The new drug combinations: their place in the treatment of uncomplicated Plasmodium falciparum malaria

Malaria is a leading cause of morbidity and mortality in developing countries. Selection of mutant Plasmodium falciparum malaria strains under drug pressure has led to the development of drug resistance. There is a pressing need for effective, safe, practicable drug combinations that hve lower selection pressure. A review of the mein drug combinations, which are recently registered or are still under development, was undertaken, with special attention to the atovaquone-proguanil and artemether-lumefantrine combination.     

2005-2008年中国报告恶性疟病例流行病学分析

目的明确中国2005-2008年报告恶性疟病例的流行病学特征,为当前恶性疟防控提供参考数据。方法本文所采用资料来源于中国疾病预防控制中心疾病监测信息报告管理系统,输入性病例仅指除云南和海南省外的其他地区报告的恶性疟病例,采用构成比等相对数描述中国恶性疟报告病例的三间分布和诊断情况,并采用χ2检验、秩和检验和Watson-Willian检验等方法对云南和海南省与其他地区的情况进行了分析比较。结果中国云南和海南省恶性疟报告发病率近年下降明显(P0.001);而其他地区输入性恶性疟病例有上升迹象;云南和海南省的恶性疟发病高峰月份为4-6月,与其他地区的5-8月高峰不同(P0.01);恶性疟发病以农民和民工为主,发病年龄主要集中在20～40岁年龄组;中国除云南、海南省外的其他地区恶性疟病死率(3.39%)、发病-诊断时间(中位数=5d)和病例订正报告比例(52.30%)均明显高于云南和海南省(分别为0.76%,3d和11.91%)(P0.01),而实验室诊断比例(78.18%)低于云南和海南省(92.64%)(P0.001)。结论近年来,中国恶性疟发病逐年下降,而云南、海南省以外的其他地区恶性疟报告病例上升,且诊断能力较低;建议在这些恶性疟非流行区,大力加强培训和宣传,提高医疗机构对恶性疟病例的诊断能力和诊断及时性,降低病死率。     

Severe falciparum malaria (21 cases)

The incidence of severe falciparum malaria is increasing in the developed countries and mortality remains high despite progress in intensive care management and schizonticide treatment. Many authors emphasize the importance of exchange transfusion (EXT) in the most severe cases. We studied 21 cases (34±12 years, 6 females; SAPS: 8.4±3.7) of severe malaria (according to WHO criteria) consecutively admitted to ICU between 1985 and 1990: 3 patients underwent EXT. Twenty were febrile above 39°C, 10 had cerebral malaria, 14 hepatic impairment, 8 acute renal failure, 5 pulmonary oedema. Nine patients required mechanical ventilation, 1 haemodialysis, 1 intracranial pressure monitoring. Mean parasitemia was 13%, 16 patients had thrombocytopenia <50×10⁹/l, 3 anemia <7 g/dl and 3 leucopenia <2.8×10⁹/l. Nineteen received quinine i.v., 1 mefloquine, 1 chloroquine. Sixteen patients received blood products transfusion, 3 were treated by EXT in addition. Twenty were cured and discharged from hospital without sequelae (mean stay: 14 days); 4 had nosocomial infection, 1 a splenic infarction. One patient (17-years-old; SAPS: 17; parasitemia: 7.8%) died 12 h after admission from non-cardiogenic pulmonary oedema with multi-organ failure. The literature and this study lead us to propose EXT in patients with unfavourable evolution after conventional treatment rather than in all the patients with a parasitemia above 10% at admission. A randomized study to compare conventional treatment in ICU with or without EXT is necessary.     

Childhood Plasmodium falciparum malaria complicated by splenic abscess

We report on an 8‐year‐old girl with Plasmodium falciparum malaria complicated by splenic abscess during the course of her infection. The diagnosis of malaria was based upon the demonstration of trophozoites of P. falciparum in the peripheral blood smear. The trophozoites of the same organism were visualized on the Giemsa‐stained smear prepared from the percutaneous splenic aspirate specimen. The patient failed to respond to parenteral Artesunate alone, which demanded emergent splenectomy. To our knowledge, this is the first report of splenic abscess complicating the course of childhood P. falciparum malaria in the English literature.     

