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[PMID]:29482394
[Au] Autor:Marcinkowska M; Kotanska M; Zagórska A; Sniecikowska J; Kubacka M; Siwek A; Bucki A; Pawlowski M; Bednarski M; Sapa J; Starek M; Dabrowska M; Kolaczkowski M
[Ad] Endereço:a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland.
[Ti] Título:Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents.
[So] Source:J Enzyme Inhib Med Chem;33(1):536-545, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC of 26.9 µM and 20.5 µM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.
[Mh] Termos MeSH primário: Isoquinolinas/farmacologia
Piperazinas/farmacologia
Inibidores da Agregação de Plaquetas/farmacologia
Receptores Adrenérgicos alfa 2/metabolismo
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Seres Humanos
Isoquinolinas/síntese química
Isoquinolinas/química
Modelos Moleculares
Estrutura Molecular
Piperazinas/síntese química
Piperazinas/química
Agregação Plaquetária/efeitos dos fármacos
Inibidores da Agregação de Plaquetas/síntese química
Inibidores da Agregação de Plaquetas/química
Testes de Função Plaquetária
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ADRA2B protein, human); 0 (Isoquinolines); 0 (Piperazines); 0 (Platelet Aggregation Inhibitors); 0 (Receptors, Adrenergic, alpha-2); 1RTM4PAL0V (piperazine)
[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:180228
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2018.1437155


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[PMID]:28455168
[Au] Autor:Cummings CS; Fein K; Murata H; Ball RL; Russell AJ; Whitehead KA
[Ad] Endereço:Center for Polymer-based Protein Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, United States; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, United States.
[Ti] Título:ATRP-grown protein-polymer conjugates containing phenylpiperazine selectively enhance transepithelial protein transport.
[So] Source:J Control Release;255:270-278, 2017 Jun 10.
[Is] ISSN:1873-4995
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Despite its patient-friendliness, the oral route is not yet a viable strategy for the delivery of biomacromolecular therapeutics. This is, in part, due to the large size of proteins, which greatly limits their absorption across the intestinal epithelium. Although chemical permeation enhancers can improve macromolecular transport, their positive impact is often accompanied by toxicity. One element potentially contributing to this toxicity is the lack of co-localization of the enhancer with the protein drug, which can result in non-specific permeation of the intestine as well as enhancer overdosing in some areas due to non-uniform distribution. To circumvent these issues, this study describes a new way of increasing protein permeability via a polymer conjugation process that co-localizes permeation enhancer with the protein. Based on previous reports demonstrating the utility of 1-phenylpiperazine as an intestinal permeation enhancer, we synthesized protein-polymer conjugates with a phenylpiperazine-containing polymer using polymer-based protein engineering. A novel phenylpiperazine acrylamide monomer was synthesized and chain extended using atom transfer radical polymerization from the model protein bovine serum albumin (BSA). At non-cytotoxic doses, the protein-polymer conjugates induced a dose dependent reduction in the trans-epithelial electrical resistance of Caco-2 monolayers and an impressive ~30-fold increase in BSA permeability. Furthermore, this permeability increase was selective, as the permeability of the small molecule calcein co-incubated with the protein-polymer conjugate increased only 5-fold. Together, these data represent an important first step in the development of protein polymer conjugates that facilitate selective protein transport across membranes that are typically impermeable to macromolecules.
[Mh] Termos MeSH primário: Piperazinas/administração & dosagem
Soroalbumina Bovina/administração & dosagem
[Mh] Termos MeSH secundário: Células CACO-2
Sobrevivência Celular/efeitos dos fármacos
Seres Humanos
Absorção Intestinal
Permeabilidade
Piperazinas/química
Polimerização
Transporte Proteico
Soroalbumina Bovina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Piperazines); 27432CM55Q (Serum Albumin, Bovine); J9225CBI7D (phenylpiperazine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:29330466
[Au] Autor:Carney B; Kossatz S; Lok BH; Schneeberger V; Gangangari KK; Pillarsetty NVK; Weber WA; Rudin CM; Poirier JT; Reiner T
[Ad] Endereço:Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
[Ti] Título:Target engagement imaging of PARP inhibitors in small-cell lung cancer.
[So] Source:Nat Commun;9(1):176, 2018 01 12.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo. We measure PARP1/2 inhibition over time to calculate effective doses for individual drugs. Using patient-derived xenografts, we demonstrate that different therapeutics achieve similar integrated inhibition efficiencies under different dosing regimens. This imaging approach to non-invasive, quantitative assessment of dynamic intratumoral target inhibition may improve patient care through real-time monitoring of drug delivery.
