Lipoprotein-biomimetic nanostructure enables tumor-targeted penetration delivery for enhanced photo-gene therapy towards glioma.

Glioma is one of the most malignant primary tumors affecting the brain. The efficacy of therapeutics for glioma is seriously compromised by the restriction of blood-brain barrier (BBB), interstitial tumor pressure of resistance to chemotherapy/radiation, and the inevitable damage to normal brain tissues. Inspired by the natural structure and properties of high-density lipoprotein (HDL), a tumor-penetrating lipoprotein was prepared by the fusion tLyP-1 to apolipoprotein A-I-mimicking peptides (D4F), together with indocyanine green (ICG) incorporation and lipophilic small interfering RNA targeted HIF-1α (siHIF) surface anchor for site-specific photo-gene therapy. tLyP-1 peptide is fused to HDL-surface to facilitate BBB permeability, tumor-homing capacity and -site accumulation of photosensitizer and siRNA. Upon NIR light irradiation, ICG not only served as real-time targeted imaging agent, but also provided toxic reactive oxygen species and local hyperthermia for glioma phototherapy. The HIF-1α siRNA in this nanoplatform downregulated the hypoxia-induced HIF-1α level in tumor microenvironment and enhanced the photodynamic therapy against glioma. These studies demonstrated that the nanoparticles could not only efficiently across BBB and carry the payloads to orthotopic glioma, but also modulate tumor microenvironment, thereby inhibiting tumor growth with biosafety. Overall, this study develops a new multifunctional drug delivery system for glioma theranostic, providing deeper insights into orthotopic brain tumor imaging and treatment.

Improved efficacy of Panax notoginseng saponin loaded into BSP/alginate microspheres for the treatment of alcoholic gastric ulcers.

Previously, we have reported the evaluations of alginate and Bletilla striata polysaccharide (BSP) in formulation of microsphere, which is a muco-adhesive carrier and can achieve a long duration of gastric retention. The combination of Panax notoginseng (Burk.) and B. striata is a traditional Chinese herbal formula that is used to treat gastric ulcers. BSP, an effective ingredient of B. striata, possesses both medicinal and excipient functions. Panax notoginseng saponin (PNS), which can easily dissolve in water, is the main effective ingredient in P. notoginseng (Burk.) for the treatment of gastric ulcers. However, microspheres containing PNS could directly cause drug leakage, ultimately reducing the encapsulation rate. In this study, PNS was fabricated into a hydrophobic dispersion with slow-release characteristics. Subsequently, PNS was packaged into BSP/alginate microspheres to improve the encapsulation rate. The prepared PNS-loaded microspheres were round, the release characteristics aligned with the Weibull equation, and the active ingredients were released by diffusion and erosion. The developed microspheres improved the effects of PNS and synergistically exerted the pharmaceutical effects of BSP on acute gastric ulcers.

Challenges and strategies in progress of drug delivery system for traditional Chinese medicine Salviae Miltiorrhizae Radix et Rhizoma (Danshen).

Traditional Chinese medicines (TCMs), with a history of thousands of years, are widely used clinically with effective treatment. However, the drug delivery systems (DDSs) for TCMs remains major challenges due to the characteristics of multi-components including alkaloids, flavones, anthraquinones, glycosides, proteins, volatile oils and other types. Therefore, the novel preparations and technology of modern pharmaceutics is introduced to improve TCM therapeutic effects due to instability and low bioavailability of active ingredients. Salviae Miltiorrhizae Radix et Rhizoma, the radix and rhizomes of Salvia miltiorrhiza Bunge (Danshen in Chinese), is a well known Chinese herbal medicine for protecting the cardiovascular system, with active ingredients mainly including lipophilic tanshinones and hydrophilic salvianolic acids. In this review, this drug is taken as an example to present challenges and strategies in progress of DDSs for TCMs. This review would also summary the characteristics of active ingredients in it including physicochemical properties and pharmacological effects. The purpose of this review is to provide inspirations and ideas for the DDSs designed from TCMs by summarizing the advances on DDSs for both single- and multi-component from Danshen.

