Base de dados : MEDLINE
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[PMID]:29248751
[Au] Autor:Can NÖ; Osmaniye D; Levent S; Saglik BN; Korkut B; Atli Ö; Özkay Y; Kaplancikli ZA
[Ad] Endereço:Department of Analytical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey; Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey.
[Ti] Título:Design, synthesis and biological assessment of new thiazolylhydrazine derivatives as selective and reversible hMAO-A inhibitors.
[So] Source:Eur J Med Chem;144:68-81, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:In the recent works, it was shown that numerous thiazolylhydrazine derivatives display hMAO inhibitory activity in the range of micromolar concentration. Hence, in the present study a new series of new thiazole-hydrazines (3a-3n) were designed, synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro flurometric method. The enzyme inhibition assay revealed that most of the synthesized compounds have selective inhibition potency against hMAO-A. The compounds 3f and 3h showed promising hMAO-A inhibition with an IC values of 0.012 µM and 0.011 µM and significant selectivity indexes of 1214 and 1601 towards hMAO-A, respectively. The mechanism of hMAO-A inhibition of compounds 3f and 3h was investigated by Lineweaver-Burk graphics and reversible-competitive inhibition of hMAO-A was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 3h was found as non-cytotoxic and non-genotoxic. Theoretical calculation of ADME properties suggested that synthesized compounds may have a good pharmacokinetic profile. The docking study of compound 3f and 3h revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound.
[Mh] Termos MeSH primário: Inibidores da Monoaminoxidase/química
Inibidores da Monoaminoxidase/farmacologia
Monoaminoxidase/metabolismo
Tiazóis/química
Tiazóis/farmacologia
[Mh] Termos MeSH secundário: Domínio Catalítico/efeitos dos fármacos
Desenho de Drogas
Seres Humanos
Hidrazinas/química
Hidrazinas/farmacologia
Simulação de Acoplamento Molecular
Monoaminoxidase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydrazines); 0 (Monoamine Oxidase Inhibitors); 0 (Thiazoles); EC 1.4.3.4 (Monoamine Oxidase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:29233614
[Au] Autor:Paterna A; Khonkarn R; Mulhovo S; Moreno A; Madeira Girio P; Baubichon-Cortay H; Falson P; Ferreira MU
[Ad] Endereço:Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
[Ti] Título:Monoterpene indole alkaloid azine derivatives as MDR reversal agents.
[So] Source:Bioorg Med Chem;26(2):421-434, 2018 01 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aiming at generating a library of bioactive indole alkaloid derivatives as multidrug resistance (MDR) reversers, two epimeric indole alkaloids (1 and 2) were submitted to chemical transformations, giving rise to twenty-four derivatives (5-28), bearing new aromatic or aliphatic azine moieties. The structure of the compounds was established by 1D and 2D NMR (COSY, HMBC, HMQC and NOESY) experiments. Two different strategies were employed for assessing their anti-MDR potential, namely through the evaluation of their activity as inhibitors of typical MDR ABC transporters overexpressed by cell transfection, such as ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP), or by evaluating their ability as collateral sensitivity (CS) agents in cells overexpressing MRP1. A considerable MDR reversing activity was observed for compounds bearing the aromatic azine moiety. The strongest and most selective P-gp inhibition was found for the epimeric azines 5 and 6, bearing a para-methylbenzylidene moiety. Instead, compounds 17 and 18 that possess a di-substituted benzylidene portion with methoxy and hydroxyl groups, selectively inhibited MRP1 drug-efflux. None of these compounds inhibited BCRP. Compounds 5, 6 and 18 were further investigated in drug combination experiments, which corroborated their anti-MDR potential. Moreover, it was observed that compound 12, with an aromatic azine moiety, and compounds 23-26, sharing a new aliphatic substituent, displayed a CS activity, selectively killing MRP1-overexpressing cells. Among these last compounds, it could be established that addition of 19, 23 and 25 to MRP1-overexpressing cells led to glutathione depletion triggering cell death through apoptosis.
