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1.
PLoS Pathog ; 17(9): e1009898, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34478458

RESUMO

The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 µM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Etacridina/farmacologia , Inibidores de Proteases/farmacologia , Ativação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Chlorocebus aethiops , Proteases 3C de Coronavírus/antagonistas & inibidores , Genes Reporter , Proteínas de Fluorescência Verde/genética , Humanos , Células Vero , Vírion/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
2.
Zhonghua Fu Chan Ke Za Zhi ; 56(6): 418-424, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34154317

RESUMO

Objective: To study the risk assessment, method selection and clinical management of pregnancy termination during the first and second trimester of pregnant women with cardiovascular disease. Methods: This study focused on pregnant women with cardiovascular diseases who were admitted to Beijing Anzhen Hospital during the first and second trimester of pregnancy from January 2016 to September 2019, to summarize their clinical characteristics, reasons and methods of pregnancy termination, management and outcomes. Results: Among 167 pregnant women, 119 cases (71.3%, 119/167) were in early pregnancy and 48 cases (28.7%, 48/167) were in middle pregnancy. The reasons for termination of pregnancy were cardiovascular disease (109 cases; 65.3%, 109/167), unwanted pregnancy (54 cases; 32.3%, 54/167) and other reasons (4 cases). Vacuum aspiration was performed in 98 cases and forceps curettage was performed in 19 cases, medical abortion was performed in 2 cases in early pregnancy. There was no change in cardiac function after pregnancy termination and all survived in early pregnancy. In the second trimester, 16 cases were induced by intraamniotic injection of ethacridine, 2 cases by water balloon, 1 case by oxytocin intravenous drip, and 29 cases by hysterotomy delivery. The ratio of patients with hysterotomy delivery with cardiac function grade Ⅲ-Ⅳ was significantly higher than that in the patients with vaginal labor induction in the second trimester [79% (23/29) vs 4/19; P<0.01]; the ratio of pregnancy risk grade Ⅳ-Ⅴ was also significantly higher [100% (29/29) vs 14/19; P=0.007]. The mean length of hospital stay of patients with hysterotomy delivery was significantly longer than that in the patients with vaginal labor induction [(7.1±3.4) vs (2.4±1.8) days; P<0.01]. Cardiac function was improved in 4 patients induced by ethacridine and rapid recovery without serious complications. Cardiac function decreased in 5 cases and 1 case died on the first day after hysterotomy delivery. Conclusions: Pregnancy risk assessment should be conducted as early as possible in patients with cardiovascular disease. If it is not suitable to continue the pregnancy, terminate pregnancy as early as possible to reduce the risk. Pregnancy termination methods and analgesic methods should be selected according to different gestational age and complications. The indications for hysterotomy delivery should not be relaxed at will, so as to minimize trauma and hemodynamic changes. After the termination of pregnancy, contraceptive measures should be implemented and the next treatment plan should be guided.


Assuntos
Aborto Induzido , Doenças Cardiovasculares , Etacridina , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Gestantes
3.
Acta Bioeng Biomech ; 22(2): 185-197, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32868952

RESUMO

PURPOSE: The polymeric porous surface of fibres (PLA) may influence the kinetics of release of biologically active compounds (gentamicin, G and ethacridine lactate, R) affecting development of a bacterial biofilm. METHODS: The porous fibres with different morphology were manufactured by the electrospinning method from ternary systems composed of PLA and selected solvents. Fibres morphology was examined using a scanning electron microscopy (SEM), their structure was analyzed by FT-IR ATR spectroscopy and differential scanning calorimetry (DSC). Changes in the drug release profile were measured using ICP/UV-Vis methods and the resulting bactericidal or bacteriostatic properties were tested by two-layer disk diffusion test in relation to various drug incorporation methods. RESULTS: The porous fibres can be applied to produce drug-bearing membranes. The spectroscopic studies confirmed incorporation of gentamicin into the fibres and the presence of ethacridine lactate on their surface. Bimodal fibres distribution (P3) promoted faster release of gentamicin and ethacridine lactate from P3G and P3R materials. The electrospinning process coupled with the vapor induced phase separation influenced the glass transition temperature of the porous polymer fibres. The pre/post-electrospinning modification influenced the glass transition, maximum temperature of cold crystallization and melting point of the porous membrane, compared to the neat polymer. The polylactide fibres with gentamicin showed strong bactericidal effect on Gram-positive bacteria, while fibres with ethacridine lactate were bacteriostatic. CONCLUSIONS: The obtained fibres with complex surface morphology can be used as a membrane in active dressings as they make it possible to control the release profile of the active compounds.


