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[PMID]:28012176
[Au] Autor:Webster SP; McBride A; Binnie M; Sooy K; Seckl JR; Andrew R; Pallin TD; Hunt HJ; Perrior TR; Ruffles VS; Ketelbey JW; Boyd A; Walker BR
[Ad] Endereço:Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
[Ti] Título:Selection and early clinical evaluation of the brain-penetrant 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor UE2343 (Xanamem™).
[So] Source:Br J Pharmacol;174(5):396-408, 2017 Mar.
[Is] ISSN:1476-5381
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: Reducing glucocorticoid exposure in the brain via intracellular inhibition of the cortisol-regenerating enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment in early Alzheimer's disease (AD). We sought to discover novel, brain-penetrant 11ß-HSD1 inhibitors as potential medicines for the treatment of AD. EXPERIMENTAL APPROACH: Medicinal chemistry optimization of a series of amido-thiophene analogues was performed to identify potent and selective 11ß-HSD1 inhibitors with optimized oral pharmacokinetics able to access the brain. Single and multiple ascending dose studies were conducted in healthy human subjects to determine the safety, pharmacokinetic and pharmacodynamic characteristics of the candidate compound. RESULTS: UE2343 was identified as a potent, orally bioavailable, brain-penetrant 11ß-HSD1 inhibitor and selected for clinical studies. No major safety issues occurred in human subjects. Plasma adrenocorticotropic hormone was elevated (a marker of systemic enzyme inhibition) at doses of 10 mg and above, but plasma cortisol levels were unchanged. Following multiple doses of UE2343, plasma levels were approximately dose proportional and the terminal t ranged from 10 to 14 h. The urinary tetrahydrocortisols/tetrahydrocortisone ratio was reduced at doses of 10 mg and above, indicating maximal 11ß-HSD1 inhibition in the liver. Concentrations of UE2343 in the CSF were 33% of free plasma levels, and the peak concentration in CSF was ninefold greater than the UE2343 IC . CONCLUSIONS AND IMPLICATIONS: UE2343 is safe, well tolerated and reaches the brain at concentrations predicted to inhibit 11ß-HSD1. UE2343 is therefore a suitable candidate to test the hypothesis that 11ß-HSD1 inhibition in brain improves memory in patients with AD.
[Mh] Termos MeSH primário: 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores
Encéfalo/metabolismo
Inibidores Enzimáticos/administração & dosagem
Tiofenos/administração & dosagem
Tropanos/administração & dosagem
[Mh] Termos MeSH secundário: Adolescente
Adulto
Animais
Cães
Relação Dose-Resposta a Droga
Método Duplo-Cego
Inibidores Enzimáticos/efeitos adversos
Inibidores Enzimáticos/farmacocinética
Feminino
Meia-Vida
Seres Humanos
Hidrocortisona/sangue
Concentração Inibidora 50
Masculino
Meia-Idade
Ratos
Ratos Sprague-Dawley
Tetra-Hidrocortisol/urina
Tetra-Hidrocortisona/urina
Tiofenos/efeitos adversos
Tiofenos/farmacocinética
Distribuição Tecidual
Tropanos/efeitos adversos
Tropanos/farmacocinética
Adulto Jovem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Thiophenes); 0 (Tropanes); 0 (UE2343); 5HF9TM2D15 (Tetrahydrocortisone); 7P2O6MFN8O (Tetrahydrocortisol); EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 1); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161225
[St] Status:MEDLINE
[do] DOI:10.1111/bph.13699


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[PMID]:27310211
[Au] Autor:Chiesa L; Panseri S; Pavlovic R; Cannizzo FT; Biolatti B; Divari S; Villa R; Arioli F
[Ad] Endereço:a Department of Veterinary Science and Public Health , University of Milan , Milan , Italy.
[Ti] Título:HPLC-ESI-MS/MS assessment of the tetrahydro-metabolites of cortisol and cortisone in bovine urine: promising markers of dexamethasone and prednisolone treatment.
