Protection function of 18ß-glycyrrhetinic acid on rats with high-altitude pulmonary hypertension based on 1H NMR metabonomics technology.

18ß-Glycyrrhetinic acid (GA) is the triterpenoid aglycone component of glycyrrhizic acid, a natural product of traditional Chinese medicine, and has been proven to possess a variety of pharmacological effects. The protection function and the mechanism of GA on rats with high-altitude pulmonary hypertension (HAPH) are studied using proton nuclear magnetic resonance (1H NMR) metabonomics technology and biochemical analysis. An HAPH model is established, and 60 male rats are randomly divided into the following groups: Control(normal saline, 0.4 mL/100 g), model (normal saline, 0.4 mL/100 g), Nifedipine (nifedipine, 2.7 mg/kg), and high-, medium-, and low-dose GA groups (100, 50, and 25 mg/kg GA designated as GA.H, GA.M, and GA.L, respectively). Serum biochemical indicators of rats in each group are measured, and pathological changes in the pulmonary artery are observed. 1H NMR metabonomics technology is used for serum analysis. Results show that GA can significantly reduce pulmonary arterial pressure and malondialdehyde levels and increase the glutathione peroxidase and superoxide dismutase activities in HAPH rats. Pathological results show that GA can alleviate pulmonary artery injuries of HAPH rats. Metabolomics analytical findings show that GA can alleviate the metabolic disorder of HAPH rats through anti-oxidation and anti-inflammatory effects, improve their bodies' ability to resist hypoxia, and restore various metabolic pathways (energy metabolism, amino acid metabolism, and lipid metabolism). GA has potential therapeutic effects on HAPH rats, but its target needs to be further studied.

Functional recovery in human partial thickness skin wounds after application of multicomponent hydrolipidic film (MAS063DP): A prospective, open-label, comparative clinical trial.

Acute and minor skin wounds are common in daily life. However, in clinical practice, after initial management in the acute phase, the wounds are managed mainly through observation, and the patients are usually lost to follow-up. Considering a multicomponent hydrolipidic dressing (MAS063DP) long-known for its safe application in eczema and recently in laser-induced wounds, we aimed to evaluate its ability in functional recovery of impaired skin integrity during wound healing. Sixteen patients (N = 16) were enrolled and completed (n = 8 vs n = 8) this prospective, open-label, vehicle-controlled clinical trial with 12-week follow-up. Transepidermal water, skin viscoelasticity and bioimpedance analysis were measured initially, at the 1st, 4th, 8th, and 12th weeks. Improvements in these parameters were greater in the MAS063DP group (from 31.4 ± 9.0 to 16.4 ± 4.3 g/m2 h, P < .001; from 77 ± 16% to 88 ± 9%, P < .05; from 4182 ± 3823 to 2644 ± 1772 Ω) than in the white petrolatum group. No significant adverse events occurred, and all participants were more satisfied with the intervention. In this study, MAS063DP can restore skin integrity and reinstitute physiologic function as a feasible and safe intervention more markedly than management through observation during the healing process by providing protective hydrolipidic layer on the skin with simultaneous anti-inflammatory and antioxidant activities from its key ingredients such as glycyrrhetinic acid, Vitis vinifera, telmesteine, and vitamins C and E.

Synergistic breast cancer suppression efficacy of doxorubicin by combination with glycyrrhetinic acid as an angiogenesis inhibitor.

