口服青蒿琥酯对伯氏鼠疟和诺氏猴疟的杀灭效果

目的:研究青蒿琥酯口服对伯氏鼠疟和诺氏猴疟的血液裂殖体杀灭效果。方法:分别在鼠疟和猴疟模型上采用“4-day试验法”、“28-day试验法”和“7-day试验法”检测了青蒿琥酯和氯喹的药效。结果:口服青蒿琥酯对伯氏鼠疟民K_(173)株的抑制效果低于氯喹,但其原虫血症下降50％、90％和转阴的时间比氯喹快10-15h,对抗株RC/K_(173)的疗效优于氯喹,无交叉抗性,I_(90)仅为1.4。青蒿琥酯和氯喹对诺氏猴疟在31.6,10.0和3.16mg·kg~(-1)剂量组的试验猴全部治愈。结论:口服青蒿琥酯在鼠、猴疟模型上的药效研究为临床研究提供有益参考。     

青蒿琥酯经皮肤吸收治疗猴疟的疗效

青蒿琥酯为高效、速效、低毒的抗疟新药,但近期复燃率较高。为了提高疗效,方便使用,乃研究其经皮肤吸收制剂。青蒿琥酯经皮肤吸收对鼠疟的疗效,在小鼠及兔体内的药代动力学研究已取得较好的结果,现报告对猴疟的疗效。     

疟疾防治药物的研究——Ⅸ.2,4-二氨基-6-[N-(取代苄基)-N-(取代氨基甲基)氨基]-喹唑啉类衍生物的合成

Thompson曾报道2,4-二氨基-6-(3,4-二氯苄基)-氨基喹唑啉PAM-1392 WR-9055(I_1)对伯氏鼠疟原虫,鸡疟原虫和食蟹猴疟原虫以及诺氏猴疟原虫均有较强的抗疟活性。并对伯氏鼠疟抗性株同样有明显作用。Peters报道PAM-1392对鼠疟原虫-斯氏按蚊系统Plas-     

抗疟药磷酸咯萘啶的研究进展

<正> 磷酸咯萘啶(pyronaridine phosphate)是本所1970年合成的疟原虫红内期裂殖体杀灭剂,代号7351。是我国创制的第一个能口服、肌肉注射和静脉滴注多途径给药的化学合成抗疟药。剂型稳定,高效、低毒,与氯喹无交叉抗药性。治疗疟疾疗效显著,也适于治疗抗氯喹株恶性疟和抢救脑型疟等凶险型疟疾。 1 实验疗效 1.1 鼠疟与猴疟疗效 治疗感染伯氏原虫(Plasmodium berghei)敏感株的鼠疟,测得ED_(50)口服为6.8±1.4mg/kg(基质,下同),肌注为4.97±0.65mg/kg;氯喹分别为     

达比喹及其衍生物的抗疟作用

Dabequine及其衍生物M8132、M8133、M8135对伯氏鼠疟原虫ANKA株氯喹敏感系的ED_(50)分别为19.2、5.2、23.5、4.2mg/kg/d×4。对伯氏鼠疟原虫ANKA株中等程度抗氯喹系则分别为84.1、94.2、30.9、39.0mg/kg/d×4。M8133与氯喹无交叉抗性。Dabequine等化合物都有一定的持效作用。猴疟的试验结果显示M8135的杀血内裂殖体作用较佳。它们的急性毒性均低,其中以M8132最低。     

青蒿琥酯

青蒿琥酯为一种对恶性疟有快速治疗效果的抗疟药，既能口服，又可经直肠和胃肠外给药，因此，成为治疗严重疟疾，包括脑型疟的理想药物。至今没有明显的计算所说明青蒿琥酯治疗的脑型疟病人的的死亡率比标准奎宁疗法要高。     

青蒿琥酯对小鼠免疫功能的影响

研究青蒿琥酯对小鼠免疫功能的影响，溶血素含量用分光光度法测定，血清ＩｇＧ和Ｃ３含量用单向免疫扩散法测定，淋巴细胞转化率、巨噬细胞吞噬百分率和吞噬指数镜检计数。青蒿琥酯ｉｍ７５ｍｇｋｇ＾－１ｂｉｄｆｏｒ５－７ｄ能降低ＳＲＢＣ致敏小鼠血清溶血素和ＩｇＧ的含量，抑制抗体生成，但增加疟鼠补体Ｃ３的含量。     