Laser-triggered polymeric lipoproteins for precision tumor penetrating theranostics.

Natural particles ranging from various cell membranes to nascent proteins are highly optimized for their specific functions in vivo and possess features that are desired in drug delivery carriers. However, the current endeavor in research on bioparticles is still seeking the appropriate strategy to shield multiple agents and circumvent biological hurdles. These issues have propelled the advancement of lipid-polymer hybrid nanocarriers, which could be employed as drug reservoirs and strive to meet these expectations. We thereby proposed functionalized biopeptide-lipid hybrid particles, which were applied to encapsulating a PLGA polymeric core together with indocyanine green (ICG) and packaged by a lipoprotein-inspired structural shell. To initiate precision tumor-penetrating performance, tLyP-1-fused apolipoprotein A-I-mimicking peptides (D4F) were exploited to impart tumor-homing and tumor-penetrating biological functions. The sub-100 nm drug vehicle possessed a long circulation time with uniform mono-dispersity but was stable enough to navigate freely, penetrate deeply into tumors and deliver its cargoes to the targeted sites. Moreover, ICG-encapsulated penetrable polymeric lipoprotein particles (PPL/ICG) could realize real-time fluorescence/photoacoustic imaging for monitoring in vivo dynamic distribution. Upon near-infrared (NIR) laser irradiation, PPL/ICG demonstrated a highly efficient phototherapeutic effect to eradicate orthotopic xenografted tumors, resulting in an 88.77% decrease from the initial tumor volume and inhibited tumor metastasis with good biosafety. Therefore, the described bio-strategy opens new avenues for creating polymeric lipoproteins with varied hybrid functionalities, which may be applied to provide a basis and inspiration for improved nanoparticle-based precision theranostic nanoplatforms.

Treatment of metastatic lung cancer via inhalation administration of curcumin composite particles based on mesoporous silica.

Curcumin attracted attention due to its promising anti-cancer properties and safety performance. However, its poor aqueous solubility and low bioavailability have to be overcome before it goes into clinic use. Here, porous composite particles are prepared by loading curcumin into mesoporous material SBA-15, and its therapeutic effect on lung cancer via inhalation administration have also been evaluated. The inclusion of curcumin in host material SBA-15 was confirmed by the reduced surface area and pore diameter of the composite material, and the aerodynamic performance of the composite material was investigated by FT-4 and NGI. Phagocytosis experiments on RAW264.7, the toxicity of material extracts on BEAS-2B cells, and the haemolysis experiments showed that the mesoporous materials had good biocompatibility at 10-400 µg/mL. The B16F10 melanoma metastatic lung mouse model was used to investigate the therapeutic effect of lung cancer after inhalable administration. It was found that the body weight of the curcumin composite particle-administered group decreased more slowly and the lung disease developed slower than the curcumin crude drug group, indicating that the composite particles has a certain inhibitory effect on tumours.

A simplified and miniaturized glucometer-based assay for the detection of ß-glucosidase activity.

ß-Glucosidase activity assays constitute an important indicator for the early diagnosis of neonatal necrotizing enterocolitis and qualitative changes in medicinal plants. The drawbacks of the existing methods are high consumption of both time and reagents, complexity in operation, and requirement of expensive instruments and highly trained personnel. The present study provides a simplified, highly selective, and miniaturized glucometer-based strategy for the detection of ß-glucosidase activity. Single-factor experiments showed that optimum ß-glucosidase activity was exhibited at 50 °C and pH 5.0 in a citric acid-sodium citrate buffer when reacting with 0.03 g/mL salicin for 30 min. The procedure for detection was simplified without the need of a chromogenic reaction. Validation of the analytical method demonstrated that the accuracy, precision, repeatability, stability, and durability were good. The linear ranges of ß-glucosidase in a buffer solution and rat serum were 0.0873-1.5498 U/mL and 0.4076-2.9019 U/mL, respectively. The proposed method was free from interference from ß-dextranase, snailase, ß-galactosidase, hemicellulase, and glucuronic acid released by baicalin. This demonstrated that the proposed assay had a higher selectivity than the conventional dinitrosalicylic acid (DNS) assay because of the specificity for salicin and unique recognition of glucose by a personal glucose meter. Miniaturization of the method resulted in a microassay for ß-glucosidase activity. The easy-to-operate method was successfully used to detect a series of ß-glucosidases extracted from bitter almonds and cultured by Aspergillus niger. In addition, the simplified and miniaturized glucometer-based assay has potential application in the point-of-care testing of ß-glucosidase in many fields, including medical diagnostics, food safety, and environmental monitoring.

