Plasma stability plays an important role in the druggability of lead compound. Improving the plasma stability of compounds by structural modification can lead to good pharmacokinetic and pharmacodynamics properties. This review provides a summary of varieties of structure modification strategies for improving plasma stability including bioisosterism, increasing steric hindrance, ring closure, scaffold hopping and etc.

Geographic information system for global medicinal plants (GMPGIS) and MaxEnt modeling are adopted to analyze the ecological suitability of the endangered plant Acanthopanax senticosus. Response curves were created by the raster data of 6 ecological factors, including mean annual temperature, mean temperature of warmest quarter, mean temperature of coldest quarter, mean annual precipitation, mean annual humidity, and mean annual radiation. The relationship between the syringin content of this plant and these ecological factors was analyzed using a redundancy analysis method (RDA), which could be used to predict the most relevant ecological factors influencing the active constituents of Acanthopanax senticosus plants. GMPGIS and MaxEnt results suggest that China, Russia, Japan, and North Korea, are the main producing areas in the world for Acanthopanax senticosus, while there are also other potential areas with maximum similarities of ecological distribution in the United States, Canada, Ukraine, Romania, Hungary, Germany and 22 other countries. In addition, the genuine producing areas in China mainly include Heilongjiang, Jilin and Liaoning, while there are the maximum similarities of ecological distribution of Acanthopanax senticosus in Hebei, Shanxi, Shaanxi and Sichuan. RDA results suggest that the mean annual humidity, precipitation, temperature are the most important eco-factors positively affecting the content of syringin in Acanthopanax senticosus. Our research provides scientific support to the utilization of ecological suitability areas for endangered plant Acanthopanax senticosus and the resource regeneration.

Microspheres (MS) are an excellent transarterial chemoembolization carrier for cancer treatment. Then the Bletilla striata polysaccharide (BSP) that was isolated from the rattan of Bletilla striata was used as skeleton material, and the matrine (ME) loaded Bletilla striata polysaccharide microspheres (ME-BSPMS) were prepared by emulsify-chemical crosslinking method. ME-BSPMS was characterized for appearance shape, particle size, drug loading, swelling ratio, suspension property, drug entrapment condition and in vitro release characteristics. The results showed that the ME-BSPMS appeared as round spherical and smooth shape by SEM, with an average size of (85 ±7) μm. ME-BSPMS with a good suspension in physiological saline and the swelling ratio could reach upwards of (53 ±4.2)% in 20 minutes, also with a large amount of drug loading of (30.12 ±3.25)%. The results of DSC scanning indicate that good compatibility exists between the ME and BSP, and the ME could be embedded fully in the matrix of the ME-BSPMS. The accumulation drug release from ME-BSPMS was (25.38 ±1.57)% at 12 h, this suggests that the ME-BSPMS has a good sustained release effect. These results indicate that the ME-BSPMS may be a promising transarterial chemoembolization carrier for cancer treatment.

A simple and sensitive method was developed for quantitation of obeticholic acid in rat plasma with liquid chromatography-tandem mass spectrometry (LC-MS/MS). After liquid-liquid extraction by methyl tert-butyl ether, the chromatographic separation was carried out on an ACE Excel 2 Super C18 column (50 mm×2.1 mm ID, 1.7 μm) with a gradient mobile phase consisting of acetonitrile and 2 mmol·L^-1 ammonium formate at a flow rate of 0.2 mL·min^-1. The quantitation analysis was performed using multiple reaction monitoring (MRM) at the specific ion transitions of m/z418.9[M-H]^-→401.2 for obeticholic acid and m/z469.0[M-H]^-→ 425.2 for glycyrrhetinic acid (internal standard) in the negative ion mode with electrospray ionization (ESI) source. This validated LC-MS/MS method yielded a good linearity over the range of 5 -5 000 ng·mL^-1 with the lower limit of quantitation (LLOQ) of 5 ng·mL^-1. The intra and inter-assay precisions (RSD) were all less than 9.82% and the accuracy (RE) was within ±6.90%. The extraction recovery of obeticholic acid was from 85.4% to 88.5%, and the matrix effect of obeticholic acid ranged from 78.9% to 82.5%. Stability test suggest that obeticholic acid in rat plasma was stable for 24 h on workbench, up to 1 month at -70℃, and after three cycles of freeze-thaw. Extracted samples were stable for more than 24 h in an auto-sampler at 6℃. The precision was less than 7.25%, and the accuracy was within ±11.2%, after being diluted 10 times by blank rat plasma. The method has been successfully applied to a pharmacokinetic study of obeticholic acid in rats following oral administration at the dose of 2.5 mg·kg^-1.