Assuntos
Bandagens , Portadores de Fármacos/química , Poliésteres/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/ultraestrutura , Etacridina/farmacologia , Gentamicinas/química , Gentamicinas/farmacologia , Testes de Sensibilidade Microbiana , Porosidade , Soluções , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/ultraestrutura
4.
Zhonghua Bing Li Xue Za Zhi ; 49(8): 782-787, 2020 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-32746543

RESUMO

Objective: Placental pathology reflects the health condition of both mother and fetus during pregnancy, providing information about pathogenesis especially in adverse pregnancies, and may provide guidance on subsequent pregnancies. Description on the placental changes after long-term use of rivanol is lacking, and this evaluated the placental changes, with emphasis on the differential diagnosis from other primary placental lesions. Methods: A total of 85 placentas from rivanol induced abortion submitted to the Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University from Januaury 2017 to October 2019 were reviewed; and 81 gestational-age-matched cases of spontaneous abortion or preterm delivery during the same period were also included as the control group. Diagnoses were based on the consensus statement of 2016 Amsterdam Placental Workshop Group. Statistical differences were analyzed by individual diagnostic terms. Results: The maternal age in rivanol group was (30.5±4.1) (range 22-41) years, compared with (30.9±4.3) (range 22-44) years in the control group. Gestational age was (23.2±3.5) (range 17-35) weeks and (23.3±2.8) (range 17-33) weeks in the rivanol and control groups. The incidence of chorioamnionitis in rivanol group was 91.8%, significantly higher than the control (63.0%, P<0.05); and there were more stage 1 (subchorionic) maternal response in rivanol than in the control (61.0% vs.28.6%, P<0.05) groups. In addition, acute deciduitis was also more common in rivanol group (27.1% vs. 13.6%, P<0.05). No significant difference was observed in fetal inflammatory responses (vasculitis of vessels in chorion plate and umbilical cord); maternal malperfusion (narrowing of intervillous space, increased intervillous fibrin deposition, decidual arteriopathy, villous infarction and retroplacental hematoma); and fetal malperfusion (villous stromal hemorrhage and avascular villi). Conclusions: The chemical chorioamnionitis caused by rivanol is characterized by maternal inflammatory response of low stage and high grade. The use of rivanol has no obvious impact on the fetal inflammatory response, maternal malperfusion and fetal malperfusion. Such morphologic changes may reflect the original placental lesions.


Assuntos
Aborto Induzido , Corioamnionite , Etacridina , Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Placenta , Gravidez
5.
J Int Med Res ; 48(7): 300060520933811, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32643981

RESUMO

Impetigo herpetiformis is a rare variant of generalized pustular psoriasis that occurs during pregnancy or is triggered by pregnancy, often in association with hypocalcemia. This condition is associated with increased maternal and fetal morbidity and mortality. We report a 29-year-old pregnant woman who presented to hospital at the gestational age of 20 weeks with widespread erythema covered with pustules that coalesced to form lakes of pus. She did not respond to corticosteroids, immunosuppressants, or phototherapy. Finally, intra-amniotic injection of ethacridine lactate was administered to terminate the pregnancy, and the patient showed complete recovery in 3 months. Insight from this case report may facilitate optimal management of this relatively rare entity.


