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[PMID]:26375719
[Au] Autor:Ozolins TR; Weston AD; Perretta A; Thomson JJ; Brown NA
[Ad] Endereço:Department of Biomedical and Molecular Sciences, Program in Pharmacology and Toxicology, Queen's University, Botterell Hall, Kingston, ON K7L 3N6, Canada. Electronic address: ozolinst@queensu.ca.
[Ti] Título:Dimethadione embryotoxicity in the rat is neither correlated with maternal systemic drug concentrations nor embryonic tissue levels.
[So] Source:Toxicol Appl Pharmacol;289(1):89-97, 2015 Nov 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pregnant rats treated with dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant trimethadione, produce offspring having a 74% incidence of congenital heart defects (CHD); however, the incidence of CHD has high inter-litter variability (40-100%) that presents a challenge when studying the initiating events prior to the presentation of an abnormal phenotype. We hypothesized that the variability in CHD incidence was the result of differences in maternal systemic concentrations or embryonic tissue concentrations of DMO. To test this hypothesis, dams were administered 300 mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses). Maternal serum levels of DMO were assessed on GD 11, 12, 13, 14, 15, 18 and 21. Embryonic tissue concentrations of DMO were assessed on GD 11, 12, 13 and 14. In a separate cohort of GD 12 embryos, DMO concentrations and parameters of growth and development were assessed to determine if tissue levels of DMO were correlated with these endpoints. Embryos were exposed directly to different concentrations of DMO with whole embryo culture (WEC) and their growth and development assessed. Key findings were that neither maternal systemic concentrations nor tissue concentrations of DMO identified embryos that were sensitive or resistant to DMO in vivo. Direct exposure of embryos to DMO via WEC also failed to show correlations between embryonic concentrations of DMO with developmental outcomes in vitro. We conclude that neither maternal serum nor embryonic tissue concentrations of DMO predict embryonic outcome.
[Mh] Termos MeSH primário: Dimetadiona/toxicidade
Embrião de Mamíferos/efeitos dos fármacos
Desenvolvimento Embrionário/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Anticonvulsivantes/toxicidade
Dimetadiona/sangue
Relação Dose-Resposta a Droga
Técnicas de Cultura Embrionária
Feminino
Idade Gestacional
Gravidez
Ratos
Ratos Sprague-Dawley
Trimetadiona/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anticonvulsants); ALU9NPM703 (Dimethadione); R7GV3H6FQ4 (Trimethadione)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:151031
[Lr] Data última revisão:
151031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150917
[St] Status:MEDLINE


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[PMID]:26311034
[Au] Autor:Aasa KL; Maciver RD; Ramchandani S; Adams MA; Ozolins TR
[Ad] Endereço:*Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6 and Analytics for Life, Toronto, Ontario, Canada M5B 1N8.
[Ti] Título:In Utero Exposure to a Cardiac Teratogen Causes Reversible Deficits in Postnatal Cardiovascular Function, But Altered Adaptation to the Burden of Pregnancy.
[So] Source:Toxicol Sci;148(1):155-66, 2015 Nov.
[Is] ISSN:1096-0929
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Congenital heart defects (CHD) are the most common birth anomaly and while many resolve spontaneously by 1 year of age, the lifelong burden on survivors is poorly understood. Using a rat model of chemically induced CHD that resolve postnatally, we sought to characterize the postnatal changes in cardiac function, and to investigate whether resolved CHD affects the ability to adapt to the increased the cardiovascular (CV) burden of pregnancy. To generate rats with resolved CHD, pregnant rats were administered distilled water or dimethadione (DMO) [300 mg/kg b.i.d. on gestation day (gd) 9 and 10] and pups delivered naturally. To characterize structural and functional changes in the heart, treated and control offspring were scanned by echocardiography on postnatal day 4, 21, and 10-12 weeks. Radiotelemeters were implanted for continuous monitoring of hemodynamics. Females were mated and scanned by echocardiography on gd12 and gd18 during pregnancy. On gd18, maternal hearts were collected for structural and molecular assessment. Postnatal echocardiography revealed numerous structural and functional differences in treated offspring compared with control; however, these resolved by 10-12 weeks of age. The CV demand of pregnancy revealed differences between treated and control offspring with respect to mean arterial pressure, CV function, cardiac strain, and left ventricular gene expression. In utero exposure to DMO also affected the subsequent generation. Gd18 fetal and placental weights were increased in treated F2 offspring. This study demonstrates that in utero chemical exposure may permanently alter the capacity of the postnatal heart to adapt to pregnancy and this may have transgenerational effects.
