Use of Failure Mode and Effects Analysis (FMEA) for Risk Analysis of Drug Use in Patients with Lung Cancer.

It is crucial to investigate the risk factors inherent in the medication process for cancer patients since improper antineoplastic drug use frequently has serious consequences. As a result, the Severity, Occurrence, and Detection rate of each potential failure mode in the drug administration process for patients with lung cancer were scored using the Failure Mode and Effect Analysis (FMEA) model in this study. Then, the risk level of each failure mode and the direction of improvement were investigated using the Slacks-based measure data envelopment analysis (SBM-DEA) model. According to the findings, the medicine administration process for lung cancer patients could be classified into five links, with a total of 60 failure modes. The risk of failure modes for patient medication and post-medication monitoring ranked highly, with unauthorized use of traditional Chinese medicine and folk prescription and unauthorized drug addition (incorrect self-medication) ranking first (1/60); doctor prescription was also prone to errors. The study advises actively looking at ways to decrease the occurrence and difficulty of failure mode detection to continually enhance patient safety when using medications.

[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.

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.

Geniposidic acid protected against ANIT-induced hepatotoxity and acute intrahepatic cholestasis, due to Fxr-mediated regulation of Bsep and Mrp2.

ETHNOPHARMACOLOGICAL RELEVANCE: Geniposidic acid (GPA) is the main constituent of Gardenia jasminoides Ellis (Rubiaceae), which has long been used to treat inflammation, jaundice and hepatic disorders. The cholagogic effect of Gardenia jasminoides Ellis (Rubiaceae) and GPA have been widely reported, but the underlying occurrence mechanism remains unclear. AIM OF THE STUDY: This investigation was designed to evaluate the hepatoprotection effect and potential mechanisms of GPA derived from Gardenia jasminoides Ellis (Rubiaceae) on fighting against α-naphthylisothiocyanate (ANIT) caused liver injury with acute intrahepatic cholestasis. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were intragastrically (i.g.) administered with the GPA (100, 50 and 25mg/kg B.W. every 24h) for seven consecutive days, and then they were treated with ANIT (i.g. 65mg/kg once in the 5th day) which induced liver injury with acute intrahepatic cholestasis. Serum and bile biochemical analysis, bile flow rate and liver histopathology were measured to evaluate the protective effect of GPA fight against ANIT treatment. The protein and mRNA expression levels of farnesoid X receptor (Fxr), bile-salt export pump (Bsep), multidrug resistance associated protein2 (Mrp2), were evaluated to study the effect of liver protection about GPA against ANIT induced hepatotoxicity and underlying mechanisms. RESULTS: Some abnormalities were observed on ANIT treated rats including weight loss, reduced food intake and hair turned yellow. Obtained results demonstrated that at dose 100 and 50mg/kg B.W. (P<0.01) and 25mg/kg B.W. (P<0.05) of GPA pretreated dramatically prevented ANIT induced decreased in bile flow rate. Compared with ANIT treated group, the results of bile biochemical parameters about total bile acid (TBA) was increased by GPA at groups with any dose (P<0.01), glutathione (GSH) was increased significantly at high dose (P<0.01) and medium dose (P<0.05), total bilirubin (TB) was increased at high and medium dose (P<0.05), direct bilirubin (DB) was only increased at high dose (P<0.01). Serum levels of glutamic-Oxalacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), γ-glutamyltranspeptidase (γ-GT), TB, DB and TBA in comparison with ANIT treated group (P<0.01) were reduced by GPA (between 100 and 50mg/kg B.W.) pretreatment. Histopathology of the liver tissue showed that pathological damages and hepatic portal area filled with bile were relieved after GPA pretreatment compared with ANIT treated group. The protein and mRNA expression of Fxr, Bsep and Mrp2 were decreased in ANIT treated group. On the contrary, the protein and mRNA of Fxr, Bsep and Mrp2 were up regulated significantly pretreatment by GPA at dose of high and medium groups. On protein level of Bsep and Mrp2 the result shown no statistical difference in GPA (25mg/kg B.W.), but it was not same shown in mRNA level. CONCLUSION: The results of this investigation have demonstrated that the GPA exerts a dose dependent hepatoprotection effect on ANIT induced liver damage with acute intrahepatic cholestasis in rats, which may due to Fxr mediated regulation of bile transporters like Bsep and Mrp2.