BACKGROUND: Therapeutic regimens of breast cancer treatment are increasingly inclined to adopt combination strategy based on the broad spectrum antitumor effect of doxorubicin (Dox). Currently, combination therapy comprises of conventional anti-cancer drugs and angiogenesis inhibitors have been corroborated as an effective approach in cancer treatment. PURPOSE: We explored the ability of a natural anti-angiogenic compound glycyrrhetinic acid (GA), derived from an edible-medicinal herb licorice, to enhance the breast cancer suppression effect of Dox. STUDY DESIGN: The drug ratio of GA and Dox with synergistic anticancer effect against MCF-7 cells was optimized by combination index (CI) value in vitro, followed by evaluation of the improved anticancer effects and reduced side-effects of this combination in vitro and in vivo. METHODS: Cell viability was measured by MTT assay. Analyses of mitochondrial membrane potential and cell apoptosis on MCF-7 cells were performed by JC-1 dye and Annexin V-FITC/PI assays. The cellular accumulation of Dox when combined with GA was evaluated. Levels of apoptosis-related proteins in MCF-7 cells were measured by Western blot analysis. Synergistic anti-angiogenic effects on HUVECs were evaluated. A breast cancer mouse model was established to investigate the anti-tumor effects in vivo. RESULTS: Based on the optimization by CI value, Dox and GA at 1:20 molar ratio was chosen as the optimal combination drug ratio that exhibited synergistic effect against MCF-7 breast cancer cells. In addition, the combination of GA and Dox exhibited significantly enhanced cytotoxicity, apoptosis, and loss of mitochondrial membrane potential via the upregulation of a mitochondrial-dependent apoptosis pathway against MCF-7 cells. Interestingly, the addition of GA increased the intracellular accumulation of Dox in MCF-7 cells. Moreover, VEGF-induced HUVECs proliferation, migration, and tube formation were strongly inhibited by Dox when used with GA via the significant down-regulation of VEGFR2-mediated pathway, indicating that the combination of Dox and GA could exhibit ideal synergistic anti-angiogenesis effect. Expectedly, the enhanced anti-tumor efficacy of Dox and reduced Dox-induced cardiotoxicity when used in combination with GA were evident in a mouse breast tumor model. CONCLUSIONS: These findings support that the combination of Dox with GA is a novel and promising therapeutic strategy for the treatment of breast cancer.

3D-printed microfluidic chip for the preparation of glycyrrhetinic acid-loaded ethanolic liposomes.

18-α-Glycyrrhetinic acid (GA) is a bioactive compound extracted from licorice that exhibits many biological and pharmacological effects such as anti-inflammatory and antioxidant activities on the skin. However, its lipophilic nature results in poor bioavailability that limits clinical applications. Liposomes, presenting the ability to carry both hydrophobic and hydrophilic payloads and a good cytocompatibility, are effective to overcome this barrier. Furthermore, the addition of permeation enhancers such as ethanol into liposomal formulations helps the diffusion of these systems through the skin barrier. Here, we aimed to formulate GA-loaded ethanolic liposomes, using a natural soybean lecithin via a microfluidic approach. Using a fused deposition modeling (FDM) 3D printer we customized a microfluidic chip, and manufactured vesicles that presented spherical shape with a size of 202 ± 5.2 nm, a narrow size distribution and a good stability over a period of 30 days. After reaching a drug encapsulation efficiency of 63.15 ± 2.2%, liposomes were evaluated for their cytocompatibility and skin permeation potentiality after hydrogelation using xanthan gum. The in vitro release and permeation studies were performed using Franz diffusion cells comparing two different media and three synthetic membranes including a polymeric skin-mimicking membrane. The selected formulation presented no cytotoxicity and an increased permeation compared to GA saturated hydrogel. It could perform therapeutically better effects than conventional formulations containing free GA, as prolonged and controlled release topical dosage forms, which may lead to improved efficiency and better patient compliance.

A Previously Unknown Drug-Drug Interaction Is Suspected in Delayed Elimination of Plasma Methotrexate in High-Dose Methotrexate Therapy.