[Mh] Termos MeSH primário: Sistema Cardiovascular/fisiopatologia
Modelos Animais de Doenças
Cardiopatias Congênitas/fisiopatologia
Complicações Cardiovasculares na Gravidez/fisiopatologia
[Mh] Termos MeSH secundário: Animais
Peso ao Nascer/efeitos dos fármacos
Cardiotoxinas/toxicidade
Sistema Cardiovascular/efeitos dos fármacos
Dimetadiona/toxicidade
Feminino
Regulação da Expressão Gênica/efeitos dos fármacos
Cardiopatias Congênitas/induzido quimicamente
Cardiopatias Congênitas/diagnóstico por imagem
Cardiopatias Congênitas/metabolismo
Ventrículos do Coração/diagnóstico por imagem
Ventrículos do Coração/efeitos dos fármacos
Ventrículos do Coração/metabolismo
Ventrículos do Coração/fisiopatologia
Hemodinâmica/efeitos dos fármacos
Masculino
Troca Materno-Fetal
Placentação/efeitos dos fármacos
Gravidez
Complicações Cardiovasculares na Gravidez/diagnóstico por imagem
Complicações Cardiovasculares na Gravidez/metabolismo
Distribuição Aleatória
Ratos Sprague-Dawley
Recuperação de Função Fisiológica
Teratogênios/toxicidade
Ultrassonografia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cardiotoxins); 0 (Teratogens); ALU9NPM703 (Dimethadione)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150828
[St] Status:MEDLINE
[do] DOI:10.1093/toxsci/kfv169


  3 / 223 MEDLINE  
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[PMID]:25446330
[Au] Autor:Rodger I; Lam I; Purssell E; Thompson M; Rutter A; Ozolins TR
[Ad] Endereço:Faculty of Medicine and Dentistry, University of Alberta, Edmonton AB T6G 2R7, Canada. Electronic address: irodger@ualberta.ca.
[Ti] Título:Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung.
[So] Source:Toxicology;326:142-52, 2014 Dec 04.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:To investigate mechanisms of chemical-induced congenital heart defects (CHD) we have developed a rat model using dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant, trimethadione (TMD). Dosing pregnant rats with 300mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses) produces a mean 74% incidence of CHD with inter litter variability ranging from 40 to 100%. The goal of this study was to determine if the variability in maternal serum concentrations of DMO on GD 14, a surrogate marker for total exposure, was related to the inter-litter differences in teratogenic outcomes. To test this hypothesis, pregnant rats were dosed as described above and serum levels of DMO assessed on GD 14. On GD 21, foetuses were collected by caesarean section, assessed for a number endpoints and the outcomes were correlated with the GD 14 serum concentrations of DMO. DMO exposure was associated with decreased foetal body weight, increased incidence of sternal defects and CHD, but these endpoints were not meaningfully correlated with maternal concentrations of DMO. Novel findings were decreased viability as measured one-hour following caesarean section, and delayed alveolar maturation. The major conclusions from these studies were first, that serum DMO concentrations on GD 14 did not predict teratogenicity, and second, delayed lung development may contribute to the decreased survival of foetuses at the time of caesarean section.
