Volume dynamics and volume management in intensive care unit patients / 中华危重病急救医学

Volume dynamics is a two-compartment dynamical model using hemoglobin (Hb) derived plasma diluted level as input data and urine output as input variable through consecutive repeated measurements of Hb concentration in the blood during infusion. It could be applied to evaluate and guide crystalloid fluid rehydration for patients with dehydration or hypovolemia and during anesthesia or surgery. Volume dynamics could be also used to quantificate of strains, hypovolume, and the change of fluid distribution and elimination caused by anesthesia or surgery. The factors which influence the volume resuscitation are complex, including gender, age, hemodynamic state [mean arterial pressure (MAP)], health and stress state, renal function, consciousness, surgical or anesthesia state and so on, which may affect the half-life, distribution, and volume of the fluid. This article summarizes and analyzes the pathophysiological changes of crystalloids fluid in vivo, in order to provide reference for volume management in critically ill patients.

Assessment of the Benefits of Targeted Interventions for Pandemic Control in China Based on Machine Learning Method and Web Service for COVID-19 Policy Simulation / 生物医学与环境科学（英文）

Taking the Chinese city of Xiamen as an example, simulation and quantitative analysis were performed on the transmissions of the Coronavirus Disease 2019 (COVID-19) and the influence of intervention combinations to assist policymakers in the preparation of targeted response measures. A machine learning model was built to estimate the effectiveness of interventions and simulate transmission in different scenarios. The comparison was conducted between simulated and real cases in Xiamen. A web interface with adjustable parameters, including choice of intervention measures, intervention weights, vaccination, and viral variants, was designed for users to run the simulation. The total case number was set as the outcome. The cumulative number was 4,614,641 without restrictions and 78 under the strictest intervention set. Simulation with the parameters closest to the real situation of the Xiamen outbreak was performed to verify the accuracy and reliability of the model. The simulation model generated a duration of 52 days before the daily cases dropped to zero and the final cumulative case number of 200, which were 25 more days and 36 fewer cases than the real situation, respectively. Targeted interventions could benefit the prevention and control of COVID-19 outbreak while safeguarding public health and mitigating impacts on people's livelihood.

Simulation study of spinal cord stimulation evoked compound action potential / 生物医学工程学杂志

Spinal cord stimulation (SCS) for pain is usually implanted as an open loop system using unchanged parameters. To avoid the under and over stimulation caused by lead migration, evoked compound action potentials (ECAP) is used as feedback signal to change the stimulating parameters. This study established a simulation model of ECAP recording to investigate the relationship between ECAP component and dorsal column (DC) fiber recruitment. Finite element model of SCS and multi-compartment model of sensory fiber were coupled to calculate the single fiber action potential (SFAP) caused by single fiber in different spinal cord regions. The synthetized ECAP, superimposition of SFAP, could be considered as an index of DC fiber excitation degree, because the position of crests and amplitude of ECAP corresponds to different fiber diameters. When 10% or less DC fibers were excited, the crests corresponded to fibers with large diameters. When 20% or more DC fibers were excited, ECAP showed a slow conduction crest, which corresponded to fibers with small diameters. The amplitude of this slow conduction crest increased as the stimulating intensity increased while the amplitude of the fast conduction crest almost remained unchanged. Therefore, the simulated ECAP signal in this paper could be used to evaluate the degree of excitation of DC fibers. This SCS-ECAP model may provide theoretical basis for future clinical application of close loop SCS base on ECAP.

Limitations and improvements of classical models of pharmacokinetics / 西安交通大学学报(医学版)

Compartment model and statistical moment model are important theories of pharmacokinetics. However, they have obvious limitations due to the influence of drug distribution. Sometimes, the demarcation point between the distribution phase and the elimination phase of the compartment model is difficult to determine, which results in inconvenience for its application. The nature of zero order moment, AUC of statistical moment model, is blood drug concentration, but not drug amount in the body. For drugs of two-compartment or multi-compartment models, the results reflect alterations in blood drug concentration, not necessarily changes in the amount of drug in the body. In the slow and steady intravenous drip, the drug distribution in the body is basically balanced, and the alteration of blood drug concentration can reflect the alteration of drug amount in the body. Over 5 half-life, the blood drug concentration basically reaches a stable status. And the alteration of the blood drug concentration only reflects the drug elimination. For first-order kinetic drugs, the elimination rate constant (K) can be calculated by linear regression according to the elimination rule (lnC=lnC0-Kt). And then, the half-life (t1/2), the amount of drug in the body, the apparent distribution volume (Vd), and the clearance rate (CL) can be calculated successively. During slow and constant velocity intravenous dripping, drug amount is proportional to blood drug concentration in the body. And there is an exponential relationship between the blood drug concentration and time [Ct=C0+(Css-C0) (1-e-Kt)]. The first-order exponential regression is performed between Ct and t to calculate elimination threshold concentration (C0), steady blood drug concentration (Css) and K. Then, t1/2, steady drug amount (Ass), Vd and CL are calculated. The distributed equilibrium model avoids the interference of drug distribution, and is closer to reality.

