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[PMID]:28189123
[Au] Autor:Zitzmann M; Rohayem J; Raidt J; Kliesch S; Kumar N; Sitruk-Ware R; Nieschlag E
[Ad] Endereço:Institute of Reproductive Medicine, University Clinics, Muenster, Germany.
[Ti] Título:Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial.
[So] Source:Andrology;5(3):516-526, 2017 May.
[Is] ISSN:2047-2927
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Although several progestins have been tested for hormonal male contraception, the effects of dosage and nature of various progestins on gonadotropin suppression combined with and without additional testosterone has not been performed in a comparative trial. The aim of this study was to evaluate the differential impact of four oral or transdermal progestins on the suppression of gonadotropins in healthy men: oral: cyproterone acetate (CPA), levonorgestrel (LNG), norethisterone acetate (NETA), and transdermal: Nestorone (NES), all in combination with transdermal testosterone (T). Randomized clinical trial testing was performed with four progestins at two doses each. After a 2-week progestin-only treatment, transdermal T was added for further 4 weeks and was followed by a 3-week recovery period. Progestin-dose per day: CPA 10 mg/20 mg, NES 2 mg/3 mg/dose e.g. 200/300 µg/day absorbed, NETA 5 mg/10 mg, LNG 120 µg/240 µg. From an andrology outpatient clinic, 56 healthy men aged 18-50 years, with body mass index ≤33 kg × m were included in the study. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied. Secondary outcome measure included were serum testosterone concentrations, sperm concentrations, and safety parameters. Intergroup comparisons demonstrated that CPA and LNG had the strongest effect on LH/FSH suppression. Nevertheless, every substance showed significant inhibitory effects on gonadotropin secretion, especially in combination with transdermal T. A decrease in hematocrit and insulin sensitivity as well as cholesterol subfractions and triglycerides was uniformly seen for every group. The combination of oral or transdermal progestins with a transdermal testosterone preparation is able to suppress gonadotropins. Further dose titration studies with sperm suppression as an end-point should be conducted to determine the lowest effective dose for hormonal male contraception.
[Mh] Termos MeSH primário: Anticoncepcionais Masculinos/administração & dosagem
Acetato de Ciproterona/administração & dosagem
Levanogestrel/administração & dosagem
Noretindrona/análogos & derivados
Norprogesteronas/administração & dosagem
Testosterona/administração & dosagem
[Mh] Termos MeSH secundário: Adolescente
Adulto
Anticoncepção/métodos
Anticoncepcionais Masculinos/efeitos adversos
Acetato de Ciproterona/efeitos adversos
Hormônio Foliculoestimulante/sangue
Seres Humanos
Levanogestrel/efeitos adversos
Hormônio Luteinizante/sangue
Masculino
Meia-Idade
Noretindrona/administração & dosagem
Noretindrona/efeitos adversos
Norprogesteronas/efeitos adversos
Progestinas
Espermatozoides/efeitos dos fármacos
Testosterona/efeitos adversos
Testosterona/sangue
Adesivo Transdérmico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Contraceptive Agents, Male); 0 (Norprogesterones); 0 (Progestins); 3XMK78S47O (Testosterone); 4KM2BN5JHF (Cyproterone Acetate); 5W7SIA7YZW (Levonorgestrel); 7759-35-5 (ST 1435); 9002-67-9 (Luteinizing Hormone); 9002-68-0 (Follicle Stimulating Hormone); 9S44LIC7OJ (norethindrone acetate); T18F433X4S (Norethindrone)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170212
[St] Status:MEDLINE
[do] DOI:10.1111/andr.12328


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[PMID]:27824503
[Au] Autor:Kumar N; Fagart J; Liere P; Mitchell SJ; Knibb AR; Petit-Topin I; Rame M; El-Etr M; Schumacher M; Lambert JJ; Rafestin-Oblin ME; Sitruk-Ware R
[Ad] Endereço:Population Council, Center for Biomedical Research, New York, New York 10065.
[Ti] Título:Nestorone® as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies.