[Mh] Termos MeSH primário: Anormalidades Induzidas por Medicamentos/etiologia
Anticonvulsivantes/toxicidade
Dimetadiona/toxicidade
Cardiopatias Congênitas/induzido quimicamente
Exposição Materna/efeitos adversos
Alvéolos Pulmonares/efeitos dos fármacos
[Mh] Termos MeSH secundário: Anormalidades Induzidas por Medicamentos/sangue
Animais
Anticonvulsivantes/sangue
Biomarcadores/sangue
Dimetadiona/sangue
Feminino
Peso Fetal/efeitos dos fármacos
Idade Gestacional
Cardiopatias Congênitas/sangue
Gravidez
Alvéolos Pulmonares/embriologia
Alvéolos Pulmonares/fisiopatologia
Ratos Sprague-Dawley
Esterno/anormalidades
Esterno/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Biomarkers); ALU9NPM703 (Dimethadione)
[Em] Mês de entrada:1502
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


  4 / 223 MEDLINE  
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[PMID]:25239635
[Au] Autor:Aasa KL; Purssell E; Adams MA; Ozolins TR
[Ad] Endereço:Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6.
[Ti] Título:In utero dimethadione exposure causes postnatal disruption in cardiac structure and function in the rat.
[So] Source:Toxicol Sci;142(2):350-60, 2014 Dec.
[Is] ISSN:1096-0929
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In utero exposure of rat embryos to dimethadione (DMO), the N-demethylated teratogenic metabolite of the anticonvulsant trimethadione, induces a high incidence of cardiac heart defects including ventricular septal defects (VSDs). The same exposure regimen also leads to in utero cardiac functional deficits, including bradycardia, dysrhythmia, and a reduction in cardiac output (CO) and ejection fraction that persist until parturition (10 days after the final dose). Despite a high rate of spontaneous postnatal VSD closure, we hypothesize that functional sequelae will persist into adulthood. Pregnant Sprague Dawley rats were administered six 300 mg/kg doses of DMO, one every 12 h in mid-pregnancy beginning on the evening of gestation day 8. Postnatal cardiac function was assessed in control (CTL) and DMO-exposed offspring using radiotelemetry and ultrasound at 3 and 11 months of age, respectively. Adult rats exposed to DMO in utero had an increased incidence of arrhythmia, elevated blood pressure and CO, greater left ventricular volume and elevated locomotor activity versus CTL. The mean arterial pressure of DMO-exposed rats was more sensitive to changes in dietary salt load compared with CTL. Importantly, most treated rats had functional deficits in the absence of a persistent structural defect. It was concluded that in utero DMO exposure causes cardiovascular deficits that persist into postnatal life in the rat, despite absence of visible structural anomalies. We speculate this is not unique to DMO, suggesting possible health implications for infants with unrecognized gestational chemical exposures.
[Mh] Termos MeSH primário: Anticonvulsivantes/toxicidade
Dimetadiona/toxicidade
Desenvolvimento Fetal/efeitos dos fármacos
Coração Fetal/efeitos dos fármacos
Cardiopatias Congênitas/induzido quimicamente
Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
[Mh] Termos MeSH secundário: Animais
Pressão Sanguínea/efeitos dos fármacos
Ecocardiografia
Feminino
Cardiopatias Congênitas/embriologia
Cardiopatias Congênitas/patologia
Cardiopatias Congênitas/fisiopatologia
Frequência Cardíaca/efeitos dos fármacos
Masculino
Atividade Motora/efeitos dos fármacos
Organogênese/efeitos dos fármacos
Gravidez
Efeitos Tardios da Exposição Pré-Natal/patologia
Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
Ratos Sprague-Dawley
Telemetria
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anticonvulsants); ALU9NPM703 (Dimethadione)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:141203
[Lr] Data última revisão:
141203
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140921
[St] Status:MEDLINE
[do] DOI:10.1093/toxsci/kfu190


  5 / 223 MEDLINE  
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[PMID]:22127902
[Au] Autor:Purssell E; Weston AD; Thomson JJ; Swanson TA; Brown NA; Ozolins TR
[Ad] Endereço:Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
[Ti] Título:Noninvasive high-resolution ultrasound reveals structural and functional deficits in dimethadione-exposed fetal rat hearts in utero.
