This study was aimed to investigate the effects of six Schisandra lignans of Wuzhi tablet (WZ, a preparation of ethanol extract of Schisandra sphenanthera) on the pharmacokinetic process of digoxin (DG, a classical P-gp substrate) after intravenous and oral administration in rats. The effect of Schisandra lignans on the transportion of DG in Caco-2 cells was further elucidated. Our data showed that the plasma concentrations of DG were increased to different extent following co-administration of schisandrin A, schisandrin B, schisandrol B and schisantherin A, respectively. Schisandrol B showed the most potent effect among the six lignans. However, schisandrin C and schisandrol A showed little effect on pharmacokinetic of DG. Schisandrol B led to 99.0% (P < 0.05) and 109.2% (P < 0.05) increase in the AUC after orally or intravenously administered of DG, suggesting that co-administration of schisandrol B induced a more potent effect on increasing hepatic bioavailability of DG than that of intestinal. Furthermore, in vitro transport experiment showed that schisandrin A, schisandrin B, schisandrol B and schisantherin A inhibited P-gp-mediated efflux of DG, suggested that these lignans inhibited the P-gp-mediated efflux of DG. In conclusion, the exposure of DG in rats was increased when co-administered with Schisandra lignans, and schisandrol B showed the strongest effect. The dramatic increase in oral bioavailability of digoxin in the presence of schisandrol B may be due to the inhibition of hepatic/renal P-gp activity.

Flavonol glycoside is in clinical trials for treatment of hyperlipidemia. An accurate and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of flavonol glycoside (M0), aglycone (M1) and glucuronide conjugate (M2) in rat plasma. d₆-Flavonol glycoside was used as internal standard (IS). After extraction from the plasma by protein precipitation, the analytes and internal standard were separated on a XDB C₁₈ column (50 mm×4.6 mm, 1.8 μm) using a gradient elution procedure. The mobile phase consisted of methanol and water (0.2% formic acid) at a flow rate of 0.6 mL·min^-1. The total run time was 4.5 min. Positive electrospray ionization was performed using multiple reaction monitoring (MRM) with transitions of m/z 461.3 → m/z 299.1 for M0, m/z 299.1 → m/z 283.1 for M1, m/z 475.0 → m/z 299.1 for M2, and m/z 467.3 → m/z 305.1 for d₆-flavonol glycoside. The method was validated and successfully applied to the pharmacokinetics study of flavonol glycoside in SD rats which were given flavonol glycoside (30 mg·kg^-1) by gavage. The C_max of M0 is (341 ±106) ng·mL^-1 and AUC_0-t is (1 960 ±725) h·ng·mL^-1, while the C_max of M2 is (1 720 ±843) ng·mL^-1and AUC_0-t is (8 510 ±2 920) h·ng·mL^-1. The results suggest that flavonol glycoside existed mainly in the form of M0 and M2 in rats. After flavonol glycoside being hydrolyzed by the intestinal flora, it was absorbed in the form of aglycone and further metabolized to M2 after the first-pass effect. In this paper, the main metabolites of flavonol glycoside in rat plasma were determined for the first time, which provided a basis for the design of clinical pharmacokinetic experiment.

The study was aimed to identify the related substances of vortioxetine hydrobromide by hyphenated techniques. The separation of the six related substances was performed on a Phenomenex Luna Phenyl- Hexyl column (150 mm×4.6 mm, 3 μm) by linear gradient elution of acetonitrile and ammonium formate solution. Electrospray and atmospheric pressure chemical ionization were interfaced respectively with high resolution Q-TOF/MS for the determination of the accurate mass and elemental composition of the parent ions of the related substances, and triple quadrupole tandem mass was employed for the product mass spectra determination. The structures of the related substances were identified through elucidation of the fragment ions. Vortioxetine hydrobromide and its related substances were adequately separated under the established HPLC conditions. Six major related substances were detected and identified for the first time. The data provides a reference for optimization of the synthetic process and quality assurance of vortioxetine hydrobromide.