Tacrolimus is commonly used in the treatment for the refractory primary nephrotic syndrome (PNS) in the pediatric patients. Data were retrospectively obtained from 100 children with 357 tacrolimus trough concentrations in our center between May 2010 and March 2016. Information of age, sex, body weight, drug dose, co-therapy medications, laboratory tests and sampling time were collected. The population pharmacokinetic model was developed using nonlinear mixed effect modeling (NONMEM) software. A one-compartment model with first-order absorption and elimination best described the data. The population estimate of apparent clearance (CL/F) and apparent volume of distribution (V/F) was 6.54 L·h^-1 and 86.2 L, respectively. Body weight (WT, kg), daily dose of tacrolimus (DD, mg·day^-1) and co-therapy azole antifungal agent have a significant impact on the CL/F. The final PPK model of CL/F was:CL/F=6.54×${\left( {\frac{{{\rm{WT}}}}{{25}}} \right)^k}$×${\left( {\frac{{{\rm{DD}}}}{{1.5}}} \right)^{0.293}}$×0.657^Azole, K=$\frac{{{\rm{W}}{{\rm{T}}^{ - 30.9}}}}{{{\rm{W}}{{\rm{T}}^{ - 30.9}} + {{10.4}^{ - 30.9}}}} $. When combined with azole antifungal agents, Azole was 1, whereas vice versa was 0. This is the first PPK study of tacrolimus conducted in pediatric patients with PNS, which may facilitate individualized drug therapy of tacrolimus.

Twenty target compounds were synthesized by the reduction reaction of HUANG Minglong and Friedel-Crafts acylation reaction in this study. The inhibitory effects of the new compounds were tested on NO production in LPS-induced mouse macrophage RAW264.7 cells, a cellular inflammation model. The structure-activity relationships were discussed. The structures of target compounds were confirmed by ESI-MS, ¹H NMR and ¹³C NMR. In vitro activity experiments showed that 18 compounds had certain anti-inflammatory effects at the concentration of 40 μmol·L^-1, of which 9a, 8b, 7c and 9c showed strong anti-inflammatory activities, and IC₅₀ of 7c and 9c were comparable to the positive control drug ibuprofen.

Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid) is the primary anthraquinone in the roots of rhubarb. A recent study showed that rhein can inhibit tumor cell proliferation and induce apoptosis in human tumor cells. However, the clinical application of rhein has been hampered by its poor bioavailability, low aqueous solubility and gastrointestinal disorders. In current study, twenty-four target compounds were designed and synthesized by coupling various hydrophilic alkanolamines to the 2-carboxyl of rhein, and their structures were established by IR, HR-MS, ¹H NMR spectra. Solubility test showed that all compounds were 10.04 to 15.08 mg·mL^-1 in water, which was 220 to 330-fold better than that of rhein (0.045 6 mg·mL^-1). All of rhein derivatives displayed more potent anti-tumor activity than rhein, and most of them were comparable to adriamycin, particularly, compound 4t exhibited IC₅₀ value of 2.08 μmol·L^-1, more effective than adriamycin (IC₅₀=2.35 μmol·L^-1). Hydroxyapatite adsorption experiment suggests that compound 4t has a better bone affinity than that of tetracycline.

