青蒿素及其衍生物抗疟机制研究概况

WHO的疟疾报告,2017年,估计在87个国家中存在2.19亿疟疾病例;死亡人数估计为43.5万例。每2分钟就有1名儿童死于疟疾。中国自2016年8月以来,未发生1例本土疟疾病例。青蒿素类药物对全球疟疾的控制起到了重要作用,现有的最佳治疗方法,特别是恶性疟治疗方法,仍是以青蒿素为基础的联合疗法。青蒿素全新的化学结构,改写了只有含N杂环的生物碱成分抗疟的历史。但青蒿素类药物的抗疟机制目前仍是久而未决的问题,大湄公河次区域的一些地区也出现了青蒿素耐药性现象,WHO因此发起了"紧急应对青蒿素耐药性"行动。深入探讨青蒿素类药物抗疟机制,不仅可以加深对药物的认识,而且对于指导合理用药、提高临床疗效、防止抗药株的产生、发现新的青蒿素抗疟组合以及拓宽其应用范围都有重要意义。青蒿素抗疟机理解释的难点可能在于青蒿素是原药(本身活性不强),激活和靶标都不确定。目前有关青蒿素类药物抗疟机制主要有以下假说:碳自由基假说、血红素靶标假说、肌内质网Ca~(2+)-ATP酶(钙泵)假说、线粒体靶标假说和血红素激活的多靶标假说。另外也有研究证明疟原虫的膜系结构、血红素聚合产物、一些特定蛋白、诱导疟原虫环状体休眠/沉默、自噬相关蛋白18(ATG18)都可能是青蒿素类药物的作用靶标。但这些假说尚不能单独、完全解释青蒿素的抗疟机制。由于疟原虫的主要致病阶段是红细胞内期的裂体增殖期。下一步的研究工作,除进一步证实上述假说外,可以根据青蒿素选择性杀灭处于红内期的疟原虫、针对疟原虫的膜系结构(表膜-线粒体功能)、疟原虫顶质体内的"蓝藻型"铁代谢通路、染虫红细胞表面膜蛋白、染虫红细胞表面膜离子通道和染虫红细胞改生物力学特征等方面开展研究工作。     

非洲135例疟疾回顾性分析

目的了解非洲疟疾的临床特点、诊治方法及其转归。方法分析135例疟疾患者的临床资料。结果临床表现中,发热135例(占100%),其中以贫血31例(占22.96%),脾肿大27例(占20.00%),腹泻21例(占15.56%),呕吐19例(占14.07%)最为常见;其次是咳嗽17例(占12.59%),寒战7例(占5.19%)等多种症状。135例均接受青蒿素类抗疟药的综合治疗,治愈135例,无死亡病例。结论非洲疟疾大多数是恶性疟,且发病率很高,临床表现复杂多样且不够典型;尽早诊断、及时治疗是改善本病预后的关键;青蒿素类药物是治疗疟疾安全、有效的首选药物。     

抗疟疾新药筛选结果

现在每年仍有近2．5亿疟疾病例见诸报道,死亡人数超过80万,其中大多数死亡者是5岁以下儿童。疟疾寄生虫镰刀形疟原虫以精于产生抗药性而著称,所以迫切需要新药。本期Nature上的两篇研究报告让我们看到了这样的希望：通过识别数以千计能够抑制红细胞中无性阶段镰刀形疟原虫生长的化合物,也许可以找到青蒿素的替代药物,它们很多在结构和机制上都与目前的药物截然不同。     

转基因合成青蒿素取得进展

青蒿素是目前最有效的抗疟疾药物之一，但对最需要的贫困患者来说仍过于昂贵。美国科学家最近成功地用转基因酵母合成了青蒿素的前体物质——青蒿酸，有望大幅增加青蒿素产量、降低治疗疟疾的费用。青蒿素从菊科蒿属植物青蒿中提取，是中国科学家开发出的强效抗疟药物。在非洲和亚洲许多地区，疟原虫已经对其他多数抗疟药物具有抗药性，这些地区对青蒿素类药物的需求格外迫切。     

漫话青蒿素

20世纪70年代,我国药物学家从中药黄花蒿中提取了名为"青蒿素"的新化合物.由于青蒿素能在短时间内迅速杀灭疟原虫、消除高热,因此成为疟疾的克星.在世界上每年仍有200万人死于疟疾的今天,青蒿素被世界卫生组织认为是"治疗疟疾的最大希望".     