[Mh] Termos MeSH primário: Alcaloides/farmacologia
Resistência a Múltiplos Medicamentos/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Hidrazinas/farmacologia
Indóis/farmacologia
[Mh] Termos MeSH secundário: Alcaloides/síntese química
Alcaloides/química
Animais
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cricetinae
Relação Dose-Resposta a Droga
Células HEK293
Seres Humanos
Hidrazinas/síntese química
Hidrazinas/química
Indóis/síntese química
Indóis/química
Camundongos
Estrutura Molecular
Células NIH 3T3
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Alkaloids); 0 (Hydrazines); 0 (Indoles)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE


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[PMID]:28463762
[Au] Autor:Paixão DA; Marzano IM; Jaimes EHL; Pivatto M; Campos DL; Pavan FR; Deflon VM; Maia PIDS; Da Costa Ferreira AM; Uehara IA; Silva MJB; Botelho FV; Pereira-Maia EC; Guilardi S; Guerra W
[Ad] Endereço:Instituto de Química, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil.
[Ti] Título:Novel copper(II) complexes with hydrazides and heterocyclic bases: Synthesis, structure and biological studies.
[So] Source:J Inorg Biochem;172:138-146, 2017 Jul.
[Is] ISSN:1873-3344
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Five new copper(II) complexes of the type [Cu(NO)(NN)(ClO ) ], in which NO=4-fluorophenoxyacetic acid hydrazide (4-FH) or 4-nitrobenzoic hydrazide (4-NH) and NN=1,10-phenanthroline (phen), 4-4'-dimethoxy-2-2'-bipyridine (dmb) or 2,2-bipyridine (bipy) were synthesized and characterized using various spectroscopic methods. The X-ray structural analysis of one representative compound indicates that the geometry around the copper ion is distorted octahedron, in which the ion is coordinated to hydrazide via the terminal nitrogen and the carbonyl oxygen, and to heterocyclic bases via their two nitrogen atoms. Two perchlorate anions occupy the apical positions, completing the coordination sphere. The cytotoxic activity of compounds was investigated in three tumor cell lines (K562, MDA-MB-231 and MCF-7). Concerning K562 cell line, the complexes with 1,10-phenanthroline exhibit high cytotoxic activity and are more active than carboplatin, free ligands and [Cu(phen) ] . Considering the cytotoxicity results, further investigations for the compounds [Cu(4-FH)(phen)(ClO ) ] I and [Cu(4-NH)(phen)(ClO ) ]∙H O III were performed. Flow cytometric analysis revealed that these complexes induce apoptotic cell death in MDA-MB-231 cell line and bind to DNA with K values of 4.38×10 and 2.62×10 , respectively. These compounds were also evaluated against wild type Mycobacterium tuberculosis (ATCC 27294) and exhibited antimycobacterial activity, displayed MIC values lower than those of the corresponding free ligands.
[Mh] Termos MeSH primário: Complexos de Coordenação/síntese química
Complexos de Coordenação/farmacologia
Cobre/química
Compostos Heterocíclicos/química
Hidrazinas/química
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/farmacologia
Antituberculosos/síntese química
Antituberculosos/farmacologia
Apoptose/efeitos dos fármacos
Neoplasias da Mama/tratamento farmacológico
Linhagem Celular Tumoral
Complexos de Coordenação/química
Cristalografia por Raios X
Feminino
Seres Humanos
Concentração Inibidora 50
Células K562
Testes de Sensibilidade Microbiana
Estrutura Molecular
Mycobacterium/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Antitubercular Agents); 0 (Coordination Complexes); 0 (Heterocyclic Compounds); 0 (Hydrazines); 27RFH0GB4R (hydrazine); 789U1901C5 (Copper)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:29172661
[Au] Autor:Kovács G; Kiss C
[Ad] Endereço:II. Gyermekgyógyászati Klinika, Semmelweis Egyetem, Általános Orvostudományi Kar Budapest, Tuzoltó u. 7-9., 1094.
[Ti] Título:[Novelties in the treatment of pediatric immune thrombocytopenia - 2017].
[Ti] Título:Újdonságok a gyermekkori immunthrombocytopenia kezelésében ­ 2017..