Erythrocytapheresis for Plasmodium falciparum infection complicated by cerebral malaria and hyperparasitemia

In malaria due to Plasmodium falciparum, life-threatening complications are in part related to the degree of parasitemia. Whole blood exchange and red blood cell exchange (RCE) have been used for the rapid removal of parasites from the circulation of patients with a high parasite load complicated by cerebral, pulmonary, and renal dysfunction. We have treated three 5-45-year-old patients with hyperparasitemia and end-organ dysfunction with red cell exchange by automated apheresis as an adjunct to specific anti-malarial chemotherapy. Parasitemia dropped more than 80% in all three patients immediately after the exchange, and all patients had an uneventful and full recovery. In combination with effective anti-malarial chemotherapy, apheresis RCE is a safe and rapid approach to treat complicated malaria due to P. falciparum.     

Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria

Severe malaria due to Plasmodium falciparum causes more than 800,000 deaths every year. Primary therapy with quinine or artesunate is generally effective in controlling P. falciparum parasitemia, but mortality from cerebral malaria and other forms of severe malaria remains unacceptably high. Long-term cognitive impairment is also common in children with cerebral malaria. Of the numerous adjunctive therapies for cerebral malaria and severe malaria studied over the past five decades, only one (albumin) was associated with a reduction in mortality. In this article, we review past and ongoing studies of adjunctive therapy, and examine the evidence of efficacy for newer therapies, including inhibitors of cytoadherence (e.g., levamisole), immune modulators (e.g., rosiglitazone), agents that increase nitric oxide levels (e.g., arginine) and neuroprotective agents (e.g., erythropoietin).     

Shock complicating severe falciparum malaria in European adults

Objective: To study adult patients with severe falciparum malaria who developed shock. Design: Retrospective study from 1987 to 1993. Setting: Medical intensive care unit in a university hospital. Patients: 14 patients admitted with severe falciparum malaria who developed shock. All received intravenous quinine. Measurements and results: The mean Simplified Acute Physiology Score II was 59.5 ± 7.1; 2.6 ± 0.4 criteria defining severe disease were present on admission in 12 patients; and initial parasitemia was 21 ± 6 %. Twelve patients received inotropic drugs. Pulmonary artery catheterization showed the following results in 7 patients: mean arterial pressure 57 ± 4 mmHg; pulmonary artery occlusion pressure 11 ± 1 mmHg; cardiac index 5.5 ± 0.9 l · min⁻¹· m⁻²; and systemic vascular resistance index 783 ± 122 dyne · s · cm⁻⁵· m⁻². Seven patients had evidence of bacterial infection at the time of shock. Of the 7 deaths (50 %), 5 were due to shock, with documented bacterial infection in all patients and persistent parasitemia in 4. Conclusions: Shock complicating severe falciparum malaria in adults is associated with peripheral vasodilation and carries a poor prognosis. In falciparum malaria with shock, bacterial coinfection should be suspected immediately and treated empirically with broad-spectrum antibiotics. Nevertheless, Plasmodium falciparum may contribute directly or indirectly to the onset of shock. Received: 26 May 1996 Accepted: 1 April 1997     

Acute renal failure in severe chloroquine resistant falciparum malaria

We observed 3 patients with a severe falciparum malaria infection. Although the patients appeared not to be seriously ill on admission, severe complications occurred. Renal impairment was a prominent feature and haemodialysis was sometimes necessary. Many hypotheses have been proposed regarding the aetiology of renal failure in Plasmodium falciparum but cannot yet be fully substantiated. Whatever the aetiology of renal failure might be, we believe that treatment should not differ essentially from that of acute tubular necrosis after circulatory shock and early diagnosis and treatment is imperative in spite of an initially ostensibly good clinical condition.     

临床护理路径在输入性恶性疟疾中的应用

目的探讨临床护理路径(CNP)在输入性恶性疟疾中的应用效果。方法对2011年7—12月收治的45例输入性恶性疟疾患者实施CNP,并与2011年1—6月收治的40例患者进行比较,分析实施CNP前后患者住院天数、并发症发生率、健康知识知晓率、患者满意度等情况。结果实施CNP后,患者住院天数、并发症发生率、健康知识知晓率、患者满意度优于未实施CNP的对照组,差异有统计学意义(P<0.05)。结论与常规护理相比,应用CNP更有利于减少住院时间、降低并发症发生率、提高健康知识知晓率及患者满意度。     

Acute respiratory distress syndrome due to falciparum malaria in a pregnant woman

