Antineutrophil properties of natural gingerols in models of lupus.

Ginger is known to have antiinflammatory and antioxidative effects and has traditionally been used as an herbal supplement in the treatment of various chronic diseases. Here, we report antineutrophil properties of 6-gingerol, the most abundant bioactive compound of ginger root, in models of lupus and antiphospholipid syndrome (APS). Specifically, we demonstrate that 6-gingerol attenuates neutrophil extracellular trap (NET) release in response to lupus- and APS-relevant stimuli through a mechanism that is at least partially dependent on inhibition of phosphodiesterases. At the same time, administration of 6-gingerol to mice reduces NET release in various models of lupus and APS, while also improving other disease-relevant endpoints, such as autoantibody formation and large-vein thrombosis. In summary, this study is the first to our knowledge to demonstrate a protective role for ginger-derived compounds in the context of lupus. Importantly, it provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity.

Preparation and evaluation of phytantriol liquid crystal as a liquid embolic agent.

Transcatheter arterial chemoembolization (TACE) is the preferred treatment for patients with advanced hepatocellular carcinoma (HCC), but it lacks safe and effective embolic agents. 5-Fluorouracil (5-FU) is a broad-spectrum anticancer drug, but its clinical application is limited due to drug resistance and toxic side effects. Therefore, in this study, we developed a new liquid embolic agent with 5-FU as the model drug. We found that this liquid embolic agent possesses good gelling properties and embolic effects. An in vitro drug release model of the agent conformed to the Weibull model. Cumulative release of the drug over 7 d was ∼90%, consisting of an initial burst followed by sustained release. Cytotoxicity testing showed that each liquid embolic composition is cytocompatible and only mildly cytotoxic. Pharmacokinetic experiments showed that the formulation significantly prolongs the t1/2 of 5-FU (approximately five times that of 5-FU solution) and 5-FU residence time in the body (approximately three times that of 5-FU solution). These results indicate that the liquid embolic agent has embolic capacity and could be used as a potential therapeutic method for TACE.

Safety, Tolerability, Pharmacokinetics, and Food Effects on TAC-302 in Healthy Participants: Randomized, Double-Blind, Placebo-Controlled, Single-Dose and Multiple-Dose Studies.

TAC-302 stimulates neurite outgrowth activity and is expected to restore urinary function in patients with lower urinary tract dysfunction. We conducted 2 phase 1, randomized, placebo-controlled studies to confirm the safety and pharmacokinetics (PK) of TAC-302 in healthy adult Japanese male volunteers. In the first-in-human single-dose study (n = 60), TAC-302 was administered at doses from 100 to 1200 mg after an overnight fast. The effects of a meal on the PK of TAC-302 400 mg were also examined. A multiple-dose study (n = 36) evaluated the effects of meal fat content on the PK of single doses of TAC-302 (100, 200, or 400 mg) and multiple doses of TAC-302 administered for 5 days (100, 200, and 400 mg twice daily). TAC-302 showed linear PK up to doses of 1200 mg in the fasting state, and across the dose range of 100-400 mg in the fed state. No accumulation of TAC-302 was observed. Food, particularly with high fat content, increased TAC-302 plasma concentrations. No differences were observed in the adverse event incidence between the TAC-302 and placebo groups in either study. TAC-302 showed a wide safety margin.

Blood-brain barrier permeability study of ginger constituents.

