口服青蒿琥酯对伯氏鼠疟和诺氏猴疟的杀灭效果

目的：研究青芒琥酯口服对伯氏鼠疟和诺氏猴疟的血液开明植体杀灭效果。方法：分别在鼠疟和猴疟模型上采用“４－ｄａｙ试验法”、“２８ｄａｙ”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Ｋ１７３株的抑制效果低于氯喹,但其原虫血症下降５０％、９０％和有的时间比氯喹快１０－１５ｈ,对抗株ＲＣ／Ｋ１７３的疗效优于氯喹,无交叉抗性,Ｉ９０仅为１．４。青蒿琥酯和氯喹对诺氏猴疟在３１     

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。     

青蒿酯钠在体外对六株恶性疟原虫的作用

在体外测定青蒿酯钠对恶性疟原虫6个分离虫株的作用,结果表明6个虫株(包括抗氯喹株)对该药均敏感,各株之间无明显差异。与氯喹和喹哌等5种常用抗疟药比较,青蒿酯钠的有效浓度最低。完全抑制恶性疟原虫裂殖体成熟的浓度在0.018μM,完全杀灭浓度为0.O63μM;半数抑制浓度(IC_(50))为0.0013-0.0029μM,90％抑制浓度(IC_(90))为0.0071-0.0098μM。     

青蒿琥酯对小鼠免疫功能的影响(英文)

目的:研究青蒿琥酯对小鼠免疫功能的影响. 方法: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.结果:青蒿琥酯im 75 mg kg~(-1) bidfor 5—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.青蒿琥酯能促进PHA诱导的小鼠体内淋巴细胞转化,能提高DNFB所致的迟发型超敏反应,并减少腹腔巨噬细胞的吞噬百分率和吞噬指数.结论:青蒿琥酯对体液免疫有抑制作用,但对细胞免疫有促进作用.     

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     

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。     

Malaria: an update on current chemotherapy

Introduction: Chemotherapy of malaria has become a rapidly changing field. Less than two decades ago, treatment regimens were increasingly bound to fail due to emerging drug resistance against 4-aminoquinolines and sulfa compounds. By now, artemisinin-based combination therapies (ACTs) constitute the standard of care for uncomplicated falciparum malaria and are increasingly also taken into consideration for the treatment of non-falciparum malaria.

Areas covered: This narrative review provides an overview of the state-of-art antimalarial drug therapy, highlights the global portfolio of current Phase III/IV clinical trials and summarizes current developments.

Expert opinion: Malaria chemotherapy remains a dynamic field, with novel drugs and drug combinations continuing to emerge in order to outpace the development of large-scale drug resistance against the currently most important drug class, the artemisinin derivatives. More randomized controlled studies are urgently needed especially for the treatment of malaria in first trimester pregnant women. ACTs should be used for the treatment of imported malaria more consequently. Gaining sufficient efficacy and safety information on ACT use for non-falciparum species including Plasmodium ovale and malariae should be a research priority. Continuous investment into malaria drug development is a vital factor to combat artemisinin resistance and successfully improve malaria control toward the ultimate goal of elimination.     

Methnaridine is an orally bioavailable,fast‐killing and long‐acting antimalarial agent that cures Plasmodium infections in mice

Background and PurposeMalaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread Plasmodium resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy.Experimental ApproachAn integrated pharmacological approach was used to evaluate the antimalarial profile of methnaridine. The pharmacokinetic properties of methnaridine were investigated along with the associated safety profile. Host immune response patterns were also analysed.Key ResultsMethnaridine exhibited potent antimalarial activity against P. falciparum (3D7: IC₅₀ = 0.0066 μM; Dd2: IC₅₀ = 0.0056 μM). In P. berghei‐infected mice, oral administration effectively suppressed parasitemia (ED₅₀ = 0.52 mg·kg⁻¹·day⁻¹) and cured the established infection (CD₅₀ = 10.13 mg·kg⁻¹·day⁻¹). These results are equivalent to or better than those of other antimalarial agents in clinical use. Notably, a four‐dose oral regimen at a dosage of 25 mg·kg⁻¹ achieved a complete cure of P. berghei infection in mice. Methnaridine exhibited a rapid parasiticidal profile (PCT₉₉ = 36.0 h) and showed no cross‐resistance to chloroquine. Pharmacokinetic studies revealed that methnaridine is readily absorbed, long‐lasting and slowly cleared. The safety profile of methnaridine is also satisfactory (maximum tolerated dose = 1,125 mg·kg⁻¹). In addition, following methnaridine treatment, infection‐induced Th1 immune response was almost fully alleviated in mice.Conclusion and ImplicationsMethnaridine is an orally bioavailable, fast‐acting and long‐lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.     

