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[PMID]:28463149
[Au] Autor:Lawton CAF; Lin X; Hanks GE; Lepor H; Grignon DJ; Brereton HD; Bedi M; Rosenthal SA; Zeitzer KL; Venkatesan VM; Horwitz EM; Pisansky TM; Kim H; Parliament MB; Rabinovitch R; Roach M; Kwok Y; Dignam JJ; Sandler HM
[Ad] Endereço:Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: clawton@mcw.edu.
[Ti] Título:Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-Term Update of NRG Oncology RTOG 9202.
[So] Source:Int J Radiat Oncol Biol Phys;98(2):296-303, 2017 06 01.
[Is] ISSN:1879-355X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease. METHODS AND MATERIALS: Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150 ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4 months of flutamide 250 mg 3 times per day and goserelin 3.6 mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24 months of monthly goserelin). RESULTS: Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6 years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non-prostate cancer) did not differ (5% relative reduction, P=.48). CONCLUSIONS: LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.
[Mh] Termos MeSH primário: Adenocarcinoma/terapia
Antagonistas de Androgênios/uso terapêutico
Neoplasias da Próstata/terapia
[Mh] Termos MeSH secundário: Adenocarcinoma/sangue
Adenocarcinoma/mortalidade
Adenocarcinoma/patologia
Adulto
Idoso
Idoso de 80 Anos ou mais
Antagonistas de Androgênios/administração & dosagem
Antagonistas de Androgênios/efeitos adversos
Terapia Combinada/efeitos adversos
Terapia Combinada/métodos
Terapia Combinada/estatística & dados numéricos
Intervalo Livre de Doença
Flutamida/administração & dosagem
Flutamida/efeitos adversos
Flutamida/uso terapêutico
Seguimentos
Gosserrelina/administração & dosagem
Gosserrelina/efeitos adversos
Gosserrelina/uso terapêutico
Seres Humanos
Masculino
Meia-Idade
Antígeno Prostático Específico/sangue
Neoplasias da Próstata/sangue
Neoplasias da Próstata/mortalidade
Neoplasias da Próstata/patologia
Fatores de Tempo
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Androgen Antagonists); 0F65R8P09N (Goserelin); 76W6J0943E (Flutamide); EC 3.4.21.77 (Prostate-Specific Antigen)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:29176856
[Au] Autor:Huber SE; Lenz B; Kornhuber J; Müller CP
[Ad] Endereço:Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
[Ti] Título:Prenatal androgen-receptor activity has organizational morphological effects in mice.
[So] Source:PLoS One;12(11):e0188752, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prenatal sex hormones exert organizational effects. It has been suggested that prenatal sex hormones affect adult morphological parameters, such as the finger length. Especially the second-to-fourth finger length (2D:4D) ratio has been implicated to be modified when exposed to higher androgen levels in utero. Here we show in a mouse model that experimental manipulation of the prenatal androgen level, by blocking the androgen receptor with flutamide or activating the androgen receptor with dihydrotestosterone (DHT), leads to changes in the length of the fingers of all paws in males and females. In addition to that, also total paw length and the 2D:4D ratio was affected. In males treated with DHT, the 2D:4D ratio was increased, while flutamide-treatment in females led to a reduced 2D:4D ratio. We also measured other parameters, such as head size, body length and tail length and demonstrate that body morphology is affected by prenatal androgen exposure with more prominent effects in females. Another factor that is thought to be influenced by early androgens is handedness. We tested mice for handedness, but did not find a significant effect of the prenatal treatment. These findings demonstrate that prenatal androgen activity is involved in the development of body morphology and might be a useful marker for prenatal androgen exposure.
[Mh] Termos MeSH primário: Extremidades/anatomia & histologia
Efeitos Tardios da Exposição Pré-Natal/metabolismo
Receptores Androgênicos/metabolismo
[Mh] Termos MeSH secundário: Animais
Tamanho Corporal
Di-Hidrotestosterona/farmacologia
Feminino
Flutamida/farmacologia
Lateralidade Funcional/efeitos dos fármacos
Hormônios Esteroides Gonadais/metabolismo
Masculino
Camundongos
Gravidez
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gonadal Steroid Hormones); 0 (Receptors, Androgen); 08J2K08A3Y (Dihydrotestosterone); 76W6J0943E (Flutamide)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188752


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[PMID]:29017178
[Au] Autor:Haque R; UlcickasYood M; Xu X; Cassidy-Bushrow AE; Tsai HT; Keating NL; Van Den Eeden SK; Potosky AL
[Ad] Endereço:Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA 91101, USA.
