左旋肉碱修饰的壳聚糖-硬脂酸协载槲皮素口服紫杉醇纳米胶束的制备、表征及在体肠循环研究

目的 制备左旋肉碱修饰的壳聚糖-硬脂酸（LC-SA/CS-SA）纳米胶束，包载紫杉醇（PTX）且协载槲皮素，考察胶束特性，并以大鼠在体肠循环评估给药系统对PTX口服吸收的促进作用。方法 将硬脂酸（SA）通过酰胺化反应接枝于壳聚糖（CS），形成共聚物CS-SA；采用核磁共振H谱、红外光谱鉴定产物结构；以PTX为主药，槲皮素为辅药，采用激光粒径分析、Zeta电位分析和HPLC分析分别考察了胶束的粒径、Zeta电位、载药量、包封率；透射电子显微镜观察胶束形貌；芘荧光探针法测定LC-SA/CS-SA胶束的临界胶束浓度（critical micelle concentration，CMC）；透析袋法考察胶束的体外释放行为；大鼠在体肠吸收实验评估载药胶束的促吸收作用。结果 红外与核磁结果表明SA通过酰胺键接枝于CS；协载槲皮素的LC-SA/CS-SA载PTX胶束呈类球形，粒径为（148.3±1.7）nm，多分散系数（PDI）为0.16±0.07，Zeta电位为（24.600±0.167）mV，CMC为14.31 μg/mL；体外释放结果表明，与市售紫杉醇注射剂相比，协载槲皮素的LC-SA/CS-SA载PTX胶束、LC-SA/CS-SA载PTX胶束具有明显缓释效应；大鼠在体肠吸收实验表明，协载槲皮素的LC-SA/CS-SA胶束对载药PTX的胃肠吸收具有显著促进作用。结论 构建的协载槲皮素的LC-SA/CS-SA载PTX胶束性能优良，促进了PTX的大鼠肠吸收，具有增强药物口服吸收潜力。     

Oral levothyroxine therapy postbariatric surgery: Biopharmaceutical aspects and clinical effects

Background

Bariatric surgery can lead to changes in the oral absorption of many drugs. Levothyroxine is a narrow therapeutic drug for hypothyroidism, a common condition among patients with obesity.

Compressive Properties and Energy Absorption Characteristics of Extruded Mg-Al-Ca-Mn Alloy at Various High Strain Rates

This paper is focused on the mechanical properties and the energy absorption characteristics of the extruded Mg-Al-Ca-Mn alloy in different compression directions under high strain rate compression. Compressive characterization of the alloy was conducted from the high strain rate (HSR) test by using a Split Hopkinson Pressure Bar (SHPB). Results show that the investigated alloy exhibits a strong strain rate sensitivity. With the rise of strain rate, the compressive strength is increased significantly, and the deformation ability also improves. When compressed along the extrusion direction, as the strain rate increases, the total absorbed energy E, the crush force efficiency (CFE), and the specific energy absorption SEA of Mg-Al-Ca-Mn alloy are all greatly improved as compared with those obtained along other compression directions.     

Temperature Measurement by Sublimation Rate as a Process Analytical Technology Tool in Lyophilization

Product temperature (T_b) and drying time constitute critical material attributes and process parameters in the lyophilization process and especially during the primary drying stage. In the study, we performed a temperature measurement by the sublimation rate (TMbySR) to monitor the T_b value and determine the end point of primary drying. First, the water vapor transfer resistance coefficient through the main pipe from the chamber to the condenser (C_r) was estimated via the water sublimation test. The use of C_r value made it possible to obtain the time course of T_b from the measurement of pressure at the drying chamber and at the condenser. Second, a Flomoxef sodium bulk solution was lyophilized by using the TMbySR system. The outcome was satisfactory when compared with that obtained via conventional sensors. The same was applicable for the determination of the end point of primary drying. A laboratory-scale application of the TMbySR system was evidenced via the experiment using 220-, 440-, and 660-vial scales of lyophilization. The outcome was not dependent on the loading amount. Thus, the results confirmed that the TMbySR system is a promising tool in laboratory scale.     