[So] Source:Birth Defects Res B Dev Reprod Toxicol;95(1):35-46, 2012 Feb.
[Is] ISSN:1542-9741
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: We previously showed dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant trimethadione, induces ventricular septation defects (VSD) and other heart anomalies in rat (Weston et al., 2011). Because of the relationship between cardiac structure and function, we hypothesized that DMO-induced structural defects of the heart are associated with in utero functional deficits. To test the hypothesis, the goals were (1) define the parameters for ultrasound in the rat conceptus, and; (2) use ultrasound to identify structural and functional deficits following DMO treatment. METHODS: Different ultrasound modes (B-mode, M-mode, and Pulse-wave Doppler) using four high-resolution ultrasound transducer heads of varying frequency (25-40 MHz) were tested on gestational day (GD) 14, 15, 16, 17, and 21. Having identified the optimal conditions, pregnant Sprague-Dawley rats were administered six 300 mg/kg doses of DMO every 12 hr beginning at 19:00 hr on GD 8 to generate conceptuses with a high incidence of VSD. RESULTS: The three ultrasound modalities were used to identify VSD and several novel and rare structural heart anomalies (cardiac effusions and bifurcated septum) in live rat fetuses. DMO-treated hearts had an array of functional deficits including a decrease in mean heart rate, ejection fraction, and cardiac output and increased incidence of bradycardia and dysrhythmia. CONCLUSIONS: The ultrasound biomicroscope is an effective tool for the real-time characterization of the structure and function of embryo/fetal rat hearts. DMO causes significant deficits to in utero heart function for up to ten days (GD 21) following its final administration, suggesting long-term or possible permanent changes cardiac function.
[Mh] Termos MeSH primário: Dimetadiona/efeitos adversos
Feto/efeitos dos fármacos
Feto/fisiopatologia
Coração/embriologia
Coração/fisiopatologia
Ultrassom
[Mh] Termos MeSH secundário: Animais
Feminino
Coração/efeitos dos fármacos
Testes de Função Cardíaca
Frequência Cardíaca/efeitos dos fármacos
Comunicação Interventricular/diagnóstico por imagem
Isoflurano/efeitos adversos
Contração Miocárdica/efeitos dos fármacos
Gravidez
Ratos
Ratos Sprague-Dawley
Ultrassonografia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
ALU9NPM703 (Dimethadione); CYS9AKD70P (Isoflurane)
[Em] Mês de entrada:1405
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:111201
[St] Status:MEDLINE
[do] DOI:10.1002/bdrb.20339


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[PMID]:22070604
[Au] Autor:Liu W; Lau F; Liu K; Wood HB; Zhou G; Chen Y; Li Y; Akiyama TE; Castriota G; Einstein M; Wang C; McCann ME; Doebber TW; Wu M; Chang CH; McNamara L; McKeever B; Mosley RT; Berger JP; Meinke PT
[Ad] Endereço:Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States. weiguo_liu@merck.com
[Ti] Título:Benzimidazolones: a new class of selective peroxisome proliferator-activated receptor γ (PPARγ) modulators.
[So] Source:J Med Chem;54(24):8541-54, 2011 Dec 22.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARγ modulators (SPPARγMs) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPARγ full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARγMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARγ transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARγ receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl)-5-methyloxazolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.
