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1.
BMJ ; 368: m237, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075794

RESUMO

OBJECTIVE: To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine. DESIGN: Cohort study nested in the Medicaid Analytic eXtract for 2004-13. SETTING: Publicly insured pregnancies in the United States. PARTICIPANTS: Pregnant women 18 to 55 years of age and their liveborn infants. INTERVENTIONS: Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy. MAIN OUTCOME MEASURES: Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage. RESULTS: Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses. CONCLUSIONS: On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient. TRIAL REGISTRATION: EUPAS 15946.


Assuntos
Cloridrato de Duloxetina/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Resultado da Gravidez/epidemiologia , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Adolescente , Adulto , Estudos de Coortes , Cloridrato de Duloxetina/uso terapêutico , Feminino , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/epidemiologia , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Pessoa de Meia-Idade , Hemorragia Pós-Parto/induzido quimicamente , Hemorragia Pós-Parto/epidemiologia , Pré-Eclâmpsia/induzido quimicamente , Gravidez , Complicações na Gravidez/epidemiologia , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Estados Unidos/epidemiologia , Adulto Jovem
2.
Medicine (Baltimore) ; 98(18): e15352, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045777

RESUMO

BACKGROUND: Previous studies have investigated heavy metal exposure could increase the occurrence of congenital heart defects (CHDs). However, there are limited data regarding the relationship between exposure to nickel and CHDs occurrence in offspring. The aim of this study was to analyze the association between nickel exposure in mothers and the risk of CHDs in offspring. MATERIALS AND METHODS: To explore the association of nickel exposure and occurrence of CHD, a case-control study with 490 controls and 399 cases with CHDs in China were developed. The concentrations of nickel in hair of pregnant woman and fetal placental tissue were measured and used a logistic regression analysis to explore the relationship between nickel exposure and risk of CHD. RESULTS: The median concentrations of nickel were 0.629 ng/mg, P < .05 (adjusted odds ratio [aOR], 1.326; 95% CI, 1.003-1.757) and 0.178 ng/mg, P < .05 (aOR, 2.204; 95% CI, 0.783-6.206), in maternal hair and in fetal placental tissue in the CHD group, respectively. Significant differences in the level of nickel in hair were also found in the different CHD subtypes including septal defects (P < .05), conotruncal defects (P < .05), right ventricular outflow tract obstruction (P < .01), and left ventricular outflow tract obstruction (P < .05). Dramatically different nickel concentrations in fetal placenta tissue were found in cases with other heart defects (P < .05). CONCLUSIONS: The finding suggested that the occurrence of CHDs may be associated with nickel exposure.


Assuntos
Cardiopatias Congênitas/induzido quimicamente , Exposição Materna/efeitos adversos , Níquel/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Estudos de Casos e Controles , China/epidemiologia , Feminino , Idade Gestacional , Cabelo/química , Humanos , Razão de Chances , Placenta/química , Gravidez , Análise de Regressão , Fatores de Risco , Adulto Jovem
3.
PLoS One ; 14(5): e0214873, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31086358

RESUMO

BACKGROUNDS: Reducing toxicants transplacental rates could contribute to the prevention of congenital heart defects (CHDs). Placental P-glycoprotein (P-gp) plays a vital role in fetal toxicants exposure and subsequently affects the risk of toxicants-induced birth defects. However, data on the role of placental P-gp in decreasing toxicants-induced cardiac anomalies is extremely limited. This study aimed to explore the protective role of placental P-gp in reducing the risk of Di-(2-ethylhexyl)-phthalate (DEHP) induced cardiac anomalies in mice. METHODS: The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 500mg/Kg DEHP group (n = 15), 3mg/Kg verapamil group (n = 10) and 500mg/Kg DEHP & 3mg/Kg verapamil group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from E6.5-14.5. Maternal weights were monitored every day and samples were collected at E15.5. HE staining was used to examine fetal cardiac malformations. Real-time quantitative PCR (RT-qPCR) and Western-Blot were applied to detect Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. The mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) was also determined using RT-qPCR. RESULTS: Co-administration of verapamil and DEHP significantly elevated fetal cardiac malformation rates, in comparison with the DEHP group, the verapamil group and the vehicle group. Different phenotypes of cardiac anomalies, including septal defects and ventricular myocardium noncompaction, were noted both in the DEHP group and the DEHP & verapamil group. The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group. Fetal cardiac PPARγ mRNA expression was notably increased and Gata4/Mef2c/Chf1 expression was markedly decreased in the DEHP & verapamil group. CONCLUSION: Placental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Dietilexilftalato/toxicidade , Coração Fetal/efeitos dos fármacos , Cardiopatias Congênitas/patologia , Placenta/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Feminino , Coração Fetal/metabolismo , Coração Fetal/patologia , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/metabolismo , Proteína Homeobox Nkx-2.5/genética , Proteína Homeobox Nkx-2.5/metabolismo , Exposição Materna , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo , Gravidez , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Verapamil/farmacologia
4.
Methods Mol Biol ; 1965: 405-420, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069689