[Mh] Termos MeSH primário: Neoplasias Pulmonares/tratamento farmacológico
Terapia de Alvo Molecular/métodos
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
Ensaios Antitumorais Modelo de Xenoenxerto
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Seres Humanos
Neoplasias Pulmonares/diagnóstico por imagem
Neoplasias Pulmonares/enzimologia
Camundongos Endogâmicos NOD
Camundongos Knockout
Camundongos SCID
Ftalazinas/farmacologia
Piperazinas/farmacologia
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores
Poli(ADP-Ribose) Polimerase-1/metabolismo
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem
Carcinoma de Pequenas Células do Pulmão/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Phthalazines); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 9QHX048FRV (talazoparib); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180114
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02096-w


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[PMID]:29184402
[Au] Autor:Wu X; Wang L; Qiu Y; Zhang B; Hu Z; Jin R
[Ad] Endereço:Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
[Ti] Título:Cooperation of IRAK1/4 inhibitor and ABT-737 in nanoparticles for synergistic therapy of T cell acute lymphoblastic leukemia.
[So] Source:Int J Nanomedicine;12:8025-8034, 2017.
[Is] ISSN:1178-2013
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:T cell acute lymphoblastic leukemia (T-ALL) is caused by clonal expansion of variant T cell progenitors and is considered as a high risk leukemia. Contemporary single chemotherapy has a limited effect due to dynamic and versatile properties of T-ALL. Here IRAK1/4 inhibitor and ABT-737 were co-encapsulated into polyethylene glycol modified poly (lactic-co-glycolic acid) nanoparticles (IRAK/ABT-NP) to enhance synergistic therapy of T-ALL. The formulation was optimized to achieve high drug loading using Box-Behnken design and response surface methodology. The optimal parameter comprised 2.98% polymer in acetonitrile, a ratio of oil phase to water phase of 1:8.33, and 2.12% emulsifier concentration. High drug loading and uniform spherical shape was achieved. In vitro release study showed sustained release of IRAK1/4 inhibitor for 72 hours as well as sustained release of ABT-737 for more than 120 hours. Uptake efficiency of IRAK/ABT-NP and induced apoptotic T-ALL fraction by IRAK/ABT-NP were much higher than the IRAK1/4 and ABT-737 combined solution. IC of IRAK/ABT-NP was two-fold lower than free drug combination in Jurkat cells. Additionally, we conducted in vivo experiments in which IRAK/ABT-NP exhibited greater cytotoxicity toward T-ALL cells, the capacity to significantly restore white blood cell number in peripheral blood, and improved survival time of T-ALL mouse model compared to the IRAK1/4 and ABT-737 combined solution.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores
Nanopartículas/química
Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Compostos de Bifenilo/administração & dosagem
Compostos de Bifenilo/farmacologia
Liberação Controlada de Fármacos
Sinergismo Farmacológico
Feminino
Seres Humanos
Células Jurkat
Ácido Láctico/química
Camundongos
Nanopartículas/administração & dosagem
Nitrofenóis/administração & dosagem
Nitrofenóis/farmacologia
Piperazinas/administração & dosagem
Piperazinas/farmacologia
Ácido Poliglicólico/química
Sulfonamidas/administração & dosagem
Sulfonamidas/farmacologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABT-737); 0 (Biphenyl Compounds); 0 (Nitrophenols); 0 (Piperazines); 0 (Sulfonamides); 0 (polylactic acid-polyglycolic acid copolymer); 26009-03-0 (Polyglycolic Acid); 33X04XA5AT (Lactic Acid); EC 2.7.11.1 (IRAK1 protein, human); EC 2.7.11.1 (IRAK4 protein, human); EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.2147/IJN.S146875


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[PMID]:28464864
[Au] Autor:Shimazu K; Tada Y; Morinaga T; Shingyoji M; Sekine I; Shimada H; Hiroshima K; Namiki T; Tatsumi K; Tagawa M
[Ad] Endereço:Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
[Ti] Título:Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways.
[So] Source:BMC Cancer;17(1):309, 2017 May 02.
