Numerical validation and properties of a rapid binding approximation of a target-mediated drug disposition pharmacokinetic model

Target mediated drug disposition (TMDD) describes the phenomenon where high affinity binding of a drug to its pharmacological target (enzymes or receptors) significantly alters the pharmacokinetic profile of the drug. A rapid binding model replaces the often inestimable binding micro-constants (k _on and k _off) of TMDD models with the equilibrium dissociation constant (K _D) by assuming rapid binding of the drug to its target. The purpose of this study is to examine the validity of the rapid binding assumption and the pharmacokinetic properties of this model. Temporal profiles of free drug in plasma and a non-specific distribution site, free receptor, and the pharmacodynamically relevant, drug–receptor complex obtained from the rapid binding model compared favorably with the full TMDD model for small values of the parameter ɛ, which represents the ratio of the time required for drug–receptor binding relative to the time required for drug to be cleared from the system. The effect of escalating drug doses on the temporal characteristics and the comparison between the two models has been numerically investigated. A closer match between the full and rapid binding models is observed for high doses. Analysis for very large doses (Dose/V _c) relative to endogenous steady-state receptor concentration (R _ss), reveals that the rapid binding model reduces to a standard two compartmental model with a plasma compartment with linear drug elimination and a peripheral compartment. Decreasing clearance with increasing dose and decreasing R _ss indicates that for drugs exhibiting TMDD, the relative ratio of R _ss and dose is an important determinant of the pharmacokinetic properties rather than the individual parameters alone. An analytical solution derived for clearance shows that the primary elements of the apparent clearance of the drug are the linear clearance given by k _el V _c, the non-linear clearance due to drug–receptor complex internalization (k _int), and the ratio of AUC values of the receptor complex to that of free drug. Overall, simulations and analytical techniques applied here provide a better understanding of the validity of the rapid binding model and provide guidelines for its application. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

兔心肌缺血再灌注损伤后心功能与心率变异性的非线性动力学分析的研究

目的　探讨兔心肌缺血再灌注损伤后，心功能与心率变异（ＨＲＶ） 非线性动力学分析的关系。方法　采用结扎新西兰兔左冠状动脉前降支的方法制备缺血再灌注动物模型，用电磁血流量计测量心输出量，应用美国物理学会出版的Ｃｈｏａｓ Ｄａｔａ Ａｎａｌｙｚｅｒ（ＣＤＡ） 软件对所采集的ＨＲＶ 进行非线性动力学分析，并与心排血量比较，分析其相关性。结果　①左冠状动脉前降支结扎后ＨＲＶ 的非线性动力学各指标（ 除关联维外） 与结扎前相比均明显降低（ Ｐ＜０ ．０５）。结扎前后复杂度、熵、李氏指数及关联维分别为０ ．６６ ±０．１１ ，０ ．５０ ±０ ．０８ ，０．１６±０．０３，５．４７ ±０．４５；０ ．４１ ±０ ．１１ ，０ ．４４ ±０ ．０５ ，０ ．１２ ±０ ．０４ 及５ ．３７ ±０．５０ ；②再灌注组与缺血组，及再灌注前后比较各指标均无明显差异（ Ｐ＞０ ．０５） ；③复杂度、熵和李雅普诺夫指数与心输出量呈正相关（Ｐ＜ ０．０１）。结论　非线性动力学指标可以反映心肌缺血及心功能的改变。     

Model selection tests for nonlinear dynamic models

This paper generalizes 73 asymptotically normal tests for model selection in several important directions. First, it allows for incompletely parametrized models such as econometric models defined by moment conditions. Second, it allows for a broad class of estimation methods that includes most estimators currently used in practice. Third, it considers model selection criteria other than the models’ likelihoods such as the mean squared errors of prediction. Fourth, the proposed tests are applicable to possibly misspecified nonlinear dynamic models with weakly dependent heterogeneous data. Cases where the estimation methods optimize the model selection criteria are distinguished from cases where they do not. We also consider the estimation of the asymptotic variance of the difference between the competing models’ selection criteria, which is necessary to our tests. Finally, we discuss conditions under which our tests are valid. It is seen that the competing models must be essentially nonnested.     