Analytical solution of linear multi-compartment models with non-zero initial condition and its implementation with R

The analytical solution for multi-compartment models with a non-zero initial condition is complex because of the inter-compartmental transfer. An elegant solution and its implementation in the ‘wnl' R package can be useful in solving examples of textbooks and developing software of therapeutic drug monitoring, pharmacokinetic simulation, and parameter estimation. This solution uses Laplace transformation, convolution, matrix inversion, and the fact that the general solution of an inhomogeneous ordinary differential equation is the sum of a homogenous and a particular solution, together.

A non-linear mixed-effects model to describe the effect of acarbose intake on postprandial glycaemia in a single rat / Um modelo não linear de efeitos mistos para descrever o efeito da ingestão de acarbose na glicemia pós-prandial em um único rato

A non-linear mixed-effects model is proposed to assess the impact of acarbose over time on postprandial glycaemia in a single rat. The model is based on two compartments, one representing the entry of glucose in the blood and the other its exit. The rat was submitted to two treatments: ingestion of starch and ingestion of starch plus acarbose. The model showed great suitability, with inferences on the behavior of glucose levels in response to treatments and supplying a richer description than just the area under the curve. The marginal curves for the two treatments are similar during the first moments; however, after reaching the peak of glucose concentration, they progressively became separate due to acarbose treatment and reached the initial levels more quickly. The proposed model, albeit with a single sample unit, showed similar results to those with larger samples; in other words, acarbose significantly attenuates glycaemia after ingestion of starch.

Neste estudo, foi proposto um modelo não linear de efeitos mistos para verificar o impacto da acarbose ao longo do tempo na glicemia pós -prandial de um único rato. Adotou-se um modelo de dois compartimentos: um representando a entrada de glicose no sangue e outro, a saída. O rato foi submetido a dois tratamentos: ingestão de amido e de amido com adição de acarbose. O modelo proposto apresentou um ótimo ajuste, permitindo fazer inferências do comportamento da glicose para os tratamentos e fornecendo uma descrição muito mais rica do que simplesmente a área sob a curva. As curvas marginais para os dois tratamentos foram semelhantes nos primeiros tempos observados, porém, após o pico de concentração de glicose, elas se distanciaram progressivamente com o tratamento da acarbose atingindo os níveis iniciais mais rapidamente. O modelo adotado, com uma única unidade amostral, mostrou resultados similares a outros estudos com maior número de unidades amostrais, isto é, a acarbose pode atenuar consideravelmente a glicemia após ingestão de amido.

In vivo pharmacokinetics of tectorigenin floating sustained-release tablets in rabbits and evaluation of in vitro-in vivo correlation / 中草药

Objective: To evaluate therelease characteristicsin vitro, pharmacokinetics in rabbits and in vivo-in vitro correlation of tectorigenin floating sustained-release tablets (TFSRT). Methods: The release characteristics of TFSRTin vitro was detected with HPLC in the artificial gastric fluid. Six Japanese Giant Ear Rabbits as self crossover control, which were given TFSRT and suspension liquid (200mg). The concentration of tectorigenin in plasma was determined with HPLC and the data were processed with PKsolver 2.0 software. Results:The cumulative releaserate of TFSRTin vitro was over 70% in 10 h.The pharmacokineticsin rabbits showed that TFSRT and tectorigenin suspension liquid conformed to the single compartment model and the pharmacokinetic parameters were obtained: tmax: (2.809±0.371) and (0.442±0.138)h, Cmax: (6.317±1.337) and (9.662±2.759) μg/mL, AUC0-t: (74.156±10.420) and (57.059±13.309) μg∙h/mL. The relative bioavailability of TFSRT was (134.63±27.94)%, so there was significant difference between them. Conclusion: TFSRT can release slowly, so it increase the relative bioavailability significantly. The correlation between the absorption in vivo and release in vitro is fine (r=0.9879), so the release rate in vitro can control the quality of TFSRT.

