Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by...Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by the absorption enhancement, which is a decisive factor for the clinical application of SMV nanoliposome(SMV-Lipo), but has not been studied systematically and reported so far. In this study, organ toxicity of SMV-Lipo was evaluated in mice in the presence and absence of isoproterenol and compared to those of free SMV. Results demonstrated that compared to free SMV, the SMV-Lipo administrated at an equal dose of 25 mg/kg/d led to severe myocardiotoxicity, hepatotoxicity at baseline and more pronounced liver injury with elevation of alanine aminotransferase. In addition, muscular adverse effect was also observed in SMV-Lipo treated group but not in SMV group. Pharmacokinetic studies revealed that compared to free SMV, the SMV-Lipo administration significantly improved the plasma SMV concentration, and the oral bioavailability was 6.5 times of free SMV. Notably, when the dosage of free SMV increased to 50 mg/kg/d, yielding the comparable plasma concentration as SMV-Lipo given at 25 mg/kg/d, the myocardiotoxicity was observed in free SMV treated mice as well, which further confirmed that the enhanced absorption of SMV by the nanoliposomal formulation resulted in more severe myocardiotoxicity than the equal dose of free SMV.展开更多
Tanshinone ⅡA（TSⅡA） is the major bioactive constituent of Salvia miltiorrhiza Bunge,a Chinese herbal medicine,which has protective effects on myocardial ischemia/reperfusion（MIR） injury.However,the cardioprotect...Tanshinone ⅡA（TSⅡA） is the major bioactive constituent of Salvia miltiorrhiza Bunge,a Chinese herbal medicine,which has protective effects on myocardial ischemia/reperfusion（MIR） injury.However,the cardioprotective effects of TSⅡA as well as its clinical use were limited due to its poor water solubility.The objective of this study was to evaluate whether Tanshinone ⅡA derivative（TD）,a new water soluble compound synthesized by TSⅡA and N-Methyl-D-Glucamine,had protective effects on MIR injury and what the related mechanism was.The cardioprotective effects of TD were evaluated and compared with TSⅡA in a rat MIR model.The results show that pretreatment with TD significantly alleviated inflammatory infiltration and exhibited antioxidant effect in MIR injury by reducing the activity of lactate dehydrogenase（LDH） and malondialdehyde（MDA）,decreasing expression of nuclear factor-κ-gene binding（NF-κB） and upregulating expression of heme oxygenase（HO-1）,but having no effect on the content of total superoxide dismutase（T-SOD） and m RNA expression of superoxide dismutase（SOD-1）.Thus,our study reveals that TD exerted significant protective effects on MIR injury through attenuating oxidative stress and inflammatory responses.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(No.81770268)the National Basic Research Program of China(No.2015CB932100).
文摘Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by the absorption enhancement, which is a decisive factor for the clinical application of SMV nanoliposome(SMV-Lipo), but has not been studied systematically and reported so far. In this study, organ toxicity of SMV-Lipo was evaluated in mice in the presence and absence of isoproterenol and compared to those of free SMV. Results demonstrated that compared to free SMV, the SMV-Lipo administrated at an equal dose of 25 mg/kg/d led to severe myocardiotoxicity, hepatotoxicity at baseline and more pronounced liver injury with elevation of alanine aminotransferase. In addition, muscular adverse effect was also observed in SMV-Lipo treated group but not in SMV group. Pharmacokinetic studies revealed that compared to free SMV, the SMV-Lipo administration significantly improved the plasma SMV concentration, and the oral bioavailability was 6.5 times of free SMV. Notably, when the dosage of free SMV increased to 50 mg/kg/d, yielding the comparable plasma concentration as SMV-Lipo given at 25 mg/kg/d, the myocardiotoxicity was observed in free SMV treated mice as well, which further confirmed that the enhanced absorption of SMV by the nanoliposomal formulation resulted in more severe myocardiotoxicity than the equal dose of free SMV.
基金The National Natural Science Foundation of China(Grant No.81360054)
文摘Tanshinone ⅡA（TSⅡA） is the major bioactive constituent of Salvia miltiorrhiza Bunge,a Chinese herbal medicine,which has protective effects on myocardial ischemia/reperfusion（MIR） injury.However,the cardioprotective effects of TSⅡA as well as its clinical use were limited due to its poor water solubility.The objective of this study was to evaluate whether Tanshinone ⅡA derivative（TD）,a new water soluble compound synthesized by TSⅡA and N-Methyl-D-Glucamine,had protective effects on MIR injury and what the related mechanism was.The cardioprotective effects of TD were evaluated and compared with TSⅡA in a rat MIR model.The results show that pretreatment with TD significantly alleviated inflammatory infiltration and exhibited antioxidant effect in MIR injury by reducing the activity of lactate dehydrogenase（LDH） and malondialdehyde（MDA）,decreasing expression of nuclear factor-κ-gene binding（NF-κB） and upregulating expression of heme oxygenase（HO-1）,but having no effect on the content of total superoxide dismutase（T-SOD） and m RNA expression of superoxide dismutase（SOD-1）.Thus,our study reveals that TD exerted significant protective effects on MIR injury through attenuating oxidative stress and inflammatory responses.
