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1.
Biosci Rep ; 40(6)2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32441299

RESUMO

Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.


Assuntos
Betacoronavirus/enzimologia , Maraviroc/farmacologia , Inibidores de Proteases/farmacologia , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Maraviroc/química , Maraviroc/metabolismo , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
2.
Z Gastroenterol ; 58(5): 451-455, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32392606

RESUMO

BACKGROUND: Relapses after therapy with direct-acting antiviral agents (DAA) in chronic hepatitis C virus (HCV) infections are rare due to high efficacy of interferon-free therapy regimens. The presence of resistance-associated substitutions (RAS) in proteins targeted by therapy can lead to lower rates of sustained virological response (SVR) in patients receiving DAA-therapy, and little evidence exists as to how to treat these patients. CASE SUMMARY: We present a case of a multi-drug-resistant HCV-genotype-3a-infection in a 50-year-old female without confirmed cirrhosis but with advanced fibrosis (liver stiffness 11.6 kPa) and low viral load. Resistance testing revealed a Y93H mutation in the NS5A gene. Therapies using sofosbuvir and daclatasvir (1st), sofosbuvir, velpatasvir and ribavirin (2nd), and subsequently with sofosbuvir, velpatasvir, and voxilaprevir (3st) did not achieve SVR. Compliance was good with rapid negativity of HCV RNA at 4 weeks of treatment on all 3 occasions. No virological breakthrough was recorded with all regimens. As a rescue attempt, the patient received 24 weeks of sofosbuvir, glecaprevir/pibrentasvir, and weight-based ribavirin at 1000 mg. With this approach, she achieved SVR but developed hepatocellular carcinoma. CONCLUSION: The combination of sofosbuvir, glecaprevir/pibrentasvir and ribavirin could be a rescue therapy after previous relapses on DAA-therapy, especially in patients with relapse after therapy with sofosbuvir, velpatasvir, and voxilaprevir.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Benzimidazóis/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Quinoxalinas/uso terapêutico , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resultado do Tratamento
3.
PLoS One ; 15(3): e0229239, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155165

RESUMO

BACKGROUND: Directly acting antivirals (DAA) against hepatitis C virus (HCV) infection have facilitated sustained virologic response (SVR) rates >90% in clinical studies. Yet, real life data regarding DAA treatment in people who inject drugs (PWIDs) are scarce. We evaluated the effectiveness of glecaprevir/pibrentasvir (G/P) in difficult-to-treat PWIDs with presumed high risk of non-adherence to DAA therapy using the concept of directly observed therapy involving their opioid substitution therapy (OST) facility. METHODS: N = 145 patients (m/f: 91/54; median age: 41.1 (IQR 19.5) years; HCV-genotype (GT) 1/2/3/4: 82/1/56/5, GT3: 38.6%; cirrhosis: n = 6; 4.1%) treated with G/P were included. PWIDs at high risk for non-adherence to DAA therapy received HCV treatment together with their OST under the supervision of medical staff ("directly observed therapy", DOT). The effectiveness of G/P given as DOT in PWIDs with presumed high risk of non-adherence to DAA therapy was compared to patients with suspected "excellent compliance" in the "standard setting" (SS) of G/P prescription at a tertiary care center and self-managed G/P intake at home. Treatment duration was 8-16 weeks according to the G/P drug label. RESULTS: DOT-patients (n = 74/145; 51.0%) were younger than SS-patients (median 38.7, IQR 12.5 vs. median 50.6, IQR 20.3 years), all had psychiatric co-morbidities and most had a poor socioeconomic status. 50/74 (67.6%) reported ongoing intravenous drug use (IDU). SVR was achieved in n = 70/74 (94.6%) patients with n = 3 being lost to follow-up (FU) and n = 1 showing nonresponse to therapy. SS-patients achieved SVR in 97.2% (69/71) with n = 1 patient being lost to FU and n = 1 patient with GT3 showing HCV relapse. CONCLUSION: G/P given as DOT along with OST in PWIDs with high risk of non-adherence to DAA therapy resulted in similarly high SVR rates (94.6%) as in patients with presumed "excellent compliance" under standard drug intake.