Meropenem regimens based on the simple mathematical model of T>MIC for two-compartment model / 药学实践杂志

Objective To simplify the calculation of T>MIC and evaluate meropenem regimens based on the simple mathematical model of T>MIC reported in literature for two-compartment model.Methods Six meropenem regimens were designed according to the recommended dose with the infusion duration of 0.5 h and 3 h.Four different MIC susceptibility breakpoint of meropenem against clinical microbiologic flora were used to formulate different T>MIC.Each T>MIC was calculated by both the simple and two-compartment model of T>MIC.Meropenem regimens were evaluated for different bacterial infections based on the simple model of T>MIC with 40%~100% of the T>MIC% as the target.The t-test suggested no significant difference between the pairs of T>MIC calculated by the two models.Results and Conclusion Simple model of T>MIC can replace the two-compartment model.Meropenem regimens can be optimized based on this simple model of T>MIC conveniently and quickly.

Pharmacokinetic behavior of docetaxel lipid emulsion injection in rats / 中国药科大学学报

@#The aim of this study was to prepare and characterise docetaxel lipid emulsion injection and to conduct the characterization of its pharmacokinetics in rats after tail-vein injection. High pressure homogenization method was used to prepare docetaxel lipid emulsion. 12 Wistar rats were randomly divided into docetaxel lipid emulsion injection group and docetaxel injection group, and dosed at 6 mg/kg through tail-vein injection. Docetaxel concentration in plasma was determined by HPLC. The pharmacokinetic parameters of docetaxel in rats were obtained using the 3P97 program. Particle size, polydispersion index, Zeta potential of docetaxel lipid emulsion were found to be(221. 6±13. 4)nm, (0. 092±0. 003)and -30. 3 mV, respectively. t1/2(α) of docetaxel lipid emulsion injection and docetaxel injection were(0. 072±0. 014)and(0. 066±0. 015)h; t1/2(β) were(0. 573±0. 253)and(0. 432±0. 184)h; AUC0-12 h were(7. 98±1. 25)and(6. 26±1. 83)μg ·h/mL, respectively. Docetaxel lipid emulsion injection had similar pharmacokinetic characteristics to docetaxel injection. The pharmacokinetic data obtained for both preparations fitted a two-compartment model.

Pharmacokinetic study of gallocatechin-7-gallate from Pithecellobium clypearia Benth. in rats

The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C 0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration-time curve (AUC0-t ) values ranged from 1.75 to 11.80 (mg·h/L). J10688 lacked dose-dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688.

Study of Simulation Application of Simulink Pharmacokinetic Compartment Model / 中国药师

Objective:To dynamically describe the drug concentration change in different time in vivo to understand the in vivo be-havior patterns and rules of drugs, provide reference for performing individual treatment and avoiding adverse drug reactions and lay foundation for dynamic description of physiological pharmacokinetic model. Methods:A two-compartment model was established using Simulink dynamic simulation and used in curve fitting and parameter estimation. The results from the model were compared with those from 3P97 software. Results:There was no significant difference between the results from the dynamic model and those from 3P97 soft-ware. Conclusion:The dynamic model can be used to dynamically simulate two-compartment model for oral administration. The re-sults from the dynamic simulation are more direct, and can correct the fitting error in 3P97 software.

Study on the efficacy of quarantine during outbreaks of acute hemorrhagic conjunctivitis outbreaks at schools through the susceptive-infective-quarantine-removal model / 中华流行病学杂志

To assess the efficacy of quarantine for acute hemorrhagic conjunctivitis (AHC)outbreaks control in schools,by using the Compartment Model.Through combining the characteristics of both AHC and compartment model,we built a susceptive-infective-removal (SIR) model suited for AHC outbreaks control in schools,and then quarantine was added into the model to develop a susceptive-infective-quarantine-removal (SIQR) model.An outbreak of AHC in Changsha in 2011 was employed as a sample to assess the effect of quarantine for the prevention and control of AHC.Basic reproduction number (λ 0) of the AHC outbreak without intervention was 6.80,thus the transmission speed of the disease became quite fast.If no intervention had been adopted,almost all the students,faculties and staff members would have been infected within 23 days,and the accumulative cases would become 738,with the total attack rate (TAR) as 99.73％.The peak of the outbreak was at Sep.11th and the number of new cases was 126 on that day.The efficacy would have been different if quarantine forces had been taken at different time and differently.The bigger and earlier the quarantine force had been adopted,the lower morbidity peak and the smaller TAR would have been appeared,with better efficacy of outbreak control.If the quarantine rate had been taken at the level of 90％ on the sixth day,the accumulative case would have been reduced to 132 and the TAR had become 17.84％ consequently.Quarantine program could be used as a main intervention approach to be employed for ACH outbreak at schools.

