青蒿琥酯钠对体外大鼠红细胞膜钠-钾交换ATP酶的抑制

体外测定青蒿琥酯钠(SA)对大鼠红细胞膜Na~( )-K~( )-交换ATP酶活性的影响.方法:在反应系统中分别加入不同浓度的SA(0,0.5,1,5和10 μmol·L~(-1)),通过测定反应系统中释放的无机磷含量,计算酶活性.结果:随着SA浓度(O,0.5,1,5和10 μmol·L~(-1))的增高,对Na~( )-K~( )-交换ATP酶活性的抑制作用也随之增强,抑制率分别为15％,29％,46％和75％.将底物ATP浓度增加为125,250,375和500 μmol·L~(-1),进行了酶的动力学测定.用直线回归分析作Eadie-Hofstee动力学曲线,结果表明,SA对该酶的抑制作用为竞争性抑制.结论:提示SA可影响宿主红细胞膜的离子转运及膜的功能.     

青蒿琥酯和巴利捷克治疗塞内加尔恶性疟病儿的比较

目的：比较青蒿琥酯和巴利捷克治疗西非塞内加尔恶性疟的疗效。方法：西非恶性疟病儿１９０例，随机分为青蒿琥酯组７６例（男性４７例，女性２９例，年龄６±ｓ３ａ），用青蒿琥酯每次１５ｍｇ／ｋｇ，ｉｖ或１ｍ，于入院后即刻，ｈ４，ｈ２４，ｈ４８给药，２ｄ为一个疗程；巴利捷克组１１４例（男性６８例，女性４６例；年龄６±３ａ），用巴利捷克剂量２５ｍｇ奎宁基质／（ｋｇ·ｄ），ｉｖ或ｉｍ，ｂｉｄ，３ｄ为一个疗程。结果２组血检疟原虫转阴率，退热时间和住院时间各为９４．７％，７８．９％；１．３±０．５ｄ，２．７±１．１ｄ和３．２±１．１ｄ，４．５±１．５ｄ；差别皆有非常显著意义（Ｐ均＜０．０１）。结论：青蒿琥酯疗效优于巴利捷克。     

青蒿琥酯对小鼠Heps肝癌的抑瘤作用

[目的]探讨青蒿琥酯(Artesunate,Art)的抑瘤作用.[方法]小鼠皮下接种Heps肝癌细胞(1.2×10 5),56只NIH雌性小鼠分7组,每组8只,其中1,2,3组为Art腹腔注射(ip)组,其Art剂量分别为15mg/kg(低)、30mg/kg(中)、60mg/kg(高).第4组为Art灌胃(po)30mg/kg;第5组po铁剂6.5mg/kg同时ip Art 30mg/kg.第6组ip环磷酰胺(CY)阳性对照,第7组ip生理盐水(NS)空白对照.[结果]腹腔注射Art低、中、高剂量其抑瘤率分别为16.2%、12.2%和80.4%;高剂量Art对小鼠Heps肝癌有显著的抑瘤率(P<0.01).在该3个剂量下小鼠的脾重随Art剂量的加大而增加,提示Art似有提升机体免疫水平的作用.中剂量的Art口服与腹腔注射效果不同,前者获77.6%的抑瘤率而后者仅为12.2%.Art与铁剂合用有协同抑瘤作用.[结论]在一定的剂量下,Art对小鼠Heps肝癌有抑制作用;给药途径不同,其抑瘤效果也不同;与铁剂合用可增加抑瘤率.     

A randomized trial of amodiaquine and artesunate alone and in combination for the treatment of uncomplicated falciparum malaria in children from Burkina Faso