Assuntos
Benzimidazóis/administração & dosagem , Terapia Diretamente Observada/métodos , Hepatite C Crônica/tratamento farmacológico , Tratamento de Substituição de Opiáceos/métodos , Pirrolidinas/administração & dosagem , Quinoxalinas/administração & dosagem , Abuso de Substâncias por Via Intravenosa/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adulto , Idoso , Áustria , Benzimidazóis/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Cooperação do Paciente , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Classe Social , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento , Adulto Jovem
4.
Cancer Treat Rev ; 86: 102000, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32203842

RESUMO

Therapeutic options for metastatic bladder cancer (BC) have seen minimal evolution over the past 30 years, with platinum-based chemotherapy remaining the mainstay of standard of care for metastatic BC. Recently, five immune checkpoint inhibitors (ICIs) have been approved by the FDA as second-line therapy, and two ICIs are approved as first-line treatment in selected patients. Molecular alterations of muscle-invasive bladder cancer (MIBC) have been reported by The Cancer Genome Atlas. About 15% of patients with MIBC have molecular alterations in the fibroblast growth factor (FGF) axis. Several ongoing trials are testing novel FGF receptor (FGFR) inhibitors in patients with FGFR genomic aberrations. Recently, erdafitinib, a pan-FGFR inhibitor, was approved by the FDA in patients with metastatic BC who have progressed on platinum-based chemotherapy. We reviewed the literature over the last decade and provide a summary of current knowledge of FGF signaling, and the prognosis associated with FGFR mutations in BC. We cover the role of FGFR inhibition with non-selective and selective tyrosine kinase inhibitors as well as novel agents in metastatic BC. Efficacy and safety data including insights from mechanism-based toxicity are reported for selected populations of metastatic BC with FGFR aberrations. Current strategies to managing resistance to anti-FGFR agents is addressed, and the importance of developing reliable biomarkers as the therapeutic landscape moves towards an individualized therapeutic approach.


Assuntos
Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/uso terapêutico , Humanos , Metástase Neoplásica , Pirazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
7.
PLoS One ; 15(3): e0230230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214328

RESUMO

OBJECTIVE: To investigate the effect and mechanism of SB525334 on self-renewal, migration and invasion of ovarian cancer stem cells. METHODS: ALDHhigh-expressing cancer stem cells (CSCs) were isolated from human ovarian cancer cell line SKOV-3 by flow cytometry and treated with 2µg/mL SB525334 for 6h. The sphere forming assay was used to detect the ability of self-renewal of CSCs and the colony formation assay was used to detect the tumorigenicity in vitro. Transwell migration and invasion assay were used to detect the migration and invasion ability of CSCs. To further explore the mechanism, real-time quantitative PCR and flow cytometry were used to detect the mRNA and protein expression of TGF-ß, Smad2, Smad3, phosphorylated Smad2, phosphorylated Smad3 and Smad4, respectively. Expressions of epithelial-mesenchymal transition (EMT)-related genes E-cadherin, Snail, Vimentin were also assessed. RESULTS: The self-renewal ability, tumorigenicity in vitro, migration and invasion ability of CSCs were significantly attenuated after SB525334 treatment. The expressions of TGF-ß, phosphorylated Smad2, phosphorylated Smad3, Snail, and Vimentin were decreased, while Smad4 and E-cadherin expressions were increased. CONCLUSION: SB525334 may inhibit the self-renewal, invasion and migration of ovarian CSCs by blocking the TGF-ß/Smad/EMT pathway.


Assuntos
Movimento Celular/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Imidazóis/farmacologia , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Quinoxalinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Fosforilação/efeitos dos fármacos , RNA Mensageiro/metabolismo , Proteínas Smad/metabolismo , Vimentina/metabolismo
8.
Bull Environ Contam Toxicol ; 104(4): 471-476, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32088734

RESUMO

A hydrolytic transformation study was conducted in water of pH 4.0, 7.0 and 9.2 to evaluate the effect of pH on persistence of a new readymix formulation of fomesafen and quizalofop-ethyl. The water samples were fortified at 0.5 and 1 µg mL-1 levels and analysed at 0 (2 h), 1, 3, 7, 15, 30, 60, 90, 120, 150 days interval. Both the analytical methods were validated following SANTE guideline and found accurate based on average recovery of 80-100%, Relative standard deviation (RSD) < 20% and Coefficient of Determination (R2) 0.99. The dissipation of both the molecules was pH dependent and followed first order kinetics. Higher persistence of fomesafen was observed in alkaline pH as compared to neutral and acidic pH with half-life of 41.56-63.24 days, whereas higher stability of quizalofop-ethyl was observed in the water of acidic pH followed by neutral and alkaline pH with half-life of 1.26-8.09 days.