青蒿酯和青蒿素的放射免疫测定法

青蒿素是一种新型抗疟药,青蒿酯是其活性衍生物之一。药理研究和临床试验均证明二者对一般恶性疟、脑型疟和间日疟有较好疗效,且对耐氯喹株疟原虫感染也有效。为了深入进行青蒿酯的代谢和临床药理研究,我们建立了放射免疫测定法,并用此法研究了青蒿酯在狗体内的血药时程。     

青蒿琥酯及其与放疗联用对CNE细胞的作用

目的研究青蒿琥酯及其与放疗联用对鼻咽癌CNE细胞增殖和凋亡的影响。方法采用细胞集落计数法和原位末端标记（TUNEL）法,测定单用青蒿琥酯及其与放疗联用对CNE细胞增殖的抑制作用和对凋亡的诱导。结果青蒿琥酯能够抑制CNE细胞增殖,并呈现明显的剂量效应,药物浓度2．5～50μg／ml的细胞存活率为15．75％～93．64％。青蒿琥酯可诱导CNE细胞凋亡,高浓度组（10μg／ml）作用比低浓度组（5μg／ml）强（P〈0．05）。当青蒿琥酯与放疗联用时作用更为明显,联用组的作用效果均优于单用青蒿琥酯组或单纯放疗组。结论青蒿琥酯对CNE细胞增殖有明显的抑制和诱导凋亡作用,且和放疗联用作用更强。     

青蒿琥酯对非小细胞肺癌A549放射增敏的初步研究

目的初筛青蒿素及其衍生物联合放射线对非小细胞肺癌A549细胞的放射增敏效应,并以青蒿琥酯为主要研究对象,研究其对A549细胞的体内、外放射增敏效应,初步探讨其对A549细胞的放射增敏作用机制。方法通过MTT法初筛低毒剂量的青蒿素及其衍生物对非小细胞肺癌细胞株A549的放射增敏作用,发现青蒿琥酯具有较强放射增敏效应;采用裸鼠移植瘤模型,观察青蒿琥酯联合β电子线对荷痛裸鼠移植瘤生长抑制作用。同时采用Giemsa染色、流式细胞术,观察青蒿琥酯联合电子线对A549细胞的形态学变化以及细胞周期、凋亡的影响,初步探讨青蒿琥酯联合电子线对肿瘤细胞A549的放射增敏作用机制。结果MTT法得到青蒿素及其衍生物对非小细胞肺癌A549细胞生长抑制的IC10,以IC10为剂量参考,发现青蒿琥酯、双氢青蒿素具有放射增敏效应：联合射线后20rtM和40州的青蒿琥酯对A549细胞有生长抑制作用（p〈0．05）并呈一定量效关系,10μM、20μM和40μM的双氧青蒿素也有一定放射增敏作用（p〈0．05）。体内移植瘤实验结果表明青蒿琥酯（30mg／kg）可显著增加荷瘤裸鼠肿瘤组织B放射线的敏感性,肿瘤生长抑制率达50．90％。体外Giemsa染色结果表明,80μM的青蒿琥酯可以引起A549细胞出现显著的凋亡形态学变化;流式细胞术结果提示,20μM青蒿琥酯可将A549细胞周期阻滞于G2仃订期;凋亡结果分析,20μM青蒿琥酯联合放射线不引起A549细胞凋亡。结论青蒿素衍生物中双氢青蒿素、青蒿琥酯对A549细胞有一定的放射增敏作用。青蒿琥酯联合放射线在体内、外实验中均表现出较强的放射增敏效应,其放射增敏作用机制可能与青蒿琥酯的过氧桥断裂,产生自由基导致细胞周期的延迟以及诱导细胞凋亡相关,其具体机制与青蒿琥酯剂量之间的联系有待进一步研究。     

胍丁胺对伯氏疟原虫K173株的抗疟作用(英文)

AIM: To study the antimalarial effect of agmatine (Agm) on chloroquine-susceptible Plasmodium berghei K173strain (S strain) and the P berghei K173 resistant strain (R strain). METHODS: The antimalarial effects of Agm onP berghei K173 S strain and R strain were evaluated by Peters 4-d suppression test in mice. RESULTS: Agm(12.5-200 mg/kg,ig,daily) decreased the parasitemia for both P berghei K173 S strain (IC50=139 mg/kg) and Rstrain (IC50=126mg/kg) in mice. Subcutaneous injection (sc) of Agm (5-40mg/kg,tid) showed relatively strongerantimalarial effect than intragastric gavage (IC50=30 mg/kg) in P berghei K 173 S strain. Spermidine antagonized theantimalarial effect of Agm for P berghei K173 S strain and R strain. Agm did not reverse the chloroquine resistanceof P berghei K173 S strain, dl-α-Difluoromethylornithine (DFMO, sc) decreased the parasitemia of P BergheiK173 S strain and this effect was antagonized by spermidine. CONCLUSION: Agm has an antimalarial effect andthe mechanism is related to its inhibition of polyamine synthesis.     