Antimalarial quassinoids: past,present and future

This review is a compilation of the investigations reported to date on the sources, isolation, chemistry and antimalarial activities of natural quassinoids and their synthetic and semisynthetic analogs. It also provides an analysis of the in vitro structure–activity relationship of quassinoids for further evaluation in animal models. The introduction of non-nitrogenous antimalarial drugs has created a new era of malaria chemotherapy to treat Plasmodium falciparum strains that are resistant to existing nitrogenous drugs and the rising incidence of the deadly cerebral malaria. Many antimalarial quassinoids are discovered from simaroubaceous plants that are used traditionally to treat fever and malaria, thereby reiterating the critical role of ethnopharmacology as a rich source of novel drug discovery.     

瑞香素的抗疟作用及其高效液相色谱分析方法

目的研究中药瑞香素在体外和体内的杀疟原虫裂殖体作用、抗红细胞外期疟原虫作用及其高效液相色谱(HPLC)分析方法。方法在恶性疟原虫FCC1株常规体外培养中测试瑞香素杀裂殖体活性,并按“4d抑制试验”在感染伯氏疟原虫ANKA株的小鼠中测定不同剂量瑞香素的体内抗疟活性。于癌症研究所(ICR)小鼠腹腔注射约氏疟原虫子孢子后0.5h灌胃给药,连续4d。不同剂量的瑞香素及瑞香素与伯氨喹(PQ)配伍用药的抗疟作用分别以第8天ICR小鼠阴性率及第12天或第13天ICR小鼠每千个红细胞被原虫感染数评价。再以高效液相色谱及质谱的方法分析鉴定瑞香素及其两个结构类似物:香豆素,7-羟基香豆素。结果体外试验中瑞香素在1~10滋mol/L剂量范围内有明显杀裂殖体作用,而体内试验中按第5天减虫率与感染鼠在30d内的平均生存天数评价,50或100mg·kg-1·d-1×4d瑞香素灌胃以及10、50或100mg·kg-1·d-1×4d瑞香素腹腔注射给药在伯氏疟原虫ANKA株感染鼠中的抗疟作用与10mg·kg-1·d-1×4d氯喹(CQ)灌胃的疗效相似。瑞香素的剂量范围为每天10～100mg/kg,连服4d,第8天原虫阴性小鼠数及第12天红细胞被感染程度与对照组相比差异均无显著性;瑞香素每天50mg/kg和每天PQ5mg/kg配伍组的第8天小鼠阴性率与PQ每天10mg/kg组相当。运用特定的高效液相色     

Brine shrimp cytotoxicity and antimalarial activity of plants traditionally used in treatment of malaria in Msambweni district

Abstract

Context: In Kenya, most people use traditional medicine and medicinal plants to treat many diseases including malaria. To manage malaria, new knowledge and products are needed. Traditional herbal medicine has constituted a good basis for antimalarial lead discovery and drug development.

Objectives: To determine in vivo antimalarial activity and brine shrimp toxicity of five medicinal plants traditionally used to treat malaria in Msambweni district, Kenya.

Materials and methods: A 0.2?ml saline solution of 100?mg/kg aqueous crude extracts from five different plant parts were administered orally once a day and evaluated for their in vivo chemosuppressive effect using Plasmodium berghei berghei-infected Swiss mice for four consecutive days. Their safety was also determined using Brine shrimp lethality test: Grewia trichocarpa Hochst ex A. Rich (Tiliaceae) root, Dicrostachys cinerea (L) Wight et Am (Mimosaceae) root, Tamarindus indica L. (Caesalpiniaceae) stem bark, Azadirachta indica (L) Burn. (Meliaceae) root bark, and Acacia seyal Del. (Mimosaceae) root.

Results: Parasitaemia was as follows: A. indica, 3.1%; D. cinerea, 6.3%; T. indica, 25.1%; A. seyal, 27.8%; and G. trichocarpa, 35.8%. In terms of toxicity, A. indica root bark extract had an LC₅₀ of 285.8?µg/ml and was considered moderately toxic. T. indica stem bark extract and G. trichocarpa root extract had an LC₅₀ of 516.4 and 545.8?µg/ml, respectively, and were considered to be weakly toxic while A. seyal and D. cinerea root extracts had a LC₅₀ >1000?µg/ml and were, therefore, considered to be non-toxic.

Discussion and conclusion: All extracts had antimalarial activity that was not significant compared to chloroquine (p?≥?0.05). No extract was toxic to the arthropod invertebrate, Artemia salina L. (Artemiidae) larvae, justifying the continued use of the plant parts to treat malaria.     

Novel approaches in antimalarial drug discovery

Introduction: The development of new antimalarial drugs remains of the utmost importance, since Plasmodium falciparum has developed resistance against nearly all chemotherapeutics in clinical use. In an effort to contain the resistance of P. falciparum against artemisinins and to further eradication efforts, studies are ongoing to identify novel and more efficacious approaches to develop antimalarials.