Assuntos
Impetigo/complicações , Impetigo/mortalidade , Impetigo/terapia , Aborto Induzido/métodos , Corticosteroides , Adulto , China , Etacridina/farmacologia , Feminino , Humanos , Imunossupressores , Gravidez , Psoríase/complicações
6.
Thyroid ; 30(11): 1666-1675, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32345138

RESUMO

Objective: It has been demonstrated that the transcription factors TAZ (transcriptional coactivator with PDZ-binding motif), paired box gene 8 (PAX8), and NK2 homeobox 1 (NKX2-1) are coexpressed in the nucleus of thyroid cells. Furthermore, TAZ is known to enhance the transcriptional activity of PAX8 and NKX2-1 as well as the key thyroid-specific gene, thyroglobulin (TG), suggesting a critical role for TAZ in the control of thyroid cell speciation. We previously reported that the small molecule ethacridine, identified as a TAZ activator, was able to induce thyroid-specific transcription in endodermal cells differentiated from human embryonic stem (hES) cells using activin A. Since transcription factors are epigenetically regulated in cell differentiation, we investigated the epigenetic changes in the promoter regions of these key transcription factors during in vitro differentiation of hES cells into thyrocytes. Methods: We initially profiled chromatin accessibility using the technique of Assay for Transposase Accessible Chromatin sequencing (ATAC-seq), and then examined DNA methylation and histone acetylation in the promoter regions of the three selected thyroid transcription factors and the thyroid-specific genes during hES cell differentiation. Results: ATAC-seq analysis showed enriched chromatin accessibility of TAZ, NKX2-1, and PAX8 after exposure to activin A and ethacridine. There were no methylation changes found in the NKX2-1, PAX8, and TAZ promoters by bisulfite sequencing. In contrast, acetylation of histone H4, specifically acetylation of lysine 16, was observed in each of the promoters when measured by chromatin immunoprecipitation polymerase chain reaction assays, which correlated with the activity and expression of NKX2-1 and PAX8 as well as sodium/iodide symporter, thyroid stimulating hormone receptor, and TG genes. Conclusions: These results indicate that ethacridine treatment of activin A-derived endodermal hES cells leads to enhanced chromatin accessibility, which, in turn, allows histone H4 acetylation in the regulation of active genes for speciation of thyroid follicular cells from hES cells.


Assuntos
Diferenciação Celular , Metilação de DNA , Epigênese Genética , Glândula Tireoide/citologia , Glândula Tireoide/imunologia , Ativinas/metabolismo , Cromatina/química , Etacridina/farmacologia , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lisina , Fator de Transcrição PAX8/biossíntese , Fator de Transcrição PAX8/genética , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Células Epiteliais da Tireoide/citologia , Fator Nuclear 1 de Tireoide/biossíntese , Fator Nuclear 1 de Tireoide/genética
7.
Curr Drug Res Rev ; 11(2): 118-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513003

RESUMO

BACKGROUND: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. OBJECTIVE: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. METHODS: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. RESULTS: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. CONCLUSION: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.


Assuntos
Amsacrina/análogos & derivados , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Isoxazóis/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Amsacrina/química , Amsacrina/farmacocinética , Amsacrina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Simulação por Computador , Desenho de Fármacos , Etacridina/farmacologia , Feminino , Humanos , Ligação de Hidrogênio , Isoxazóis/química , Isoxazóis/farmacocinética , Modelos Moleculares , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Tamoxifeno/farmacologia
8.
Anticancer Res ; 39(8): 4095-4100, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366493

RESUMO

BACKGROUND/AIM: Ethacridine is used as a topical antiseptic as well as for second-trimester abortion. Recent studies showed that ethacridine is an inhibitor of poly(ADP-ribose) glycohydrolase (PARG) and an activator of the transcriptional coactivator with PDZ-binding motif (TAZ). This study examined the effects of ethacridine on thyroid cancer cells. MATERIALS AND METHODS: Thyroid cancer cell lines (FTC133 and SW1736) and thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with ethacridine. Viability, clonogenicity, cell-cycle distribution, and apoptosis were evaluated. The expression of thyroid differentiation markers (TTF-1, PAX8, and NIS) was determined by real-time PCR. RESULTS: Ethacridine suppressed cell growth and clonogenic ability of thyroid cancer cells in a time- and dose-dependent manner (p<0.001). No cell-cycle arrest was found, but ethacridine dose-dependently induced apoptosis of thyroid cancer cells (p<0.001). The PAX8 and NIS expressions were significantly increased in SW1736 (3.41-fold and 1.53-fold, respectively) and Nthy-ori 3-1 cells (2.73-fold and 4.12-fold, respectively). CONCLUSION: Ethacridine elicits apoptotic cell death in thyroid cancer cells and promotes differentiation in a subset of thyroid follicular cells.