2016~2019年铜陵地区输入性疟疾病例分析

目的 分析铜陵地区输入性疟疾病例特点，为本地区疟疾诊治提供参考。方法 回顾性分析2016年1月至2019年11月铜陵市人民医院收治并经实验室确诊的28例输入性疟疾患者的资料，分析所有患者的一般特征、相关实验室检查结果及疟原虫分布特征。结果 28例患者中，男性占比96.4%，以青壮年为主，职业主要为境外劳务输出工人。患者发病高峰月份分别为2月、4月和7月，占所有病例的42.9%。患者感染来源均为非洲国家，以恶性疟原虫疟疾（64.3%）多见。非重症患者27例（96.4%），重症1例，无死亡病例。19例（67.9%）患者血小板计数不同程度下降，25例（89.3%）患者C反应蛋白升高，18例（81.8%）患者降钙素原不同程度升高。结论 铜陵地区输入性疟疾病例全年散发，以青壮年男性为主，恶性疟原虫疟疾多见，患者血液炎症指标不同程度升高；临床医师应继续提高对疟疾的诊治能力，防止漏诊、重症及死亡病例的发生。     

青嵩素及其衍生物的开发和产业化

近年来，中、南美洲、非洲及东南亚地区频频出现具有抗疟性的疟原虫株，其中恶性疟原虫抗氯喹株的增多使问题更加严重。疟原虫对氯喹、乙胺嘧啶以及奎宁和伯喹比较容易产生耐药性。据知1998年WHO开始实行“击退疟疾”计划，计划在12年间把疟疾致死人数降低一半。然而到2004年，疟疾致死人数反而由每年60—80万升至100多万。主要原因是疟原虫已经对传统一线药物氯喹和磺胺多辛-乙胺嘧啶产生了抗药性，但青蒿素及其衍生物制剂却保持非常好的疗效。目前有51个国家将其列为抗疟首选用药。     

青蒿素耐药与脾脏清除疟原虫机制研究进展

疟原虫对青蒿素类药物产生耐药性的定义是:疟疾患者进行青蒿素联合疗法(artemisinin-based combination therap,ACTs)三日治疗后,患者血液内的疟原虫清除时间延长。疟原虫的体内清除不单单与抗疟药物的杀虫效用相关,还受疟原虫本身的变异、人体免疫功能调节如吞噬细胞的识别处理、免疫器官如脾脏的外排异物等因素的影响。本文主要从疟原虫本身的变异、脾脏清除疟原虫的研究进行了综述:包括K13突变;脾脏的两条血液循环通路;脾静脉窦可通过物理机械传感方式截留疟原虫或红细胞碎片;红髓是过滤血液的主要场所,其中的免疫细胞负责疟原虫残留物的清除工作;脾静脉窦截留疟原虫的过程称为孔蚀,其发生率受疟原虫的生长周期及治疗药物的影响。现就脾脏清除疟原虫的功能进行阐述,以期为疟原虫对青蒿素产生耐药性的生物学本质提供新的思路和参考。     

非洲135例疟疾回顾性分析

目的:了解非洲疟疾的临床特点、诊治方法及其转归。方法:分析135例疟疾患者的临床资料。结果:临床表现中,发热135例(100%),其中以贫血31例(22.96%),脾肿大27例(20.00%),腹泻21例(15.56%),呕吐19例(14.07%),咳嗽17例(12.59%),寒战7例(5.19%)等多种症状。135例均接受青蒿素类抗疟药的综合治疗,全部治愈。结论:非洲疟疾大多数是恶性疟,临床表现复杂多样且不够典型;尽早诊断、及时治疗是改善本病预后的关键;青蒿素类药物是治疗疟疾安全、有效的首选药物。     

1950～2015年广西桂林市疟疾防制效果分析

目的分析桂林市65年疟疾防制效果,为今后疟疾防制提供科学依据。方法收集整理该市下辖的12个县1950~2015年历年疟疾防治资料,采用Excel软件进行统计分析和图表制作。结果 20世纪70年代以前该地区疟疾在当地居民中呈自然流行状况,感染的疟原虫种类有3种,有3种主要传疟按蚊种群存在。疟疾发病率最高的1955年和1961年分别为3513.46/10万和3354.91/10万,50年代和60年代疟疾死亡病例数分别为810例和252例。70年代恶性疟流行被有效控制。21世纪以来当地居民未发现疟疾病例。80年代的输入性疟疾病例均在国内疟疾流行区感染,90年代有4.87%的疟疾病例在东南亚国家感染,近五年有97.47%疟疾病例在国外感染,在非洲感染的占72.73%,恶性疟占62.34%,每年均有重症疟疾病例出现。结论目前该市各县区均已达到国家消除疟疾标准,但仍然受到输入性疟疾威胁,需继续加强监测和控制。     

