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1.
SAR QSAR Environ Res ; 35(4): 285-307, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38588502

RESUMO

Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals. This study addresses the absence of PBPK-type data for myclobutanil, oxyfluorfen, and pronamide by generating in vitro data for key input PBPK parameters (Caco-2 permeability, rat plasma binding, rat blood to plasma ratio, and rat liver microsomal half-life), followed by generation of PBPK models for these three chemicals via the GastroPlusTM software. Incorporating these experimental input parameters into PBPK models, the prediction accuracy of plasma AUC (area under curve) was significantly improved. Validation against rat oral administration data demonstrated substantial enhancement. Steady-state plasma concentrations (Css) of pronamide aligned well with published data using measured PBPK parameters. Following validation, parent-based tissue concentrations for these agrochemicals were predicted in humans and rats after single or 30-day repeat exposure of 10 mg/kg/day. These predicted concentrations contribute valuable information for future human toxicity risk assessments of these agrochemicals.


Assuntos
Modelos Biológicos , Triazóis , Animais , Humanos , Ratos , Administração Oral , Masculino , Nitrilas/farmacocinética , Nitrilas/toxicidade , Relação Quantitativa Estrutura-Atividade , Células CACO-2 , Medição de Risco , Microssomos Hepáticos/metabolismo , Distribuição Tecidual , Fungicidas Industriais/farmacocinética , Fungicidas Industriais/toxicidade , Fungicidas Industriais/administração & dosagem , Fungicidas Industriais/sangue
2.
SAR QSAR Environ Res ; 33(5): 323-339, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35301938

RESUMO

A physiologically based pharmacokinetic (PBPK) model for the important chemical phenoxyethanol (PhE) and its metabolite phenoxyacetic acid (PhAA) was built via GastroPlusTM software (version 9.0) using currently available analytically measured plasma and urinary time-courses of both PhE and its metabolite PhAA. This model was validated and used to predict tissue and urine concentrations of PhE and its metabolite PhAA in rats and humans after oral and dermal exposures. The prediction results showed that most predicted tissue concentrations of PhE or PhAA were lower than the experimental tissue concentrations based on total radioactivity. The predicted cumulative excretion of PhAA in both rats and humans fits very well with most experimental data. With this GastroPlusTM-based model, the margins of exposure (MOE) of PhE and PhAA were also calculated as 194 and 73.7, respectively. The predicted MOE of PhE is two-fold higher than the previous PBPK model built using total radioactivity-based tissue time courses, and the predicted MOE of PhAA was comparable to the previous PBPK model. These data indicate that for chemicals like PhE, GastroPlusTM can integrate multiple data sets into PBPK models to predict PK parameters for parent and metabolites in both rats and humans following intravenous, dermal, or oral exposures.


Assuntos
Modelos Biológicos , Relação Quantitativa Estrutura-Atividade , Acetatos , Animais , Etilenoglicóis/farmacocinética , Humanos , Ratos
3.
Regul Toxicol Pharmacol ; 81: 421-429, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27664318

RESUMO

In a National Toxicology Program (NTP) chronic inhalation study with methyl isobutyl ketone (MIBK), increases in hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were observed in male and female B6C3F1 mice at 1800 ppm. A DNA reactive Mode-of-Action (MOA) for this liver tumor response is not supported by the evidence as MIBK and its major metabolites lack genotoxicity in both in vitro and in vivo studies. Constitutive androstane receptor (CAR) nuclear receptor-mediated activation has been hypothesized as the MOA for MIBK-induced mouse liver tumorigenesis. To further investigate the MOA for MIBK-induced murine liver tumors, male and female B6C3F1, C57BL/6, and CAR/PXR Knockout (KO) mice were exposed to either 0 or 1800 ppm MIBK for 6 h/day, 5 days/week for a total of 10 days. On day 1, mice were implanted with osmotic mini-pumps containing 5-Bromo-2-deoxyuridine (BrdU) 1 h following exposure and humanely euthanized 1-3 h following the final exposure. B6C3F1 and C57BL/6 mice had statistically significant increases in liver weights compared to controls that corresponded with hepatocellular hypertrophy and increased mitotic figures. Hepatocellular proliferation data indicated induction of S-phase DNA synthesis in B6C3F1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to control, and no increase was observed in MIBK exposed CAR/PXR KO mice. Liver gene expression changes indicated a maximally-induced Cyp2b10 (CAR-associated) transcript and a slight increase in Cyp3a11(PXR-associated) transcript in B6C3F1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to controls, but not in Cyp1a1 (AhR-associated) or Cyp4a10 (PPAR-α-associated) transcripts. CAR/PXR KO mice exposed to 1800 ppm MIBK showed no evidence of activation of AhR, CAR, PXR or PPAR-α nuclear receptors via their associated transcripts. MIBK induced hepatic effects are consistent with a phenobarbital-like MOA where the initiating events are activation of the CAR and PXR nuclear receptors and resultant hepatocellular proliferation leading to rodent liver tumors.