Assuntos
Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Etacridina/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Transcrição PAX8/genética , Simportadores/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Fator Nuclear 1 de Tireoide/genética
12.
Invest Ophthalmol Vis Sci ; 58(7): 3118-3126, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28632878

RESUMO

Purpose: GPR143 regulates melanosome biogenesis and organelle size in pigment cells. The mechanisms underlying receptor function remain unclear. G protein-coupled receptors (GPCRs) are excellent pharmacologic targets; thus, we developed and applied a screening approach to identify potential GPR143 ligands and chemical modulators. Methods: GPR143 interacts with ß-arrestin; we therefore established a ß-arrestin recruitment assay to screen for compounds that modulate activity. Because GPR143 is localized intracellularly, screening with the wild-type receptor would be restricted to agents absorbed by the cell. For the screen we used a mutant receptor, which shows similar basal activity as the wild type but traffics to the plasma membrane. We tested two compound libraries and investigated validated hits for their effects on melanocyte pigmentation. Results: GPR143, which showed high constitutive activity in the ß-arrestin assay, was inhibited by several compounds. The three validated inhibitors (pimozide, niclosamide, and ethacridine lactate) were assessed for impact on melanocytes. Pigmentation and expression of tyrosinase, a key melanogenic enzyme, were reduced by all compounds. Because GPR143 appears to be constitutively active, these compounds may turn off its activity. Conclusions: X-linked ocular albinism type I, characterized by developmental eye defects, results from GPR143 mutations. Identifying pharmacologic agents that modulate GPR143 activity will contribute significantly to our understanding of its function and provide novel tools with which to study GPCRs in melanocytes and retinal pigment epithelium. Pimozide, one of three GPR143 inhibitors identified in this study, maybe be a good lead structure for development of more potent compounds and provide a platform for design of novel therapeutic agents.


Assuntos
Albinismo Ocular/genética , Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Glicoproteínas de Membrana/genética , Mutação , RNA/genética , Albinismo Ocular/tratamento farmacológico , Albinismo Ocular/metabolismo , Células Cultivadas , Análise Mutacional de DNA , Etacridina/farmacologia , Éxons , Proteínas do Olho/antagonistas & inibidores , Proteínas do Olho/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/dietoterapia , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Ligantes , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Niclosamida/farmacologia , Linhagem , Pimozida/farmacologia
13.
Thyroid ; 27(2): 292-299, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27829313

