Plasmodium vivax malaria in spite of atovaquone/proguanil (malarone) prophylaxis

A 70-year-old male scientist, who had returned 5 weeks earlier from Ethiopia, was admitted to the hospital with symptoms consistent with malaria. On physical examination, he had orthostatic hypotension. He was dehydrated and showed a mild clinical delirium. Abdominal examination revealed a possible spleen tip, and he had petechial lesions bilaterally below his knees. Laboratory data revealed his white blood cell count to be 4,500/mL, with 67% polymorphonuclear cells and 15% band forms. The hemoglobin level was 13.9 g/dL, and the platelet count was low, at 32,000/mL.     

Atovaquone–Proguanil (Malarone): an Effective Treatment for Uncomplicated Plasmodium falciparum Malaria in Travelers from Denmark

Background Previous experience with unacceptable adverse effects with mefloquine as treatment for uncomplicated Plasmodium falciparum malaria prompted an evaluation of the effectiveness and side effects of atovaquone–proguanil (Malarone) in a hospital setting.
Methods Atovaquone–proguanil was given as standard treatment (1,000/400mgq.d. for 3 days) to 50 adults who had traveled in Africa and returned with uncomplicated Plasmodium falciparum malaria. Half of the treated patients were African and had lived outside Africa for varying periods of time; the other half were Danish-born persons without any previous immunity towards malaria.
Results All patients treated with Malarone were cured without complications. The mean fever clearance times differed among the groups and according to various degrees of prior exposure to malaria and ranged from 1.3 to 2.2 days. Adverse effects during treatment were mild, and were likely to be due to the malaria itself. Fourteen people who had acquired falciparum malaria in spite of taking proguanil–chloroquine prophylaxis were also cured uneventfully without recrudescence.
Conclusions Malarone appears to be an effective, safe and acceptable oral treatment for uncomplicated malaria.     

Dihydroartemisinin/Piperaquine: a review of its use in the treatment of uncomplicated Plasmodium falciparum malaria

Artemisinin-based combination regimens are recommended by WHO for the treatment of uncomplicated Plasmodium falciparum malaria. One such combination comprises the artemisinin derivative dihydroartemisinin and the bisquinolone piperaquine. Eurartesim? is the only dihydroartemisinin/piperaquine formulation that meets international good manufacturing practice standards. This article reviews the pharmacological properties of dihydroartemisinin and piperaquine, and the therapeutic efficacy and tolerability of dihydroartemisinin/piperaquine in the treatment of uncomplicated P. falciparum malaria. A number of trials have shown dihydroartemisinin/piperaquine to be highly effective in the treatment of uncomplicated P. falciparum malaria. Two pivotal, randomized, open-label, multicentre trials demonstrated the Eurartesim? formulation of dihydroartemisinin/piperaquine to be noninferior to artesunate plus mefloquine in children and adults in Asia and noninferior to artemether/lumefantrine in children in Africa, in terms of polymerase chain reaction-corrected cure rates. In both trials, dihydroartemisinin/piperaquine recipients were significantly less likely than artesunate plus mefloquine recipients or artemether/lumefantrine recipients to experience reinfection. Gametocyte carriage was greater in patients receiving dihydroartemisinin/piperaquine than in those receiving comparator antimalarial regimens. The Eurartesim? formulation of dihydroartemisinin/piperaquine was generally well tolerated in the treatment of uncomplicated P. falciparum malaria, and was associated with significantly less nausea, vomiting and dizziness than artesunate plus mefloquine. Although prolongation of the corrected QT interval has been reported in patients receiving dihydroartemisinin/piperaquine, there are currently no clinical data signalling that it is associated with clinically significant arrhythmias. In conclusion, dihydroartemisinin/piperaquine is a valuable option for use in the first-line treatment of uncomplicated P. falciparum malaria.     