Based on the natural affinity between macrophages and atherosclerotic lesions, we made a novel macrophage membrane-coated polylactic acid-glycolic acid copolymer (PLGA) nanoparticle (MPLNPs), and examined its ability targeting atherosclerotic lesions. PLGA nanoparticle (PLGANPs) were prepared by precipitation and MPLNPs were prepared by membrane extrusion. Their morphology, particle size and retainment of functional proteins were characterized. Their targeting capabilities were investigated with cell uptake assay in vitro and fluorescence imaging in vivo. The results showed that MPLNPs were spherical, with obvious core/shell structure, the average particle size was (167 ±6.12) nm, and integrin α4β1 was retained on the surface. Vascular cell adhesion molecule 1 (VCAM-1) receptor was highly expressed in the LPS (lipopolysaccharides)-HUVEC (human umbilical vein endothelial cells) and atherosclerotic lesions in ApoE^-/- mouse model, and the nanoparticles could effectively recognize the VCAM-1 receptor and had good targeting properties in vitro and in vivo. The results suggest that the cell membrane biomimetic nano-carrier may provide a new approach for the targeting strategy in the treatment of atherosclerosis and related diseases.

The study is aimed to evaluate the anti-HIV-1 effect of chloroquine in combination with antihuman immunodeficiency virus (HIV) drugs, and inhibition of plasmacytoid dendritic cells (pDC) activation and type Ⅰ interferon (IFN-I) production by Toll-like receptor 7 (TLR7) agonist stimulation. We investigated the anti-HIV-1_ⅢB, HIV-1_KM018 activity of chloroquine and chloroquine combined with rategrivir (RAL), enfuvirtide (T-20), indinavir (IDV) and efavirenz (EFV) in vitro by luciferase activity assay system and ELISA method for p24 antigen. We measured the effect of chloroquine on the activation of pDC in combination with RAL and IDV, respectively. Quantitative PCR was used to evaluate the activity of chloroquine in combination with RAL and IDV in the upregulation of interferon (IFN)-α and IFN-β. Chloroquine showed less cytotoxicity to C8166, TZM-bl and PBMC cells, and the 50% cytotoxic concentration values were 85.02 ±0.28, 73.67 ±5.10 and 91.84 ±4.10 μmol·L^-1, respectively. The anti-HIV-1_ⅢB activity of chloroquine combination with RAL, T-20, IDV and EFV were moderate in synergy, strong in synergy, additive and moderate antagonism, respectively. The anti-HIV-1_KM018 activity of chloroquine in combination with RAL, IDV were moderate synergy, minor synergy. There was no significant difference between the chloroquine monotherapy and chloroquine combined with RAL, IDV in the down-regulation of pDC activation and IFN-α, IFN-β expression levels. We have found that chloroquine combined with different anti-HIV drugs represent different degrees of synergism, antagonism or additive anti-HIV-1 effect. Chloroquine in combination with RAL and IDV did not have influence on the inhibitory effect of chloroquine on pDC activation and type Ⅰ interferon secretion induced by TLR7 agonist. The results suggest that chloroquine may be used to enhance the therapeutic activities of anti-HIV medicines.

In this study, we developed a rapid and sensitive ultra high-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) method to detect a sulfide bond doxorubicin conjugation prodrug (DOX-S-DOX) in human breast cancer tumor cells (MCF-7). The samples were prepared by acetonitrile precipitation using daunorubicin as internal standard (IS). A reversed phase C18 analytical column (Agilent Eclipse plus C18 RRHD 1.8 μm, 2.1 mm×50 mm) was utilized to separate the samples under gradient elution conditions. Mobile phase was a mixture of 0.1% formic acid in water and methanol at a flow rate of 0.4 mL ·min^-1. The analysis was conducted on the mass spectrometer using an electrospray interface (ESI) in the positive ionization model. The calibration range was 20.0-400 ng·mL^-1 with the correlation coefficients (r²) ≥ 0.99. The inter-and intra-assay precision (relative standard deviation, RSD%) of quality control samples was within 3.77%-8.35% and relative error (RE%) for accuracy was between -2.04% and 2.62%. Recovery (97.67%-104.2%) and matrix effect (104.8%-113.9%) were consistent, precise, and reproducible at different quality control levels in accordance with FDA guidance. The assay was successfully used in the cellular pharmacokinetics study of DOX-S-DOX, which may provide a clue to explore analytical methods of other prodrug forms of DOX.