青蒿素类抗疟药的作用机制及耐药机制研究进展

青蒿素作为重要的抗疟药物,因其抗疟作用效率高、速度快、毒性低并且与大部分其他类别的抗疟药无交叉抗性等优点,成为目前全球抗疟的主要药物,虽然在泰柬边境地区已出现了青蒿素耐药性,但就目前全球各．地使用青蒿素及其衍生物为基础的联合疗法（ACT）疗效来看仍能达到90％以上,因此必须对刚刚出现的青蒿素耐药性现象迅速采取遏制行动。本文主要通过描述青蒿素的抗疟机制,讨论其耐药性机制,以及对青蒿素的发展前景作一综述。     

Modifying national malaria treatment policies in Peru

Between 1998 and 2001, the Peruvian Ministry of Health made sweeping changes in its malaria treatment policies in response to a resurgence of disease and the spread and intensification of antimalarial drug resistance. On the Pacific Coast, the first-line treatment for uncomplicated Plasmodium falciparum malaria was changed to combination therapy with sulfadoxine-pyrimethamine plus artesunate; in the Amazon region, mefloquine-artesunate combination therapy was introduced. With these changes in treatment policy, Peru became the first country in the Americas to use combination therapy with an artemisinin drug as its first-line treatment for falciparum malaria and the first country in the world to use two different drug combination therapy regimens based on an artemisinin drug in different regions of the country. This paper describes the process involved in assessing the geographic distribution and intensity of antimalarial drug resistance throughout the country and the use of that information to guide decisions related to national malaria treatment policy.     

Can pharmacogenomics improve malaria drug policy?

Coordinated global efforts to prevent and control malaria have been a tour-de-force for public health, but success appears to have reached a plateau in many parts of the world. While this is a multifaceted problem, policy strategies have largely ignored genetic variations in humans as a factor that influences both selection and dosing of antimalarial drugs. This includes attempts to decrease toxicity, increase effectiveness and reduce the development of drug resistance, thereby lowering health care costs. We review the potential hurdles to developing and implementing pharmacogenetic-guided policies at a national or regional scale for the treatment of uncomplicated falciparum malaria. We also consider current knowledge on some component drugs of artemisinin combination therapies and ways to increase our understanding of host genetics, with the goal of guiding policy decisions for drug selection.     

Malaria and HIV co-infection in pregnancy in sub-Saharan Africa: impact of treatment using antimalarial and antiretroviral agents

Malaria and HIV infection represent severe public health problems in sub-Saharan Africa, and pregnant women are at increased risk because the two diseases intersect in pregnancy, causing adverse perinatal outcome. As access to antiretroviral drugs is increasing in the sub-region, and new combinations of antimalarial drugs are being implemented while more are being evaluated, there is potential for interactions between these therapies. In this report, the impact of treatment using antimalarial and antiretroviral agents in pregnant women with malaria and HIV co-infection was reviewed, using scientific publications identified through a Medline Entrez-Pubmed search with reference to sub-Saharan Africa. The safety and operational feasibility of use of antimalarial and antiretroviral agents to treat co-infected pregnant women were evaluated. Although use of these therapies was shown to improve the health of pregnant women with co-infection, low adherence, poor-quality drugs, resource scarcity, lack of infrastructure and inadequate treatment in sub-Saharan Africa continue to hamper treatment outcome. The absence of studies on interaction between antimalarials and antiretrovirals, as well as mounting evidence of treatment failure due to drug resistance and adverse drug reactions, in most parts of sub-Saharan Africa, make the establishment of new guidelines for the prevention of malaria and HIV infection during pregnancy imperative.     

Factors contributing to antimalarial drug resistance in Rachuonyo district, Kenya

