Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia

In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003-2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS + SP) or AQ (AS + AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS + SP and AS + AQ, proved to be highly efficacious with cure rates of 98-100% supporting the choice of AS + SP combination as first line treatment for uncomplicated malaria for Somalia.     

Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines

Artemisinin derivatives are well-tolerated anti-malaria drugs that also exert anti-cancer activity. Here, we investigated artemisinin and its derivatives dihydroartemisinin and artesunate in a panel of chemosensitive and chemoresistant human neuroblastoma cells as well as in primary neuroblastoma cultures. Only dihydroartemisinin and artesunate affected neuroblastoma cell viability with artesunate being more active. Artesunate-induced apoptosis and reactive oxygen species in neuroblastoma cells. Of 16 cell lines and two primary cultures, only UKF-NB-3^rCDDP¹⁰⁰⁰ showed low sensitivity to artesunate. Characteristic gene expression signatures based on a previous analysis of artesunate resistance in the NCI60 cell line panel clearly separated UKF-NB-3^rCDDP¹⁰⁰⁰ from the other cell lines. l-Buthionine-S,R-sulfoximine, an inhibitor of GCL (glutamate-cysteine ligase), resensitised in part UKF-NB-3^rCDDP¹⁰⁰⁰ cells to artesunate. This finding together with bioinformatic analysis of expression of genes involved in glutathione metabolism showed that this pathway is involved in artesunate resistance. These data indicate that neuroblastoma represents an artesunate-sensitive cancer entity and that artesunate is also effective in chemoresistant neuroblastoma cells.     

毛细管GC法测定青蒿琥酯中有机溶剂的残留量

目的:建立青蒿琥酯中有机溶剂(甲醇和乙酸乙酯)残留量的测定方法。方法:应用毛细管气相色谱法,氢火焰离子化检测器温度为250℃。结果:甲醇、乙酸乙酯检测浓度的线性范围分别为0.03～0.605mg·mL-(1r=0.9998)、0.05～1.002mg·mL-1(r=0.9997);平均回收率分别为98.7%(RSD=3.0%)、99.1%(RSD=2.1%)。样品中只检出乙酸乙酯。结论:本方法简单、准确,可用于青蒿琥酯中有机溶剂残留量的测定。     

An evaluation of rectal artesunate for the pre-hospital management of severe malaria

ABSTRACT

Introduction

Severe falciparum malaria stills accounts for around half a million childhood deaths per year in sub-Saharan Africa. Prompt treatment of sick children close to home starting with artesunate given rectally by appropriately trained people can be lifesaving.     

Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma

Sorafenib is the first-line medication for advanced hepatocellular carcinoma(HCC),but it can only extend limited survival.It is imperative to find a combination strategy to increase sorafenib efficacy.Artesunate is such a preferred candidate,because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms.In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms.We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7,SNU-449,and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice.The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic.Compared with the treatment with artesunate or sorafenib alone,combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis,which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate,but not by inhibitors of other types of cell death(z-VAD,necrostatin-1 and belnacasan).In Huh7 cells,we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy,two essential aspects of ferroptosis.Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion.Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation,ferritin degradation,lipid peroxidation,and consequent ferroptosis.Taken together,artesunate could be repurposed to sensitize sorafenib in HCC treatment.The combined treatment can be easily translated into clinical applications.     

Efficacy of Amodiaquine/Artesunate Combination Therapy for Uncomplicated Malaria in Children Under Five Years in Ghana

Background

In 2005, following several years of declining efficacy of chloroquine, the Ministry of Health recommended the use of Amodiaquine/Artesunate combination therapy for the treatment of uncomplicated malaria. A system of continuous monitoring of therapeutic responses has been established in 10 district hospitals across the country. The data gathered will enable National Malaria Control Programme (NMCP) to respond to changes in the efficacy of the new treatment in a timely manner.

Objectives

To determine the 28 day therapeutic efficacy of Amodiaquine/Artesunate (AQ/AS) combination treatment in children with uncomplicated malaria in Ghana.

Methods

Children aged 6 – 59 months attending clinic with signs/symptoms of uncomplicated malaria at 9 district hospitals (3 in each of the 3 eco-epidemiological zones of the country) were eligible for enrolment. Enrolled children were followed up after treatment for a total of 28 days to record the clinical and parasitological resolution of their malaria episode as well as any adverse drug reactions.

Results

Treatment resulted in rapid and complete cure in almost all the children; 99.3% 14 days after treatment and 93.0%, 28 days after treatment. The majority of treatment failures on D28 were seen in the 3 sites located in the forest zones (Sunyani, Bekwai and Begoro). There was no case of Early Treatment Failure at both D14 and D28 assessments. Adverse events (AE''s) were minimal, less than 4%, with the most common complaint being vomiting.

Conclusion

AQ/AS combination for uncomplicated malaria is efficacious and safe in children less than 5 years.     