[Is] ISSN:1471-2407
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma. METHODS: We examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses. An involvement of p53 was tested with siRNA for p53. RESULTS: Metformin suppressed cell growth of 9 kinds of mesothelioma including immortalized cells of mesothelium origin irrespective of the p53 functional status, whereas susceptibility to nutlin-3a was partly dependent on the p53 genotype. We investigated combinatory effects of metformin and nutlin-3a on, nutlin-3a sensitive MSTO-211H and NCI-H28 cells and insensitive EHMES-10 cells, all of which had the wild-type p53 gene. Knockdown of p53 expression with the siRNA demonstrated that susceptibility of MSTO-211H and NCI-H28 cells to nutlin-3a was p53-dependent, whereas that of EHMES-10 cells was not. Nevertheless, all the cells treated with both agents produced additive or synergistic growth inhibitory effects. Cell cycle analyses also showed that the combination increased sub-G1 fractions greater than metformin or nutlin-3a alone in MSTO-211H and EHMES-10 cells. Western blot analyses showed that metformin inhibited downstream pathways of the mammalian target of rapamycin (mTOR) but did not activate the p53 pathways, whereas nutlin-3a phosphorylated p53 and suppressed mTOR pathways. Cleaved caspase-3 and conversion of LC3A/B were also detected but it was dependent on cells and treatments. The combination of both agents in MSTO-211H cells rather suppressed the p53 pathways that were activated by nutrin-3a treatments, whereas the combination rather augmented the p53 actions in NCI-H28 and EHMES-10 cells. CONCLUSION: These data collectively indicated a possible interactions between mTOR and p53 pathways, and the combinatory effects were attributable to differential mechanisms induced by a cross-talk between the pathways.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Imidazóis/farmacologia
Neoplasias Pulmonares/metabolismo
Mesotelioma/metabolismo
Metformina/farmacologia
Piperazinas/farmacologia
Serina-Treonina Quinases TOR/metabolismo
Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Imidazoles); 0 (Piperazines); 0 (Tumor Suppressor Protein p53); 53IA0V845C (nutlin 3); 9100L32L2N (Metformin); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s12885-017-3300-y


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[PMID]:29355909
[Au] Autor:Temmingh HS; Williams T; Siegfried N; Stein DJ
[Ad] Endereço:Department of Psychiatry and Mental Health, University of Cape Town, Valkenberg Hospital, Private Bage X1, Cape Town, Western Cape, South Africa, 7935.
[Ti] Título:Risperidone versus other antipsychotics for people with severe mental illness and co-occurring substance misuse.
[So] Source:Cochrane Database Syst Rev;1:CD011057, 2018 Jan 22.
[Is] ISSN:1469-493X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Up to 75% of people with serious mental illness (SMI) such as schizophrenia and bipolar disorder have co-occurring substance use disorders (dual diagnosis). Dual diagnosis can have an adverse effect on treatment and prognosis of SMI. OBJECTIVES: To evaluate the effects of risperidone compared to treatment with other antipsychotics (first-generation and other second-generation antipsychotics) used in people with serious mental illness and co-occurring substance misuse. SEARCH METHODS: On 6 January 2016 and 9 October 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers). SELECTION CRITERIA: We selected randomised trials of risperidone versus any other antipsychotic in people with SMI and substance abuse (dual diagnosis). We included trials meeting our inclusion criteria and reporting useable data. We excluded trials that either did not meet our inclusion criteria or met our inclusion criteria but did not report any useable data. DATA COLLECTION AND ANALYSIS: We independently inspected citations and selected studies. For included studies, we independently extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals. For continuous outcomes we calculated the mean differences (MDs) and their 95% confidence intervals. We pooled data using random-effects meta-analyses and assessed the quality of evidence, creating a 'Summary of findings' table using the GRADE approach. MAIN RESULTS: We identified eight randomised trials containing a total of 1073 participants with SMI and co-occurring substance misuse. Seven of these contributed useable data to the review. There was heterogeneity in trial design and measurement. Risperidone was compared to clozapine, olanzapine, perphenazine, quetiapine and ziprasidone. Few trials compared