Areas covered: The authors review the classical and new approaches to antimalarial drug discovery, with a special emphasis on the various stages of the parasite's life cycle and the different Plasmodium species. The authors discuss the methodologies and strategies for early efficacy testing that aim to narrow down the portfolio of promising compounds.

Expert opinion: The increased efforts in the discovery and development of new antimalarial compounds have led to the recognition of new promising hits. However, there is still major roadblock of selecting the most promising compounds and then further testing them in early clinical trials, especially in the current restricted economy. Controlled human malaria infection has much potential for speeding-up the early development process of many drug candidates including those which target the pre-erythrocytic stages.     

Changes in the visceral functions of Plasmodium berghei-infected and -uninfected rats following administration of artemether

1. The effects of artemether (12.5, 25.0 and 50.0 mg/kg per day, i.m.), administered to different groups of Plasmodium berghei-infected and -uninfected adult Wistar rats for 1 week, were investigated. 2. The parameters evaluated were the feeding, drinking and urinating patterns of the rats and these were compared with those of rats that received normal saline. 3. Artemether caused a significant dose-dependent reduction in food consumption of both P. berghei-infected and -uninfected rats (P < 0.05). Food intake in infected rats was reduced by approximately 7 g/24 h. This reduction in food intake was further reduced during drug treatment with artemether. Artermether also reduced food intake in uninfected rats. The food consumption of rats that received 12.5 and 25.0 mg/kg artemether was restored after stopping treatment, in contrast with rats that received 50.0 mg/kg, in which the significant reduction in food consumption persisted 1 week after drug administration. 4. During treatment with artemether, the water intake of infected rats was significantly lower than that of uninfected rats in the 12.5 mg/kg artemether-treated group, but was significantly higher in infected rats than in uninfected rats dosed with 25.0 and 50.0 mg/kg artemether. 5. For all doses of artemether tested, a significant increase in urine output was observed in infected rats during treatment and 1 week after treatment, whereas in uninfected rats a significant increase in urine output was observed only following 25.0 and 50.0 mg/kg artemether 1 week after drug administration. 6. The present study confirms the anorexic activity of a high dose of artemether in both P. berghei-infected and -uninfected rats. It also indicates that high doses of the drug could cause impaired renal function in rats and that the significant increase in urine output could also be due to other effects of artemether, namely those on thirst, anti-diuretic hormone output and the osmotic pressure of the blood.     

芴甲醇类化合物的合成及抗疟作用

芴甲醇类化合物的合成及抗疟作用邓蓉仙钟景星赵德昌张洪北盛杏英丁德本杨俊德（军事医学科学院微生物流行病研究所，北京１０００７１）为寻找与氯喹无交叉抗药性的新抗疟药，国外合成了大量的芳基甲醇类化合物，其中甲氟喹（ｍｅｆｌｏｑｕｉｎｅ，Ｉ）经临床应用的结果...     

Synthesis of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine hybrids as potential antimalarial agents

We report herein synthesis of a series of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine hybrids and evaluate their antimalarial activity against D6 and W2 strains of Plasmodium falciparum. To study the structure-activity relationship of substituted 4-aminoquinoline-based hybrids, 34 structurally diverse compounds were synthesized and tested against D6 and W2 strains of P. falciparum. Some of the compounds have shown promising antimalarial activity without toxicity against Vero cells.     

A pharmacokinetic approach to assess artemisinin–naphthoquine combination therapy for uncomplicated pediatric malaria

Evaluation of: Batty KT, Salman S, Moore BR et?al. Artemisinin–naphthoquine combination therapy for uncomplicated pediatric malaria: a pharmacokinetic study. Antimicrob. Agents Chemother. 56(5), 2472–2484 (2012).

Artemisinin-based combination therapies (ACTs) have been adopted as the first line of treatment against malaria in nearly all malaria-endemic countries, mainly as a result of Plasmodium falciparum infection, as this species of malaria parasite has developed resistance to most of the available non-artemisinin antimalarial drugs. Artemisinin–naphthoquine (ART–NQ, also named as ARCO?; Kunming Pharmaceuticals, Kunming, China) is one of the several currently available ACTs that show a promising approach to dealing with drug-resistant malaria rather than monotherapies. Unlike other ACTs, ART–NQ requires either a single-dose treatment or a two-dose treatment within 24?h against uncomplicated P. falciparum malaria; however, this was mainly validated in adults rather than children. Batty et?al. performed the first pharmacokinetic study of ART–NQ combination therapy for uncomplicated pediatric malaria, and the authors’ results are described and discussed below.