[So] Source:Orv Hetil;158(48):1891-1896, 2017 Dec.
[Is] ISSN:0030-6002
[Cp] País de publicação:Hungary
[La] Idioma:hun
[Ab] Resumo:Immune thrombocitopenia in children is a very variable disease. International recommendations give therapeutic possibilities without strong protocols. In 2011, a therapeutic algorithm was published based on Hungarian practice. Recently, new innovative drugs have been available even in Hungary, so there is a need for modification of the therapeutic protocols. In this summary we give an overview about the current up-to-date management. In infancy and in childhood, high-dose immunglobulin treatment is recommended henceforward. In older children an alternative can be steroid therapy (pulses or long-term low-dose treatment). In resistant cases, a new thrombopoetin receptor stimulant, eltrombopag can be administered. This drug is registered in Hungary, and can very effectively influence the prognosis. Splenectomy is very rare nowadays in children. Immune thrombocytopenia is an unpredictable disease. Cure rate is about 70-80% of the cases, but management of the patients needs special care and specialist. Orv Hetil. 2017; 158(48): 1891-1896.
[Mh] Termos MeSH primário: Benzoatos/uso terapêutico
Hidrazinas/uso terapêutico
Imunoglobulinas Intravenosas/uso terapêutico
Conduta do Tratamento Medicamentoso
Púrpura Trombocitopênica Idiopática/tratamento farmacológico
Pirazóis/uso terapêutico
Esteroides/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Resistência a Medicamentos
Seres Humanos
Lactente
Recém-Nascido
Pediatria
Prognóstico
Púrpura Trombocitopênica Idiopática/cirurgia
Esplenectomia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoates); 0 (Hydrazines); 0 (Immunoglobulins, Intravenous); 0 (Pyrazoles); 0 (Steroids); S56D65XJ9G (eltrombopag)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1556/650.2017.30934


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[PMID]:28468797
[Au] Autor:Kuruvilla J; Savona M; Baz R; Mau-Sorensen PM; Gabrail N; Garzon R; Stone R; Wang M; Savoie L; Martin P; Flinn I; Jacoby M; Unger TJ; Saint-Martin JR; Rashal T; Friedlander S; Carlson R; Kauffman M; Shacham S; Gutierrez M
[Ad] Endereço:Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
[Ti] Título:Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma.
[So] Source:Blood;129(24):3175-3183, 2017 06 15.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter's transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m (60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892.
[Mh] Termos MeSH primário: Núcleo Celular/metabolismo
Hidrazinas/administração & dosagem
Hidrazinas/farmacocinética
Linfoma não Hodgkin/tratamento farmacológico
Linfoma não Hodgkin/metabolismo
Triazóis/administração & dosagem
Triazóis/farmacocinética
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Adulto
Idoso
Idoso de 80 Anos ou mais
Anemia/induzido quimicamente
Anemia/metabolismo
Anemia/patologia
Apoptose/efeitos dos fármacos
Núcleo Celular/patologia
Relação Dose-Resposta a Droga
Feminino
Seres Humanos
Hidrazinas/efeitos adversos
Hiponatremia/induzido quimicamente
Hiponatremia/metabolismo
Hiponatremia/patologia
Linfoma não Hodgkin/patologia
Masculino
Meia-Idade
Proteínas de Neoplasias/metabolismo
Neutropenia/induzido quimicamente
Neutropenia/metabolismo
Neutropenia/patologia
Trombocitopenia/induzido quimicamente
Trombocitopenia/metabolismo
Trombocitopenia/patologia
Triazóis/efeitos adversos
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Hydrazines); 0 (KPT-330); 0 (Neoplasm Proteins); 0 (Triazoles)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180121
[Lr] Data última revisão:
180121
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170505
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-11-750174


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[PMID]:29178132
[Au] Autor:Zhang X; Chuai Y; Nie W; Wang A; Dai G
[Ad] Endereço:Department of Oncology, Chinese PLA General Hospital, Beijing, China.