[Mh] Termos MeSH primário: Benzimidazóis/síntese química
Dimetadiona/análogos & derivados
Hipoglicemiantes/síntese química
PPAR gama/metabolismo
[Mh] Termos MeSH secundário: Animais
Benzimidazóis/química
Benzimidazóis/farmacologia
Sítios de Ligação
Células COS
Cercopithecus aethiops
Cristalografia por Raios X
Diabetes Mellitus Tipo 2/tratamento farmacológico
Dimetadiona/síntese química
Dimetadiona/química
Dimetadiona/farmacologia
Agonismo Parcial de Drogas
Perfilação da Expressão Gênica
Seres Humanos
Hipoglicemiantes/química
Hipoglicemiantes/farmacologia
Masculino
Camundongos
Modelos Moleculares
Mutagênese
Coativadores de Receptor Nuclear/metabolismo
Oxazóis/síntese química
Oxazóis/química
Oxazóis/farmacologia
PPAR gama/agonistas
PPAR gama/genética
Conformação Proteica
Ratos
Ratos Zucker
Relação Estrutura-Atividade
Tiazolidinedionas/química
Tiazolidinedionas/farmacologia
Ativação Transcricional
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-(3-((3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl)methyl)phenyl)-5-methyloxazolidinedione); 0 (Benzimidazoles); 0 (Hypoglycemic Agents); 0 (Nuclear Receptor Coactivators); 0 (Oxazoles); 0 (PPAR gamma); 0 (Thiazolidinediones); 05V02F2KDG (rosiglitazone); ALU9NPM703 (Dimethadione); X4OV71U42S (pioglitazone)
[Em] Mês de entrada:1203
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:111111
[St] Status:MEDLINE
[do] DOI:10.1021/jm201061j


  7 / 223 MEDLINE  
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[PMID]:21638752
[Au] Autor:Weston AD; Brown NA; Ozolins TR
[Ad] Endereço:Department of Developmental and Reprodutive Toxicology, Pfizer Global Research and Development, Groton, Connecticut, USA.
[Ti] Título:Co-variation in frequency and severity of cardiovascular and skeletal defects in Sprague-Dawley rats after maternal administration of dimethadione, the N-demethylated metabolite of trimethadione.
[So] Source:Birth Defects Res B Dev Reprod Toxicol;92(3):206-15, 2011 Jun.
[Is] ISSN:1542-9741
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The anticonvulsant trimethadione is a potent inducer of ventricular septation defects, both clinically and in rodents. Teratogenicity requires its N-demethylation to dimethadione, the proximate teratogen. It was previously demonstrated trimethadione only induced membranous ventricular septation defects in rat (Fleeman et al., 2004), and our present goal is to determine whether direct administration of dimethadione increases the incidence and severity of septation defects. METHODS: Pregnant Sprague-Dawley rats were divided into five groups and administered either distilled water (control) or four different regimens of dimethadione. The core treatment was 300 mg/kg dimethadione b.i.d. on gestation day 9, 10 with additional groups given one additional dose of dimethadione 12 hr earlier, 12 hr later or two additional doses 12 hr earlier and later. Caesarian sections occurred on gestation day 21 and fetuses were examined for standard developmental toxicity endpoints. RESULTS: The broadest dosing regimen yielded the highest incidence and the most severe heart and axioskeletal findings with a decrease in mean fetal body weight. The overall incidence of ventricular septation defects was 74%, of which 68% were membranous and 9% muscular. Outflow tract anomalies (17%) were also observed, as were malformations of the axioskeleton (97%), but not of the long bones, and of particular interest was the high incidence of sternoschesis. CONCLUSIONS: Unlike trimethadione, dimethadione induces more serious muscular septation defects that are believed to be more clinically relevant. This, when taken together with the high incidence of total septation anomalies suggests dimethadione is useful for the study of chemically induced ventricular septation defects.
[Mh] Termos MeSH primário: Osso e Ossos/anormalidades
Osso e Ossos/efeitos dos fármacos
Anormalidades Cardiovasculares/induzido quimicamente
Dimetadiona/toxicidade
Exposição Materna
Trimetadiona/análogos & derivados
Trimetadiona/toxicidade
[Mh] Termos MeSH secundário: Animais
Anormalidades Cardiovasculares/patologia
Cesárea
Dimetadiona/administração & dosagem
Feminino
Coração/efeitos dos fármacos
Gravidez
Efeitos Tardios da Exposição Pré-Natal/patologia
Ratos
Ratos Sprague-Dawley
Trimetadiona/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
ALU9NPM703 (Dimethadione); R7GV3H6FQ4 (Trimethadione)
[Em] Mês de entrada:1201
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110604
[St] Status:MEDLINE
[do] DOI:10.1002/bdrb.20302


  8 / 223 MEDLINE  
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[PMID]:20615756
[Au] Autor:Zander-Fox DL; Mitchell M; Thompson JG; Lane M
[Ad] Endereço:Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, South Australia, Australia.
