[Mechanism of Gardenia jasminoides against cholestasis based on network pharmacology].

To screen the active ingredients of Gardenia jasminoides and potential targets,and investigate the mechanisms against cholestasis based on network pharmacology technology. Twenty-one active components of G. jasminoides were retrieved and the target sites were screened by using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform( TCMSP). Cytoscape3. 2. 1 was used to construct the component-target network. Two hundred and eight targets related to cholestasis were searched and screened through Dis Ge NET,KEGG and OMIM databases. The key targets of G. jasminoides components and cholestasis were integrated and screened,and the component-target-disease network was constructed with Cytoscape 3. 2. 1 software to screen out the core network whose freedom degree was greater than the average value. The Clue GO plug-in of Cytoscape 3. 2. 1 software was used to analyze the biological processes and pathway enrichment of G. jasminoides in regulation of cholestasis. GO biological process analysis revealed 17 biological processes,involving 3 signaling biological processes related to cholestasis,i.e. acute inflammatory response,positive regulation of reactive oxygen species metabolic process,and nitric oxide biosynthetic process. KEGG-KEEG-305 terms and REACTOME pathways analysis revealed 17 regulatory pathways,involving 4 signaling pathways related to cholestasis,i.e. metabolism of xenobiotics by cytochrome P450,nuclear receptor transcription pathway,GPVI-mediated activation cascade and platelet activation. It was found that aqueous extract of G. jasminoides could improve serum biochemical abnormalities in ANIT-induced cholestasis rats. Aqueous extract of G. jasminoides could decrease the protein and mRNA expression levels of ESR1 in liver tissues,and increase the protein and mRNA expression levels of PPARG,NOS2,F2 R,NOS3,and NR3 C1. To sum up,the possible mechanisms of G. jasminoides against cholestasis may be related with the above three processes and four pathways.

An exploration of the role of a fish-oriented diet in cognitive decline: a systematic review of the literature.

Epidemiological studies have presented inconsistent evidence of the correlation between a fish-oriented dietary intake (FDI) and the risk of cognitive decline. To address these controversies, we performed this systematic review of prospective studies published in December 2016 and earlier using PubMed, Embase, and Web of Science. Two independent researchers conducted the eligibility assessment and data extraction; all discrepancies were solved by discussion with a third researcher. The pooled relative risks (RRs) focused on the incidence of events were estimated with 95% confidence intervals (CIs). Overall, nine studies containing 28,754 subjects were analyzed. When the highest and lowest categories of fish consumption were compared, the summary RR for dementia of Alzheimer type (DAT) was 0.80 (95%CI = 0.65-0.97); i.e., people with a higher intake of fish had a 20% (95%CI = 3-35%) decreased risk of DAT. Additionally, the dose-response synthesized data indicated that a 100-g/week increase in fish intake reduced the risk of DAT by an additional 12% (RR = 0.88, 95%CI = 0.79-0.99). Non-significant results were observed for the risk of dementia of all causes (DAC) and mild cognitive impairment (MCI). Limited evidence involving heterogeneity was found within subgroups or across studies. In conclusion, this review confirmed that a higher intake of fish could be correlated with a reduced risk of DAT. Further research, especially prospective studies that specifically quantify FDI, will help find a more accurate assessment of the different levels of dietary intake.

Role of Medicinal Plants for Liver-Qi Regulation Adjuvant Therapy in Post-stroke Depression: A Systematic Review of Literature.