The study was designed to establish an LC-MS/MS method for the simultaneous determination of scutellarin and its major metabolite isoscutellarin in rat tissues and plasma, and to investigate the effect of different route of administration on the tissue distribution of scutellarin and its metabolite in rats. Rats were treated both intravenously and intragastrically with 20 and 80 mg·kg^-1 scutellarin, respectively. Blood and tissues were collected at predetermined intervals. The concentrations of scutellarin and isoscutellarin were determined by a validated LC-MS/MS method. The method was linear in concentration ranges of 10.0/5.00 - 5 000/2 500 ng·mL^-1 for scutellarin/isoscutellarin in the rat plasma and 30.0/15.0 - 10 000/5 000 ng·g^-1 in tissues with acceptable accuracy and precision. Data obtained after an intravenous administration of scutellarin to rats showed that the drug was distributed predominantly into the small intestine, bladder and kidney. The exposures of the metabolite isoscutellarin in plasma and tissue were both less than 5%of the parent drug. After an intragastric administration, stomach wall and small intestine were the preferred sites for scutellarin disposition, followed by bladder, adrenal gland and lung at concentrations significantly higher than its plasma concentration. The plasma exposure of isoscutellarin was higher than that of the parent drug, but its tissue exposure was significantly lower than that of scutellarin. The method established in this study was successfully applied to characterization of the tissue profiles of scutellarin and its metabolite in rats. The route of administration has a marked impact on the disposition of scutellarin and its metabolite in rats. Ratios of the tissue to plasma concentrations after intragastric administration were obviously higher than those after intravenous administration. Scutellarin could pass the blood-brain barrier in a marked extent, but isoscutellarin was not detected in the rat brain, which may be attributed to the fact that scutellarin is a higher-affinity substrate for OATP than isoscutellarin.

As an important drug carrier, liposome has the advantages of high biocompatibility and low immunogenicity. It has been widely used in the field of drug delivery, especially the targeted treatment of tumors. However, traditional liposomes are composed of flowing dynamic phospholipid membranes, which are easy to fuse together, resulting in aggregation and drug leakage. In addition, the lower degree of polyethylene glycol (PEG) modification also limits the targeted delivery performance of the vector in vivo. In view of the problems, a nanoparticle-targeted drug delivery system combining the inorganic carrier calcium phosphate with liposomes was designed, namely lipid calcium phosphate (LCP). Using doxorubicin (DOX) as a model drug, doxorubicin-loaded lipid calcium phosphate nanoparticles (DOX/LCP) were prepared by reverse microemulsion method, and the preparation conditions were investigated. The structure and morphology of calcium phosphate cores were observed by infrared spectroscopy, EDS spectroscopy, and transmission electron microscopy. The particle size, encapsulation efficiency, drug loading, stability and release behavior in vitro of DOX/LCP were investigated. Confocal microscopy and flow cytometry were used to qualitatively and quantitatively evaluate the uptake of DOX in drug-resistant tumor cell line MCF-7/DOX by LCP, respectively, and the thiazolium MTT colorimetric method was used to examine its cytotoxicity. LCP exhibited a typical core-shell structure with good size uniformity and dispersibility. The particle size was in (48.6 ±3.9) nm, the potential was in (-12.1 ±1.2) mV, and the encapsulation efficiency was above 80%. Moreover, it has a good stability in simulated plasma. In vitro release of LCP had a significant pH dependence. When the pH of the environment was 7.4, the cumulative release within 24 hours was less than 20%; as the pH of the release medium decreases, the release rate of DOX/LCP was accelerated gradually. Accumulated release over 24 hours exceeded 90% in the pH 4.5 medium. LCP significantly promoted the uptake and accumulation of DOX by drug-resistant cells, and the inhibition rate of drug-resistant tumors was significantly increased in vitro. The half maximal inhibitory concentrations (IC₅₀) of LCP/DOX and free DOX were 4.6 and 11.8 μg·mL^-1, respectively, and there was a significant difference between the two groups (P < 0.05). In summary, the LCP prepared in this study had a small particle size, high encapsulation efficiency and good stability. It had environmental responsiveness and potential inhibition of tumor drug resistance, which suggests a potential in the clinical application.

Microneedles is an efficient, safe and novel transdermal drug delivery technology that has attracted much attention in recent decades. Microneedles could break through the skin's stratum corneum barrier and have an especially significant effect on the transdermal delivery of water-soluble small molecules and biological macromolecules. In this paper, a rapid onset local anesthetic preparation of lidocaine hydrochloride was prepared based on dissolving microneedles, and related quality evaluations were carried out. The key quality indicators of prepared lidocaine hydrochloride dissolving microneedles such as drug loading amount, appearance morphology, mechanical properties, skin penetration performance, in vitro dissolution performance and local anesthetic efficacy were investigated with HPLC, SEM, texture analyzer, organic staining, histological section, in vitro dissolution test and pharmacodynamics experiments respectively. The drug loading of the dissolving microneedles array reached 68.19 ±1.55 mg, and the needle tip contained 3.57 ±0.21 mg. The microneedles has good needle shape and sufficient mechanical strength to penetrate into the skin, which is a prerequisite for the successful administration of the preparation. The in vitro dissolution time was 28.28 ±1.12 s. When applied to guinea pig back acupuncture model which was modified by guinea pig intradermal papules model, although the efficacy maintenance time was shorter than that of compound lidocaine cream, dissolving microneedles can be activated within 1 min, which was much faster than compound lidocaine cream. It is possible to increase the duration of drug efficacy by increasing the density of microneedles and preparing microneedles for sustained and controlled release in future studies. Lidocaine hydrochloride dissolving microneedles and its evaluation methods for local anesthesia were established systematically here for the first time. The rapid effect of anesthesia with lidocaine hydrochloride dissolving microneedles on the skin was worthy of further investigation.