Tertian malaria (Plasmodium vivax and Plasmodium ovale) in two travelers despite atovaquone-proguanil prophylaxis

There is limited data regarding the efficacy of prophylaxis with atovaquone/proguanil (A/P) against non-falciparum malaria in travelers. Two cases, one Plasmodium vivax infection and another Plasmodium ovale infection, in travelers despite A/P prophylaxis are presented.     

Descriptive study on the efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Sudan

Purpose  

The aim of this study was to investigate the efficacy of artemether-lumefantrine in treating uncomplicated Plasmodium falciparum malaria in four sentinel areas in Sudan with different malaria transmission (Damazin, Sinnar, and Kosti in the north, and Juba in the south).     

青蒿素哌喹片治疗无并发症恶性疟的剂量探索试验

目的探索青蒿素哌喹片治疗无并发症恶性疟的安全有效的适宜剂量。方法收治7～65岁男性和女性病人共100例,按区组随机化方案分成2组,成人总量1400 mg组年龄(22±s12)岁,1750 mg组年龄(21±12)岁。分别于0h和24h给药一次,比较2组的平均原虫转阴和退热时间、28d治愈率及原虫复燃率。结果2组的平均原虫转阴时间分别是(61±19)h和(57±21)h,平均退热时间为(20±15)h和(18±10)h,P>0.05;28 d治愈率是80%和96%,原虫复燃率为20%和4%,总量1750 mg组显著优于1400 mg组(P<0.05)。2组耐受性均良好,未发现明显的不良反应。结论推荐青蒿素哌喹片的临床治疗剂量为总量1750 mg,每日1次,分2d服完为1个疗程。     

Artemether/lumefantrine in the treatment of uncomplicated falciparum malaria

At present, artemether/lumefantrine (AL) is the only fixed-dose artemisinin-based combination therapy recommended and pre-qualified by WHO for the treatment of uncomplicated malaria caused by Plasmodium falciparum. It has been shown to be effective both in sub-Saharan Africa and in areas with multi-drug resistant P. falciparum in southeast Asia. It is currently recommended as first-line treatment for uncomplicated malaria in several countries. However, AL has a complex treatment regimen and the issues of adherence to treatment with AL by adult patients and real-life effectiveness in resource-poor settings will be critical in determining its useful therapeutic life, especially in Africa, where the major burden of malaria is felt. There are also issues of safety of the artemisinin derivatives, including AL, which will need to be monitored as their use in resource-poor settings becomes more widespread. There are limited pharmacokinetic studies of AL in African patients, and the relationship between plasma drug concentration and efficacy in these patients is unknown. Moreover, the effects of factors such as concurrently administered drugs, malnutrition and co-infections with HIV and helminths in malaria patients are not well understood. These will need to be addressed, although a few studies on possible drug-drug interactions with commonly used drugs, such as quinine, mefloquine and ketoconazole, have been reported. This review focuses on the status of clinical pharmacology, efficacy and real-life effectiveness of AL under a variety of settings, and highlights some of the challenges that face policy makers during the deployment of AL, especially in Africa, with regards to ensuring that those who most need this therapy will not be denied access due to official inefficiency in procurement and distribution processes.     

Evaluation of plasma lactate as a parameter for disease severity on admission in travelers with Plasmodium falciparum malaria

BACKGROUND: Rapid immunochromatographic dipstick assays are used increasingly in many tropical and Western countries as a tool to diagnose Plasmodium falciparum malaria. However, these tests do not provide any information about the severity of the infection. We evaluated the usefulness of plasma lactate as a parameter for disease severity on admission in imported P. falciparum malaria. METHODS: In a cohort of 61 nonimmune travelers with imported P. falciparum malaria, plasma lactate levels on admission were related to the severity of the infection. Results from 12 of 61 patients fulfilled the criteria of severe malaria. RESULTS: Logistic regression analysis showed that a plasma lactate level above the upper range of normal was associated with an odds ratio of 31 (95% CI 6-164) for severe malaria. As a continuous variable, a 1 mmol/L increase in plasma lactate level was associated with an odds ratio of 12 (95% CI 3-50) for severe malaria. The sensitivity of an increased plasma lactate level on admission for severe malaria was 67% with a specificity of 94%. CONCLUSIONS: A timely determination of plasma lactate on admission may be helpful in the assessment of disease severity in travelers with imported P. falciparum malaria. An increased plasma lactate level should raise suspicion of a severe P. falciparum malaria infection, in particular when concomitant infections are not considered likely.     