Background: High-dose methotrexate (HD-MTX) therapy is widely implemented for leukemia, osteosarcoma, and lymphoma. Although various measures have been taken to avoid toxicity from high serum MTX concentrations, there are many cases of delayed elimination of MTX. Objective: We suspected that delayed elimination of serum MTX was caused by unknown interactions between MTX and concomitant drugs. Methods: Concerning concomitant drugs in the case of delayed elimination of MTX, we performed screening tests in 35 patients who had undergone HD-MTX therapy. We then investigated the risk factors for delayed MTX elimination in 94 patients with leukemia, lymphoma, or osteosarcoma retrospectively. Results: The percentages of concomitant use of Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, and vincristine were higher in the delayed group. The percentage of delayed MTX elimination in patients receiving HD-MTX therapy was 41%. Multiple logistic regression analysis revealed that the concomitant use of SNMC solely was a significant risk factor for delayed MTX (odds ratio = 12.20; 95% CI = 1.06-139.84). Conclusion and Relevance: Concomitant use of SNMC was shown to be related to delayed elimination of serum MTX, and our results suggested a previously unknown drug-drug interaction between MTX and SNMC.

What's new in atopic eczema? An analysis of systematic reviews published in 2016. Part 1: treatment and prevention.

This review is part of a series of annual updates summarizing the evidence base for atopic eczema (AE). It provides a summary of key findings from 28 systematic reviews that were published or indexed during 2016 with a focus on treatment and prevention of AE. There is reasonable evidence of benefit for topical corticosteroids, calcineurin inhibitors, a glycyrrhetinic acid-containing preparation (Atopiclair® ), oral ciclosporin, oral azathioprine, narrowband ultraviolet B radiation and education programmes. Overall, there is evidence that topical corticosteroids and calcineurin inhibitors have similar efficacy and that both can prevent AE flares when used twice weekly as maintenance therapy. However, topical calcineurin inhibitors are costlier and have more adverse reactions, thus topical corticosteroids should remain the standard of care for patients with AE. There is no evidence that multiple applications are better than once-daily application of topical corticosteroid. There is inconsistent evidence to support omalizumab and specific allergen immunotherapy use in AE. There is some evidence that vitamin D supplementation and synbiotics reduce AE severity, although the margin of improvement may not be clinically meaningful. There is little evidence to support the use of wet wraps or of complementary/alternative medicine (including Chinese herbal medicine). There is some evidence to suggest that a diet high in fish in infancy may be preventative for AE, but other dietary interventions for the prevention of AE show little promise. This review provides a succinct guide for clinicians and patients wishing to remain up to date with the latest evidence for the treatment and prevention of AE.

A starch, glycyrretinic, zinc oxide and bisabolol based cream in the treatment of chronic mild-to-moderate atopic dermatitis in children: a three-center, assessor blinded trial.

BACKGROUND: Atopic dermatitis (AD) is a very common chronic inflammatory and eczematous skin condition characterized by flares and remissions. Skin barrier alteration or dysfunction is the most relevant patogenetic factor. Topical corticosteroids are the mainstay treatment of AD, especially during flare periods. The daily use of emollients and moisturizers is also considered a relevant adjunctive strategy to improve skin barrier function and skin appearance in AD patients. Long-term use of topical corticosteroids is associated with important drawbacks and side effects. A corticosteroid-free cream containing starch, glycyrretinic acid, zinc oxide and bisabolol (Dermamid™; Difa Cooper, Caronno Pertusella, Varese, Italy) has been designed for the treatment of acute eczematous conditions like diaper dermatitis. However, this formulation could be particularly suitable also for AD. We evaluated in a three-center, assessor-blinded prospective 6-week treatment trial the efficacy and tolerability of this cream in children with chronic mild-to-moderate atopic dermatitis. METHODS: A total of 30 children (mean age 5 years, 18 males and 12 females) with chronic mild to moderate AD, affecting face, lower and upper limbs or trunk, were enrolled after parents' written informed consent. Exclusion criteria were a condition of immunosuppression, acute flares or a positive history of allergy to one of the components of the cream. The primary outcome was the evolution total eczema severity score (TESS) calculated as the sum of the single eczema severity score for each body area involved. Single area Eczema Severity Score (ESS) was calculated assessing eczema, infiltration, lichenification and scraching lesions using a 4-point scale grade (with 0=no sign, and 4=severe sign). A secondary endpoint was the percentage of subjects reaching at least 50% of TESS reduction at week 6 in comparison with baseline. The TESS was evaluated at baseline and after 3 and 6 weeks of treatment (twice daily application) in an assessor-blind fashion. RESULTS: At baseline the mean (SD) TESS was 11.6 (4.7). TESS was reduced significantly (P=0.0001) to 5.7 (3) after 3 weeks (-51%), and to 3.0 (2.3) at week 6 (-74%). Similar reductions were observed for single area ESS values. The percentage of subjects with at least a >50% reduction of TESS value at the end of the study was 87%. The product was very well tolerated. Only for one patient a mild burning sensation at the application site was reported. All the subjects concluded the trial. CONCLUSIONS: This trial supports the efficacy and the tolerability of a corticosteroid-free cream containing starch, glycyrretinic acid and bisabolol in the treatment of chronic mild to moderate atopic dermatitis in children.

