RESEARCH ON THE ESTIMATE OF SAFETY AND TOXICITY OF P-NITROPHENOL SODIUM WITHA PHYSIOLOGICALLY BASED PHARMACOKINETICS MODEL

The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which is scientifically a way lack of grounds. To make a change of the old method, we designed a Physiologically Based Pharmacokinetics Medel for the estimate of safety and toxicity of chemicais. As an example,p-nitrophenol sodium (PNP-Na) is used in the research work. Studies of the PNP-Na pharmacokinetics in bodies of rat as well as humans are made, and possibilities of making use of the Model in the estimate of safety and toxicity of chemicals are discussed.

Evaluating the Combined Optimization of Oxygenation and Ventilation in a Patient Simulator

The use of mathematical models can aid in optimizing therapy settings in ventilated patients to achieve certain therapy goals. Especially when multiple goals have to be met, the use of individualized models can be of great help. The presented work shows the potential of using models of respiratory mechanics and gas exchange to optimize minute ventilation and oxygen supply to achieve a defined oxygenation and carbon dioxide removal in a patient while guaranteeing lung protective ventilation. The venti-lator settings are optimized using respiratory mechanics models to compute a respira-tion rate and tidal volume that keeps the maximum airway pressure below the critical limit of 30 cm H2O while ensuring a sufficient expiration. A three-parameter gas ex-change model is then used to optimize both minute ventilation and oxygen supply to achieve defined arterial partial pressures of oxygen and carbon dioxide in the patient. The presented approach was tested using a JAVA based patient simulator that uses various model combinations to compute patient reactions to changes in the ventilator settings. The simulated patient reaction to the optimized ventilator settings showed good agreement with the desired goals.

Determination of a Numerical Analysis Algorithm for the Regulation of Blood Sugar in Diabetics

Acceptable glycemic control when examining the effects of meals was achieved when combining basal insulin therapy and high concentration insulin injection before a meal, when using a PID controller (Proportionality, Integrity and Derivative actions) alone, when using a PID controller with basal insulin therapy and when combining the three methods of insulin delivery. Naturally, a type 1 diabetic must inject himself with insulin in well-measured doses. Thus, the management and control of diabetes become a complex task when one must be considered the disturbance due to nutrition and sports activity. This concern has been at the center of much research through different approaches through mathematical methods and Artificial Intelligence methods. This article simulates a physiological model of glycemic control in type 1 diabetics by a PID regulatory mechanism, in the context of disturbances caused by the patient’s meals and athletic activity.

Benchmark Dose for Dioxin Based on Gestational Diabetes Mellitus Using Coexposure Statistical Methods and an Optimized Physiologically Based Toxicokinetic Model

Dioxins are ubiquitous endocrine-disrupting substances,but determining the effects and benchmark doses in situations of coexposure is highly challenging.The objective of this study was to assess the relationship between dioxin andgestational diabetes mellitus(GDM),calculate the benchmark dose(BMD)of dioxin in coexposure scenarios,and derive a daily exposure threshold using an optimized physiologically based toxicokinetic(PBTK)model.Based on a nested casecontrol study including 77 cases with GDM and 154 controls,serum levels of 29 dioxin-like compounds(DLCs)along with 10 perfluoroalkyl acids(PFAAs),seven polybrominated diphenyl ethers(PBDEs),and five non-dioxin-like polychlorinated biphenyls(ndl-PCBs)were measured at 9−16 weeks of gestation.Bayesian machine kernel regression(BKMR)was employed to identify significant chemicals,and probit and logistic models were used to calculate BMD adjusted for significant chemicals.A physiologically based toxicokinetic(PBTK)model was optimized using polyfluorinated dibenzo-p-dioxins and dibenzofurans(PFDD/Fs)data by the Bayesian−Monte Carlo Markov chain method and was used to determine the daily dietary exposure threshold.The median serum level of total dioxin toxic equivalent(TEQ)was 7.72 pg TEQ/g fat.Logistic regression analysis revealed that individuals in the fifth quantile of total TEQ level had significantly higher odds of developing GDM compared to those in the first quantile(OR,8.87;95%CI 3.19,27.58).The BKMR analysis identified dioxin TEQ and BDE-153 as the compounds with the greatest influence.The binary logistic and probit models showed that the BMD10(benchmark dose corresponding to a 10%extra risk)and BMDL_(10)(lower bound on the BMD_(10))were 3.71 and 3.46 pg TEQ/g fat,respectively,when accounting for coexposure to BDE-153 up to the 80%level.Using the optimized PBTK model and modifying factor,it was estimated that daily exposure should be below 4.34 pg TEQ kg^(−1)bw week^(−1)in order to not reach a harmful serum concentration for GDM.Further studies should utilize coexposure statistical methods and physiologically based pharmacokinetic(PBTK)models in reference dose calculation.

Global Existence of Periodic Solutions in a Physiological Model with Delay

A physiological model with delay is considered. The time delay being regarded as a parameter, a group of conditions that guarantee the model have multiple periodic solutions is obtained by the global Hopf bifurcation theorem for FDE and Bendixson＇s criterion for high-dimensional ODE. The results are illustrated by some numerical simulations.

