with the ICIs.


Assuntos
Benzofuranos , Diferenciação Celular , Inibidores de Checkpoint Imunológico , Linfócitos do Interstício Tumoral , Receptor de Morte Celular Programada 1 , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Animais , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Humanos , Diferenciação Celular/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Feminino , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linhagem Celular Tumoral
5.
Neurochem Res ; 49(8): 2148-2164, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38822986

RESUMO

Carbon monoxide poisoning (COP) represents a significant global health burden, characterized by its morbidity and high mortality rates. The pathogenesis of COP-induced brain injury is complex, and effective treatment modalities are currently lacking. In this study, we employed network pharmacology to identify therapeutic targets and associated signaling pathways of Zhuli Decoction (ZLD) for COP. Subsequently, we conducted both in vitro and in vivo experiments to validate the therapeutic efficacy of ZLD in combination with N-butylphthalide (NBP) for acute COP-induced injury. Our network pharmacology analysis revealed that the primary components of ZLD exerted therapeutic effects through the modulation of multiple targets and pathways. The in vitro and in vivo experiments demonstrated that the combination of NBP and ZLD effectively inhibited apoptosis and up-regulated the activities of P-PI3K (Tyr458), P-AKT (Ser473), P-GSK-3ß (Ser9), and Bcl-2, thus leading to the protection of neuronal cells and improvement in cognitive function in rats following COP, which was better than the effects observed with NBP or ZLD alone. The rescue experiment further showed that LY294002, a PI3K inhibitor, significantly attenuated the therapeutic efficacy of NBP + ZLD. The neuroprotection effects of NBP and ZLD against COP-induced brain injury are closely linked to the activation of the PI3K/AKT/GSK-3ß signaling pathway.


Assuntos
Apoptose , Benzofuranos , Glicogênio Sintase Quinase 3 beta , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Apoptose/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Masculino , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Quimioterapia Combinada
6.
Neurochem Res ; 49(8): 2215-2227, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38834844

RESUMO

Post-stroke emotional disorders such as post-stroke anxiety and post-stroke depression are typical symptoms in patients with stroke. They are closely associated with poor prognosis and low quality of life. The State Food and Drug Administration of China has approved DL-3-n-butylphthalide (NBP) as a treatment for ischemic stroke (IS). Clinical research has shown that NBP alleviates anxiety and depressive symptoms in patients with IS. Therefore, this study explored the role and molecular mechanisms of NBP in cases of post-stroke emotional disorders using network pharmacology and experimental validation. The results showed that NBP treatment significantly increased the percentage of time spent in the center of the middle cerebral artery occlusion (MCAO) rats in the open field test and the percentage of sucrose consumption in the sucrose preference test. Network pharmacology results suggest that NBP may regulate neuroinflammation and cell death. Further experiments revealed that NBP inhibited the toll-like receptor 4/nuclear factor kappa B signaling pathway, decreased the level of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and interleukin-6, and M1-type microglia markers (CD68, inducible nitric oxide synthase), and reduced the expression of PANoptosis-related molecules including caspase-1, caspase-3, caspase-8, gasdermin D, and mixed lineage kinase domain-like protein in the hippocampus of the MACO rats. These findings demonstrate that the mechanisms through which NBP ameliorates post-stroke emotional disorders in rats are associated with inhibiting neuroinflammation and PANoptosis, providing a new strategy and experimental basis for treating post-stroke emotional disorders.


Assuntos
Benzofuranos , Infarto da Artéria Cerebral Média , Doenças Neuroinflamatórias , Ratos Sprague-Dawley , Animais , Benzofuranos/uso terapêutico , Benzofuranos/farmacologia , Masculino , Doenças Neuroinflamatórias/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Ratos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/complicações , Farmacologia em Rede , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Citocinas/metabolismo , NF-kappa B/metabolismo
7.
Biochem Pharmacol ; 226: 116339, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38848781

RESUMO

Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.