Simultaneous Determination of Twenty-Five Compounds in Rat Plasma Using Ultra-High Performance Liquid Chromatography-Polarity Switching Tandem Mass Spectrometry and Its Application to a Pharmacokinetic Study.

An attempt was made to characterize the pharmacokinetic profiles of Qishen Keli (QSKL) that has been widely proved to be effective in clinical practice. A method using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) for the simultaneous determination of 25 analytes in rat plasma was developed and validated. Satisfactory chromatographic separation was achieved on an ACQUITY UPLC HSS T3 column with gradient elution using mobile phase consisting of 0.02% aqueous formic acid (A) and acetonitrile fortified with 0.02% formic acid (B), and analyte detection was carried out using polarity-switching multiple reaction monitoring mode. Method validation assays in terms of selectivity, linearity, inter- and intra-day variations, matrix effect, and recovery demonstrated the newly developed method to be specific, sensitive, accurate, and precise. Following the oral administration of QSKL at a single dose, the qualified method was successfully applied for pharmacokinetic investigations in sham and model rats. Mild differences occurred for the pharmacokinetic patterns of most components between those two groups, whereas significant differences were observed for glycyrrhizic acid and glycyrrhetic acid. The obtained findings could provide meaningful information for the clarification of the effective material basis of QSKL.

Synthesis, characterization and liver targeting evaluation of self-assembled hyaluronic acid nanoparticles functionalized with glycyrrhetinic acid.

Recently, polymeric materials with multiple functions have drawn great attention as the carrier for drug delivery system design. In this study, a series of multifunctional drug delivery carriers, hyaluronic acid (HA)-glycyrrhetinic acid (GA) succinate (HSG) copolymers were synthesized via hydroxyl group modification of hyaluronic acid. It was shown that the HSG nanoparticles had sub-spherical shape, and the particle size was in the range of 152.6-260.7nm depending on GA graft ratio. HSG nanoparticles presented good short term and dilution stability. MTT assay demonstrated all the copolymers presented no significant cytotoxicity. In vivo imaging analysis suggested HSG nanoparticles had superior liver targeting efficiency and the liver targeting capacity was GA graft ratio dependent. The accumulation of DiR (a lipophilic, NIR fluorescent cyanine dye)-loaded HSG-6, HSG-12, and HSG-20 nanoparticles in liver was 1.8-, 2.1-, and 2.9-fold higher than that of free DiR. The binding site of GA on HA may influence liver targeting efficiency. These results indicated that HSG copolymers based nanoparticles are potential drug carrier for improved liver targeting.

Pharmacokinetics and pharmacodynamics of glycyrrhetinic acid with Paeoniflorin after transdermal administration in dysmenorrhea model mice.