RESUMO

Congenital heart defects (CHD) are the most prevalent anomaly both clinically and in laboratory animal species. Historically, it was difficult to assess the longitudinal progression or repair of such anomalies because assessment methodologies were too invasive (gross exams and/or histology). Recently, technological advances in the field of diagnostic imaging have led to the manufacture of high-resolution ultrasound (HRUS), capable of characterizing both embryonic and maternal cardiovascular structure and function in small animals (rat and mouse). HRUS is relatively noninvasive, facilitating the longitudinal assessment of heart development throughout gestation and postnatally, providing a comprehensive evaluation of changes in cardiovascular performance following toxicant exposure.Described herein is a brief overview of important theoretical and practical considerations when applying HRUS to understand the impact of perturbations on the fetal heart. Examples are given from our own work to help the reader interpret their own HRUS images and more readily identify anomalies in utero. In addition to embryonic assessment, maternal pathologies may adversely affect the cardiovascular performance of the conceptus indirectly. Umbilical blood flow is particularly vulnerable to such effects and procedures to assess this endpoint are described. Neonatal rats, born with CHD, may respond pathologically to cardiovascular challenges as they mature, and we outline the use of HRUS to evaluate cardiac performance over the lifetime of the animal. Some of the caveats related to HRUS are discussed, particularly with the emphasis on how this may impact experimental design.


Assuntos
Ecocardiografia/métodos , Cardiopatias Congênitas/diagnóstico por imagem , Coração/crescimento & desenvolvimento , Teratogênios/toxicidade , Animais , Modelos Animais de Doenças , Feminino , Idade Gestacional , Coração/diagnóstico por imagem , Coração/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Camundongos , Gravidez , Ratos , Ultrassonografia
5.
Chemosphere ; 227: 551-560, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004822

RESUMO

Precise in vivo toxicological assays to determine the cardiotoxicity of pharmaceuticals and their waste products are essential in order to evaluate their risks to humans and the environment following industrial release. In the present study, we aimed to develop the sensitive imaging-based cardiotoxicity assay and combined 3D light-sheet microscopy with a zebrafish model to identify hidden cardiovascular anomalies induced by valproic acid (VPA) exposure. The zebrafish model is advantageous for this assessment because its embryos remain transparent. The 3D spatial localization of fluorescence-labeled cardiac cells in and around the heart using light-sheet technology revealed dislocalization of the heart from the outflow tract in two-day-old zebrafish embryos treated with 50 µM and 100 µM VPA (P < 0.01) and those embryos exposed to 20 µM VPA presented hypoplastic distal ventricles (P < 0.01). These two observed phenotypes are second heart field-derived cardiac defects. Quantitative analysis of the light-sheet imaging demonstrated that folic acid (FA) supplementation significantly increased the numbers of endocardial and myocardial cells (P < 0.05) and the accretion of second heart field-derived cardiomyocytes to the arterial pole of the outflow tract. The heart rate increased in response to the cellular changes occurring in embryonic heart development (P < 0.05). The present study disclosed the cellular mechanism underlying the role of FA in spontaneous cellular changes in cardiogenesis and in VPA-associated cardiotoxicity. The 3D light-sheet assay may be the next-generation test to evaluate the risks of previously undetected pharmaceutical and environmental cardiotoxicities in both humans and animals.


Assuntos
Cardiotoxicidade/diagnóstico por imagem , Ácido Fólico/uso terapêutico , Cardiopatias Congênitas/induzido quimicamente , Ácido Valproico/toxicidade , Peixe-Zebra/embriologia , Animais , Bioensaio/métodos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Diagnóstico por Imagem/métodos , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Microscopia Intravital/métodos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia
6.
J Perinat Med ; 47(4): 455-463, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-30794526

RESUMO

Objective To examine the association between maternal diseases and congenital heart defects (CHDs) and to evaluate whether those associations vary with corresponding medication use. Methods A multi-hospital case-control study conducted from February 2010 to December 2014 analysed 916 controls and 1236 cases. Participating mothers were asked whether they suffered from influenza, common cold, herpes and threatened abortion or had used corresponding medication during the periconception period or the early pregnancy period. We used a random-effects logistic regression model to compute the odds ratios (ORs), adjusted odds ratios (AORs) and 95% confidence intervals (CIs) while controlling for potential confounders. Results Compared with the results for mothers with no exposure, there were significant associations between maternal diseases with medication non-use and CHDs in the aggregate, including influenza (AOR, 1.83; 95% CI, 1.13-2.95), common cold (AOR, 2.05; 95% CI, 1.60-2.64) and herpes (AOR, 7.00; 95% CI, 2.15-22.84). There was no significant association between medication users and offspring with any subtype of CHDs, except that maternal common cold with medication use slightly increased the risk of the specific subtype, namely, isolated cardiac defects. However, an association was observed between maternal threatened abortion and medication and isolated cardiac defects (AOR, 1.33; 95% CI, 1.01-1.75). Conclusion Maternal influenza, common cold, herpes and threatened abortion from 3 months before pregnancy through the first trimester were associated with an increased risk of congenital heart disease in offspring. The teratogenic effect of these conditions may be attenuated by medication use, except for threatened abortion.


