抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Inference of macromolecular assemblies from crystalline state.

A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in
vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no
in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes. This classification scheme provides a basis for establishing in vitro-in vivo correlations and for estimating the absorption of drugs based on the fundamental dissolution and permeability properties of physiologic importance.

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A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability

Reviewing the thermodynamic parameters characterizing self-association and ligand binding of proteins at 25 OC, we find AGO, AHo, AS\", and ACpo are often all of negative sign. It is thus not possible to account for the stability of association complexes of proteins on the basis of hydrophobic interactions alone. We present a conceptual model of protein association consisting of two steps: the mutual penetration of hydration layers causing disordering of the solvent followed by further short-range interactions. The net AGO for the complete association process is primarily determined by the positive entropy change accompanying the first step and the negative enthalpy change of the second step. On the basis of the thermochemical behavior of small molecule interactions, we conclude that the strengthening of hydrogen bonds in the I n the past decade, a complete thermodynamic description of the self-association of many proteins and their interactions From the Laboratory of Molecular Biology (P.D.R.) and Laboratory of Nutrition and Endocrinology (S.S.), National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20205. Received September 23, 1980. low dielectric macromolecular interior and van der Waals' interactions introduced as a consequence of the hydrophobic effect are the most important factors contributing to the observed negative values of AHo and ASo and hence to the stability of protein association complexes. The X-ray crystallographic structures of these complexes are consonant with this analysis. The tendency for protein association reactions to become entropy dominated and/or entropy-enthalpy assisted at low temperatures and enthalpy dominated at high temperatures (a consequence of the typically negative values of AC,\") arises from the diminution of the hydrophobic effect with increasing temperature which is a general property of the solvent, water. with small molecular substrates has become available. Concomitantly, X-ray crystallography has provided a detailed picture of some of these associations, and this has stimulated a number of theoretical studies (Levitt & Warshel, 1975; Gelin & Karplus, 1975; Chothia & Janin, 1975), based upon energetic considerations, to account for these structures. The This article not subject to U S . Copyright. Published 1981 by the American Chemical Society T H E R M O D Y N A M I C S O F P R O T E I N A S S O C I A T I O N V O L . 2 0 , N O . 1 1 , 1 9 8 1 3097 Table I: Thermodynamics of Protein Association' association process A G \" ~ AiY A s o , A c p o (kcal mol-') (kcal mol-l) (cal K-I mol-') (cal K-I mol-I) refb trypsin (bovine) + inhibitor (soybean) -14.6 8.6 78 -440 c, d deoxyhemoglobin S gelation -3.4 2.0 18 -200 e, f lysozyme self-association (indefinite) -3.9 -6 .4 -8.3 g glucagon trimerization -12.1 -3 1 -64 -430 h, i hemoglobin t haptoglobin -11.5 -3 3 -7 3 -940 i a-chymotrypsin dimerization -7.1 -35 -9 5 k, I S-peptide + S-protein (ribonuclease) -13 -40 -90 -1100 m, n All thermodynamic parameters expressed per mole of complex formed except the indefinite association cases of hemoglobin S and lysozyme for which the mole refers to the monomeric protein reacted. Unitary entropy and free energy are given for processes of defined stoichiometry. Standard states are hypothetical 1 M protein, pH at which the reaction was measured. All pHs were close to 7 except for trypsin, pH 5, haptoglobin, pH 5.5, and glucagon, pH 10.5. All data for 25 \"C except glucagon, T = 30 \"C. ence is to calorimetric work and the second is to X-ray crystallographic structure determination. al. (1974). e Rosset al. (1977). Wishner e t al. (1975). g Banerjee et al. (1975). Johnson et al. (1979). * Sasaki et al. (1975). For each entry, the first referSweet et Baugh & Trowbridge (1972). Lavialle et al. (1974). Shiao & Sturtevant (1969). lVandlen &Tulinsky (1973). Hearn et al. (1971). Wyckoff e t al. (1970). methodology and problems involved in such calculations have been critically reviewed by NBmethy & Scheraga (1977). In this paper we review the thermodynamics of protein association processes for the examples best characterized in terms of their chemistry and structure. From this survey we find that the thermodynamic parameters AGO, Ai?, AS\", and ACpo are predominantly of negative sign. This result poses severe difficulties for interpretations of protein association based upon the entropically driven hydrophobic effect. The aim of this paper is to attempt to account for the signs and magnitudes of these thermodynamic parameters for protein association reactions in terms of known molecular forces and the thermochemistry of small molecule interactions.

