蒿甲醚和双氢青蒿素治疗维和部队疟疾93例分析

目的 为了保证维和部队的任务完成及官兵的身体健康,防治维和部队的疟疾患者并总结疟疾的防治经验.方法 对所属维和部队官兵参与进行抗疟药物分组治疗效果观察.结果 双氢青蒿素(科泰新)防治效果肯定,用于进人高疟区的易感人群疟疾防治效果显著.结论 蒿甲醚对疟疾的疗效肯定;双氢青蒿素作为一种新的选择更适应未来的战争需要.     

蒿甲醚对C57BL/Ks J-db/db小鼠糖脂代谢的影响

目的研究蒿甲醚对db/db小鼠糖脂代谢的影响。方法取8周龄雄性C57BL/KsJ-db/db小鼠,分为模型组(ig给予1%甲基纤维素)和蒿甲醚400、200、100、50组(分别ig给予400、200、100、50 mg/kg蒿甲醚+1%甲基纤维素),每组6只。另选6只雄性C57BL/KsJ-db/+小鼠为对照组,共给药4周。每2天测量小鼠体质量;每3天检测小鼠摄食量并评估平均每日摄食量及体质量变化;每2天测定小鼠饮水量;每3天测量小鼠尿量;每7天于禁食8 h后,尾静脉采血,用罗氏血糖仪及配套试纸分别测量小鼠空腹血糖。通过葡萄糖耐量试验(IPGTT)和胰岛素耐量试验(IPITT)评估小鼠对葡萄糖的耐受力及对胰岛素的敏感性,通过生化试剂盒测定小鼠血清总胆固醇(TC)、三酰甘油(TG)、游离脂肪酸(FFA)水平。HE染色法观察小鼠胰腺和肝脏的形态改变。Westernblotting法分析小鼠肝脏中AMP活化蛋白激酶(AMPK)、葡萄糖转运蛋白体4(GLUT-4)和胰岛素受体β(IRβ)蛋白的表达。结果与对照组比较,模型组小鼠的摄食量、摄水量、尿量均明显升高(P0.001)。与模型组比较,各剂量蒿甲醚均能显著降低小鼠摄水量及尿量(P0.01、0.001);蒿甲醚400、200、100 mg/kg均能显著降低小鼠体质量及摄食量,并呈剂量依赖性(P0.05、0.01);蒿甲醚400、200、100mg/kg均显著降低小鼠空腹血糖水平,减少IPGTT的曲线下面积(AUCs),改善小鼠的胰岛素抵抗(P0.01、0.001)。与对照组比较,模型组小鼠的TC、TG及FFA水平均显著升高(P0.05)。与模型组比较,蒿甲醚可显著降低小鼠血清中的TC、TG及FFA水平,并呈剂量依赖性(P0.05);可显著改善db/db小鼠的胰岛空泡变性和肝脂肪变性,使小鼠肝脏中的AMPK、GLUT-4及IRβ蛋白表达增加(P0.05)。随着干预时间的延长,剂量越高的小鼠呈现出较高的死亡率及不良反应发生率。结论蒿甲醚可显著改善糖尿病小鼠的高脂状态及胰岛素抵抗,治疗脂肪肝,可能通过AMPK途径上调GLUT-4以及IRβ蛋白的表达发挥作用,有望用于代谢综合征为主的2型糖尿病的治疗。但较高剂量蒿甲醚及较长时间应用会导致较多不良反应的发生。     

蒿甲醚对胃癌细胞增殖、侵袭和迁移的抑制作用研究

目的:研究蒿甲醚对胃癌细胞（AGS和SGC-7901）的增殖、侵袭以及迁移的影响并探讨其分子机制。方法:分别利用MTT、集落形成试验检测胃癌细胞的活力和生长;流式细胞技术检测胃癌细胞的凋亡率;利用细胞侵袭和划痕愈合试验检测胃癌细胞的侵袭和迁移;Western blot检测相关蛋白的表达水平。结果:蒿甲醚（0~800 μmol/L）能够浓度和时间依赖性的抑制 AGS和SGC-7901细胞的增殖（P＜0.05）。集落形成试验以及流式细胞术结果显示蒿甲醚（400 和 600 μmol/L）能够抑制AGS和SGC-7901细胞的生长以及促进细胞凋亡（P＜0.05）。细胞侵袭和划痕愈合试验发现蒿甲醚（400 和 600 μmol/L）能够抑制AGS和SGC-7901细胞的侵袭和迁移（P＜0.05）。Western blot结果显示蒿甲醚(400 和 600 μmol/L)能够增加AGS和SGC-7901细胞的cleaved caspase-3,cleaved caspase-9以及Bax的蛋白水平（P＜0.05）;同时能够抑制N-cadherin 和vimentin的蛋白表达并促进E-cadherin蛋白的表达。结论:蒿甲醚可以显著抑制胃癌细胞的增殖、侵袭以及迁移,其机制可能是与促进细胞凋亡以及抑制上皮间质转化有关。     