Assuntos
Ameaça de Aborto/tratamento farmacológico , Cardiopatias Congênitas/induzido quimicamente , Complicações Infecciosas na Gravidez/tratamento farmacológico , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Gravidez
7.
J Oncol Pharm Pract ; 25(3): 699-702, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29207935

RESUMO

Preclinical animal studies have demonstrated an association between maternal use of tyrosine kinase inhibitors and embryofetal toxicity; yet, multiple clinical case series have reported normal pregnancy outcomes and healthy infants in women on these medications during the course of their pregnancy. We describe a case of a woman with chronic myeloid leukemia who had taken the second-generation tyrosine kinase inhibitor dasatinib during the first 12 weeks of her dichorionic diamniotic twin pregnancy and subsequently delivered two low-birth weight infants, one with severe cardiac malformations and the other without apparent birth abnormalities. To our knowledge, this is the first reported case of fetal cardiovascular defects in an infant born to a woman on dasatinib during a twin pregnancy and supports current recommendations to avoid this medication during pregnancy. We also review relevant preclinical and clinical studies of tyrosine kinase inhibitor use during pregnancy and explore alternative therapeutic options for patients with chronic myeloid leukemia during pregnancy to aid clinicians in the appropriate management of these patients so as to minimize both maternal and fetal risks.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Dasatinibe/efeitos adversos , Doenças em Gêmeos/induzido quimicamente , Cardiopatias Congênitas/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Adulto , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez
8.
Environ Int ; 122: 381-388, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30551805

RESUMO

BACKGROUND: Natural gas drilling may pose multiple health risks, including congenital anomalies, through air pollutant emissions and contaminated water. Two recent studies have evaluated the relationship between natural gas activity and congenital anomalies, with both observing a positive relationship. OBJECTIVES: We aimed to evaluate whether residence near natural gas wells is associated with critical congenital heart defects (CCHD), neural tube defects (NTD), and oral clefts in Oklahoma, the third highest natural gas producing state in the US. METHODS: We conducted a retrospective cohort study among singleton births in Oklahoma (n = 476,600) to evaluate natural gas activity and congenital anomalies. We calculated an inverse distance-squared weighted (IDW) score based on the number of actively producing wells within a two-mile radius of the maternal residence during the month of delivery. We used modified Poisson regression with robust error variance to estimate prevalence proportion ratios (PPR) and 95% confidence intervals (CI) for the association between tertiles of natural gas activity (compared to no wells) and CCHD, NTD, and oral clefts adjusted for maternal education. RESULTS: We observed an increased, though imprecise, prevalence of NTDs among children with natural gas activity compared to children with no wells (2nd tertile PPR: 1.34, 95% CI: 0.93, 1.93; 3rd tertile PPR: 1.20, 95% CI: 0.82, 1.75). We observed no association with CCHD or oral clefts overall. Specific CCHDs of common truncus, transposition of the great arteries, pulmonary valve atresia and stenosis, tricuspid valve atresia and stenosis, interrupted aortic arch, and total anomalous pulmonary venous connection were increased among those living in areas with natural gas activity compared to those living in areas without activity, though not statistically significant. DISCUSSION: Our results were similar to previous studies for NTDs and specific CCHDs. Future directions include evaluating the association between specific phases of the drilling process and congenital anomalies to better refine the relevant exposure period.


Assuntos
Poluição do Ar/efeitos adversos , Anormalidades Congênitas/etiologia , Cardiopatias Congênitas/induzido quimicamente , Gás Natural/toxicidade , Poluição da Água/efeitos adversos , Adulto , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Oklahoma , Estudos Retrospectivos , Transposição dos Grandes Vasos/induzido quimicamente , Adulto Jovem
9.
Chemosphere ; 219: 557-566, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30553216

RESUMO

α-Bisabolol, an unsaturated monocyclic sesquiterpene alcohol, is a common ingredient in many pharmaceuticals and personal care products (PPCPs). Despite being widely used, little is known about its toxic effects on organisms and aquatic environment. In this study, we investigated the developmental toxicity of α-Bisabolol, especially its effects on the cardiac development using zebrafish embryos as a model. Embryos at 4 h post-fertilization (hpf) were exposed to 10, 30, 50, 70, 90, and 100 µM α-Bisabolol until 144 hpf. α-Bisabolol caused phenotypic defects and the most striking one is the heart malformation. Treatment of α-Bisabolol significantly increased the cardiac malformation rate, the SV-BA distance, as well as the pericardial edema area, and reduced heart rate in a concentration-dependent manner. Notably, considerable numbers of apoptotic cells were mainly observed in the heart region of zebrafish treated with α-Bisabolol. Further study on α-Bisabolol induced apoptosis in the zebrafsh heart suggested that an activation of Fas/FasL-dependent apoptotic pathway. Taken together, our study investigated the cardiotoxicity of α-Bisabolol on zebrafish embryonic development and its underlying molecular mechanism, shedding light on the full understanding of α-Bisabolol toxicity on living organisms and its environmental impact.