[So] Source:Food Addit Contam Part A Chem Anal Control Expo Risk Assess;33(7):1175-89, 2016 Jul.
[Is] ISSN:1944-0057
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The effects of long-term administration of low doses of dexamethasone (DX) and prednisolone (PL) on the metabolism of endogenous corticosteroids were investigated in veal calves. In addition to cortisol (F) and cortisone (E), whose interconversion is regulated by 11ß-hydroxysteroid dehydrogenases (11ßHSDs), special attention was paid to tetrahydrocortisol (THF), allo-tetrahydrocortisol (aTHF), tetrahydrocortisone (THE) and allo-tetrahydrocortisone (aTHE), which are produced from F and E by catalytic activity of 5α and 5ß-reductases. A specifically developed HPLC-ESI-MS/MS method achieved the complete chromatographic separation of two pairs of diastereoisomers (THF/aTHF and THE/aTHE), which, with appropriate mass fragmentation patterns, provided an unambiguous conformation. The method was linear (r(2) > 0.9905; 0.5-25 ng ml(-1)), with LOQQ of 0.5 ng ml(-1). Recoveries were in range 75-114%, while matrix effects were minimal. The experimental study was carried out on three groups of male Friesian veal calves: group PL (n = 6, PL acetate 15 mg day(-1) p.o. for 31 days); group DX (n = 5, 5 mg of estradiol (E2) i.m., weekly, and 0.4 mg day(-1) of DX p.o. for 31 days) and a control group (n = 8). Urine was collected before, during (twice) and at the end of treatment. During PL administration, the tetrahydro-metabolite levels decreased gradually and remained low after the suspension of treatment. DX reduced urinary THF that persisted after the treatment, while THE levels decreased during the experiment, but rebounded substantially after the DX was withdrawn. Both DX and PL significantly interfered with the production of F and E, leading to their complete depletion. Taken together, the results demonstrate the influence of DX and PL administration on 11ßHSD activity and their impact on dysfunction of the 5-reductase pathway. In conclusion, profiling tetrahydro-metabolites of F and E might serve as an alternative, indirect but reliable, non-invasive procedure for assessing the impact of synthetic glucocorticosteroids administration.
[Mh] Termos MeSH primário: Cortisona/urina
Dexametasona/urina
Hidrocortisona/urina
Prednisolona/urina
Tetra-Hidrocortisol/análogos & derivados
Tetra-Hidrocortisona/urina
[Mh] Termos MeSH secundário: 11-beta-Hidroxiesteroide Desidrogenases/antagonistas & inibidores
11-beta-Hidroxiesteroide Desidrogenases/urina
Animais
Biomarcadores/urina
Biotransformação
Bovinos
Cromatografia Líquida de Alta Pressão
Dexametasona/farmacologia
Masculino
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/urina
Prednisolona/farmacologia
Espectrometria de Massas por Ionização por Electrospray
Estereoisomerismo
Espectrometria de Massas em Tandem
Tetra-Hidrocortisol/urina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 302-91-0 (allotetrahydrocortisol); 5HF9TM2D15 (Tetrahydrocortisone); 7P2O6MFN8O (Tetrahydrocortisol); 7S5I7G3JQL (Dexamethasone); 9PHQ9Y1OLM (Prednisolone); EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenases); EC 1.3.- (Oxidoreductases Acting on CH-CH Group Donors); EC 1.3.1.22 (cortisone alpha-reductase); V27W9254FZ (Cortisone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170303
[Lr] Data última revisão:
170303
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160617
[St] Status:MEDLINE
[do] DOI:10.1080/19440049.2016.1202453


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[PMID]:26990942
[Au] Autor:Torchen LC; Idkowiak J; Fogel NR; O'Neil DM; Shackleton CH; Arlt W; Dunaif A
[Ad] Endereço:Division of Endocrinology, Metabolism, and Molecular Medicine (A.D.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; Division of Pediatric Endocrinology (L.C.T., N.R.F.), Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northweste
[Ti] Título:Evidence for Increased 5α-Reductase Activity During Early Childhood in Daughters of Women With Polycystic Ovary Syndrome.