Assuntos
Carcinoma Hepatocelular/induzido quimicamente , Neoplasias Hepáticas/induzido quimicamente , Metil n-Butil Cetona/toxicidade , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Receptor Constitutivo de Androstano , Feminino , Exposição por Inalação , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Metil n-Butil Cetona/administração & dosagem , Camundongos , Camundongos Endogâmicos , Camundongos Knockout
4.
Orthop Traumatol Surg Res ; 102(6): 781-4, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27499115

RESUMO

INTRODUCTION: Adult forearm fractures account for 1-2% of all fractures of the limbs. The main objective of this retrospective multicenter study was to evaluate pre- and postoperative complications of forearm fractures. The secondary objective was to evaluate functional and radiological results of plate osteosynthesis for these fractures. MATERIAL AND METHODS: Between January 2008 and March 2014, 131 forearm fractures were reviewed retrospectively. Fractures were classified preoperatively according to the AO classification. Clinical outcomes were classified into four categories according to the Tschnerne and Oestern classification. Pre- and postoperative complications were sought systematically. RESULTS: Before surgery, 12 patients had neurological impairment (9%). At the last follow-up, nine patients had persistent neurological disorders (6.9%). Union of forearm fractures was obtained in 122 patients at 4.6 months on average (±2.6). Nine patients with nonunion were observed (6.9%) and five patients had radioulnar synostosis (3.8%). DISCUSSION: The frequency of neurological complications concomitant to forearm fractures is noteworthy. Similar cases with essentially irritative neurological disease have been reported in the literature, in particular for the ulnar nerve. Fracture nonunion is a relatively common complication: between 2 and 10% of cases depending on the study. LEVEL OF EVIDENCE: IV.


Assuntos
Placas Ósseas , Fixação Interna de Fraturas , Fraturas do Rádio/complicações , Fraturas do Rádio/cirurgia , Adulto , Feminino , Consolidação da Fratura , Fraturas não Consolidadas/etiologia , Humanos , Masculino , Parestesia/etiologia , Complicações Pós-Operatórias , Rádio (Anatomia)/anormalidades , Estudos Retrospectivos , Sinostose/etiologia , Ulna/anormalidades
5.
Orthop Traumatol Surg Res ; 100(5): 545-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25155091

RESUMO

INTRODUCTION: Epidemiological study of femoral fractures has been dominated by proximal fractures. Distal fracture requires equal attention for correct management. PATIENTS AND METHODS: A prospective study in 12 French hospital centres between June 1st, 2011 and May 31st, 2012 recruited cases of non-pathologic distal femoral fracture in patients over 15 years of age without ipsilateral knee prosthesis. RESULTS: There were 183 fractures in 177 patients. Mean age was 63.5 years. Female patients (60.5%) were significantly older than males (mean age, respectively 73 versus 48.4 years). Walking was unrestricted in only 83 patients (46.89%). On the AO/OTA (Orthopaedic Trauma Association) classification, there were 86 type A fractures (47%), 29 type B (15.8%) and 68 type C (37.2%). Fractures were open in 32 cases (17.5%), most frequently in male, young patients and type C fracture. Causal trauma was low-energy (fall from own height) in 108 cases, most frequently in female patients and type A fracture. Forty-five patients were proximal femoral implant bearers. CONCLUSION: Distal femoral fracture shows highly variable epidemiology. AO/OTA type A fracture mainly involves elderly, relatively dependent female subjects. Outcome study requires radiographic data and assessment of functional capacity. LEVEL OF EVIDENCE IV: Prospective cohort study.


