The effects on the endocrine system under hepatotoxicity induction by phenobarbital and di(2-ethylhexyl)phthalate in intact juvenile male rats

Yamaguchi, Takafumi; Maëda, Minoru; Ogata, Keiko; Abe, Jun; Utsumi, Toru; Kimura, Koji

doi:10.2131/jts.44.459

Cited by 12 publications

(8 citation statements)

References 41 publications

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“…Mitochondrial toxicity and oxidative stress is involved in the hepatotoxicity induced by phenobarbital [38,39]. Laboratory animal studies have reported the hepatotoxicity of high dose phenobarbital in juvenile male rats [40]. The hepatoxicity is suggested to be related to defect in phenobarbital detoxi cation and hypersensitivity [28].…”

Section: Discussionmentioning

confidence: 99%

Phenobarbital is Associated with Cholestasis in low birth weight Infants with Hemo-dynamically Significant Patent Ductus Arteriosus

Shen

Huang

Peng

et al. 2022

Preprint

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Objectives: This retrospective cohort study aimed to assess whether phenobarbital was associated with cholestasis in low birth weight (LBW) infants with hemo-dynamically significant patent ductus arteriosus (hsPDA).Methods: This study included 148 LBW infants (24~34 weeks, birth weight<2000 g) diagnosed with hsPDA, admitted to neonatal intensive care unit (NICU) from September 2016 to September 2019. Of the 148 infants, twenty infants were diagnosed with cholestasis. To assess the independent association with cholestasis or direct bilirubin, binary logistic or multivariable linear regression was done, adjusting for major confounders (birth weight, gestational age, critical risk index for babies, invasive mechanical ventilation, any sepsis onset in 28 days and etc). Result: Binary logistic regression analysis was done adjusting for 12 related confounders. After adjustment, the “delay of full enteral feeding” was still associated with “duration of phenobarbital” (DOP) (OR: 1.571; P = 0.015) or “duration of phenobarbital before cholestasis onset” (DOPBCO) (OR: 1.662; P = 0.014); Cholestasis was still associated with “DOP” (OR: 1.553; P = 0.005) or “DOPBCO” (OR: 1.353; P = 0.088); “High direct bilirubin summit” (>1.5 mg/dl) was still associated with “DOP” (OR: 1.686; P = 0.003) or “DOPBCO” (OR: 1.511; P = 0.021). Multivariate linear regression revealed that “persist time of cholestasis” was associated with “DOB” (B: 2.254; P = 0.050) after adjustment of “delay of full enteral feeding”.Conclusion: This study found that phenobarbital was associated with neonatal cholestasis in LBW infants with hsPDA. Phenobarbital should be used cautiously in this population.

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Section: Discussionmentioning

confidence: 99%

Phenobarbital is Associated with Cholestasis in low birth weight Infants with Hemo-dynamically Significant Patent Ductus Arteriosus

Shen

Huang

Peng

et al. 2022

Preprint

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“…Nonparametric tests (e.g., Kruskal-Wallis or Mann-Whitney tests [34]) are commonly used for ordinal response data but tied data are considered only an approximation and confidence intervals are hard to obtain or to interpret. New proposals for related trend tests, e.g., Altunkaynak and Gamgam [3] suffer from the same issues.…”

Section: A Nonparametric Approach Based On Relative Effect Sizementioning

confidence: 99%

Evaluation of histological findings with severity grade, to analyze toxicology in-vivo studies

Hothorn¹,

Weber²

2022

Preprint

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In-vivo toxicological studies are characterized by multiple primary endpoints with quite different scales. Whereas guidelines and publications provide various statistical tests for normally distributed endpoints (such as organ weights) and proportions (such as tumor rates), few approaches are available for graded histopathological findings, such as 0, +, ++, +++. This represents a basic contradiction of the statistical analysis because these graded findings sometimes show a high predictive value for potential toxic effects. Here we discuss different methods comparatively, especially from the viewpoints of i) designs for very small sample sizes and ii) interpretability by toxicologists. A new approach is recommended where a simultaneous test is performed over all class combinations of score levels, such as (0, +) vs (++, +++). Corresponding R code is provided by way of a data example.

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“…1,5 For example, phenobarbital (PB), a common drug, is a well-known liver-mediated thyroid toxicant in rodents. 6,7…”

Section: Introductionmentioning

confidence: 99%

“…1,5 For example, phenobarbital (PB), a common drug, is a well-known liver-mediated thyroid toxicant in rodents. 6,7 Both MIEs (direct or indirect) trigger a decrease of circulating thyroid hormone concentrations, which lead to an activation of the hypothalamus-pituitary axis via a negative feedback and then a stimulation of thyroid gland by thyroid stimulating hormone. If this stimulation is prolonged, histomorphological changes like follicular cell hypertrophy, hyperplasia, and potentially neoplasia could be observed.…”

Section: Introductionmentioning

confidence: 99%

Artificial Intelligence in Toxicological Pathology: Quantitative Evaluation of Compound-Induced Follicular Cell Hypertrophy in Rat Thyroid Gland Using Deep Learning Models

et al. 2021

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Digital pathology has recently been more broadly deployed, fueling artificial intelligence (AI) application development and more systematic use of image analysis. Here, two different AI models were developed to evaluate follicular cell hypertrophy in hematoxylin and eosin-stained whole-slide-images of rat thyroid gland, using commercial AI-based-software. In the first, mean cytoplasmic area measuring approach (MCA approach), mean cytoplasmic area was calculated via several sequential deep learning (DL)-based algorithms including segmentation in microanatomical structures (separation of colloid and stroma from thyroid follicular epithelium), nuclear detection, and area measurements. With our additional second, hypertrophy area fraction predicting approach (HAF approach), we present for the first time DL-based direct detection of the histopathological change follicular cell hypertrophy in the thyroid gland with similar results. For multiple studies, increased output parameters (mean cytoplasmic area and hypertrophic area fraction) were shown in groups given different hypertrophy-inducing reference compounds in comparison to control groups. Quantitative results correlated with the gold standard of board-certified veterinary pathologists’ diagnoses and gradings as well as thyroid hormone dependent gene expressions. Accuracy and repeatability of diagnoses and grading by pathologists are expected to be improved by additional evaluation of mean cytoplasmic area or direct detection of hypertrophy, combined with standard histopathological observations.

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The effects on the endocrine system under hepatotoxicity induction by phenobarbital and di(2-ethylhexyl)phthalate in intact juvenile male rats

Cited by 12 publications

References 41 publications

Phenobarbital is Associated with Cholestasis in low birth weight Infants with Hemo-dynamically Significant Patent Ductus Arteriosus

Phenobarbital is Associated with Cholestasis in low birth weight Infants with Hemo-dynamically Significant Patent Ductus Arteriosus

Evaluation of histological findings with severity grade, to analyze toxicology in-vivo studies

Artificial Intelligence in Toxicological Pathology: Quantitative Evaluation of Compound-Induced Follicular Cell Hypertrophy in Rat Thyroid Gland Using Deep Learning Models

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