RESUMO

OBJECTIVE: The differentiation program for human thyroid follicular cells (TFCs) relies on the interplay between sequence-specific transcription factors and transcriptional co-regulators. Transcriptional co-activator with PDZ-binding motif (TAZ) is a co-activator that regulates several transcription factors, including PAX8 and NKX2-1, which play a central role in thyroid-specific gene transcription. TAZ and PAX8/NKX2-1 are co-expressed in the nuclei of thyroid cells, and TAZ interacts directly with both PAX8 and NKX2-1, leading to their enhanced transcriptional activity on the thyroglobulin (TG) promoter and additional genes. METHODS: The use of a small molecule, ethacridine, recently identified as a TAZ activator, in the differentiation of thyroid cells from human embryonic stem (hES) cells was studied. First, endodermal cells were derived from hES cells using Activin A, followed by induction of differentiation into thyroid cells directed by ethacridine and thyrotropin (TSH). RESULTS: The expression of TAZ was increased in the Activin A-derived endodermal cells by ethacridine in a dose-dependent manner and followed by increases in PAX8 and NKX2-1 when assessed by both quantitative polymerase chain reaction and immunostaining. Following further differentiation with the combination of ethacridine and TSH, the thyroid-specific genes TG, TPO, TSHR, and NIS were all induced in the differentiated hES cells. When these cells were cultured with extracellular matrix-coated dishes, thyroid follicle formation and abundant TG protein expression were observed. Furthermore, such hES cell-derived thyroid follicles showed a marked TSH-induced and dose-dependent increase in radioiodine uptake and protein-bound iodine accumulation. CONCLUSION: These data show that fully functional human thyroid cells can be derived from hES cells using ethacridine, a TAZ activator, which induces thyroid-specific gene expression and promotes thyroid cell differentiation from the hES cells. These studies again demonstrate the importance of transcriptional regulation in thyroid cell development. This approach also yields functional human thyrocytes, without any gene transfection or complex culture conditions, by directly manipulating the transcriptional machinery without interfering with intermediate signaling events.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Etacridina/farmacologia , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Células Epiteliais da Tireoide/efeitos dos fármacos , Tireotropina/farmacologia , Ativinas/farmacologia , Autoantígenos/efeitos dos fármacos , Autoantígenos/genética , Diferenciação Celular/genética , Células-Tronco Embrionárias Humanas/citologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Iodeto Peroxidase/efeitos dos fármacos , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/efeitos dos fármacos , Proteínas de Ligação ao Ferro/genética , Fator de Transcrição PAX8/efeitos dos fármacos , Fator de Transcrição PAX8/genética , Receptores da Tireotropina/efeitos dos fármacos , Receptores da Tireotropina/genética , Simportadores/efeitos dos fármacos , Simportadores/genética , Tireoglobulina/efeitos dos fármacos , Tireoglobulina/genética , Células Epiteliais da Tireoide/citologia , Fator Nuclear 1 de Tireoide/efeitos dos fármacos , Fator Nuclear 1 de Tireoide/genética , Transativadores , Fatores de Transcrição
14.
Arch Gynecol Obstet ; 295(1): 119-124, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27658386

RESUMO

PURPOSE: This study was aimed to evaluate the safety and efficacy of the second-trimester medical abortions using mifepristone and ethacridine lactate in women with placenta previa and/or prior cesarean deliveries. METHODS: The patients who underwent a second-trimester pregnancy termination from January 2009 to December 2015 were retrospectively analyzed. The eligible patients were assigned to four groups based on placentation and cesarean history. The abortion interval (AI), blood loss, hospital stays, incidence of curettage, and transfusion were reviewed. RESULTS: Two women underwent cesarean sections for placenta increta. Finally, 443 patients were enrolled in this study, including 92 with placenta previa, 153 with prior cesarean deliveries, 36 with the both factors, and 236 with normal placentation and no cesarean delivery history. All the included cases had a successful vaginal delivery. There was no significant difference in AI, hospital stay, rate of hemorrhage, and transfusion among the four groups. Patients with prior cesarean section had higher blood loss than the normal group (P = 0.0017), as well as patients with both placenta previa and prior cesarean (P = 0.0018). However, there was no obvious blood loss in patients with placenta previa when compared with normal placetal patients (P = 0.23). No uterine rupture occurred in all patients. CONCLUSIONS: Mifepristone combined with ethacridine lactate is safe and effective for patients with low placentation or/and prior cesarean in the second-trimester pregnancy termination.


Assuntos
Aborto Induzido/métodos , Cesárea/métodos , Etacridina/uso terapêutico , Mifepristona/uso terapêutico , Placenta Prévia/tratamento farmacológico , Adulto , Etacridina/administração & dosagem , Etacridina/farmacologia , Feminino , Humanos , Mifepristona/administração & dosagem , Gravidez , Segundo Trimestre da Gravidez
15.
Drug Discov Ther ; 11(6): 346-348, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29332894

RESUMO

A lot of diseases occur on the skin of elderly persons. We report four elderly cases of bullous dermatosis that did not meet various differential diagnoses. Japanese, heart failure, atrophic skin and leg edema probably due to aging, as well as flaccid or tense bullae localized in legs were the common factors to our patients. Such conditions may be increased in coming aging society. Accordingly, it is worth regarding such symptom as the new clinical entity, which may comfort patients with similar condition and attract further attention.