Constructing an In Silico Three-Class Predictor of Human Intestinal Absorption With Caco-2 Permeability and Dried-DMSO Solubility

Absorption of drugs is the first step after dosing, and it largely affects drug bioavailability. Hence, estimating the fraction of absorption (Fa) in humans is important in the early stages of drug discovery. To achieve correct exclusion of low Fa compounds and retention of potential compounds, we developed a freely available model to classify compounds into 3 levels of Fa capacity using only the chemical structure. To improve Fa prediction, we added predicted binary classification results of membrane permeability measured using Caco-2 cell line (Papp) and dried–dimethyl sulfoxide solubility (accuracy, 0.836; kappa, 0.560). The constructed models can be accessed via a web application.     

环境水样中痕量铜的浊点萃取-火焰原子吸收光谱测定法

目的建立环境水样中痕量铜的浊点萃取(cloud point extraction,CPE)-火焰原子吸收光谱(flame atomic absorption spectrometry,FAAS)测定法。方法样品在p H 9.5的条件下,加入0.4 ml的1 mmol/L 2-(5-溴-2-吡啶偶氮)-5-二乙氨基酚(5-Br-PADAP)溶液,0.1%氯化钙溶液0.1 ml,5%(W/V)Triton X-114溶液0.8 ml,40℃加热15 min后离心,采用火焰原子吸收光谱法进行检测。结果在2~240μg/L的线性范围内,所得回归方程为A=0.002 7c+0.024 6,r=0.995 8。以3倍信噪比计算,方法的检出限为0.62μg/L,富集倍数为36.58倍,平均加标回收率为96.28%~98.08%,RSD为1.67%~3.13%。结论该方法简单、灵敏,具有良好的重现性,适用于环境水样中痕量铜的测定。     

Nonadiabatic coupling of the dynamical structure to the superconductivity in YSr2Cu2.75Mo0.25O7.54 and Sr2CuO3.3

A crucial issue in cuprates is the extent and mechanism of the coupling of the lattice to the electrons and the superconductivity. Here we report Cu K edge extended X-ray absorption fine structure measurements elucidating the internal quantum tunneling polaron (iqtp) component of the dynamical structure in two heavily overdoped superconducting cuprate compounds, tetragonal YSr₂Cu_2.75Mo_0.25O_7.54 with superconducting critical temperature, T_c = 84 K and hole density p = 0.3 to 0.5 per planar Cu, and the tetragonal phase of Sr₂CuO_3.3 with T_c = 95 K and p = 0.6. In YSr₂Cu_2.75Mo_0.25O_7.54 changes in the Cu-apical O two-site distribution reflect a sequential renormalization of the double-well potential of this site beginning at T_c, with the energy difference between the two minima increasing by ∼6 meV between T_c and 52 K. Sr₂CuO_3.3 undergoes a radically larger transformation at T_c, >1-Å displacements of the apical O atoms. The principal feature of the dynamical structure underlying these transformations is the strongly anharmonic oscillation of the apical O atoms in a double-well potential that results in the observation of two distinct O sites whose Cu–O distances indicate different bonding modes and valence-charge distributions. The coupling of the superconductivity to the iqtp that originates in this nonadiabatic coupling between the electrons and lattice demonstrates an important role for the dynamical structure whereby pairing occurs even in a system where displacements of the atoms that are part of the transition are sufficiently large to alter the Fermi surface. The synchronization and dynamic coherence of the iqtps resulting from the strong interactions within a crystal would be expected to influence this process.