[So] Source:Endocrinology;158(1):170-182, 2017 Jan 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nestorone® (NES) is a potent nonandrogenic progestin being developed for contraception. NES is a synthetic progestin that may possess neuroprotective and myelin regenerative potential as added health benefits. In receptor transactivation experiments, NES displayed greater potency than progesterone to transactivate the human progesterone receptor (PR). This was confirmed by docking experiments where NES adopts the same docking position within the PR ligand-binding domain (LBD) as progesterone and forms additional stabilizing contacts between 17α-acetoxy and 16-methylene groups and PR LBD, supporting its higher potency than progesterone. The analog 13-ethyl NES also establishes similar contacts as NES with Met909, leading to comparable potency as NES. In contrast, NES is not stabilized within the human androgen receptor LBD, leading to negligible androgen receptor transactivation. Because progesterone acts in the brain by both PR binding and indirectly via binding of the metabolite allopregnanolone to γ-aminobutyric acid type A receptor (GABAAR), we investigated if NES is metabolized to 3α, 5α-tetrahydronestorone (3α, 5α-THNES) in the brain and if this metabolite could interact with GABAAR. In female mice, low concentrations of reduced NES metabolites were identified by gas chromatography/mass spectrometry in both plasma and brain. Electrophysiological studies showed that 3α, 5α-THNES exhibited only limited activity to enhance GABAAR-evoked responses with WSS-1 cells and did not modulate synaptic GABAARs of mouse cortical neurons. Thus, the inability of reduced metabolite of NES (3α, 5α-THNES) to activate GABAAR suggests that the neuroprotective and myelin regenerative effects of NES are mediated via PR binding and not via its interaction with the GABAAR.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Anticoncepcionais Femininos/metabolismo
Norprogesteronas/metabolismo
Receptores de GABA-A/metabolismo
[Mh] Termos MeSH secundário: Animais
Células HEK293
Seres Humanos
Camundongos
Técnicas de Patch-Clamp
Pregnanolona/metabolismo
Receptores Androgênicos/metabolismo
Receptores de Progesterona/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Contraceptive Agents, Female); 0 (Norprogesterones); 0 (Receptors, Androgen); 0 (Receptors, GABA-A); 0 (Receptors, Progesterone); 7759-35-5 (ST 1435); BXO86P3XXW (Pregnanolone)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161109
[St] Status:MEDLINE
[do] DOI:10.1210/en.2016-1426


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[PMID]:27706226
[Au] Autor:Louw-du Toit R; Perkins MS; Snoep JL; Storbeck KH; Africander D
[Ad] Endereço:Department of Biochemistry, University of Stellenbosch, Private Bag X1, Matieland, 7602, South Africa.
[Ti] Título:Fourth-Generation Progestins Inhibit 3ß-Hydroxysteroid Dehydrogenase Type 2 and Modulate the Biosynthesis of Endogenous Steroids.
[So] Source:PLoS One;11(10):e0164170, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Progestins used in contraception and hormone replacement therapy are synthetic compounds designed to mimic the actions of the natural hormone progesterone and are classed into four consecutive generations. The biological actions of progestins are primarily determined by their interactions with steroid receptors, and factors such as metabolism, pharmacokinetics, bioavailability and the regulation of endogenous steroid hormone biosynthesis are often overlooked. Although some studies have investigated the effects of select progestins on a few steroidogenic enzymes, studies comparing the effects of progestins from different generations are lacking. This study therefore explored the putative modulatory effects of progestins on de novo steroid synthesis in the adrenal by comparing the effects of select progestins from the respective generations, on endogenous steroid hormone production by the H295R human adrenocortical carcinoma cell line. Ultra-performance liquid chromatography/tandem mass spectrometry analysis showed that the fourth-generation progestins, nestorone (NES), nomegestrol acetate (NoMAC) and drospirenone (DRSP), unlike the progestins selected from the first three generations, modulate the biosynthesis of several endogenous steroids. Subsequent assays performed in COS-1 cells expressing human 3ßHSD2, suggest that these progestins modulate the biosynthesis of steroid hormones by inhibiting the activity of 3ßHSD2. The Ki values determined for the inhibition of human 3ßHSD2 by NES (9.5 ± 0.96 nM), NoMAC (29 ± 7.1 nM) and DRSP (232 ± 38 nM) were within the reported concentration ranges for the contraceptive use of these progestins in vivo. Taken together, our results suggest that newer, fourth-generation progestins may exert both positive and negative physiological effects via the modulation of endogenous steroid hormone biosynthesis.
