A comparative study of capillary zone electrophoresis and pH-potentiometry for determination of dissociation constants

Acidity constants of six cephalosporin antibiotics, cefalexin, cefaclor, cefadroxil, cefotaxim, cefoperazon and cefoxitin are determined using capillary zone electrophoresis (CZE) and pH-potentiometric titrations. Since CZE is a separation method, it is not necessary for the samples to be of high purity and known concentration because only mobilities are measured. The effect on determination of dissociation constants of different matrices (serum, 0.9% NaCl, fermentation matrix) was examined. The advantages of CZE can be utilized in those fields where potentiometry has limitations (sample quantity, solubility, purity, simultaneous determinations), although pK_a values that are close to each other can be determined by potentiometry with more accuracy.     

Determination of the dissociation constants of the cephalosporins cefepime and cefpirome using UV spectrometry and pH potentiometry

UV spectrometry and pH potentiometry were used for the determination and direct characterization of the dissociation constants of cefepime (Cef) and cefpirome. The absorbance/pH profiles at two analytical wavelengths and different conditions were assessed and found to conform to those of diprotic acids. The titration curves indicated a triprotic acid profile with two overlapping dissociation constants. The comparison of the results of both techniques permitted the direct attribution of the three dissociation constants to the carboxylic group at position 4 of the Delta-3 cephem nucleus, the aminothiazole group and the amide group at position 7 of the Delta-3 cephem nucleus. Stability studies of Cef in alkaline solutions were also performed in order to evaluate the accuracy of the measurements carried out for the determination of the third pK(a) value. The experimental pK(a) values were compared to the corresponding predicted values derived by PALLAS/PKALC and Advanced Chemical Development (ACD) software packages.     

Predictive correlations for the toxicity of alkyl- and halogen- substituted phenols

The structure-activity relationships between toxicity (log BR), monitored as cell population growth, and the log 1-octanol/water partition coefficient (log Kow) for a series of 20 alkyl- and halogen-substituted phenols have been examined. The equation log BR = 0.9455 log Kow -1.9190 has been found to be an excellent linear model for these compounds. It explains 93.8% of the variability in toxicity. Subdivision of the tested derivatives based on substituent field electronic effects reveals that those with electron-releasing effects, e.g. methyl or ethyl groups, are slightly less toxic than those with electron-withdrawing effects, e.g. halogen groups.     

一种用于制剂学材料可压性评价的新方程研究(英文)

本文提出了一种新的压缩方程用于评价制剂粉体的可压性。该方程基于假设粉体可压缩体积随着压力的变化率与可压缩体积成正比。采用该模型方程将几种辅料的压缩数据进行非线性拟合,达到了良好的拟合效果,且方程中的参数可较好的反映粉末的压缩行为。该方程被证实对粉体压缩性的评价结果与川北方程一致。     

Physiologic-pharmacologic interpretation of the constants in the Hill equation for neuromuscular block: a hypothesis

Neuromuscular block (NMB) is simulated in pharmacodynamic models using the concentration of a muscle relaxant (MR) in the effect compartment and two constants, and IC50. No physiologic or pharmacologic interpretation is offered for either constant. We desired to explore whether the constants are properties of the muscle or the MR and to simulate NMB when the MR binds to two sites at a single receptor. Based on steady state conditions, we defined receptor occupancy using the equilibrium dissociation constants. Two concepts are introduced: threshold occupancy and occupancy at half-maximal NMB, Occ_NMB50. Threshold occupancy is defined as receptor occupancy at the motor end plate of a muscle fiber when the fiber fails to contract and Occ_NMB50 as the median threshold occupancy. NMB may be simulated as a function of either the concentration of the muscle relaxant or receptor occupancy. We suggest: (1) The distribution of threshold occupancies is an intrinsic property of a muscle and is characterized by two constants (_O and Occ_NMB50); (2) _O is numerically equal to the slope of the NMB vs. concentration curves and is independent of the equilibrium dissociation constants. IC50 is codetermined by Occ_NMB50 and by the equilibrium dissociation constants. (3) Binding of a muscle relaxant to the second binding site influences only the estimate of IC50 but not .     