The pharmacokinetics change of cefepime after Shuanghuanglian injection administration in subjects with the renal damage.

Shuanghuanglian injection (SHLI) has been widely used for administration with cephalosporin in China for long time. The objective of this study was to evaluate the pharmacological properties and biochemical changes of cefepime combined with SHLI. The SD rats included were received either an intravenous (iv. 4 mL/kg) dose of normal saline, or intravenous (iv. 0.74, 0.37, 0.185 g/kg, respectively) doses of SHLI once daily for 7 days. After last administration, cefepime (0.41 g/kg) was intravenous injected to the animals. The serum and urine samples were acquired and stored at 4 °C. They were used for quantitative determination of urea nitrogen (BUN), creatinine (CRE), urine protein, alkaline phosphatase (ALP) and N-acetyl-B-d-glucosaminidase (NAG). At different time points, the levels of cefepime in rat plasma were estimated for pharmacokinetic measures by HPLC. Aspirin was selected as internal standard (IS). The results showed that there were positive effects by increasing the total amount of CRE, BUN, NAG and urine protein (p < 0.01 or <0.05) and decreasing the levels of ALP (especially the high dose group of SHLI with cefepime) (p < 0.01). Besides, the pharmacokinetic results indicated that cefepime was distributed as non-compartment model after intravenous administration. Compared with the corresponding values for the compounds given alone, the area under the blood drug concentration time curve (AUC0-t and AUC0-∞) was better increased in middle- and high-dose groups (pall < 0.01), the mean residence time (MRT) of cefepime was larger (pall < 0.01) and the total clearance (CL) was lower at different levels. The results mean that the duration and concentration of cefepime could be prolonged and the clearance reduced while in combination with SHLI. Furthermore, the cefepime in the three tested doses caused changes of renal tubular epithelial cells while the severity of changes mainly dependent on the specific doses. In conclusion, the results above-mentioned suggest a possible contribution of drug combination in the nephrotoxicity and biochemical alterations especially at high doses. Further, monitoring measures for the renal functions are warranted to evaluate during the combination of these two drugs.

Can Chinese Herbal Medicine Adjunctive Therapy Improve Outcomes of Senile Vascular Dementia? Systematic Review with Meta-analysis of Clinical Trials.

Many publications have reported the growing application of complementary and alternative medicine, particularly the use of Chinese herbal medicine (CHM) in combination with routine pharmacotherapy (RP) for senile vascular dementia (SVD), but its efficacy remains largely unexplored. The purpose of this study is to evaluate the efficacy of CHM adjunctive therapy (CHMAT), which is CHM combined with RP, in the treatment of SVD. Publications in seven electronic databases were searched extensively, and 27 trials with a total of 1961 patients were included for analysis. Compared with RP alone, CHMAT significantly increased the effective rate [odds ratio (OR) 2.98, 95% confidence interval (CI) 2.30, 3.86]. In addition, CHMAT showed benefits in detailed subgroups of the Mini-Mental State Exam (MMSE) score from time of onset to 4 weeks (WMD 3.01, 95% CI 2.15, 3.87), 8 weeks (weighted mean difference (WMD) 2.30, 95% CI 1.28, 3.32), 12 weeks (WMD 2.93, 95% CI 2.17, 3.69), and 24 weeks (WMD 3.25, 95% CI 2.61, 3.88), and in the activity of daily living scale score from time of onset to 4 weeks (WMD -4.64, 95% CI -6.12, -3.17), 8 weeks (WMD -4.30, 95% CI -6.04, -2.56), 12 weeks (WMD -3.89, 95% CI -4.68, -3.09), and 24 weeks (WMD -4.04, 95% CI -6.51, -1.57). Moreover, CHMAT had positive effects on changes in the Hasegawa dementia scale, National Institutes of Health Stroke Scale, Clinical Dementia Rating, and Montreal Cognitive Assessment scores, as well as blood fat levels (total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apolipoprotein E), platelet aggregation rate (1-min platelet aggregation rate, 5-min platelet aggregation rate, and maximal platelet aggregation rate), and blood rheology (whole-blood viscosity and hematocrit). No serious or frequently occurring adverse effects were reported. Weaknesses of methodological quality in most trials were assessed using the Cochrane risk of bias tool, while the quality level of Grades of Recommendations Assessment Development and Evaluation (GRADE) evidence classification indicated 'very low'. This systematic review suggests that CHM as an adjunctive therapy can improve cognitive impairment and enhance immediate response and quality of life in SVD patients. However, because of limitations of methodological quality in the included studies, further research of rigorous design is needed.