Assuntos
Dermatoses da Perna/diagnóstico , Dermatopatias Vesiculobolhosas/diagnóstico , Fatores Etários , Idoso de 80 Anos ou mais , Anti-Infecciosos Locais/uso terapêutico , Diagnóstico Diferencial , Etacridina/uso terapêutico , Feminino , Insuficiência Cardíaca/complicações , Humanos , Mordeduras e Picadas de Insetos/diagnóstico , Dermatoses da Perna/complicações , Dermatoses da Perna/patologia , Dermatoses da Perna/terapia , Masculino , Penfigoide Bolhoso/diagnóstico , Pênfigo/diagnóstico , Dermatopatias Vesiculobolhosas/complicações , Dermatopatias Vesiculobolhosas/patologia , Dermatopatias Vesiculobolhosas/terapia , Meias de Compressão
16.
Forensic Sci Int ; 268: e18-e22, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27789047

RESUMO

Approximately during the 30th week of pregnancy, a woman gave birth to a still-born child in a hospital. After first citing an extraneous cause for the premature still-birth, the woman later admitted to having self-induced the abortion by injecting the antiseptic Rivanol® (active agent: ethacridine lactate) through her abdominal wall into the amniotic cavity. The investigating authorities ordered an autopsy of the fetus along with additional toxicological investigations. To the naked eye, no obvious cause of death was apparent. The main autopsy findings were four skin defects (puncture/stabbing wounds) on the ball of the fetus's left thumb, with slight bleeding around the punctures and into the underlying fatty tissue, and a yellowish discoloration of the fetus's body surface, especially of the umbilical cord and fingernails. On basis of the results, the child would have been viable. Femoral vein blood and urine from the fetus were analyzed for ethacridine, as were an amniotic fluid sample and maternal blood and urine samples, which had been collected as evidence. The concentration of ethacridine in the amniotic fluid was 16mg/l. In the postmortem fetal blood and urine samples, the concentrations were 0.36mg/l and 0.34mg/l, respectively, while concentrations of 0.091mg/l and 0.42mg/l, respectively, were found in the serum and urine samples from the mother. In many countries, foremost in China, ethacridine lactate, to which both mother and child are exposed, is widely used as safe abortion method. Although the ethacridine concentrations found in blood and urine samples of the mother in our case are consistent with published values, we believe to be the first to report postmortem ethacridine concentrations in a fetus. While exposure to ethacridine is not toxicologically relevant for the mother, it is fatal for the fetus because it causes the placental decidua capsularis to separate from the decidua parietalis or decidua placentalis, respectively. Prostaglandins that are then produced induce labor. In medicolegal contexts, the proof for an abortion through the administration of ethacridine lactate lies in the typical yellow discoloration of the fetus in conjunction with the toxicological demonstration of the substance in fetal body fluids, and if possible also in maternal body fluids.


Assuntos
Aborto Criminoso , Anti-Infecciosos Locais/administração & dosagem , Etacridina/administração & dosagem , Injeções Intraperitoneais , Adulto , Líquido Amniótico/química , Anti-Infecciosos Locais/análise , Etacridina/análise , Feminino , Sangue Fetal/química , Humanos , Masculino , Gravidez
17.
Talanta ; 160: 489-498, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27591643

RESUMO

A simple and reliable method for preparing a selective dopamine (DA) sensor based on a molecularly imprinted polymer of ethacridine was proposed. The molecularly imprinted polymer electrode was prepared through electrodepositing polyethacridine-dopamine film on the glassy carbon electrode and then removing DA from the film via chemical induced elution. The molecular imprinted sensor was tested by cyclic voltammetry as well as by differential pulse voltammetry (DPV) to verify the changes in oxidative currents of DA. In optimized DPV conditions the oxidation peak current was well-proportional to the concentration of DA in the range from 2.0×10(-8)M up to 1×10(-6)M. The limit of detection (3σ) of DA was found to be as low as 4.4nM, by the proposed sensor that could be considered a sensitive marker of DA depletion in Parkinson's disease. Good reproducibility with relative standard deviation of 1.4% and long term stability within two weeks were also observed. The modified sensor was validated for the analysis of DA in deproteinized human serum samples using differential pulse voltammetric technique.