We report the case of a pregnant woman (29 th week), living in a Paris suburb, about 20 miles from an international airport. She presented with septic shock and severe acute respiratory distress syndrome (ARDS). A few parasitized erythrocytes were discovered in a hemorrhagic bronchoalveolar lavage (BAL), specimen and many were found on examination of the placenta after a caesarean section had been performed. The patient's condition dramatically improved once given quinine therapy. This is an uncommon case on account of: (1) the unusual clinical course with no organ failure but ARDS, (2) the unusual way the diagnosis was made, (3) the very unusual way the patient became contaminated (airport malaria), (4) the pregnant condition of the patient. Received: 28 October 1996 Accepted: 15 April 1997     

Immunopathogenesis of falciparum malaria: implications for adjunctive therapy in the management of severe and cerebral malaria

Despite optimal antimalarial treatment and advances in malaria eradication, the mortality rate associated with severe malaria due to Plasmodium falciparum infection, including cerebral malaria (CM), remains unacceptably high. This suggests that strategies directed solely at parasite eradication may be insufficient to prevent neurological complications and death in all cases of CM. Therefore, there is an urgent need to develop innovative adjunctive therapeutic strategies to effectively reduce CM-associated mortality. CM pathogenesis is believed to be due, in part, to an aberrant host immune response to P. falciparum, resulting in deleterious consequences, including vascular activation and dysfunction. Development of effective and affordable therapeutic strategies that act to modulate the underlying host-mediated immunopathology should be explored to improve outcome. In this article, we summarize immunomodulatory therapies that have been assessed in clinical trials to date, and highlight novel and promising treatment strategies currently being investigated to address this major global health challenge.     

Immunomodulation in Plasmodium falciparum malaria: experiments in nature and their conflicting implications for potential therapeutic agents

Effective Plasmodium falciparum immunity requires a precisely timed and balanced response of inflammatory and anti-inflammatory immune regulators. These responses begin with innate immune effectors and are modulated over the course of an infection and between episodes to limit inflammation. To date, there are no effective immunomodulatory therapies for severe malaria. Some of the most potent immunomodulators are naturally occurring infections, including helminthic and chronic viral infections. This review examines malaria coinfection with these organisms, and their impact on malaria morbidity and immune responses. Overall, there is compelling evidence to suggest that chronic coinfections can modulate deleterious malaria-specific immune responses, suggesting that therapeutic agents may be effective if utilized early in infection. Examination of the mechanisms of these effects may serve as a platform to identify more targeted and effective malaria immunomodulatory therapeutics.     

2006-2010年浙江省台州市疟疾流行态势分析

目的 了解浙江省台州市疟疾流行形势和特征,为防治策略提供参考依据.方法 采用描述流行病学方法对台州市2006-2010年疟疾流行情况进行分析.结果 在2006-2010年报告的317例疟疾病例中,间日疟292例,占92.11％,恶性疟25例,占7.89％;疟疾病例报告数由2007年最高峰106例下降至2010年1...     

Experiences with severe P. falciparum malaria in the intensive care unit

Objective: To review the clinical profiles and therapies instituted for patients with severe malaria admitted to an ICU.¶Design: Retrospective study.¶Setting: Internal ICU of a tertiary care centre.¶Patients and participants: Between January, 1992, and February, 1999, 104 patients with malaria were admitted to the General Hospital of Vienna. Sixty-nine patients suffered from Plasmodium falciparum malaria (66 %), seven of these were admitted to the ICU.¶Measurement and results: Seven patients were admitted to the ICU, of whom three died (4 % in hospital case-fatality rate). Four patients required mechanical ventilation because of respiratory insufficiency and adult respiratory distress syndrome (ARDS), of whom three died. Three patients were treated with inhaled nitric oxide (NO) and kinetic therapy; one patient required extracorporeal veno-venous oxygenation. All patients who died required haemofiltration because of acute renal failure.¶Conclusion: As P. falciparum is a potentially life-threatening disease, reliable criteria for ICU admission should be defined and risk factors identified. Early ICU monitoring should be attempted, especially under the following conditions: (1) lack of clinical response to anti-malarial treatment within 48 h and/or (2) any signs of neurological disturbance (hypoglycaemia excluded). Prospective multicentre trials and guidelines for supportive intensive care are urgently needed.     