More than 30 y after the discovery of unconventional superconductivity in cuprates (1) and subsequently in analogous materials its underlying mechanism and in particular the role of the lattice are still under debate. Proposed microscopic theories range from purely electronic Mott–Hubbard and t-J approaches at one extreme to Bose–Einstein condensates of bipolarons at the other (2–4). Experimentally, however, anomalous isotope effects (5), resonant ultrasound (6), angle-resolved photoemission spectroscopy (7–9), femtosecond optical pump terahertz (10)/megaelectron-volt transmission electron microscopy probe (11), infrared pump (12), and so on have demonstrated that specific phonons not only couple to the superconductivity but correlate directly with the gap energy and may even transiently induce it well above the superconducting critical temperature, T_c. Cuprates also exhibit a plethora of superstructures indicative of strong electron–lattice coupling, stripes that have been proposed to stabilize the superconductivity (13), and charge-density waves (14, 15) and the pseudogap (PG) (16) that compete with it. Another possibility is mechanisms that boost T_c from a low value expected within a conventional Bardeen-Cooper-Schrieffer (BCS) scheme. That this question remains unanswered suggests considering more unconventional approaches (4). One candidate is the dynamical structures of cuprates, S(Q, E) or experimentally S(Q, t = 0), specifically their internal quantum tunneling polarons (iqtp). An iqtp is a set of atoms oscillating between two structures that possess different geometries, energy levels, and charge distributions (17–19). A chemist would describe these endpoints as separate species, adapting this term that applies more intuitively to solutions to the atoms in crystalline solids. Neutron scattering and X-ray absorption fine structure (XAFS) measurements identified O-centered iqtps and their correlation with the superconductivity 30 y ago (17–25). We now present Cu K edge extended XAFS (EXAFS) results from “overdoped” YSr₂Cu_2.75Mo_0.25O_7.54 (YSCO-Mo) that is isostructural with YBa₂Cu₃O₇ (Fig. 1A and SI Appendix, Fig. S1), T_c = 84 K (26) and hole doping p (excess charge on the planar Cu2 site) = 0.3 to 0.5 (27) and Sr₂CuO_3.3 (SCO) that is structurally analogous to La₂CuO₄ (Fig. 1B and SI Appendix, Fig. S1), T_c = 95 K (28, 29), and p = 0.6, both synthesized via high-pressure oxygenation (HPO) (30, 31). In YSCO-Mo the Cu2-apical O (Oap) double-well potential is degenerate in the normal state but renormalizes below T_c with the energy difference between its two minima increasing with decreasing temperature by ∼6 meV. SCO is already unique among cuprates in not having intact CuO₂ planes (32, 33). Its Cu EXAFS demonstrate that it is unique among superconductors in that its Oap shift by >1 Å at its superconducting transition, challenging our conception of superconductivity as an electronic transition that is incompatible with structural transformations.Open in a separate windowFig. 1.Structures and modulus and real components of the Fourier transforms of the EXAFS spectra, χ(R), of YSCO-Mo and SCO across temperature ranges bracketing their superconducting transitions. (A) Structure representation of YSCO-Mo. The CuO₂ planes are turqoise (Cu2) and magenta (Opl), Cu-O chains are blue (Cu1) and gold (Och), Oap is red, and Sr is green. In the actual structure one-fourth of Cu1 are substituted by Mo. The orientation is shown underneath. (B) The same as A for SCO, except a significant number of Oap and half of the O sites in the a direction in the CuO₂ planes are vacant. The CuO₂ planes are blue (Cu) and gold (O). For the χ(R) spectra the blue traces denote the lowest temperatures, then green to yellow, purple, and red-orange to brown at the highest ones. (C) YSCO-Mo spectra for E of the X-ray probe beam in the aa plane, with the modulus peaks labeled with their principal sources. The first temperature above T_c is red. (D) YSCO-Mo spectra for E||c, with the Cu1- and Cu2-Oap contributions overlapping at R = 1.6 Å. The peaks at higher R are a combination of direct, two-leg path contributions from more distant neighbor atom shells and ordered multiple scattering paths. (E) SCO spectra for E||H used for the orientation that is assigned to the a direction of the orthorhombic O sublattice. T_c is red and double width. (F–I) SCO over the designated temperature ranges for E⊥H spectra that will be the contributions in the bc plane defined by the orthorhombic O sublattice. (F) The extent of the change in the spectra, and by inference in their originating structures, across the superconducting transition. The features appearing at R = 2 to 2.5 Å below T_c result from the ∼2 Å shift of the O depicted in Fig. 3 B–D. In G the first temperature above T_c is orange and double width.We have recently shown that HPO cuprates are described by their own phase diagram (34). The principal feature of the well-known one for non-HPO cuprates is the superconducting “dome” that begins at p ∼0.06, peaks at p ∼ 0.16, and ends at p ∼ 0.27. Subsequent augmentations with the microstrain in the planes (35) and hole density on the O atoms (36) explain some of the material specificity but do not modify this overall pattern. For HPO compounds the superconductivity may begin at p < 0.06 and continues to increase beyond p = 0.27 with possible flattening but no reduction in T_c. Although we have found that the excess O in YSCO-Mo is mostly taken up by domains enriched in octahedral Mo(VI) substituting in the Cu(1) chains, much of the extra charge resides in the CuO₂ planes (27) and some of the carriers constitute a normal Fermi liquid that coexists with the superconductivity (26). The inherent inhomogeneity (37) in YSCO-Mo and SCO was probed by EXAFS, which is arguably the most incisive experimental method for characterizing short-range order and is especially sensitive to its changes. Diffraction patterns originate in the long-range average structure of a material and provide precise information on the symmetry and symmetry-constrained locations of the atoms that dominate the Bragg peaks. In contrast, EXAFS—and pair distribution function (pdf) analysis—are sensitive to local order separate from the crystallographic symmetry. The element selectivity of EXAFS provides further advantages by separating the atom pairs comprising the distribution function. Especially important for this study, EXAFS measures the instantaneous structure factor, S(Q, t = 0), that incorporates the dynamic structure components, S(Q, E), observed with inelastic scattering. EXAFS therefore accesses time and energy scales corresponding to collective dynamical phenomena (25, 38, 39). Dynamical structures such as the iqtp are demonstrated when S(Q, E/t = 0) gives locations for atoms that differ from those (19, 38) obtained from diffraction and elastic scattering measurements (20–22, 40). This complementarity was the basis for the original identification of the Cu-Oap two-site distribution (41) and its assignment to the double-well potential of the iqtp (17, 19, 42).     