Dynamic Contrast-Enhanced MRI for Monitoring Antiangiogenic Treatment: Determination of Accurate and Reliable Perfusion Parameters in a Longitudinal Study of a Mouse Xenograft Model

OBJECTIVE: To determine the reliable perfusion parameters in dynamic contrast-enhanced MRI (DCE-MRI) for the monitoring antiangiogenic treatment in mice. MATERIALS AND METHODS: Mice, with U-118 MG tumor, were treated with either saline (n = 3) or antiangiogenic agent (sunitinib, n = 8). Before (day 0) and after (days 2, 8, 15, 25) treatment, DCE examinations using correlations of perfusion parameters (Kep, Kel, and AH from two compartment model; time to peak, initial slope and % enhancement from time-intensity curve analysis) were evaluated. RESULTS: Tumor growth rate was found to be 129% +/- 28 in control group, -33% +/- 11 in four mice with sunitinib-treatment (tumor regression) and 47% +/- 15 in four with sunitinib-treatment (growth retardation). Kep (r = 0.80) and initial slope (r = 0.84) showed strong positive correlation to the initial tumor volume (p < 0.05). In control mice, tumor regression group and growth retardation group animals, Kep (r : 0.75, 0.78, 0.81, 0.69) and initial slope (r : 0.79, 0.65, 0.67, 0.84) showed significant correlation with tumor volume (p < 0.01). In four mice with tumor re-growth, Kep and initial slope increased 20% or greater at earlier (n = 2) than or same periods (n = 2) to when the tumor started to re-grow with 20% or greater growth rate. CONCLUSION: Kep and initial slope may a reliable parameters for monitoring the response of antiangiogenic treatment.

Pharmacokinetic comparison between Kushenin Injection Nanoparticles and common injection in rats / 中草药

Objective: To compare the in vivo pharmacokinetic properties of Kushenin Injection Nanoparticles (KU-PLGA-NS) with the ordinary Kushenin Injection (KUI) of rats. Methods: A method has been developed and validated for the quantification of kushenin in rat plasma. Using ANOVA method to choose the compartment model, The plasma concentration-time data were measured and then analyzed by DAS program on the computer. According to F values, the AIC choice compartment model pharmacokinetic parameters were calculated. Results: The main pharmacokinetic parameters of KU-PLGA-NS and KUI were as follows: AUC 0-t, were (785.57±170.92) and (342.43±54.49) mg·L-1·min, respeticevly; Cmax were (18.51±2.47) and (28.48±5.40) mg/L, respeticevly; t 1/2Ke were (91.69±1.94) and (11.51±2.47) min, respeticevly. Conclusion: Comparison of in vivo pharmacokinetic characteristics of rats between KU-PLGA-NS and KUI has a significant change with AUC and C max increase and t1/2 extension.

Whole Body Simulation and Visualization of Metabolic Process of ~(18)F 2-fluoro-2-deoxy-D-glucose / 航天医学与医学工程

Objective To simulate the metabolic distribution process of 18F 2-fluoro-2-deoxy-D-glucose(FDG) in human body and to visualize this distribution process through 3D images with high resolution and high quality. Methods The model parameters of FDG metabolism in tissues were estimated through clinical experiments, and the curves which represent the FDG metabolic process in tissues were calculated using the model parameters and blood input function. This FDG distribution process in human body was visualized basing on the high-resolution anatomical structure. Results The simulation and visualization results directly and clearly displayed the FDG metabolic distribution process after injection to human body. The properties of the FDG distribution process represented by our simulation were consistent with that represented by clinical experiment. Conclusion The method presented in this study is effective to simulate and visualize human functional information of metabolism, and it may provide a useful tool for education and research on nuclear imaging.

Positron emission tomography and microvascular research / 国际生物医学工程杂志

Positron emission tomography(PET) plays an important role in the research of substance distribution in Human body. The distribution of substance in whole body is carried out by the transport via circulation system and exchange between blood and tissue which occurs in microvascular. Both the research of PET and of microvascular are focused on the transport and exchange of substance in human body. So it should be meaningful to apply PET image to the research of microvascular, and to use the microvascular theory to improve on the analysis of PET image. In this article, some research in this domain are introduced, and foreground is reviewed.