Pharmacokinetics and electrocardiographic pharmacodynamics of artemether-lumefantrine (Riamet) with concomitant administration of ketoconazole in healthy subjects

AIMS: To evaluate whether the potent CYP3A4 inhibitor ketoconazole has any influence on the pharmacokinetic and electrocardiographic parameters of the antimalarial co-artemether (artemether-lumefantrine) in healthy subjects. METHODS: Sixteen subjects were randomized in an open-label, two period crossover design study. Subjects received a single dose of co-artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine. RESULTS: The pharmacokinetics of artemether, its metabolite DHA, and lumefantrine were influenced by the presence of ketoconazole. AUC(0, infinity ) was increased from 320 to 740 ng ml-1 h (ratio 2.4, 90% CI 2.00, 2.86) for artemether, from 331 to 501 ng ml-1 h (ratio 1.7, 90% CI 1.40, 1.98) for DHA, and from 207 to 333 micro g ml-1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. Cmax also increased in similar proportions for the three compounds (ratio 2.2 (90% CI 1.78, 2.83), 1.4 (90% CI 1.12, 1.74), and 1.3 (90% CI 0.96, 1.64), respectively). The terminal elimination half-life was increased for artemether (2.5 vs 1.9 h, 90% CI 1.12, 1.72) and DHA (3.1 vs 2.1 h, 90% CI 0.02, 3.36), but remained unchanged for lumefantrine (88 vs 95 h, 90% CI 0.81, 1.04). These increases in exposure to the antimalarial combination were much smaller than observed with food intake (up to 16 fold), and were not associated with increased side-effects or changes in electrocardiographic parameters. The study medications were well tolerated. CONCLUSIONS: The concurrent administration of ketoconazole with co-artemether led to modest increases in artemether, DHA, and lumefantrine exposure in healthy subjects. Dose adjustment of co-artemether is probably unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.     

复方蒿甲醚和组份之一本芴醇两种剂型治疗恶性疟疾临床对比试验

目的 观察复方蒿甲醚及其组份之一本芴醇两种剂型治疗恶性疟疾的疗效和安全性。方法采用双盲（复方蒿甲醚组和本芴醇片剂组），随机对比的方法。病人入院后实行２８天封闭观察。结果 收治１５０例病人，其中复方蒿甲醚组（Ａ）５１例，本芴醇片剂组（Ｂ）５０例，本芴醇胶丸组（Ｃ）４９例；Ａ、Ｂ、Ｃ三组的平均退热时间分别为１７．１±８．６、３４．０±２３．２、２９．４±２４．９小时；平均原虫转阴时间分别为２９．７ ± ８．９、５１．６±１４ ．１、５４．７±１７．４小时；Ａ、Ｂ、Ｃ三组的治愈率分别为９８．２％、９２．０％、９５．８％。三组病人在观察期间均无明显不良反应发生，各项化验检查未见明显异常。结论 复方蒿甲醚和本芴醇两种剂型对恶性疟疾均有良好的治疗作用，但复方蒿甲醚在杀虫速度和控制患者症状方面明显优于本芴醇单药。     

Distinction of recrudescences from new infections by pcr-rflp analysis in a comparative trial of cgp 56 697 and chloroquine in Tanzanian children.

Summary objective To test the efficacy of a new compound drug (CGP 56 697) against acute, uncomplicated falciparum malaria. method Reappearing parasites were analysed by PCR-RFLP within a randomized controlled trial. 130 patients received chloroquine and 130 patients were treated with CGP 56 697. Samples from 96 patients with parasitological failure were tested by PCR-RFLP for MSP2 of Plasmodium falciparum. Seven days after treatment 32 patients of the chloroquine control group with reappearing parasites were tested by PCR and one infection was unequivocally determined as a new infection. After 7 days, in the CGP 56 697 group, 6 samples were tested in which one new infection was identified. Similar observations were made one and three weeks later in both groups. results Although a high multiplicity of infections on admission was observed, there was no significant correlation between multiplicity and either recrudescence or new infection. Patients in both treatment groups with subsequent recrudescent parasites had higher initial mean parasite densities than patients who cleared. Those of the patients with recrudescent parasites who were treated with CGP 56 697 had higher initial parasite densities than those treated with chloroquine. The rate of re-infection increased with time as expected in holoendemic areas and appeared to be higher in chloroquine patients. Generally, CGP 56 697 showed a superior clearance rate, successfully cleared higher parasite densities and suppressed new infections over a longer period of time. conclusion The PCR analysis confirmed that reinfections beyond day 7 are significant in areas highly endemic for malaria and showed the necessity of excluding these when estimating 14 day clearance rates. Provided new infections are excluded, the 28-day clearance rate can also be used to determine the efficacy of antimalarial drugs in highly endemic areas, and adds to our knowledge of drug resistance and dynamics of infections in people living in such areas.     