Magnitude of malaria admissions and deaths at hospitals and health centers in Oromia, Ethiopia

Health facility records are important sources of malaria data, not only to describe the disease patterns and trends, but also useful for planning malaria control and evaluating the impact of health interventions. The aim of this study was to assess the burden of malaria admissions and deaths on the services of hospitals and health centers in Oromia, over a period of five years, 1995-2000. A retrospective record review of data routinely collected on malaria admissions and deaths was conducted at all hospitals and health centers located in Oromia during March-May 2001. The total number of admissions and deaths from all causes registered at hospitals and health centers for the overall 1995-2000 period were 302,035 and 16,061. respectively. Malaria accounted for 11.20% of all admissions and 14.26% of all deaths. From 33,808 malaria inpatients, 2,291 (6.78%) died during the period Two thousand and one hundred thirty (92.97%) deaths occurred in hospitals and 161 (7.03%) deaths in health centers. A total of 78,062 (25.85%) admissions among children < 15 years occurred, of whom 12,273 (15.72%) had malaria. The overall percentage of malaria specific admissions during the period was higher for children in the age group of 1-4 (16.59%) and 5-14 years old (20.40%), compared to 7.93% for infants < 1 year and 9:62% for adults greater than 15 years old. Malaria specific admission ratios ranged from 2.95% in Jimma hospital to 47.12% at Merti hospital. Similarly, the proportionate malaria mortality ranged from 7.60% in Jimma hospital to 44.20% in Merti hospital. The majority of malaria admissions and deaths were due to Plasmodium falciparum. This retrospective analysis of records of hospitals and health centers reveals the heavy burden of malaria. Although cost-effective interventions for malaria are available, the burden of the disease is still unacceptably high. In this context, improving the quality of services at health care facilities for accurate diagnosis and effective antimalarial treatment, and increasing the accessibility of health services are crucial steps to reduce the burden of the disease. In addition, improving the quality of surveillance systems to pick up malaria cases and deaths at health care facilities enables decision makers to evaluate the impact of current interventions against the disease.     

146例输入性疟疾的临床分析

目的我院为湖北省疟疾防治定点医院之一,分析在我院体检及就诊的输入性疟疾的临床特点,做到早预防、早发现、早诊断、早治疗这种疾病,减少误诊、并发症的发生、降低病死率,防止出现疟疾的流行。方法主要对2007年7月至2013年12月在我院就诊的146例输入性疟疾进行回顾性分析。结果在146例疟疾患者中间日疟124例,恶性疟疾病22例;其中体检发现79例,另外67例为就诊的患者,表现为典型症状:畏寒、发热、汗出、热退的占66例,1例仅表现为乏力,头痛。出现溶血性贫血3例、黑热病2例、脑型疟1例。平均住院16.3 d,治愈率100%,治疗后复发3例。结论早预防、早发现、早诊断、早治疗是在疟疾的防治中的关键。及时切断传染源可以阻止疟疾的流行。     

The WHO 'Roll Back Malaria Project': planning for adverse event monitoring in Africa.

Artemisinin combination therapies (ACTs) have been recommended for the treatment of malaria in countries where there is widespread resistance to commonly used antimalarial drugs. Several sub-Saharan African countries are, therefore, in the process of introducing ACTs in their malaria drug policies. However, there is limited information about the safety of ACTs outside South East Asia, where their use has been well documented. As with all other new medicinal compounds, the monitoring of a drug's safety or 'pharmacovigilance' is important, especially in areas where co-morbid conditions, such as HIV/AIDS, malnutrition and tuberculosis, are common. Because in most malaria endemic countries, particularly Africa, there are no pharmacovigilance programmes in place, it has been suggested that the introduction of ACTs offers an opportunity for these countries to put drug safety monitoring systems in place. Backed by the WHO Roll Back Malaria department and other international cooperating partners, five African countries, which are in the process of introducing ACTs (Burundi, Democratic Republic of the Congo, Mozambique, Zambia and Zanzibar), have drawn up action plans to introduce pharmacovigilance in their health sector. It is planned that once the safety monitoring of antimalarials has been established, these activities can then be extended to cover medicinal compounds used in other public health programmes, such as HIV/AIDS, tuberculosis and the immunisation programmes. This article looks at the rationale for pharmacovigilance, the process of setting up monitoring centres and the challenges of implementing the project in the region.     