Rheological and mucoadhesive properties of polysaccharide from Bletilla striata with potential use in pharmaceutics as bio-adhesive excipient.

This study described the rheological and mucoadhesive properties of one natural water-soluble polysaccharide from Bletilla striata (BSP). The rheological characteristics of BSP in aqueous solutions and BSP mixed with other polymers were investigated under various conditions, including concentration, temperature, pH, and salt addition. Viscometric studies and ex vivo mucoadhesion tests were also conducted to examine the mucoadhesive properties of BSP. Results indicated that BSP behaved as a shear-thinning fluid at various concentrations, and its viscosity decreased at high temperatures. The viscous flow properties of the BSP mixtures changed at high pH (>5.0). Conversely, the viscosity of the BSP solutions was slightly affected by electrolytes. The viscosities of the BSP mixtures with four other commonly used polymers (sodium alginate, sodium carboxymethyl cellulose, hypromellose, and chitosan) were enhanced. The synergistic viscosity of BSP/mucin mixtures increased as BSP concentrations increased, and the maximum value was observed in the SIF medium without enzymes. The adhesive abilities of 5.0% and 10.0% BSP were almost equivalent to that of 0.5% sodium alginate, suggesting that BSP exhibited a certain mucoadhesive property, although it was weaker than that of the other commonly used mucoadhesive materials. BSP showed potential for pharmaceutical excipient applications in bioadhesive drug delivery systems.

Orally delivered polycurcumin responsive to bacterial reduction for targeted therapy of inflammatory bowel disease.

Inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis is a chronic autoimmune disease affecting nearly five million people worldwide. Among all drug delivery system, oral administration is the most preferable route for colon-specific targeting and the treatment of IBD. Herein, an amphiphilic curcumin polymer (PCur) composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic curcumin (Cur) linked by disulfide bond was synthesized and characterized. The sufficient solubility, nano-scaled size and close to the neutral surface potential of PCur lead to preferential accumulation of the active drug in the inflamed regions of the gut. Moreover, PCur showed limited drug release and enhanced robustness under the physiological pH of the gastrointestinal tract (GIT), and a significantly elevated release was observed when responding to a bacterial reduction in the colon. Furthermore, cellular studies confirmed PCur had low cytotoxicity and increased transmembrane permeability, resulting in improved oral bioavailability evidenced by in vivo pharmacokinetics of rats. Finally, with DSS-induced murine model of IBD, we demonstrated that orally administered PCur ameliorated the inflammatory progression in the colon and could protect mice from IBD. In conclusion, it is illustrated that the developed PCur conjugate could potentially be employed as a colon-specific candidate for IBD treatment.

Simultaneous Determination of 10 Flavonoids in Crude and Wine-Processed Radix scutellariae by UHPLC.