Assuntos
Benzamidas/análise , Água Doce/química , Herbicidas/análise , Propionatos/análise , Quinoxalinas/análise , Poluentes Químicos da Água/análise , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Modelos Teóricos
10.
Expert Opin Pharmacother ; 21(5): 581-590, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32011186

RESUMO

Introduction: Rates of tobacco smoking are high in people with schizophrenia with greater difficulty of quitting smoking compared to the general population, which also relate to the increased cardiovascular and cancer risks in this co-occurring disorder. Therefore, effective smoking cessation pharmacotherapies addressing tobacco co-morbidity are imperative.Areas covered: In this review, the authors performed an extensive systematic electronic literature review examining the efficacy and safety of first-line pharmacotherapies for smoking cessation, including varenicline, sustained-release bupropion, and nicotine replacement therapies (NRT) using continuous abstinence rates over 10-12-week periods in smokers with schizophrenia. Twelve trials reporting smoking cessation outcomes using interventions in schizophrenia were included and risk ratio (RR) was used.Expert opinion: Our findings support the efficacy and safety of first-line pharmacotherapies for the treatment of tobacco use disorder in smokers with schizophrenia. Further research on the long-term effectiveness and safety of these agents in community samples is warranted. Smoking cessation pharmacotherapies may warrant the consideration of the emerging use of electronic nicotine delivery systems while neuromodulation techniques also offer promise.


Assuntos
Esquizofrenia/tratamento farmacológico , Abandono do Hábito de Fumar/métodos , Fumar/tratamento farmacológico , Benzazepinas/uso terapêutico , Bupropiona/uso terapêutico , Humanos , Agonistas Nicotínicos/uso terapêutico , Quinoxalinas/uso terapêutico , Fumar/psicologia , Dispositivos para o Abandono do Uso de Tabaco , Vareniclina/uso terapêutico
11.
Parasitol Res ; 119(2): 695-711, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31907668

RESUMO

Amoebiasis is caused by the protozoan Entamoeba histolytica that affects millions of people throughout the world. The standard treatment is metronidazole, however, this drug causes several side effects, and is also mutagenic and carcinogenic. Therefore, the search for therapeutic alternatives is necessary. Quinoxaline 1,4-di-N-oxides (QdNOs) derivatives have been shown to exhibit activity against different protozoan. In the present study, the effects of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate QdNOs) derivatives on E. histolytica proliferation, morphology, ultrastructure, and oxidative stress were evaluated, also their potential as E. histolytica thioredoxin reductase (EhTrxR) inhibitors was analyzed. In vitro tests showed that 12 compounds from n-propyl and isopropyl series, were more active (IC50 = 0.331 to 3.56 µM) than metronidazole (IC50 = 4.5 µM). The compounds with better biological activity have a bulky, trifluoromethyl and isopropyl group at R1-, R2-, and R3-position, respectively. The main alterations found in trophozoites treated with some of these compounds included changes in chromatin, cell granularity, redistribution of vacuoles with cellular debris, and an increase in reactive oxygen species. Interestingly, docking studies suggested that 7-carboxylate QdNOs derivatives could interact with amino acid residues of the NADPH-binding domain and/or the redox-active site of EhTrxR. Enzymatic assays demonstrated that selected 7-carboxylate QdNOs inhibits EhTrxR disulfide reductase activity, and diaphorase activity shows that these compounds could act as electron acceptor substrates for the enzyme. Taken together, these data indicate that among the mechanisms involved in the antiamoebic effect of the 7-carboxylate QdNOs derivatives studied, is the induction of oxidative stress and the inhibition of EhTrxR activity.