Drug resistance has been identified as one of the factors that lead to severe malaria and high mortality as observed in malaria endemic areas. The main objective of this study was to establish the factors that contribute to essential drug resistance in the treatment of malaria in Rachuonyo District, Kenya. Qualitative and quantitative data were collected among 380 respondents including health care providers, people seeking malaria treatment and Community Own Resource (CORPs), from 47 registered health facilities. The study revealed that all health facilities were using general-purpose trucks to transport antimalarial drugs and did not have functional wall thermometers and that eighty seven per cent (87%) of health care providers did not check storage conditions of drugs upon reception. Ninety seven per cent (97%) of the health care providers used physical examination for clinical diagnoses that is subject to errors that may lead to irrational drug use. Thirteen per cent (13%) of health care providers had no idea that antimalarials suspensions can undergo fermentation when not properly stored. Forty percent (40%) of the selected health facilities had current recommended antimalarial treatment drugs in stock. The use of such vehicles can affect the potency of the drugs, as they do not have the necessary equipments to control adverse temperatures and this may contribute to loss of potency. Some health facilities did not have the current recommended antimalarial drugs in stock implying that patients attending treatment in these facilities could have been treated with less effective drugs or they could have been sent to purchase them yet they are expensive and not easily available. In conclusion the results of this study indicate that management, administrative factors and policy issues could be a leading cause of antimalarial drug resistance and a case control study to explore the exact extent of drug resistance in this population in relation to the identified factors is urgently recommended.     

Combination therapy for malaria in Africa: hype or hope?

The development of resistance to drugs poses one of the greatest threats to malaria control. In Africa, the efficacy of readily affordable antimalarial drugs is declining rapidly, while highly efficacious drugs tend to be too expensive. Cost-effective strategies are needed to extend the useful life spans of antimalarial drugs. Observations in South-East Asia on combination therapy with artemisinin derivatives and mefloquine indicate that the development of resistance to both components is slowed down. This suggests the possibility of a solution to the problem of drug resistance in Africa, where, however, there are major obstacles in the way of deploying combination therapy effectively. The rates of transmission are relatively high, a large proportion of asymptomatic infection occurs in semi-immune persons, the use of drugs is frequently inappropriate and ill-informed, there is a general lack of laboratory diagnoses, and public health systems in sub-Saharan Africa are generally weak. Furthermore, the cost of combination therapy is comparatively high. We review combination therapy as used in South-East Asia and outline the problems that have to be overcome in order to adopt it successfully in sub-Saharan Africa.     

Subsidized artemisinin based combination treatments for Africa

Malaria-associated mortality and morbidity have increased in recent decades, with the worldwide spread of chloroquine and sulfadoxine-pyrimethamine resistant parasites. Artemisinin-based combination therapies (ACTs) have been proposed as an alternative to conventional antimalarial drugs. ACTs are effective against multidrug-resistant infections, work quickly, are safe and well tolerated, and seem to decrease transmission by inactivating gametocytes. The affordable medicines facility-malaria (AMFm) - an initiative aiming at increasing the availability of affordable ACTs through public and private practice - is trying to accelerate the large-scale use of ACT worldwide. This began with an initial pilot phase in a selected group of African countries. However, the epidemiology of malaria, the economic context, and healthcare infrastructure of African countries differ considerably from those prevailing in Asia, where ACTs were first implemented in the 1990s. ACT implementation in Africa must therefore be accompanied by control and operational measures to maintain the efficacy of ACT and to protect patients against misuse. We discuss the expected benefits of the AMFm initiative in Africa and stress the importance of dealing with operational issues before implementation in the field, focusing particularly on drug resistance.     

Drug treatment and the control of malaria in Africa: a time of hope?

A wide selection of drugs is available to treat malaria. In many countries, however, the resistance of Plasmodium falciparum to drug therapy is problematic. For example, resistance to chloroquine is a problem in most tropical areas. Sulphadoxine/pyrimethamine, quinine, mefloquine, and artemisinin remain available and effective in many scenarios. Malarone and benflumetol/artemether are new drug combinations to apply against malaria infection. Each country needs an agreed-upon antimalarial drugs policy which takes into account the epidemiological factors affecting parasite distribution and the pattern of drug resistance. The prevailing health service characteristics, including the levels of health care at which different drugs are available, the risks and benefits of different drug regimens, compliance factors, and the logistics and cost of drug delivery must also be considered. Policy should be to reduce malaria mortality and morbidity and the development of drug resistance, while remaining within the limits of each country's budgetary and staffing capacity. Indications for treatment, genotyping and the reinfection problem in drug evaluation, amodiaquine reappraisal, new drug combinations, the role of drugs in preventing mosquito infection, and molecular biology in the surveillance of drug resistance are discussed.     