[Ti] Título:Cardiovascular disease risk and androgen deprivation therapy in patients with localised prostate cancer: a prospective cohort study.
[So] Source:Br J Cancer;117(8):1233-1240, 2017 Oct 10.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: As androgen deprivation therapy (ADT) is increasingly being used in men with localised prostate cancer, our goal was to examine the association between ADT and the risk of cardiovascular disease (CVD). METHODS: We conducted a prospective cohort study using records of a large health-care system in California. The study included men with newly diagnosed localised prostate cancer (1998-2008) who initially underwent active surveillance (N=7637) and were followed through 2010. We examined 10 individual CVD outcomes. Cox proportional hazard models incorporated time-varying treatment variables and controlled for race/ethnicity, age, and tumour characteristics, recurrence risk, CVD medication use, and CVD risk factors. RESULTS: Of the 7637 subjects, nearly 30% were exposed to ADT. In the multivariable analyses, ADT was associated with an increased risk of heart failure (adjusted HR=1.81, 95% CI 1.40-2.32) in men without preexisting CVD. Elevated risks of arrhythmia (adjusted HR=1.44, 95% CI 1.02-2.01), and conduction disorder (adjusted HR=3.11, 95% CI 1.22, 7.91) were only observed among patients with preexisting CVD. CONCLUSIONS: In men with clinically localised prostate cancer who were initially under active surveillance, ADT was associated with a greater risk of heart failure in men without any preexisting CVD. We also found an increased risk of arrhythmia and conduction disorder in men with preexisting CVD. This study provides the basis for identifying high-risk men treated with ADT who might benefit from regular cardiac monitoring and lifestyle modification recommendations.
[Mh] Termos MeSH primário: Antagonistas de Androgênios/uso terapêutico
Antineoplásicos Hormonais/uso terapêutico
Arritmias Cardíacas/epidemiologia
Insuficiência Cardíaca/epidemiologia
Neoplasias da Próstata/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso
Anilidas/uso terapêutico
California/epidemiologia
Doenças Cardiovasculares/epidemiologia
Estudos de Coortes
Flutamida/uso terapêutico
Hormônio Liberador de Gonadotropina/agonistas
Gosserrelina/uso terapêutico
Seres Humanos
Imidazolidinas/uso terapêutico
Leuprolida/uso terapêutico
Masculino
Meia-Idade
Análise Multivariada
Gradação de Tumores
Nitrilos/uso terapêutico
Modelos de Riscos Proporcionais
Estudos Prospectivos
Neoplasias da Próstata/epidemiologia
Neoplasias da Próstata/patologia
Fatores de Risco
Compostos de Tosil/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgen Antagonists); 0 (Anilides); 0 (Antineoplastic Agents, Hormonal); 0 (Imidazolidines); 0 (Nitriles); 0 (Tosyl Compounds); 0F65R8P09N (Goserelin); 33515-09-2 (Gonadotropin-Releasing Hormone); 51G6I8B902 (nilutamide); 76W6J0943E (Flutamide); A0Z3NAU9DP (bicalutamide); EFY6W0M8TG (Leuprolide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.280


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[PMID]:28717109
[Au] Autor:Ogihara T; Arakawa H; Jomura T; Idota Y; Koyama S; Yano K; Kojima H
[Ad] Endereço:Laboratory of Biopharmaceutics, Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare.
[Ti] Título:Utility of human hepatocyte spheroids without feeder cells for evaluation of hepatotoxicity.
[So] Source:J Toxicol Sci;42(4):499-507, 2017.