Ginger, the rhizome of Zingiber officinale Roscoe is of great importance in the traditional medicine for the treatment of various diseases. More than 400 constituents have been reported in the plant, the most important ones being the gingerol and shogaol derivatives. Positive effects of ginger extracts and isolated [6]-gingerol have been proved in animal models of anxiety, Alzheimer's disease, Parkinson's disease and epilepsy. Taken in consideration these promising positive effects of ginger and its constituents in the central nervous system, the isolation of gingerol and shogaol derivatives ([6]-gingerol (1), [8]-gingerol (2), [10]-gingerol (3), [6]-shogaol (4), [10]-shogaol (5), 1-dehydro-[6]-gingerdione (6), 1-dehydro-[10]-gingerdione (7)) and investigation of their transcellular passive diffusion across the blood-brain barrier (BBB) were carried out. For this purpose, a Parallel Artificial Membrane Permeability Assay for the Blood-Brain Barrier (PAMPA-BBB) was chosen that had previously been validated for natural compounds. Based on our results, [6]-gingerol, [8]-gingerol and [6]-shogaol were found to be able to penetrate the BBB via passive diffusion, suggesting them to contribute to the positive effects of ginger extracts in the central nervous system.

Deposition of Aerosolized Lucinactant in Nonhuman Primates.

Background: Lucinactant for inhalation is an investigational noninvasive, aerosolized surfactant replacement therapy for treatment of preterm neonates with respiratory distress syndrome. Lucinactant for inhalation consists of lyophilized lucinactant and the Aerosurf® Delivery System (ADS). The objective of this study was to characterize the total and regional pulmonary deposition of lucinactant delivered by the ADS in nonhuman primates (NHPs). Methods: Lucinactant was radiolabeled by the addition of technetium-99m (99mTc)-sulfur colloid. The radiolabeled aerosol was characterized and validated using a Mercer cascade impactor. An in vivo deposition study was performed in three cynomolgus macaques. Radiolabeled lucinactant was aerosolized using the ADS and delivered via nasal cannula under 5 cm H2O nasal continuous positive airway pressure (nCPAP) for 5-9 minutes. A two-dimensional planar image was acquired immediately after aerosol administration, followed by a three-dimensional single-photon emission computed tomography (SPECT) image and a second planar image. The images were analyzed to determine the pulmonary (lungs) and extrapulmonary (nose + mouth, trachea, stomach) distribution. The SPECT data were used to determine regional deposition. Results: The radiolabed lucinactant aerosol had a mass median aerodynamic diameter = 2.91 µm, geometric standard deviation (GSD) = 1.81, and an activity median aerodynamic diameter = 2.92 µm, GSD = 2.06. Aerosolized lucinactant was observed to deposit in the lungs (11.4%), nose + mouth (79.9%), trachea (7.3%), and stomach (1.4%). Analysis of the SPECT image demonstrated that the regional deposition within the lung was generally homogeneous. Aerosolized lucinactant was deposited in both the central (52.8% ± 1.2%) and peripheral (47.2% ± 1.2%) regions of the lungs. Conclusion: Aerosolized lucinactant, delivered using the ADS via constant flow nCPAP, is deposited in all regions of the lungs demonstrating that surfactant can be aerosolized and delivered noninvasively to NHPs.

Preparation and in vitro/in vivo evaluation of 6-Gingerol TPGS/PEG-PCL polymeric micelles.

6-Gingerol, an active herbal ingredient of ginger has various bioactivities such as anti-neurodegenerative disease, anti-inflammatory and so on. The aim of the present study was to enhance the oral bioavailability and brain distribution of 6-Gingerol via polymeric micelles. A polymeric micelles drug delivery system of 6-Gingerol consisting of D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) and Poly (ethylene glycol)-poly (ε-caprolactone) (PEG-PCL) was prepared via solvent injection method. The developed 6-Gingerol-loaded TPGS/PEG-PCL micelles (6-GTPMs) were characterized based on particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE), drug loading (DL) and in vitro release profile. The pharmacokinetics and tissue distribution studies were also evaluated. The nanoformulation produced a particle size of 73.24 ± 2.84 nm with acceptable PDI (0.129 ± 0.03), zeta potential (-2.74 ± 0.92 mV), DL (4.64%) and EE (79.68%). The in vitro release profile showed that the 6-GTPMs enhanced the solubility of 6-Gingerol, while the pharmaceutical analysis in rats indicated that 6-GTPMs significantly improved the oral bioavailability of 6-Gingerol (about 3 folds) in circulation. The 6-GTPMs exhibited remarkable brain targetability in the tissue distribution analysis. Collectively, a 6-Gingerol polymeric micelle with enhanced oral bioavailability coupled with excellent brain distribution was successfully developed.