[Ti] Título:Thrombopoietin receptor agonists for prevention and treatment of chemotherapy-induced thrombocytopenia in patients with solid tumours.
[So] Source:Cochrane Database Syst Rev;11:CD012035, 2017 11 27.
[Is] ISSN:1469-493X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Chemotherapy-induced thrombocytopenia (CIT) is defined as a peripheral platelet count less than 100×10 /L, with or without bleeding in cancer patients receiving myelosuppressive chemotherapy. CIT is a significant medical problem during chemotherapy, and it carries the risk of sub-optimal overall survival and bleeding. Alternative interventions to platelet transfusion are limited. Different stages of preclinical and clinical studies have examined the thrombopoietin receptor agonists (TPO-RAs) for CIT in patients with solid tumours. OBJECTIVES: To assess the effects of TPO-RAs to prevent and treat CIT in patients with solid tumours:(1) to prevent CIT in patients without thrombocytopenia before chemotherapy, (2) to prevent recurrence of CIT, and (3) to treat CIT in patients with thrombocytopenia during chemotherapy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, to 28 September 2017), MEDLINE (from 1950 to 28 September 2017), as well as online registers of ongoing trials (Clinical Trials, Chinese Clinical Trial Register, Australian New Zealand Clinical Trial Registry, WHO ICTRP Search Portal, International Standard Randomised Controlled Trial Number registry, GlaxoSmithKline Clinical Study Register, and Amgen Clinical Trials) and conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, European Society of Medical Oncology, and Conference Proceedings Citation Index-Science, from 2002 up to September 2017) for studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing TPO-RAs alone, or in combination with other drugs, to placebo, no treatment, other drugs, or another TPO-RAs for CIT in patients with solid tumours. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard methodological methods expected by Cochrane. MAIN RESULTS: We identified six trials eligible for inclusion, of which two are ongoing, and one awaiting classification study. The three included trials were conducted at many different sites in Europe, America, and Asia. All of the three studies recruited adult and elder participants (no children were included) with solid tumours, and compared TPO-RAs with placebo. No studies compared TPO-RAs alone, or in combination with other drugs, to no treatment, or other drugs, or another TPO-RAs.We judged the overall risk of bias as high as we found a high risk for detection bias. We assessed the risk of bias arising from inadequate blinding of outcome assessors as high for number and severity of bleeding episodes (one of the primary outcomes).To prevent CIT: We included two trials (206 participants) comparing TPO-RAs (eltrombopag, multiple-dose oral administration with chemotherapy) with placebo. The use of TPO-RAs may make little or no difference to the all-cause mortality at 33 weeks of follow-up (RR 1.35, 95% CI 0.53 to 3.45; one trial, 26 participants; low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 0.62, 95% CI 0.22 to 1.78; two trials, 206 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (RR 0.36, 95% CI 0.06 to 2.06; two trials, 206 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life.To prevent recurrence of CIT: We included one trial (62 participants) comparing TPO-RAs (romiplostim, single-dose subcutaneous administration with chemotherapy) with placebo. There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 2.80, 95% CI 0.17 to 47.53; one trial, 62 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (no severe/life-threatening bleeding episodes; one trial, 62 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life. We found one ongoing study (expected recruitment 74 participants), it is planned to give TPO-RAs (romiplostim, subcutaneous administration with chemotherapy) to participants, but to date this trial has not reported any outcomes.To treat CIT: We found one ongoing study (expected recruitment 83 participants), which is planned to give TPO-RAs (eltrombopag, seven days orally) to participants when their platelet counts are less than 75×10 /L during chemotherapy. This trial was originally planned to complete in March 2017, however, the completion date has passed and no results are reported.The one awaiting classification study included patients without thrombocytopenia before chemotherapy (to prevent CIT), patients with thrombocytopenia during chemotherapy (to prevent recurrence of CIT), and other patients during chemotherapy (uncertain whether CIT had happened). There was no evidence for a difference in the number of patients with at least one bleeding episode of any severity (RR 0.27, 95% CI 0.07 to 1.02; one trial, 75 participants). There was no evidence for a difference in the number of patients with at least one severe/life-threatening bleeding episode (RR 0.44, 95% CI 0.03 to 6.77; one trial, 75 participants). This study did not address overall survival or quality of life. AUTHORS' CONCLUSIONS: No certain conclusions can be drawn due to the lack of strong evidence in the review. The available weak evidence did not support the use of TPO-RAs for preventing CIT or preventing recurrence of CIT in patients with solid tumours. There was no evidence to support the use of TPO-RAs for treating CIT in patients with solid tumours.