[Is] ISSN:1880-3989
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:We investigated the utility of three-dimensionally cultured hepatocytes (spheroids) without feeder cells (Sph(f-)) for the prediction of drug-induced liver injury (DILI) in humans. Sph(f-) and spheroids cultured on feeder cells (Sph(f+)) were exposed to the hepatotoxic drugs flutamide, diclofenac, isoniazid and chlorpromazine at various concentrations for 14 days, and albumin secretion and cumulative leakages of toxicity marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and γ-glutamyl transpeptidase (γ-GTP), were measured. The cumulative AST, LDH or γ-GTP leakages from Sph(f-) were similar to or greater than those from Sph(f+) for all drugs tested, although ALT leakages showed no consistent difference between Sph(f+) and Sph(f-). In the case of Sph(f-), significant correlations among all the toxicity markers except for γ-GTP were observed. As regards the drug concentrations causing 1.2-fold elevation of enzyme leakage (F ), no consistent difference between Sph(f+) and Sph(f-) was found, although several F values were undetermined, especially in Sph(f+). The IC of albumin secretion and F of AST leakage from Sph(f-) were equal to or lower than those of Sph(f+) for all the tested drugs. These results indicate that feeder cells might contribute to resistance to hepatotoxicity, suggesting DILI could be evaluated more accurately by using Sph(f-). We suggest that long-term exposure of Sph(f-) to drugs might be a versatile method to predict and reproduce clinical chronic toxicity, especially in response to repeated drug administration.
[Mh] Termos MeSH primário: Doença Hepática Induzida por Substâncias e Drogas/etiologia
Clorpromazina/toxicidade
Diclofenaco/toxicidade
Flutamida/toxicidade
Hepatócitos/citologia
Isoniazida/toxicidade
Esferoides Celulares
Testes de Toxicidade/métodos
[Mh] Termos MeSH secundário: Alanina Transaminase/metabolismo
Albuminas/secreção
Aspartato Aminotransferases/metabolismo
Células Cultivadas
Células Alimentadoras
Seres Humanos
L-Lactato Desidrogenase/metabolismo
Fígado/efeitos dos fármacos
Fígado/enzimologia
Fígado/secreção
Fatores de Tempo
gama-Glutamiltransferase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Albumins); 144O8QL0L1 (Diclofenac); 76W6J0943E (Flutamide); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 2.3.2.2 (gamma-Glutamyltransferase); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase); U42B7VYA4P (Chlorpromazine); V83O1VOZ8L (Isoniazid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.2131/jts.42.499


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[PMID]:28717101
[Au] Autor:Kawamoto T; Ito Y; Morita O; Honda H
[Ad] Endereço:Safety Science Research, Kao Corporation.
[Ti] Título:Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.
[So] Source:J Toxicol Sci;42(4):427-436, 2017.
[Is] ISSN:1880-3989
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.
[Mh] Termos MeSH primário: Clorpromazina/administração & dosagem
Clorpromazina/toxicidade
Colestase/induzido quimicamente
Ciclosporina/administração & dosagem
Ciclosporina/toxicidade
Diclofenaco/administração & dosagem
Diclofenaco/toxicidade
Medição de Risco/métodos
Toxicogenética/métodos
[Mh] Termos MeSH secundário: Administração Oral
Animais
Colesterol/biossíntese
Relação Dose-Resposta a Droga
Flutamida/administração & dosagem
Flutamida/toxicidade
Expressão Gênica
Seres Humanos
Imipramina/administração & dosagem
Imipramina/toxicidade
Inflamação/genética
Cetoconazol/administração & dosagem
Cetoconazol/toxicidade
Fígado
Metiltestosterona/administração & dosagem
Metiltestosterona/toxicidade
Estresse Oxidativo/genética
Ratos
Sulindaco/administração & dosagem
Sulindaco/toxicidade
Tamoxifeno/administração & dosagem
Tamoxifeno/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
094ZI81Y45 (Tamoxifen); 144O8QL0L1 (Diclofenac); 184SNS8VUH (Sulindac); 76W6J0943E (Flutamide); 83HN0GTJ6D (Cyclosporine); 97C5T2UQ7J (Cholesterol); OGG85SX4E4 (Imipramine); R9400W927I (Ketoconazole); U42B7VYA4P (Chlorpromazine); V9EFU16ZIF (Methyltestosterone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.2131/jts.42.427


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[PMID]:28697876
[Au] Autor:Mendoza FJ; Serrano-Rodriguez JM; Buzon-Cuevas A; Perez-Ecija A
[Ad] Endereço:Department of Animal Medicine and Surgery, University of Cordoba, Campus Rabanales, Cordoba 14104, Spain. Electronic address: fjmendoza@uco.es.
