蒿甲醚对日本血吸虫糖原、蛋白质、硷性磷酸酶和酸性磷酸酶的影响

感染日本血吸虫尾蚴３２－３５ｄ的小鼠１次ｉｇ蒿甲醚（Ａｒｔ）３００ｍｇ·ｋｇ－１后２４ｈ，其体内♀、血吸虫的糖原含量较对照组减少约５０％，７２ｈ后则分别减少６４．１％和７７．９％。给药后７２ｈ，♀、虫的蛋白质含量较对照组分别减少６８．１％和４９．３％。给药２４ｈ，♀、虫的硷性磷酸酶（ＡＫＰ）活力的抑制率约为２５％，７２ｈ后，♀虫的ＡＫＰ进一步被抑制，抑制率达６１．６％。酸性磷酸酶（ＡＣＰ）的活力受抑制亦以♀虫较为明显，给药７２ｈ♀、虫抑制率分别为７５．７％和４７．６％。     

mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate,arteether, and artemether

The antimalarial artemisinin derivatives artesunate (ART), arteether (ARE), and artemether (ARM) reveal remarkable antineoplastic activity. In the present investigation, we identified mRNA expression profiles associated with the response of tumor cells to ART, ARE, and ARM. We performed correlation and hierarchical cluster analyses of inhibition concentration 50% (IC(50)) values and basal mRNA expression levels of 464 genes deposited in the database of the National Cancer Institute, USA. Correlating IC(50) values of ART, ARE, and ARM and of 16 established antineoplastic drugs revealed that the artemisinin derivatives could not be assigned with a known class of drugs with defined mode(s) of action. The basal mRNA expression of 208 out of 464 genes (45%) correlated significantly with IC(50) values of at least one artemisinin derivative. These genes were from different classes (drug resistance genes, DNA damage and repair genes, apoptosis-regulating genes, proliferation-associated genes, oncogenes, tumor suppressor genes and cytokines). We identified two different gene clusters by hierarchical cluster analysis. One cluster contained predominately genes significantly correlated to all three artemisinin derivatives. This overlapping set of genes points to common molecular mechanisms of tumor inhibition by all three drugs in which genes affecting cellular proliferation may play an important role. The second cluster contained genes differentially associated with the response of artemisinin derivatives to cancer cells. The number of correlating drug resistance genes in this cluster increased in the order ART相似文献   

蒿甲醚对小鼠体内日本血吸虫磷酸化酶、乳酸脱氢酶、三磷酸腺苷酶和磷酸葡萄糖脱氢酶的影响

目的:观察蒿甲醚(Art)对日本血吸虫磷酸化酶(PP)、乳酸脱氢酶(LDH)、6-磷酸葡萄糖脱氢酶(G-6-PDH)和三磷酸腺苷酶(ATPase)的影响。方法:感染32-38天的小鼠于灌服Art 100-300mg·kg~(-1)后24-72h剖杀,收集雌()、雄虫(),按NADH和NADPH的形成和无机磷的释放量测定虫的上述4种酶。结果:感染小鼠用Art 300mg·kg~(-1)治疗后24-48h,、虫的总PP和PPa(激活型)活力明显增加,而PPb则无或仅有轻度增加。上述小鼠用Art 100-300mg·kg~(-1)治疗后24-72h,LDH和G-6-PDH的抑制率分别为9％-59％()和41％-75％()及22％-42％()和74%-80%()。用300mg·kg~(-1)治疗后24h,仅虫的Mg~2-ATPase明显受抑制,48h后,Ca~(2 )-ATPase、Mg~(2 )-ATPase和Na~ -K~ -ATPase分别抑制17％()和19％(),32％()和48％(),及29％()和44％()。结论:Art引起血吸虫PPa活力的增加,使虫的糖原分解,并抑制LDH使虫糖酵解的终产物乳酸明显减少。此外,对血吸虫虫的G-6-PDH有明显的抑制作用。     

青蒿素、蒿甲醚、青蒿琥酯对伯氏鼠疟原虫的疗效及杀虫速度比较研究

报告了以伯氏鼠疟原虫正常株红内期无性体感染小鼠为模型，在同一实验条件下，用青蒿素及其衍生物蒿甲醚、青蒿琥酯的不同剂型、不同给药途径所进行的疗效和杀虫速度实验结果。发ＥＤ＿（９０）比较疗效，青蒿素水悬剂口服疗效较低，改为水悬剂、油悬剂肌注，效价分别提高２．５和１２倍；其衍生物蒿甲醚油溶剂肌注、青蒿琥酯（钠盐）水溶液肌注、静注，效价分别提高５２、１５和８倍。其中蒿甲醚效价最高。以疟原虫下降回归系数（ｂ）比较杀虫速度，青蒿琥酯的杀虫速度最快。上述结果表明，青蒿素在改变给药途径、剂型及化学结构改变为蒿甲醚、青蒿琥酯后，抗疟活性显著提高。提示青蒿素的抗疟活性有进一步研究改进的潜力．     