[Mh] Termos MeSH primário: 17-Hidroxiesteroide Desidrogenases/metabolismo
Androstenos/farmacologia
Megestrol/farmacologia
Norpregnadienos/farmacologia
Norprogesteronas/farmacologia
Progestinas/farmacologia
Esteroides/biossíntese
[Mh] Termos MeSH secundário: 17-Hidroxiesteroide Desidrogenases/genética
Animais
Células COS
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Cercopithecus aethiops
Cromatografia Líquida
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androstenes); 0 (Norpregnadienes); 0 (Norprogesterones); 0 (Progestins); 0 (Steroids); 7759-35-5 (ST 1435); 83J78V5W05 (nomegestrol acetate); EA6LD1M70M (Megestrol); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.1.51 (3 (or 17)-beta-hydroxysteroid dehydrogenase); N295J34A25 (drospirenone)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161006
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0164170


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[PMID]:26453296
[Au] Autor:Roth MY; Page ST; Bremner WJ
[Ad] Endereço:Department of Medicine and Center for Research in Reproduction and Contraception, University of Washington, Seattle, WA, USA.
[Ti] Título:Male hormonal contraception: looking back and moving forward.
[So] Source:Andrology;4(1):4-12, 2016 Jan.
[Is] ISSN:2047-2927
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Despite numerous contraceptive options available to women, approximately half of all pregnancies in the United States and worldwide are unplanned. Women and men support the development of reversible male contraception strategies, but none have been brought to market. Herein we review the physiologic basis for male hormonal contraception, the history of male hormonal contraception development, currents agents in development as well as the potential risks and benefits of male hormonal contraception for men.
[Mh] Termos MeSH primário: Anticoncepção/métodos
Anticoncepcionais Masculinos/farmacologia
[Mh] Termos MeSH secundário: Seres Humanos
Masculino
Norprogesteronas/farmacologia
Testosterona/farmacologia
Congêneres da Testosterona/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Contraceptive Agents, Male); 0 (Norprogesterones); 0 (Testosterone Congeners); 3XMK78S47O (Testosterone); 7759-35-5 (ST 1435)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151011
[St] Status:MEDLINE
[do] DOI:10.1111/andr.12110


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[PMID]:26408374
[Au] Autor:Archer DF; Thomas MA; Conard J; Merkatz RB; Creasy GW; Roberts K; Plagianos M; Blithe D; Sitruk-Ware R
[Ad] Endereço:Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA. Electronic address: archerdf@evms.edu.
[Ti] Título:Impact on hepatic estrogen-sensitive proteins by a 1-year contraceptive vaginal ring delivering Nestorone® and ethinyl estradiol.
[So] Source:Contraception;93(1):58-64, 2016 Jan.
[Is] ISSN:1879-0518
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150mcg Nestorone® (NES) and 15mcg ethinyl estradiol (EE). STUDY DESIGN: A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers). RESULTS: Mean values at baseline were within the normal range for all four proteins but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to nonusers. During NES/EE CVR use, factor VIII, fibrinogen and PS were within the normal range; however, SHBG levels were increased by nearly 100% at Cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in nonusers. The change in recent users was significant for factor VIII at Cycle 6 and for SHBG at Cycles 6 and 13, but not for PS or fibrinogen. CONCLUSION: NES/EE CVR for up to 13cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen and PS that were within the normal range, with SHBG levels above the normal range by Cycle 6. Nonusers of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous EE exposure. IMPLICATIONS: Recent use of CHCs demonstrated significant changes in all four measured hepatic proteins at baseline compared to nonusers. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Prebaseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC.
[Mh] Termos MeSH primário: Anticoncepcionais Femininos/administração & dosagem
Dispositivos Anticoncepcionais Femininos
Estrogênios/administração & dosagem
Etinilestradiol/administração & dosagem
Norprogesteronas/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Anticoncepcionais Orais Combinados/farmacologia
Anticoncepcionais Orais Hormonais/farmacologia
Fator VIII/efeitos dos fármacos
Feminino
Fibrinogênio/efeitos dos fármacos
Seres Humanos
Proteína S/efeitos dos fármacos
Globulina de Ligação a Hormônio Sexual/efeitos dos fármacos
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Contraceptive Agents, Female); 0 (Contraceptives, Oral, Combined); 0 (Contraceptives, Oral, Hormonal); 0 (Estrogens); 0 (Norprogesterones); 0 (Protein S); 0 (Sex Hormone-Binding Globulin); 423D2T571U (Ethinyl Estradiol); 7759-35-5 (ST 1435); 9001-27-8 (Factor VIII); 9001-32-5 (Fibrinogen)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150927
[St] Status:MEDLINE


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[PMID]:25917108
[Au] Autor:Kurihara H; Shimizu C; Miyakita Y; Yoshida M; Hamada A; Kanayama Y; Yonemori K; Hashimoto J; Tani H; Kodaira M; Yunokawa M; Yamamoto H; Watanabe Y; Fujiwara Y; Tamura K
[Ad] Endereço:Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. hikuriha@ncc.go.jp.