BACKGROUND: Glycyrrhetinic acid (GA) and paeoniflorin (PF) are the main active ingredients in Chinese peony- Liquorice Decoction, a widely used Traditional Chinese Medicine. HYPOTHESIS/PURPOSE: The aim of this work was to investigate the combinatory analgesic effect of GA and PF after percutaneous administration and to define their pharmacokinetic/pharmacodynamic (PK/PD) characteristics. STUDY DESIGN AND METHODS: GA and PF were produced to transdermal patches based on previous research, and the permeation parameters of GA and PF in the patches were investigated with in vitro experiments. Dysmenorrhea model mice were then produced to compare the analgesic effects of the patches with different proportions of GA-PF. In the in vivo assessment, the number of writhes exhibited by the dysmenorrhea mice was recorded at designated time points, and skin, muscle under skin and plasma samples were collected, for assessments of drug distribution, pharmacokinetics parameters and PK/PD characteristics. RESULTS AND CONCLUSION: In dysmenorrhea mice, GA-PF and meloxicam (the positive control drug) could relieve pain to equal degrees. Specifically, a single dose of the optimized patches (10%GA-10%PF, wt) exerted a steady analgesic effect for 48h in dysmenorrhea mice, but this effect lagged behind the changes in the plasma concentration. Evaluation with the Bliss Independence criterion revealed that the two ingredients displayed a synergistic effect. Then the PK/PD relationship of GA in this compound preparation was defined with this synergistic effect. The preparation might be suitable for topical spasmolysis and anti-inflammatory therapy.

Glycyrrhetic Acid Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Vivo.

Glycyrrhizae Radix (GR) is a Korean traditional herb medicine that is widely used in clinical health care. Glycyrrhetic acid (GA) is an aglycone saponin extracted from GR that has anti-inflammatory, anti-cancer, and anti-viral effects. However, the anti-inflammatory effects of GA in colitis have not been reported. This study investigated the role of GA on ulcerative colitis in a dextran sulfate sodium (DSS)-induced mouse colitis model. DSS-treated mice displayed weight loss and shortened colon length compared with control mice. Mice administered GA showed less weight loss and longer colon length than the DSS-treated group. Interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha were decreased by GA treatment. GA treatment also reduced DSS-induced microscopic damage to colon tissue. GA regulates the phosphorylation of transcription factors including nuclear factor-kappa B (NF-κB) and IκB alpha, and regulates the expression of cycloxygenase-2 and prostaglandin E2. GA thus showed beneficial effects in a mouse model of colitis, implicating GA might be a useful herb-derived medicine in the treatment of ulcerative colitis.

[Effects of baicalin, matrine, glycyrrhetinic acid and emodin in three kinds of emulsifier cream system on transdermal absorption in vitro].

To study effects of APG, Span-Tween and A6/25 emulsifier cream system on transdermal absorption in vitro of baicalin, matrine, glycyrrhetinic acid and emodin in emulsifier. Permeations studies were carried out in vitro with excised mice skin by improved Franz diffusion cells. The cumulative penetration amounts and the retention amounts of Chinese herbal medicinal ingredients in three kinds of emulsifier cream systems were determined by HPLC. The effects of different Chinese herbal medicinal ingredients in the same emulsifier system and the same herbal medicinal ingredients in different emulsifier systems on cumulative permeation amount, skin retention amount and permeation rate were investigated. According to the results, the order of different Chinese herbal medicinal ingredients in same kinds of emulsifier system by the cumulative permeation amount and the permeation rate were matrine>baicalin>glycyrrhetinic acid>emodin. With respect to the effect of different emulsifier systems on cumulative permeation amount and permeation rate of the same herbal medicinal ingredients, glycyrrhetinic acid and emodin showed no significant difference, Span-Tween emulsifier cream system had higher cumulative permeation amount and permeation rate. The cumulative permeation amount and the permeation rate of Chinese herbal medicinal ingredients in the three kinds of emulsifier cream systems had an identical regularity. However, the cumulative permeation amount, the skin retension amount and the permeation rate of the same herbal medicinal ingredients in different emulsifier systems had no regularity.

The influence of compatibility of processed radix Aconiti Kusnezoffii on the pharmacokinetic of four components in Glycyrrhiza uralensis Fisch.

ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhiza uralensis Fisch. and processed radix Aconiti kusnezoffii are the main components in many Chinese traditional patent medicines with the ratio of 1:1, which are used for treatment of rheumatoid arthritis, heart failure and so on. Glycyrrhizic acid, glycyrrhetic acid, liquiritigenin and isoliquiritigenin are the essential bioactive triterpenes and flavones in the extract of G. uralensis, which were analysis by a simple but accurate method. MATERIALS AND METHODS: In the present study, a specific HPLC method was developed and validated for simultaneous determination of pharmacokinetic parameters of glycyrrhizic acid, glycyrrhetic acid, liquiritigenin and isoliquiritigenin in G. uralensis after oral administration of single herb extract and a combination of two herbs extracts respectively. RESULTS: The calibration curves of the four components had good linearity higher than 0.9991 in the measured range. The intra-day and inter-day precisions (RSD) at different levels were both within 9.73%, and the accuracies (RE) were in the range of -7.9-8.0%. Compared with pharmacokinetic parameters of G. uralensis administered orally, values of AUC and Cmax of liquiritigenin and isoliquiritigenin decreased significantly (p<0.05), plasma concentrations of glycyrrhizic acid rose slightly and bimodal phenomenon of concentration-time of isoliquiritigenin and glycyrrhetinic acid disappeared after combined administration. DISCUSSION AND CONCLUSIONS: Some components in the extract of processed radix A. kusnezoffii showed different effects on the pharmacokinetics of the four ingredients in G. uralensis.

Effect of the liquorice root derivatives on salt and water balance in a teleost fish, rainbow trout (Oncorhynchus mykiss).

The effect of liquorice root derivatives (LRDs) glycyrrhizic acid (GL) and glycyrrhetinic acid (18ßGA) on salt and water balance and end points of gill ion transport in a freshwater teleost, (rainbow trout) was examined after feeding fish diets containing GL or 18ßGA (0, 5, 50 or 500 µg/g diet) for a two week period. Serum cortisol levels and gill 11ß-hydroxysteroid dehydrogenase type 2 mRNA abundance decreased in fish fed GL but increased (at select doses) in fish fed 18ßGA. At higher doses of GL, gill Na(+)-K(+)-ATPase and H(+)-ATPase activity increased, while cystic fibrosis transmembrane conductance regulator type II mRNA abundance significantly decreased at the lowest dose of GL. End points of gill transcellular ion transport were not significantly altered in fish fed 18ßGA, except for a reduction in Na(+)-K(+)-ATPase activity at a 50 µg/g dose. In contrast, high doses of GL and 18ßGA increased gill transcript abundance of the tight junction protein claudin-31 (cldn-31). Other end points of gill paracellular transport differed in fishes fed LRDs. Tricellulin mRNA abundance was increased by high dose GL and decreased by high dose 18ßGA, and cldn-23a and cldn-27b mRNA abundance significantly decreased in response to GL irrespective of dose. Despite the above observations, systemic end points of salt and water balance (i.e. serum [Na(+)] and [Cl(-)] as well as muscle moisture) were unaffected by LRDs. Therefore data suggest that LRDs can alter end points of ion transport in fishes but that overall salt and water balance need not be perturbed.

Metabonomics study of the effects of pretreatment with glycyrrhetinic acid on mesaconitine-induced toxicity in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum carmichaelii Debx. (Fuzi), a commonly use traditional Chinese medicine (TCM), has often been used in combination with Rhizoma Glycyrrhizae (Gancao) to reduce its toxicity due to diester diterpenoid alkaloids aconitine, mesaconitine, and hypaconitine. However, the mechanism of detoxication is still unclear. Glycyrrhetinic acid (GA) is the metabolite of glycyrrhizinic acid (GL), the major component of Gancao. In present study, the effect of GA on the changes of metabolic profiles induced by mesaconitine was investigated using NMR-based metabolomic approaches. MATERIALS AND METHODS: Fifteen male Wistar rats were divided into a control group, a group administered mesaconitine alone, and a group administered mesaconitine with one pretreatment with GA. Their urine samples were used for NMR spectroscopic metabolic profiling. Statistical analyses such as orthogonal projections to latent structures-discriminant analysis (OPLS-DA), t-test, hierarchical cluster, and pathway analysis were used to detect the effects of pretreatment with GA on mesaconitine-induced toxicity. RESULTS: The OPLS-DA score plots showed the metabolic profiles of GA-pretreated rats apparently approach to those of normal rats compared to mesaconitine-induced rats. From the t-test and boxplot results, the concentrations of leucine/isoleucine, lactate, acetate, succinate, trimethylamine (TMA), dimethylglycine (DMG), 2-oxo-glutarate, creatinine/creatine, glycine, hippurate, tyrosine and benzoate were significantly changed in metabolic profiles of mesaconitine-induced rats. The disturbed metabolic pathways include amino acid biosynthesis and metabolism. CONCLUSIONS: GA-pretreatment can mitigate the metabolic changes caused by mesaconitine-treatment on rats, indicating that prophylaxis with GA could reduce the toxicity of mesaconitine at the metabolic level.