risperidone with first-generation agents. Few trials examined participants with a dual diagnosis from the outset and most trials only contained separate analyses of subgroups with a dual diagnosis or were secondary data analyses of subgroups of people with a dual diagnosis from existing larger trials.For risperidone versus clozapine we found no clear differences between these two antipsychotics in the reduction of positive psychotic symptoms (1 randomised controlled trial (RCT), n = 36, mean difference (MD) 0.90, 95% CI -2.21 to 4.01, very low quality evidence), or reduction in cannabis use (1 RCT, n = 14, risk ratio (RR) 1.00, 95% CI 0.30 to 3.35, very low quality evidence), improvement in subjective well-being (1 RCT, n = 36, MD -6.00, 95% CI -14.82 to 2.82, very low quality evidence), numbers discontinuing medication (1 RCT, n = 36, RR 4.05, 95% CI 0.21 to 78.76, very low quality evidence), extrapyramidal side-effects (2 RCTs, n = 50, RR 2.71, 95% CI 0.30 to 24.08; I² = 0%, very low quality evidence), or leaving the study early (2 RCTs, n = 45, RR 0.49, 95% CI 0.10 to 2.51; I² = 34%, very low quality evidence). Clozapine was associated with lower levels of craving for cannabis (1 RCT, n = 28, MD 7.00, 95% CI 2.37 to 11.63, very low quality evidence).For risperidone versus olanzapine we found no clear differences in the reduction of positive psychotic symptoms (1 RCT, n = 37, MD -1.50, 95% CI -3.82 to 0.82, very low quality evidence), reduction in cannabis use (1 RCT, n = 41, MD 0.40, 95% CI -4.72 to 5.52, very low quality evidence), craving for cannabis (1 RCT, n = 41, MD 5.00, 95% CI -4.86 to 14.86, very low quality evidence), parkinsonism (1 RCT, n = 16, MD -0.08, 95% CI -1.21 to 1.05, very low quality evidence), or leaving the study early (2 RCT, n = 77, RR 0.68, 95% CI 0.34 to 1.35; I² = 0%, very low quality evidence).For risperidone versus perphenazine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 281, RR 1.05, 95% CI 0.92 to 1.20, low-quality evidence).For risperidone versus quetiapine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 294, RR 0.96, 95% CI 0.86 to 1.07, low-quality evidence).For risperidone versus ziprasidone, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 240, RR 0.96, 95% CI 0.85 to 1.10, low-quality evidence).For many comparisons, important outcomes were missing; and no data were reported in any study for metabolic disturbances, global impression of illness severity, quality of life or mortality. AUTHORS' CONCLUSIONS: There is not sufficient good-quality evidence available to determine the effects of risperidone compared with other antipsychotics in people with a dual diagnosis. Few trials compared risperidone with first-generation agents, leading to limited applicability to settings where access to second-generation agents is limited, such as in low- and middle-income countries. Moreover, heterogeneity in trial design and measurement of outcomes precluded the use of many trials in our analyses. Future trials in this area need to be sufficiently powered but also need to conform to consistent methods in study population selection, use of measurement scales, definition of outcomes, and measures to counter risk of bias. Investigators should adhere to CONSORT guidelines in the reporting of results.
[Mh] Termos MeSH primário: Antipsicóticos/uso terapêutico
Transtornos Mentais/tratamento farmacológico
Risperidona/uso terapêutico
Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
[Mh] Termos MeSH secundário: Benzodiazepinas/uso terapêutico
Clozapina/uso terapêutico
Diagnóstico Duplo (Psiquiatria)
Seres Humanos
Pacientes Desistentes do Tratamento/estatística & dados numéricos
Perfenazina/uso terapêutico
Piperazinas/uso terapêutico
Fumarato de Quetiapina/uso terapêutico
Ensaios Clínicos Controlados Aleatórios como Assunto
Esquizofrenia/tratamento farmacológico
Transtornos Relacionados ao Uso de Substâncias/psicologia
Tiazóis/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (Piperazines); 0 (Thiazoles); 12794-10-4 (Benzodiazepines); 2S3PL1B6UJ (Quetiapine Fumarate); 6UKA5VEJ6X (ziprasidone); FTA7XXY4EZ (Perphenazine); J60AR2IKIC (Clozapine); L6UH7ZF8HC (Risperidone); N7U69T4SZR (olanzapine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE
[do] DOI:10.1002/14651858.CD011057.pub2


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[PMID]:29291438
[Au] Autor:Gu ZS; Zhou AN; Xiao Y; Zhang QW; Li JQ
[Ad] Endereço:Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China.
[Ti] Título:Synthesis and antidepressant-like activity of novel aralkyl piperazine derivatives targeting SSRI/5-HT /5-HT .