Current evidence demonstrated certain beneficial effects of medicinal herbs as an adjuvant therapy for post-stroke depression (PSD) in China; Chai-hu (Chinese Thorowax Root, Radix Bupleuri) is an example of a medicinal plant for Liver-Qi regulation (MPLR) in the treatment of PSD. Despite several narrative reports on the antidepressant properties of MPLR, it appears that there are no systematic reviews to summarize its outcome effects. Therefore, the aim of this review was to assess the effectiveness and safety of MPLR adjuvant therapy in patients with PSD. Seven databases were extensively searched from January 2000 until July 2016. Randomized control trials (RCTs) involving patients with PSD that compared treatment with and without MPLR were taken into account. The pooled effect estimates were calculated based on Cochrane Collaboration's software RevMan 5.3. Finally, 42 eligible studies with 3612 participants were included. Overall, MPLR adjuvant therapy showed a significantly higher effective rate (RR = 1.23; 95% CI = 1.19, 1.27; p < 0.00001) compared to those without. Moreover, the administration of MPLR was superior to abstainers regarding Hamilton Depression Scale (HAMD) score changes after 3 weeks (WMD = -4.83; 95% CI = -6.82, -2.83; p < 0.00001), 4 weeks (WMD = -3.25; 95% CI = -4.10, -2.40; p < 0.00001), 6 weeks (WMD = -4.04; 95% CI = -5.24, -2.84; p < 0.00001), 8 weeks (WMD = -4.72; 95% CI = -5.57, -3.87; p < 0.00001), and 12 weeks (WMD = -3.07; 95% CI = -4.05, -2.09; p < 0.00001). In addition, there were additive benefits in terms of response changes for the National Institutes of Health Stroke Scale (NIHSS) and other self-rating scores. No frequently occurring or serious adverse events were reported. We concluded that there is supporting evidence that adjuvant therapy with MPLR is effective in reducing the depressive symptoms and enhancing quality of life for patients with PSD. More well-designed RCTs are necessary to explore the role of MPLR in the treatment of PSD. Copyright © 2016 John Wiley & Sons, Ltd.

Is adjunctive treatment with medication of liver-soothing-oriented method beneficial for depression after cerebrovascular accident?: A PRISMA-compliant meta-analysis.

BACKGROUND: Adjunctive treatment with medication of liver-soothing-oriented method (MLSM) is one of the most commonly used approaches for subjects with depression after cerebrovascular accident (DCVA) in China. The purpose of this meta-analysis was to evaluate the outcome of MLSM treatment in subjects with DCVA using relevant published literature. METHODS: The PubMed, Cochrane Library, Embase, Chinese databases of China National Knowledge Infrastructure, WanFang, Sinomed, and VIP were used to collect all publications until March 2016. Randomized controlled trials comparing treatments with and without MLSM for subjects with DCVA were included. The quality of each publication was assessed based on the recent Handbook (5.1 version) for Cochrane Reviewers. Cochrane Collaboration's software RevMan 5.3 software was applied for data analysis. RESULTS: Thirty studies, including 2599 cases, were identified and collected. Adjunctive treatment with MLSM noticeably enhanced total effective rates (odds ratio 3.76; 95% confidence interval [CI] 2.92-4.85, I = 0%, P = 0.96) in comparison to non-MLSM conventional pharmacotherapy. Compared to non-MLSM treatment, the changes of Hamilton Depression Scale in adjunctive treatment with MLSM, respectively, decreased and showed beneficial effects after 3 weeks (weighted mean difference [WMD] -4.83; 95% CI -6.82 to -2.83; I = 86%, P < 0.001), 4 weeks (WMD -4.20; 95% CI -5.06 to -3.33; I = 78%, P < 0.001), 6 weeks (WMD -3.36; 95% CI -4.05 to -2.68; I = 54%, P = 0.02), 8 weeks (WMD -4.83; 95% CI -5.62 to -4.04; I = 73%, P < 0.001), and 12 weeks (WMD -2.88; 95% CI -4.09 to -1.67; I = 58%, P = 0.09). As for changes in inflammatory cytokine levels, adjunctive treatment with MLSM was associated with a significant decrease in tumor necrosis factor-α, IL-6, and interleukin-1ß levels in comparison to non-MLSM treatment. Moreover, there were positive effects on score changes for National Institute of Health Stroke Scale, activities of daily living, Hamilton Anxiety Scale, Modified Edinburgh Scandinavian Stroke Scale, and Self-Rating Anxiety Scale. No serious adverse events were reported. CONCLUSION: MLSM appears to improve symptoms of depressive disorders, enhance immediate responses, and the quality of life in subjects with DCVA. The positive action of MLSM might be potentially connected with its immunoregulating effects. More prospective trials with strict design and larger sample sizes are warranted to clarify its effectiveness and safety.