[Mh] Termos MeSH primário: Antineoplásicos/efeitos adversos
Benzoatos/administração & dosagem
Hidrazinas/administração & dosagem
Pirazóis/administração & dosagem
Receptores Fc/administração & dosagem
Receptores de Trombopoetina/agonistas
Proteínas Recombinantes de Fusão/administração & dosagem
Trombocitopenia/tratamento farmacológico
Trombocitopenia/prevenção & controle
Trombopoetina/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Idoso
Seres Humanos
Meia-Idade
Neoplasias/tratamento farmacológico
Ensaios Clínicos Controlados Aleatórios como Assunto
Trombocitopenia/induzido quimicamente
Trombocitopenia/mortalidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzoates); 0 (Hydrazines); 0 (Pyrazoles); 0 (Receptors, Fc); 0 (Receptors, Thrombopoietin); 0 (Recombinant Fusion Proteins); 9014-42-0 (Thrombopoietin); GN5XU2DXKV (romiplostim); S56D65XJ9G (eltrombopag)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180111
[Lr] Data última revisão:
180111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1002/14651858.CD012035.pub2


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[PMID]:29069576
[Au] Autor:Wen S; Wang J; Liu P; Li Y; Lu W; Hu Y; Liu J; He Z; Huang P
[Ad] Endereço:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, China; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: wenshj@
[Ti] Título:Novel combination of histone methylation modulators with therapeutic synergy against acute myeloid leukemia in vitro and in vivo.
[So] Source:Cancer Lett;413:35-45, 2018 Jan 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Acute myeloid leukemia (AML) is a hematological malignancy with rapid disease progression and often becomes lethal without treatment. Development of effective new therapies is essential to improve the clinical outcome of AML patients. Enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1) play important roles in epigenetic regulation and their altered expressions have been observed in cancer. Although EZH2 and LSD1 have opposite histone methylation functions, we found that both enzymes were paradoxically up-regulated in AML cells. Importantly, a combined inhibition of EZH2 and LSD1 resulted in a synergistic activity against AML in vitro and in vivo. Such synergy was mechanistically correlated with up-regulation of H3K4me1/2 and H3K9Ac and down-regulation of H3K27me3, leading to a decrease of anti-apoptotic protein Bcl-2. These epigenetic alterations also compromised the mitochondrial respiration capacity and glycolytic activity and resulted in ATP depletion, a key event contributing to the potent cytotoxic effect of the drug combination. Taken together, our work identified a novel therapeutic approach against AML by combining two small molecules that inhibit different histone methylation-modulating proteins with apparently opposite enzyme activities. Such a new drug combination strategy likely has significant clinical implications since epigenetic modulators are currently in clinical trials.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Benzamidas/farmacologia
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores
Inibidores Enzimáticos/farmacologia
Histona Desmetilases/antagonistas & inibidores
Histonas/metabolismo
Hidrazinas/farmacologia
Leucemia Mieloide Aguda/tratamento farmacológico
Piridonas/farmacologia
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Metabolismo Energético/efeitos dos fármacos
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo
Epigênese Genética/efeitos dos fármacos
Feminino
Células HL-60
Histona Desmetilases/genética
Histona Desmetilases/metabolismo
Seres Humanos
Leucemia Mieloide Aguda/enzimologia
Leucemia Mieloide Aguda/genética
Leucemia Mieloide Aguda/patologia
Metilação
Camundongos Endogâmicos BALB C
Camundongos Nus
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Fatores de Tempo
Células Tumorais Cultivadas
Regulação para Cima
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL2 protein, human); 0 (Benzamides); 0 (EPZ-6438); 0 (Enzyme Inhibitors); 0 (Histones); 0 (Hydrazines); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Pyridones); 0 (SP2509); 0 (Sulfonamides); EC 1.14.11.- (Histone Demethylases); EC 1.5.- (KDM1A protein, human); EC 2.1.1.43 (EZH2 protein, human); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171204
[Lr] Data última revisão:
171204
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171026
[St] Status:MEDLINE


  8 / 9254 MEDLINE  
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[PMID]:29069007
[Au] Autor:Gao Y; Gong M; Zhang C; Kong X; Ma Y
[Ad] Endereço:aDepartment of Hematology bDepartment of Pharmacology, China-Japan Friendship Hospital, Beijing, China.