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.

Effects of sustained-release composite on the oxygen levels and sediment phosphorus fractions of an urban river in Shanghai.

The eutrophication of many rivers and lakes is attributed to the anoxia and the increasing internal loading of nutrients from sediment. A novel sustained-release composite (SRC) synthesis of stearic acid and calcium peroxide (CaO2) was applied to supply a water body with oxygen endured in this study. The influences of SRC on the dissolved oxygen (DO) level, pH and total phosphorus (TP) of an urban river in Shanghai were studied. The results show that SRC has a longer oxygen-releasing cycle and a more tender effect on pH with the comparison of CaO2 powder. Reduction of 79.6% in the concentration of TP was observed in the water column. After 35 days of SRC addition, there was a significant positive correlation between TP and DO. As a consequence, the phosphorus fractions in sediment, including loosely sorbed P (NH4Cl-P), redox-sensitive P (Fe-P), calcium bound P (Ca-P), aluminium bound P (Al-P) and residual P (organic and refractory P) were affected by the addition of SRC. The NH4Cl-P and Fe-P fractions in the sediment that could release P easily were well constrained under the positive effect of SRC.

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 oleanolic acid, p-coumaric acid, ferulic acid, kaemperol and quercetin in rat plasma by LC-MS-MS and application to a pharmacokinetic study of Oldenlandia diffusa extract in rats.

A simple, rapid and sensitive liquid chromatography tandem mass spectrometry method is presented for the simultaneous determination of oleanolic acid, p-coumaric acid, ferulic acid, kaemperol and quercetin in rat plasma. Glycyrrhetinic acid was used as an internal standard, and sample pretreatment consisted of a liquid-liquid extraction. Chromatographic separation was achieved on a Gemini 110A C18 column (50 × 2.0 mm i.d., 5 µm) by gradient elution with a mobile phase consisting of methanol, acetonitrile and 0.01% formic acid in water. Tandem mass spectrometric detection was conducted using multiple reaction monitoring under negative ionization mode. Calibration curves offered linear ranges of two orders of magnitude with r > 0.99. The method was validated in terms of matrix effect, intra-day and inter-day precision, accuracy, linearity, specificity and stability. The relative standard deviation of intra-day and inter-day variations ranged from 2.66 to 14.74% and 1.9 to 14.55%. No substantial endogenous interference from blank plasma was observed. The method has been successfully applied to a pharmacokinetic study of Oldenlandia diffusa extract after oral administration in rats.

An LC-MS/MS method for determination of jujuboside A in rat plasma and its application to pharmacokinetic studies.