Oral Chinese herbal medicine for kidney nourishment in Alzheimer's disease: a systematic review of the effect on MMSE index measures and safety.

OBJECTIVE: To evaluate the effectiveness and safety of the Chinese herbal medicine for kidney nourishment (CHMK) assessed with the Mini-Mental Status Examination (MMSE) index objective outcome measures in individuals with Alzheimer's disease. METHODS: Searches were conducted in 7 medical databases from their inceptions until July 19, 2014 for randomized controlled trials (RCTs) that compared the oral administration of CHMK plus conventional pharmacotherapy with the same conventional pharmacotherapy alone with MMSE index measures as outcomes. Relevant resources were also manually retrieved. Two reviewers screened the citations of the reports, assessed the risk of bias and extracted data independently. Data analysis was carried out with Cochrane Collaboration's RevMan5.2.6 software and evidence quality grading evaluation of the systematic review was conducted with Grades of Recommendations Assessment Development and Evaluation (GRADE) profiler software. RESULTS: A total of 20 studies involving 1682 participants were included in the meta-analysis. There were 15 trials that compared CHMK with conventional pharmacotherapy and 5 trials that compared CHMK plus conventional pharmacotherapy with conventional pharmacotherapy alone. The main meta-analysis results showed relative benefits in effective rates in five studies (odds ratio [OR] 2.74, 95% confidence interval [CI] 1.55-4.85) and cure rate/clinical-control rates in five studies (OR 1.91, 95% CI 1.27-2.88) in favor of the CHMK plus conventional pharmacotherapy group. As for CHMK compared with conventional pharmacotherapy, no significant differences were noted in the effective rate (OR 1.09, 95% CI 0.82-1.46; cure rate (OR 1.06, 95% CI 0.81-1.38) and detailed sub-group of MMSE scores from the onset time to 4 weeks (weighted mean difference [WMD] 0.31, 95% confidence interval [CI] -0.81 to 1.42, 8 weeks WMD 1.12, 95% CI -0.54 to 2.78, 12 weeks (WMD 0.43, 95% CI -1.62 to 2.48, or 24 weeks WMD 1.92, 95% CI -1.60 to 5.44) follow-up and the overall effect (WMD 0.79, 95% CI -0.11 to 1.69). Moreover, weaknesses in methodological quality were identified in most studies according to Cochrane Risk of Bias tool assessment, while the quality level of GRADE classification indicated "very low". The incidence of adverse events with CHMK (0.87%) was lower than in the conventional pharmacotherapy group (4.08%), which revealed use of CHMK was relatively safer than conventional pharmacotherapy alone. CONCLUSION: The effectiveness and safety of oral administration of CHMK cannot be currently determined because of publication bias and the low quality level of the included trials. Further studies on a larger scale and with more rigorous designs are required to define the role of CHMK in the treatment of AD.

Determination and pharmacokinetics of amygdalin in rats by LC-MS-MS.

A sensitive and specific liquid chromatography-tandem mass spectrometric (LC-MS-MS) method was developed for the determination and pharmacokinetics of amygdalin in rats. Rat plasma pretreated by solid-phase extraction was analyzed by LC-MS-MS with negative electrospray ionization in the multiple reaction monitoring mode. Amygdalin and geniposide [the internal standard (IS)] were separated on a C18 column eluted with a mobile phase of methanol and water (85:15; v/v) at a flow rate of 0.25 mL/min in a run time of 3.0 min. The precursor to product ion transitions were monitored at m/z 457.2 → 279.1 for amygdalin and m/z 387.1 → 224.9 for the IS. The calibration curve of amygdalin showed good linearity over a concentration range of 10-2,000 ng/mL. The limit of quantification was 10 ng/mL. Intra-day and inter-day precisions and accuracy (percent relative standard deviation) were both within 10%. The method was fully validated for its selectivity, sensitivity, matrix effect, recovery and stability. This accurate and specific assay produced a useful LC-MS-MS method, which was successfully applied to pharmacokinetic studies after the oral administration of amygdalin to rats.