过氧化物酶体通路氧化应激基因与青蒿琥酯抗胰腺癌敏感性的相关性研究

目的：探讨过氧化物酶体通路活性氧氧化应激关键基因的筛选及其与青蒿琥酯抗胰腺癌敏感性的相关性。方法基于美国国立癌症研究所（NCI）公共数据库55株肿瘤细胞表达谱基因芯片数据,采用 Kendall 相关分析方法筛选出与青蒿琥酯抗肿瘤半抑制浓度（IC50）显著相关的过氧化物酶体通路关键基因。利用荧光定量 PCR 验证候选基因在不同青蒿琥酯敏感性胰腺癌细胞的 mRNA 表达差异,并通过 DAB 染色检测胰腺癌细胞内过氧化物酶体含量。结果13个过氧化物酶体生物合成、增殖及其活性氧氧化应激通路关键基因 mRNA 表达与青蒿琥酯抗肿瘤药敏浓度 IC50有显著相关性。与正常肝细胞 HL-7702（1．00）比较,对青蒿琥酯敏感的胰腺癌 Panc-1细胞过氧化物酶体生物合成基因CRAT（2．89±0．06）、PEX11B（1．90±0．07）、PEX16（1．35±0．07）mRNA 相对表达水平均显著增高（t ＝33．00,P ＜0．01;t ＝17．85,P ＜0．01;t ＝4．54,P ＜0．05）;其活性氧氧化应激的抗氧化基因 CAT（1．43±0．03）、SOD1（2．07±0．04）、SOD2（1．15±0．01）mRNA 相对表达水平亦显著增高（t ＝11．71,P ＜0．01;t ＝35．85,P ＜0．01;t ＝13．22,P ＜0．01）;对青蒿琥酯不敏感的胰腺癌 BXPC-3细胞的 PEX12（0．51±0．02）、CAT（0．47±0．02）、PRDX1（0．43±0．01）、SOD1（0．44±0．01）mRNA 相对表达水平显著低于正常肝细胞 HL-7702（t ＝37．53,P ＜0．01;t ＝16．52,P ＜0．01;t ＝84．20,P ＜0．01,t ＝48．24,P ＜0．01）。DAB 染色显示对青蒿琥酯敏感的胰腺癌 Panc-1细胞过氧化物酶体阳性表达率（61．5％）明显高于HL-7702细胞（43．8％）,差异有统计学意义（χ2＝16．11,P ＜0．01）。结论过氧化物酶体及其活性氧相关抗氧化酶 CAT、PRDX1、SOD 基因表达可能是影响青蒿琥酯抗胰腺癌作用敏感性的重要因素。     

青蒿琥酯对Ⅰ～Ⅳ型变态反应的影响

目的 研究青蒿琥酯对过敏反应的作用 方法 分别建立Ⅰ、Ⅲ、Ⅳ型过敏反应的动物模型.腹腔注射青蒿琥酯100～125mg·kg^-1·d^-1, 连续6天, 观察实验动物的反应, 设立体外溶血反应体系, 加入一定浓度的青蒿琥酯, 测定其抑制作用 结果 青蒿琥酯15mg·kg^-1·d^-1腹腔注射、抑制Wistar大鼠的被动皮肤过敏反应(P<0.01)及Arthus反应(P<0.05), 100mg·kg^-1·d^-1腹腔注射, 减轻小鼠迟发型过敏反应中足肿胀及炎性细胞浸润, 试管内浓度3.10×10^-5mol/L时抑制体外溶血(P<0.05) 结论 青蒿琥酯明显抑制Ⅰ～Ⅳ型过敏反应.     

青蒿琥酯对实验性免疫性肌炎动物模型的影响

目的 建立类似于人类多发性肌炎/皮肌炎(PM/DM)的豚鼠模型,观察青蒿琥酯对此模型的影响.方法 用兔肌匀浆加完全佛氏佐剂免疫注射豚鼠,造成实验性免疫性肌炎(EIM)动物模型,将EIM豚鼠随机分为青蒿琥酯治疗组和生理盐水对照组进行对比观察.结果 治疗组血清中肌酸激酶(CPK)、乳酸脱氢酶(LDH)、天冬氨酸转氨酶(AST)较对照组显着降低.肌电图显示治疗组较对照组波幅明显增高,时限显着延长,但多相波阳性率无明显改变.肌肉病理可见治疗组较对照组在炎性细胞浸润,肌纤维断裂,坏死程度方面明显减轻.结论 本实验所建立的EIM豚鼠模型与人类PM相似,青蒿琥酯对EIM豚鼠有治疗作用,为今后临床上使用青蒿琥酯治疗PM/DM及其它免疫性疾病提供了可靠的依据.     

青蒿琥酯两种给药方案预防血吸虫病的费用效果分析

目的为青蒿琥酯现场推广应用提供优化方案.方法选择安徽省铜陵市灰河乡太阳村江滩型血吸虫病重流行区,采用随机的方法将人群分为A、B两组,A组在整个感染季节实施全民口服青蒿琥酯预防药物;B组则根据试区人群接触疫水特点而给予不同预防服药方案,各实验组均设安慰剂对照组.统计两方案的各项成本费用并进行各方案的费用效果分析.结果实施A、B两个方案经过感染季节后人群感染率分别为0和0.14%,对照组的感染率分别为5.25%和6.61%.实施A方案的人均成本费用为45.44元.B方案为24.65元,每减少1例病人的费用A方案为866.25元,B方案为380.70元.A、B两方案的费用效益比分别为18.03和110.77.结论根据人群接触疫水特点而有针对性地给予不同的给药方案其成本费用明显低于全民口服预防药物,而且同样可以达到预防血吸虫感染的效果.