伯氏疟原虫K173株对喹哌抗药性的实验研究

用小剂量递增法培育伯氏疟原虫对喹哌的抗药性,起始剂量7 mg/kg×1,每传三代递增3.5 mg/kg,至20代,历时5个多月,培育出对喹哌有110倍以上抗性的虫系。抗喹哌伯氏疟原虫系对羟基喹哌、甲氟喹、青蒿酯、青蒿素都有明显的交叉抗性,对咯萘啶、氯喹和伯喹仅有微弱交叉抗性;对乙胺嘧啶和硝喹显示高敏效应。但该虫系的抗性尚不稳定,停药后连续血传12代,抗性水平由110多倍降至8倍.     

Synthesis and antimalarial activity of artemisinin derivatives containing an amino group

In search of water-soluble artemisinin derivatives that are more stable than sodium artesunate, over 30 derivatives containing an amino group (compounds 3-5) were synthesized and tested in mice. All products tested (except 5a and 5b) are the beta isomers. These basic compounds combined with organic acids (oxalic acid, maleic acid, etc. ) to yield the corresponding salts. Generally, the maleates have better solubility in water than the corresponding oxalates. The aqueous solutions of these salts can be kept at room temperature for several weeks without any discernible decomposition. Compounds 3f, 3h, and 3r are much more active against P. berghei than artesunic acid by oral administration and therefore were further tested in monkeys. However, their oral efficacies are poorer than that of artesunic acid against P. knowlesi in rhesus monkeys. It is interesting to note that 3f, 3h, and 3r showed much lower efficacies against P. berghei when they were administered subcutaneously than orally.     

伯氏疟原虫对青蒿素抗药性的研究

仿Peters剂量递增法用伯氏疟原虫ANKA株及N株对QHS进行了抗药性的研究。经14个月的培育至第58代,QHS im注射“4日抑制性实验”的ED_(50)在RQ/ANKA系及RQ/N系分别为其亲代系的53.4及54.6倍,但经蚊传未获成功。在第40代(I_(50)=25)时,其50%的治愈剂量为其亲代系的5.4倍。停药传代其抗性会逐渐消失。该虫系对青蒿酯钠及蒿甲醚有明显的交叉抗性,其ED_(50)分别为其亲代系的13.1及11.7倍,对伯喹的抗性为2.9倍,对氯喹未见明显交叉抗性。     

In vivo antimalarial activity of ethanolic leaf extract of Stachytarpheta cayennensis

Objective:

To evaluate the in vivo antiplasmodial activity of the ethanol leaf extract of Stachytarpheta cayennensis in the treatment of various ailment in Niger Delta region of Nigeria, in Plasmodium berghei infected mice.

Materials and Methods:

The ethanolic leaf extract of Stachytarpheta cayennensis (90-270 mg/kg/day) was screened for blood schizonticidal activity against chloroquine sensitive Plasmodium berghei berghei in mice. The schizonticidal effect during early and established infections was investigated.

Result:

Stachytarpheta cayennensis (90-270 mg/kg/day) exhibited significant (P< 0.05) blood schizonticidal activity both in 4-day early infection test and in established infection with a considerable mean survival time comparable to that of the standard drug, chloroquine, 5 mg/kg/day.

Conclusion:

The leaf extract possesses significant (P< 0.05) antiplasmodial activity which confirms it''s use in folkloric medicine in the treatment of malaria.     

Antimalarial pyrido[1,2-a]benzimidazoles

A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 μM v 0.17 μM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.     

Ameliorative Effects of Curcumin on Artesunate-Induced Subchronic Toxicity in Testis of Swiss Albino Male Mice

India is one of the endemic areas where control of malaria has become a formidable task. Artesunate is the current antimalarial drug used to treat malaria, especially chloroquine resistant. The objective of the present study was to investigate the dose-dependent effect of oral administration of artesunate on the oxidative parameters in testes of adult male Swiss albino mice and ameliorative efficacy of curcumin, a widely used antioxidant. An oral dose of 150 mg/kg body weight (bwt; low dose) and 300 mg/kg bwt (high dose) of artesunate was administered for a period of 45 days to male mice, and ameliorative efficacy of curcumin was also assessed. The results revealed that artesunate caused significant alteration in oxidative parameters in dose-dependent manner. Administration of artesunate brought about significant decrease in activities of superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase, whereas lipid peroxidation and glutathione-S-transferase activity were found to be significantly increased. The results obtained show that oxidative insult is incurred upon the intracellular antioxidant system of testis tissue by artesunate treatment. Further, administration of curcumin at the dose level of 80 mg/kg bwt along with both doses of artesunate attenuated adverse effects in male mice.     