Assuntos
Entamoeba histolytica/efeitos dos fármacos , Quinoxalinas/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Óxidos N-Cíclicos , Entamoeba histolytica/enzimologia , Ésteres , Humanos , Metronidazol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Quinolinas , Espécies Reativas de Oxigênio/metabolismo
12.
Am J Physiol Heart Circ Physiol ; 318(3): H508-H518, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31975626

RESUMO

Cigarette smoking is a major risk factor for aortic aneurysm and dissection; however, no causative link between smoking and these aortic disorders has been proven. In the present study, we investigated the mechanism by which cigarette smoke affects vascular wall cells and found that cigarette smoke extract (CSE) induced a novel form of regulated cell death termed ferroptosis in vascular smooth muscle cells (VSMCs). CSE markedly induced cell death in A7r5 cells and primary rat VSMCs, but not in endothelial cells, which was completely inhibited by specific ferroptosis inhibitors [ferrostatin-1 (Fer-1) and Liproxstatin-1] and an iron chelator (deferoxamine). CSE-induced VSMC death was partially inhibited by a GSH precursor (N-acetyl cysteine) and an NADPH oxidase inhibitor [diphenyleneiodonium chloride (DPI)], but not by inhibitors of pan-caspases (Z-VAD), caspase-1 (Z-YVAD), or necroptosis (necrostatin-1). CSE also upregulated IL-1ß, IL-6, TNF-α, matrix metalloproteinase (MMP)-2, MMP-9, and TIMP-1 (tissue inhibitor of metalloproteinase)in A7r5 cells, which was inhibited by Fer-1. Furthermore, CSE induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. VSMC ferroptosis was induced by acrolein and methyl vinyl ketone, major constituents of CSE. Furthermore, CSE caused medial VSMC loss in ex vivo aortas. Electron microscopy analysis showed mitochondrial damage and fragmentation in medial VSMCs of CSE-treated aortas. All of these manifestations were partially restored by Fer-1. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death and suggest that ferroptosis is a potential therapeutic target for preventing aortic aneurysm and dissection.NEW & NOTEWORTHY Cigarette smoke extract (CSE)-induced cell death in rat vascular smooth muscle cells (VSMCs) was completely inhibited by specific ferroptosis inhibitors and an iron chelator. CSE also induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. CSE caused medial VSMC loss in ex vivo aortas. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death.


Assuntos
Ferroptose/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fumaça , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Cicloexilaminas/farmacologia , Desferroxamina/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , NADPH Oxidases/metabolismo , Fenilenodiaminas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Sideróforos/farmacologia , Compostos de Espiro/farmacologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo
13.
Expert Rev Clin Pharmacol ; 13(1): 1-6, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810398

RESUMO

Introduction: Since the approval of immune checkpoint inhibitors (ICIs), there has been continuing and significant progress in urothelial cancer (UC) treatment. However, only about one fifth of UC patients respond to ICI. Recently, erdafitinib was developed for treating locally advanced or metastatic UC (mUC) with FGFR3 or FGFR2 alterations, accounting for 15-20% of patients. Erdafitinib is the first targeted therapy ever approved for mUC.Areas covered: This review summarizes the preclinical and clinical data on erdafitinib for UC. PubMed search and relevant articles presented at international conferences were used for the literature search.Expert opinion: The FDA approval of erdafitinib provided a new treatment option for FGFR-altered UC progressing on platinum-based chemotherapy. It is not clear whether FGFR inhibitor is a preferred second-line treatment choice to ICI. Compared to ICI, erdafitinib has a better response rate in patients with visceral metastases. However, a shorter duration of response and toxicity profile of erdafitinib, particularly ocular toxicity, is an important consideration. Regular eye exams are recommended by the FDA. Tumor profiling during upfront therapy may help identify those who benefit at the time of progression. In summary, a high unmet need remains for new drugs in chemotherapy- and ICI-refractory UC.


Assuntos
Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Quinoxalinas/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Humanos , Metástase Neoplásica , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Quinoxalinas/efeitos adversos , Quinoxalinas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias da Bexiga Urinária/patologia
14.
Oncogene ; 39(2): 356-367, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31477836

RESUMO

Reactive oxygen species (ROS) and ROS-induced oxidative stress are associated with prostate cancer (PCa) development and castrate-resistant tumor progression. This is in part through the activation of the androgen receptor (AR) signaling. However, the molecular underpinning of ROS to activate AR remains poorly understood. Here, we report that the thioredoxin domain-containing 9 (TXNDC9) is an important regulator of ROS to trigger AR signaling. TXNDC9 expression is upregulated by ROS inducer, and increased TXNDC9 expression in patient tumors is associated with advanced clinical stages. TXNDC9 promotes PCa cell survival and proliferation. It is required for AR protein expression and AR transcriptional activity under oxidative stress conditions. Mechanistically, ROS inducers promote TXNDC9 to dissociate from PRDX1, but enhance a protein association with MDM2. Concurrently, PRDX1 enhances its association with AR. These protein interaction exchanges result in not only MDM2 protein degradation, but also PRDX1 mediated AR protein stabilization, and subsequent elevation of AR signaling. Blocking PRDX1 by its inhibitor, Conoidin A (CoA), suppresses AR signaling, PCa cell proliferation, and xenograft tumor growth even under androgen-deprived conditions. These tumor-suppressive effects of CoA were further strengthened when in combination with enzalutamide treatment. Together, these studies demonstrate that the TXNDC9-PRDX1 axis plays an important role for ROS to activate AR functions. It provides a proof-of-principle that co-targeting AR and PRDX1 may be more effective to control PCa growth.