Thermodynamics of protein association reactions: forces contributing to stability

We investigated the intracellular uptake of different sized and shaped colloidal gold nanoparticles. We showed that kinetics and saturation concentrations are highly dependent upon the physical dimensions of the nanoparticles (e.g., uptake half-life of 14, 50, and 74 nm nanoparticles is 2.10, 1.90, and 2.24 h, respectively). The findings from this study will have implications in the chemical design of nanostructures for biomedical applications (e.g., tuning intracellular delivery rates and amounts by nanoscale dimensions and engineering complex, multifunctional nanostructures for imaging and therapeutics).

Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells.

Pharmaceutical stabilization of adenoviral vectors

A dynamic approach to evaluating reversible competitive antagonists has been used in estimating the dissociation constant (apparent KB) for (+/-)-sotalol at beta adrenergic receptors which mediate a positive chronotropic response in rat atria. Cumulative dose-response curves to the beta agonists (-)-isoproterenol and (-)-soterenol were obtained after mixing each agonist with (+/-)-sotalol at fixed ratios (Q = [antagonist]/[agonist]). Experimental and theoretical dose-response curves obtained with the dynamic approach were in good agreement and the lowered maximum responses to the agonist-antagonist mixtures were dependent on Q. Also, apparent KB values for (+/-)-sotalol determined by three methods were independent of Q and agonist employed in the experiment. Apparent KB values for (+/-)-sotalol obtained by the dynamic method (6 x 10(-7)-2 x 10(-6) M) were similar to those obtained by the traditional equilibrium or static approach. As judged by the similarity of the apparent KB values derived by the two independent theoretical models, the dynamic approach may be considered an effective and alternative means to evaluate reversible competitive antagonists.

On the use of a dynamic approach to the estimation of dissociation constants for reversible competitive antagonists.

Meeting Report. Second AAPS-NIH Frontier Symposium 1999: Membrane Transporters and Drug Therapy

The purpose of this study was to predict in vivo performance of three oral products of Etoricoxib (Arcoxia® as reference and two generic formulations in development) by conducting in vivo predictive dissolution with GIS (Gastro Intestinal Simulator) and computational analysis. Those predictions were compared with the results from previous bioequivalence (BE) human studies. Product dissolution studies were performed using a computer-controlled multicompartmental dissolution device (GIS) equipped with three dissolution chambers, representing stomach, duodenum, and jejunum, with integrated transit times and secretion rates. The measured dissolved amounts were modelled in each compartment with a set of differential equations representing transit, dissolution, and precipitation processes. The observed drug concentration by in vitro dissolution studies were directly convoluted with permeability and disposition parameters from literature to generate the predicted plasma concentrations. The GIS was able to detect the dissolution differences among reference and generic formulations in the gastric chamber where the drug solubility is high (pH 2) while the USP 2 standard dissolution test at pH 2 did not show any difference. Therefore, the current study confirms the importance of multicompartmental dissolution testing for weak bases as observed for other case examples but also the impact of excipients on duodenal and jejunal in vivo behavior.

An In Vivo Predictive Dissolution Methodology (iPD Methodology) with a BCS Class IIb Drug Can Predict the In Vivo Bioequivalence Results: Etoricoxib Products.

Gordon L. Amidon

Papers

Pharmaceutical stabilization of adenoviral vectors

On the use of a dynamic approach to the estimation of dissociation constants for reversible competitive antagonists.

Meeting Report. Second AAPS-NIH Frontier Symposium 1999: Membrane Transporters and Drug Therapy

An In Vivo Predictive Dissolution Methodology (iPD Methodology) with a BCS Class IIb Drug Can Predict the In Vivo Bioequivalence Results: Etoricoxib Products.

The Effect of Enzymatic Reaction on Dissolution Rate: Theoretical Analysis and Experimental Test