A Novel Phytantriol-Based In Situ Liquid Crystal Gel for Vaginal Delivery.

The purpose of this paper was to evaluate the potential of in situ liquid crystal (LC) gels based on phytantriol (PYT) for vaginal delivery. The PYT-based in situ liquid crystal gels (PILGs) were prepared by a vortex method using PYT, ethanol (ET), and water (in the ratio of 64:16:20, w/w). The internal structures of PILGs and cubic LC gels (formed by PILG phase conversion) were confirmed by crossed polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). And the rheological tests showed that PILGs had small viscosity and excellent fluidity. The viscosities of cubic LC gels were 4~5 orders of magnitude higher than PILGs. In vitro phase conversion experiment showed that PILGs required little vaginal fluid (64.56 µL/100 mg) and time (3.92 s) to transform to LC gels. Furthermore, cubic LC gels could reside in the vaginas for more than 12 h in vivo. The in vitro release revealed that sinomenine hydrochloride (SMH) could be sustained released from the cubic gels over a period of 144 h, which was prior to SMH solution and carbomer gels. An in vivo vaginal mucosa irritation study indicated that PILGs were nonirritant and might be suitable for various vaginal applications. In conclusion, PILGs might represent a potential vaginal delivery strategy to overcome the limitations of traditional treatments.

Pharmacokinetics and Tissue Distribution of Gingerols and Shogaols from Ginger (Zingiber officinale Rosc.) in Rats by UPLC⁻Q-Exactive⁻HRMS.

Gingerols and shogaols are recognized as active ingredients in ginger and exhibit diverse pharmacological activities. The preclinical pharmacokinetics and tissue distribution investigations of gingerols and shogaols in rats remain less explored, especially for the simultaneous analysis of multi-components. In this study, a rapid, sensitive, selective, and reliable method using an Ultra-Performance Liquid Chromatography Q-Exactive High-Resolution Mass Spectrometer (UPLC-Q-Exactive⁻HRMS) was established and validated for simultaneous determination of eight compounds, including 6-gingerol, 6-shogaol, 8-gingerol, 8-shogaol, 10-gingerol, 10-shogaol, Zingerone, and 6-isodehydrogingenone in plasma and tissues of rats. The analytes were separated on a Syncronis C18 column (100 × 2.1 mm, 1.7 µm) using a gradient elution of acetonitrile and 0.1% formic acid in water at a flow rate of 0.25 mL/min at 30 °C. The method was linear for each ingredient over the investigated range with all correlation coefficients greater than 0.9910. The lowest Lower Limit of quantitation (LLOQ) was 1.0 ng/mL. The intra- and inter-day precisions (Relative Standard Deviation, RSD%) were less than 12.2% and the accuracy (relative error, RE%) ranged from -8.7% to 8.7%. Extraction recovery was 91.4⁻107.4% and the matrix effect was 86.3⁻113.4%. The validated method was successfully applied to investigate the pharmacokinetics and tissue distribution of eight components after oral administration of ginger extract to rats. These results provide useful information about the pharmacokinetics and biodistribution of the multi-component bioactive ingredients of ginger in rats and will contribute to clinical practice and the evaluation of the safety of a Chinese herbal medicine.

Constitutive androstane receptor weakens the induction of panaxytriol on CYP3A4 by repressing the activation of pregnane X receptor.

Nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) play a vital role in regulating CYP3A4. Our previous studies have demonstrated that panaxytriol (PXT) upregulates the expression of CYP3A4 via the PXR regulatory pathway. This study aimed to explore how CAR mediates the regulation of CYP3A4 in the presence of PXT using HepG2 cell, hCAR-overexpressing HepG2 cell and hCAR-silenced HepG2 cell models. In HepG2 cells, PXT induced the expression of CYP3A4 in a concentration-dependent manner (10-80 µM) and the high concentration of PXT (80 µM) upregulated the expression of CAR. The concentrations of PXT (10-40 µM) had no impact on the expression of CAR, but could significantly induce the expression of CYP2B6 target gene by activating CAR. The dual-luciferase reporter gene assay also showed that CAR-mediated CYP3A4 luciferase activity can be promoted by 80 µM of PXT (1.54-fold), while 5, 10, 20, and 40 µM of PXT had no influence on CAR-mediated CYP3A4 luciferase activity. In hCAR-overexpressing HepG2 cells, PXT concentrations (10-40 µM) that significantly induced PXR and CYP3A4 in HepG2 cells had no impact on the expression of CYP3A4, CAR and PXR, whereas a high concentration of PXT (80 µM) could weakly induce the mRNA and protein levels of CAR and CYP3A4. Moreover, the expression of PXR and CYP3A4 in hCAR-silenced HepG2 cells was markedly elevated compared with the blank control or with normal HepG2 cells treated with 10-80 µM of PXT. In conclusion, CAR significantly weakens the ability of PXT to induce CYP3A4 expression by repressing the activation of PXR. There may be a cross-talk mechanism between PXR and CAR on the regulation of CYP3A4 in the presence of PXT. Additionally, a high concentration of PXT (80 µM) induced CYP3A4 via the CAR regulatory pathway.

Formulation, Characterization, and Pharmacokinetic Studies of 6-Gingerol-Loaded Nanostructured Lipid Carriers.

In this study, an optimized nanostructured lipid carriers (NLCs) were developed and investigated for improving the solubility and oral availability of 6-Gingerol (6G), an active and abundant component of ginger with limited applications due to its poor water solubility plus oral biological availability. The NLCs consisted of a solid lipid (glyceryl monostearate), another liquid lipid (decanoyl/octanoyl-glycerides) and mixed surfactants (Tween 80 and Poloxamer 188), and was prepared by high pressure homogenization method. The optimal 6G-NLC formulation was evaluated through physical properties such as appearance, mean particle size, zeta potential, encapsulation efficiency, and in vitro drug release, alongside techniques viz., transmission electron microscopy (TEM), differential scanning calorimetry (DSC), as well as powder X-ray diffraction (XRD). Pharmacokinetics were also evaluated in rats. The 6G-NLCs prepared with optimal formulation exhibited a homogenous spherical shape with mean particle size and zeta potential of 63.59 ± 5.54 nm and - 12.18 ± 1.06 mV. Encapsulation efficiency and drug loading were 76.71 ± 1.11 and 1.17 ± 0.35%, respectively. In vitro release profile of 6G from NLCs was sustained and fitted with Weibull equation. After oral administration of the 6G-NLCs, drug concentrations in serum, MRT, and AUC0-t were significantly higher as compared with the free 6G suspension. All these results indicated that the developed NLC formulation could be effective and promising drug carriers to improve the water solubility of 6G while sustaining the drug release as well as prolonging in vivo acting time of the drug coupled with oral bioavailability enhancement.

On the Structure and Transdermal Profile of Liquid Crystals Based on Phytantriol.

BACKGROUND: There has been a growing concern in transdermal drug technology over the past several decades. As a novel transdermal delivery system, Lyotropic liquid crystals (LLC) still face challenges such as drug loading, limited drug permeation and instability of systems. LLC system is so sensitive that a very subtle change in composition may induce a phase transformation or conversion of spatial configuration, and result in a diverse percutaneous delivery subsequently. OBJECTIVE: To find out the effects of hydrophilic and lipophilic components on the structure and transdermal properties of LLCs, hydrophilic sinomenine hydrochloride (SH) and lipophilic cinnamaldehyde (CA) was chosen as a model drug and a skin permeation enhancer, respectively, several formulations were prepared and compared. METHOD: The structure of LLC was evaluated by visual observation, Cross-polarizing light microscopy (CPLM) and Small angle X-ray diffraction (SAXS). The Franz diffusion cell was applied to investigate its skin penetration of SH across the rat skins. Fourier transform infrared spectroscopy (FTIR) was recorded to evaluate the intermolecular interaction between the LC samples and stratum corneum (SC). CONCLUSION: The results showed that a controlled transdermal process might be obtained by adjusting the ratios of different drugs or loading doses when LLCs with dual-components were applied.