Imported Plasmodium vivax malaria: demographic and clinical features in nonimmune travelers

BACKGROUND: Imported malaria is an important problem in nonendemic countries due to increasing travel to and immigration from malaria-endemic countries. Plasmodium vivax malaria is relatively common in travelers but there are few published data regarding the outcome of P. vivax malaria in this group. METHODS: We analyzed 209 cases of P. vivax malaria that were reported to the GeoSentinel network and the VIDS database, Royal Melbourne Hospital. Analyses were performed on data including demographics, pretravel encounter, antimalarial prophylaxis, exposure history, type of travel, countries of recent and past travel, clinical presentation, treatment, outcome and final diagnoses. RESULTS: The majority of patients were travelers (61%), followed by expatriates (13%) and recent immigrants or foreign visitors (12%). Recent travel to Oceania, sub-Saharan Africa, and South and Central America was significantly more likely to be associated with P. vivax malaria than travel to all other regions. The clinical presentation of P. vivax malaria acquired in the Pacific region is indistinguishable from infection with P. falciparum. The use of chloroquine prophylaxis did not prolong the incubation period. Relapse of infection was not infrequent, and the only significant predictor of relapse was travel to Papua New Guinea (PNG), regardless of primaquine dose. Travelers returning from PNG were eight times more likely to relapse after primaquine treatment compared to travelers with P. vivax malaria acquired elsewhere. CONCLUSIONS: We have presented details of the epidemiology, clinical presentation and management of infection with P. vivax malaria in travelers. P. vivax malaria is an important cause of morbidity in travelers, and relapse following primaquine treatment is especially problematic with P. vivax malaria acquired in PNG.     

双氢青蒿素哌喹片治疗无并发症恶性疟的临床随机对照试验

目的 :探讨双氢青蒿素哌喹片在柬埔寨马德望省治疗无并发症恶性疟的有效性和安全性。方法 :无并发症恶性疟疾病人 5 0例 ,按随机数字表随机分成 2组 ,每组 2 5例 ,一组用双氢青蒿素哌喹片 ,一组用复方双氢青蒿素片 ,采用 2d内 4次给药 ,成人总量 8片的给药方案 ,观察治愈率、复燃率、平均原虫转阴时间、退热时间和不良反应。结果 :双氢青蒿素哌喹片组的原虫转阴时间为 (36±s 2 0 )h ,复方双氢青蒿素片组为 (36± 17)h ;退热时间双氢青蒿素哌喹片组为 (4 2± 2 5 )h ,复方双氢青蒿素片为(31± 2 1)h ;随访 2 8d ,双氢青蒿素哌喹片组治愈率为 10 0 % ,复方双氢青蒿素片组有 1例于d 2 1复燃 ,治愈率为 96 %。病人对两药均有较好的耐受性 ,个别病人在服药过程中出现恶心、腹痛等症状 ,均轻微而且是自限性的。结论 :双氢青蒿素复方具有高效、速效、低毒、病人顺应好等优点。     

