Analysis of Selective Serotonin Reuptake Inhibitors Associated with QT Prolongation and Torsade de Pointes Adverse Events Based on Data Mining Methods / 中国药学杂志

OBJECTIVE: To excavate and evaluate the risk signals of QT prolongation and torsade de pointes(TdP) induced by selective serotonin reuptake inhibitors(SSRIs), provide references for clinical use. METHODS: Data from FDA adverse event reporting system (FAERS, from January 2004 through June 2018) were analyzed for each SSRIs, including fluoxetine, sertraline, citalopram, escitalopram, paroxetine, and fluvoxamine. When QT prolongation and TdP cases were identified using preferred terms (PT) and standardised MedDRA queries (SMQ), three different data mining algorithms were used to detect signalsreporting odds ratio (ROR), medicines and healthcare products regulatory agency (MHRA), and bayesian confidence popagation neural network (BCPNN), if all the three algorithms were positive, suggesting the generation of signals. RESULTS: A total of 3 912 reports of QT prolongation and TdP associated with SSRIs were retrieved through the SMQ. Among which, more females than males(2 349 vs. 1 150), mainly aged 18-44 and 45-64 years, and 90.64% were serious adverse events. The signals were found for fluoxetine, sertraline, citalopram, escitalopram, paroxetine and fluvoxamine at the SMQ level, the RORs (95%CI) were 5.25(4.79-5.76), 2.08(1.79-2.27), 2.86(6.32-7.44), 3.41(3.03-3.84), 2.09(1.84-2.37) and 10.44(8.17-13.33) respectively; the PRRs (X2) were 5.20(1 494.43), 2.01(140.41), 6.77(2 911.71), 3.93(462.34), 2.09(136.58) and 10.21(538.26) respectively; the Ics (IC-2SD) were 2.15(2.12), 1.54(1.52), 2.67(2.65), 2.34(2.31) 1.14(1.12) and 3.16(3.10) respectively. Analysis of the PT included in the SMQ for TdP/QT prolongation, except paroxetine was only detected electrocardiogram QT prolonged signal, all the other SSRIs were detected electrocardiogram QT prolonged and TdP signals. CONCLUSION: QT prolongation may be a SSRIs class effect, but TdP just for fluoxetine, sertraline, citalopram, escitalopram and fluvoxamine. Clinical staff should pay more attention to the differences in adverse drug reaction related to SSRIs, and take pertinence measure to prevent.

Attenuation mechanism of gamboges during processing based on inflammatory toxicity and AQP3, AQP4 protein and mRNA expressions in rat gastric and duodenal tissues / 中国中药杂志

To expand the clinical application of gamboges, it is necessary to study crude gamboges' toxicity after oral administration and attenuation mechanism during processing. In this study, crude gamboges' toxicity was judged by multiple assays, including inflammatory mediums [such as nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6)] released by macrophage RAW264.7, and pathological manifestations of rat stomach and duodenal tissues after oral administration with crude and processed gamboges. The attenuation mechanism during processing was studied by detecting AQP3, AQP4 protein and mRNA expression in rat gastric and duodenal tissues using immunohistochemical assay and real-time fluorescent quantitative PCR technique. According to the results, crude gamboges group showed promotion in release of NO, TNF-α and IL-6 by macrophage RAW264.7 in a dose-dependent manner; Compared with crude gamboges group, processed gamboges group showed reduction in release of NO and IL-6, with increase in TNF-α. Crude gamboges could cause rat diarrhea, white blood cells increase, lymphocytes decrease, hyperemia and edema in rat gastric mucosa, duodenal mucosal necrosis and inflammatory cells infiltration. All of these results proved that gamboges had the inflammatory toxicity in gastric and duodenal tissues after oral administration in a dose-dependent manner, which however reduced after processing. In addition to the inflammatory toxicity, the mRNA and protein expressions of aquaporin 3 (AQP3), aquaporin 4 (AQP4) in gastric and duodenal tissues of high-dose crude gamboges group were increased significantly (P<0.05), while the protein and mRNA expressions of AQP3, AQP4 were weakened in processed gamboges group. The results showed that AQP3, AQP4 protein and mRNA expressions were positively correlated with the inflammatory toxicity. In conclusion, down-regulation of AQP3, AQP4 protein and mRNA expressions may be one of attenuation mechanisms in processing gamboges.