[Ti] Título:Molecular imaging using PET for breast cancer.
[So] Source:Breast Cancer;23(1):24-32, 2016 Jan.
[Is] ISSN:1880-4233
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Molecular imaging can visualize the biological processes at the molecular and cellular levels in vivo using certain tracers for specific molecular targets. Molecular imaging of breast cancer can be performed with various imaging modalities, however, positron emission tomography (PET) is a sensitive and non-invasive molecular imaging technology and this review will focus on PET molecular imaging of breast cancer, such as FDG-PET, FLT-PET, hormone receptor PET, and anti-HER2 PET.
[Mh] Termos MeSH primário: Neoplasias da Mama/diagnóstico por imagem
Carcinoma Ductal de Mama/diagnóstico por imagem
Imagem Molecular/métodos
Tomografia por Emissão de Pósitrons/métodos
Compostos Radiofarmacêuticos
[Mh] Termos MeSH secundário: Bevacizumab
Neoplasias da Mama/metabolismo
Carcinoma Ductal de Mama/metabolismo
Cetuximab
Didesoxinucleosídeos
Feminino
Radioisótopos de Flúor
Fluordesoxiglucose F18
Seres Humanos
Norprogesteronas
Receptor do Fator de Crescimento Epidérmico/metabolismo
Receptor ErbB-2/metabolismo
Receptor IGF Tipo 1/metabolismo
Receptores Estrogênicos/metabolismo
Receptores de Progesterona/metabolismo
Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo
Trastuzumab
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Dideoxynucleosides); 0 (Fluorine Radioisotopes); 0 (Norprogesterones); 0 (Radiopharmaceuticals); 0 (Receptors, Estrogen); 0 (Receptors, Progesterone); 0Z5B2CJX4D (Fluorodeoxyglucose F18); 2S9ZZM9Q9V (Bevacizumab); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.10.1 (Receptor, IGF Type 1); EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor); P188ANX8CK (Trastuzumab); PG53R0DWDQ (alovudine); PQX0D8J21J (Cetuximab)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150429
[St] Status:MEDLINE
[do] DOI:10.1007/s12282-015-0613-z


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[PMID]:26964401
[Au] Autor:Szabó P; Kovács-Kiss D; Zelkó R
[Ti] Título:[Development possibilities of hormone-containing implants for gynecological applications: A review].
[Ti] Título:Nogyógyászati célra szánt, hormontartalmú implantátumok fejlesztési lehetoségeinek áttekintése: irodalmi áttekintés..
[So] Source:Acta Pharm Hung;85(4):131-8, 2015.
[Is] ISSN:0001-6659
[Cp] País de publicação:Hungary
[La] Idioma:hun
[Ab] Resumo:Implantable gynecological drug delivery devices are applied for contraceptive, hormone replacement purposes and for the treatments of other gynecological diseases, e.g. endometriosis. The review provides a comprehensive overview about the indications, advantages, limitation of application and the applied technologies of hormone-containing implants, as well. The study comprises the relevant patents and the recently published papers.
[Mh] Termos MeSH primário: Anticoncepcionais Femininos/administração & dosagem
Bombas de Infusão Implantáveis
[Mh] Termos MeSH secundário: Animais
Desogestrel/administração & dosagem
Estradiol/administração & dosagem
Feminino
Seres Humanos
Bombas de Infusão Implantáveis/normas
Bombas de Infusão Implantáveis/tendências
Levanogestrel/administração & dosagem
Norprogesteronas/administração & dosagem
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Contraceptive Agents, Female); 0 (Norprogesterones); 304GTH6RNH (etonogestrel); 4TI98Z838E (Estradiol); 5W7SIA7YZW (Levonorgestrel); 7759-35-5 (ST 1435); 81K9V7M3A3 (Desogestrel)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:160311
[Lr] Data última revisão:
160311
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160312
[St] Status:MEDLINE


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[PMID]:26953452
[Au] Autor:Müller T
[Ti] Título:[The "pill" for him remains a long-term pious aspiration].