[Ti] Título:Pharmacokinetics of the anti-androgenic drug flutamide in healthy stallions.
[So] Source:Vet J;224:50-54, 2017 Jun.
[Is] ISSN:1532-2971
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Alternatives to surgical castration are necessary for controlling the sexual behaviour of stallions with breeding potential in training and competition. Flutamide is a potent selective non-steroidal androgen receptor competitive antagonist that has been used in human beings as an anti-androgenic drug. In this study, the pharmacokinetics and bioavailability of flutamide and its main active metabolite, 2-hydroflutamide, were determined in seven healthy mature stallions. Single doses of flutamide (1mg/kg intravenously, 1mg/kg orally in fasted horses, 5mg/kg orally in fasted horses and 5mg/kg orally in fed horses) were administered randomly at intervals of 2 weeks. All horses had full physical examinations and blood samples were collected for pharmacokinetics, complete blood counts and biochemistry before and after drug administration. Administration of flutamide did not result in any abnormalities on physical examination or in blood parameters. After intravenous administration of flutamide, the volume of distribution was 0.83L/kg and clearance was 1.20L/h/kg. Flutamide and its metabolite had high protein binding values (93-97%). After oral administration, flutamide was rapidly transformed to 2-hydroxyflutamide, with areas under the concentration-time curve ratios of metabolite:drug ∼7. Oral bioavailability was 6.63% after 1mg/kg flutamide in fasted horses, 6.50% after 5mg/kg flutamide in fasted horses and 6.95% after 5mg/kg in fed horses. Half lives of flutamide were close to 1h after intravenous administration and 2h after oral administration. Half lives of 2-hydroxyflutamide were 4.79-6.84h for all routes and doses. After oral administration, oral flutamide reached plasma concentrations that could be effective as an anti-androgenic agent in horses, but further studies are needed to determine whether flutamide has clinical value as an alternative to castration for controlling sexual behaviour in stallions.
[Mh] Termos MeSH primário: Antagonistas de Androgênios
Flutamida/farmacocinética
Cavalos/metabolismo
[Mh] Termos MeSH secundário: Administração Oral
Animais
Área Sob a Curva
Disponibilidade Biológica
Jejum
Flutamida/administração & dosagem
Flutamida/análogos & derivados
Flutamida/sangue
Meia-Vida
Injeções Intravenosas/veterinária
Masculino
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgen Antagonists); 31D90UKP5Y (hydroxyflutamide); 76W6J0943E (Flutamide)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE


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[PMID]:28581398
[Au] Autor:Rodda S; Morris WJ; Hamm J; Duncan G
[Ad] Endereço:BC Cancer Agency, Vancouver Centre, Vancouver, British Columbia, Canada.
[Ti] Título:ASCENDE-RT: An Analysis of Health-Related Quality of Life for a Randomized Trial Comparing Low-Dose-Rate Brachytherapy Boost With Dose-Escalated External Beam Boost for High- and Intermediate-Risk Prostate Cancer.
[So] Source:Int J Radiat Oncol Biol Phys;98(3):581-589, 2017 Jul 01.
