Alternative therapies are necessary for the treatment of malaria due to emerging drug resistance.However,many promising antimalarial compounds have poor water solubility and suffer from the lack of suitable delivery s...Alternative therapies are necessary for the treatment of malaria due to emerging drug resistance.However,many promising antimalarial compounds have poor water solubility and suffer from the lack of suitable delivery systems,which seriously limits their activity.To address this problem,we synthesized a series of azacarbazoles that were evaluated for antimalarial activity against D10(chloroquine-sensitive)and W2(chloroquine-resistant)strains of P.falciparum.The most active compound,9H-3-azacarbazole(3),was encapsulated in a novel o/w nanoemulsion consisting of ethyl esters of polyunsaturated fatty acids n-3 and n-6 obtained from flax oil as the oil phase,Smix(Tween 80 and Transcutol HP)and water.This formulation was further analyzed using transmission electron microscopy,dynamic light scattering and in vitro and in vivo studies.It was shown that droplets of the 3-loaded nanosystem were spherical,with satisfactory stability,without cytotoxicity towards fibroblasts and intestinal cell lines at concentrations corresponding to twice the IC50 for P.falciparum.Moreover,the nanoemulsion with this type of oil phase was internalized by Caco-2 cells.Additionally,pharmacokinetics demonstrated rapid absorption of compound 3(tmax=5.0 min)after intragastric administration of 3-encapsulated nanoemulsion at a dose of 0.02 mg/kg in mice,with penetration of compound 3 to deep compartments.The 3-encapsulated nanoemulsion was found to be 2.8 and 4.2 times more effective in inhibiting the D10 and W2 strains of the parasite,respectively,compared to non-encapsulated 3.Our findings support a role for novel o/w nanoemulsions as delivery vehicles for antimalarial drugs.展开更多
为了解我国饮食中3-氯-1,2-丙二醇(3-monochloro-1,2-propanediol,3-MCPD)及3-MCPD酯的含量范围,并为制定我国饮食中3-MCPD酯的最大每日耐受摄入量提供数据支撑,本实验以菜肴(39种)为分析对象,样品经酸水解,七氟丁酰基咪唑衍生后,进气...为了解我国饮食中3-氯-1,2-丙二醇(3-monochloro-1,2-propanediol,3-MCPD)及3-MCPD酯的含量范围,并为制定我国饮食中3-MCPD酯的最大每日耐受摄入量提供数据支撑,本实验以菜肴(39种)为分析对象,样品经酸水解,七氟丁酰基咪唑衍生后,进气相色谱-串联质谱定量分析。该方法线性良好,相关系数为0.9972~0.9995;3-MCPD的加标回收率在95.0%~115.0%之间,相对标准偏差在2.9%~6%之间。结果表明,所有检测菜肴中均检出3-MCPD酯和3-MCPD,其在菜肴中的存在具有普遍性;餐馆菜肴中3-MCPD酯和3-MCPD的平均含量为516.11μg/kg和17.88μg/kg,而食堂菜肴中的含量较低,分别为75.86μg/kg和10.43μg/kg。在不同的烹饪方式产生3-MCPD酯和3-MCPD的量不同,含量由高到低依次为炸>干锅>炒>烧>炖。根据3-MCPD和3-MCPD酯暴露量计算结果,食堂菜肴均未超联合国粮食与农业组织/世界卫生组织联合食品添加剂专家委员会推荐的暂定每日最大耐受摄入量(provisional maximum tolerable daily intake,PMTDI),餐馆菜肴中3-MCPD的摄入量未超标,而3-MCPD酯为PMTDI值的2.2倍。展开更多
基金the statutory activity of subsidy from the Polish Ministry of Science and Higher Education for the Faculty of Biotechnology and Faculty of Chemistry of the University of Wroclaw and by Ministero dell’Istruzione,dell’Universit`a e della Ricerca[PRIN 2015.4JRJPP_004].Publication costs were supported by Wroclaw Center of Biotechnology program“The Leading National Research Center(KNOW)for years 2014-2018”.
文摘Alternative therapies are necessary for the treatment of malaria due to emerging drug resistance.However,many promising antimalarial compounds have poor water solubility and suffer from the lack of suitable delivery systems,which seriously limits their activity.To address this problem,we synthesized a series of azacarbazoles that were evaluated for antimalarial activity against D10(chloroquine-sensitive)and W2(chloroquine-resistant)strains of P.falciparum.The most active compound,9H-3-azacarbazole(3),was encapsulated in a novel o/w nanoemulsion consisting of ethyl esters of polyunsaturated fatty acids n-3 and n-6 obtained from flax oil as the oil phase,Smix(Tween 80 and Transcutol HP)and water.This formulation was further analyzed using transmission electron microscopy,dynamic light scattering and in vitro and in vivo studies.It was shown that droplets of the 3-loaded nanosystem were spherical,with satisfactory stability,without cytotoxicity towards fibroblasts and intestinal cell lines at concentrations corresponding to twice the IC50 for P.falciparum.Moreover,the nanoemulsion with this type of oil phase was internalized by Caco-2 cells.Additionally,pharmacokinetics demonstrated rapid absorption of compound 3(tmax=5.0 min)after intragastric administration of 3-encapsulated nanoemulsion at a dose of 0.02 mg/kg in mice,with penetration of compound 3 to deep compartments.The 3-encapsulated nanoemulsion was found to be 2.8 and 4.2 times more effective in inhibiting the D10 and W2 strains of the parasite,respectively,compared to non-encapsulated 3.Our findings support a role for novel o/w nanoemulsions as delivery vehicles for antimalarial drugs.
文摘为了解我国饮食中3-氯-1,2-丙二醇(3-monochloro-1,2-propanediol,3-MCPD)及3-MCPD酯的含量范围,并为制定我国饮食中3-MCPD酯的最大每日耐受摄入量提供数据支撑,本实验以菜肴(39种)为分析对象,样品经酸水解,七氟丁酰基咪唑衍生后,进气相色谱-串联质谱定量分析。该方法线性良好,相关系数为0.9972~0.9995;3-MCPD的加标回收率在95.0%~115.0%之间,相对标准偏差在2.9%~6%之间。结果表明,所有检测菜肴中均检出3-MCPD酯和3-MCPD,其在菜肴中的存在具有普遍性;餐馆菜肴中3-MCPD酯和3-MCPD的平均含量为516.11μg/kg和17.88μg/kg,而食堂菜肴中的含量较低,分别为75.86μg/kg和10.43μg/kg。在不同的烹饪方式产生3-MCPD酯和3-MCPD的量不同,含量由高到低依次为炸>干锅>炒>烧>炖。根据3-MCPD和3-MCPD酯暴露量计算结果,食堂菜肴均未超联合国粮食与农业组织/世界卫生组织联合食品添加剂专家委员会推荐的暂定每日最大耐受摄入量(provisional maximum tolerable daily intake,PMTDI),餐馆菜肴中3-MCPD的摄入量未超标,而3-MCPD酯为PMTDI值的2.2倍。