[Ti] Título:Successful eltrombopag treatment of severe refractory thrombocytopenia in chronic myelomonocytic leukemia: Two cases reports: A CARE-compliant article.
[So] Source:Medicine (Baltimore);96(43):e8337, 2017 Oct.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Thrombocytopenia in chronic myelomonocytic leukemia (CMML) is usually attributed to impaired marrow production resulting from cytotoxic drug use or CMML itself ("CMML-induced thrombocytopenia"). In very rare cases, immune thrombocytopenia (ITP) can be a complication of CMML ("CMML-associated ITP"). However, treatment of severe thrombocytopenia in patients with CMML is still a challenge. PATIENT CONCERNS: Case 1 was a 61-year-old female patient admitted to our hospital because of skin petechiae and purpura for 6 days. She had increased monocyte cell count (1.82 × 10/L), markedly decreased platelet count (2 × 10/L), hypercellularity of the megakaryocyte lineage with many immature megakaryocytes, and ZRSR2(zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2) mutation. She failed to the treatment of corticosteroids, intravenous immunoglobulin (IVIg), TPO (thrombopoietin), and cyclosporin A (CsA). Case 2 was a 72-year-old female patient with thrombocytosis and monocytosis for 4 years, and thrombocytopenia for 6 months. After 10 courses of decitabine therapy, she had a persistent severe thrombocytopenia and decreased number of megakaryocytes, TET2 (tet methylcytosine dioxygenase 2) and SRSF2 (serine and arginine rich splicing factor 2) mutations were detected. She was dependent on platelet transfusion. DIAGNOSES: Case 1 was diagnosed as CMML-associated ITP, and case 2 as CMML with decitabine therapy-induced thrombocytopenia. INTERVENTIONS: Both patients were treated with eltrombopag. OUTCOMES: In both patients, the platelet counts returned to the normal within 1 week after eltrombopag therapy. The platelet count in case 1 patient remained stable at 141-200 × 10/L for 20 months with stopping therapy for 3 months. In case 2 patient, eltrombopag was stopped 1 month later. Her platelet count decreased to 41 × 10/L, but was stable at ∼30 × 10/L for 3 months with platelet transfusion independency for 12 months. Both patients had no adverse effects with eltrombopag. LESSONS: CMML-associated ITP is very rare and easily misdiagnosed. To the best of our knowledge, case 1 is the first reported case of the successful treatment of CMML-associated ITP with eltrombopag. Both CMML-associated ITP and decitabine therapy-induced thrombocytopenia in these 2 patients were highly sensitive and safe to eltrombopag therapy.