Assuntos
Benzofuranos , Privação do Sono , Animais , Masculino , Camundongos , Privação do Sono/tratamento farmacológico , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
8.
Eur J Pharmacol ; 978: 176751, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38897442

RESUMO

The BM7 compound, a bromo derivative of methyl 6-acetyl-5-hydroxy-2-methyl-1-benzofuran-3-carboxylate, was previously identified as cytotoxic to human leukaemia cells (K562 and HL60) and human cervical cancer (HeLa), while showing no toxicity to non-cancerous primary endothelial cells (HUVEC). In this study, we present the first demonstration of BM7's anticancer efficacy in vivo using a mouse chronic myeloid leukaemia xenograft model. Administered intraperitoneally in a mixture of 10% Solutol HS 15/10% ethanol, BM7 exhibited no visible toxicity and significantly reduced tumor weight, comparable to standard drugs imatinib and hydroxyurea. Further supporting its anticancer potential, a multi-model in vitro study involving seven human cancer cell lines revealed the most promising responses in colon cancer (SW480, SW620, HCT116), liver cancer (HEPG2), and breast adenocarcinoma (MDA-MB-231) cells. BM7 demonstrated multifaceted anticancer mechanisms, inducing apoptosis while elevating reactive oxygen species (ROS) levels and suppressing interleukin-6 (IL-6) release in these cell lines. These findings position BM7 as a candidate of significant interest for cancer therapy. Its ability to not only induce apoptosis but also modulate cellular processes such as ROS levels and immune responses, specifically IL-6 suppression, makes BM7 a versatile and promising agent for further exploration in the realm of cancer treatment.


Assuntos
Antineoplásicos , Apoptose , Benzofuranos , Interleucina-6 , Espécies Reativas de Oxigênio , Animais , Humanos , Interleucina-6/metabolismo , Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino
9.
Clin Cancer Res ; 30(15): 3100-3104, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38809262

RESUMO

On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and if RAS wild-type and medically appropriate, an anti-EGFR therapy. Approval was based on Study FRESCO-2, a globally conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival. A total of 691 patients were randomly assigned (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 [95% confidence interval (CI), 0.55, 0.80; P < 0.001]. The median OS was 7.4 months (95% CI, 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI, 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with the inhibition of VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single-country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI, 0.51, 0.83; P < 0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, an anti-EGFR therapy.


Assuntos
Benzofuranos , Neoplasias Colorretais , Aprovação de Drogas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estados Unidos , Benzofuranos/uso terapêutico , Benzofuranos/efeitos adversos , Benzofuranos/administração & dosagem , Adulto , Método Duplo-Cego , Quinazolinas/uso terapêutico , Metástase Neoplásica , United States Food and Drug Administration , Idoso de 80 Anos ou mais , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos
10.
Int Immunopharmacol ; 133: 112128, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38652966

RESUMO

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with growing incidence worldwide. Our group reported the compound 5-choro-1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01007) as H4R antagonist (pKi 6.2) and therefore the effects and pharmacological efficacy on a DSS-induced mice model of UC were assessed in this work. Experimental acute colitis was induced in male BALB/c mice (n = 5-10) by administering 3 % DSS in the drinking water for six days. The test compound LINS01007 was administered daily i.p. (5 mg/kg) and compared to control group without treatment. Body weight, water and food consumption, and the presence of fecal blood were monitored during 7-day treatment period. The levels of inflammatory markers (PGE2, COX-2, IL-6, NF-κB and STAT3) were also analyzed. Animals subjected to the acute colitis protocol showed a reduction in water and food intake from the fourth day (p < 0.05) and these events were prevented by LINS01007. Histological signs of edema, hyperplasia and disorganized intestinal crypts, as well as neutrophilic infiltrations, were found in control mice while these findings were significantly reduced in animals treated with LINS01007. Significant reductions in the levels of PGE2, COX-2, IL-6, NF-κB and STAT3 were observed in the serum and tissue of treated animals. The results demonstrated the significant effects of LINS01007 against DSS-induced colitis, highlighting the potential of H4R antagonism as promising treatment for this condition.


Assuntos
Benzofuranos , Sulfato de Dextrana , Piperazinas , Receptores Histamínicos H4 , Animais , Masculino , Camundongos , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Benzofuranos/uso terapêutico , Benzofuranos/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/patologia , Colo/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Interleucina-6/metabolismo , Interleucina-6/sangue , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Receptores Histamínicos H4/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores
11.
Expert Opin Pharmacother ; 25(4): 371-382, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38568032

RESUMO

INTRODUCTION: Available treatments for colorectal cancer are limited. However, in the last few years several advances and new treatment options became available and expanded the continuum of care in metastatic colorectal cancer (mCRC). AREAS COVERED: Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both. Preclinical studies have shown that fruquintinib inhibits with high selectivity VEGFR 1-2-3, leading to a blockade in angiogenesis process, but also acts, with weak inhibition, on RET, FGFR-1, and c-kit kinases. Fruquintinib demonstrated good efficacy and tolerance in chemorefractory mCRC in two phase III trial: FRESCO and FRESCO 2. These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. EXPERT OPINION: Fruquintinib is a valid therapeutic option for heavily pretreated mCRC patients. However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRASG12C or HER2 amplification) and in non-oncogenic driven patients.