Effect of borneol on cytochrome P450 3A enzyme and midazolam pharmacokinetics in rats.

Borneol is a commonly used herbal medication in China and Japan. Previous studies have indicated that borneol could reduce the plasma concentrations of oneself and concomitant drugs, and its first-pass metabolism could be catalyzed by the cytochrome P450 3A (CYP3A) enzyme as well. The impact of borneol on CYP3A activity and efficacy in influencing the pharmacokinetics of co-administrated drugs is currently unknown. Therefore, the purpose of the current study is to investigate the effect of borneol on CYP3A enzyme in vivo. After treatment with borneol twice daily for 3 days, rat liver microsomes were exposed to probe substrates to determine CYP3A enzyme activity, protein, and RNA harvested using microsomal testosterone 6ß-hydroxylation as a marker of enzyme activity. To verify the result, the effect of borneol on the pharmacokinetics of the CYP3A model substrate midazolam was further examined. The results showed that borneol treatment had increased CYP3A expression at the mRNA, protein, and activity (testosterone 6ß hydroxylase activity) level in rat liver microsomes. In addition, borneol accelerated the metabolism of midazolam, which was consistent with the enhancement in CYP3A metabolic capacity. The hepatic clearance (Cl) of midazolam injected via the caudal vein in rats following borneol co-administration was higher; however, the area under the curve (AUC0-∞) was lower than the solvent. Hence, it was proposed that borneol could increase the metabolic activity of the CYP3A enzyme, which might cause drug-drug interactions in humans when using Chinese herbal or Western medicine with borneol.

[The anti-portal hypertension effect of oleanolic acid in CCl4-induced cirrhosis rats].

OBJECTIVE: To study the anti-portal hypertension effect of oleanolic acid (OA) in CCl4-induced cirrhosis rats and its mechanism. METHODS: Rats were induced to portal hypertension by CCl4. After treatment with low dose of OA (30 mg/kg) and high dose of OA (60 mg/kg) by intragastrically for a month, the parameters in serum or liver tissue including ALT, AST, MDA, GSH-Px, NOx, eNOS, cGMP and type I collagen were measured. The MAP, PP and HR were determined by hameodynamic method and the eNOS expression in liver was measured by western blot. The pathological changes of liver tissue were also tested by Masson dye. The normal group and model group were given 0.25% of CMC-Na solution. RESULTS: Compared with the model group, treatment with 30 mg/kg and 60 mg/kg OA significantly decreased the levels of ALT, AST, ALP, gamma-GT and MDA and enhanced the level of GSH-Px in liver (P<0.05). Moreover, the collagen content also notably lowered in CCl4-induced cirrhosis rats, thus decreasing the portal pressure (PP). However, the MAP and HR were not affected by OA treatment. In addition, the expression of eNOS in liver markedly increased after one mouth treatment of OA, hereof enhancing the level of cGMP and NOx in the CCl4-induced portal hypertensive rats (P<0.05). CONCLUSION: OA could inhibit the progress of fibrosis and lower the PP in CCl4-induced portal hypertensive rats and the anti-portal hypertension effect might be related to increasing the expression of eNOS and enhance the NOx level in liver.

Simultaneous determination of esculin and its metabolite esculetin in rat plasma by LC-ESI-MS/MS and its application in pharmacokinetic study.