Assuntos
Cardiotoxicidade/etiologia , Embrião não Mamífero/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Sesquiterpenos/toxicidade , Animais , Apoptose , Relação Dose-Resposta a Droga , Proteína Ligante Fas/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Receptor fas/metabolismo
10.
JAMA ; 320(23): 2429-2437, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30561479

RESUMO

Importance: Evidence for the fetal safety of ondansetron, a 5-HT3 receptor antagonist that is commonly prescribed for nausea and vomiting during pregnancy, is limited and conflicting. Objective: To evaluate the association between ondansetron exposure during pregnancy and risk of congenital malformations. Design, Setting, and Participants: A retrospective cohort study nested in the 2000-2013 nationwide Medicaid Analytic eXtract. The cohort consisted of 1 816 414 pregnancies contributed by 1 502 895 women enrolled in Medicaid from 3 months before the last menstrual period through 1 month or longer after delivery; infants were enrolled in Medicaid for at least 3 months after birth. The final date of follow-up was December 31, 2013. Analyses were conducted between November 1, 2017, and June 30, 2018. Propensity score stratification was used to control for treatment indication and other confounders. Exposures: Ondansetron dispensing during the first trimester, the period of organogenesis. Main Outcomes and Measures: Primary outcomes were cardiac malformations and oral clefts diagnosed during the first 90 days after delivery. Secondary outcomes included congenital malformations overall and subgroups of cardiac malformations and oral clefts. Results: Among 1 816 414 pregnancies (mean age of mothers, 24.3 [5.8] years), 88 467 (4.9%) were exposed to ondansetron during the first trimester. Overall, 14 577 of 1 727 947 unexposed and 835 of 88 467 exposed infants were diagnosed with a cardiac malformation, for an absolute risk of 84.4 (95% CI, 83.0 to 85.7) and 94.4 (95% CI, 88.0 to 100.8) per 10 000 births respectively. The absolute risk of oral clefts was 11.1 per 10 000 births (95% CI, 10.6 to 11.6; 1921 unexposed infants) and was 14.0 per 10 000 births (95% CI, 11.6 to 16.5; 124 exposed infants). The risk of any congenital malformation was 313.5 per 10 000 births (95% CI, 310.9 to 316.1; 54 174 unexposed infants) and was 370.4 (95% CI, 358.0 to 382.9; 3277 exposed infants). The adjusted relative risk (RR) for cardiac malformations was 0.99 (95% CI, 0.93 to 1.06) and the adjusted risk difference (RD) was -0.8 (95% CI, -7.3 to 5.7 per 10 000 births). For oral clefts, the adjusted RR was 1.24 (95% CI, 1.03 to 1.48) and the RD was 2.7 (95% CI, 0.2 to 5.2 per 10 000 births). The adjusted estimate for congenital malformations overall was an RR of 1.01 (95% CI, 0.98 to 1.05) and an RD of 5.4 (95% CI, -7.3 to 18.2 per 10 000 births). Conclusions and Relevance: Among offspring of mothers enrolled in Medicaid, first-trimester exposure to ondansetron was not associated with cardiac malformations or congenital malformations overall after accounting for measured confounders but was associated with a small increased risk of oral clefts.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Antieméticos/efeitos adversos , Fenda Labial/induzido quimicamente , Fissura Palatina/induzido quimicamente , Cardiopatias Congênitas/induzido quimicamente , Náusea/tratamento farmacológico , Ondansetron/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Adulto , Antieméticos/uso terapêutico , Feminino , Humanos , Recém-Nascido , Ondansetron/uso terapêutico , Gravidez , Primeiro Trimestre da Gravidez , Pontuação de Propensão , Estudos Retrospectivos , Risco , Vômito/tratamento farmacológico , Adulto Jovem
11.
Int J Hyg Environ Health ; 221(8): 1116-1123, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30072236