增强化学发光法标记的DNA探针诊断恶性疟疾

采用增强化学发光法（ＥＣＬ）标记的ＤＮＡ探针诊断恶性疟疾。结果显示，ＥＣＬ标记的探针能检出２５ｐｇ纯化的恶性疟ＤＮＡ或原虫率为０．００１％体外培养的恶性疟原虫血，并且和人白细胞ＤＮＡ无交叉反应。对１４６份疟疾病人血样进行检测，ＤＮＡ探钉法和常规镜检法有较好的相关性。对于镜检中确诊的９９例恶性疟，ＥＣＬ法检出９３例；对于４７例间日疟血样，ＥＣＬ法仅和１例有阳性反应；该探针和４８例正常人血均无交叉反应。结果表明，ＥＣＬ标记的探针具有较好的特异性和敏感性，可用于恶性疟疾的特异性诊断和大规模流行病学调查。     

Current developments in malaria transmission-blocking vaccines

Malaria is still a leading cause of morbidity and mortality in human populations. Problems, including drug-resistant parasites and insecticide resistant mosquitoes, ensure the continued hold of malaria in the tropics and sub-tropics. Each year around 100 million cases of malaria result in at least 50,000 deaths outside of sub-Saharan Africa; within sub-Saharan Africa itself, malaria causes around one million child deaths per year. New approaches for malaria control are badly needed and much effort has gone to develop malaria vaccines. In addition to giving personal protection, most such vaccines would also tend to reduce the transmission of malaria. One class of vaccine is being developed specifically for this purpose - the malaria transmission-blocking vaccines (TBVs). TBVs are based upon antigens expressed on the surface of the sexual and mosquito mid-gut stages of malaria parasites. These antigens are the targets of antibodies induced by vaccination of the host and ingested with the parasites in a mosquito blood meal. The antibodies act by inhibiting the parasite’s development within the mosquito itself and they thereby prevent the onward transmission of the parasites. TBVs could contribute to the total interruption of malaria transmission in many locations with relatively low transmission rates, mostly outside sub-Saharan Africa. Under almost all transmission rates, however, TBVs would help reduce malaria incidence and malaria-related morbidity and mortality. Promising recombinant TBV candidate antigens for the two main human malaria parasite species, Plasmodium falciparum and Plasmodium vivax, have been produced and tested in the laboratory; one has undergone early clinical trials.     

Discovery,mechanisms of action and combination therapy of artemisinin

Despite great international efforts, malaria still inflicts an enormous toll on human lives, especially in Africa. Throughout history, antimalarial medicines have been one of the most powerful tools in malaria control. However, the acquisition and spread of parasite strains that are resistant to multiple antimalarial drugs have become one of the greatest challenges to malaria treatment, and are associated with the increase in morbidity and mortality in many malaria-endemic countries. To deal with this grave situation, artemisinin-based combinatory therapies (ACTs) have been introduced and widely deployed in malarious regions. Artemisinin is a new class of antimalarial compounds discovered by Chinese scientists from the sweet wormwood Artemisia annua. The potential development of resistance to artemisinins by Plasmodium falciparum threatens the usable lifespan of ACTs, and therefore is a subject of close surveillance and extensive research. Studies at the Thai–Cambodian border, a historical epicenter of multidrug resistance, have detected reduced susceptibility to artemisinins as manifested by prolonged parasite-clearance times, raising considerable concerns on resistance development. Despite this significance, there is still controversy on the mode of action of artemisinins. Although a number of potential cellular targets of artemisinins have been proposed, they remain to be verified experimentally. Here, we review the history of artemisinin discovery, discuss the mode of action and potential drug targets, and present strategies to elucidate resistance mechanisms.     

Current status of malaria chemotherapy and the role of pharmacology in antimalarial drug research and development

Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to currently used antimalarials, and the lack of affordable new drugs are the limiting factors in the fight against malaria. In addition, other problems with some existing agents include unfavorable pharmacokinetic properties and adverse effects/toxicity. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. In recent years, major advances have been made in the pharmacology of several antimalarial drugs both in pharmacokinetics and pharmacodynamics aspects. These include the design, development, and optimization of appropriate dosage regimens of antimalarials, basic knowledge in metabolic pathways of key antimalarials, as well as the elucidation of mechanisms of action and resistance of antimalarials. Pharmacologists have been working in close collaboration with scientists in other disciplines of science/biomedical sciences for more understanding on the biology of the parasite, host, in order to exploit rational design of drugs. Multiple general approaches to the identification of new antimalarials are being pursued at this time. All should be implemented in parallel with focus on the rational development of new agents directed against newly identified parasite targets. With major advances in our understanding of malaria parasite biology coupled with the completion of the malaria genome, has presented exciting opportunities for target-based antimalarial drug discovery.