预测输尿管结石进展为尿脓毒血症的列线图模型的外部验证

目的 对已建立的输尿管结石进展为尿脓毒血症的预测模型进行外部验证,明确该预测模型是否适用于 临床实践。方法 收集2016年1—12月我院收治的输尿管结石患者317例,其中进展为尿脓毒血症者29例（尿脓毒 血症组）,未进展为尿脓毒血症者288例（非尿脓毒血症组）。采用我科建立的预测模型,通过患者性别、功能性孤立 肾、肾积液平均CT值、尿白细胞计数（WBC）及尿亚硝酸盐等指标对2组患者进行尿脓毒血症风险预测,比较预测结 果与实际观测结果之间的差异。分别利用受试者工作特征（ROC）曲线和GiViTI校准曲线带验证预测模型的区分度 和校准度。结果 预测模型外部验证的ROC曲线下面积（AUC）=0.874（95%CI：0.804~0.945）,能较好地将尿脓毒血 症结局患者区分出来。GiViTI校准曲线带的95%CI区域均未穿过45°对角平分线（P=0.176）,预测模型的预测概率与 实际观测概率接近,校准度良好。结论 模型预测输尿管结石进展为尿脓毒血症风险概率的准确性高,有助于提高 此类高危患者的早期识别和筛选能力。     

A novel method for improvement of predictability of the CNIBS/R-K equation

A new method for obtaining the model constants of the combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K) equation, via least square analysis has been presented. Predictability of CNIBS/R-K in a previous method and the new one of least square analysis has been compared using some experimental solubility data sets. The results have indicated that the new method improved the predictability of the CNIBS/R-K equation about 63%.     

A new nonlinear equation for the tissue/blood partition coefficients of neutral compounds

A nonlinear model equation based on tissue composition (a content of lipids, proteins, and water) for the tissue/blood partition coefficients of compounds was developed. Based on this model, our nonlinear regression analysis for neutral compounds partitioning into the kidney, brain, muscle, lung, liver, heart, and fat resulted in equations with high fitting power (training set: n = 166, r(2) = 0.851, s = 0.260, Q(2) = 0.833) and strong predictive power (test set: n = 49, r(2) = 0.851, s = 0.246, Q(2) = 0.836). This model shows that the tissue/blood partition coefficients of a compound depend strongly on tissue compositions. The magnitudes of partition coefficients of a compound in different tissues are mainly modulated by volume fractions or weight fractions of tissue compositions.     

基于流线跟踪法的气动热工程计算研究

运用结构化网格求解三维Euler方程,计算得到边界层外缘无粘流场气流参数;利用无粘流场气流参数和表面流函数的方法计算了飞行器无粘表面流线分布;在理论和半经验公式的基础上,计算了定比热比和变比热比情况下驻点热流密度,非驻点区域采用参考焓、局部相似性等方法来确定飞行器表面的气动加热,实现了数值算法与工程算法的耦合。上述方法用于求解高超声速钝双锥的表面热流分布,计算结果与经典的热流公式和实验结果进行对比,平均精度为10%左右,满足高超声速飞行器概念研究和初步设计的需要.     

A sensitive method for the quantification of fluticasone propionate in human plasma by high-performance liquid chromatography/atmospheric pressure chemical ionisation mass spectrometry

A highly sensitive and selective method has been developed for the quantification of fluticasone propionate (FP) in human plasma. The drug was isolated from human plasma using C₁₈ solid-phase extraction cartridges. The analysis was based on high-performance liquid chromatography/atmospheric pressure chemical ionisation mass spectrometry (HPLC/APCI/MS), using the 22R epimer of budesonide (BUD) acetate, synthesised using acetic anhydride, as internal standard. The mass spectrometer was operated in APCI mode with selected ions at tune masses of 473.2 and 501.2 m/z, corresponding to the MH⁺ of acetylated (22R)BUD and FP, respectively. The mobile phase used was a mixture of 50% ethanol in water with a flow rate of 0.45 ml min⁻¹. The system was optimised by tuning the capillary and tube lens with a concentrated solution of FP. The recovery of FP from human plasma was 86.3%. Linearity of response was obtained over the concentration range 0.2–4.0 ng ml⁻¹. The intra-assay and inter-assay variability were 6.3 and 2.9%, respectively. The lower limit of quantification was 0.2 ng ml⁻¹ when a solid-phase extraction preceded the HPLC/APCI/MS.     

