湿痛喜康的药动学模型

对家兔静注或口服湿痛喜康,从获得的血药浓度—时间曲线上,发现无论静注还是口服都多出一个吸收峰,产生的原因是由于该药在体内有肠肝循环。为了描述这个过程,选择了含有受控房室的一个特殊的三房室模型,并运用该模型在IBM—PC微型计算机上对该药的C—t数据进行曲线拟合,获得较理想的结果。     

Variability of the Model-Independent AUC: The One Sample Per Individual Case

A theory is developed for estimation of a population value of AUC along with its standard deviation, in the case, when only one concentration–time (C–t) sample is available for each individual. This theory is based on model-independent pharmacokinetics. Integration methods are classified due to their applicability to the presented approach. The main goal of this work is to establish a statistical hypothesis-testing procedure which would make single C–t samples usable for bioequivalence studies. An application of the theory to a number of integration methods currently in use is analyzed in detail. A real data illustration is included.     

Serine 447 in the carboxyl tail of human VPAC1 receptor is crucial for agonist-induced desensitization but not internalization of the receptor

The VPAC1 receptor for vasoactive intestinal peptide (VIP) belongs to the class II family of G protein-coupled receptors and is coupled to Gs protein/adenylyl cyclase. We assessed whether 10 different Ser/Thr residues in human VPAC1 receptor intracellular domains play a role in the process of VIP-induced desensitization/internalization by performing a site-directed mutagenesis study. The Ser/Thr residues mutated to Ala include potential G protein-coupled receptor kinase, protein kinase A and protein kinase C targets that are of particular interest for VPAC1 receptor desensitization. The data show that when Chinese hamster ovary cells expressing wild-type receptors were pretreated for 5 min with VIP (50 nM), receptor desensitization occurred with a 10-fold right shift of the ED50 for adenylyl cyclase activation. When the construct with the widest span of mutations was studied, there was no longer any short-term desensitization. By using constructs with fewer and fewer mutations, we identified Ser447 in the C-terminal tail to be crucial for rapid desensitization. We also showed that Ser447 plays an essential role for VIP-induced VPAC1 phosphorylation in Chinese hamster ovary cells. Furthermore, we demonstrated that none of the mutated Ser/Thr residues was involved in down-regulation after a 12-h treatment of cells with 50 nM VIP. Neither were they involved in VIP and VIP-induced receptor internalization as shown using a novel fluorescein-tagged VIP and VPAC1 receptor bearing a Flag epitope in the N-terminal domain and a green fluorescent protein at the C terminus. We conclude that Ser447, a likely G protein-coupled receptor kinase target, is crucial for VIP-induced phosphorylation and rapid desensitization of VPAC1 receptor.     

A simple model for complex dissolution kinetics: a case study of norfloxacin

A new semi-empirical model, particularly useful for studying complex dissolution kinetics, is presented here. It uses only two 'fit parameters', each possessing physically relevant units (in the time domain). The model is based on the idea that dispersion (variation) in the activation energy barrier may arise in certain cases, as a result of (quantized) molecular kinetic energies affecting the speed of the rate-determining step (r.d.s.) of the dissolution event. For such 'dispersive dissolutions', the r.d.s. is assumed to involve 2D denucleation. The author's dispersive kinetic model is shown to be applicable to the dissolution of various formulations of norfloxacin which produce very asymmetric, sigmoidal concentration versus time (C-t) profiles. It is derived by assuming an activation energy distribution having the functional form of the Maxwell-Boltzmann (M-B) distribution, coupled with a first-order rate expression. However, this model can also be reduced to give the same functional form as the classical Noyes-Whitney equation, in order to accurately fit/describe dissolution profiles which appear logarithmic (such profiles are due to dissolution phenomena that are not dispersive; i.e. for cases where the activation energy is essentially single-valued). Thus, the kinetic model presented in this work may potentially find broad applicability to the modeling of various dissolution trends observed in the literature.     