[Ti] Título:Die "Pille" für ihn bleibt auch auf lange Sicht nur ein frommer Wunsch..
[So] Source:MMW Fortschr Med;157 Spec No 2:18, 2015 Nov 12.
[Is] ISSN:1438-3276
[Cp] País de publicação:Germany
[La] Idioma:ger
[Mh] Termos MeSH primário: Anticoncepcionais Masculinos/administração & dosagem
Anticoncepcionais Masculinos/efeitos adversos
Espermatogênese/efeitos dos fármacos
[Mh] Termos MeSH secundário: Desogestrel/administração & dosagem
Desogestrel/efeitos adversos
Implantes de Medicamento
Seres Humanos
Injeções Intramusculares
Masculino
Nandrolona/administração & dosagem
Nandrolona/efeitos adversos
Nandrolona/análogos & derivados
Norprogesteronas/administração & dosagem
Norprogesteronas/efeitos adversos
Contagem de Espermatozoides
Testosterona/administração & dosagem
Testosterona/efeitos adversos
Testosterona/análogos & derivados
[Pt] Tipo de publicação:COMPARATIVE STUDY; NEWS
[Nm] Nome de substância:
0 (Contraceptive Agents, Male); 0 (Drug Implants); 0 (Norprogesterones); 0 (dimethandrolone-undecanoate); 304GTH6RNH (etonogestrel); 3XMK78S47O (Testosterone); 6PG9VR430D (Nandrolone); 7759-35-5 (ST 1435); 7Z6522T8N9 (testosterone enanthate); 81K9V7M3A3 (Desogestrel)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:160308
[Lr] Data última revisão:
160308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160309
[St] Status:MEDLINE


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[PMID]:26349009
[Au] Autor:Meyer M; Gonzalez Deniselle MC; Garay L; Sitruk-Ware R; Guennoun R; Schumacher M; De Nicola AF
[Ad] Endereço:Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Obligado 2490, 1428 Buenos Aires, Argentina.
[Ti] Título:The progesterone receptor agonist Nestorone holds back proinflammatory mediators and neuropathology in the wobbler mouse model of motoneuron degeneration.
[So] Source:Neuroscience;308:51-63, 2015 Nov 12.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Wobbler mutant mice suffer from progressive motoneuron degeneration and glial cell reactivity in the spinal cord. To prevent development of these abnormalities, we employed Nestorone, a high-affinity progesterone receptor agonist endowed with neuroprotective, promyelinating and anti-inflammatory activities in experimental brain ischemia, preventing neuroinflammation and chemical degeneration. Five-month-old Wobbler mice (wr-/wr-) received s.c. injections of 200µg/day/mouse of Nestorone in vegetable oil or vehicle for 10days. Control NFR/NFR mice (background strain for Wobbler) received vehicle only. Vehicle-treated Wobblers showed typical spinal cord abnormalities, such as vacuolated motoneurons, decreased immunoreactive choline-acetyltransferase, decreased expression of glutamine synthase (GS), increased glial fibrillary acidic protein-positive (GFAP) astrogliosis and curved digits in forelimbs. These cell-specific abnormalities were normalized in Nestorone-treated Wobblers. In addition, vehicle-treated Wobblers showed Iba1+ microgliosis, high expression of the microglial marker CD11b mRNA and up-regulation of the proinflammatory markers TNFα and iNOS mRNAs. In Nestorone-treated Wobblers, Iba1+ microgliosis subsided, whereas CD11b, TNFα and iNOS mRNAs were down-regulated. NFκB mRNA was increased in Wobbler spinal cord and decreased by Nestorone, whereas expression of its inhibitor IκBα was increased in Nestorone-treated Wobblers compared to control mice and vehicle-treated Wobblers. In conclusion, our results showed that Nestorone restraining effects on proinflammatory mediators, microgliosis and astrogliosis may support neurons in their resistance against degenerative processes.