A novel approach for predicting the dissolution profiles of pharmaceutical tablets

In this paper, the intrinsic dissolution profiles of naproxen (NAP) at pH values of 1.5 and 3.0 and of trimethoprim (TMP) at pH values of 1.5, 3.0, 5.0, 6.5 and 7.2 were measured. Meanwhile, the dissolution profiles of NAP and TMP from cylindrical tablets were measured at different temperatures (298.15 K, 305.15 K, 301.15 K and 310.15 K) and stirring speeds (50 rpm, 100 rpm and 150 rpm) as well as at different pH values (1.5, 3.0, 5.0, 6.5 and 7.2). Additionally the pH-dependent solubilities of both APIs were measured and modeled. The chemical-potential-gradient model combined with the perturbed-chain statistical associating fluid theory (PC-SAFT) was applied to predict the dissolution profiles of the cylindrical tablets of NAP and TMP under different conditions based on the analysis of their intrinsic dissolution profiles as well as on the determination of the surface-area reduction of the API tablets during dissolution. It was shown that the predicted dissolution profiles of the tablets under different conditions were in a good accordance with the experimental findings.     

A comparison between two powder compaction parameters of plasticity: The effective medium A parameter and the Heckel 1/K parameter

The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K).     

A limited sampling method for the estimation of AUC and Cmax of carbamazepine and carbamazepine epoxide following a single and multiple dose of a sustained-release product

Aims The objectives of this study are to develop a model to predict area under the curve (AUC) and maximum plasma concentration ( C _max ) of carbamazepine (CBZ) and its active metabolite carbamazepine epoxide (CBZE) following single and multiple dose of CBZ using one or two samples in volunteers.
Methods Limited sampling models (LSM) were developed for CBZ and CBZE following 200–800  mg single oral dose and 400–800  mg twice daily dose for 14 days of a sustained-release product (CBZ-SR) to estimate AUC and C _max. The LSM was developed from a training data set of 15 subjects using one blood sample taken at 48  h following a single dose. The model was validated on 60 subjects who received different doses of CBZ. Following multiple dosing, the LSM was developed from a training data set of 10 subjects using the steady state C _min (plasma concentration obtained 5  min before the last CBZ-SR dose).
Results The model provided good estimates of AUC and C _max for CBZ and CBZE. The bias and the precision of the predicted AUC and C _max for CBZ and CBZE were less than 10% and 15%, respectively. Similar results were obtained when CBZ was given as multiple dose.
Conclusions The method described here may be used to estimate AUC and C _max for CBZ and CBZE without detailed pharmacokinetic studies following single or multiple dose of CBZ.     

DSP4 and Herrnstein's equation: further evidence for a role of noradrenaline in the maintenance of operant behaviour by positive reinforcement

The effect of the selective noradrenaline neurotoxin DSP4 on steady-state operant behaviour was examined using a quantitative behavioural paradigm based on Herrnstein's (1970) equation, which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Eleven rats received injections of DSP4 (two doses of 50 mg/kg, intraperitoneally), and 12 rats received injections of the vehicle alone. The rats were trained to steady state in a series of six variable-interval schedules of sucrose reinforcement, affording scheduled reinforcement frequencies of 4–360 reinforcers per hour. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The value ofK _H (the parameter expressing the reinforcement frequency needed to maintain the half-maximal response rate) was higher in the DSP4-treated rats than in the control rats; the value ofR _max (the parameter expressing the maximum response rate) did not differ significantly between the two groups. At the end of the behavioural experiment the rats were sacrificed for determination of the concentrations of catecholamines in the brain by high-performance liquid chromatography. The levels of noradrenaline in the parietal cortex, hippocampus and cerebellum of the DSP4-treated rats were less than 20% of those of the control rats. The results provide further evidence that central noradrenergic neurones are involved in the maintenance of operant behaviour by positive reinforcement.     

