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.     

青蒿酯钠抗人肝癌(BEL-7402)与诱导凋亡

应用体内外抑瘤实验、细胞形态学观察、流式细胞仪、Westernblot实验进行检测和观察，探讨青蒿酯钠抗肿瘤作用及机制。结果表明，青蒿酯钠对人肝癌有体内、外抗肿瘤作用；诱导人肝癌细胞凋亡，可能是其抗肿瘤作用机制之一；诱导体外人肝癌细胞凋亡通过P53非依赖性途径。     

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。     

青蒿琥酯对人乳腺癌MCF-7血管生成和肿瘤浸润作用研究

目的:观察青蒿琥酯对人乳腺癌MCF-7血管生成及浸润转移的抑制作用.方法:建立人乳腺癌MCF-7裸鼠移植瘤模型,给予不同剂量青蒿琥酯治疗并观察其对移植瘤的抑制作用;用免疫组化检测移植瘤组织细胞中VEGF、HIF-1α、uPA、E-cadherin蛋白表达和Western blot检测移植瘤组织细胞中HIF-lα、VEGF蛋白表达.结果:青蒿琥酯低、高剂量组抑瘤率分别为(24.39±10.20)％、(40.24±7.02)％;免疫组化结果显示,与生理盐水组比较,青蒿琥酯低、高剂量组VEGF、HIF-1α蛋白表达显著降低,差异具有统计学意义(P＜0.05);uPA和E-cadherin蛋白在生理盐水组和青蒿琥酯低、高剂量组中的表达水平差异均无统计学意义(P＞0.05),HIF-1 α/VEGF之间表达呈正相关(r =0.983,P=0.000);West-em blot结果显示,青蒿琥酯低、高剂量组中VEGF、HIF-1α蛋白下调,表达量低于生理盐水组,青蒿琥酯高剂量组的蛋白表达量最低.HIF-lα与VEGF蛋白表达之间存在一致性.结论:青蒿琥酯可显著抑制乳腺癌裸鼠移植瘤的生长,其机制可能与抗肿瘤血管及抑制肿瘤侵袭相关.     

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。     

青蒿琥酯对高糖诱导的肾小管上皮细胞TLR4、NF-κB表达及合成的影响

目的：探讨青蒿琥酯( Art)对高糖诱导下的大鼠肾小管上皮细胞(NRK-52E)Toll样受体4(TLR4)、核转录因子-κB( NF-κB)表达及合成的影响。方法体外培养NRK-52E细胞,分为6组：正常对照组、高糖组、Art小剂量组、Art中剂量组、Art高剂量组、依那普利组。培养48 h后收集各组细胞,采用逆转录-聚合酶链反应( RT-PCR)法检测细胞TLR4、NF-κB mRNA 含量;采用 Western blot 法检测细胞TLR4、NF-κB蛋白表达水平。结果①与正常对照组比较,高糖组细胞TLR4、NF-κB mRNA和蛋白表达水平明显升高( P <0．05);②与高糖组比较, Art 小、中、高剂量组细胞TLR4、NF-κB mRNA和蛋白表达水平明显降低,且呈剂量依赖性(P<0．05);③与依那普利组比较,Art小、中、高剂量组细胞TLR4水平表达均升高,且Art高剂量组与依那普利组差异无统计学意义。与依那普利组比较,Art小、中剂量组细胞NF-κB水平表达升高,Art高剂量组细胞NF-κB水平表达降低,且Art中、高剂量组与依那普利组差异无统计学意义。结论 Art可呈剂量依赖性地抑制高糖环境下NRK-52E细胞TLR4、NF-κB的高表达及合成。