[So] Source:J Clin Endocrinol Metab;101(5):2069-75, 2016 May.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CONTEXT: Polycystic ovary syndrome (PCOS) is a heritable, complex genetic disease. Animal models suggest that androgen exposure at critical developmental stages contributes to disease pathogenesis. We hypothesized that genetic variation resulting in increased androgen production produces the phenotypic features of PCOS by programming during critical developmental periods. Although we have not found evidence for increased in utero androgen levels in cord blood in the daughters of women with PCOS (PCOS-d), target tissue androgen production may be amplified by increased 5α-reductase activity analogous to findings in adult affected women. It is possible to noninvasively test this hypothesis by examining urinary steroid metabolites. OBJECTIVE: We performed this study to investigate whether PCOS-d have altered androgen metabolism during early childhood. DESIGN, SETTING, AND PARTICIPANTS: Twenty-one PCOS-d, 1-3 years old, and 36 control girls of comparable age were studied at an academic medical center. MAIN OUTCOME MEASURES: Urinary steroid metabolites were measured by gas chromatography/mass spectrometry. Twenty-four hour steroid excretion rates and precursor to product ratios suggestive of 5α-reductase and 11ß-hydroxysteroid dehydrogenase activities were calculated. RESULTS: Age did not differ but weight for length Z-scores were higher in PCOS-d compared to control girls (P = .02). PCOS-d had increased 5α-tetrahydrocortisol:tetrahydrocortisol ratios (P = .04), suggesting increased global 5α-reductase activity. There was no evidence for differences in 11ß-hydroxysteroid dehydrogenase activity. Steroid metabolite excretion was not correlated with weight. CONCLUSIONS: Our findings suggest that differences in androgen metabolism are present in early childhood in PCOS-d. Increased 5α-reductase activity could contribute to the development of PCOS by amplifying target tissue androgen action.
[Mh] Termos MeSH primário: Filho de Pais Incapacitados
Colestenona 5 alfa-Redutase/metabolismo
Núcleo Familiar
Síndrome do Ovário Policístico
[Mh] Termos MeSH secundário: Adulto
Pré-Escolar
Feminino
Seres Humanos
Lactente
Tetra-Hidrocortisol/urina
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
7P2O6MFN8O (Tetrahydrocortisol); EC 1.3.1.22 (Cholestenone 5 alpha-Reductase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160319
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2015-3926


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[PMID]:26444587
[Au] Autor:Stirrat LI; O'Reilly JR; Barr SM; Andrew R; Riley SC; Howie AF; Bowman M; Smith R; Lewis JG; Denison FC; Forbes S; Seckl JR; Walker BR; Norman JE; Reynolds RM
[Ad] Endereço:MRC Centre for Reproductive Health, University of Edinburgh, United Kingdom; Tommy's Centre for Maternal and Fetal Health, University of Edinburgh, United Kingdom.
[Ti] Título:Decreased maternal hypothalamic-pituitary-adrenal axis activity in very severely obese pregnancy: Associations with birthweight and gestation at delivery.
[So] Source:Psychoneuroendocrinology;63:135-43, 2016 Jan.
[Is] ISSN:1873-3360
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation. METHOD: Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects. RESULTS: Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation). CONCLUSION: In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy.