Assuntos
Benzofuranos , Neoplasias Colorretais , Metástase Neoplásica , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Benzofuranos/uso terapêutico , Benzofuranos/farmacologia , Quinazolinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antineoplásicos/uso terapêutico , Animais
12.
Eur J Pharmacol ; 974: 176593, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38636800

RESUMO

Recent studies have highlighted the involvement of pyroptosis-mediated cell death and neuroinflammation in ischemic stroke (IS) pathogenesis. DL-3-n-butylphthalide (NBP), a synthesized compound based on an extract from seeds of Apium graveolens, possesses a broad range of biological effects. However, the efficacy and the underlying mechanisms of NBP in IS remain contentious. Herein, we investigated the therapeutic effects of NBP and elucidated its potential mechanisms in neuronal cell pyroptosis and microglia inflammatory responses. Adult male mice underwent permanent distal middle cerebral artery occlusion (dMCAO), followed by daily oral gavage of NBP (80 mg/kg) for 1, 7, or 21 consecutive days. Gene Expression Omnibus (GEO) dataset of IS patients peripheral blood RNA sequencing was analyzed to identify differentially expressed pyroptosis-related genes (PRGs) during the ischemic process. Our results suggested that NBP treatment effectively alleviated brain ischemic damage, resulting in decreased neurological deficit scores, reduced infarct volume, and improved neurological and behavioral functions. RNA sequence data from human unveiled upregulated PRGs in IS. Subsequently, we observed that NBP downregulated pyroptosis-associated markers at days 7 and 21 post-modeling, at both the protein and mRNA levels. Additionally, NBP suppressed the co-localization of pyroptosis markers with neuronal cells to variable degrees and simultaneously mitigated the accumulation of activated microglia. Overall, our data provide novel evidence that NBP treatment significantly attenuates ischemic brain damage and promotes recovery of neurological function in the early and recovery phases after IS, probably by negatively regulating the pyroptosis cell death of neuronal cells and inhibiting toxic neuroinflammation in the central nervous system.


Assuntos
Benzofuranos , Modelos Animais de Doenças , AVC Isquêmico , Piroptose , Animais , Piroptose/efeitos dos fármacos , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Masculino , Camundongos , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/patologia , Doenças Neuroinflamatórias/tratamento farmacológico , Humanos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/complicações
13.
Int J Clin Pharm ; 46(4): 872-880, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38642249

RESUMO

BACKGROUND: Colorectal cancer is a significant health concern worldwide, with metastatic CRC (mCRC) presenting a particularly challenging prognosis. The FRESCO-2 trial highlighted the potential of fruquintinib in heavily pretreated mCRC patients. AIM: Given the recent changes in drug pricing in China and the evolving mCRC treatments, this study aimed to evaluate the cost-effectiveness of fruquintinib in the context of current Chinese healthcare standards. METHOD: This study utilized data from the FRESCO-2 trial, incorporating a partitioned-survival model to simulate three health states: Progression-Free Survival, Progressive Disease, and death. Costs and utility values were derived from published literature and the FRESCO-2 trial. Sensitivity analyses were conducted to assess the robustness of the base-case result and to understand the impact of various parameters on the ICER. RESULTS: The base-case analysis revealed a total cost of $11,089.05 for the fruquintinib group and $5,374.48 for the placebo group. The overall QALYs were higher in the fruquintinib group (0.61 QALYs) compared to the placebo group (0.43 QALYs). The ICER was calculated to be $31,747.67 per QALY. Sensitivity analyses identified the utility of progression-free survival, the cost of fruquintinib, and the costs of best supportive care as significant determinants of ICER. CONCLUSION: Fruquintinib emerges as a promising therapeutic option for refractory mCRC. However, its cost-effectiveness depends on selected willingness-to-pay (WTP) threshold. While the drug's ICER surpasses the WTP based on China's 2022 GDP per capita, it remains below the threshold set at three times the national GDP.