Assuntos
Dopamina/análise , Carbono/química , Dopamina/sangue , Dopamina/química , Técnicas Eletroquímicas , Eletrodos , Etacridina/química , Humanos , Limite de Detecção , Impressão Molecular , Polimerização , Polímeros/química
19.
Oncotarget ; 7(3): 2765-79, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26624983

RESUMO

Targeting Bruton's tyrosine kinase (BTK) with the small molecule BTK inhibitor ibrutinib has significantly improved patient outcomes in several B-cell malignancies, with minimal toxicity. Given the reported expression and constitutive activation of BTK in acute myeloid leukemia (AML) cells, there has been recent interest in investigating the anti-AML activity of ibrutinib. We noted that ibrutinib had limited single-agent toxicity in a panel of AML cell lines and primary AML samples, and therefore sought to identify ibrutinib-sensitizing drugs. Using a high-throughput combination chemical screen, we identified that the poly(ADP-ribose) glycohydrolase (PARG) inhibitor ethacridine lactate synergized with ibrutinib in TEX and OCI-AML2 leukemia cell lines. The combination of ibrutinib and ethacridine induced a synergistic increase in reactive oxygen species that was functionally important to explain the observed cell death. Interestingly, synergistic cytotoxicity of ibrutinib and ethacridine was independent of the inhibitory effect of ibrutinib against BTK, as knockdown of BTK did not sensitize TEX and OCI-AML2 cells to ethacridine treatment. Thus, our findings indicate that ibrutinib may have a BTK-independent role in AML and that PARG inhibitors may have utility as part of a combination therapy for this disease.


Assuntos
Apoptose/efeitos dos fármacos , Etacridina/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/genética , Pirazóis/farmacologia , Pirimidinas/farmacologia , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Animais , Linhagem Celular Tumoral , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Taninos Hidrolisáveis/farmacologia , Células Jurkat , Camundongos , Camundongos SCID , Piperidinas , Interferência de RNA , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo
20.
J Biochem ; 158(5): 413-23, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25979969

RESUMO

Transcriptional co-activator with PSD-95/Dlg-A/ZO-1 (PDZ)-binding motif (TAZ) regulates in cell proliferation and differentiation. In mesenchymal stem cells it promotes osteogenesis and myogenesis, and suppresses adipogenesis. TAZ activators are expected to prevent osteoporosis, obesity and muscle atrophy. TAZ activation induces epithelial-mesenchymal transition, confers stemness to cancer cells and leads to poor clinical prognosis in cancer patients. In this point of view, TAZ inhibitors should contribute to cancer therapy. Thus, TAZ attracts attention as a two-faced drug target. We screened for TAZ modulators by using human lung cancer A549 cells expressing the fluorescent reporter. Through this assay, we obtained TAZ activator candidates. We unexpectedly found that ethacridine, a widely used antiseptic and abortifacient, enhances the interaction of TAZ and protein phosphatases and increases unphosphorylated and nuclear TAZ. Ethacridine inhibits adipogenesis in mesenchymal C3H10T1/2 cells through the activation of TAZ. This finding suggests that ethacridine is a bona fide TAZ activator and supports that our assay is useful to discover TAZ activators.


Assuntos
Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Etacridina/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/agonistas , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteína Fosfatase 1/metabolismo , Proteína Fosfatase 2/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/agonistas , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Genes Reporter/efeitos dos fármacos , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Fosfoproteínas/agonistas , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Proteína Fosfatase 1/química , Proteína Fosfatase 1/genética , Proteína Fosfatase 2/química , Proteína Fosfatase 2/genética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , /genética , Interferência de RNA , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Transativadores , Fatores de Transcrição , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
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