[Mh] Termos MeSH primário: Anti-Inflamatórios/farmacologia
Doença dos Neurônios Motores/tratamento farmacológico
Fármacos Neuroprotetores/farmacologia
Norprogesteronas/farmacologia
Receptores de Progesterona/agonistas
Medula Espinal/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Astrócitos/efeitos dos fármacos
Astrócitos/metabolismo
Astrócitos/patologia
Modelos Animais de Doenças
Gliose/tratamento farmacológico
Gliose/patologia
Gliose/fisiopatologia
Masculino
Camundongos Mutantes
Microglia/efeitos dos fármacos
Microglia/metabolismo
Microglia/patologia
Doença dos Neurônios Motores/patologia
Doença dos Neurônios Motores/fisiopatologia
Neurônios Motores/efeitos dos fármacos
Neurônios Motores/metabolismo
Neurônios Motores/patologia
Neuroimunomodulação/efeitos dos fármacos
Neuroimunomodulação/fisiologia
Receptores de Progesterona/metabolismo
Medula Espinal/metabolismo
Medula Espinal/patologia
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Neuroprotective Agents); 0 (Norprogesterones); 0 (Receptors, Progesterone); 7759-35-5 (ST 1435)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:151010
[Lr] Data última revisão:
151010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150909
[St] Status:MEDLINE


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[PMID]:26032952
[Au] Autor:Brache V; Merkatz R; Kumar N; Jesam C; Sussman H; Hoskin E; Roberts K; Alami M; Taylor D; Jorge A; Croxatto H; Lorange E; Mishell DR; Sitruk-Ware R
[Ad] Endereço:Profamilia, Santo Domingo 10401, Dominican Republic. Electronic address: vbrache@gmail.com.
[Ti] Título:A dose-finding, cross-over study to evaluate the effect of a Nestorone®/Estradiol transdermal gel delivery on ovulation suppression in normal ovulating women.
[So] Source:Contraception;92(4):289-97, 2015 Oct.
[Is] ISSN:1879-0518
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: This study aims to determine the lowest effective of three Nestorone (NES)/estradiol (E2) transdermal gel doses to ensure ovulation suppression in 90-95% of cycles. METHODS: This was a randomized, open-label, three-treatment-period cross-over study to evaluate the effects of NES/E2 transdermal gel on ovulation inhibition, suppression of follicular growth and pharmacokinetic parameters. The doses were low (1.5 mg NES/0.5 mg E2), medium (3.0 mg NES/1.0 mg E2) and high (4.5 mg NES/1.5 mg E2). Participants applied gel daily to a fixed area on the abdomen for 21 consecutive days. They were interviewed regarding their experiences using the gel. RESULTS: Eighteen participants were randomized; 16 completed the study. Median NES C(max) values for low, medium and high dose groups at day 21 were 318.6 pmol/L, 783.0 pmol/L and 1063.8 pmol/L, respectively. Median maximum follicular diameter was higher with the lowest dose with 16.2 mm versus 10.0 and 10.4 mm with the medium and high doses, respectively. Among adherent participants, ovulation was inhibited in all dose groups, except for one participant in the medium dose (6.7%) that had luteal activity and an ultrasound image suggestive of a luteinized unruptured follicle. There were few reports of unscheduled bleeding, with more episodes reported for the lower dose. Adverse events were mild, and no skin irritation was reported from gel application. CONCLUSION: While all three doses blocked ovulation effectively and were evaluated as safe and acceptable, the medium dose was considered the lowest effective dose based on a more adequate suppression of follicular development. Further development of this novel contraceptive delivering NES and E2 is warranted and has potential for improved safety compared to ethinyl-estradiol-based methods.
[Mh] Termos MeSH primário: Anticoncepcionais Femininos/administração & dosagem
Norprogesteronas/administração & dosagem
Ovulação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Administração Cutânea
Adulto
Anticoncepcionais Femininos/farmacocinética
Estudos Cross-Over
Combinação de Medicamentos
Endométrio/efeitos dos fármacos
Estradiol/administração & dosagem
Estrogênios/administração & dosagem
Feminino
Géis
Seres Humanos
Adesão à Medicação
Ciclo Menstrual/efeitos dos fármacos
Norprogesteronas/farmacocinética
Globulina de Ligação a Hormônio Sexual/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Contraceptive Agents, Female); 0 (Drug Combinations); 0 (Estrogens); 0 (Gels); 0 (Norprogesterones); 0 (Sex Hormone-Binding Globulin); 4TI98Z838E (Estradiol); 7759-35-5 (ST 1435)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:150919
[Lr] Data última revisão:
150919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150603
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE



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