Simplified methods for the evaluation of the parameters of the time course of plasma concentration in the one-compartment body model with first-order invasion and first-order drug elimination including methods for ascertaining when such rate constants are equal

The many limitations in determining the pharmacokinetic parameters of firstorder invasion of, and elimination from, the onecompartment body model by the method of residuals or by feathering Ct data can be minimized by applying the simplified methods outlined herein. Comparisons of the apparent volumes of distribution, V, calculated on the premises that the Bateman Function represents k_a>k_e or its converse, k_e>k_a,i.e., flip-flop, can permit a proper choice of the correct version. Estimation of k_e can be obtained by regression of (A₀/V)/C(oncentration) on AUC₁/ Cwhere A₀/Vis estimable from knowledge of C_max and t_max since .The ratio of the magnitude of the rate constant of invasion to that of elimination, m=k_a/k_e,is related to k_et_max by the expression k_et_max=ln m/ (m–1)for all possible values of m.A table for the determination of m from values of k_et_max is given. When bioavailability, =A₀/Dose,is known or complete, k_e and Vcan be determined from the respective ordinate and abscissa of the intersection of and Cl(clearance)/k_e,both plotted against arbitrary k_e values. The two functions may not intersect at low values of mdue to errored C-t values but the k_e value when the two curves are closest (k_min)may approximate k_e.The intersections of and k_eAUCT (AUC_trap)plotted against variable k_e values (Method A) provide estimates of k_e from their abscissa values and A/Vfrom their ordinate values when is unknown. Method B appears to give more reliable estimates of k_e at the k_min of the difference plotted against k_e.Since k_min of this plot is 1/t_max when m=1,the identity of the mas unity underlying the C-t data is indicated when either k_mint_max is approximately unity or k_min ispractically synonymous with 1/t_max.This was clearly shown when 12 constructed m=1,C-t cases with 10% random error were evaluated by Method B. Better estimates were effected by all procedures when the raw C-t data were smoothed.We regretfully announce that Dr. Edward Garrett passed away on October 25, 1993, after an extended illness.     

Assessment of beta-blocking activity of trimepranol in man.

The beta-blocking potency and the duration of action of trimepranol were measured in healthy volunteers using isoprenaline antagonism and reduction in exercise tachycardia. Based on isoprenaline antagonism, trimepranol was four times as potent as propranolol on a weight basis. The degree of beta blockade increased linearly with dose from 5 mg to 20 mg, excluding a dose-dependent first-pass metabolism in this dose range. There was a significnat correlation between plasma concentration and the effect of 14C-trimepranol on isoprenaline and exercise tests. The elimination half-life of trimepranol, calculated both on the basis of its effects and plasma concentrations, was approximately three to four hours. The beta blockade due to 10 or 20 mg of trimepranol was extended at least up to 12 hours following p.o. administration, based both on isoprenaline and exercise tests and on the effect of resting heart rate. Twice-a-day administration thus seems sufficient to provide a continuous beta blockade in the clinical use of trimepranol.     

Use of the proportionality equations for analyses of dose-response curves.

A proportionality-oriented theory was applied to analyze dose-response curves commonly generated in pharmacology. The principle of the proportionality theory is to express changes of two associated variables in reference to their asymptotes. Thus, a linear relationship between the two associated variables can be obtained if proper dimensions and scales are used. Based on this proportionality approach, we have developed equations which are used to analyze dose-response curves (1). generated by simulation data based on the Michaelis-Menten equation and the Hill equation and (2). obtained from the contractile effect of acetylcholine (ACh) in isolated guinea pig ileum and the contractile effect of neurokinin NK(1) agonists (NK(1)) in guinea pig trachea muscle strips. Graphic methods are provided for plotting the graphs and for simultaneous determination of asymptote, slope parameter, and position constant. The slope parameter and position constant relate the concentration of an agonist to its response. Apparent equilibrium dissociation constant (K(A)), which is the product of position constant and asymptote in this approach, can be determined directly from the analysis of agonist dose-response curves. It is demonstrated that the proportionality theory and equations are useful for analyzing dose-response curves and for interpreting drug-receptor interactions.     

一室模型药物吸收计算的概率论法

目的:从概率论角度为吸收动力学研究提供两种具体方法。方法:在一室模型时,药物分子从给药部位进入体循环和从体内消除的过程为相互独立的随机过程。将一次血管外给药后的总滞留时间(Th)视为在给药部位的滞留时间(Tf)与在体内的滞留时间(Tg)之和,Tf与Tg相互独立,且Th、Tf及Tg均为非负连续型随机变量。根据卷积公式及一室模型特征,得到一室模型药物吸收计算的概率论方法:概率法(A法)与数值反卷积分法(B法)。结果:概率论方法所需条件与Wagner-Nelson(W-N)法一致。A法所求吸收分数的准确度与W-N法相同。在已知消除速率常数K的准确值时,B法所求吸收分数的准确度低于W-N法,但B法尚可推测出同一药物注射剂型在血管内快速给药后的概率密度函数及相关信息。在K估计值有误差(±10%)时,B法所求吸收分数的准确度略高于W-N法。结论:概率论方法可用于计算吸收分数及有关概率。     