Assuntos
Fraturas do Fêmur/epidemiologia , Acidentes por Quedas/estatística & dados numéricos , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Fraturas do Fêmur/classificação , Fraturas do Fêmur/cirurgia , Fixação Interna de Fraturas/estatística & dados numéricos , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Distribuição por Sexo , Adulto Jovem
6.
Orthop Traumatol Surg Res ; 100(5): 555-60, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25129706

RESUMO

BACKGROUND: The blade-plate is the earliest of the contemporary internal fixation devices introduced for distal femoral fractures. The recent development of dedicated, fixation devices has considerably limited its use. The objective of this study was to evaluate outcomes after blade-plate fixation and after fixation using other devices. HYPOTHESIS: Outcomes after blade-plate fixation are similar to those after condylar screw-plate, distal femoral nail, or locking condylar plate fixation. MATERIAL AND METHODS: We reviewed outcomes after 62 patients managed with blade-plate fixation and included in a multicentre retrospective study (n=57) or a multicentre prospective study (n=5) and we compared them to outcomes after fixation using condylar screw-plates (n=82), distal femoral nail (n=219), or locking condylar plates (n=301). The four groups were comparable for age, gender distribution, occupational status, prevalence of skin wounds, patient-related factors, type of accident, and type of fracture. The evaluation relied on the clinical International Knee Society (IKS) score and on radiographs. RESULTS: No significant differences existed across the four groups for operative time, blood transfusion use, complications, need for bone grafting, non-union rate, or IKS score values. The early surgical revision rate for removal of the fixation material was 4% with the blade-plate and 16% with the other three fixation devices (P=0.02). Post-operative fracture deformity was similar in the four groups with, however, a higher proportion of residual malalignment in the screw-fixation group. The final anatomic axis was 3.3±1.4° with the blade-plate versus 2.3±3.7° with the other three fixation devices. The blade-plate group had few patients with axial malalignment, and the degree of malalignment was limited to 3° of varus and 10° of valgus at the most, compared to 10° and 18° respectively, with the other three fixation devices. CONCLUSION: Despite the now extremely limited use and teaching of blade-plate fixation, as well as the undeniable technical challenges raised by the implantation of this device, the blade-plate is a simple, strong, and inexpensive fixation method. It remains reliable for the fixation of distal femoral fractures. The disfavour into which the blade-plate is currently falling is not warranted. LEVEL OF EVIDENCE: III, case-control study.


Assuntos
Placas Ósseas , Fraturas do Fêmur/cirurgia , Fixação Interna de Fraturas/instrumentação , Adolescente , Adulto , Mau Alinhamento Ósseo/etiologia , Pinos Ortopédicos , Parafusos Ósseos , Estudos de Casos e Controles , Remoção de Dispositivo , Feminino , Fraturas do Fêmur/diagnóstico por imagem , Consolidação da Fratura , França , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Prospectivos , Radiografia , Reoperação , Estudos Retrospectivos , Adulto Jovem
7.
Rapid Commun Mass Spectrom ; 25(20): 3123-30, 2011 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-21953968

RESUMO

The possible interaction of environmental contaminants with the endocrine system has been an environmental concern since the early 1990s. To examine these interactions test guidelines have been introduced by regulatory agencies to screen for possible endocrine active compounds. One of these guidelines is the EPA's OPPTS 890.1550 [Steroidogenesis (Human Cell Line-H295R)]. This guideline requires the quantification of two major biomarkers (testosterone and estradiol) in various biological test systems. Traditional quantitation methodologies such as Radioimmunoassay (RIA) and Enzyme-linked Immunosorbent Assay (ELISA) have been used to quantify low levels of steroids. However, those methodologies have drawbacks such as the radioactive safety, antibody availability, separate assay for each biomarker, and lack of selectivity. In the current study, a rapid and sensitive liquid chromatography/positive atmospheric pressure photoionization tandem mass spectrometry method (LC/APPI-MS/MS) has been developed and validated for the simultaneous quantitation of testosterone and estradiol in the H295R cell line. Briefly, the media from cultured cells was extracted with dichloromethane (CH(2)Cl(2)) containing internal standards of both testosterone-d(3) and estradiol-(13)C(3); then, the extracted organic layer was concentrated down to dryness. The final residue was derivatized with dansyl chloride solution, and directly analyzed by LC/APPI-MS/MS. The calibration curves, with concentration ranging from 10 to 2500 pg/mL, were linear with coefficient >0.99. The lower limits of quantitation for both testosterone and estradiol were 10 pg/mL. This method was successfully validated to support requirements of the current EPA Steroidogenesis guideline. This type of method may also provide value for rapid and precise measurements of these two hormones in other in vitro or in vivo test systems.