Combining artesunate (AR) with existing antimalarial drugs may improve cure rates, delay emergence of resistance and reduce parasite clearance time. In order to investigate the latter, we conducted a randomized clinical trial testing the AR plus amodiaquine (AQ) combination for the treatment of uncomplicated Plasmodium falciparum malaria in Burkina Faso. Children aged 1-15 years were randomly assigned to either AQ (10 mg/kg) or AR (4 mg/kg first day then half dose) or AQ + AR (AQAR) as a single daily dose under supervision for three consecutive days for all groups. Follow-up lasted 28 days. Primary endpoints were parasite and fever clearance time. Eighty-seven children were evaluated: 27 received AQ, 27 AR and 33 AQAR. Using an intention to treat analysis, fever clearance time was similar in the three groups. However, it was significantly faster in the AR (1.21 days; P = 0.02) and AQAR groups (1.19 days; P < 0.01) than in the AQ group (1.46 days) when excluding other concomitant causes of fever. Parasite clearance time was faster in AR (1.13 days; P = 0.008) and AQAR groups (1.13 days; P < 0.01) than in the AQ group (1.6 days). All children cleared their parasites by day 14, including the child with Late Parasitological Failure (LPF) at day 7 after rescue treatment. Only one child (4%) from the AR group and one (4%) from the AQ group presented with asymptomatic parasitaemia at day 7 and day 21, respectively (LPF). Gametocyte carriage was not detectable in any group during follow-up nor was any adverse reaction observed. While resistance to first-line treatment (chloroquine) is already established in the country, AQ and AR used alone or in combination therapy proved highly efficacious in our study. Burkina Faso stands in a very good situation for an internationally recommended switch to AR-containing combination as first-line treatment for uncomplicated malaria. Including AQ in this regimen seems the best option.     

青蒿琥酯聚乳酸微球栓塞治疗兔VX2移植性肝癌的研究

目的 研究青蒿琥酯聚乳酸微球栓塞治疗兔VX2移植性肝癌的疗效。方法 将VX2瘤粒直接种植于新西兰大白兔左肝内2周,CT证实已成功接种VX2的荷瘤兔随机分为4组,每组10只,经股动脉微导管超选择性肝动脉插管分别给予不同处理：青蒿琥酯聚乳酸微球(ART-PLA-MS)组,注入ART-PLA-MS 76.0 mg·kg^-1;青蒿琥酯(artesunate,ART)溶液组,注入ART溶液23.4 mg·kg^-1;空白微球组,注入空白聚乳酸微球52.6 mg·kg^-1;空白对照组,注入2 mL复方泛影葡胺溶液。每天观察动物生长情况,术后2周处死动物,测量肿瘤体积、坏死区面积,计算肿瘤生长率、坏死率;实验兔于治疗前及治疗后第1,3,7天经耳缘静脉采血,检测谷丙转氨酶(ALT)、谷草转氨酶(AST)、尿素氮(BUN)及肌酐(Cr)值,评价肝肾功能情况。结果 术前1 d 4组动物肿瘤体积差异无统计学意义。治疗后2周,与其他3组比较,ART-PLA-MS组肿瘤体积、肿瘤生长率和肿瘤坏死率差异均具有统计学意义(P<0.01);与空白对照组比较,空白微球组肿瘤体积和坏死率差异有显著统计学意义(P<0.01),肿瘤生长率有统计学意义(P<0.05);与ALT溶液组比较,空白微球组肿瘤坏死率差异有显著统计学意义(P<0.01),肿瘤体积和生长率有统计学意义(P<0.05);与空白对照组比较,ALT溶液组差异无统计学意义。治疗前,4组ALT、AST、BUN及Cr值值无统计学差异;治疗后1,3 d,ART-PLA-MS组、ALT溶液组和空白微球组ALT、AST、BUN及Cr值均显著升高(P<0.05);治疗后7 d,各组肝肾功能均恢复至治疗前水平。结论 ART-PLA-MS经肝动脉栓塞对兔VX2肝癌具有一定的治疗作用。     

Opposite malaria and pregnancy effect on oral bioavailability of artesunate – a population pharmacokinetic evaluation

Aim

The aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7.

Methods

Non-linear mixed-effects modelling was used to compare plasma concentration–time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously.

Results

Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%.

Conclusions

The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy.     