Comparative pharmacokinetic study of four major components after oral administration of pure compounds, herbs and Si-Ni-San to rats.

The pharmacokinetic differences of paeoniflorin, naringin, naringenin and glycyrrhetinic acid (GA) following oral administration of pure compounds, single herbs and Si-Ni-San (SNS) decoction to rats were studied. Blood samples were analyzed with a validated UPLC-MS/MS method. Student's t-test was used for the statistical comparison. The Cmax and AUC0-∞ were 1470±434 ng/mL and 4663±916 ng h/mL for paeoniflorin, 64.29±59.21 ng/mL and 311.8±131.8 ng h/mL for naringin, 244.2±138.8 ng/mL and 4761±3167 ng h/mL for naringenin, and 1183±294 ng/mL and 38 994±14 377 ng h/mL for GA after oral administration of paeoniflorin, naringin and glycyrrhizic acid. The Cmax and AUC0-∞ were 812.6±259.6 ng/mL and 2489±817 ng h/mL for paeoniflorin, 344.3±234.9 ng/mL and 1479±531 ng h/mL for naringin, 981.9±465.4 ng/mL and 12 284±6378 ng h/mL for naringenin, and 3164±742 ng/mL and 78 817±16 707 ng h/mL for GA after oral administration of SNS decoction. There were significant differences between the pharmacokinetic behavior after oral administration of SNS decoction compared with pure components or herbs. The results indicated that some components in the other herbs of SNS had a pharmacokinetic interaction with paeoniflorin, naringin, naringenin and GA.

A wogonin-loaded glycyrrhetinic acid-modified liposome for hepatic targeting with anti-tumor effects.

Liver cancer has become one of the most common fatal cancers worldwide, with morbidity rates increasing each year. Wogonin (WG) is an attractive candidate for the development of new anti-cancer drugs. In this study, a novel glycyrrhetinic acid (GA)-modified WG liposome was developed for use in targeted anti-cancer therapy. Three types of WG preparations were investigated: free wogonin in solution (WG), passively targeted wogonin liposomes (WG-Lip) and GA-modified wogonin liposomes (GA-WG-Lip). The entrapment efficiency, size and zeta potential were measured. Cellular uptake, cytotoxicity, in vivo bio-distribution and anti-tumor efficacy were also investigated. Addition of GA to the liposomes did not diminish the high entrapment efficiency observed in the liposomes without GA. GA-WG-Lip showed the greatest uptake and had an IC50 value 1.46 times higher than that of WG-Lip. The GA-modified liposomes rapidly accumulated in the liver with a long retention time, and also displayed a better tumor inhibitory ratio than that of the unmodified liposomes. Overall, the data indicated that use of the GA-modified WG liposomes conferred improvements in bio-distribution, accumulation at the tumor and therapeutic efficacy, perhaps due to increased receptor-mediated uptake of liposomes by liver-targeted cells. Together, these data show that GA-WG-Lip is a promising means of targeted therapy for liver cancer.

Pharmacokinetic study of multiple active constituents after oral gavage of Guizhi decoction in rats using a LC-MS/MS method.