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method operated in the negative electrospray ionization (ESI) switching mode has been developed and validated for the simultaneous determination of esculin and its metabolite esculetin in rat plasma. After addition of internal standards scopoletin, the plasma sample was pretreated by solid-phase extraction (SPE), and separated on a reversed phase C(18) column with a mobile phase of 0.01% formic acid in water (solvent A) and methanol (solvent B) using isocratic elution (A:B=20:80, v/v). The detection of target compounds was done in multiple reaction monitoring (MRM) mode. The MRM detection was operated in the negative ESI mode using the transitions of m/z 339.1 ([M-H](-))→176.7 for esculetin, m/z 176.9 ([M-H](-))→133.0 and m/z 191.0 ([M-H](-))→175.9 for scopoletin. The standard curves, which ranged from 25 to 3200 ng/mL for esculin with the lowest limit of quantification (LLOQ) of 0.25 ng/mL and from 1.25 to 160 ng/mL for esculetin with the LLOQ of 1.25 ng/mL, were fitted to a 1/x weighted quadratic regression model. The method also afforded satisfactory results in terms of the sensitivity, specificity, precision (intra- and inter-day, RSD<8.73%), accuracy, recovery as well as the stability of the analyte under various conditions. The method was successfully applied to study the pharmacokinetics of esculin and its metabolite esculetin in rat plasma after oral administration of esculin at a dose of 100mg/kg.

Determination of geniposidic acid in rat plasma by LC-MS/MS and its application to in vivo pharmacokinetic studies.

A simple, rapid and sensitive method for the determination of geniposidic acid (GSA) in rat plasma was developed using liquid chromatography tandem mass spectrometry (LC-MS/MS). Geniposide (GS) was used as the internal standard. Rat plasma pretreated by solid-phase extraction (SPE) was analyzed by LC-MS/MS with negative ion mode electrospray ionization (ESI) in the multiple reaction monitoring (MRM) mode. The analytical column was C8 column and the mobile phase was methanol (A) and water (B). The flow rate was set at 0.8 mL/min with split ratio of 1:3, the total run time was 15 min. The MS/MS ion transitions monitored were m/z 373.3-211.1 for GSA and m/z 387.3-225.3 for GS. The quantification limit was 5 ng/mL within a linear range of 10-4000 ng/mL. The inter-day and intra-day accuracy and precision were within ±10%. The method was fully validated for its sensitivity, selectivity, matrix effect, stability study and recovery. The data indicate that our LC-MS/MS assay is an effective method for the pharmacokinetics study of GSA in rat plasma.

Pharmacokinetics of natural borneol after oral administration in mice brain and its effect on excitation ratio.

Previous studies have indicated that borneol has double side effects on the central nervous system (CNS), but the mechanism is unknown. The aim of this study was to clarify the relationship between excitation ratio [contents of excitatory amino acids (AAs) versus that of inhibitory] and the content of natural borneol after a single oral dose. Mice were administered a 1.2 g/kg dose of natural borneol (containing 98% D: -borneol) by oral ingestion. Brain samples were collected before administration and at 0.083, 0.167, 0.25, 0.333, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4 and 5 h after administration. The brain concentration of natural borneol and contents of AA neurotransmitters in mice brain were determined by GC-MS and HPLC-FLU, respectively. After per oral application, natural borneol was absorbed rapidly into the brain and could be determined 5 min after dosing. The maximal brain concentration (86.52 µg/g) was reached after 1 h post-dosing. Natural borneol could affect the contents of AA neurotransmitters in mice brain: L: -aspartic acid increased significantly from 0.083 to 1 h after administration, L: -glutamic acid increased significantly at 0.333 h and decreased from 1.5 to 5 h, gamma-amino-N-butyric acid increased significantly from 0.167 to 5 h, whereas glycine was not affected. The excitation ratio is the contents of excitatory AAs versus that of inhibitory AAs, which reflects the excitatory or inhibitory state of the body. The excitation ratio elevated transitorily and then declined 0.5 h post-dosing; there were significant differences between 1.5-5 h post-dose compared with pre-dose. The present study indicated that natural borneol could affect the contents of AA neurotransmitters, and the change in excitatory ratio led to borneol's double side effects on the CNS.

[Anticoagulative effect and antiplatelet aggregation effect of combination of Hirudo and Tabanus on rat model of blood stasis syndrome].