[Is] ISSN:1879-355X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: To report the patient-reported health-related quality of life (HR-QoL) outcomes for a multicenter randomized trial evaluating the safety and efficacy of 2 different techniques for dose escalation. METHODS AND MATERIALS: A total of 357 men with intermediate- and high-risk prostate cancer were stratified by risk group and randomized (1:1) to either a dose-escalated external beam (DE-EBRT) boost (n=177) or a low-dose-rate prostate brachytherapy (LDR-PB) boost (n=180) as part of combined modality therapy. The HR-QoL was assessed using the SF36v2 questionnaire, with additional scales for urinary, bowel, and sexual function. Date of starting androgen deprivation therapy was considered time zero, the median follow-up of 6 years. Scales were scored from 0 to 100; a decline in a mean score ≥10 compared with baseline was considered a clinically significant decline. This was an intent-to-treat analysis. RESULTS: Mean domain scores at baseline were well balanced between the 2 treatment arms. A clinically significant decline in mean scores in both the arms compared with baseline was noted for role physical (DE-EBRT [-11.4] and LDR-PB [-15.3]) and sexual function scale (DE-EBRT [-15.1] and LDR-PB [-19.2]). There was a significantly larger drop in mean scores in the LDR-PB group compared with the DE-EBRT group for physical function (-15.3 vs -6.9; P=.03), urinary function (-3.6 vs -0.5; P=.04). CONCLUSION: At 6 years' follow up, there were no significant differences in mean scores in 9 of 11 scales compared with baseline in both arms. A clinically significant decline in mean scores was noted in both arms for role physical and sexual function scales. There was a statistically significant decline in physical function and urinary function scales in the LDR-PB arm compared with the DE-EBRT arm.
[Mh] Termos MeSH primário: Braquiterapia/métodos
Neoplasias da Próstata/radioterapia
Qualidade de Vida
Reirradiação/métodos
[Mh] Termos MeSH secundário: Atividades Cotidianas
Idoso
Idoso de 80 Anos ou mais
Antagonistas de Androgênios/uso terapêutico
Antineoplásicos Hormonais/uso terapêutico
Estudos de Viabilidade
Flutamida/administração & dosagem
Hormônio Liberador de Gonadotropina/agonistas
Seres Humanos
Análise de Intenção de Tratamento
Masculino
Meia-Idade
Neoplasias da Próstata/tratamento farmacológico
Risco
Comportamento Sexual
Inquéritos e Questionários
Fatores de Tempo
Transtornos Urinários/etiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Androgen Antagonists); 0 (Antineoplastic Agents, Hormonal); 33515-09-2 (Gonadotropin-Releasing Hormone); 76W6J0943E (Flutamide)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170606
[St] Status:MEDLINE


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[PMID]:28530711
[Au] Autor:Licciardello MP; Ringler A; Markt P; Klepsch F; Lardeau CH; Sdelci S; Schirghuber E; Müller AC; Caldera M; Wagner A; Herzog R; Penz T; Schuster M; Boidol B; Dürnberger G; Folkvaljon Y; Stattin P; Ivanov V; Colinge J; Bock C; Kratochwill K; Menche J; Bennett KL; Kubicek S
[Ad] Endereço:CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
[Ti] Título:A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor.
[So] Source:Nat Chem Biol;13(7):771-778, 2017 Jul.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for γ-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.
[Mh] Termos MeSH primário: Avaliação Pré-Clínica de Medicamentos
Receptores Androgênicos/metabolismo
Bibliotecas de Moléculas Pequenas/análise
Bibliotecas de Moléculas Pequenas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Flutamida/farmacologia
Seres Humanos
Masculino
Estrutura Molecular
Femprocumona/farmacologia
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/metabolismo
Neoplasias da Próstata/patologia
Bibliotecas de Moléculas Pequenas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Androgen); 0 (Small Molecule Libraries); 76W6J0943E (Flutamide); Q08SIO485D (Phenprocoumon)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2382


  9 / 2533 MEDLINE  
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[PMID]:28379593
[Au] Autor:Giorgetti R; di Muzio M; Giorgetti A; Girolami D; Borgia L; Tagliabracci A
[Ad] Endereço:Section of Legal Medicine, Università Politecnica delle Marche, Ancona, Italy. r.giorgetti@univpm.it.
[Ti] Título:Flutamide-induced hepatotoxicity: ethical and scientific issues.
[So] Source:Eur Rev Med Pharmacol Sci;21(1 Suppl):69-77, 2017 Mar.