青蒿素衍生物体外抗卡氏肺孢子虫作用的扫描电镜观察

目的 观察体外培养的卡氏肺孢子虫(Pc)经双氢青蒿素、青蒿琥酯作用后不同时相虫体表面结构变化。方法 将Pc接种入含HepG-2细胞的培养皿内并分别加入双氢青蒿素50μmol/L、青蒿琥酯100μmol/L、喷他脒15μmol/L、0.3％乙醇与空白对照。双氢青蒿素组于用药后1、2、4、8、12、16h作扫描电镜观察,后4组于用药后12h取样作扫描电镜观察。结果 双氢青蒿素作用2h后,Pc表面开始出现损伤,最初为表面绒毛脱落,残存绒毛肿胀呈球状,虫体体积增大。随着时间延长,虫体表面损伤明显,8h后表膜出现大小不等孔洞。青蒿琥酯组改变相同,但较轻微。结论 青蒿素衍生物可引起Pc虫体表膜损伤,通透性增加,功能障碍。     

The combination of artesunate and carboplatin exerts a synergistic anti-tumour effect on non-small cell lung cancer

Carboplatin (CBP) is a widely used targeted anticancer therapeutic drug; however, multi-drug resistance induced by the accumulation of CBP eventually causes diseases progression. The anti-malarial drug artesunate (ART) also exerts anticancer effects in various cancers; however, the combined effect of ART and CBP on non-small cell lung cancer (NSCLC) remains unclear. In the present study, the NSCLC cell line A549 was pretreated with various concentrations of CBP, ART and gemcitabine (GEM). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were conducted to detect cell viability. Cell apoptosis was evaluated by both flow cytometry and TUNEL apoptotic assay. The expression profiles of cell cycle-related proteins and apoptotic proteins were determined by western blot. Cell clone numbers were visualized using crystal violet staining. Here, we found that both CBP and ART suppressed cell viability, and promoted cell apoptosis, and the combined application of ART and CBP at a lower concentration exhibited synergistic effects. Specifically, the combination of ART and CBP at a lower concentration suppressed cell clone numbers, promoted cell cycle arrest at the G₂/M phase, and induced the expression of the cell cycle and apoptosis-related proteins BAX, p21, p53, and Caspase-3, while decreasing Bcl-2 and Cyclin B1 expression. Based on these results, we concluded that combined application of ART and CBP exerts synergistic anti-tumour effects on NSCLC by enhancing cell apoptosis in a mitochondria-dependent manner.     

青蒿琥酯和复方双氢青蒿素序贯治疗对南苏丹恶性疟疾的疗效

目的：观察注射用青蒿琥酯和复方双氢青蒿素片序贯治疗对南苏丹恶性疟疾病人的疗效。方法：回顾性分析2011年7月-2013年11月在南苏丹瓦乌中国二级医院住院的55例恶性疟疾病历。结果：肌注或静脉注射青蒿琥酯注射液（首剂120mg,后60mg/d）1~5d[（3.2±0.9）d],最后一次静脉注射或肌注后24、30、48、72h口服复方双氢青蒿素片2片,共8片。55例疟疾病人的总治愈率为100%,其中3d治愈52例（94.5%）,3~7d治愈3例（5.5%）。4例（7.3%）病人发生恶心、呕吐、腹泻或头晕等轻度不良反应。结论：注射用青蒿琥酯和复方双氢青蒿素片序贯治疗,对南苏丹恶性疟疾病人具有非常好的临床疗效,适合多种人群,耐受性好。     

青蒿琥酯和熊果酸降血脂作用的最佳配比筛选

目的 观察青蒿琥酯和熊果酸不同剂量和配伍对大鼠脂质代谢紊乱模型的影响,寻找青蒿琥酯和熊果酸配伍应用的最佳配比。方法 利用喂养高脂饲料诱导大鼠形成脂质代谢紊乱模型,通过比较各给药组大鼠的血脂水平筛选最佳配比。结果 实验结果显示,青蒿琥酯(高剂量)+熊果酸(高剂量)均有显著降低TG、CHO、LDL-C作用,可明显升高HDL-C,对H/L值也有一定的升高作用。综合降脂效果优于阳性药非诺贝特,也优于单用同等剂量的青蒿琥酯或熊果酸。各受试样品对大鼠肝功能没有显著影响(P>0.05,与正常组比较)。结论 青蒿琥酯和熊果酸1:1配比降脂效果最佳,建议剂量为(50+50) mg/kg。