[Mh] Termos MeSH primário: Azacitidina/análogos & derivados
Benzoatos/administração & dosagem
Hidrazinas/administração & dosagem
Leucemia Mielomonocítica Crônica
Púrpura Trombocitopênica Idiopática
Pirazóis/administração & dosagem
Trombocitopenia
Trombopoetina/agonistas
[Mh] Termos MeSH secundário: Idoso
Antimetabólitos Antineoplásicos/efeitos adversos
Azacitidina/efeitos adversos
Proteínas de Ligação a DNA/genética
Monitoramento de Medicamentos
Feminino
Fármacos Hematológicos/administração & dosagem
Seres Humanos
Leucemia Mielomonocítica Crônica/sangue
Leucemia Mielomonocítica Crônica/complicações
Leucemia Mielomonocítica Crônica/diagnóstico
Leucemia Mielomonocítica Crônica/tratamento farmacológico
Meia-Idade
Mutação
Proteínas Nucleares/genética
Contagem de Plaquetas/métodos
Proteínas Proto-Oncogênicas/genética
Púrpura Trombocitopênica Idiopática/diagnóstico
Púrpura Trombocitopênica Idiopática/tratamento farmacológico
Púrpura Trombocitopênica Idiopática/etiologia
Púrpura Trombocitopênica Idiopática/fisiopatologia
Ribonucleoproteínas/genética
Fatores de Processamento de Serina-Arginina/genética
Trombocitopenia/induzido quimicamente
Trombocitopenia/diagnóstico
Trombocitopenia/tratamento farmacológico
Trombocitopenia/fisiopatologia
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Benzoates); 0 (DNA-Binding Proteins); 0 (Hematologic Agents); 0 (Hydrazines); 0 (Nuclear Proteins); 0 (Proto-Oncogene Proteins); 0 (Pyrazoles); 0 (Ribonucleoproteins); 0 (TET2 protein, human); 0 (ZRSR2 protein, human); 147153-65-9 (SRSF2 protein, human); 170974-22-8 (Serine-Arginine Splicing Factors); 776B62CQ27 (decitabine); 9014-42-0 (Thrombopoietin); M801H13NRU (Azacitidine); S56D65XJ9G (eltrombopag)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171026
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000008337


  9 / 9254 MEDLINE  
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[PMID]:28941802
[Au] Autor:Valdivieso ÁG; Mori C; Clauzure M; Massip-Copiz M; Santa-Coloma TA
[Ad] Endereço:Institute for Biomedical Research (BIOMED, UCA-CONICET), Laboratory of Cellular and Molecular Biology, School of Medical Sciences, Pontifical Catholic University of Argentina (UCA) and The National Scientific and Technical Research Council of Argentina (CONICET), Buenos Aires, C1107AFF, Argentina.
[Ti] Título:CFTR modulates RPS27 gene expression using chloride anion as signaling effector.
[So] Source:Arch Biochem Biophys;633:103-109, 2017 Nov 01.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In Cystic Fibrosis (CF), the impairment of the CFTR channel activity leads to a variety of alterations, including differential gene expression. However, the CFTR signaling mechanisms remain unclear. Recently, culturing IB3-1 CF cells under different intracellular Cl concentrations ([Cl ] ), we observed several Cl -dependent genes and further characterized one of them as RPS27. Thus, we hypothesized that Cl might act as a signaling effector for CFTR signaling. Here, to test this idea, we study RPS27 expression in T84 cells modulating the CFTR activity by using CFTR inhibitors. First, we observed that incubation of T84 cells with increasing concentrations of the CFTR inhibitors CFTR(inh)-172 or GlyH-101 determined a progressive increase in the relative [Cl ] (using the Cl fluorescent probe SPQ). The [Cl ] rise was concomitant with a dose-dependent down-regulation of RPS27. These results imply that CFTR inhibition produce Cl accumulation and that RPS27 expression can be modulated by CFTR inhibition. Therefore, Cl behaves as a signaling effector for CFTR in the modulation of RPS27 expression. In addition, the IL-1ß receptor antagonist IL1RN or the JNK inhibitor SP600125, both restored the down-regulation of RPS27 induced by CFTRinh-172, implying a role of autocrine IL-1ß and JNK signaling downstream of Cl in RPS27 modulation.