Assuntos
Peroxirredoxinas/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genética , Tiorredoxinas/genética , Animais , Proliferação de Células/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Masculino , Camundongos , Estresse Oxidativo/genética , Peroxirredoxinas/antagonistas & inibidores , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Próstata/metabolismo , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-mdm2/genética , Quinoxalinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
15.
Res Vet Sci ; 128: 261-268, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31837514

RESUMO

The culture of preantral follicles as an in vitro model to evaluate the toxicity of new anticancer drug has being established. Therefore, the aim of this study was to evaluate the effect of quinoxaline derivative the 2 2- (XYZC 6H 3 -CH=N-NH)-quinoxaline, 1 (QX) on caprine preantral follicles. We evaluate the follicular morphology and activation, proliferation and apoptosis of granulosa cells and finally the protein (ABCB1) and genes expression (cyclin/Cdks), respectively involved in multidrug resistance and cell cycle progression. Ovarian fragments containing primordial and developing follicles were exposed (in vitro culture) to different concentrations of QX (QX1.5, QX3.0 or QX6.0 µM/mL) during 6 days. To evaluate the effect of QX, the ovarian tissue was exposed to Paclitaxel 0.1 µg/mL (PTX - negative control) or in culture media without QX (MEM). At the end of exposure time, we realized that the QX (all concentrations) increased (P < .05) the normal morphology of preantral follicles compared to control (not treated ovarian tissue) or MEM. However, QX6.0 showed a enhanced (P < .05) on follicular activation (burnout) and apoptosis than QX1.5 and QX3.0. Expression of ABCB1 was similar between QX1.5 and QX6.0 and both were lower than control, MEM and PTX. Interestingly, the apoptosis rate in QX3.0 was similar to control and MEM and lower then QX1.5; QX6.0 and PTX. We conclude that quinoxaline may be a promising chemotherapeutic agent, however, other concentrations within a defined range (2-5.5 µM) could be widely investigated.


Assuntos
Células da Granulosa/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Quinoxalinas/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Cabras , Células da Granulosa/metabolismo , Células da Granulosa/patologia , Técnicas In Vitro , Folículo Ovariano/citologia , Quinoxalinas/toxicidade
16.
Bioelectrochemistry ; 132: 107398, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31837616

RESUMO

In this paper, an advanced molecularly imprinted electrochemical sensor (MIECS) based on electropolymerized olaquindox (OLA) surface molecularly imprinted polymer thin film on a modified glassy carbon electrode (GCE) was developed for the detection of OLA. It was fabricated by coating dopamine@graphene (DGr) on GCE, then electropolymerizing pyrrole (Py) and molecularly imprinted polymers (MIPs). Graphene (Gr) was introduced for improving conductivity and sensitivity. Dopamine (DA) was used for dispersion and adhesion of Gr. Polypyrrole (PPy) could fix DGr and enhance the current response evidently. The established sensor could selectively recognize OLA but not the analogs of OLA. Some essential parameters controlling the performance of the developed sensor were investigated and optimized. Under optimal conditions, the linear relationship between the current intensity and OLA concentration was obtained from 50 nmol L-1 to 500 nmol L-1 with a limit of detection (LOD) of 7.5 nmol L-1. Analytical results of OLA based on the developed MIECS for fish and feedstuffs showed a good agreement with the results based on high performance liquid chromatography (HPLC).