Economic prospects for a new antimalarial drug

The market for antimalarial drugs consists of the 2·8 billion (2·8 × 10⁹) people living in malaria endemic areas and about 20–30 million people, mainly Europeans and North Americans, who travel or live in malarious areas, and the wealthy élite of malarious developing countries. Some of the largest markets include China, India, and Indonesia with a total of 1·9 billion people exposed; Latin America, with 119 million; and sub-Saharan Africa with 400 million. An estimated 200 million clinical cases occur each year, with around 2 million deaths annually, primarily in African children. Antimalarial drugs are distributed through several different networks and are purchased by governments and private individuals. At present the world market is dominated by chloroquine by virtue of its safety, wide availability and low price. Approximately 20% of the total production of chloroquine was distributed through national control programmes and 80% through other channels; chloroquine is probably the second or third most widely consumed drug in the world. The global market for antimalarial drugs is likely to be of the order of US$100–120 million, with chloroquine making up about US$64–80 m, sulfadoxine/pyrimethamine about US$20 m, and other drugs making up US$10–20 m. Chloroquine is rapidly losing its effectiveness against the malaria parasite, and a safe, effective, cheap replacement is urgently needed. Another product which was found to be safe and effective against malaria, with a price per treatment held at or near the present price of chloroquine, could quickly replace chloroquine as the first-line treatment against malaria. However, most purchasers of chloroquine are very price sensitive, and governments in particular have to balance the number of treatments they can buy with a limited budget against the potentially greater effectiveness of a more expensive drug. Sales of the 2 newest widely available antimalarial drugs, mefloquine and halofantrine, are virtually limited to the travellers' market because of their high price. Since there is no cheap, safe, and effective alternative ready to take the place of chloroquine in the treatment of some 200 million cases of clinical malaria which occur each year, conditions are optimal for further development of promising compounds which might fulfill this major therapeutic gap. The rewards, both financial and in terms of public recognition, are likely to be great, and the risks of marketing such a product appear to be manageable.     

Chloroquine resistance of Plasmodium falciparum is associated with severity of disease in Nigerian children

Chloroquine resistance of Plasmodium falciparum in vitro was significantly higher in isolates from patients with severe malaria than those with uncomplicated disease. This association may be due to either progression of uncomplicated to severe disease following chloroquine failure or increased virulence of chloroquine-resistant parasites. The implication of this for antimalarial treatment policy is discussed.     

Review of the prevalence of malaria in Zimbabwe with specific reference to parasite drug resistance (1984-96)

The response of Plasmodium falciparum malaria to antimalarial drugs, mainly chloroquine, the first-line drug of choice for the treatment of malaria in Zimbabwe is reported here for the period 1984-96. Earlier studies (1982-83) had shown that Zimbabwe was free from drug-resistant falciparum malaria. The first chloroquine-resistant cases of malaria were reported in 1984 in the Zambezi Valley in the north-east of Zimbabwe. Following this report several cases of chloroquine resistance have been reported throughout the malaria-endemic regions of the country thus prompting the Ministry of Health to develop a sustainable national surveillance strategy to monitor, on an annual basis, the spread and extent of P. falciparum resistance to antimalarial drugs available to the National Malaria Control Programme (NMCP). Of all the antimalarial drugs assessed in vivo, only chloroquine and halofantrine have shown resistance, while no resistance in vivo was observed for sulfadoxine-pyrimethamine (Fansidar), quinine and mefloquine. The study shows the need to replace chloroquine with alternative antimalarial drugs in areas where chloroquine resistance is high, and an increase in the drug pool against malaria is also recommended considering that all the alternative antimalarial drugs available to the NMCP have faced resistance in various parts of the world.     

Efficacy and safety of artemether-lumefantrine (Coartem) tablets (six-dose regimen) in African infants and children with acute, uncomplicated falciparum malaria

Approximately one million children die from malaria each year. A recently approved artemisinin-based tablet, Coartem (co-artemether), comprising artemether 120 mg plus lumefantrine 20 mg, given in four doses, provides effective antimalarial treatment for children in many sub-Saharan countries. However, this regimen is considered insufficient for non-immune infants and in areas where multidrug-resistant Plasmodium falciparum predominates. This open-label study assessed the efficacy and safety of co-artemether administered to 310 African children weighing 5-25 kg, with acute, uncomplicated falciparum malaria. Six doses of co-artemether were given over 3 days, with follow-up at 7, 14 and 28 days. Treatment rapidly cleared parasitemia and fever. The overall 28-day cure rate was 86.5%, and 93.9% when corrected by PCR for reinfection. Cure rates at 7 and 14 days exceeded 97.0% (uncorrected) and, on day 28, were similar in infants (5-<10 kg) previously exposed to malaria infection (partially immune: 88.6% uncorrected; 93.3% corrected), and in those who were non-immune (82.5% uncorrected; 95.0% corrected). Adverse events were mostly mild. There was no electrocardiographic evidence of cardiotoxicity. The co-artemether six-dose regimen, treating acute uncomplicated falciparum malaria in African children, achieved rapid parasite clearance and a high cure rate. Treatment was generally safe and well tolerated.     