The prevention of maternal deaths: a continuing challenge

This report studies the principal causes of maternal death at Harare Maternity Hospital. In 1983 the maternal mortality rate for the greater Harare unit was 52/100,000 compared to 11.9/100,000 for England and Wales. Puerperal sepsis, hemorrhage, post-abortal sepsis and hypertensive disease accounted for 78.5% of the deaths. 12 of the deaths were due to puerperal sepsis, 8 of which had normal vaginal delivery and 4 were delivered by Caesarian section. 3 patients died within 48 hours of delivery. Hemorrhage was most commonly a result of ruptured uterus. Avoidable factors were considered present in all cases. Delay in diagnosis, availability of blood or performing laparotomy was evident in 4 of 5 who died from ruptured uterus; 2 were due to pulmonary edema from excessive transfusion, and 2 were attributable to the patient (refusal of transfusion, attempt to self abort.) Post-abortal sepsis occurred in 9 patients, most of whom were septicemic on admission. 8 patients died from hypertensive disease, 7 of which were eclamptic. Reduction in mortality has gone from 34% (1976) to 23.7% (1983) for puerperal sepsis and can be affected by encouraging patients to book for antenatal care. An observed increase in hemorrhagic deaths since 1976 may reflect a decreased staff-patient ratio at Harare Maternity Hospital. Post-abortal sepsis mortality has decreased from 32% (1976) to 17.7% (1983). Reduction in deaths from hypertensive disease necessitates prediction and early detection. Value of a post-mortem exam in all cases of maternal death is stressed.     

Current status and progresses made in malaria chemotherapy

Malaria is the most important parasitic disease worldwide, affecting more than 500 million people and causing close to 1 million deaths per annum. This serious fact is mainly attributable to the emergence of drug resistant strains of Plasmodium falciparum. The advances made in malaria chemotherapy based on unique aspects of the biochemistry and physiology of the responsible agents for this disease, parasites of Plasmodium genus, are covered in this review. Increasing resistance to conventional antimalarial drugs constitutes the main drawback for the persistence of this disease. In the present article, a comprehensive analysis of selected molecular targets is depicted in terms of their potential utility as chemotherapeutic agents. Our review focuses on different and important molecular targets for drug design that include proteases that hydrolyze hemoglobin, protein farnesyltransferase, heme detoxification pathway, polyamine pathways, dihydrofolate reductase, artemisinin-based combination therapies (ACTs), etc. Therefore, rational approaches to control malaria targeting metabolic pathways of malaria parasites which are essential for parasites survival are presented.     

98例老年人高血压临床分析

目的：探讨分析老年人高血压的临床特点,在临床上提高对老年人高血压的诊疗水平。方法：回顾性分析本院2009年6月～2010年6月收治的98例60岁以上的老年高血压患者的临床资料。结果：98例患者以头昏、头痛、心悸、气促多见;其中85%的患者有合并症如脑卒中、蛋白尿、冠心病、高心病等,经1个月左右临床治疗好转出院93例占94.90%,血压控制在收缩压〈150mmHg,舒张压〉65mmHg;临床死亡5例占6.85%,其中脑卒中2例,心肌梗死2例,多器官衰竭1例。结论：老年人高血压的合并症多,临床治疗要有效地控制血压,减少血压波动,减少靶器官的损害,从而进一步降低该病的病死率,改善预后。     

Preventing deaths from malaria.

To reduce the number of avoidable deaths from malaria in Britain the following five points are recommended. Parliament should pass a Malaria Prevention Act that compels travel agents and airlines to give written and verbal advice on prevention and diagnosis of malaria to people travelling to countries where the disease occurs. To improve diagnostic and therapeutic efficiency for all diseases the Department of Health and Social Security should prepare a procedure manual for the NHS that gives guidance for doctors and other medical staff. Avoidable deaths from all diseases should be the subject of open inquiries at district medical committees, with recorded evidence. Failure to perform diagnostic tests such as blood films for malaria in cases of sickness in people returning from the tropics should automatically be considered negligent. Compensation should be offered by the State to the next of kin of people who have died because of medical negligence from malaria or other diseases.     

45例胃肠道间质瘤诊断及外科治疗

目的对胃肠道间质瘤诊疗的探讨。方法河北省邯郸市第一医院2009年至2011年例胃肠道间质瘤患者45例,对这些病例的诊断、检查、治疗及疗效回顾性分析。结果此次讨论的所有病例中43例患者酪氨酸激酶受体CD117呈阳性,占95．6％;28例CD34阳性患者,占75．6％,CD117、CD34均为阳性的患者24例,占53．3％。治疗方法以手术为主,所有病例无围手术期死亡,无严重并发症且痊愈出院,对40例患者随访,半年至3年。结论胃肠道间质瘤临床表现无显著特性,术前诊断率较低,免疫化验对此病起着独特的作用,主要的治疗方法为外科手术切除。