Radix scutellariae is a well-known traditional Chinese medicine used for the treatments of inflammation, pyrexia, hepatitis, etc. Flavonoids are its main active compounds. The aim of this study is to develop and validate the ultra high-performance liquid chromatography (UHPLC) method for simultaneous determination of 10 flavonoids (baicalin, wogonoside, baicalein, wogonin, oroxylin A, chrysin, scutellarin, oroxylin A-7-O-glucuronide, apigenin and apigenin-7-glucuronide) in crude and wine-processed R. scutellariae. The quantitative determination was conducted by UHPLC. Optimal separation was achieved by gradient elution with mobile phase consisting of 0.01% aqueous formic acid and methanol on a Waters ACQUITY UHPLC BEH C18 column. Detection wavelength was set at 275 nm. Method validation was accomplished with linearity, precision and recovery tests. All calibration curves showed good linearity (R(2) > 0.9993). The limit of detection and limit of quantification of these compounds were from 0.08 to 0.24 µg/mL and from 0.23 to 0.76 µg/mL, respectively. The average recoveries of these compounds were from 96.95 to 109.51% with relative standard deviation (RSD) values from 2.14 to 3.26% for crude R. scutellariae, while from 94.73 to 108.38% with RSD values from 1.83 to 3.47% for wine-processed R. scutellariae. The developed method can be applied to the intrinsic quality control of crude and wine-processed R. scutellariae.

The effects of co-administration of butter on the absorption, metabolism and excretion of catechins in rats after oral administration of tea polyphenols.

In Southwest China, tea polyphenols are usually utilized by way of butter tea. Tea polyphenols inhibit the absorption and biosynthesis of fatty acids in vivo, but the effects of butter on the pharmacokinetics of tea polyphenols have drawn less concern. A rapid UHPLC-MS/MS method was used to quantitatively determine the catechins in the plasma, feces and bile of rats after the oral administration of tea polyphenol or its combination with butter. In comparison with the single tea polyphenol treatment, the maximum plasma concentrations (Cmax) of the free EGCG, EGC, EC, GCG, GC and ECG significantly decreased after the co-administration of butter. The mean residence times (MRT) of the free EGCG, EGC, EC, GC and ECG were also significantly prolonged. When the plasma samples were treated with ß-glucuronidase and arylsulfatase, the pharmacokinetic parameters of the total catechins (free and conjugated forms) were not affected by the co-administration of butter. These results indicated that the total absorption of catechins was not affected by butter, but the metabolism of catechins had been changed. Furthermore, the fecal catechins were significantly increased by butter. The total fecal amount and excretion ratio of all catechins were increased highly. The biliary excretion of EGCG, EGC, EC, GCG and GC was significantly increased by the co-administration of butter. To sum up, the butter changed the metabolism of catechins in vivo by decreasing the plasma concentration of the free catechins but increasing the conjugated catechins.

[HPLC specific chromatogram spectrum-effect relationship for Shuanghuanglian on MDCK cell injury induced by influenza A virus (H1N1)].

To establish HPLC specific chromatogram and its correlation with the protection effect of Shuanghuanglian on MDCK (Madin-Darby canine kidney) cell injury induced by influenza A virus( H1N1). Nine recipes of Shuanghuanglian based on the official prescription were prepared according to orthogonal test for HPLC analysis and MDCK cells protection experiment separately (cytopathic effect (CPE) method was used for observing the virus infectivity and MTT staining results were used as the determining indexes for drug concentration selection and analyzing cell viability). The results suggested that all the other Shuang-Huang-Lian recipes except recipe1 demonstrate protecting effect on MDCK cell injury induced by influenza A virus (P < 0.01, P < 0.001). Stepwise regression analysis was used for analyzing the relationships between HPLC fingerprint and the protecting effect of Shuanghuanglian on influenza A virus induced MDCK cell injury. Peak 2, 3, 6, 8 and 12 were found to be strongly related with anti-influenza A virus efficacy. Stepwise regression analysis of recipes data and efficacy data showed that Lonicerae Japonicae Flos and Forsythiae Fructus were positively associated with the protecting effect of cells injury. From HPLC fingerprints, we found that peak 2, 3, 12 were from Lonicerae Japonicae Flos and peak 6, 8 were from Forsythiae Fructus. Four peaks were identified through comparing the retention time between the standard and Shuanghuanglian recipes, and they were chlorogenicacid, cryptochlorogenic acid, forsythoside B and 3,4-dicaffeoylquinic acid respectively. Caffeic acid derivatives in Lonicerae Japonicae Flos and Forsythiae Fructus were found to be greatly correlated with anti-influenza A virus efficacy and maybe the substance basis of Shuanghuanglian.