[Mh] Termos MeSH primário: Peso ao Nascer
Idade Gestacional
Hidrocortisona/metabolismo
Sistema Hipotálamo-Hipofisário/metabolismo
Obesidade Mórbida/metabolismo
Sistema Hipófise-Suprarrenal/metabolismo
Complicações na Gravidez/metabolismo
[Mh] Termos MeSH secundário: Adulto
Estudos de Casos e Controles
Hormônio Liberador da Corticotropina/metabolismo
Cortisona/urina
Estradiol/metabolismo
Estriol/metabolismo
Feminino
Seres Humanos
Recém-Nascido de Baixo Peso
Recém-Nascido
Masculino
Gravidez
Pregnanos/urina
Progesterona/metabolismo
Tetra-Hidrocortisol/urina
Transcortina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Pregnanes); 3J9D9J550A (cortolone); 4G7DS2Q64Y (Progesterone); 4TI98Z838E (Estradiol); 516-38-1 (cortol); 7P2O6MFN8O (Tetrahydrocortisol); 9010-38-2 (Transcortin); 9015-71-8 (Corticotropin-Releasing Hormone); FB33469R8E (Estriol); V27W9254FZ (Cortisone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151008
[St] Status:MEDLINE


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[PMID]:26349936
[Au] Autor:Buehlmeier J; Remer T; Frings-Meuthen P; Maser-Gluth C; Heer M
[Ad] Endereço:Institute of Aerospace Medicine, German Aerospace Center (DLR), Linder Hoehe, 51147, Cologne, Germany. judith.buehlmeier@gmail.com.
[Ti] Título:Glucocorticoid activity and metabolism with NaCl-induced low-grade metabolic acidosis and oral alkalization: results of two randomized controlled trials.
[So] Source:Endocrine;52(1):139-47, 2016 Apr.
[Is] ISSN:1559-0100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid-base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases.
[Mh] Termos MeSH primário: Acidose/induzido quimicamente
Acidose/metabolismo
Álcalis/farmacologia
Glucocorticoides/metabolismo
Cloreto de Sódio
[Mh] Termos MeSH secundário: Equilíbrio Ácido-Base/efeitos dos fármacos
Adulto
Bicarbonatos/farmacologia
Cortisona/urina
Estudos Cross-Over
Dieta
Água Potável
Glucocorticoides/urina
Seres Humanos
Hidrocortisona/urina
Masculino
Compostos de Potássio/farmacologia
Tetra-Hidrocortisol/urina
Tetra-Hidrocortisona/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Alkalies); 0 (Bicarbonates); 0 (Drinking Water); 0 (Glucocorticoids); 0 (Potassium Compounds); 451W47IQ8X (Sodium Chloride); 5HF9TM2D15 (Tetrahydrocortisone); 7P2O6MFN8O (Tetrahydrocortisol); HM5Z15LEBN (potassium bicarbonate); V27W9254FZ (Cortisone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150910
[St] Status:MEDLINE
[do] DOI:10.1007/s12020-015-0730-7


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[PMID]:25668797
[Au] Autor:Zhai X; Chen F; Zhu C; Lu Y
[Ad] Endereço:Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China.
[Ti] Título:A simple LC-MS/MS method for the determination of cortisol, cortisone and tetrahydro-metabolites in human urine: assay development, validation and application in depression patients.
[So] Source:J Pharm Biomed Anal;107:450-5, 2015 Mar 25.