Determination of the Bioaccessibility of Cadmium in Golden Thread by Physiologically Based Extraction Test Digestion Using the in vitro/Caco2 Cell Model and Subsequent Risk Assessment

Background:The ingestion of golden thread contaminated with heavy metals through the food chain leads to detrimental effects to human health.During digestion,not all of the heavy metals could be released to the gastrointestinal tract and readily to be absorbed by human body.Thus,bioaccessibility is an important issue in health risk assessments.Aims and Objectives:The aims and objectives of this study were to investigate the bioaccessibility of Cd in golden thread and assess the associated health risks based on the exposure to bioaccessible Cd.Materials and Methods:Inductively coupled plasma mass spectrometry(ICP-MS)has been applied to determine the Cd content in golden thread.Physiologically based extraction test(PBET)digestion was performed in the in vitro/Caco2 cell model to investigate the bioaccessibility of Cd in golden thread.Furthermore,the target hazard quotient(THQ)was used to assess the risks of the total and the bioaccessible content of Cd in golden thread.Results:The results revealed that the total Cd content in six batches of golden thread ranged from 3.203 to 5.723 mg/kg.After uptake by Caco2 cells,the bioaccessibility of Cd ranged from 42.36%to 59.73%.The results of the risk assessment indicated that prior to uptake by Caco2 cells,the THQ values of Cd for all batches of golden thread were greater than 1.However,after uptake by Caco2 cells,the THQ values of Cd in all samples were less than 1,thus suggesting that the risks were at a safe level.Conclusion:This study was the first to perform health risk assessment with bioaccessible heavy metals present in traditional Chinese medicine by PBET digestion using an in vitro/Caco2 cell model,thus enabling us to obtain more accurate and objective results while allowing us to avoid unnecessary government intervention and to establish more reasonable limit standards for heavy metals.

Slowly Oscillating Periodic Solutions for a Delayed Physiological Model

In this paper, we study a simplified model with delay for a control oftestosterone secretion. Employing the ejective fixed point principle due to Nussbaum, the existenceof slowly oscillating periodic solution of the model is proven when the delay parameter r 】 r_0, forsome constant r_0 】 0.

Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine,liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin

Body is equipped with organic cation transporters(OCTs).These OCTs mediate drug transport and are also involved in some disease process.We aimed to investigate whether liver failure alters intestinal,hepatic and renal Oct expressions using bile duct ligation(BDL)rats.Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure,associated with decreased intestinal absorption and increased urinary excretion.Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2.In vitro cell experiments show that chenodeoxycholic acid(CDCA),bilirubin and farnesoid X receptor(FXR)agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1,which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR.Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL,which are confirmed using CDCA-treated and bilirubin-treated rats.A disease-based physiologically based pharmacokinetic model characterizing intestinal,hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats.In conclusion,BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats,finally,decreasing plasma exposure and impairing hypoglycemic effects of metformin.BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.

Development of a bioheat model for older people under hot and cold exposures

Physiological modeling is important to evaluate the effects of heat and cold conditions on people’s thermal comfort and health. Experimental studies have found that older people (above 65 year old) undergo age-related weakening changes in their physiology and thermoregulatory activities, which makes them more vulnerable to heat or cold exposure than average aged young adults. However, addressing the age-related changes by modeling has been challenging due to their wide variability among the older population. This study develops a two-node physiological model to predict the thermal response of older people. The model is built on a newly developed two-node model for average-age young adults by accounting for the age-related attenuation of thermoregulation and sensory delays in triggering thermoregulatory actions. A numerical optimization method is developed to compute the model parameter values based on selected benchmark data from the literature. The proposed model is further validated with published measurement data covering large input ranges. The model predictions are in good agreement with the measurements in hot and cold exposure conditions with a discrepancy 0.60 °C for the mean skin temperature and of 0.30 °C for the core temperature. The proposed model can be integrated into building simulation tools to predict heat and cold stress levels and the associated thermal comfort for older people in built environments.

An update on placental drug transport and its relevance to fetal drug exposure

Pregnant women are often complicated with diseases that require treatment with medication.Most drugs administered to pregnant women are off-label without the necessary dose,efficacy,and safety information.Knowledge concerning drug transfer across the placental barrier is essential for understanding fetal drug exposure and hence drug safety and efficacy to the fetus.Transporters expressed in the placenta,including adenosine triphosphate(ATP)-binding cassette efflux transporters and solute carrier uptake transporters,play important roles in determining drug transfer across the placental barrier,leading to fetal exposure to the drugs.In this review,we provide an update on placental drug transport,including in vitro cell/tissue,ex vivo human placenta perfusion,and in vivo animal studies that can be used to determine the expression and function of drug transporters in the placenta as well as placental drug transfer and fetal drug exposure.We also describe how the knowledge of placental drug transfer through passive diffusion or active transport can be combined with physiologically based pharmacokinetic modeling and simulation to predict systemic fetal drug exposure.Finally,we highlight knowledge gaps in studying placental drug transport and predicting fetal drug exposure and discuss future research directions to fill these gaps.