The Embryonic Stem Cell Test as Tool to Assess Structure-Dependent Teratogenicity: The Case of Valproic Acid

Teratogenicity can be predicted in vitro using the embryonic stem cell test (EST). The EST, which is based on the morphometric measurement of cardiomyocyte differentiation and cytotoxicity parameters, represents a scientifically validated method for the detection and classification of chemicals according to their teratogenic potency. Furthermore, an abbreviated protocol applying flow cytometry of intracellular marker proteins to determine differentiation into the cardiomyocyte lineage is available. Although valproic acid (VPA) is in worldwide clinical use as antiepileptic drug, it exhibits two severe side effects, i.e., teratogenicity and hepatotoxicity. These limitations have led to extensive research into derivatives of VPA. Here we chose VPA as model compound to test the applicability domain and to further evaluate the reliability of the EST. To this end, we study six closely related congeners of VPA and demonstrate that both the standard and the molecular flow cytometry-based EST are well suited to indicate differences in the teratogenic potency among VPA analogs that differ only in chirality or side chain length. Our data show that identical results can be obtained by using the standard EST or a shortened protocol based on flow cytometry of intracellular marker proteins. Both in vitro protocols enable to reliably determine differentiation of murine stem cells toward the cardiomyocyte lineage and to assess its chemical-mediated inhibition

Estrogen and Progestogen Correlates of the Structure of Female Copulation Calls in Semi-Free-Ranging Barbary Macaques (Macaca sylvanus)

Females of many Old World primates produce conspicuous vocalizations in combination with copulations. Indirect evidence exists that in Barbary macaques (Macaca sylvanus), the structure of these copulation calls is related to changes in reproductive hormone levels. However, the structure of these calls does not vary significantly around the timing of ovulation when estrogen and progestogen levels show marked changes. We here aimed to clarify this paradox by investigating how the steroid hormones estrogen and progesterone are related to changes in the acoustic structure of copulation calls. We collected data on semi-free-ranging Barbary macaques in Gibraltar and at La Forêt des Singes in Rocamadour, France. We determined estrogen and progestogen concentrations from fecal samples and combined them with a fine-grained structural analysis of female copulation calls (N = 775 calls of 11 females). Our analysis indicates a time lag of 3 d between changes in fecal hormone levels, adjusted for the excretion lag time, and in the acoustic structure of copulation calls. Specifically, we found that estrogen increased the duration and frequency of the calls, whereas progestogen had an antagonistic effect. Importantly, however, variation in acoustic variables did not track short-term changes such as the peak in estrogen occurring around the timing of ovulation. Taken together, our results help to explain why female Barbary macaque copulation calls are related to changes in hormone levels but fail to indicate the fertile phase

Data for: Data on ADME parameters of bisphenol A and its metabolites for use in physiologically based pharmacokinetic modelling

The material in this repository is related to the article entitled "Data on ADME parameters of bisphenol A and its metabolites for use in physiologically based pharmacokinetic modelling" to be published in Data in Brief (Wiśniowska et al., 2023). The related article provides the physicochemical parameters of bisphenol A (BPA) and its sulfate (BPAS) and glucuronide (BPAG) conjugates, as well as parameters characterizing their absorption, distribution, metabolism, and excretion (ADME) behaviour following oral administration of BPA. This set of parameters was used to implement a physiologically based pharmacokinetic (PBPK) model in Simcyp® Simulator V21. The PBPK model was used to simulate the human toxicokinetic studies of Thayer et al. (2015) and Teeguarden et al. (2015). This repository contains the Simcyp workspace (*.wksz), two files with the observed data (Observed*.xml, Observed*.xlsx), and the Simcyp output file (Simulation*.xlsx) for each simulated study. The Simcyp workspace contains all of the simulation details, including compound and population data, as well as trial design information. The PBPK model parameters are additionally be compiled in an Excel file named "PBPK model parameters.xlsx". This repository also contains an R script (*.R) which was used to extract the predicted and observed plasma/serum concentration-time profiles and cumulative urinary excretion-time profiles from the Excel files to generate a graphical representation of all data in a single figure (*.pdf). The PBPK model can be used to test various scenarios with oral exposure to BPA. It can also be extended to include other exposure routes, such as the dermal route. Therefore, the developed PBPK model can be used to support the assessment of human health risk of BPA, the interpretation of human biomonitoring data, and the establishment of the relationship between external and internal exposure measures

Data for: Data on ADME parameters of bisphenol A and its metabolites for use in physiologically based pharmacokinetic modelling

The material in this repository is related to the article entitled "Data on ADME parameters of bisphenol A and its metabolites for use in physiologically based pharmacokinetic modelling" to be published in Data in Brief (Wiśniowska et al., 2023). The related article provides the physicochemical parameters of bisphenol A (BPA) and its sulfate (BPAS) and glucuronide (BPAG) conjugates, as well as parameters characterizing their absorption, distribution, metabolism, and excretion (ADME) behaviour following oral administration of BPA. This set of parameters was used to implement a physiologically based pharmacokinetic (PBPK) model in Simcyp® Simulator V21. The PBPK model was used to simulate the human toxicokinetic studies of Thayer et al. (2015) and Teeguarden et al. (2015). This repository contains the Simcyp workspace (*.wksz), two files with the observed data (Observed*.xml, Observed*.xlsx), and the Simcyp output file (Simulation*.xlsx) for each simulated study. The Simcyp workspace contains all of the simulation details, including compound and population data, as well as trial design information. The PBPK model parameters are additionally be compiled in an Excel file named "PBPK model parameters.xlsx". This repository also contains an R script (*.R) which was used to extract the predicted and observed plasma/serum concentration-time profiles and cumulative urinary excretion-time profiles from the Excel files to generate a graphical representation of all data in a single figure (*.pdf). The PBPK model can be used to test various scenarios with oral exposure to BPA. It can also be extended to include other exposure routes, such as the dermal route. Therefore, the developed PBPK model can be used to support the assessment of human health risk of BPA, the interpretation of human biomonitoring data, and the establishment of the relationship between external and internal exposure measures.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

Avacopan for the Treatment of ANCA-Associated Vasculitis

BACKGROUND: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority. RESULTS: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone. CONCLUSIONS: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.)

Avacopan for the Treatment of ANCA-Associated Vasculitis.

BACKGROUND: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority. RESULTS: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone. CONCLUSIONS: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.)