Statistical Modeling of a Pharmacokinetic System

Abstract

The aim of the article is to investigate the drug concentration behavior in a three-compartment open pharmacokinetic model which describes the disposition of an antibiotic drug used in Lyme disease, coumermycin A ₁.

We study a system of random differential equations representing this model. The three rate constants that are used in the system of differential equations are simulated using the trivariate truncated normal probability distribution. The initial values of the rate constants that are used in the simulation are calculated from the pharmacokinetic profile of coumermycin A ₁ determined in four human subjects based on the serum level data obtained from the report of a clinical study. The extensive numerical solutions for the system of random differential equations under different combinations of the covariance structure and the initial conditions are developed.

Numerical comparisons of the deterministic characterizations of the drug concentration as a function of time of the individual compartments to study the effect of various combinations of the covariance structure and the initial conditions on these characterizations are presented. A similar comparison between the deterministic and the stochastic characterizations is also presented.     

Analytical characterization of chitosan nanoparticles for peptide drug delivery applications

Chitosan-cyclodextrin hybrid nanoparticles (NPs) were obtained by the ionic gelation process in the presence of glutathione (GSH), chosen as a model drug. NPs were characterized by means of transmission electron microscopy and zeta-potential measurements. Furthermore, a detailed X-ray photoelectron spectroscopy study was carried out in both conventional and depth-profile modes. The combination of controlled ion-erosion experiments and a scrupulous curve-fitting approach allowed for the first time the quantitative study of the GSH in-depth distribution in the NPs. NPs were proven to efficiently encapsulate GSH in their inner cores, thus showing promising perspectives as drug carriers.     

Facile conversion of Biginelli 3,4-dihydropyrimidin-2(1H)-thiones to 2-(2-hydroxy-2-arylvinyl) dihydropyrimidines via Eschenmoser coupling

A one-pot, two-step synthesis protocol for the conversion of Biginelli 3,4-dihydropyrimidin-2(1H)-thiones to 2-(2-hydroxy-2-arylvinyl) dihydropyrimidine (DHPM) derivatives via Eschenmoser sulfide contraction coupling is described. Solution phase as well as solid-supported protocol was carried out for the decoration of the Biginelli DHMP scaffold at the C-2 position. The scope of the optimized protocol is demonstrated for different DHMP precursors.     

Determination of gamma-hydroxybutyric acid in serum and urine by headspace solid-phase dynamic extraction combined with gas chromatography–positive chemical ionization mass spectrometry

Gamma-hydroxybutyric acid is an emerging drug of abuse. Beside relaxation and euphoria it causes hypnosis and unconsciousness. Therefore the substance is misused as recreational drug and at drug-facilitated sexual assaults. An automated and effortless method for quantitation of gamma-hydroxybutyric acid in serum and urine was optimized and validated. Five hundred microliters sample volume are used for both matrices. The acid catalyzed conversion of gamma-hydroxybutyric acid to the corresponding gamma-butyrolactone is applied. Furthermore the method is based on headspace solid-phase dynamic extraction coupled with gas chromatography–mass spectrometry. The extraction process is performed by repeated aspiration and ejection of the headspace through a steel cannula which is coated on the inside with a polydimethylsiloxane sorbent. Thus absorption of analyte molecules by the sorbent is achieved. The influence of parameters as sorbent type, incubation temperature, number of extraction strokes, injection port temperature and injection flow speed on extraction recovery was investigated. The validation revealed good accuracy with a bias less than ±5%. Intra- and interday precision determined at 10, 50 and 150 μg/ml for each matrix were in following ranges: 1.96–3.49% (intraday, serum), 2.38–4.31% (intraday, urine), 2.33–5.13% (interday, serum) and 2.53–5.64% (interday, urine). The method provided good linearity between 2 and 200 μg/ml yielding coefficients of determination R² ≥ 0.9985. Limit of detection were determined at 0.16 μg/ml for serum and 0.17 μg/ml for urine, respectively. This method exhibits a fast, solvent-free and widely automated extraction process. It has been applied to toxicological routine analysis and therapeutic drug monitoring successfully.     