[Is] ISSN:1873-264X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chronic stress as well as major depressive disorders is associated with cortisol metabolism. Two enzymes modulate cortisol (F) and cortisone (E) interconversion: 11ß-hydroxysteroid dehydrogenase type 1 and type 2 (11ß-HSD1 and 11ß-HSD2). Furthermore, F and E were inactivated by 5α and 5ß reductases to their tetrahydro-metabolites: tetrahydrocortisol (THF), allo-tetrahydrocortisol (5α-THF) and tetrahydrocortisone (THE). To better understand depression a LC-MS/MS method for simultaneous determination of F, E THF, 5α-THF and THE in human urine has been developed and validated. The quantification range was 0.1-160 ng mL(-1) for F and E, and 0.2-160 ng mL(-1) for the tetrahydro-metabolites, with >86.1% recovery for all analytes. The nocturnal urine concentrations of F, E and tetrahydro-metabolites in 12 apparently healthy male adult volunteers and 12 drug-free male patients (age range, 20-50 years) with a diagnosis of depression were analyzed. A series of significant changes in glucocorticoid metabolism can be detected: F/E ratios and (THF+5α-THF)/THE ratios as well as F and THF concentrations were significantly higher in depression patients than in healthy subjects (p<0.05); 5α-THF/F ratios, 5α-THF/THF ratios as well as 5α-THF concentrations were significantly lower in depression patients (p<0.05). The results pointed to the decreased 11ß-HSD2 activity and a dysfunction in the 5α-reductase pathway in depressed patients. This method allows the assessment of 11ß-HSD1/2 and 5α/ß-reductase activities in a single analytical run providing an innovative tool to explain the potential etiology of depression.
[Mh] Termos MeSH primário: Cortisona/química
Cortisona/urina
Transtorno Depressivo Maior/urina
Hidrocortisona/química
Hidrocortisona/urina
Tetra-Hidrocortisona/química
Tetra-Hidrocortisona/urina
[Mh] Termos MeSH secundário: 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo
Adulto
Estudos de Casos e Controles
Colestenona 5 alfa-Redutase/metabolismo
Cromatografia Líquida/métodos
Cortisona/metabolismo
Transtorno Depressivo Maior/metabolismo
Glucocorticoides/química
Glucocorticoides/metabolismo
Glucocorticoides/urina
Seres Humanos
Hidrocortisona/metabolismo
Masculino
Meia-Idade
Espectrometria de Massas em Tandem/métodos
Tetra-Hidrocortisol/análogos & derivados
Tetra-Hidrocortisol/química
Tetra-Hidrocortisol/metabolismo
Tetra-Hidrocortisol/urina
Tetra-Hidrocortisona/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Glucocorticoids); 302-91-0 (allotetrahydrocortisol); 5HF9TM2D15 (Tetrahydrocortisone); 7P2O6MFN8O (Tetrahydrocortisol); EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 1); EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 2); EC 1.1.1.146 (HSD11B2 protein, human); EC 1.3.1.22 (Cholestenone 5 alpha-Reductase); V27W9254FZ (Cortisone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:150304
[Lr] Data última revisão:
150304
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150211
[St] Status:MEDLINE


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[PMID]:25492292
[Au] Autor:Hu X; Zhao Y; Chen B; Liang Y; Li L; Xie C; Zhang Y; Lin Z; Xie A; Chen S
[Ad] Endereço:Department of Pediatrics, Second Affiliated Hospital of WenZhou Medical University, Wenzhou 325027, China.
[Ti] Título:[11beta-hydroxysteroid dehydrogenase type 2 enzyme activity effect after exposures phthalate esters in maternal].
[So] Source:Zhonghua Yu Fang Yi Xue Za Zhi;48(9):800-4, 2014 Sep.