[Is] ISSN:2284-0729
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Flutamide (FLU) is a non-steroidal antiandrogen drug approved for the treatment of advanced prostate cancer. While this indication limits the use to male patients, FLU is widely prescribed to women, off-label, for the treatment of polycystic ovary syndrome (POCS) related hirsutism and acne. According to the literature, its assumption is associated with a higher incidence of adverse events in women than in male patients. MATERIALS AND METHODS: A literature search was conducted in main databases targeting unwilling FLU effects in hepatic and reproductive function. References in the selected paper were also considered as an additional source of data. Human- and animal-based studies were separately considered. RESULTS: Twenty-three human-based studies were evaluated: ten were case reports, six were retrospective studies, four were prospective, two were surveillance studies, while the last was an observational study. Nine animal-based studies were also evaluated. CONCLUSIONS: Scientific contributions highlight that FLU is responsible for specific hepatotoxic profiles in the female gender. From the ethical point of view, off-label prescribing of FLU in women is not only substantially unlawful, but also, without major safeguards being granted, a potential source of liability for prescribers.
[Mh] Termos MeSH primário: Antagonistas de Androgênios/efeitos adversos
Doença Hepática Induzida por Substâncias e Drogas
Flutamida/efeitos adversos
[Mh] Termos MeSH secundário: Feminino
Seres Humanos
Masculino
Estudos Prospectivos
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Androgen Antagonists); 76W6J0943E (Flutamide)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE


  10 / 2533 MEDLINE  
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[PMID]:28324051
[Au] Autor:Laird M; Thomson K; Fenwick M; Mora J; Franks S; Hardy K
[Ad] Endereço:Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
[Ti] Título:Androgen Stimulates Growth of Mouse Preantral Follicles In Vitro: Interaction With Follicle-Stimulating Hormone and With Growth Factors of the TGFß Superfamily.
[So] Source:Endocrinology;158(4):920-935, 2017 04 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Androgens are essential for the normal function of mature antral follicles but also have a role in the early stages of follicle development. Polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, is characterized by androgen excess and aberrant follicle development that includes accelerated early follicle growth. We have examined the effects of testosterone and dihydrotestosterone (DHT) on development of isolated mouse preantral follicles in culture with the specific aim of investigating interaction with follicle-stimulating hormone (FSH), the steroidogenic pathway, and growth factors of the TGFß superfamily that are known to have a role in early follicle development. Both testosterone and DHT stimulated follicle growth and augmented FSH-induced growth and increased the incidence of antrum formation among the granulosa cell layers of these preantral follicles after 72 hours in culture. Effects of both androgens were reversed by the androgen receptor antagonist flutamide. FSH receptor expression was increased in response to both testosterone and DHT, as was that of Star, whereas Cyp11a1 was down-regulated. The key androgen-induced changes in the TGFß signaling pathway were down-regulation of Amh, Bmp15, and their receptors. Inhibition of Alk6 (Bmpr1b), a putative partner for Amhr2 and Bmpr2, by dorsomorphin resulted in augmentation of androgen-stimulated growth and modification of androgen-induced gene expression. Our findings point to varied effects of androgen on preantral follicle growth and function, including interaction with FSH-activated growth and steroidogenesis, and, importantly, implicate the intrafollicular TGFß system as a key mediator of androgen action. These findings provide insight into abnormal early follicle development in PCOS.
[Mh] Termos MeSH primário: Androgênios/farmacologia
Di-Hidrotestosterona/farmacologia
Hormônio Foliculoestimulante/farmacologia
Folículo Ovariano/efeitos dos fármacos
Testosterona/farmacologia
[Mh] Termos MeSH secundário: Antagonistas de Receptores de Andrógenos/farmacologia
Animais
Células Cultivadas
Regulação para Baixo/efeitos dos fármacos
Feminino
Flutamida/farmacologia
Células da Granulosa/efeitos dos fármacos
Células da Granulosa/metabolismo
Camundongos
Folículo Ovariano/crescimento & desenvolvimento
Folículo Ovariano/metabolismo
Receptores do FSH/genética
Receptores do FSH/metabolismo
Transdução de Sinais/efeitos dos fármacos
Fator de Crescimento Transformador beta/genética
Fator de Crescimento Transformador beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgen Receptor Antagonists); 0 (Androgens); 0 (Receptors, FSH); 0 (Transforming Growth Factor beta); 08J2K08A3Y (Dihydrotestosterone); 3XMK78S47O (Testosterone); 76W6J0943E (Flutamide); 9002-68-0 (Follicle Stimulating Hormone)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1210/en.2016-1538



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