Simultaneous Automatic Control of Oxygen and Carbon Dioxide Blood Gases During Cardiopulmonary Bypass

In this work an automatic control strategy is presented for the simultaneous control of oxygen and carbon dioxide blood gas partial pressures to be used during cardiopulmonary bypass surgery with heart–lung machine support. As the exchange of blood gases in the artificial extracorporeal lung is a highly nonlinear process comprising varying time delays, uncertainties, and time‐varying parameters, it is currently being controlled manually by specially trained perfusionist staff. The new control strategy includes a feedback linearization routine with augmented time‐delay compensation and two external linear gain‐scheduled controllers, for partial oxygen and carbon dioxide pressures. The controllers were robustly tuned and tested in simulations with a detailed artificial lung (oxygenator) model in cardiopulmonary bypass conditions. Furthermore, the controllers were implemented in an ex vivo experiment using fresh porcine blood as a substitute fluid and a special deoxygenation technique to simulate a patient undergoing cardiopulmonary bypass. Both controllers showed robust stability during the experiments and a good disturbance rejection to extracorporeal blood flow changes. This automatic control strategy is proposed to improve patient's safety by fast control reference tracking and good disturbance rejection under varying conditions.     

Dynamical model of salience gated working memory, action selection and reinforcement based on basal ganglia and dopamine feedback

A simple working memory model based on recurrent network activation is proposed and its application to selection and reinforcement of an action is demonstrated as a solution to the temporal credit assignment problem. Reactivation of recent salient cue states is generated and maintained as a type of salience gated recurrently active working memory, while lower salience distractors are ignored. Cue reactivation during the action selection period allows the cue to select an action while its reactivation at the reward period allows the reinforcement of the action selected by the reactivated state, which is necessarily the action which led to the reward being found. A down-gating of the external input during the reactivation and maintenance prevents interference. A double winner-take-all system which selects only one cue and only one action allows the targeting of the cue–action allocation to be modified. This targeting works both to reinforce a correct cue–action allocation and to punish the allocation when cue–action allocations change. Here we suggest a firing rate neural network implementation of this system based on the basal ganglia anatomy with input from a cortical association layer where reactivations are generated by signals from the thalamus. Striatum medium spiny neurons represent actions. Auto-catalytic feedback from a dopamine reward signal modulates three-way Hebbian long term potentiation and depression at the cortical–striatal synapses which represent the cue–action associations. The model is illustrated by the numerical simulations of a simple example — that of associating a cue signal to a correct action to obtain reward after a delay period, typical of primate cue reward tasks. Through learning, the model shows a transition from an exploratory phase where actions are generated randomly, to a stable directed phase where the animal always chooses the correct action for each experienced state. When cue–action allocations change, we show that this is noticed by the model, the incorrect cue–action allocations are punished and the correct ones discovered.     

Quantitative measurements of second harmonic Doppler using ultrasound contrast agents

Quantitative measurements of second harmonic and first harmonic Doppler were carried out using two ultrasound contrast agents, Albunex^® and FS069. The RMS amplitudes of the Doppler shift spectra were measured as a function of the concentration of the agents, frequency and transmitted acoustic pressure. The results showed that, for a given lot of contrast agent investigated, FS069 was able to produce higher levels of first and, especially, second harmonic signals compared to Albunex. Under the same experimental conditions, the RMS Doppler amplitude (RDA) of FS069 was 3.8 ± 0.8 dB higher than Albunex at first harmonic and 12.6 ± 0.8 dB higher at second harmonic. The ratio of the second harmonic to first harmonic RDA, which we called R₂/R₁, decreases at a rate of 7 dB/MHz for both agents with increasing frequency. The difference in the value of R₂/R₁ between FS069 and Albunex at any frequency was approximately 4.5 dB. R₂/R₁ was found to increase linearly as a function of the transmitted acoustic pressure for both agents. Simulations using the Rayleigh-Plesset equation show a decrease of R₂/R₁ at a rate of 5 dB/MHz. Comparison of experimental results with theory indicates that the shell elasticity parameter may be an increasing function of the mean diameter of the bubbles.     

Interindividual functional mapping: a nonlinear local approach

Within the scope of three-dimensional brain imaging, we propose an interindividual fusion scheme to register functional activations according to anatomical cortical structures, the sulci. This paper is based on the assumption that an important part of functional intersubject variability is encoded in anatomical variability. The aim of this paper is therefore to propose a generic framework to register functional activations according to the relevant anatomical landmarks. Compared to "classical" interindividual fusion schemes, this approach is local. It relies on a statistical sulci shape model accounting for the interindividual variability of a population of subjects and providing deformation modes relative to a reference shape (a mean sulcus). The deformation field obtained between a given sulcus and the reference sulcus is extended to a neighborhood of the given sulcus by using the thin-plate spline interpolation. It is then applied to functional activations located in the vicinity of this sulcus. This approach is compared with rigid and nonrigid registration methods. In this paper, we present results on MEG somatosensory data acquired on 18 subjects. We show that the nonlinear local fusion scheme significantly reduces the observed functional variability.     