[Comparison of total phenol of magnolia solid dispersion prepared by different methods].

To compare the difference of total phenol of magnolia solid dispersion prepared by different methods. Hot melt extrusion, solvent evaporation method, and fusion-cooling method were used to prepare total phenol of Magnolia accessory solid dispersion, Plastone S-630 and HPC. The drug dispersion state in the prepared solid dispersion was evaluated with DSC and X-ray diffraction; FT-IR method was used to analyze the possible connections between drug and accessories. Finally, accelerated stability-in vivo dissolution test was use to compare the stability differences between these three processes. The results of DSC and X-ray diffraction showed that all of the drug in solid dispersion processed by three processes can exist in amorphous form; FT-IR results also could not distinguish the difference between the three processes; accelerated stability-in vivo dissolution test showed the stability of solid dispersion prepared by HPC was better than Plastone S-630, and the same kinds of materials solid dispersion prepared by hot melt extrusion showed a better stability than the other two processes.

Simultaneous determination of ten flavonoids of crude and wine-processed Radix Scutellariae aqueous extracts in rat plasma by UPLC-ESI-MS/MS and its application to a comparative pharmacokinetic study.

Radix Scutellariae (RS) is a herbal medicine with various pharmacological activities to treat inflammation, respiratory and gastrointestinal infections, etc. In this study, a rapid, sensitive and selective UPLC-ESI-MS/MS method was developed for simultaneous determination of 10 flavonoids - scutellarin, scutellarein, chrysin, wogonin, baicalein, apigenin, wogonoside, oroxylin A-7-O-glucuronide, oroxylin A and baicalin - from RS aqueous extracts in rat plasma with propyl paraben as internal standard (IS). Chromatographic separation was achieved on a C18 column using gradient elution with the mobile phase consisting of methanol and water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min. The detection was performed in multiple reaction monitoring mode using electrospray ionization in negative mode. The validated method showed good linearity over a wide concentration range (r >0.9935). The intra- and interday assay variabilities were <9.5% and <12.4% for all analytes, respectively. The extraction recovery ranged from 71.2 to 89.7% for each analyte and IS. This method was successfully applied to pharmacokinetic comparision after oral administration of crude and wine-processed RS aqueous extracts. There were significant differences in some pharmacokinetic parameters of most analytes between crude and wine-processed RS. This suggested that wine-processing exerted effects absorption of most flavonoids.

Simultaneous determination of ten alkaloids of crude and wine-processed Rhizoma Coptidis aqueous extracts in rat plasma by UHPLC-ESI-MS/MS and its application to a comparative pharmacokinetic study.

Rhizoma coptidis (R.C.), a widely used traditional Chinese medicine, has been used for centuries in the treatment of hypertension, inflammation, dysentery and liver diseases, etc. Wine-processing is a specialized technology by sautéing crude herbal medicine using Chinese rice wine. This paper was designed to establish a simultaneous quantitative method of ten alkaloids (berberine, coptisine, palmatine, jatrorrhizine, epiberberine, magnoflorine, columbamine, noroxyhydrastinine, oxyberberine and 8-oxocoptisine) in rat plasma. Furthermore, the pharmacokinetics of those alkaloids after administration of crude and wine-processed R.C. aqueous extracts was compared. As a result, a ultra high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) method was developed and validated for the first time. Chromatographic separation was achieved on a C18 column using gradient elution with the mobile phase consisting of acetonitrile and water (containing 0.2% formic acid) at a flow rate of 0.2 ml/min. The validated method showed good linearity over a wide concentration range (r>0.99), and lower limits of quantification less than 5.46 ng/ml for the each analyte. The intra- and inter-day assay variability was below 9.9% and 10.5% for all analytes, respectively. The extraction recovery of those alkaloids and I.S. ranged from 65.3% to 90.7%. The validated method has been successfully applied to pharmacokinetic comparison after administration of crude and wine-processed R.C. aqueous extracts. Pharmacokinetic comparative study showed that Cmax of coptisine and 8-oxocoptisine and AUC0-t of coptisine, palmatine and 8-oxocoptisine were increased significantly (p<0.05) after wine-processing, while other compounds didn't show significant difference, which suggested that wine-processing exerted limited effects on the absorption of alkaloids. These results might be helpful for R.C.' clinical reasonable application and further studies on its wine-processing mechanism.