Prediction of the Oral Absorption of Low-Permeability Drugs Using Small Intestine-Like 2/4/A1 Cell Monolayers

Purpose. To characterize the paracellular route of 2/4/A1 monolayers and to compare the permeabilities of incompletely absorbed oral drugs in 2/4/A1 with those in Caco-2 monolayers. Methods. The cells were cultivated on permeable supports. The 2/4/A1 expression of genes associated with tight junctions was compared with that in the small intestine using RT-PCR. The aqueous pore radii were determined using paracellular marker molecules. The permeabilities of a series of incompletely absorbed drugs (defined as having a fraction absorbed 0 to 80%) after oral administration to humans were studied. Results. Occludin and claudin 1 and 3 were expressed in 2/4/A1. The pore radius of 2/4/A1 was 9.0 ± 0.2 Å, which is similar to that in the human small intestine, although the pore radius was smaller (3.7 ± 0.1 Å) in Caco-2. The relationship between permeability and fraction absorbed of 13 drugs was stronger in 2/4/A1 than in Caco-2. The relationships were used to predict the intestinal absorption of another seven drugs. The prediction was more accurate in 2/4/A1 (RMSE = 15.6%) than in Caco-2 (RMSE = 21.1%). Further, Spearman's rank coefficient between FA and permeability was higher in 2/4/A1. Conclusion. The improved 2/4/A1 cell culture model has a more in vivo-like permeability and predicted the oral absorption of incompletely absorbed drugs better than Caco-2 cells.     

A modification of the dialytrode for simultaneous CNS recording and chemical stimulation.

Currently, chemical stimulation of the brain is done either with a single cannula that is inserted at the time the drug is delivered or with two cannulae that permit perfusion of the area of interest. The dialytrode is a push-pull cannula consisting of two concentric tubes, a porous membrane covering the tip of the tubing and a platinum wire loop that extends around the membrane and is used for EEG recordings. Studies with the dialytrode indicate that while the membrane is relatively impermeable to bacteria, molecules the size of neurotransmitters pass easily through the membrane. Therefore, the dailytrode is well suited for chronic chemical stimulation studies.     

乳鼠心肌成纤维细胞培养方法的改进

目的建立乳鼠心肌成纤维细胞培养模型.方法通过对经典的差速贴壁分离法稍作改进,采用每次贴壁60min、两次差速贴壁分离法收集、培养心肌成纤维细胞.结果形态学观察和免疫细胞化学染色鉴定显示,成功培养心肌成纤维细胞,纯度达95%以上.结论该研究成功建立乳鼠心肌成纤维细胞培养模型,为高纯度心肌成纤维细胞的获得和对其病理生理学的进一步研究打下良好基础.     

A kinetic model for predicting the release rate of sparingly-water-soluble drugs from a hydrogel-coated polymeric matrix

Medical devices used for on-target drug delivery are often coated with a hydrogel coating for friction-reduction purpose. Thus, the delivery of a sparingly-water-soluble drug by such a device must diffuse through a nonerodable hydrogel layer. An empirical rate equation has been derived for such a kinetic model and predicts that the rate of drug release from such a device is directly proportional to the loading of the drug in the polymeric matrix. The validity of this kinetic model was examined by measuring the rate of release of 2,4,4'-trichloro-2'-hydroxydiphenyl ether from different hydrogel-coated (ethylene-vinyl acetate) copolymer stents containing a wide range of the drug. The experimentally determined release rates are in reasonably good agreement with those calculated from the empirical rate equation. Bioefficacy test results based on zone-of-inhibition test against Escherichia coli are also in good agreement with the release rate and drug-loading data predicted according to the empirical rate equation.