青蒿琥酯增加小鼠腹腔巨噬细胞内化内毒素、大肠埃希菌的作用及可能机制

目的:观察青蒿琥酯(artesunate,AS)对小鼠腹腔巨噬细胞内化清除脂多糖/内毒素(li-popolysaccharide/endotoxin,LPS)和吞噬大肠埃希菌的影响,并初步探讨其可能的作用机制。方法:MTT法检测不同浓度网格蛋白抑制剂(monodansylcadaverine,MDC)、内体酸化抑制剂氯喹(chloroquine,CQ)对小鼠腹腔巨噬细胞活力的影响,以选择恰当的药物工作浓度;激光共聚焦法检测青蒿琥酯及MDC、CQ对小鼠腹腔巨噬细胞内化FITC-LPS的影响;分别采用激光共聚焦和菌落集落形成计数实验观察青蒿琥酯对小鼠腹腔巨噬细胞内化大肠埃希菌的影响;逆转录PCR检测青蒿琥酯对小鼠腹腔巨噬细胞清道夫受体A(class A scavenger receptor,SR-A)mR-NA表达的影响。结果:MDC和CQ浓度分别小于25μg/mL和20μg/mL时对小鼠腹腔巨噬细胞活力无影响;MDC、CQ可抑制小鼠腹腔巨噬细胞内化LPS,青蒿琥酯可增加小鼠腹腔巨噬细胞对LPS的内化,而且青蒿琥酯可增加MDC和CQ处理的巨噬细胞内化LPS的功能。激光共聚焦和菌落集落形成计数实验均显示青蒿琥酯可增加小鼠腹腔巨噬细胞对大肠埃希菌的内化能力。逆转录PCR结果显示青蒿琥酯可增强LPS处理或未处理的小鼠腹腔巨噬细胞SR-A mRNA的表达。结论:青蒿琥酯可增强小鼠腹腔巨噬细胞内化LPS、大肠埃希菌的能力,该作用可能与SR-A mRNA表达升高有关。     

青蒿琥酯治疗在马里共和国的恶性疟疾321例

目的 :观察青蒿琥酯对恶性疟疾的疗效。方法 :96 1例恶性疟疾病人随机分成青蒿琥酯组 32 1例 (男性 152例 ,女性 16 9例 ) ,用青蒿琥酯 6 0mg +5%葡萄糖注射液 5mL ,iv ,qd ,首剂加倍 ,疗程 5d ;奎宁 雷琐辛组 32 0例 (男性 140例 ,女性 180例 ) ,用奎宁 雷琐辛 50 0mg + 5%葡萄糖注射液 50 0mL ,iv ,gtt ,qd ,疗程 3d ;氯喹组 32 0例 (男性 143例 ,女性 177例 ) ,用氯喹 50 0mg ,po ,qd ,首剂加倍 ,疗程 3d。各组经 1个疗程治疗后未愈者 ,均继续治疗 1个疗程。结果 :治愈率青蒿琥酯组为 10 0 % ,奎宁 雷琐辛组为 97.5% ,氯喹组为 6 7.2 %。青蒿琥酯组第 2疗程和第 1疗程治愈率分别为 10 0 %和82 .6 % (P <0 .0 1) ,复燃率为 2 .8% ,无不良反应。结论 :青蒿琥酯治疗恶性疟疾安全有效     

伯氏疟原虫K173株对喹哌抗药性的实验研究

用小剂量递增法培育伯氏疟原虫对喹哌的抗药性,起始剂量7 mg/kg×1,每传三代递增3.5 mg/kg,至20代,历时5个多月,培育出对喹哌有110倍以上抗性的虫系。抗喹哌伯氏疟原虫系对羟基喹哌、甲氟喹、青蒿酯、青蒿素都有明显的交叉抗性,对咯萘啶、氯喹和伯喹仅有微弱交叉抗性;对乙胺嘧啶和硝喹显示高敏效应。但该虫系的抗性尚不稳定,停药后连续血传12代,抗性水平由110多倍降至8倍.