OBJECTIVE: To observe anticoagulative effect and antiplatelet aggregation effect of the combination of Hirudo and Tabanus with different dose-ratio on rat model of blood stasis syndrome. METHODS: The rat model of blood stasis syndrome was established by subcutaneous injection of adrenaline combined with stimulation of icy water. Then prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) contents and inhibition rate of blood platelet aggregation were determined. RESULTS: Platelet aggregation increases, APTT and PT reduced, and FIB contents increased in model control group significantly (P<0.001). Hirudo, Tabanus and the combination of Hirudo and Tabanus had antiplatelet aggregation effect in varying degrees. APTT and PT were prolonged significantly (P<0.05 and P<0.01, respectively) in Hirudo group, Tabanus group and combination groups, especially in the group with dose-ratio of Hirudo to Tabanus being 4:3. FIB contents decreased significantly in combination group with dose-ratio being 3:1 (P<0.05). CONCLUSIONS: The combination groups of Hirudo and Tabanus have better effect of anticoagulation and antiplatelet aggregation than Hirudo group and Tabanus group. While in the four combination groups, the group recommended by classical TCM monograph with dose-ratio of Hirudo to Tabanus being 4:3, has the best anticoagulation effect.

[Effects of Realgar and prescription containing Realgar on stress response proteins, inflammatory mediators and complements in fever rat models].

OBJECTIVE: To explore the pharmacological mechanism of Realgar by the way of studying the effects of Realgar and the prescription containing Realgar named Niuhuang Jiedu Tablet on stress response proteins (heat shock protein 70, HSP70 and heme oxygenase-1, HO-1), inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha), activities of nitric oxide synthetase (NOS) and its isoenzyme (inducible nitric oxide synthetase, iNOS), and complements C3, CA under pathologic status (fever model). METHODS: SD rats were randomly divided into four groups, 15 rats in each: untreated normal group, fever model group, Realgar (90 mg/kg) group and Niuhuang Jiedu Tablet (NJT, 1.404 g/kg) group. Each group was divided into three subgroups (5 rats/subgroup). Blood samples of the rats in subgroups were collected at 1 h, 2 h and 4 h after administration, respectively. ELISA method was used to determine HSP70, IL-1beta, IL-6, and TNF-alpha levels in serum. Dual wavelength spectrophotometry was used to determine activity of HO-1 in serum. Spectrophotometry was used to test activities of nitric oxide synthetase (NOS) and its isoenzyme (inducible nitric oxide synthetase, iNOS) in serum. Immunonephelometery method was used to test complements C3, C4 in serum. RESULTS: Realgar and NJT significantly increased the level of HSP70 in rat serum as compared with the fever model group. Realgar and NJT significantly enhanced the activity of HO-1 in rat serum as compared with the fever model group. The increase ranges of HO-1 activities at different time post administration changed with the arsenic concentration in rat serum. Realgar and NJT significantly decreased the level of IL-1beta in rat serum as compared with fever model group, and the level of IL-lbeta recovered normaly at 4 h after administration. NJT significantly inhibited activities of NOS and iNOS in rat serum as compared with the fever model group at 2 h after administration. CONCLUSION: Realgar as contained in certain prescriptions, at certain specific levels, assists in removal of internal toxins by inducing stress protein (HSP70, HO-1) to improve the positive stress level in the body and inhibiting some over-releasing inflammatory mediators (IL-1beta) to reduce the inflammatory reactions under pathologic status.

[Effects of Rhizoma zingiberis and Pericarpium citri reticulatae extracts on myocardial ischemia in rats].

OBJECTIVE: To observe the effects of Rhizoma Zingiberis and Pericarpium Citri Reticulatae extracts on acute myocardial ischemia rats and explore the mechanism. METHODS: The model of myocardial ischemia in rats was established by ligating the front descending anterior branch of the coronary artery. With Fufang Danshen Pill as positive control drug,the effects of Rhizoma Zingiberis and Pericarpium Citri Reticulatae extracts on the electrocardiogram (ECG), the extension of myocardial infarction, the hemorheology indexes, lactic dehydrogenase (LDH), creatine kinase (CK), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in rats were evaluated. RESULTS: Rhizoma Zingiberis and Pericarpium Citri Reticulatae extracts decreased the ST-segment of ECG (P < 0.01), reduced the extension of myocardial infarction (P < 0.05), decreased the contents of CK and LDH in serum (P < 0.01 or P < 0.05), improved hemorheology (P < 0.05), increased SOD and GSH-Px activity and decreased MDA content (P < 0.05). CONCLUSION: Rhizoma Zingiberis and Pericarpium Citri Reticulatae extracts have protective effect on myocardial ischemia in rats, and its mechanism may be related to inhibiting lipid peroxidation.