Assuntos
Benzofuranos , Neoplasias Colorretais , Análise Custo-Benefício , Quinazolinas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/economia , Benzofuranos/economia , Benzofuranos/uso terapêutico , Quinazolinas/uso terapêutico , Quinazolinas/economia , China , Anos de Vida Ajustados por Qualidade de Vida , Metástase Neoplásica , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Intervalo Livre de Progressão , Custos de Medicamentos , Masculino , Feminino , Pessoa de Meia-Idade , Análise de Custo-Efetividade
14.
Am Surg ; 90(6): 1682-1701, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38530772

RESUMO

BACKGROUND: Prolonged postoperative ileus (PPOI) contributes to morbidity and prolonged hospitalization. Prucalopride, a selective 5-hydroxytryptamine receptor agonist, may enhance bowel motility. This review assesses whether the perioperative use of prucalopride compared to placebo is associated with accelerated return of bowel function post gastrointestinal (GI) surgery. METHODS: OVID, CENTRAL, and EMBASE were searched as of January 2024 to identify randomized controlled trials (RCTs) comparing prucalopride and placebo for prevention of PPOI in adult patients undergoing GI surgery. The primary outcomes were time to stool, time to flatus, and time to oral tolerance. The secondary outcomes were incidence of PPOI, length of stay (LOS), postoperative complications, adverse events, and overall costs. The Cochrane risk of bias tool for randomized trials and the Grading of Recommendations, Assessment, Development, and Evaluations framework were used. An inverse variance random effects model was used. RESULTS: From 174 citations, 3 RCTs with 139 patients in each treatment group were included. Patients underwent a variety of GI surgeries. Patients treated with prucalopride had a decreased time to stool (mean difference 36.82 hours, 95% CI 59.4 to 14.24 hours lower, I2 = 62%, low certainty evidence). Other outcomes were not statistically significantly different (very low certainty evidence). Postoperative complications and adverse events could not be meta-analyzed due to heterogeneity; yet individual studies suggested no significant differences (very low certainty evidence). DISCUSSION: Current RCT evidence suggests that prucalopride may enhance postoperative return of bowel function. Larger RCTs assessing patient important outcomes and associated costs are needed before routine use of this agent.


Assuntos
Benzofuranos , Procedimentos Cirúrgicos do Sistema Digestório , Íleus , Complicações Pós-Operatórias , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Benzofuranos/uso terapêutico , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Motilidade Gastrointestinal/efeitos dos fármacos , Íleus/prevenção & controle , Íleus/etiologia , Tempo de Internação/estatística & dados numéricos , Complicações Pós-Operatórias/prevenção & controle , Agonistas do Receptor 5-HT4 de Serotonina/uso terapêutico
15.
J Med Chem ; 67(7): 5502-5537, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38552183

RESUMO

Patients with arterial embolic disease have benefited greatly from antiplatelet therapy. However, hemorrhage risk of antiplatelet agents cannot be ignored. Herein, we describe the discovery of 2,3-dihydro[1,4]dioxino[2,3-g]benzofuran compounds as novel PAR4 antagonists. Notably, the isomers 36 and 37 with the chemotype of phenoxyl methylene substituted on the 2,3-dihydro-1,4-dioxine ring exhibited potent in vitro antiplatelet activity (IC50 = 26.13 nM for 36 and 14.26 nM for 37) and significantly improved metabolic stability in human liver microsomes (T1/2 = 97.6 min for 36 and 11.1 min for BMS-986120). 36 also displayed good oral PK profiles (mice: T1/2 = 7.32 h and F = 45.11%). Both of them showed overall potent ex vivo antiplatelet activity at concentrations of 6 and 12 mg/kg, with no impact on the coagulation system and low bleeding liability. Our work will facilitate development of novel PAR4 antagonists as a safer therapeutic option for arterial embolism.


Assuntos
Benzofuranos , Trombose , Humanos , Camundongos , Animais , Receptores de Trombina , Inibidores da Agregação Plaquetária/metabolismo , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/metabolismo , Coagulação Sanguínea , Trombose/tratamento farmacológico , Benzofuranos/uso terapêutico , Agregação Plaquetária , Receptor PAR-1/metabolismo , Receptor PAR-1/uso terapêutico , Plaquetas/metabolismo
16.
J Int Med Res ; 52(3): 3000605231223081, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38546241