权重配方模型的非线性混合效应分析:一个药物相互作用研究实例

目的:基于权重配方模型,采用非线性混合效应分析(NONMEM),对尿囊素、甲硝唑及地塞米松联合抗炎作用的组方合理性进行定量评价,结果与原算法比较。方法:实验数据为昆明种小鼠组织纤溶酶原激活物(t-PA)样品于405nm处的吸光度值,以权重配方模型为基本模型,组方间相互作用为固定效应,并考虑随机效应,通过NONMEM法建立最终模型,定量评价尿囊素、甲硝唑和地塞米松的联合抗炎作用及其交互作用。结果:基于整体效应的权重配方模型建立成功(P<0.001),X1X2(X1尿囊素,X2地塞米松)作为固定效应加入模型,最终模型中甲硝唑对整体药效作用不明显,尿囊素与地塞米松存在较强协同作用,都是主要起效组分,最优剂量配比尿囊素∶甲硝唑∶地塞米松=400∶131∶8.0(mg/kg,i.p.)。结论:采用NONMEM法,可全面考虑各组分间交互作用及个体间和个体内误差等随机效应,使权重配方模型更加严谨,与原算法比较,提供的信息量更大。     

50步混沌强度在冠状动脉支架植入术治疗前后的改变及其临床意义

目的探索一个新的非线性检测指标在冠状动脉支架植入术（PCI）评定预后中的价值。方法选取2009年11月至2010年3月哈尔滨医科大学第四附属医院住院的冠心病患者且行经皮冠状动脉介入治疗的PCI者18例,均给予常规检查,分别在行PCI术的前1夜、术后第3天、术后3个月的固定时间进行心电数据采集,剔除分析的心搏数RR间期小于90%者,最终15例符合实验要求。RR间期数据是由仰卧的受试者在稳定状态下,连续监测30 min的12导心电图所获得的,由试验者仔细检查后盲性移交给专业人员,进行数据过滤、由50步混沌强度公式分析计算后输出。运用单因素重复测量的方差分析进行统计分析。结果 （1）50步混沌强度（50SCM）在PCI术前与术后3 d之间相比无明显变化,无统计学意义（F=2.57,P〉0.05）,而PCI术后3个月的50SCM较术前有明显差异,有统计学意义（F=12.50,P〈0.001）。结论 PCI术后3 d的50SCM与术前比较无统计学意义,提示此时除冠脉狭窄所致冠脉缺血缓解外,冠脉通过内分泌因子分泌异常而反馈于自主神经导致的心脏电活动可能仍未恢复;术后3个月50SCM与术前比较明显升高,提示该指标对预测预后可能有意义。     

虚拟中国人足底韧带结构失效后的足弓负荷机制研究

目的　建立虚拟中国人的足内侧纵弓与外侧纵弓的有限元模型,研究跖腱膜松解术或足底韧带损伤后足骨与内在肌群的生物力学特性,探讨骨性结构、足底韧带、足底腱膜、足底固有肌群之间的协调作用机制。方法　采用虚拟中国人“女性1号”CT图像和MRI图像;采用非线性有限元方法进行足弓术后或韧带损伤后的平衡直立负荷状态仿真;并应用足底固有肌群的3种被动张力（微弱、适度、强烈）模拟术后或韧带损伤后的肌肉状态。结果　建立了虚拟中国人“女性1号”足内侧纵弓第2跖列与外侧纵弓第5跖列的生物力学有限元模型,计算得到内侧纵弓和外侧纵弓在平衡直立时,韧带损伤时,固有肌群活动时的张应力矢量图、压应力矢量图和von Mises应力整体分布数据。结论　跖腱膜松解术和足底韧带损伤等增加了足纵弓von Mises应力峰值,改变了张应力与压应力的流向;而足底固有肌活动的被动张力能降低足纵弓von Mises应力集中程度,调节张应力、压应力矢量接近平衡状态,减小了并发骨折和腱炎的危险性。骨性结构、韧带、腱膜、固有肌群的内在应力具有定量的相互调节功能。