[Mh] Termos MeSH primário: Cloretos/metabolismo
Regulador de Condutância Transmembrana em Fibrose Cística/genética
Células Epiteliais/metabolismo
Metaloproteínas/genética
Proteínas Nucleares/genética
Proteínas de Ligação a RNA/genética
Proteínas Ribossômicas/genética
Transdução de Sinais
[Mh] Termos MeSH secundário: Antracenos/farmacologia
Comunicação Autócrina
Benzoatos/farmacologia
Linhagem Celular Tumoral
Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo
Células Epiteliais/citologia
Células Epiteliais/efeitos dos fármacos
Corantes Fluorescentes/metabolismo
Regulação da Expressão Gênica
Glicina/análogos & derivados
Glicina/farmacologia
Seres Humanos
Hidrazinas/farmacologia
Proteína Antagonista do Receptor de Interleucina 1/farmacologia
Interleucina-1beta/antagonistas & inibidores
Interleucina-1beta/genética
Interleucina-1beta/metabolismo
Transporte de Íons/efeitos dos fármacos
MAP Quinase Quinase 4/antagonistas & inibidores
MAP Quinase Quinase 4/genética
MAP Quinase Quinase 4/metabolismo
Metaloproteínas/metabolismo
Proteínas Nucleares/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Proteínas de Ligação a RNA/metabolismo
Proteínas Ribossômicas/metabolismo
Tiazolidinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone); 0 (Anthracenes); 0 (Benzoates); 0 (CFTR protein, human); 0 (Chlorides); 0 (Fluorescent Dyes); 0 (Hydrazines); 0 (IL1B protein, human); 0 (IL1RN protein, human); 0 (Interleukin 1 Receptor Antagonist Protein); 0 (Interleukin-1beta); 0 (Metalloproteins); 0 (N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide); 0 (Nuclear Proteins); 0 (Protein Kinase Inhibitors); 0 (RNA-Binding Proteins); 0 (RPS27 protein, human); 0 (Ribosomal Proteins); 0 (Thiazolidines); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); 1TW30Y2766 (pyrazolanthrone); EC 2.7.12.2 (MAP Kinase Kinase 4); TE7660XO1C (Glycine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170925
[St] Status:MEDLINE


  10 / 9254 MEDLINE  
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[PMID]:28881295
[Au] Autor:Song L; Gao D; Li S; Wang Y; Liu H; Jiang Y
[Ad] Endereço:Department of Chemistry, Tsinghua University, Beijing 100084, China; State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
[Ti] Título:Simultaneous quantitation of hydrazine and acetylhydrazine in human plasma by high performance liquid chromatography-tandem mass spectrometry after derivatization with p-tolualdehyde.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1063:189-195, 2017 Sep 15.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for simultaneous quantitative analysis of hydrazine and acetylhydrazine in human plasma based on the strategy of p-tolualdehyde derivatization. The derivatization reactions were easily realized by ultrasonic manipulation for 40min. Good separation of the derivatization products was achieved using a C column by gradient elution. The optimized mass transition ion-pairs (m/z) monitored for the two hydrazine derivatives were m/z 237.1≫>119.9 and m/z 176.9≫>117.8, respectively. The limit of detection (LOD) and limit of quantification (LOQ) for hydrazine were 0.002 and 0.005ngmL separately. And they were 0.03 and 0.05ngmL for acetylhydrazine, respectively. The linear range was 0.005-50ngmL for hydrazine and 0.05-500ngmL for acetylhydrazine with R greater than 0.999. The recovery range was determined to be 95.38-108.12% with the relative standard deviation (RSD) in the range of 1.24-14.89%. The method was successfully applied to detect 30 clinical plasma samples of pulmonary tuberculosis patients treated with isoniazid. The concentrations were from 0.04-1.99ngmL for hydrazine and 0.06-142.43ngmL for acetylhydrazine. The results indicated that our developed method had the potential for the detection of hydrazine toxicology in complex biological samples. Furthermore, the method has an important significance to clinical treatment with drugs.
[Mh] Termos MeSH primário: Benzaldeídos/química
Cromatografia Líquida de Alta Pressão/métodos
Hidrazinas/sangue
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Antituberculosos/uso terapêutico
Seres Humanos
Hidrazinas/química
Isoniazida/uso terapêutico
Modelos Lineares
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
Tuberculose Pulmonar/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Benzaldehydes); 0 (Hydrazines); 104-87-0 (4-methylbenzaldehyde); 27RFH0GB4R (hydrazine); SK0DPC9098 (acetylhydrazine); V83O1VOZ8L (Isoniazid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE



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