Plasma pharmacokinetics and tissue distribution of [6]-gingerol in rats.

[6]-Gingerol is one of the pungent components in ginger which has been found to possess various pharmacological effects. However, there is insufficient information on the properties of [6]-gingerol based on controlled pharmacokinetic studies. The aim of this study was to clarify distribution profiles of [6]-gingerol in blood and biological tissues of experimental rats. Rats were administered a 240 mg/kg dose of Gs (a ginger extract, containing 53% [6]-gingerol) by oral ingestion. Plasma samples were collected at 2.5, 5, 7.5, 10, 15, 20, 30, 45 min, and 1, 1.5, 2, 3, 4 h after dosing (eight samples per time point), and brain, heart, lung, spleen, liver, kidney, stomach and small intestine tissues were collected at 5, 15, 30 min and 1, 2, 4 h after dosing (five animals per time point). Samples were prepared by a liquid-liquid extraction procedure and the extracts were assayed by HPLC-UV. After per oral application, [6]-gingerol was absorbed rapidly into the plasma, and the maximal concentration (4.23 microg/ml) was reached after 10 min post dosing. [6]-Gingerol plasma concentrations declined with time in a biexponential pattern. The elimination half-time at the terminal phase was 1.77 h and the apparent total body clearance was 40.8 l/h. When administered orally, [6]-gingerol was well distributed to the tissues examined, with the highest concentrations found in the gastrointestinal tract. Maximal concentrations of [6]-gingerol were reached in most tissues at 0.5 h post-dosing. The concentrations of [6]-gingerol in tissues all were higher than in plasma with corresponding tissue to plasma ratios greater than 1 after 0.25 h post-dose, showing high tissue partitioning and extensive distribution.

Effect of Danggui and Honghua on Cytochrome P450 1A2, 2C11, 2E1 and 3A1 mRNA Expression in Liver of Rats.

As alternative medicines or dietary supplements, herbal medicines have received increasing interest in recent years. Danggui and Honghua are two of the most popular traditional Chinese herbal medicines. However, little is known about the pharmacokinetics interactions between Danggui/Honghua and prescription drugs. Therefore, the present study was undertaken to investigate the effect of Danggui or Honghua on the gene expression of cytochrome P450 (CYP) using reverse- transcriptase-polymerase chain reaction (RT-PCR) in Wistar rats. Commercial Danggui (0.35 and 0.7 g/kg, twice a day), Honghua (0.35 g/kg or 0.7 g/kg, twice a day) or water (control group) were given to rats (3 rats for each group) for 5 consecutive days. Treatment of rats with 0.7 and 1.4 g/kg per day Danggui or Honghua for 5 days caused mild to strong increase of CYP 3A1 and decrease of CYP 2E1 RNA expression. However, only Honghua (0.7 and 1.4 g/kg per day) induced the increase of CYP 1A2 RNA expression, while CYP 2C11 RNA was unaffected by both Danggui and Honghua. These data demonstrated that Danggui or Honghua affected the expression of hepatic CYP isoforms in the rats; they elevated CYP 1A2 and 3A1 RNA expression but inhibited CYP 2E1 RNA expression. Such alterations may change the therapeutic actions of the drugs metabolized primarily by P450 system when they are co-administered to people with Danggui or Honghua. Therefore, patients should be cautioned about the potential drug-herb interactions between Danggui or Honghua and prescription drugs that were metabolized by CYP1A2, 2E1 and 3A1 isoforms.