[So] Source:Eur J Med Chem;144:701-715, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of novel aralkyl piperazine derivatives were synthesized, and evaluated for their serotonin reuptake inhibitory and 5-HT /5-HT receptors affinities activity. Antidepressant activities in vivo of the compounds were screened using the forced swimming test (FST) and tail suspension test (TST). The results indicated that compounds 21k (RUI, IC = 31 nM; 5-HT , 5-HT , k = 62, 12 nM) and 21n (RUI, IC = 25 nM; 5-HT , 5-HT , k = 28, 3.3 nM) exhibited high affinities for the 5-HT /5-HT receptors coupled with potent serotonin reuptake inhibition. Specifically, the most promising compound 21n possessed a good oral pharmacokinetic properties and an acceptable hERG profile, and showed potent antidepressant-like effect in the FST and TST models.
[Mh] Termos MeSH primário: Antidepressivos/farmacologia
Piperazinas/farmacologia
Receptor 5-HT1A de Serotonina/metabolismo
Receptores de Serotonina/metabolismo
Inibidores da Captação de Serotonina/farmacologia
[Mh] Termos MeSH secundário: Animais
Antidepressivos/síntese química
Antidepressivos/química
Relação Dose-Resposta a Droga
Seres Humanos
Masculino
Estrutura Molecular
Piperazinas/síntese química
Piperazinas/química
Ratos
Ratos Sprague-Dawley
Inibidores da Captação de Serotonina/síntese química
Inibidores da Captação de Serotonina/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Piperazines); 0 (Receptors, Serotonin); 0 (Serotonin Uptake Inhibitors); 0 (serotonin 7 receptor); 112692-38-3 (Receptor, Serotonin, 5-HT1A); 1RTM4PAL0V (piperazine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180102
[St] Status:MEDLINE


  8 / 40783 MEDLINE  
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[PMID]:28454547
[Au] Autor:Pignochino Y; Capozzi F; D'Ambrosio L; Dell'Aglio C; Basiricò M; Canta M; Lorenzato A; Vignolo Lutati F; Aliberti S; Palesandro E; Boccone P; Galizia D; Miano S; Chiabotto G; Napione L; Gammaitoni L; Sangiolo D; Benassi MS; Pasini B; Chiorino G; Aglietta M; Grignani G
[Ad] Endereço:Sarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy. ymera.pignochino@ircc.it.
[Ti] Título:PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models.
[So] Source:Mol Cancer;16(1):86, 2017 04 28.
[Is] ISSN:1476-4598
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death. METHODS: We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role. RESULTS: Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing. CONCLUSIONS: PARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Dioxóis/administração & dosagem
Poli(ADP-Ribose) Polimerase-1/genética
Sarcoma/tratamento farmacológico
Tetra-Hidroisoquinolinas/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Hibridização Genômica Comparativa
Dano ao DNA/efeitos dos fármacos
Sinergismo Farmacológico
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Camundongos
Ftalazinas/administração & dosagem
Piperazinas/administração & dosagem
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores
Sarcoma/genética
Sarcoma/patologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Dioxoles); 0 (Phthalazines); 0 (Piperazines); 0 (Tetrahydroisoquinolines); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); ID0YZQ2TCP (trabectedin); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1186/s12943-017-0652-5


  9 / 40783 MEDLINE  
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[PMID]:29372687
[Au] Autor:Stefaniková A; Klacanová K; Pilchová I; Hatok J; Racay P
[Ad] Endereço:1 Department of Medical Biochemistry Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. racay@jfmed.uniba.sk.
[Ti] Título:Cyclin-dependent kinase 2 inhibitor SU9516 increases sensitivity of colorectal carcinoma cells Caco-2 but not HT29 to BH3 mimetic ABT-737.
[So] Source:Gen Physiol Biophys;36(5):539-547, 2017 Dec.