Simultaneous determination of 11 alkaloids in crude and wine-processed Rhizoma Coptidis by HPLC-PAD.

A high-performance liquid chromatography method coupled with photo array diode detector has been developed and validated for simultaneous quantification of 11 active alkaloids in Rhizoma Coptidis (R.C.). The analysis was performed on a Benetnach-C18 column (250 × 4.6 mm, i.d., 5 µm) using binary gradient elution with 30 mmol/L ammonium bicarbonate water containing 0.7% ammonia solution and 0.1% triethylamine (A) and acetonitrile (B) at a flow rate of 1 mL/min, a column temperature of 35°C and UV detection at 275 nm. All calibration curves showed good linear regression (r > 0.9993) in the range of 6.94-111.03, 0.625-10.10, 6.27-100.14, 31.88-510.50, 16.25-260.70, 19.88-18.20, 3.13-50.70, 0.125-2.14, 16.44-263, 62.5-1,000, 0.125-2.14 µg/mL for magnoflorine, noroxyhydrastinine, jatrorrhizine, columbamine, epiberberine, coptisine, berberubine, worenine, palmatine, berberine, oxyberberine, respectively. It also showed good precision, repeatability and stability for quantification of these 11 alkaloids. The limit of detections and limit of quantitations for the analytes ranged from 0.031 to 0.423 µg/mL and from 0.094 to 1.27 µg/mL, respectively. This method was effective and rapid. The optimized method, which was applied to the determination of alkaloids in crude and wine-processed R.C. samples, was found to be feasible, reliable and suitable for their routine quality control.

Effects of food and gender on the pharmacokinetics of ginkgolides A, B, C and bilobalide in rats after oral dosing with ginkgo terpene lactones extract.

The ginkgo terpene lactones (GTL), mainly including bilobalide (BB), ginkgolide A (GA), ginkgolide B (GB) and ginkgolide C (GC) possess different biological activities such as peripheral vasoregulation, platelet-activating factor (PAF) receptor antagonism, neuroprotective properties and prevention of membrane damage caused by free radicals. To investigate the effects of food and gender on the bioavailability of BB, GA, GB and GC after oral administration of GTL extract, a rapid UPLC-MS/MS method was developed and validated. A reversed phase C18 column (100mm×2.1mm, i.d., 1.7µm) and a mobile phase consisted of methanol and 1mM ammonium acetate (70/30, v/v) were employed. Compared with the fasted group, the t1/2 values for BB, GA, GB and GC in fed were all increased (p<0.05), AUC0-t and AUC0-∞ values of BB, GA, GB and GC were all significantly increased (p<0.05), but the Cmax values of BB, GA, GB and GC were significantly decreased (p<0.05). In comparison with the male group, all of the t1/2 values and AUC0-t values for BB, GA, GB and GC in female were higher (p<0.05), but no statistical difference in Tmax values for BB, GA, GB and GC between these two groups. Food and gender factor showed significant effects on the pharmacokinetics of BB, GA, GB, and GC. The results suggested that oral doses of GTL should be lowered for fasted and female subjects, compared with the fed and male subjects, respectively.

[Studies on effects of Achyranthes bidentata on tongsaimai pellets main active ingredients chlorogenic acid, isoliquiritin, harpagoside and glycyrrhizin in vivo pharmacokinetics].