Assuntos
Cromatografia Líquida/métodos , Estradiol/análise , Espectrometria de Massas em Tandem/métodos , Testosterona/análise , Ácido Acético/química , Acetonitrilas/química , Linhagem Celular , Humanos , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Endocrinology ; 148(3): 989-1008, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17138649

RESUMO

To identify cell populations directly responsive to prolactin (PRL), GH, erythropoietin, or granulocyte-colony stimulating factor within the physiological setting of an intact mammal, we combined in situ detection of hormone-activated signal transducer and activator of transcription (Stat)-5 in rats with high-throughput tissue array analysis using cutting-edge matrix assembly (CEMA). Inducible activation of Stat5a/b, as judged by levels of nuclear-localized, phosphoTyr694/699-Stat5a/b, served as an immediate and sensitive in situ marker of receptor signaling in rat tissues after injection into male and female rats of a single, receptor-saturating dose of hormone for maximal receptor activation. CEMA tissue arrays facilitated analysis of most tissues, including architecturally complex, thin-walled, and stratified tissues such as gut and skin. In 40 tissues analyzed, 35 PRL-responsive and 32 GH-responsive cell types were detected, of which 22 cell types were responsive to both hormones. Interestingly, PRL but not GH activated Stat5 in nearly all of the endocrine glands. In mammary glands, PRL activated Stat5 in a majority of luminal epithelial cells but not myoepithelial cells, stromal fibroblasts, or adipocytes, whereas GH activated Stat5 in a significant fraction of myoepithelial cells, fibroblasts, and adipocytes but only in a minority of luminal cells. Finally, the organism-wide screening revealed a yet-to-be identified erythropoietin-responsive cell type in connective tissue. CEMA tissue arrays provide cost-effective in situ analysis of large numbers of tissues. Biomarker-based identification of cell populations responsive to individual hormones may shed new light on endocrine disease as well as improve understanding of effects and side effects of hormones and drugs.


Assuntos
Eritropoetina/farmacologia , Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hormônio do Crescimento/farmacologia , Prolactina/farmacologia , Análise Serial de Tecidos , Animais , Glândulas Endócrinas/citologia , Glândulas Endócrinas/efeitos dos fármacos , Glândulas Endócrinas/metabolismo , Feminino , Gônadas/citologia , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Hibridização In Situ , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Especificidade de Órgãos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
J Endocrinol ; 188(3): 589-601, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16522738

RESUMO

Experimental testing of growth, metastatic progression and drug responsiveness of human breast cancer in vivo is performed in immunodeficient mice. Drug candidates need to show promise against human breast cancer in mice before being allowed into clinical trials. Breast cancer growth is under endocrine control by ovarian steroids and the pituitary peptide hormone prolactin. While it is recognized that the most relevant biologic effects of prolactin are achieved with prolactin from the matching species, the biologic efficacy of mouse prolactin for human prolactin receptors has not been recorded. Thus, it is unclear whether the mouse endocrine environment adequately reflects the hormonal environment in breast cancer patients with regard to prolactin. We now show both recombinant and natural pituitary-derived mouse prolactin to be a poor agonist for human prolactin receptors. Mouse prolactin failed to induce human prolactin receptor-mediated biologic responses of cell clustering, proliferation, gene induction and signal transduction, including activation of Stat5, Stat3, Erk1/2 and Akt pathways. Consistent data were derived from human breast cancer lines T-47D, MCF-7 and ZR-75.1, as well as human prolactin receptor-transfected COS-7 and 32D cells. Failure of mouse prolactin to activate human prolactin receptors uncovers a key deficiency of the mouse endocrine environment for human xenotransplant studies. Since most human breast cancers express prolactin receptors, human breast cancer transferred into mice is unnaturally selected for growth in the absence of circulating prolactin. The new insight raises concerns about the validity of analyzing biology and drug responsiveness of human breast cancer in existing mouse xenotransplant models.