RESUMO

OBJECTIVE: To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia. METHODS: Randomized controlled trials were searched in electronic databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), Wan Fang, and China Biology Medicine from inception to 29 November 2022. Two reviewers independently screened the papers and extracted data from the included studies. The data were processed using RevMan5.4 statistical software. RESULTS: Nine randomized controlled trials (n = 1024) were included in this meta-analysis. Regarding the primary outcomes, compared with butylphthalide monotherapy, combined butylphthalide and donepezil treatment exhibited significantly greater total clinical efficacy (relative risk = 1.24, 95% confidence interval [1.17, 1.31]) and did not increase the adverse event rate (relative risk = 1.39, 95% confidence interval [0.91, 2.14]). Regarding the secondary outcomes, the meta-analysis results for the Mini-Mental State Examination, abilities of daily living, and Montreal Cognitive Assessment scores and the interleukin-6, tumor necrosis factor-α, and superoxide dismutase blood levels all supported combined butylphthalide and donepezil treatment. CONCLUSION: Butylphthalide combined with donepezil may be a better treatment strategy than donepezil alone for the treatment of vascular dementia in clinical practice.


Assuntos
Benzofuranos , Demência Vascular , Humanos , Benzofuranos/uso terapêutico , Demência Vascular/tratamento farmacológico , Donepezila/uso terapêutico , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Clin Transl Gastroenterol ; 15(5): e00687, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38357940

RESUMO

INTRODUCTION: This real-world US-based claims study compared constipation-related symptoms and complications 6 months before and after prucalopride initiation in adults with chronic idiopathic constipation (CIC). METHODS: This observational, retrospective cohort analysis used the IBM MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental Database (January 2015-June 2020). Prucalopride-treated patients (≥18 years old) who had ≥1 constipation-related International Classification of Diseases, Tenth Revision, Clinical Modification ( ICD-10-CM ) diagnosis code during the baseline or study period were included. The proportions of patients with constipation-related symptoms (abdominal pain, abdominal distension [gaseous], incomplete defecation, and nausea) and constipation-related complications (anal fissure and fistula, intestinal obstruction, rectal prolapse, hemorrhoids, perianal venous thrombosis, perianal/perirectal abscess, and rectal bleeding) were examined. Constipation-related symptoms and complications were identified using ICD-10-CM , ICD-10 - Procedure Coding System , or Current Procedural Terminology codes. Data were stratified by age (overall, 18-64 years, and ≥65 years). RESULTS: This study included 690 patients: The mean (SD) patient age was 48.0 (14.7) years, and 87.5% were women. The proportions of patients overall with constipation-related symptoms decreased 6 months after prucalopride initiation (abdominal pain [50.4% vs 33.3%, P < 0.001]; abdominal distension [gaseous] [23.9% vs 13.3%, P < 0.001]; and nausea [22.6% vs 17.7%, P < 0.01]; no improvements observed for incomplete defecation). Similarly, the proportions of patients overall with constipation-related complications decreased 6 months after prucalopride initiation (intestinal obstruction [4.9% vs 2.0%, P < 0.001]; hemorrhoids [10.7% vs 7.0%, P < 0.05]; and rectal bleeding [4.1% vs 1.7%, P < 0.05]). DISCUSSION: This study suggests that prucalopride may be associated with improved constipation-related symptoms and complications 6 months after treatment initiation.


Assuntos
Benzofuranos , Constipação Intestinal , Humanos , Constipação Intestinal/tratamento farmacológico , Benzofuranos/uso terapêutico , Benzofuranos/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Estados Unidos/epidemiologia , Estudos Retrospectivos , Doença Crônica , Idoso , Adulto Jovem , Resultado do Tratamento , Adolescente , Dor Abdominal/tratamento farmacológico , Dor Abdominal/etiologia , Agonistas do Receptor 5-HT4 de Serotonina/uso terapêutico , Agonistas do Receptor 5-HT4 de Serotonina/efeitos adversos , Agonistas do Receptor 5-HT4 de Serotonina/administração & dosagem
18.
Ceska Slov Farm ; 72(6): 267-276, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38346904