Artesunate-amodiaquine for the treatment of uncomplicated malaria

Without an effective vaccine for the prevention of malaria, a fundamental component of the strategy for the control of this disease is based on prompt and effective treatment. Due to the high resistance level of Plasmodium falciparum to the most affordable drugs such as chloroquine and sulfadoxine-pyrimethamine, artemisinin-based combination therapies are presently used in many countries or are being developed for registration. One artemisinin combination therapy that is drawing a certain degree of interest is the combination of artesunate (a short half-life drug) plus amodiaquine (a long half-life drug that is presently used in loose combination in many countries). The short half-life drug achieves substantial and rapid parasite killing, while a high concentration of the long half-life drug kills off the remaining malaria parasites. In addition to the effectiveness of 3 days of treatment (rapid clearance of fever and malaria parasites) in western and central Africa, where resistance to amodiaquine is low, the combination of artesunate plus amodiaquine may delay or prevent the emergence of resistance to both drugs. An important step is the recent registration in Morocco (the country where the drug is manufactured) of a fixed combination of artesunate plus amodiaquine by the Drugs for Neglected Diseases initiative with sanofi-aventis as the industrial partner. A prequalification dossier of this fixed combination has been submitted to the WHO. This new co-formulation will almost certainly increase its effectiveness by improving drug compliance.     

Quinoline-resistance reversing agents for the malaria parasite Plasmodium falciparum.

Resistance to quinoline antimalarials, especially to chloroquine and mefloquine has had a major impact on the treatment of malaria worldwide. In the period since 2000, significant progress has been made in understanding the origins of chloroquine resistance and to a lesser extent mefloquine resistance in Plasmodium falciparum. Chloroquine resistance correlates directly with mutations in the pfcrt gene of the parasite, while changes in another gene, pfmdr1, may also be related to chloroquine resistance in some strains. Mutations in pfcrt do not appear to correlate with mefloquine resistance, but some studies have implicated pfmdr1 in mefloquine resistance. Its involvement however, has not been definitively demonstrated. The protein products of these genes, PfCRT and Pgh-1 are both located in the food vacuole membrane of the parasite. Current evidence suggests that PfCRT is probably a transporter protein. Chloroquine appears to exit the food vacuole via this transporter in resistant PfCRT mutants. Pgh-1 on the other hand, resembles mammalian multi-drug resistance proteins and appears to be involved in expelling hydrophobic drugs from the food vacuole. Resistance reversing agents are believed to act by inhibiting these proteins. The currently known chloroquine- and mefloquine-resistance reversing agents are discussed in this review. This includes a discussion of structure-activity relationships in these compounds and hypotheses on their possible mechanisms of action. The status of current clinical applications is also briefly discussed.     

Plasmodium falciparum malaria associated with mefloquine failure in Gambia

A 25-year-old Caucasian man developed Plasmodium falciparum malaria after traveling to Gambia, despite having received chemoprophylaxis with mefloquine. The patient was hospitalized after returning to the United States. He received a 3-day course of atovaquone-proguanil and made a complete recovery. This case illustrates the potential role of pharmacists in the pharmaceutical care of travelers and underscores the importance of using current recommendations for preventing and treating malaria.     

Pharmacokinetics of oral artesunate in thai patients with uncomplicated falciparum malaria

The pharmacokinetics of artesunate and its major plasma metabolite, dihydroartemisinin, were investigated in 11 Thai male patients with acute uncomplicated falciparum malaria during the acute and recovery phases. Patients were given an oral dose of 200mg artesunate (Guilin Pharmaceutical) on the first day, followed by 100mg 12 hours later, then 100mg daily for another 4 days (total dose of 700mg). All the patients showed a rapid initial response with median (range) parasite and fever clearance times of 30 (18 to 60) and 24 (4 to 94) hours, respectively; no patients showed reappearance of parasites during the 28-day follow-up period. No significant clinical adverse effects were detected in any patient. Acute phase malaria infection significantly influenced the pharmacokinetics of artesunate and its active metabolite, dihydroartemisinin. Maximum plasma drug concentration (C(max)), absorption half-life (t((1/2)a)), area under the plasma concentration-time curve from zero to the last observed time (AUC) and terminal elimination half-life (t((1/2)z)) of artesunate were decreased, while apparent total body clearance (CL/f) was increased during the acute phase, compared with the recovery phase. In addition, a decrease in the C(max) and an increase in the AUC(DHA/ARS ) ratio were found. Optimisation of therapy with oral artesunate should therefore be based on the kinetics of the drug and dihydroartemisinin in malaria patients with acute phase infection.