The antithrombotic effect of borneol related to its anticoagulant property.

Borneol is consumed excessively in China and Southeast Asian countries particularly in combined formula for preventing cardiovascular disease, but few studies were conducted on its effects on thrombosis. In this study, the antithrombotic and antiplatelet activities of borneol were investigated on thrombosis in vivo and on platelet aggregation ex-vivo. In addition, the coagulation parameters and influence on fibrinolytic activity were also assessed. The results showed that borneol had concentration dependent inhibitory effects on arterio-venous shunt and venous thrombosis but no effect on ADP and AA-induced platelet aggregation. Meanwhile, borneol prolonged the coagulation parameters for prothrombin time (PT) and thrombin time (TT), but did not show any fibrinolytic activity. It suggested that the antithrombotic activity of borneol and its action in combined formula for preventing cardiovascular diseases might be due to anticoagulant activity rather than antiplatelet activity.

In vitro characterization of borneol metabolites by GC-MS upon incubation with rat liver microsomes.

The metabolism of borneol is studied by the analysis of incubations of in vitro-prepared rat liver microsomes. A sensitive gas chromatography (GC)-mass spectrometry (MS) method is developed for the identification of borneol and its metabolites. Four novel metabolites, which have not previously been reported, are isolated and confirmed by comparison of the GC-MS method. The biotransformation pathway of borneol in rat liver microsomes is proposed based on the in vitro results.

Pharmacokinetics of dihydroartemisinin in Artekin tablets for single and repeated dosing in Chinese healthy volunteers.

Aim. To study the pharmacokinetics of dihydroartemisinin (DHA) in Artekin (compound dihydroartemisinin) tablets in Chinese healthy volunteers. Methods. Eighteen healthy volunteers (9 males, 9 females) received Artekin tablets for oral administration. The plasma samples of DHA were analysed by liquid-liquid extraction and determined by HPLC/ESI/MS. Results. The plasma DHA concentration-time curves of single dose and repeated doses of DHA were fitted to a two-compartment open model. The mean pharmacokinetic parameters of DHA in a single dose were: t(1/2(beta))=1.245 +/- 0.495 h, C(max)=243.6 +/- 56.15 microg/l, AUC(0 --> infinity)=450 +/- 69 h x microg/l, V(d)=5.75 +/- 2.2 l/kg and Cl=3.245 +/- 0.38 l/h/kg, while in repeated doses they were: t(1/2(beta))=1.085 +/- 0.298 h, AUC(0 --> infinity)=444.35 +/- 80.43 h x ng/ml, V(d)=4.62 +/- 1.128 ml/kg, Cl=3.0125 +/- 0.875 ml/h/kg, respectively. Conclusion. The study showed that DHA in Artekin was rapidly absorbed, distributed and eliminated in the healthy subjects. The pharmacokinetic properties of DHA in Artekin were not affected by gender in a single dose. While in repeated doses accumulation of DHA did not appear after repeated doses.

Determination of CQP propionic acid in rat plasma and study of pharmacokinetics of CQP propionic acid in rats by liquid chromatography.

A sensitive method for the determination of CQP propionic acid in rat plasma was developed and validated after solid-phase extraction. Chromatographic separation was achieved on a reversed-phase Alltima C18 column with the mobile phase of methanol-0.15% (v/v) phosphoric acid solution (pH 2.5) and step gradient elution resulted in a total run time of about 20min. The analytes were detected by using UV detector at 345nm. A good linear relationship was obtained in the concentration range of 50-12,800ng/mL (r=0.9998). The intra-day RSDs and the inter-day RSDs at the concentration of 200, 800, 6400 and 12,800ng/mL were less than 7.0% and 11.0%, respectively. The intra-day accuracy ranged from 96.3 to 106.5% and the inter-day accuracy ranged from 98.6 to 113.4%, respectively. Average extraction recoveries ranged from 83.6 to 94.3% in plasma at the concentrations of 200, 800, 6400 and 12,800ng/mL. This method was successfully applied to the pharmacokinetic studies on rats.