Guizhi decoction (GZD) is a classic traditional Chinese medicine formula, clinically used for the treatment of influenza, common cold, and other pyretic conditions. A sensitive, specific, and validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed to investigate the pharmacokinetic properties of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid in rat. After single dose oral administration of 7.9 g extract/kg body weight GZD in rats, plasma concentrations of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid were measured by LC-MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration-time data. The values of AUC0-t, half-life (t 1/2), and C max were 7.2 ± 2.3 µg h/mL, 1.2 ± 0.3 h, and 9.2 ± 5.2 µg/mL for cinnamic acid, 53 ± 31 µg h/mL, 2.8 ± 2.0 h, and 17 ± 3 µg/mL for hippuric acid, 1.1 ± 0.5 µg h/mL, 1.9 ± 1.1 h, and 0.6 ± 0.3 µg/mL for paeoniflorin, and 11 ± 6 µg h/mL, 6.6 ± 2.5 h, and 0.9 ± 0.6 µg/mL for glycyrrhetic acid, respectively. The results would offer useful information for effective components of GZD in vivo.

[Effect of decoction of turtle shell for anti-fibrosis combined with stronger neo-minophagen C on indices of hepatic fibrosis in chronic hepatitis B].

OBJECTIVE: To evaluate the effect of decoction of turtle shell for anti-fibrosis combined with stronger neo-minophagen C on the indices of hepatic fibrosis in chronic hepatitis B. METHOD: The 94 cases of chronic viral hepatitis B patients were randomly divided into two groups. The treatment group was treated with stronger neo-minophagen C 100 mL dissolved in 10% dextrose 250 ml once a day intravenously, combined with decoction of turtle shell for anti-fibrosis one powder daily. And the control group was treated with stronger neo-minophagen C alone, 3 months as a course. Liver fibrosis indexes and liver function index were tested for two groups of patients before and after the treatment. RESULT: Both the difference of liver fibrosis indexes between the treatment group and the control group and before and after the treatment in the treatment group had statistical significance (P < 0.01). Both the difference of liver function index between the treatment group and the control group and before and after the treatment in the treatment group had statistical significance (P < 0.01). The basic cure rate and total effective rate were 40% and 84.0% in the treatment group and 27.27% and 86.18% in the control group respectively with significant difference. The treatment group was superior to control group in the mean size of diameter of portal vein and the thickness of spleen (P < 0.01). CONCLUSION: Decoction of turtle shell for anti-fibrosis combined with stronger neo-minophagen C could significantly improve the clinical efficacy and the liver fibrosis indexes and liver function index in chronic hepatitis B.

[Effect of oral administration of glycyrrhetinic acid on six metal elements in rat serum].

OBJECTIVE: To determine glycyrrhetinic acid concentration in rat plasma and concentration of calcium (Ca), copper (Cu), iron (Fe), potassium (K), magnesium (Mg) and sodium (Na) in rat serum after oral administration by LC-MS/MS and the flame atomic absorption method, and analyze the effect of glycyrrhetinic acid on the six elements in serum. RESULT: A similar variation trend between the concentration of glycyrrhetinic acid in plasma and that of Na, Cu elements in serum after oral administration of glycyrrhetinic acid was observed. Glycyrrhetinic acid in plasma at 2 h after administration reached the peak. Meanwhile, the concentration of Na and Cu at 4 h after the administration of glycyrrhetinic acid exhibited a significant increase (P < 0.05). Moreover, an increasing glycyrrhetinic acid dosage could result in the accumulation of Cu and Na in rat serum. Compared with the control group, the concentration of Cu and Na in the the glycyrrhetinic acid administration group with doses of 200 and 400 mg x kg(-1) revealed a significant increase (P < 0.05). However, glycyrrhetinic acid did not exhibit the great impact on the concentration of other elements in serum. CONCLUSION: This study focuses on the effect of oral administration of glycyrrhetinic acid on six metal elements in rat serum and provides an experimental basis for the adverse effect of glycyrrhetinic acid in clinical-applications.