The rheological properties of six compound gels that consists of kappa carrageenan (KC) and another excipient such as konjac gum were explored through comparison of their viscosity measured by the rotation method. The gel fluid type was dependent on the rheological curve fitted by the power-law equation. The effect of concentration on the viscosity of different compound gels was investigated by establishing the linear equation between their viscosity and concentration, the slope of which was used to determine the relation between viscosity and concentration of different compound gels. The viscous flow activation energy (E_η) was calculated by the Arrhenius equation, which was able to investigate the effect of temperature on their viscosity. The interaction between monomer and compound gels was also studied by measuring their viscosity. The results showed that six compound gels were pseudoplastic fluid. Among all compound gels, the KC-xanthan gum (KC-XG) solution exhibited the most obvious shear thinning, the strongest pseudoplasticity, while the smallest E_η, resulting in the best thermal stability of viscosity. Furthermore, the concentration of KC-sodium hyaluronate (KC-HA-Na) solution affected its viscosity significantly. The viscosity of six compound gels was greater than the summation of the two kinds of monomer gels, which suggests that there is a synergistic-viscosity interaction between KC and another excipient.

Uncaria rhynchophylla is one of the frequently used herbs in China, it is mainly used for heat-clearance, suppression of hyperactive liver, calming endogenous wind and arresting convulsion in traditional Chinese medicine (TCM). Alkaloids are the main active materials in Uncaria rhynchophylla, pharmacological studies have shown that Uncaria rhynchophylla and its alkaloids have comprehensive biological effects on the nervous system. Rhynchophylline is one of the most abundant alkaloids in Uncaria rhynchophylla. The recent studies demonstrate that rhynchophylline and its isomers (isorhynchophylline, corynoxine, corynoxine B) may be good drug candidates for treatment of Alzheimer's disease, Parkinson's disease, epilepsy, etc. Although the structures of the 4 alkaloids are very similar, they have different effects on nervous system. For example, corynoxine and corynoxine B exhibit better sedative effects than isorhynchophylline. Rhynchophylline and isorhynchophylline have been extensively studied. For development and utilization of rhynchophylline for nervous system disease, more studies are needed to unveil the structure-function relationship and the underlying mechanisms. Here, we summarizes the progresses the effects of rhynchophylline and its isomers on the nervous system.

Alzheimer's disease (AD) is a type of common neurodegenerative disease.The main clinical symptom of the disease is progressive cognitive dysfunction, which has no effective therapy yet.With the in-depth immunology study in the central nervous system, studies in different fields such as preclinical phase, genetics and bioinformatics have shown that immune dysfunction contribute to the pathogenesis of AD, including the beginning, maintenance and deterioration stage in AD.China has a wealth of natural medicine resources and clinical experiences.A large number of natural drugs and effective components both can regulate the immune function and ameliorate the symptoms in AD.This review summarizes the researches of ameliorating the symptoms in AD through immunization regulation in recent years with an aim to provide new ideas and clues in the study of new anti-AD drugs using natural medicines.

The discussion on pathophysiological of multiple sclerosis (MS) mainly focuses on T and B cells in adaptive immune response, but less involve in the myeloid cells (dendritic cells, monocytes, macrophages and microglia) in the innate immune system, which also play an important role in the pathogenesis of MS. The myeloid cell population acts as antigen-presenting cells and effector cells in neuroinflammation in the innate immune system. The interactions between T cells and myeloid cells form a vicious cycle which makes the disease continuous deterioration. At present, the studies on the therapeutic drugs for MS mainly are focused on the adaptive immune system, but pay less attention to myeloid cells. In this article, we reviewed the sub-types and functions of myeloid cells, their changes in MS patients and animal models, as well as the effects of some therapeutic drugs for MS on myeloid cells, in the purpose of finding new targets and strategies for development for MS therapy.