Perceptions on use of sulfadoxine-pyrimethamine in pregnancy and the policy implications for malaria control in Uganda

In malaria endemic areas intermittent treatment with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in pregnancy. Yet, data on perceptions regarding use of this drug are scarce. An exploratory study was conducted to assess perceptions on SP in Mukono district, Uganda. This is an initial step towards a review of the policy aimed at improving access and use of SP in pregnancy, which is currently low. Results show that SP is perceived to be an effective drug that cures malaria quickly. However there are negative perceptions related to its use in pregnancy. SP is believed to be strong and weakens pregnant women, causes abortions and foetal abnormalities. There is also a perception that resorting first to SP for malaria treatment may lead to the development of drug resistance. This perception may limit access to effective treatment of malaria in this community since the policy in Uganda recommends SP in combination with chloroquine as the first-line treatment. The policy implications of these findings include developing a health promotion package to demystify the misconceptions on the strength of SP, to explain its benefits and side-effects. This package will involve giving health workers refresher training on communication and counselling on use of SP in pregnancy targeting special groups like pregnant adolescents. These results provide important lessons to policy makers and programme managers who aim at scaling up access of SP for malaria prevention in pregnancy.     

Antimalarial drugs and their ways to use in the African milieu

In the tropical African environment, malaria is both a major public health problem and a problem of socioeconomic development. It is caused by various agents, the most virulent and only lethal one of which is Plasmodium falciparum. This parasite is controlled by the appropriate use of antimalarial drugs and methods of individual and collective protection. The principal drugs used to treat bouts of malaria without vomiting caused by P. falciparum are amino-4-quinoleines, essentially chloroquine. This is based on the level of resistance of P. falciparum to drugs in most African countries, particularly those of Central and West Africa. Malawi is the only country of southern Africa to have replaced chloroquine by sulfadoxine-pyrimethamine for this indication, in 1993. In cases of bouts of benign malaria with vomiting, but that are not serious, and severe malaria caused by P. falciparum (suspected or confirmed) with or without drug resistance, quinine should be given intravenously for at least three days. Once the patient regains consciouness or the digestive problems cease, quinine treatment should be given orally for 5 to 7 days. Sulfadoxine-pyrimethamine can be given as an alternative to quinine. The other antimalarial drugs currently on the African market (halofantrine, mefloquine, artemisinine and its derivatives) are often used inappropriately and should be used only in exceptional cases of severe bouts of complicated P. falciparum malaria, with suspected or confirmed resistance to amino-4-quinoleines. Individual protection against the Anopheles mosquito, the principal vector of malaria in Africa, is based largely on the use of mosquito nets impregnated with pyrethroid insecticide and the use of aerosols. Collective protection involves essentially environment-based measures.     

Amodiaquine combined with sulfadoxine/pyrimethamine versus artemisinin-based combinations for the treatment of uncomplicated falciparum malaria in Africa: a meta-analysis

Drug resistance in Plasmodium falciparum is a major obstacle to malaria control. Artemisinin-based combination therapy (ACT) is being advocated to improve treatment efficacy and to delay development of resistance. Here we summarise the available data on the efficacy of amodiaquine plus sulfadoxine/pyrimethamine (AQ+SP) versus ACTs in the treatment of uncomplicated malaria in sub-Saharan Africa. We searched for randomised trials in which patients with uncomplicated malaria treated with AQ+SP were compared with those treated with either amodiaquine plus artesunate (AQ+AS), artesunate plus sulfadoxine/pyrimethamine (AS+SP) or artemether/lumefantrine (AL). Medline, EMBASE, Cochrane Central Register of Controlled Trials and reference lists up to July 2005 were searched. Two reviewers independently extracted the data. The primary outcome measure was treatment failure by Day 28. Outcome measures were combined using a random effects model. Seven randomised trials of 4472 children were included. Trial quality was generally high. Treatment failure of AQ+SP was significantly reduced compared with AS+SP (relative risk (RR)=0.56, 95% CI 0.42-0.75), but increased compared with AL (RR=2.80, 95% CI 2.32-3.39). The overall failure rate of AQ+SP was similar compared with AQ+AS (RR=1.12, 95% CI 0.81-1.54), but there was significant heterogeneity of results across the studies. All the treatment regimens were safe and well tolerated. AQ+SP should be considered in some settings before the full implementation of an ACT.     