To study on the effects of Achyranthes bidentata on Tongsaimai pellets main active ingredients chlorogenic acid, isoliquiritin, harpagoside and glycyrrhizin in rats in vivo pharmacokinetic behaviors, a method for the simultaneous determination of chlorogenic acid, isoliquiritin, harpagoside and liquiritigenin in rat plasma was established by UPLC-MS/MS. The analysis was performed on a waters Acquity BEH C18 column (2.1 mm x 100 mm, 1.7 microm) with the mixture of acetonitrile and 0.1% formic acid/water as mobile phase, and the gradient elution at a flow rate of 0.3 mL x min(-1). The analytes were detected by tandem mass spectrometry with the electrospray ionization (ESI) source and in the multiple reaction monitoring (MRM) mode. It turned out that the analytes of Tongsaimai pellets groups C(max) and AUC(Q-infinity) values were higher than that with A. bidentata group, and the C(max) values of chlorogenic acid had significantly difference (P < 0.05), the AUC(0-infinity) values of chlorogenic acid and glycyrrhizin had significantly difference (P < 0.05); The T(max) and CL values of two groups had no significantly difference. Results showed that the established method was specific, rapid, accurate and sensitive for the studies of Tongsaimai pellets four main active ingredients in rat in vivo pharmacokinetic, and A. bidentata have varying degrees of effects on Tongsaimai pellets four main active ingredients in rat in vivo pharmacokinetic behaviors.

The effects of wine-processing on ascending and descending: The distribution of flavonoids in rat tissues after oral administration of crude and wine-processed Radix scutellariae.

ETHNOPHARMACOLOGICAL RELEVANCE: Ascending and descending theory is a core principle of traditional Chinese medicine (TCM) theories. It plays an essential role in TCM clinical applications. Some TCM medicine has specific properties, which could alter the inclination and direction of their actions. The properties of the ascending and floating process of one herbal medicine are affected by means of herb processing. Wine-processing, which is sautéing with rice wine, is one of the most popular technologies of herb processing. Wine-processing increases the inclination and direction of its actions, thereby producing or strengthening their efficacy in cleaning the upper-energizer heat. Radix scutellariae, the dried roots of Scutellaria baicalensis Georgi, is a well-known TCM used for the treatment of inflammation, pyrexia, jaundice, etc. Recently, wine-processed Radix scutellariae was normally applied in clinical studies for the treatment of upper-energizer syndrome. In order to investigate the effects of wine-processing on ascending and descending of Radix scutellariae, the comparative study of distribution of flavonoids in rat tissues of triple energizers (SanJiao-upper, middle, lower jiao) after oral administration of crude and wine-processed Radix scutellariae aqueous extracts was carried out. MATERIALS AND METHODS: The rats were randomly assigned to two groups and orally administered with crude and wine-processed Radix scutellariae aqueous extracts, respectively. At different pre-determined time points after administration, the concentrations of compounds in rat tissue homogenate were determined, and the main tissue pharmacokinetic parameters were investigated. Tissue pharmacokinetic parameters including AUC0-t, t1/2, Tmax and Cmax were calculated using DAS 2.0. An unpaired Student t-test was used to compare the differences in tissue pharmacokinetic parameters between the two groups. All the results were expressed as arithmetic mean±S.D. RESULTS: The parameters of Cmax and AUC0-t of some flavonoids in wine-processed Radix scutellariae were remarkably increased (p<0.05, p<0.01, p<0.001) in the rat upper-energizer tissues (lung and heart) compared with those of the crude group. However, in the rat middle- and lower-energizer tissues (spleen, liver and kidney), the Cmax and AUC0-t of some flavonoids were significantly decreased (p<0.05, p<0.01) compared with the crude group. The main explanation for these differences seems to the effects of wine-processing on ascending and descending theory. CONCLUSIONS: All of these differences in the distribution of triple energizers after oral administration of crude and wine-processed Radix scutellariae aqueous extracts may lead to the increase of efficacy on the upper-energizer tissues and were in compliance with the ascending and descending theory. Therefore, wine-processing was recommended when Radix scutellariae was used for cleaning the upper-energizer heat and humidity. The obtained knowledge can be used to evaluate the impact of these differences on the efficacy of both the drugs in clinical applications and might be helpful in explaining the effects of wine-processing on ascending and descending theory.