生物黏附辅料对葛根总黄酮类化合物在Caco-2细胞模型中转运的影响

目的:葛根总黄酮（PTF）可治疗心脑血管疾病，但膜通透性差，口服生物利用度低。一些辅料如卡波姆、壳聚糖和羟丙基甲基纤维素可以提高口服生物利用度。传统的体外评价技术，包括大鼠肠灌流和细胞模型，不能评价PTF整体的吸收机制。方法:本研究评价辅料的黏附性及对PTF在Caco-2细胞单层模型中转运的影响。采用cDNA微阵列测定PTF和PTF+辅料给药后的Caco-2细胞的基因表达变化，从基因水平揭示辅料对PTF整体吸收的影响机制。结果:体外黏附和Caco-2细胞转运实验表明，与单独PTF相比，加入辅料后对胃黏膜具有更高的黏附性，且在Caco-2细胞模型中的转运效率更高。PTF与辅料的相互作用显著改变了某些基因的表达，可能影响PTF的吸收效率。结论:不同的生物黏附聚合物能提高PTF的肠道吸收，可能与ATP结合盒(ABC)和溶质载体转运体(SLC)的表达基因有关。     

冰片对黄芪甲苷和三七总皂苷配伍有效成分在脑缺血/再灌注模型大鼠脑组织分布的影响

目的探讨冰片是否具有促进黄芪甲苷(AST IV)和三七总皂苷(PNS)配伍时主要有效成分透过大脑中动脉栓塞(MCAO)再灌注模型大鼠血脑屏障的作用。方法大鼠随机分为假手术组、模型组、冰片组、AST IV组、PNS组、AST IV+PNS组、冰片+AST IV+PNS组,制备MCAO再灌注大鼠模型,以液相色谱-质谱联用法(LC-MS/MS)测定大鼠患侧与健侧大脑皮层、小脑中AST IV和PNS有效成分(人参皂苷Rg1、Rb1和三七皂苷R1)的含量。结果 AST IV无论是单用还是与PNS、冰片配伍,其口服后主要分布在大脑皮层,尤其是患侧大脑皮层。冰片+AST IV+PNS能使患侧与健侧大脑皮层中AST IV含量显著增加。PNS单用,其有效成分人参皂苷Rg1、Rb1和三七皂苷R1主要分布在患侧小脑。冰片+AST IV+PNS能使患侧大脑皮层中人参皂苷Rb1含量显著增加,使健侧和患侧大脑皮层中人参皂苷Rg1含量增加,使大脑皮层尤其是患侧大脑皮层及小脑中三七皂苷R1含量增加。结论大鼠脑缺血再灌注后,AST IV与PNS的有效成分人参皂苷Rb1、Rg1及三七皂苷R1在大脑皮层和小脑均有一定的分布。AST IV单用时,AST IV主要分布在大脑皮层;PNS单用时,人参皂苷Rb1、Rg1及三七皂苷R1主要分布在小脑。冰片与AST IV、PNS合用后,能促进AST IV及人参皂苷Rb1、Rg1及三七皂苷R1向大脑皮层富集,尤其是向缺血再灌注侧大脑皮层富集;而且能不同程度地促进AST IV,人参皂苷Rb1、Rg1及三七皂苷R1在大脑皮层的吸收,尤其是在患侧大脑皮层的吸收。