[Is] ISSN:0253-9624
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: To study the association between phthalate esters (PAEs) metabolites in maternal urine and 11beta-hydroxysteroid dehydrogenase type 2 (11ß-HSD2 ) enzyme activity, explore the possible mechanism of PAEs effect on fetal development. METHODS: All of 33 cases of intrauterine growth retardation (IUGR) newborn were selected by random sampling in 2012. And 33 cases of normal control newborn were enrolled, use high performance liquid chromatography-tandem mass spectrometry method was used to detect 4 kinds of phthalate esters (PAEs) metabolites in maternal urine: mono-n-butyl phthalate ester (MBP), mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) and three kinds of cortisol corticosterone metabolites, tetrahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), tetrahydrocortisone (THE), and analyze the association between phthalate esters (PAEs) metabolites in maternal urine and 11ß-HSD2 enzyme activity. RESULTS: MBP, MEHP, MEHHP, MEOHP metabolites can be detected in 98% (65 cases) , 89% (59 cases), 91% (60 cases), 91% (60 cases) of all 66 maternal urine samples, respectively. The median concentrations of test material in case group were 31.20 ng/ml for MBP, 24.61 ng/ml for MEHHP, 11.72 ng/ml for MEOHP and 48.67 ng/ml for SumDEHP which were significantly higher than those of the control group (were 17.32, 12.03, 5.68 and 28.64 ng/ml); 11ß-HSD2 activity in case group ((THF+allo-THF)/THE = (0.79 ± 0.09) ng/ml) was significantly lower than that of the control group((THF+allo-THF)/THE = (0.58 ± 0.04) ng/ml); PAEs metabolites MBP (ß' = 1.12), MEHHP(ß' = 1.14), MEOHP(ß' = 1.10), SumDEHP(ß' = 1.08) in baby boy mother's urine was reversely correlated to 11ß-HSD2 activity. CONCLUSIONS: PAEs could affect fetal development by inhibit 11ß-HSD2 activity.
[Mh] Termos MeSH primário: 11-beta-Hidroxiesteroide Desidrogenase Tipo 2
Dietilexilftalato/análogos & derivados
Desenvolvimento Fetal
Ácidos Ftálicos
[Mh] Termos MeSH secundário: Cromatografia Líquida
Seres Humanos
Recém-Nascido
Masculino
Espectrometria de Massas
Tetra-Hidrocortisol/análogos & derivados
Tetra-Hidrocortisona
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phthalic Acids); 0 (mono(2-ethyl-5-hydroxyhexyl) phthalate); 302-91-0 (allotetrahydrocortisol); 40321-98-0 (mono(2-ethyl-5-oxohexyl)phthalate); 5HF9TM2D15 (Tetrahydrocortisone); 7P2O6MFN8O (Tetrahydrocortisol); C42K0PH13C (Diethylhexyl Phthalate); EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 2); FU2EWB60RT (mono-(2-ethylhexyl)phthalate); ZI46LWZ45G (monobutyl phthalate)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141211
[St] Status:MEDLINE


  8 / 260 MEDLINE  
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[PMID]:24817358
[Au] Autor:Dai W; Yin P; Chen P; Kong H; Luo P; Xu Z; Lu X; Xu G
[Ad] Endereço:Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
[Ti] Título:Study of urinary steroid hormone disorders: difference between hepatocellular carcinoma in early stage and cirrhosis.
[So] Source:Anal Bioanal Chem;406(18):4325-35, 2014 Jul.
[Is] ISSN:1618-2650
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Discovery of novel biomarkers for early HCC from other liver diseases such as cirrhosis is of great clinical benefit. In this study, a novel steroid hormone metabolomic method based on liquid chromatography-mass spectrometry combined with logistic regression analysis was applied to study the steroid hormone disorders and to screen potential urinary steroid hormone biomarkers of early HCC. Thirty-six urinary steroid hormones were detected and quantified in healthy controls, cirrhotic patients, and early HCC patients. Heat map analysis and multivariate statistical analysis suggested severe disorders of steroid hormone network and holistically decreased urinary steroid hormone pattern in cirrhotic and early HCC patients. Logistic regression analysis reveals that a panel of two urinary steroid hormones (epitestosterone and allotetrahydrocortisol) displayed excellent diagnostic capability for distinguishing early HCC from cirrhosis with area under the curve (AUC) = 0.938 of receiver operating characteristic (ROC) analysis. These results help to overcome the disadvantage of lower sensitivity and specificity of alpha-fetoprotein for distinguishing early HCC from cirrhosis. Our work shows that steroid hormone metabolomics is a promising biomarker tool for biomarker study of early HCC.