RESUMO

INTRODUCTION: Congenital anomalies (CA) are responsible for high rates of mortality and long-term disabilities. Research on their risk factors including environmental factors is needed. Studies on exposure to arsenic (As) in tap water and the risk of CA have not provided conclusive evidence, particularly when levels of exposure were low (from 10 to 50 µg As/L). The main objective of this study was to assess the association between exposure to As in tap water and the risk of any major CA. The secondary objectives were to assess this association for the most common types of congenital anomalies (in the heart, musculoskeletal, urinary and nervous systems). METHODS: A semi-ecological study was conducted from births recorded at the University Hospital of Clermont-Ferrand, France, in 2003, 2006 and 2010. The medico-obstetric data were available at individual level. Children with congenital anomalies were identified from the database of the regional registry of congenital anomalies: the Centre d'Etudes des Malformations Congénitales Auvergne (CEMC-Auvergne). As exposure was estimated from the concentrations of As measured during sanitary control of tap water supplied in the mothers' commune of residence (aggregate data). French guidelines for As in tap water were used to identify the two groups: "≥ 10 µg As/L group" and "[0-10) µg As/L group". Multivariable logistic regression models were fit. RESULTS: 5263 children (5.1% with a CA) were included. In stratified analysis by gender of the child, positive associations between As exposure exceeding 10 µg/L and risk of any major CA (adjusted OR = 2.41; 95%CI: 1.36-4.14) and of congenital heart anomalies (adjusted OR = 3.66; 95%CI: 1.62-7.64) were only shown for girls. No association was found for boys. CONCLUSION: This French semi-ecological study provides additional arguments for the association between exposure to As exceeding 10 µg/L in tap water and the risk of CA especially in a context of low exposure. Further studies are needed to better understand the interaction between arsenic exposure and child gender.


Assuntos
Arsênico/análise , Água Potável/análise , Cardiopatias Congênitas/epidemiologia , Troca Materno-Fetal , Poluentes Químicos da Água/análise , Adulto , Arsênico/efeitos adversos , Água Potável/efeitos adversos , Feminino , França/epidemiologia , Cardiopatias Congênitas/induzido quimicamente , Humanos , Recém-Nascido , Masculino , Exposição Materna , Razão de Chances , Gravidez , Fatores de Risco , Caracteres Sexuais , Poluentes Químicos da Água/efeitos adversos , Adulto Jovem
12.
Chin Med J (Engl) ; 131(17): 2080-2088, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30127218

RESUMO

Background: Valproic acid (VPA) exposure during pregnancy has been proven to contribute to congenital heart disease (CHD). Our previous findings implied that disruption of planar cell polarity (PCP) signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase (HDAC) inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes (Vangl2/Scrib/Rac1), subsequently screening out the specific HDACs regulating PCP pathway. Methods: VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day 10.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells (undifferentiated rat cardiomyoblasts) were transfected with Hdac1/2/3 specific small interfering RNA (siRNA). Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Rac1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay. Results: VPA could induce CHD (P < 0.001) and inhibit mRNA or protein expression of Hdac1/2/3 as well as Vangl2/Scrib in fetal hearts, in association with total Hdac activity repression (all P < 0.05). In vitro, Hdac3 inhibition could significantly decrease Vangl2/Scrib expression (P < 0.01), while knockdown of Hdac1/2 had no influence (P > 0.05); VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity (P < 0.01), while overexpression of Hdac3 could rescue the VPA-induced inhibition (P > 0.05). Conclusion: VPA could inhibit Hdac1/2/3, Vangl2/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.


Assuntos
Polaridade Celular , Inibidores Enzimáticos/efeitos adversos , Cardiopatias Congênitas/induzido quimicamente , Histona Desacetilases/efeitos dos fármacos , Ácido Valproico/efeitos adversos , Animais , Feminino , Coração Fetal/embriologia , Cardiopatias Congênitas/fisiopatologia , Inibidores de Histona Desacetilases , Histona Desacetilases/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso , Gravidez , Ratos , Transfecção
13.
Int J Cardiol ; 269: 111-113, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-29996977

RESUMO

BACKGROUND: A growing number of young women are exposed to statins during their first trimester of pregnancy. The goal of this study is to examine if first trimester statin exposure is associated with an increase in risk of fetal congenital cardiac anomalies. METHODS: In a cohort of 379,238 pregnancies, we examined the risk of fetal congenital cardiac anomalies in association with maternal exposure to statin therapy during the first trimester of pregnancy using logistic regression models and propensity score matching methods. RESULTS: 280 women were exposed to statins. Congenital cardiac anomalies were present in 14 (5.0%) of pregnancies exposed to statin and 5282 (1.4%) of non-exposed pregnancies. First-trimester statin exposure was associated with an increased risk of ventricular septal defect (adjusted odds ratio [OR] 3.3, 95% confidence interval [CI]l 1.8-6.0, p < 0.001). This association was confirmed in an analysis using a propensity score-matched cohort (OR 4.7, 95% CI 2.0-10.8, p < 0.001). CONCLUSIONS: Exposure to statins during the first trimester of pregnancy is associated with fetal ventricular septal defect.