A novel, simple, and sensitive method for the determination of jujuboside A in rat plasma using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed. Following solid-phase extraction, measurement of jujuboside A was performed by negative ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The limit of detection was 1.25 ng/mL, and the lower limit of quantification was 5 ng/mL in rat plasma. Good linearity was obtained over the range of 6.25-500 ng/mL, and the correlation coefficient was better than 0.998. The intra- and inter-day precisions ranged 4.4-7.5% and 2.9-10.7%, respectively. The accuracy derived from QC samples ranged 3.2-7.8% and 2.2-3.5%, respectively. The recovery ranged from 72.9 to 75.1% and the matrix effect from 96.7 to 105.3%. The analyte was stable under various conditions (at room temperature, during freeze-thaw, in the autosampler and under deep-freeze conditions). The developed method was successfully applied to the pharmacokinetic study in rats.

Pharmacokinetics of ferulic acid and potential interactions with Honghua and clopidogrel in rats.

AIM OF THE STUDY: Ferulic acid (FA), a compound isolated from herbs, has a big potential to be developed into a useful drug for the treatment of cardiovascular disease. Early estimation of potential drug interaction is critical for drug development. As a common Chinese herb and Western drug respectively, Honghua and clopidogrel are often combined with FA-containing herbs to treat cardiovascular disease in clinical practice. This study aimed to investigate the pharmacokinetics of FA and potential interaction with Honghua and clopidogrel in rats. MATERIALS AND METHODS: The experiments were performed on following three groups: FA alone (10mg/kg, P.O.), combination of FA and Honghua (700 mg/kg, P.O.), combination of FA and clopidogrel (7 mg/kg, P.O.). Blood samples were collected before dosing and at 0, 2, 4, 7, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180 and 210 min after drug administration to determine the plasma drug concentration of FA. RESULTS: FA was rapidly absorbed following oral administration with a mean time to peak plasma concentration (T(max)) of 0.03 h. The corresponding maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC) were 8174.55 ng/L and 2594.45 h ng/mL respectively. Coadministration of Honghua and clopidogrel resulted in a 63.5% and 79.7% increase in the AUC respectively. The C(max) of FA was significantly increased by coadministration with clopidogrel (74.3%, p<0.01). Moreover, the T(max) of FA when coadministered with Honghua or clopidogrel was 3 and 3.76 times slower than when administered alone. Other pharmacokinetic parameters estimated for FA were also altered by the coadministrations, but no statistically significant differences were observed. CONCLUSION: FA was rapidly absorbed with a low bioavailability after a single oral administration. The pharmacokinetics profile of FA in rats was partly altered by the coadministration of FA with Honghua or clopidogrel.

Antithrombotic effects of Danggui, Honghua and potential drug interaction with clopidogrel.

AIM OF THE STUDY: The antithrombotic effect of Danggui and Honghua, herbs commonly used in Traditional Chinese medicine to treat the syndrome corresponding to vascular thrombosis, and their potential interactions with clopidogrel were investigated. MATERIALS AND METHODS: The efficacy of Danggui, Honghua alone or combination with clopidogrel was determined in three experimental models. Bleeding time and hematology parameters were measured to evaluate safety. RESULTS: Danggui and Honghua exhibited antithrombotic effects against venous thrombosis and pulmonary embolism. Especially in the case of venous thrombosis, the thrombus weight was decreased significantly by Danggui or Honghua when compared with control. Bleeding time and coagulation time tended to be prolonged by Danggui or Honghua, but only prothrombin time (PT) and thrombin time (TT) were augmented significantly. The combinations of Danggui plus clopidogrel and of Honghua plus clopidogrel failed to significantly enhance the antithrombotic effects of clopidogrel alone against arterial thrombosis, venous thrombosis and pulmonary embolism. However, both Danggui and Honghua significantly potentiated the prolongation caused by clopidogrel on the tail bleeding time and PT. CONCLUSIONS: Danggui and Honghua possess antithrombotic activity and cannot potentiate the antithrombotic effect of clopidogrel. However, they significantly enhance the deleterious effect of clopidogrel on bleeding time, PT and TT.

[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.

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.