RESUMO

Current trends in drug design notably consider so-called privileged scaffolds as the core structural fragments with decisive impact on affinity to properly chosen biological targets, potency, selectivity and toxicological characteristics of drugs and prospective drug candidates. Fruquintinib (1) is a novel synthetic selective inhibitor of vascular endothelial growth factor receptor (VEGFR) isoforms, i.e., VEGFR-1, VEGFR-2 and VEGFR-3. The therapeutic agent (1) consists of a flat bicyclic heteroaromatic ring, in which two nitrogens are suitablyincorporated, a core bicyclic heteroaromatic ring - privileged (substituted) benzofuran scaffold, and a pair of hydrogen bond (H-bond) donor and acceptor group, i.e., amide functional moiety. Fruquintinib (1) was first approved in China for the treatment of metastatic colorectal cancer, a severe malignant disease with a high mortality rate. The review article offered a brief insight into the topic of privileged structures, their drug- -like ranges of several parameters, pharmacodynamic characteristics of fruquintinib (1) and various in silico descriptors characterizing drug's structural and physicochemical properties (molecular weight, number of heavy atoms, number of aromatic heavy atoms, fraction of sp3 C-atoms, number of H-bond acceptors, number of H-bond donors, total polar surface area, molar refractivity, molecular volume as well as parameters of lipophilicity and solubility). Some of these descriptors were related to pharmacokinetics and distribution of fruquintinib (1), and, in addition, might help predict its ability to cross passively the blood-brain barrier (BBB). Moreover, a possible connection between the induction potential on cytochrome P450 isoenzymes (CYP1A2 and CYP3A4) and passive transport of a given drug into the central nervous system via BBB was investigated. Current clinical experience and future directions regarding of fruquintinib (1) were also briefly outlined.


Assuntos
Antineoplásicos , Benzofuranos , Quinazolinas , Fator A de Crescimento do Endotélio Vascular , Antineoplásicos/farmacologia , Benzofuranos/farmacocinética , Benzofuranos/uso terapêutico , Relação Estrutura-Atividade , Biotransformação
19.
Chem Biol Interact ; 387: 110824, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38056806

RESUMO

Movement disorder Parkinson's disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer's disease, which severely affects the quality of patients' lives and imposes an increasingly heavy socioeconomic burden. Aureusidin is a kind of natural flavonoid compound with anti-inflammatory and anti-oxidant activities, while its pharmacological action and mechanism are rarely reported in PD. This study aimed to explore the neuroprotective effects and potential mechanisms of Aureusidin in PD. The present study demonstrated that Aureusidin protected SH-SY5Y cells from cell damage induced by 6-hydroxydopamine (6-OHDA) via inhibiting the mitochondria-dependent apoptosis and activating the Nrf2/HO-1 antioxidant signaling pathway. Additionally, Aureusidin diminished dopaminergic (DA) neuron degeneration induced by 6-OHDA and reduced the aggregation toxicity of α-synuclein (α-Syn) in Caenorhabditis elegans (C. elegans.) In conclusion, Aureusidin showed a neuroprotective effect in the 6-OHDA-induced PD model via activating Nrf2/HO-1 signaling pathway and prevented mitochondria-dependent apoptosis pathway, and these findings suggested that Aureusidin may be an effective drug for the treatment of PD.


Assuntos
Benzofuranos , Neuroblastoma , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Doença de Parkinson , Animais , Humanos , Antioxidantes/metabolismo , Apoptose , Caenorhabditis elegans/metabolismo , Linhagem Celular Tumoral , Mitocôndrias , Neuroblastoma/metabolismo , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico
20.
Clin Exp Pharmacol Physiol ; 51(1): 17-29, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37749921

RESUMO

Liver fibrosis is a chronic liver lesion caused by excessive deposition of the extracellular matrix after liver damage, resulting in fibrous scarring of liver tissue. The progression of liver fibrosis is partially influenced by the gut microbiota. Chitosan can play a therapeutic role in liver fibrosis by regulating the gut microbiota based on the 'gut-liver axis' theory. Salvianolic acid B can inhibit the development of liver fibrosis by inhibiting the activation of hepatic stellate cells and reducing the production of extracellular matrix. In this study, the therapeutic effect of chitosan in combination with salvianolic acid B on liver fibrosis was investigated in a mouse liver fibrosis model. The results showed that the combination of chitosan and salvianolic acid B was better than the drug alone, improving AST/ALT levels and reducing the expression of α-SAM, COL I, IL-6 and other related genes. It improved the structure of gut microbiota and increased the abundance of beneficial bacteria such as Lactobacillus. The above results could provide new ideas for the clinical treatment of liver fibrosis.


Assuntos
Benzofuranos , Quitosana , Camundongos , Animais , Quitosana/farmacologia , Quitosana/metabolismo , Quitosana/uso terapêutico , Cirrose Hepática/patologia , Fígado/metabolismo , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Benzofuranos/metabolismo , Modelos Animais de Doenças
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...