PEGylated Triacontanol Substantially Enhanced the Pharmacokinetics of Triacontanol in Rats.

Triacontanol (TA), a natural compound with various health benefits, is extensively used as a nutritional supplement. The therapeutic and nutraceutical applications of TA are limited due to its poor aqueous solubility. PEGylated triacontanol (PEGylated TA) was designed to improve the solubility and pharmacokinetics of TA. After PEGylation, the solubility (∼250 g·L-1 versus 9 × 10-14 g·L-1), body residence (MRT, 9.40 ± 2.03 h versus 2.59 ± 0.705 h, p < 0.001), and systemic exposure (AUC0-inf, 29.1 ± 5.33 µM·h versus 0.529 ± 0.248 µM·h, p < 0.001) of TA were all significantly increased compared to pristine TA. When intravenously administered (6.85, 22.8, and 68.5 µmol·kg-1) in rats, PEGylated TA exhibited a slow clearance (44.8 ± 8.62, 47.9 ± 5.18, and 46.9 ± 16.5 mL·h-1·kg-1), long elimination half-life (8.76 ± 0.96, 10.4 ± 1.66, and 11.1 ± 2.81 h), and abundant systemic exposure (AUC0- t, 155 ± 24.2, 523 ± 56.2, and 1709 ± 245 µM·h). Meanwhile, its metabolite TA showed a high AUC0- t (28.4 ± 5.14, 151 ± 25.4, and 797 ± 184 µM·h) and slow elimination ( t1/2, 10.1 ± 2.03, 7.78 ± 1.74, and 6.82 ± 0.58 h). Our results demonstrated that PEGylated TA has superior pharmacokinetics, which enhanced its nutritional and pharmacodynamic potency, and thus warrants further investigations.

Phytosome complexed with chitosan for gingerol delivery in the treatment of respiratory infection: In vitro and in vivo evaluation.

Respiratory infection is a viral spreading disease and a common issue, particularly in kids. The treatments are available but have so many limitations because the drawback of this disease is more morbidity and mortality in the severely immune compromised. Even, the phyto-constituent antibacterial drug Gingerol was selected to treat respiratory infection but it exhibits low bioavailability profile, less aqueous-solubility issue and most important is rapidly eliminated from the body. To overcome these problems, novel drug delivery (nanoparticle) based phytosome complexed with chitosan approach was implemented. In this research work, the phytosome (GP) was prepared by blending of gingerol with soya lecithin in organic solvent using anti-solvent precipitation technique and it was further loaded in the aqueous solution of chitosan to formulate the phytosome complexed with chitosan (GLPC). To optimize the formulations of gingerol, it was characterized for percentage yield, percentage entrapment efficiency, drug loading and particle size, physical compatibility studies etc. which demonstrated the confirmation of complex of GLPC with soya lecithin and chitosan. The % entrapment efficiency and % drug loading of GLPC was found (86.02 ±â€¯0.18%, 08.26 ±â€¯0.72%) and of GP (84.36 ±â€¯0.42%, 08.05 ±â€¯0.03%), respectively. The average particle size and zeta potential of GLPC and GP were 254.01 ±â€¯0.05 nm (-13.11 mV), and 431.21 ±â€¯0.90 nm (-17.53 mV), respectively which confirm the inhibition of particle aggregation by using chitosan in complex. The in vitro release rate of GP (86.03 ±â€¯0.06%) was slower than GLPC (88.93 ±â€¯0.33%) in pH 7.4 phosphate buffer up to 24 h by diffusion process (Korsmeyer Peppas model). The optimized GLPC and GP were shown irregular particle shapes & spherical and oval structures with smooth surface by SEM analysis. Furthermore, GLPC has shown the potent in vitro antioxidant activity, susceptible antibacterial activity and effective anti-inflammatory activity as compared to GP against stress, microbial infection and inflammation which were causable reason for the respiratory infections. GLPC has improved the significant bioavailability and also correlated the hematological values on rabbit blood against the incubation of microorganisms. Thus, the prepared nanoparticle based approach to deliver the gingerol, has the combined effect of chitosan and phytosome which shown better sustained-release profile and also prolonging the oral absorption rate of gingerol with effective antibacterial activity to treat respiratory infection.