Assuntos
Comunicação Interventricular/induzido quimicamente , Comunicação Interventricular/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Estudos de Coortes , Feminino , Coração Fetal/anormalidades , Coração Fetal/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologia , Comunicação Interventricular/diagnóstico , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Estudos Retrospectivos
14.
BMC Vet Res ; 14(1): 86, 2018 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-29530019

RESUMO

BACKGROUND: The teratogenic effects of immunomodulatory and certain antimicrobial therapies are described in small rodents and humans. While the described teratogenic effects in small rodents have been extrapolated to make conclusions about its use in the pregnant dam, teratogenic effects of prednisone and doxycycline have not yet been reported in the dog. Here we report and describe midline defects observed in a litter of golden retriever puppies exposed to mid-gestational immunosuppressive and antimicrobial therapy. CASE PRESENTATION: Twenty-one days into gestation, the dam of a litter of eight golden retriever puppies was administered prednisone, doxycycline, and tramadol as treatment for immune-mediated polyarthritis. The individuals in the litter were subsequently diagnosed with a variety of midline defects and congenital cardiac defects. This case series describes the variety of identified defects and presents a descriptive account of complex congenital abnormalities that are likely secondary to teratogenic effects of one or more drugs administered during gestation. The available puppies, dam, and grand dam underwent thorough physical examination, complete echocardiogram, and where indicated, advanced imaging with various surgical corrections when possible. Numerous midline congenital defects and congenital heart disease were identified in the puppies evaluated. Ultimately 5 of 8 puppies born to the dam were presented for thorough evaluation. The midline defects include: gastroschisis (1), peritoneopericardial diaphragmatic hernias (4, PPDH), umbilical hernia (4), unilateral cryptorchidism (1 of 4 males), cleft palate (1), renal agenesis (1), renal abnormalities (1), sternal and vertebral abnormalities (3), remnant liver lobe (1) and malformations consistent with ductal plate malformations with congenital hepatic fibrosis (1). The congenital cardiac defects include: ventricular septal defect (4, VSD) and subaortic stenosis (4, SAS). The presence of greater than one congenital defect was noted in all 5 of the dogs evaluated. Surgical correction was necessary for PPDH in 4 puppies. Medical intervention was recommended for congenital cardiac disease in 1 puppy. CONCLUSION: This case report is the first to describe midline defects in dogs that have been exposed to immunomodulatory therapy during gestation. A causative relationship between mid-gestational immunomodulatory exposure and midline defects cannot be proven, however, this case supports a clear association and provides case-based evidence to support its avoidance when possible.


Assuntos
Anormalidades Induzidas por Medicamentos/veterinária , Antibacterianos/toxicidade , Anti-Inflamatórios/toxicidade , Cães/anormalidades , Doxiciclina/toxicidade , Cardiopatias Congênitas/veterinária , Prednisona/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Induzidas por Medicamentos/patologia , Animais , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Artrite/complicações , Artrite/tratamento farmacológico , Artrite/veterinária , Doxiciclina/uso terapêutico , Ecocardiografia/veterinária , Feminino , Cardiopatias Congênitas/induzido quimicamente , Masculino , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/veterinária , Prednisona/uso terapêutico , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/veterinária
15.
Toxicol Appl Pharmacol ; 347: 33-44, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29596928

RESUMO

Systems toxicology approaches have been used as important tools in the drug discovery and medicine quality control processes. The aim of this study was to assess the pharmacokinetic and toxicity properties of cephalosporins with an aminothiazoyl ring at the C-7 position (CATRs). Cardiac toxicity of the compounds was assessed in zebrafish embryos, and it was determined that CATRs disturbed the formation and development of the heart in a dose-dependent manner. Differentially expressed genes (DEGs) related to the heart were also identified by transcriptome analysis, and co-DEGs were obtained in the protein-protein interaction (PPI) network. Several Gene Ontology (GO) terms and pathways that were enriched by DEGs were identified, and the most significantly enriched pathways were adrenergic signaling in cardiomyocytes, cardiac muscle contraction, and vascular smooth muscle contraction. Combined molecular docking results elucidated that cardiac toxicity mainly depends on the mother nucleus structure 7-aminocephalosporanic acid (7-ACA). The predicted absorption, distribution, metabolism and excretion (ADME) profile suggests that there is a modification at the C-3 side chain of 7-ACA that could change the compound distribution in vivo. The 7-ACA mother nucleus is responsible for the CATRs induced cardiac toxicity, and the three DEGs (nppa, adra2c, and tnni1c) may potentially be utilized as novel biomarkers for CATRs. Our results show that zebrafish embryos may be used to reveal the pathways of cardiac toxicity and they play a vital role in drug safety assessments.


Assuntos
Antibacterianos/toxicidade , Cefalosporinas/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Coração/efeitos dos fármacos , Biologia de Sistemas/métodos , Tiazóis/toxicidade , Toxicologia/métodos , Peixe-Zebra/embriologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Cardiotoxicidade , Cefalosporinas/química , Cefalosporinas/farmacocinética , Relação Dose-Resposta a Droga , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Coração/embriologia , Coração/fisiopatologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/fisiopatologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Mapas de Interação de Proteínas , Medição de Risco , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinética , Transcrição Genética/efeitos dos fármacos , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
16.
J Appl Toxicol ; 38(6): 834-842, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29377175