青蒿素及其衍生物对糖尿病小鼠血糖及炎症因子的影响

目的:探讨青蒿素及青蒿素衍生物对糖尿病小鼠血糖、体质量及炎症因子表达的影响.方法:正常对照组为4～6周龄健康db/m小鼠5只,顺应性喂养;实验组为4～6周龄健康db/db小鼠20只,随机分为4组:安慰剂组、青蒿素组、蒿甲醚组、青蒿琥酯组,每组5只.安慰剂组每天给予羟甲基纤维素灌胃,干预组分别给予青蒿素[200 mg/(...     

青蒿素类药物抗肿瘤作用机制研究概况

青蒿素是具有过氧化基团结构的倍半萜内酯化舍物。青蒿素类药物主要包括双氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯等及其衍生物。青蒿素类药物不但有很好的抗疟作用,同时还能通过延长细胞周期、促使肿瘤细胞内自由基的产生及氧化应激、改变致癌基因以及多重耐药抗性等药理作用机制来达到抗肿瘤的效果。     

Dose-finding and efficacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria

AIMS: The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. METHODS: In part I of the study three different artemotil dose regimens were explored in three groups of 6-9 patients for dose finding: 3.2 mg kg-1 on day 0 and 1.6 mg kg-1 on days 1-4 (treatment A), 1.6 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment B), 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment C). In part II of the study, artemotil treatments A and C were compared in three groups of 20-22 patients with standard i.m. artemether treatment: 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment R). RESULTS: Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to artemotil during approximately the first 2 days of treatment, and suggested that artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. CONCLUSIONS: The optimum dose regimen for artemotil in this study was identical to the standard dose regimen of artemether. The findings that artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. artemotil can be an advantage, since it may allow shorter hospitalization.     

蒿甲醚对小鼠体内日本血吸虫的己糖激酶、磷酸葡萄糖异构酶和磷酸果糖激酶的影响(英文)

目的：研究蒿甲醚（Ａｒｔ）对血吸虫己糖激酶（ＨＫ）、磷酸葡萄糖异构酶（ＧＰＩ）和磷酸果糖激酶（ＰＦＫ）的影响。方法：感染血吸虫小鼠１次ｉｇＡｒｔ１００或３００ｍｇｋｇ－１，并分别于２４ｈ和４８ｈ剖杀取虫。按生成ＮＡＤＰＨ和耗用ＮＡＤＨ的方法测定上述３种酶活力。结果：感染鼠ｉｇ．Ａｒｔ３００ｍｇｋｇ－１后２４ｈ，♀、虫体ＨＫ活力抑制率分别为３３．３％和１３．７％，ＧＰＩ活力则分别抑制１４．７％和１７．５％，４８ｈ后，♀、虫体的ＧＰＩ活力抑制率分别为４６．２％和３２．９％。但Ａｒｔ剂量为１００或３００ｍｇｋｇ－１时，给药后２４ｈ和４８ｈ的♀虫ＰＦＫ抑制率分别为６４．９％和７１％，均明显高于虫的１６．３％和５４．２％。结论：ＰＦＫ可能是Ａｒｔ作用于血吸虫糖酶解途径的靶酶之一。     

蒿甲醚对人胶质瘤细胞侵袭、转移及基质金属铁蛋白酶-2、9活性的影响

目的研究蒿甲醚对U251人胶质瘤细胞侵袭、转移能力以及基质金属铁蛋白酶-2、9活性的影响。方法将浓度为200μmol/L的蒿甲醚孵育U251胶质瘤细胞24h。利用划痕修复试验及Transwell小室建立体外迁移及侵袭模型,观察蒿甲醚对U251人胶质瘤细胞迁移及侵袭能力的影响。利用基于荧光抑制的明胶的酶动力性实验检测蒿甲醚对U251人胶质瘤细胞的基质金属铁蛋白酶-2、9活性改变。结果在200μmol/L的蒿甲醚处理下,U251胶质瘤细胞的侵袭和转移能力明显降低,同时基质金属铁蛋白酶-2、9活性受到显著抑制。结论蒿甲醚抑制人U251胶质瘤细胞侵袭和转移能力可能与下调MMP-2和MMP-9的蛋白酶活性相关。