生物工程概论的教学方法改进

根据在生物工程概论的课程教学过程中所面临的问题，提出了授课与自学结合的教学方式，运用多种教学形式以及考查与考试相结合的综合评价方式，改变传统的教学模式与评估方法，提高了教学效果。     

HPLC测定大鼠血浆中缬沙坦浓度及其药代动力学研究

目的：建立高效液相色谱法（HPLc）测定大鼠血浆中缬沙坦浓度的方法,并考察其药代动力学特征,为临床合理用药提供参考。方法：12只SD雄性大鼠随机分成2组,于8：00及20：00分别灌胃给予缬沙坦（16mg／kg）,于给药前及给药后0．33、0．67、1、2、4、8、12及24h眼内眦静脉取血,HPLC紫外法测定大鼠血浆缬沙坦浓度。结果：缬沙坦在大鼠体内浓度（C）-时间（t）曲线呈一室模型,给药后2h达血药峰值,8：00用药t1/2（6．45±1．74）h。20：00用药的C-显著下降（P〈O．05）,平均驻留时间（MRT）及t1/2延长（P〈0．05或P〈0．01）。结论：本方法测定血浆中缬沙坦浓度准确、简便,适用于缬沙坦药代动力学研究。大鼠8：00用药,血药浓度较高,而t1/2较短;20：00用药,血药浓度偏低,ttn延长。缬沙坦昼夜不同时间用药对其药代动力学有一定影响。     

Therapist techniques used during the cognitive therapy of opiate-dependent patients.

A review of current substance abuse literature indicates that although clinicians espouse cognitive and behavioral methods in the treatment of drug-dependent patients, little is known about the process of cognitive-behavioral therapy with these individuals. Our objective is to examine the specific techniques used by manual-guided cognitive-behavioral therapists during the treatment of opiate-dependent patients. Ratings of audiotaped sessions using the Collaborative Study Psychotherapy Rating Scale indicate that the cognitive-behavioral therapists did not rely on behavioral methods early in treatment as predicted by both theory and the clinical literature. Cognitive techniques and techniques oriented toward establishing a collaborative structure predominated and increased from early- to late-in-treatment sessions. We discuss the implications of the results in terms of treatment manual revisions and directions for future research.     

Test Homogeneity of Risk Difference Across Subgroups in Clinical Trials

A weighted least squares statistic is commonly used to test homogeneity of the risk difference for a series of 2 × 2 tables. Since the method is based on asymptotic theory, its type I error rate is inflated when the data are sparse. Two new methods for testing the homogeneity of risk difference across different groups in clinical trials are proposed in this paper. These methods are constructed, based on the Wilson's score test and traditional weighted least squares statistics. The performance of the new methods is evaluated and compared to the currently available approaches. Results show that one of our new methods has a type I error rate that is closest to the nominal level among all the methods and is much more powerful than those proposed by Lipsitz et al.     

The control of microbial diseases in animals: alternatives to the use of antibiotics

In animal husbandry the control and prevention of infectious diseases is of basic economic importance. The introduction of antibiotics to treat bacterial infections almost 50 years ago led to a dramatic improvement in animal production. The emergence of antibiotic resistant strains demonstrates that the treatment of bacterial infections can not rely on the use of antibiotics without some critical consideration. Special attention has been paid to the use of antibiotics in animals including antimicrobial growth promoters because these can contribute to the problems with antibiotic resistance in humans. This has strongly emphasized the need to introduce disease preventive methods. A theory and methods for the prevention of diseases is presented that is based upon the effect on the target animal population of microbial exposure, defence and immunity to infections and combinations of these. It is emphasized that antibiotics should be an integral part of other disease preventive methods and used only when other methods have failed. They should not be included in the first line of action.     