RESUMO

Accumulating evidence has suggested a link between maternal di-(2-ethylhexyl)-phthalate (DEHP) exposure and various developmental abnormalities. However, the evidence regarding the effect of maternal DEHP exposure on fetal cardiac development is scarce. The present study aimed to determine the effect of maternal DEHP exposure on fetal cardiac development in mice and explore the possible involved mechanism preliminarily. The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 250 mg kg-1 DEHP group (n = 15), 500 mg kg-1 DEHP group (n = 20) and 1 g kg-1 DEHP group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from embryonic day (E)6.5 to E14.5. Maternal weights were monitored every day and samples were collected at E15.5. Hematoxylin and eosin staining was used to examine fetal cardiac malformations. Real-time quantitative polymerase chain reaction and western blot were applied to detect peroxisome proliferator-activated receptor (PPAR)α/PPARγ/Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. Maternal DEHP exposure significantly decreased maternal body weight, fetal weight and placental weight, and remarkably elevated fetal cardiac malformations rate. The phenotypes of cardiac anomalies mainly include septal defects, ventricular myocardium noncompaction and cardiac hypoplasia. Higher doses DEHP (500 mg kg-1 and 1 g kg-1 ) could significantly decreased fetal cardiac Gata4/Mef2c/Chf1 expression, while PPARγ expression was upregulated. Maternal exposure to higher doses of DEHP could result in fetal cardiac development malformations in mice and it might have resulted from the inhibition of cardiac GATA4/Mef2c/Chf1 expression via PPARγ activation.


Assuntos
Dietilexilftalato/toxicidade , Coração Fetal/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Plastificantes/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Coração Fetal/crescimento & desenvolvimento , Coração Fetal/metabolismo , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Idade Gestacional , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/fisiopatologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Exposição Materna , Camundongos Endogâmicos C57BL , Morfogênese/efeitos dos fármacos , PPAR gama/agonistas , PPAR gama/genética , PPAR gama/metabolismo , Gravidez , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Int J Toxicol ; 37(2): 125-143, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29357719

RESUMO

The National Academy of Science has recommended that a risk of bias (RoB; credibility of the link between exposure and outcome) assessment be conducted on studies that are used as primary data sources for hazard identification and dose-response assessment. Few applications of such have been conducted. Using trichloroethylene and congenital heart defects (CHDs) as a case study, we explore the role of RoB in chemical risk assessment using the National Toxicology Program's Office of Health Assessment and Translation RoB tool. Selected questions were tailored to evaluation of CHD and then applied to 12 experimental animal studies and 9 epidemiological studies. Results demonstrated that the inconsistent findings of a single animal study were likely explained by the limitations in study design assessed via RoB (eg, lack of concurrent controls, unvalidated method for assessing outcome, unreliable statistical methods, etc). Such limitations considered in the context of the body of evidence render the study not sufficiently reliable for the development of toxicity reference values. The case study highlights the utility of RoB as part of a robust risk assessment process and specifically demonstrates the role RoB can play in objectively selecting candidate data sets to develop toxicity values.


Assuntos
Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/epidemiologia , Medição de Risco/métodos , Solventes/toxicidade , Revisão Sistemática como Assunto , Tricloroetileno/toxicidade , Animais , Viés , Feminino , Humanos , Troca Materno-Fetal , Gravidez
18.
Cardiovasc Toxicol ; 18(3): 261-267, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29185192

RESUMO

Recent experimental studies showed that ablation of the aryl hydrocarbon receptor (AhR) as well as its activation by exogenous ligands disrupt the molecular networks involved in heart formation and function, leading to congenital heart disease (CHD). However, no evidence is available about the role of AhR in humans. We assessed the prevalence of a functional AhR genetic variant (p.Arg554Lys) in CHD patients as well as its joint effects with parental exposure. A total of 128 CHD patients (76 males; age 6.2 ± 6.7 years) and 274 controls (160 males; age at birth) were genotyped for the AhR polymorphism by using the TaqMan® Drug Metabolism Genotyping assay. Both case and control parents completed a structured questionnaire on demographic, lifestyle and preconception exposures. Genotype (p = 0.001) and allele (p < 0.0001) distributions of AhR p.Arg554Lys differed significantly between patients and controls. A significant elevated CHD risk was found under dominant (OR = 2.9, 95% CI 1.9-4.6, p < 0.0001) and additive genetic models (OR = 6.2, 95% CI 2-19, p = 0.001). There was a significant interaction between 554-Lys allele and paternal smoking exposure (ORsmoking = 1.6, 95% CI = 0.9-2.9; ORallele = 2.6, 95% CI = 1.3-5; ORinteraction = 4.9, 95% CI = 2.4-9.9, p interaction < 0.0001). Additionally, 554-Lys allele exacerbated the effect of maternal periconceptional exposure (ORexposure = 1.6, 95% CI = 0.8-3; ORallele = 2.6, 95% CI = 1.5-4.5; ORinteraction = 5.7; 95% CI = 2.6-12, p interaction < 0.0001). Our findings showed that the AhR p.Arg554Lys polymorphism, alone and in combination with parental exposures, is associated with the CHD risk, highlighting the significant role of AhR in the cardiovascular development.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Interação Gene-Ambiente , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/genética , Exposição Materna/efeitos adversos , Exposição Paterna/efeitos adversos , Polimorfismo Genético , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Fumar/efeitos adversos , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Cardiopatias Congênitas/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Fatores de Risco
19.
Clin Toxicol (Phila) ; 56(2): 132-139, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28705031