[Ti] Título:Alterations in mouse embryo intracellular pH by DMO during culture impair implantation and fetal growth.
[So] Source:Reprod Biomed Online;21(2):219-29, 2010 Aug.
[Is] ISSN:1472-6491
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The preimplantation embryo is highly susceptible to in-vitro stress, and although this does not necessarily perturb blastocyst development, it can significantly affect embryo physiology and the ability to form a viable pregnancy. This study determined that the preimplantation mouse embryo is highly sensitive to a small decrease in intracellular pH (<0.2 pH units). Embryos cultured in media containing a weak acid (5,5-dimethyl-2,4-oxazolidinedione; DMO) formed blastocysts with decreased cell number and inner cell mass number, as well as increased apoptosis, even though blastocyst development and morphology were unchanged. Interestingly, the effects were similar regardless of whether the pH stress was present for a short-term 'acute' exposure (during the zygote to 2-cell, or 2-cell to 8-cell division) or an extended 'chronic' period of time (continually from the zygote to the blastocyst stage). Exposure to DMO during the first cleavage division did not alter implantation; however, fetal weight and crown-rump length were significantly decreased (P<0.05). In contrast, continuous exposure to DMO throughout preimplantation development reduced not only implantation but also fetal weight and crown-rump length. This study highlights the importance of correct intracellular pH and demonstrates that slight deviations can significantly impact embryo development and viability.
[Mh] Termos MeSH primário: Dimetadiona/farmacologia
Implantação do Embrião/efeitos dos fármacos
Desenvolvimento Embrionário/efeitos dos fármacos
Concentração de Íons de Hidrogênio
[Mh] Termos MeSH secundário: Animais
Feminino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos CBA
Gravidez
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
ALU9NPM703 (Dimethadione)
[Em] Mês de entrada:1012
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100710
[St] Status:MEDLINE
[do] DOI:10.1016/j.rbmo.2010.05.001


  9 / 223 MEDLINE  
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[PMID]:18034292
[Au] Autor:Navarro D; Zwingmann C; Chatauret N; Butterworth RF
[Ad] Endereço:Neuroscience Research Unit, CHUM (Campus Saint-Luc), University of Montreal, 1058 Saint-Denis Street, Montreal, Quebec, Canada.
[Ti] Título:Glucose loading precipitates focal lactic acidosis in the vulnerable medial thalamus of thiamine-deficient rats.
[So] Source:Metab Brain Dis;23(1):115-22, 2008 Mar.
[Is] ISSN:0885-7490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glucose loading in thiamine-deficient patients is known to precipitate Wernicke's Encephalopathy; however, the mechanisms responsible have not been fully elucidated. Lactate accumulation occurs in brains of thiamine-deficient rats. In order to determine whether glucose loading in thiamine-deficient rats causes selective lactic acidosis in vulnerable brain structures, cerebral pH was measured autoradiographically using 14-labeled 5,5-dimethyloxazolidine-2, 4-dione ([(14)C]DMO) in the medial thalamus, a vulnerable brain region, versus cerebral cortex, a brain region that is spared in thiamine deficiency. Following administration of a glucose load, regional lactate levels and de novo lactate synthesis measured by (1)H-(13)C-NMR spectroscopy, increased significantly to 21.86 +/- 3.04 mumol/g (wet weight) in the medial thalamus (p < 0.001) and pH in this brain region was decreased significantly from 7.08 +/- 0.04 to 6.87 +/- 0.05 (p < 0.001). No such changes were observed in cerebral cortex following a glucose load. These results demonstrate that the increased production and accumulation of brain lactate result in acidosis following glucose loading in thiamine deficiency. Alterations of brain pH could contribute to the pathogenesis of thalamic neuronal damage and consequent cerebral dysfunction in Wernicke's Encephalopathy.