先辐射后冻融法制备聚乙烯醇/水溶性壳聚糖/甘油水凝胶的云南白药药物释放性能研究

采用先辐射后冻融的方法制备了一系列聚乙烯醇(PVA)/水溶性壳聚糖/甘油水凝胶,通过浸泡法在水凝胶中载入云南白药,并且研究了溶液pH值、离子强度、冻融次数和PVA浓度对水凝胶溶胀性能和云南白药释放性能的影响.研究发现水凝胶的溶胀度随溶液离子强度的增大而下降,且酸性溶液大于中性溶液.水溶性壳聚糖的加入有利于云南白药载入凝胶,同时使云南白药的释放具有pH和离子强度敏感性.云南白药的释放量在模拟体液中最大,在中性溶液中次之,在水和酸性溶液中最小,与溶胀度变化关系相反.而水凝胶的溶胀度和云南白药释放量均随冻融次数和PVA浓度的增大而下降.分析表明,云南白药在不同介质中的释放量主要取决于药物和溶液中离子的交换能力;在相同介质中,不同凝胶的药物释放量受溶胀度影响明显.凝胶溶胀速率远大于药物释放速率说明后者主要由扩散过程控制.药物释放的pH敏感性表明该水凝胶具备用作云南白药的口服载体的潜力.     

Mathematical models for drug delivery to chronic patients

Mathematically, analysis of drug delivery kinetics involves two moving boundary problems: diffusion front and eroding front. In this paper, we have models for drug delivery for the sites which can be enclosed by spherical shaped matrices covered by membranes and these problems are helpful for designing the drug delivery devices to deliver the drug inside from outside and a corresponding device supplying drug from inside. Once the time required for treatment and rate of drug delivery is known from medical diagnosis, this analysis can design a device releasing the drug/active agent over a long period of time. The purpose of such drug delivery is to achieve more effective therapies while eliminating the effect of over dosing and maintaining drug levels within the desired levels. The device may work on optimal use of drug and increase the patient’s convenience. The proposed models provide design for eroding tumor or chemotherapy to cancerous regions. The results have been obtained for steady state release rate, zero order release time and life time of the device and discussed. It has been observed that zero order time and life time increase by introducing a membrane of uniform thickness.     

Determination of clefts in receptor structures

Summary The automatic determination of atoms which comprise a cleft in a receptor is of great importance in computer-aided drug design. X-ray studies of ligand/receptor pairs show that the ligand is often located in a cleft so that this structural feature will indicate a putative binding site. This information can be used in the design of new drugs by database searching and by automatic structure generation. The methods presented in this paper will find the complete accessible surface in a slice through a receptor and also all the clefts and dimples in this surface, using the properties of the Voronoi tessellation of the receptor. Clefts and binding sites can now be determined quickly and without observer bias.Prospective users of the program described herein are invited to contact the author.     

SYNTHESIS AND DRUG RELEASE OF CROSSLINKING POLYPHOSPHATES

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Novel temperature-sensitive, β-cyclodextrin-incorporated poly(N-isopropylacrylamide) hydrogels for slow release of drug

Novel temperature-sensitive poly(N-isopropylacrylamide) hydrogels containing water-soluble -cyclodextrin polymer were prepared by forming semi-interpenetrating polymeric networks. Compared to the conventional poly(N-isopropylacrylamide) gel, the -cyclodextrin-incorporated hydrogels showed the same lower critical solution temperature due to the independence of the -cyclodextrin polymer in the networks. The release time of ibuprofen from the novel gel was significantly prolonged, which was presumably attributed to the formation of the inclusion complexes between the cyclodextrin groups and the drug molecules.Jian-Tao Zhang and Shi-Wen Huang have contributed equally to this work.