Assuntos
Dopamina/química , Técnicas Eletroquímicas/instrumentação , Eletrodos , Grafite/química , Impressão Molecular , Polímeros/química , Pirróis/química , Quinoxalinas/análise , Limite de Detecção , Reprodutibilidade dos Testes , Propriedades de Superfície
17.
Clin Nucl Med ; 45(2): 133-135, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31833927

RESUMO

There is a growing interest in assessment of future remnant liver function with Tc-mebrofenin hepatobiliary scintigraphy before major hepatectomy to estimate the risk of posthepatectomy liver failure. We illustrate the case of a 42-year-old woman with liver metastasis from colorectal cancer who performed hepatobiliary scintigraphy. Tc-mebrofenin clearance rate of the total liver was considerably low. The patient recently started a treatment for active hepatitis C with a combination of 2 new direct-acting antiviral agents (grazoprevir, elbasvir). Apart from hypoalbuminemia or hyperbilirubinemia, physicians must be aware that drug interactions can interfere with Tc-mebrofenin liver uptake, thereby resulting in a dramatic underestimation of liver function.


Assuntos
Antivirais/efeitos adversos , Benzofuranos/efeitos adversos , Imidazóis/efeitos adversos , Falência Hepática/diagnóstico por imagem , Quinoxalinas/efeitos adversos , Cintilografia , Adulto , Interações Medicamentosas , Feminino , Hepacivirus , Humanos , Iminoácidos , Falência Hepática/etiologia , Compostos de Organotecnécio , Compostos Radiofarmacêuticos
19.
Eur J Med Chem ; 186: 111894, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31787361

RESUMO

Green chemistry is becoming the favored approach to preparing drug molecules in pharmaceutical industry. Herein, we developed a clean and efficient method to synthesize 3-benzoylquinoxalines via activated carbon promoted aerobic benzylic oxidation under "on-water" condition. Moreover, biological studies with this class of compounds reveal an antiproliferative profile. Further structure modifications are performed and the investigations exhibited that the most active 12a could inhibit the microtubule polymerization by binding to tubulin and thus induce multipolar mitosis, G2/M phase arrest, and apoptosis of cancer cells. In addition, molecular docking studies allow the rationalization of the pharmacodynamic properties observed. Our systematic studies provide not only guidance for applications of O2/AC/H2O system, but also a new scaffold targeting tubulin for antitumor agent discovery.


Assuntos
Antineoplásicos/farmacologia , Compostos de Benzil/química , Quinoxalinas/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Carbono/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Formiatos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Oxirredução , Polimerização/efeitos dos fármacos , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade , Ácidos Sulfúricos/química , Ácido Trifluoracético/química
20.
Gynecol Oncol ; 156(2): 301-307, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31870556

RESUMO

OBJECTIVE: To compare the combination of a MEK inhibitor (pimasertib) and a PI3K inhibitor (SAR245409) to pimasertib alone in recurrent unresectable borderline/low malignant potential (LMP) or low-grade serous ovarian carcinoma (LGSOC), determining whether combination is superior. METHODS: Patients with previously treated, recurrent LMP or LGSOC with measurable disease received either combination of pimasertib (60 mg daily) + SAR245409 (SAR) (70 mg daily) or pimasertib alone (60 mg BID) until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) by RECIST 1.1, determining whether combination was superior to pimasertib alone. Secondary endpoints included progression free survival (PFS), disease control, and adverse events. RESULTS: Sixty-five patients were randomized between September 2012 and December 2014. ORR was 9.4% (80% CI, 3.5 to 19.7) in the combination arm and 12.1% (80% CI, 5.4 to 22.8) in the pimasertib alone arm. Median PFS was 7.23 months (80% CI, 5.06 to -) and 9.99 (80% CI, 7.39 to 10.35) for pimasertib alone and pimasertib + SAR, respectively. Six-month PFS was 63.5% (80% CI, 47.2% to 75.9%) and 70.8% (80% CI, 56.9% to 80.9%). Eighteen (56.3%) patients in the combination arm and 19 (57.6%) patients in the pimasertib alone arm discontinued the trial. The study was terminated early because of low ORR and high rate of discontinuation. CONCLUSIONS: Response to pimasertib alone (ORR 12%) suggests that MEK inhibition could be used as an alternative treatment method to cytotoxic chemotherapy in this population. The MEK inhibitor alone was as effective as the combination, although the trial was limited by small numbers. Additional studies investigating the role of single agent or combination MEK and PI3K inhibition are warranted to further evaluate the utility of these treatments and describe a standard of care for LGSOC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Niacinamida/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/enzimologia , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Adulto Jovem
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