Quantification of triacontanol and its PEGylated prodrug in rat plasma by GC-MS/MS: Application to a pre-clinical pharmacokinetic study.

PEGylation techniques have been increasingly employed in drug delivery system and chemical modification of compounds with low aqueous solubility. Triacontanol (TA) is a natural product with several pharmacological activities, but its low aqueous solubility significantly limited its application. PEGylated triacontanol (PEG-TA) was designed as the prodrug to improve the aqueous solubility and pharmacokinetic properties of TA. On the basis of salting-out assisted liquid-liquid extraction (SALLE) and saponification sample preparation procedure, a reliable gas chromatography tandem mass spectrometric (GC-MS/MS) method was developed and validated for the quantification of PEG-TA and its metabolite TA in rat plasma after separation and transformation. Acetonitrile-methanol (9:1, v/v) and ammonium acetate (10 M) were utilized to separate PEG-TA and TA (including conjugated TA with fatty acid). Saponification facilitated the complete conversion of PEG-TA into TA, so PEG-TA could be indirectly quantified. The results revealed that the GC-MS/MS method had excellent selectivity, accuracy and linearity. Calibration curves were linear (R2>0.99) within the range of 20.0-1000.0 ng/mL for TA and 100.0-10,000.0 ng/mL for PEG-TA. The intra- and inter-day precision of quality control samples were within 15%, and their accuracy values varied from 93.54% to 113.38%. This analytical method has been successfully applied to pharmacokinetic study of PEG-TA. This study can facilitate the further exploration and quantification of PEGylated prodrugs.

Lyotropic Liquid Crystalline Nanoparticles of Amphotericin B: Implication of Phytantriol and Glyceryl Monooleate on Bioavailability Enhancement.

Implication of different dietary specific lipids such as phytantriol (PT) and glyceryl monooleate (GMO) on enhancing the oral bioavailability of amphotericin B (AmB) was examined. Liquid crystalline nanoparticles (LCNPs) were prepared using hydrotrope method, followed by in vitro characterization, Caco-2 cell monolayer uptake, and in vivo pharmacokinetic and toxicity evaluation. Optimized AmB-LCNPs displayed small particle size (< 210 nm) with a narrow distribution (~ 0.2), sustained drug release and high gastrointestinal stability, and reduced hemolytic toxicity. PLCNPs presented slower release, i.e., ~ 80% as compared to ~ 90% release in case of GLCNPs after 120 h. Significantly higher uptake in Caco-2 monolayer substantiated the role of LCNPs in increasing the intestinal permeability followed by increased drug titer in plasma. Pharmacokinetic studies demonstrated potential of PT in enhancing the bioavailability (approximately sixfold) w.r.t. of its native counterpart with reduced nephrotoxicity as presented by reduced nephrotoxicity biomarkers and histology studies. These studies established usefulness of PLCNPs over GLCNPs and plain drug. It can be concluded that acid-resistant lipid, PT, can be utilized efficiently as an alternate lipid for the preparation of LCNPs to enhance bioavailability and to reduce nephrotoxicity of the drug as compared to other frequently used lipid, i.e., GMO.

Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice.

Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P-gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, Kp, for the liver and kidney were higher in the piperine-pretreated group, while the Kp for kidney, brain and liver were higher in the capsaicin-pretreated group. [6]-Gingerol did not affect doxorubicin tissue distribution. The data demonstrated that the phytochemicals modulated doxorubicin tissue distribution, which suggested their potential to induce food-drug interactions and act as a strategy for the delivery of P-gp substrate drugs to target tissues and tumors.

Pharmacokinetic interaction of aconitine, liquiritin and 6-gingerol in a traditional Chinese herbal formula, Sini Decoction.

1. This study aimed to investigate the pharmacokinetic interaction of the three ingredients in a traditional Chinese herbal formulation, Sini Decoction, and provide evidence for its compatibility mechanism. 2. First, the effect of liquiritin and 6-gingerol on the pharmacokinetic parameters of aconitine was investigated in rats by using a sensitive and reliable LC-MS/MS method. Then the Caco-2 cell monolayer model and Rhodamine-123 uptake assay were used to investigate the effect of liquiritin and 6-gingerol on the absorption of aconitine and the activity of P-gp. 3. The Cmax of aconitine increased significantly (p < 0.05) from 10.34 ± 1.99 to 17.68 ± 2.65 ng/mL with the pretreatment of liquiritin (20 mg/kg), and to 17.43 ± 0.96 ng/mL with 6-gingerol (20 mg/kg). When aconitine was co-administered with liquiritin and 6-gingerol, the Cmax and AUC(0-t) of aconitine increased approximately twofold, and while t1/2 only increased 1.2-fold. The Caco-2 cell monolayer model and Rhodamine-123 uptake assay indicated that both liquiritin and 6-gingerol could increase the absorption of aconitine by inhibiting the activity of P-gp. 4. These results indicated that both liquiritin and 6-gingerol could promote the absorption of aconitine and increase its drug concentration in blood by inhibiting the activity of P-gp, and it could also provide evidence for compatibility mechanism of the traditional Chinese herbal formula, Sini Decoction.

A novel formulation of [6]-gingerol: Proliposomes with enhanced oral bioavailability and antitumor effect.

[6]-Gingerol, one of the components of the rhizome of Ginger, has a variety of biological activities such as anticoagulant, antioxidative, antitumor, anti-inflammatory, antihypertensive, and so forth. However, as one of the homologous phenolic ketones, [6]-gingerol is insoluble in water which limits its applications. Herein, we prepared [6]-gingerol proliposomes through modified thin-film dispersion method, which was spherical or oval, and physicochemically stable with narrow size distribution. Surprisingly, in vitro release of [6]-gingerol loaded proliposome compared with the free [6]-gingerol was significantly higher and its oral bioavailability increased 5-fold in vivo. Intriguingly, its antitumor effect was enhanced in the liposome formulation. Thus, our prepared [6]-gingerol proliposome proved to be a novel formulation for [6]-gingerol, which significantly improved its antitumor effect.

Pharmacokinetic profiles of falcarindiol and oplopandiol in rats after oral administration of polyynes extract of Oplopanax elatus.

Polyynes, such as facarindiol (FAD) and oplopandiol (OPD), are responsible for anticancer activities of Oplopanax elatus (O. elatus). A novel approach to pharmacokinetics determination of the two natural polyynes in rats was developed and validated using a liquid chromatography-electrospray ionization-mass spectrometry (LC-MS) method. Biosamples were prepared by liquid-liquid extraction using ethyl acetate/n-hexane (V : V = 9 : 1) and the analytes were eluted on an Agilent ZORBAX Eclipse Plus C18 threaded column (4.6 mm × 50 mm, 1.8 µm) with the mobile phase of acetonitrile-0.1% aqueous formic acid at a flow-rate of 0.5 mL·min(-1) within a total run time of 11 min. All analytes were simultaneously monitored in a single-quadrupole mass spectrometer in the selected ion monitoring (SIM) mode using electrospray source in positive mode. The method was demonstrated to be rapid, sensitive, and reliable, and it was successfully applied to the pharmacokinetic studies of the two polyynes in rat plasma after oral administration of polyynes extract of O. elatus.