[Mh] Termos MeSH primário: Corticosteroides/urina
Biomarcadores/urina
Carcinoma Hepatocelular/urina
Hormônios Esteroides Gonadais/urina
Cirrose Hepática/urina
Neoplasias Hepáticas/urina
[Mh] Termos MeSH secundário: Adulto
Área Sob a Curva
Carcinoma Hepatocelular/diagnóstico
Carcinoma Hepatocelular/patologia
Estudos de Casos e Controles
Epitestosterona/urina
Seres Humanos
Cirrose Hepática/diagnóstico
Neoplasias Hepáticas/diagnóstico
Neoplasias Hepáticas/patologia
Modelos Logísticos
Masculino
Metabolômica/métodos
Meia-Idade
Valor Preditivo dos Testes
Tetra-Hidrocortisol/análogos & derivados
Tetra-Hidrocortisol/urina
alfa-Fetoproteínas/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adrenal Cortex Hormones); 0 (Biomarkers); 0 (Gonadal Steroid Hormones); 0 (alpha-Fetoproteins); 302-91-0 (allotetrahydrocortisol); 481-30-1 (Epitestosterone); 7P2O6MFN8O (Tetrahydrocortisol)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:160512
[Lr] Data última revisão:
160512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140513
[St] Status:MEDLINE
[do] DOI:10.1007/s00216-014-7843-3


  9 / 260 MEDLINE  
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[PMID]:24534618
[Au] Autor:Steen NE; Methlie P; Lorentzen S; Dieset I; Aas M; Nerhus M; Haram M; Agartz I; Melle I; Berg JP; Andreassen OA
[Ad] Endereço:KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Drammen District Psychiatric Center, Clinic of Mental Health and Addiction, Vestre Viken Hospital Trust, Drammen
[Ti] Título:Altered systemic cortisol metabolism in bipolar disorder and schizophrenia spectrum disorders.
[So] Source:J Psychiatr Res;52:57-62, 2014 May.
[Is] ISSN:1879-1379
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is suggested as a pathophysiological factor in bipolar disorder and schizophrenia. Increased clearance of cortisol was recently indicated as a component in the HPA axis hyperdrive. The aim of the present study was to test the model of increased cortisol metabolism in a new replication sample separately and combined with a previously published sample of bipolar disorder and schizophrenia. Spot urine was sampled from 212 healthy controls (HC) and 221 patients with a schizophrenia spectrum disorder (SCZ, n = 115) and bipolar disorder (BD, n = 106). Of these, a subsample of 169 HC and 155 patients was included in a previous report. Urinary free cortisol, cortisone and their metabolites were measured, and the activities of 5α-reductase, 5ß-reductase and 11ß-HSD were estimated and analyzed for differences between groups. In the new sample, there was increased enzyme activity in SCZ for 5ß-reductase (p = 0.024 vs HC; p = 0.027 vs BD) and 11ß-HSD2 (p = 0.014 vs HC; p = 0.004 vs BD). In the combined sample, there was increased activity in SCZ for 5α-reductase (p < 0.001 vs HC; p = 0.020 vs BD), 5ß-reductase (p < 0.001 vs HC; p = 0.045 vs BD) and 11ß-HSD2 (p < 0.001 vs HC; p = 0.043 vs BD), and in BD for 5ß-reductase (p = 0.002), 11ß-HSD2 (p = 0.039) and 5α-reductase (trend, p = 0.084) (all vs HC). The findings confirm increased systemic cortisol metabolism in BD and SCZ. This is most consistent in SCZ, with BD taking an intermediate position. The design makes it impossible to determine the direction of the effect. However, the findings merit further study of cortisol metabolism as a possible component in the HPA axis dysfunction and pathophysiology of BD and SCZ.