Malaria diagnosis and treatment in a rural Health Centre in Mayotte (Comoro archipelago, 2002)

With a marked increase in both morbidity and mortality, as well as a high level of resistance to chloroquine (CQ), malaria is once again a major public health problem in Mayotte, a French overseas territory in the Comoro archipelago. The object of this study is to assess the contribution in the field of two new antimalarial fight steps taken in 2001-2002: The use of the rapid diagnostic test (RDT) for malaria OptiMAL in the rural health centres and the drop of the CQ alone for the simultaneous administration of CQ and sulfadoxine-pyrimethamine (SP) as the first-line treatment for uncomplicated malaria. All 581 suspected malaria attacks, diagnosed by RDT during the year 2002 in a rural health centre of the island, were registered. The good positive predictive value of the RDT used (97.2%) calculated during the study has permitted an important reduction of the rate of wrongly administer antimalarial treatment. Before RDT was used, through lack of emergency microscopic diagnosis, the antimalarial treatment was presumptive in the isolated health centres and that rate was superior to 90%. It is now below 3%. Before the introduction of the new protocol, in the middle of the year 2002, the rate of therapeutic failures with CQ used alone was 40.2% (33/82). With the simultaneous administration of CQ and SP as a first-line treatment, this rate fell down to 1.8% (6/337). For the time being, this new treatment policy is acceptable in Mayotte. But the experience of the countries who have adopted this therapeutic policy shows that the effectiveness of the association CQ-SP is likely to be temporary. It is necessary to set up a "durable long-term" therapy strategy in Mayotte as soon as possible by adopting as first-line treatment for uncomplicated malaria a combination therapy according to the recommendations of the World Health Organization. It could be the artemether-lumefantrine combination which has already been the subject of an efficacy survey in the island.     

Treatment of malaria: some considerations and limitations of the current methods of assessment

The currently used methods for assessing the therapeutic response to antimalarial drugs are relatively imprecise and insensitive. These methods are inadequate in severe malaria when the objectives of treatment are to save life and prevent complications. Very large studies are needed to demonstrate significant differences in mortality, but measurement of the rates of clinical, biochemical, and parasitological response may provide useful comparative information. Definitions, assessment criteria, procedures, and data collection forms should be standardized and evaluated prospectively. Antimalarial drug treatment in different clinical situations should be assessed in terms of the balance between the risks of drug toxicity and the benefits of the antimalarial drug action. This balance is considerably different in severe falciparum malaria compared with uncomplicated malaria infections.     

武汉市116例境外输入性恶性疟临床治疗效果分析

目的分析和评价境外输入性恶性疟患者临床特点及青蒿素类药物治疗效果,促进合理规范用药,提高临床治愈率。方法收集武汉市省级疟疾定点医院收治的116例输入性恶性疟病例,对患者临床症状及体征、青蒿素药物使用情况及用药效果等进行回顾性分析。结果输入性恶性疟临床表现复杂多样且并发症较多,主要为发热、纳差、贫血、黄疸等;使用青蒿素治疗后症状均减轻或消失,无明显药物不良反应,退热中位数为2d,疟原虫转阴中位数为3d,临床症状缓解中位数为3d;109例普通型恶性疟采用青蒿素复方口服或青蒿琥酯针剂联合青蒿素复方口服治疗,其中30例口服青蒿素复方治疗1~4d, 1例复燃;79例青蒿琥酯针剂联合青蒿素复方口服治疗4~6d, 4例出现复燃。7例重症病例采用青蒿琥酯针剂联合口服多种青蒿素复方长疗程大剂量后均治愈,总治愈率95.69%(111/116)。结论患者以口服和注射青蒿素杀灭疟原虫治疗恶性疟安全有效,治愈率高,但部分患者停用青蒿素类药物后出现疟原虫复燃,为遏制患者重症和抗药风险,应"规范、全程、足量"使用青蒿素类药品。