The effects of Glycyrrhizae uralenis and its major bioactive components on pharmacokinetics of daphnetin in Cortex daphnes in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhizae uralenis (GU) is often prescribed together with Cortex daphnes (CD) in traditional Chinese medicinal practice to increase the efficacy of CD on the treatment of rheumatoid arthritis (RA), but the reasons were still unknown. In order to clarify the rationality of herbaceous compatibility between CD and GU, the comparative evaluations on pharmacokinetic behaviors of daphnetin (a predominantly active ingredient in CD) after intragastric administration of CD and CD-GU (combination of CD and GU) extract were studied. In addition, the effects of glycyrrhizin and liquiritin, active ingredients of Glycyrrhiza triterpenes and Glycyrrhiza flavones respectively, on the pharmacokinetics of daphnetin were also investigated. MATERIALS AND METHODS: Five groups of rats were orally administered with CD extract, CD-GU extract, pure daphnetin, co-administration of daphnetin and glycyrrhizin as well as co-administration of daphnetin and liquiritin at the same single dose of daphnetin (20 mg/kg). The rat plasma concentrations of daphnetin were determined by our developed UPLC-MS/MS method. The pharmacokinetics of daphnetin in above groups were investigated and compared. RESULTS: Comparing with oral administration of CD extract, AUC and Tmax of daphnetin significantly increased after giving CD-GU (p<0.05). In addition, in comparison to daphnetin alone, co-administration of daphnetin with liquiritin significantly increased the AUC and Cmax of daphnetin for ~1.5-fold, while co-administered with glycyrrhizin showed limited impact on the pharmacokinetics of daphnetin. CONCLUSIONS: In this study, it was found that liquiritin, one of the major components of GU, significantly enhanced the bioavailability of the main component daphnetin in CD. In addition, the bioavailability of daphnetin in the CD-GU prescription was also significantly higher than that in CD alone, which could be due to liquiritin. Such results explained the mechanism of the increased efficacy in treating RA with the combined use of CD and GU.

[Studies on effects of calycosin-7-O-ß-D-glucoside on prim-O-glucosylcimifugin and cimifugin in vivo pharmacokinetics].

Study on the effects of Astragali Radix main active flavone calycosin-7-O-ß-D-glucoside on Saposhnikoviae Radix main active ingredients prim-O-glucosylcimifugin and cimifugin, a UPLC-MS/MS method for simultaneous determination of prim-O-glucosylcimifugin and cimifugin in rat plasma was established, and the comparative pharmacokinetics of prim-O-glucosylcimifugin and cimifugin after oral administration of prim-O-glucosylcimifugin and calycosin-7-O-ß-D-glucoside-prim-O-glucosylcimifugin to rats were carried out, which might be conductive in exploring the rationality of Astragali Radix - Saposhnikoviae Radix herb couple. Twelve male SD rats were divided into two groups. Prim-O-glucosylcimifugin and cimifugin in rat plasma of different time points after oral administration of prim-O-glucosylcimifugin and calycosin-7-O-ß-D-glucoside - prim-O-glucosylcimifugin to rats were determinated. And the main pharmacokinetic parameters were investigated using DAS 3. 2. 4. The established method was rapid, accurate and sensitive for simultaneous determination of prim-O-glucosylcimifugin and cimifugin in rat plasma. The analysis was performed on a Waters Acquity BEH C18 column (2.1 mm x 100 mm, 1.7 µm) with the mixture of acetonitrile and 0.1% formic acid/water as mobile phase, and the gradient elution at a flow rate of 0.3 mL x min(-1). The analytes were detected by tandem mass spectrometry with the electrospray ionization (ESI) source and in the multiple reaction monitoring (MRM) mode. Compared with prim-O-glucosylcimifugin group, the AUC(0-t)., and AUC(0-∞) of p-O-glucosylcimifugin as well as the C(max) of cimifugin significantly increased (P < 0.05) in calycosin-7-O-ß-D-glucoside-prim-O-glucosylcimifugin group. Calycosin-7-O-ß-D-glucoside could enhance the absorption of prim-O-glucosylcimifugin and cimifugin and improve the bioavailability, explaining preliminarily the rationality of Astragali Radix-Saposhnikoviae Radix herb couple.