Assuntos
Neoplasias da Mama/metabolismo , Prolactina/farmacologia , Receptores da Prolactina/metabolismo , Análise de Variância , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Eletroporação , Feminino , Humanos , Immunoblotting/métodos , Imunoprecipitação/métodos , Camundongos , Camundongos Nus , Modelos Animais , Transplante de Neoplasias , Prolactina/metabolismo , Ligação Proteica , Receptores da Prolactina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT5/metabolismo , Especificidade da Espécie , Transplante Heterólogo
10.
Mol Cell Endocrinol ; 183(1-2): 151-63, 2001 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-11604235

RESUMO

Milk production remains suppressed in mammals during late pregnancy despite high levels of lactogenic polypeptide hormones. At parturition, associated with a precipitous fall in circulating progesterone, rising glucocorticoid levels synergize with prolactin to initiate copious milk production. This synergy is mediated at least in part through the coordinated activation of glucocorticoid receptors and transcription factor Stat5, particularly Stat5a. Here we show that two proline-juxtaposed serine residues within the transactivation domain of Stat5a are phosphorylated in the mammary gland during late gestation and lactation, and that these phosphorylation sites inhibit the transcriptional activity of Stat5a in the absence of glucocorticoid receptor costimulation. Specifically, transfection assays revealed that phosphorylation of residues S725 and S779 of Stat5a cooperatively suppressed prolactin-stimulated transcription from the beta-casein promoter in both COS-7 kidney and MCF-7 mammary cells. This suppression was associated with shortened duration and reduced amplitude of nuclear DNA binding activity of wild type Stat5a relative to that of the serine phosphorylation-defective Stat5 mutant. However, costimulation of glucocorticoid receptors completely reversed the suppressive effect of Stat5a serine phosphorylation on beta-casein gene transcription. We propose that serine phosphorylation within the transactivation domain may limit the activity of Stat5a in the absence of proper coactivation by glucocorticoid receptors.


Assuntos
Caseínas/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Glândulas Mamárias Animais/metabolismo , Proteínas do Leite , Fosfosserina/metabolismo , Prolactina/farmacologia , Transativadores/metabolismo , Sequência de Aminoácidos , Animais , Caseínas/metabolismo , Bovinos , Linhagem Celular , Meios de Cultura Livres de Soro , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Immunoblotting , Lactação/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Fosforilação , Gravidez , Receptores de Glucocorticoides/metabolismo , Fator de Transcrição STAT5 , Alinhamento de Sequência , Transativadores/genética , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor
11.
J Neuropathol Exp Neurol ; 43(6): 568-79, 1984 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-6594438

RESUMO

Glycogenosis Type VIII, characterized ultrastructurally by an accumulation of rosettes (alpha-particles) of glycogen in the central nervous system, is an extremely rare condition; only two sporadic cases are on record. The first complete autopsy on a patient with cerebral alpha-particle glycogenosis, a 20-year-old American-Indian female, is the subject of this report. The case was clinically unique because of long survival and presumable familial incidence. The gross pathology was characterized by severe brain atrophy but preserved thickness of the cortical mantle. Vacuolation of the neuropil was the main histological abnormality and was most extensive in the striatum and less so in the cerebral cortex and some brain stem nuclei. Biochemical analysis showed glycogen levels elevated fiftyfold in the striatum and eightfold in the cerebral cortex in comparison with control tissue. Ultrastructural observations and evidence obtained from the Golgi method suggest that the distal axon was the principal site of storage. Two prominent additional abnormalities, spheroids, not previously observed in this disease, and massive accumulation of lipofuscin, were probably both related to the prolonged course of illness. The viscera, including the liver were morphologically free of storage.


Assuntos
Encéfalo/patologia , Doença de Depósito de Glicogênio Tipo VIII/patologia , Doença de Depósito de Glicogênio/patologia , Adulto , Encéfalo/ultraestrutura , Química Encefálica , Córtex Cerebral/patologia , Córtex Cerebral/ultraestrutura , Corpo Estriado/patologia , Corpo Estriado/ultraestrutura , Feminino , Humanos
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