Effect of Ginkgo biloba Tablet on the Expression of Scavenger Receptor A of the Aortic Wall in Atherosclerotic Rats / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the expression of Ginkgo biloba Tablet (GbT) on scavenger receptor A (SRA) of the aortic wall and changes of serum inflammatory factors in atherosclerotic rats, and to explore its new mechanism for fighting against atherosclerosis (AS).</p><p><b>METHODS</b>Totally 45 male Wistar rats were randomly divided into the control group, the model group, the GbT group, 15 rats in each group. Levels of blood glucose, blood lipids, blood calcium, serum C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (slCAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in all rats. The expression of SRA in the aortic wall of atherosclerotic rats was observed by immunohistochemical assay. The correlation between the expression of SRA and levels of in-flammatory factors was also observed.</p><p><b>RESULTS</b>Compared with the control group, blood glucose and blood calcium obviously increased (P < 0.05); levels of TG, TC, and LDL-C were significantly elevated (P < 0.01); neointimal areas were significantly thickened, increased intima percentage was significantly enlarged, narrowed lumen index was significantly reduced; levels of CRP, sICAM-1, and sVCAM-1 were significantly elevated in the model group (all P < 0.01). Compared with the model group, blood glucose and blood calcium obviously decreased (P < 0.05); levels of TG, TC, and LDL-C significantly decreased (P < 0.01) in the GbT group. Aortic lumens were obviously narrower in the model group than in the GbT group (P < 0.05). SRA expressed at the aortic wall. The aforesaid 3 indices were significantly improved in the GbT group than in the model group (P < 0.01). Serum levels of CRP, sICAM-1, and sVCAM-1 were significantly decreased in the GbT group than in the model group (P < 0.01). Serum levels of CRP, sICAM-1, and sVCAM-1 were positively correlated with the percentage of SRA positive expression area (r = 0.701, 0.604, 0.581, all P < 0.01).</p><p><b>CONCLUSIONS</b>Serum levels of inflammatory factors in atherosclerotic rats were elevated, and the expression of SRA in the aortic wall was enhanced. The expression of SRA was closely correlated with serum levels of inflammatory factors. GbT could decrease serum levels of inflammatory factors and inhibit the expression of SRA.</p>

Study on tissue distribution of psoraleae fructus decoction in rats / 中国中药杂志

Advanced technologies are used to clarify the meridian tropism theory of traditional Chinese medicine is an important part of theoretical studies of traditional Chinese medicine. In this article, modern pharmacokinetic method was used to investigate tissue distribution characteristics of psoralen and isopsoralen of Psoraleae Fructus decoction in rats, in order to provide research ideas and experimental basis for the meridian tropism theory. In this study, various tissue samples such as heart, liver, spleen, lung, kidney, brain and spermary were collected at different times after oral administration with FP decoction, in order to determine concentration of psoralen and isopsoralen by HPLC. Pharmacokinetic parameters were calculated by DAS 2.0 software. The study results showed that HPLC indexes of psoralen and isopsoralen in various tissues of rats met the determination requirements of biological samples. Both components were distributed in all of the tissues, with AUC(0-t) order of liver > lung approximately kidney > heart > brain approximately spleen > spermary. There was significant difference between liver, kidney, lung and other tissues (P < 0.05). MRT(0-t) of both psoralen and isopsoralen were about 10 h. Therefore, psoralen and isopsoralen showed stronger targeting selection in liver, kidney and lung.