[Is] ISSN:0231-5882
[Cp] País de publicação:Slovakia
[La] Idioma:eng
[Ab] Resumo:Colorectal carcinoma (CRC) that represents one of the major causes for cancer-related death in humans is often associated with over-expression of anti-apoptotic proteins of Bcl-2 family. The aim of presented study was to determine the effect of ABT-737 inhibitor of anti-apoptotic proteins Bcl-2, Bcl-XL and Bcl-w as well as cyclin-dependent kinase 2 (CDK2) inhibitor SU9516 alone and in combination with ABT-737 on survival of colorectal cell lines HT29 and Caco-2. We have shown that both Caco-2 and HT29 cells that are relatively resistant to ABT-737 are also partially sensitive to SU9516, which increased sensitivity of Caco-2 but not HT29 cells to ABT-737. Increased sensitivity of Caco-2 cells to ABT-737 after addition of SU9516 correlated well with SU9516-induced decrease of Mcl-1 expression while we have not observed downregulation of Mcl-1 after the treatment of HT29 cells with SU9516. Instead of this, we have shown that treatment of HT29 cells with SU9516 is associated with decreased expression of tumour suppressor protein p53. Our findings provide a rationale for clinical use of Bcl-2 family inhibitors in combination with CDK2 inhibitors for treatment of Mcl-1-dependent colorectal tumours associated with expression of Bcl-2, Bcl-XL and Bcl-w proteins. In addition, we have shown potential of CDK2 inhibitors for treatment of tumours expressing R273H mutant p53.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Compostos de Bifenilo/administração & dosagem
Neoplasias Colorretais/tratamento farmacológico
Neoplasias Colorretais/enzimologia
Quinase 2 Dependente de Ciclina/antagonistas & inibidores
Imidazóis/administração & dosagem
Indóis/administração & dosagem
Nitrofenóis/administração & dosagem
Sulfonamidas/administração & dosagem
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/química
Compostos de Bifenilo/química
Células CACO-2
Sobrevivência Celular/efeitos dos fármacos
Neoplasias Colorretais/patologia
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Células HT29
Seres Humanos
Nitrofenóis/química
Piperazinas/administração & dosagem
Piperazinas/química
Sulfonamidas/química
Resultado do Tratamento
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABT-737); 0 (BH3 Interacting Domain Death Agonist Protein); 0 (BID protein, human); 0 (Biphenyl Compounds); 0 (Imidazoles); 0 (Indoles); 0 (Nitrophenols); 0 (Piperazines); 0 (SU 9516); 0 (Sulfonamides); EC 2.7.11.22 (CDK2 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180127
[St] Status:MEDLINE
[do] DOI:10.4149/gpb_2017030


  10 / 40783 MEDLINE  
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[PMID]:29374705
[Au] Autor:Nakamura A; Matsunaga W; Gotoh A
[Ad] Endereço:Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.
[Ti] Título:Autophagy Induced by Naftopidil Inhibits Apoptosis of Human Gastric Cancer Cells.
[So] Source:Anticancer Res;38(2):803-809, 2018 02.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:AIM: Naftopidil is used to treat benign prostate hyperplasia. Moreover, previous studies have shown that naftopidil reduced viability of many types of cancer cells. Therefore, we investigated the antitumor mechanism of naftopidil in this study. MATERIALS AND METHODS: We used the HGC27 human gastric cancer cell line. It was treated with naftopidil, pan-caspase inhibitor, and chloroquine diphosphate (CQ). Cell viability and cell death were investigated by the assay and annexin V/ propidium iodide assay. Phosphorylation of protein kinase B (AKT) (Ser473) was measured by western blotting. Alteration of light chain 3B (LC3B) was investigated by western blotting and immunofluorescence. RESULTS: Naftopidil reduced phospho-AKT (Ser473) and altered LC3B. Combination of naftopidil and CQ reduced cell viability and phospho-AKT (Ser 473). CONCLUSION: Naftopidil induces apoptosis and autophagy of HGC27 cells, however, autophagy is considered to inhibit apoptosis. We concluded naftopidil and CQ have a synergistic antitumor effect.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Apoptose/efeitos dos fármacos
Autofagia/efeitos dos fármacos
Naftalenos/farmacologia
Piperazinas/farmacologia
Neoplasias Gástricas/tratamento farmacológico
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Cloroquina/administração & dosagem
Cloroquina/análogos & derivados
Cloroquina/farmacologia
Sinergismo Farmacológico
Seres Humanos
Proteínas Associadas aos Microtúbulos/metabolismo
Naftalenos/administração & dosagem
Fosforilação
Piperazinas/administração & dosagem
Proteínas Proto-Oncogênicas c-akt/metabolismo
Neoplasias Gástricas/metabolismo
Neoplasias Gástricas/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MAP1LC3B protein, human); 0 (Microtubule-Associated Proteins); 0 (Naphthalenes); 0 (Piperazines); 6E17K3343P (chloroquine diphosphate); 886U3H6UFF (Chloroquine); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); R9PHW59SFN (naftopidil)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180129
[St] Status:MEDLINE



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