RESUMO

CONTEXT: Several studies have investigated the association between heavy metal exposure and congenital heart defects (CHDs). However, there are limited data regarding the relationship between barium exposure and the occurrence of CHDs. The objective of this study was to analyze the association between barium exposure in mothers and the risk of CHD in offspring. MATERIALS AND METHODS: We developed a case-control study with 399 cases and 490 controls with normal live births in China. The concentrations of barium in hair of pregnant woman and fetal placenta were measured. We used a logistic regression analysis to explore the association between barium exposure and the risk of CHD. RESULTS: Logistic regression analysis indicated that the median concentration of barium in maternal hair in the CHD group was 4.180 ng/mg (adjusted odds ratio [aOR], 1.230; 95% confidence interval [CI], 1.146-1.321; p < .001), which was significantly higher than that in the control group (2.740 ng/mg). Furthermore, the median concentration of barium in fetal placental tissue in the CHD group was 0.617 ng/mg, while that in the control group was 0.447 ng/mg (aOR, 1.392; 95% CI, 1.074-1.659; p = .003). Significant differences in the concentration of barium in hair were also found between the different CHD subtypes and the controls. These differences were found in cases with septal defects (p < .001), conotruncal defects (p < .001), right ventricular outflow track obstruction (p < .001), left ventricular outflow track obstruction (p < .001), and anomalous pulmonary venous return (p = .010). Significantly different barium concentrations in fetal tissue were only found in cases with septal defects (p = .010). CONCLUSIONS: Maternal barium exposure was dose-dependently related to the risk of CHD in the offspring. Our findings suggest that the occurrence of some subtypes of CHD is associated with barium exposure.


Assuntos
Bário/envenenamento , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/epidemiologia , Adulto , Bário/análise , Estudos de Casos e Controles , China/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Cabelo/química , Defeitos dos Septos Cardíacos/induzido quimicamente , Defeitos dos Septos Cardíacos/epidemiologia , Humanos , Recém-Nascido , Exposição Materna , Placenta/química , Gravidez , Diagnóstico Pré-Natal , Efeitos Tardios da Exposição Pré-Natal , Fatores de Risco , Adulto Jovem
20.
Acta Pharmacol Sin ; 39(3): 382-392, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29072257

RESUMO

Short QT syndrome (SQTS) is a genetic arrhythmogenic disease that can cause malignant arrhythmia and sudden cardiac death. The current therapies for SQTS have application restrictions. We previously found that Mg· (NH2CH2CH2SO3)2· H2O, a taurine-magnesium coordination compound (TMCC) exerted anti-arrhythmic effects with low toxicity. In this study we established 3 different models to assess the potential anti-arrhythmic effects of TMCC on type 2 short QT syndrome (SQT2). In Langendorff guinea pig-perfused hearts, perfusion of pinacidil (20 µmol/L) significantly shortened the QT interval and QTpeak and increased rTp-Te (P<0.05 vs control). Subsequently, perfusion of TMCC (1-4 mmol/L) dose-dependently increased the QT interval and QTpeak (P<0.01 vs pinacidil). TMCC perfusion also reversed the rTp-Te value to the normal range. In guinea pig ventricular myocytes, perfusion of trapidil (1 mmol/L) significantly shortened the action potential duration at 50% (APD50) and 90% repolarization (APD90), which was significantly reversed by TMCC (0.01-1 mmol/L, P<0.05 vs trapidil). In HEK293 cells that stably expressed the outward delayed rectifier potassium channels (IKs), perfusion of TMCC (0.01-1 mmol/L) dose-dependently inhibited the IKs current with an IC50 value of 201.1 µmol/L. The present study provides evidence that TMCC can extend the repolarization period and inhibit the repolarizing current, IKs, thereby representing a therapeutic candidate for ventricular arrhythmia in SQT2.


Assuntos
Arritmias Cardíacas/prevenção & controle , Complexos de Coordenação/farmacologia , Sistema de Condução Cardíaco/anormalidades , Cardiopatias Congênitas/prevenção & controle , Magnésio/farmacologia , Taurina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/induzido quimicamente , Células Cultivadas , Cobaias , Cardiopatias Congênitas/induzido quimicamente , Humanos , Magnésio/química , Modelos Teóricos , Miócitos Cardíacos/fisiologia , Pinacidil/antagonistas & inibidores , Pinacidil/farmacologia , Taurina/química , Trapidil/antagonistas & inibidores , Trapidil/farmacologia
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