Tumor-targeting intravenous lipid emulsion of paclitaxel:Characteristics,stability,toxicity,and toxicokinetics / 药物分析学报

Lipid nanoemulsions are promising nanodrug delivery carriers that can improve the efficacy and safety of paclitaxel(PTX).However,no intravenous lipid emulsion of PTX has been approved for clinical treatment,and systemic safety profiles have not yet been reported.Here we outline the development of a PTX-loaded tumor-targeting intravenous lipid emulsion(PTX Emul)and describe its characteristics,colloidal stability,and systemic safety profiles in terms of acute toxicity,long-term toxicity,and tox-icokinetics.We also compare PTX Emul with conventional PTX injection.Results showed that PTX Emul exhibited an ideal average particle size(approximately 160 nm)with narrow size distribution and robust colloidal stability under different conditions.Hypersensitivity reaction and hemolysis tests revealed that PTX Emul did not induce hypersensitivity reactions and had no hemolytic potential.In addition,where the alleviated systemic toxicity of PTX Emul may be attributed to the altered toxicokinetic characteristics in beagle dogs,including the decreased AUC and increased plasma clearance and volume of distribution,PTX Emul alleviated acute and long-term toxicity as evidenced by the enhanced the median lethal dose and approximate lethal dose,moderate body weight change,decreased bone marrow suppression and organ toxicity compared with those under PTX injection at the same dose.A fundamental understanding of the systemic safety profiles,high tumor-targeting efficiency,and superior antitumor activity in vivo of PTX Emul can provide powerful evidence of its therapeutic potential as a future treatment for breast cancer.

Chlorpyrifos exposure withdrawal induces delayed cytotoxicity in rat primary hippocampal neurons / 中国药理学与毒理学杂志

OBJECTIVE To investigate the delayed cytotoxicity effect of chlorpyrifos (CPF) with?drawal on primary hippocampal neurons. METHODS Hippocampal neurons were prepared from SD rat fetuses on the 17th day of gestation. Seven days after culture,neurons were exposed to CPF 10 and 30 μmol · L-1,respectively,for 72 h or for 48 h followed by CPF withdrawal for 24 h. CCK-8 kit and neuronal nuclei(NeuN), 5-bromodeoxyuridine(BrdU) and β Ⅲ tubulin immunofluorescence expression methods were used to evaluate the cell viability. RESULTS Compared with normal control, no significant cytotoxicity was found after CPF 72 h continuous exposure. However,CPF 48 h expo?sure followed by CPF withdrawal for 24 h induced evident cytotoxicity. The amount of BrdU positive and β Ⅲ tubulin positive hippocampal neurons were both decreased significantly(P<0.05),and cell survival and viability reduced after CPF withdrawal. CONCLUSION CPF exposure withdrawal can induce more seriously delayed cytotoxicity than continuous exposure in rat primary hippocampal neurons.

Determination of B7011 in rat plasma by liquid chromatography mass spectrometer and its pharmacokinetic characteristics / 中国药理学与毒理学杂志

OBJECTlVE To estabIish a simpIe,sensitive and quick method for determination of B7011 in rat pIasma. METHODS The method of protein precipitation with methanoI was used for pre-treatment of pIasma sampIes determined by Iiquid chromatography mass spectrometer. The Iinear reIa-tionship,intra-batch and inter-batch precision,specificity,matrix effect,recovery rate,the accuracy and stabiIity of the pIasma sampIes were vaIidated. The concentration of B7011 in pIasma was determined by LC-mS/ mS foIIowing a singIe intravenous injection of B7011 0.5 mg·kg-1 to rats. RESULTS The Iinear range of B7011 was 30-20 000 μg·L-1 ,the Iower Iimit of quantification was 30 μg·L-1 in pIasma,the in-tra-batch precision of 60,1000,16 000 and 10 000 ng·mL-1 was 5.61% -13.31%,2.31% -8.35%, 2.02%-9.47% and 4.0%-15.0% respectiveIy,and inter-batch precision was 10.05%,2.55%,3.75% and 8.58% respectiveIy. The recovery of 60,1000,and 16 000 μg·L-1 was 114.12%,109.2% and 101.06%respectiveIy. The average peak concentrations were 8373.28 and 8564.59 μg·L-1 ,the mean AUC was 98 400 and 104 000 μg·L-1·h and the t1/ 2z for B7011 was 41.7 and 63.6 h in bIood of maIe and femaIe rats, respectiveIy. CONCLUSlON The estabIished method is sensitive, fast and simpIe and concentration of B7011 in pIasma is determined by LC-mS/ mS foIIowing a singIe intravenous injection of B7011 0.5 mg·kg-1 to rats. It can satisfy the requirements of pharmacokinetic and toxicokinetic studies.

Bioequivalence of Metoprolol Tartrate Tablets in healthy volunteers / 中国临床药理学与治疗学

AIM: To study the bioequivalence of domestic and imported Metoprolol Tartrate Tablets in Chinese healthy volunteers.METHODS: According to the rule published by SFDA,the serum concentration of 20 selected volunteers among 18 to 40 years old was determined by HPLC-fluorescence detection after giving domestic and imported Metoprolol Tartrate Tablets 0.1g,and the pharmacokinetic parameters were calculated by DAS software.RESULTS: The method of HPLC-fluorescence detection to study the pharmakokinetics of Metoprolol Tartrate was sensitive,reliable,accurate and reasonable.The main pharmakokinetics parameters of domestic and imported Metoprolol Tartrate Tablets were T_(max):(1.11)?(0.36 h) and(1.39)?(0.65 h) respectively;C_(max):(269.20)?(87.15)(?g?L~(-1)) and(262.03)?(75.52)(?g?L~(-1)) respectively;AUC_(0-12h):(1088.91)?(510.52)(?g?L~(-1)?h) and(1098.29)?5(55.14)(?g?L~(-1)?h) respectively.The relative bioavailability of domestic Metoprolol Tartrate Tablets was(100.09)%.CONCLUSION: The domestic and imported Metoprolol Tartrate Tablets was bioequivalents.