[Mh] Termos MeSH primário: Acidose Láctica/induzido quimicamente
Acidose Láctica/metabolismo
Glucose/farmacologia
Tálamo/metabolismo
Deficiência de Tiamina/metabolismo
[Mh] Termos MeSH secundário: Acidose Láctica/patologia
Animais
Autorradiografia
Química Encefálica/efeitos dos fármacos
Dimetadiona
Concentração de Íons de Hidrogênio
Espectroscopia de Ressonância Magnética
Masculino
Compostos Radiofarmacêuticos
Ratos
Ratos Sprague-Dawley
Tálamo/patologia
Deficiência de Tiamina/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Radiopharmaceuticals); ALU9NPM703 (Dimethadione); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:0805
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:071124
[St] Status:MEDLINE


  10 / 223 MEDLINE  
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[PMID]:17584909
[Au] Autor:Danielsson C; Azarbayjani F; Sköld AC; Sjögren N; Danielsson BR
[Ad] Endereço:Department of Medicine, Karolinska Institute, Karolinska University Hospital, S 14186 Stockholm, Sweden.
[Ti] Título:Polytherapy with hERG-blocking antiepileptic drugs: increased risk for embryonic cardiac arrhythmia and teratogenicity.
[So] Source:Birth Defects Res A Clin Mol Teratol;79(8):595-603, 2007 Aug.
[Is] ISSN:1542-0752
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The antiepileptic drugs (AEDs) phenytoin, phenobarbital, dimethadione, and carbamazepine cause a similar pattern of malformations in humans, with an increased risk after polytherapy. The teratogenicity has been linked to cardiac rhythm disturbances and hypoxic damage as a consequence of their common potential to inhibit a specific potassium ion current (IKr). The IKr is of major importance for embryonic cardiac repolarization and rhythm regulation. This study investigated whether these AEDs cause irregular rhythm and if various combinations of AEDs result in higher arrhythmia risk than exposure to a single AED. METHODS: The effects on heart rhythm of a single AED (monotherapy), and of various combinations (polytherapy) of AEDs, in gestational day 10 C57BL mouse embryos in culture were analyzed and graphically illustrated during a 25 s recording with a digitalization technique. RESULTS: All of the studied AEDs caused increased intervals between heartbeats (resulting in bradycardia) and large variations in the interval between heartbeats (resulting in irregular rhythm) in a concentration-dependent manner in cultured mouse embryos. Dimethadione caused irregular rhythm at concentrations within and phenytoin slightly above the therapeutic ranges. Polytherapy resulted in more substantial prolongation of the mean interval between heartbeats (>60 ms) than monotherapy at clinically relevant concentrations. CONCLUSIONS: The results suggest that polytherapy more than monotherapy causes substantial prolongation of the cardiac repolarization, a marker associated with high risk of developing irregular rhythm during longer exposure periods (days to months). This supports the idea that the increased risk for malformations following polytherapy is linked to an increased risk for cardiac rhythm disturbances.
[Mh] Termos MeSH primário: Anticonvulsivantes/toxicidade
Bradicardia/induzido quimicamente
Embrião de Mamíferos/efeitos dos fármacos
Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos
Coração/efeitos dos fármacos
Bloqueadores dos Canais de Potássio/toxicidade
[Mh] Termos MeSH secundário: Animais
Bradicardia/embriologia
Dimetadiona/toxicidade
Relação Dose-Resposta a Droga
Quimioterapia Combinada
Técnicas de Cultura Embrionária
Embrião de Mamíferos/fisiopatologia
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores
Canais de Potássio Éter-A-Go-Go/metabolismo
Feminino
Idade Gestacional
Coração/embriologia
Camundongos
Camundongos Endogâmicos C57BL
Fenitoína/toxicidade
Gravidez
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Ether-A-Go-Go Potassium Channels); 0 (Potassium Channel Blockers); 6158TKW0C5 (Phenytoin); ALU9NPM703 (Dimethadione)
[Em] Mês de entrada:0710
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:070623
[St] Status:MEDLINE



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