Efficacy and tolerability of artesunate‐amodiaquine (Camoquin plus®) versus artemether‐lumefantrine (Coartem®) against uncomplicated Plasmodium falciparum malaria: multisite trial in Senegal and Ivory Coast

Objective To compare, in a phase IV trial, the efficacy and tolerability of artesunate‐amodiaquine (Camoquin plus®) dosed at 300 and 600 mg of amodiaquine per tablet to artemether‐lumefantrine (Coartem®) for the treatment of Plasmodium falciparum uncomplicated malaria in Ivory Cost and Senegal. Method Multisite, randomised, open‐labelled study in patients over the age of 7 years. The primary endpoint for efficacy was adequate clinical and parasitological response (ACPR) at day 28. The secondary endpoints were fever and parasite clearance and gametocyte carriage in each treatment group. Drug tolerability was assessed comparing adverse events and modification of biological parameters between D0 and D7. Data were analysed on an intention‐to‐treat and per protocol basis. Results We included 322 patients; 316 patients completed the monitoring to D28 (155 in AS + AQ group and 161 in AL group). In ITT analysis, an ACPR corrected rate of 97.4% was observed in AS + AQ group versus 97% in AL group (P = 0.99). No parasite recrudescence was observed in AS + AQ arm. All patients in both groups had a fever and parasite clearance at D2. Gametocytes had disappeared by D14 in the AL group and by D21 in the AS + AQ group. No serious adverse events were observed. Minor adverse events were significantly more frequent in the AS + AQ arm. Biological parameters between D0 and D7 did not show any significant statistical variations except for anaemia. Conclusion This study demonstrates the efficacy and tolerability of AS + AQ for uncomplicated Plasmodium falciparum malaria treatment in African patients over the age of 7 years.     

The effect of food consumption on lumefantrine bioavailability in African children receiving artemether–lumefantrine crushed or dispersible tablets (Coartem®) for acute uncomplicated Plasmodium falciparum malaria

Objectives Artemether–lumefantrine (AL) is first‐line treatment for uncomplicated malaria in many African countries. Concomitant food consumption may affect absorption of lumefantrine but data in the most important target population, i.e. children, are lacking. Therefore, we evaluated the effect of food intake on oral lumefantrine bioavailability in African children with malaria. Methods In a randomised, investigator‐blinded, multicentre phase III efficacy trial, 899 infants and children with acute uncomplicated Plasmodium falciparum malaria received six doses of AL according to body weight over 3 days either as crushed tablets (Coartem^®) or as dispersible tablets. Single blood samples were obtained for lumefantrine plasma concentration determination in a subset of 621 patients, and a two‐compartment pharmacokinetic model was constructed. Results The mean observed lumefantrine plasma concentration for crushed tablet and dispersible tablet, respectively, was 100% and 55% higher with a concomitant meal at the time of dose intake than when taken alone. Similarly, consumption of milk (the most common meal) increased model‐estimated lumefantrine bioavailability by 57% (90% CI: 29–96%) with crushed tablets and 65% (90% CI: 28–109%) with dispersible tablets compared to no food. The 28‐day PCR‐corrected cure rate (primary study endpoint) in the evaluable population was 582/587 [99.1% (95% CI: 98.0–99.7%)] and was not related to food intake. Conclusions AL was highly efficacious. Concomitant food intake increased lumefantrine absorption in children with malaria.     

我国近几年抗疟药研究新进展

综述了我国抗疟药研究的新进展。自1985年以来有三种新药和一种制剂在国内注册,它们是:蒿甲醚、青蒿琥酯、本芴醇和青蒿素栓剂;新药萘酚喹和蒿甲醚-本芴醇复方正进行第Ⅱ期临床试验。此外,咯萘啶与其他药物伍用亦取得进展。