药物口腔黏膜吸收机理的研究进展

口腔黏膜给药途径已成为目前药学研究领域的热点之一。笔者检索国内外文献,简要介绍口腔黏膜的屏障结构和药物吸收途径,进而对口腔黏膜的吸收机理进行系统整理和分析。最终归纳出扩散理论、pH分配学说、黏膜结构变化理论、酶抑制理论、生物黏附理论、解聚理论和新型载药体系等七大理论,同时指出目前存在的问题和研究方向。主要包括:进一步完善药物口腔黏膜吸收机理的理论,使其系统化;研究和开发新型安全低毒有效的吸收促进剂以及新型载药体系;根据不同的吸收机理,改进促透剂、黏附剂、酶抑制剂等辅料筛选方法,建立合理的处方设计和评价方法。     

Experimental design, analysis of variance and slide quality assessment in gene expression arrays

A microarray experiment is a sequence of complicated molecular biology procedures relying on various laboratory tools, instrumentation and experimenter's skills. This paper discusses statistical models for distinguishing small changes in gene expression from the noise in the system. It describes methods for assigning statistical confidence to gene expression values derived from a single array slide. Some of the theory is discussed in the context of practical applications via software usage.     

Metabolic modeling: a tool of drug discovery in the post-genomic era

The Human Genome Project, DNA microarrays, proteome chips and metabolic profiles, among others, are generating unprecedented amounts of valuable information about the genetic and metabolic responses of organisms to stimuli. This wealth of information poses a great scientific challenge, namely the development of novel, effective methods for functional analysis and interpretation. It is proposed here that biomathematical systems models must accompany data generation and management. A particularly effective framework for this purpose is canonical modeling based on Biochemical Systems Theory. The key concept of this theory is the formulation of biological phenomena as systems of differential equations, in which all processes are represented as products of power-law functions.     

Representations of family: a review of the alcohol and drug literature

Family has a central role in youth socialisation, including substance use. Family is both the genesis of alcohol problems (through parental consumption or supportive attitude) and a solution, via family therapy. In contrast, family is not the primary unit of direct socialisation to drug use. Rather, attributes of family (such as structure, sentiment, and activity) lead to youth delinquency, which results in drug use. These representations of family are based on taken-for-granted notions supporting a Parsonian-style structural-functionalism, highly influenced by Freudian psychoanalytic ideas. This theory of family, permeating and uniting otherwise separate literatures on alcohol and drugs, reduces complex concepts to simple, easily measured static attributes rather than developmental or social processes; uses a limited repertoire of predominantly quantitative methods; imposes unwarranted normative assumptions; and has investigated a truncated selection of topics. A call is made for expansion of the epistemological, theoretical and methodological bases, to include contemporary social theory, such as post-modern, practice theory or Foucauldian ideas, and a range of qualitative approaches when studying family and substance use. Pluralistic, flexible, contingent, contradictory, partial and fluid depictions better represent family life in a context of rapid societal transformations, often with unpredictable outcomes, occurring via globalization, information transfer/communication and commodification.     

传统CBS教学方法结合PDG在内分泌科见习教学中的应用

目的探讨传统的病例为引导（CBS）联合使用问题-讨论-指导（PDG）教学方法在内分泌科见习教学中的可行性及有效性。方法观察在本院内分泌科进行临床见习的本院2004级临床医学系学生共113人,按随机数字表随机分为两组,一组为对照组,采用传统CBS教学法;另一组为实验组,实施CBS＋PDG教学法。两组学生在2周见习结束时进行操作、理论出科考试进行对比,同时采用自行设计的调查问卷进行主观效果评价。结果从理论及操作出科考试成绩来看,CBS＋PDG教学法明显优于传统的CBS教学法（P〈0．01）;实验组各项主观评分均超过对照组,提示学生们对CBS＋PDG教学法的主观评价明显优于传统的CBS教学法（P〈0．01）。结论CBS＋PDG教学方法对提高见习学生临床能力具有可行性及有效性。     

Benefit-risk analysis: a proposal using quantitative methods

This is the first part of a two-article series which will introduce the theory and practice of a proposed set of quantitative methods for benefit-risk analysis. Adjustments to number-needed-to-treat (NNT) analysis and a new method, minimum clinical efficacy (MCE) analysis are presented and critically discussed. The goal of these methods is to condense into a summary metric the benefit-risk profile of a product so that manufacturers, regulators, clinicians and patients can better understand and participate in risk management. A second article will present examples of these methods.     

Some considerations on the estimation of steady state apparent volume of distribution and the relationships between volume terms

Application of statistical moment theory to four methods which do not involve detailed compartmental analysis for the determination of V_ss shows them to be equal. Assuming drug to be eliminated exclusively from the central compartment results in the minimum value of V_ss being determined. A method for determining the maximum possible value of V_ss is shown which uses AUC, dose (iv), and the exponents which describe the plasma- concentration time curve. The relationships between the volume terms V_extrap, V_area and V_ss are discussed in terms of moment theory.