[Mh] Termos MeSH primário: Transtorno Bipolar/metabolismo
Hidrocortisona/metabolismo
Esquizofrenia/metabolismo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Análise de Variância
Feminino
Seres Humanos
Masculino
Meia-Idade
Escalas de Graduação Psiquiátrica
Tetra-Hidrocortisol/análogos & derivados
Tetra-Hidrocortisol/metabolismo
Tetra-Hidrocortisona/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
302-91-0 (allotetrahydrocortisol); 5HF9TM2D15 (Tetrahydrocortisone); 7P2O6MFN8O (Tetrahydrocortisol); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:140314
[Lr] Data última revisão:
140314
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140219
[St] Status:MEDLINE


  10 / 260 MEDLINE  
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[PMID]:24532078
[Au] Autor:Di Luigi L; Botrè F; Sabatini S; Sansone M; Mazzarino M; Guidetti L; Baldari C; Lenzi A; Caporossi D; Romanelli F; Sgrò P
[Ad] Endereço:Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis, 15, 00135, Rome, Italy, luigi.diluigi@uniroma4.it.
[Ti] Título:Acute effects of physical exercise and phosphodiesterase's type 5 inhibition on serum 11ß-hydroxysteroid dehydrogenases related glucocorticoids metabolites: a pilot study.
[So] Source:Endocrine;47(3):952-8, 2014 Dec.
[Is] ISSN:1559-0100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Endogenous glucocorticoids (GC) rapidly increase after acute exercise, and the phosphodiesterase's type 5 inhibitor (PDE5i) tadalafil influences this physiological adaptation. No data exist on acute effects of both acute exercise and PDE5i administration on 11ß-hydroxysteroid dehydrogenases (11ß-HSDs)-related GC metabolites. We aimed to investigate the rapid effects of exercise on serum GC metabolites, with and without tadalafil administration. A double blind crossover study was performed in eleven healthy male volunteers. After the volunteers randomly received a short-term administration of placebo or tadalafil (20 mg/die for 2 days), a maximal exercise test to exhaustion on cycle ergometer was performed. Then, after a 2-week washout period, the volunteers were crossed over. Blood samples were collected before starting exercise and at 5 and 30 min of recovery (+5-Rec, +30-Rec). Serum ACTH, corticosterone (Cn), cortisol (F), cortisone (E), tetrahydrocortisol (THF), tetrahydrocortisone (THE), cortols, cortolones and respective ratios were evaluated. Pre-Ex THF was higher after tadalafil. Exercise increased ACTH, Cn, F, E, THE, cortols and cortolones after both placebo and tadalafil, and THF after placebo. The F/E ratio increased at +5-Rec and decreased at +30-Rec after placebo. Compared to placebo, after tadalafil lower ACTH, F and Cn, higher THF/F and THE/E, and not E (at +5-Rec) and F/E modifications were observed. Acute exercise rapidly influences serum GC metabolites concentrations. Tadalafil influences both GC adaptation and 11ß-HSDs activity during acute exercise. Additional researches on the effects of both exercise and PDE5i on tissue-specific 11ß-HSDs activity at rest and during physiological adaptation are warranted.
[Mh] Termos MeSH primário: 11-beta-Hidroxiesteroide Desidrogenases/metabolismo
Carbolinas/farmacologia
Exercício/fisiologia
Inibidores da Fosfodiesterase 5/farmacologia
[Mh] Termos MeSH secundário: Hormônio Adrenocorticotrópico/sangue
Adulto
Corticosterona/sangue
Cortisona/sangue
Estudos Cross-Over
Método Duplo-Cego
Seres Humanos
Hidrocortisona/sangue
Masculino
Projetos Piloto
Tadalafila
Tetra-Hidrocortisol/sangue
Tetra-Hidrocortisona/sangue
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carbolines); 0 (Phosphodiesterase 5 Inhibitors); 5HF9TM2D15 (Tetrahydrocortisone); 742SXX0ICT (Tadalafil); 7P2O6MFN8O (Tetrahydrocortisol); 9002-60-2 (Adrenocorticotropic Hormone); EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenases); V27W9254FZ (Cortisone); W980KJ009P (Corticosterone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140218
[St] Status:MEDLINE
[do] DOI:10.1007/s12020-014-0185-2



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