Determination of Appropriate Sampling Frequency and Time of Multiple Blood Sampling Dual Exponential Method with 99mTc-DTPA for Calculating GFR / 핵의학분자영상

PURPOSE: To determine appropriate sampling frequency and time of multiple blood sampling dual exponential method with 99mTc-DTPA for calculating glomerular filtration rate (GFR). MATERIALS AND METHODS: Thirty four patients were included in this study. Three mCi of 99mTc-DTPA was intravenously injected and blood sampling at 9 different times, 5ml each, were done. Using the radioactivity of serum, measured by gamma counter, the GFR was calculated using dual exponential method and corrected with the body surface area. Using spontaneously chosen 2 data points of serum radioactivity, 15 collections of 2-sample GFR were calculated. And 10 collections of 3-sample GFR and 12 collections of 4-sample GFR were also calculated. Using the 9-sample GFR as a reference value, degree of agreement was analyzed with Kendall's tau correlation coefficients, mean difference and standard deviation. RESULTS: Although some of the 2-sample GFR showed high correlation coefficient, over or underestimation had evolved as the renal function change. The 10-120-240 min 3-sample GFR showed a high correlation coefficient (tau=0.93), minimal difference (Mean+/-SD=-1.784+/-3.972), and no over or underestimation as the renal function changed. The 4-sample GFR showed no better accuracy than the 3-sample GFR. CONCLUSIONS: In the wide spectrum of renal function, the 10-120-240 min 3-sample GFR could be the best choice for estimating the patients' renal function.

Current researches on pharmacokinetic/pharmacodynamic (PK/PD) modelling / 中国临床药理学与治疗学

Pharmacokinetic/pharmacodynamic (PK/ PD) modelling plays more and more important role in the study of pharmacology. This paper recommends some new research progress including PK models, PD models, four basic attributes of PK/PD model, population PK/PD model , physiological PK/PD model, and some questions aboututilization of Sheiner effect compartment model.

Pharmacokinetic Modeling of Phagocytic Activity of the Liver Using Superparamagnetic Iron Oxide Nanoparticles in Dynamic MR Imaging

The purpose of this study was to determine whether phagocytic activity is measurable by dynamic superparamagnetic iron oxide-enhanced MR imaging. For these experiments on New Zealand White rabbits, which were randomly allocated to normal and silica treated groups, we performed a dynamic MR study and radioisotope study with Tc99m-phytate. In this dynamic MR study, the ratio (Rv) of the distribution volumes of iron oxide (Vm/Ve) could be obtained by applying three- compartment model to the data obtained from the kidney and liver simultaneously. Changes in Rv caused by silica injection and by dosing superparamagnetic iron oxide, AMI-25, were evaluated. In the dynamic MR study using a Beagle dog model the input function could be calculated from data obtained from the hepatic artery and portal vein. Rv's reached maximum values at around 80 minutes after the AMI-25 injection. The Rv of the normal group was 5.06 +/- 1.53 whereas the Rv of the silica treated group was 2.13 +/- 1.20. The results were similar to tissue count data obtained by radioisope study. The Rv value was not dependent on the injected dose of AMI-25. The rate of transport constants (k1, k2, k3) could not be estimated using the 3 compartment model regardless of obtaining the input function. We conclude that Rv may be an quantitative index of decreased phagocytic activity in the liver as determined by dynamic superparamagnetic iron oxide- enhanced MRI.

Dosage regimen design of intravenous bolus injection administration of two-compartment model based on Microsoft EXCEL / 中国临床药理学与治疗学

AIM: To establish a calculation of dosage regimen design on multiple dosing intravenous bolus injection administration of two compartment model. METHODS: Microsoft EXCEL was used to write a program by the pharmacokinetic parameters to show the dosage regimen. RESULTS: The e table displayed maximum dose (D max ) and minimum dose (D min ) of the administration after inputting parameters (?, ?, K 21 and V 1) ,dosing interval (T s), maximum toxic concentration(MTX) and minimum effective concentration(MEC). After inputting maintenance dose and cycle number (n), the e table displayed plasma concentration at any time after the administration, including C (n,s) max and C (n,s) min , fractional number of reaching plateau, loading dose and accumulating time when the plasma concentration was above MEC in Ts or a cycle interval. CONCLUSION: This design method can provide safe and effective dosage regimen for clinical administration.