Long-term Malaria Prophylaxis Research Articles

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe toxicity. There are no alternative treatment options. To identify novel drugs with activity against Echinococcus multilocularis metacestodes, researchers have studied potentially interesting drug targets (e.g. the parasite's energy metabolism), and/or adopted drug repurposing approaches by undertaking whole organism screenings. We here focus on drug screening approaches, which utilize an in vitro screening cascade that includes assessment of the drug-induced physical damage of metacestodes, the impact on metacestode viability and the viability of isolated parasite stem cells, structure-activity relationship (SAR) analysis of compound derivatives, and the mode of action. Finally, once in vitro data are indicative for a therapeutic window, the efficacy of selected compounds is assessed in experimentally infected mice. Using this screening cascade, we found that the anti-malarial mefloquine was active against E. multilocularis metacestodes in vitro and in vivo. To shed more light into the mode of action of mefloquine, SAR analysis on mefloquine analogues was performed. E. multilocularis ferritin was identified as a mefloquine-binding protein, but its precise role as a drug target remains to be elucidated. In mice that were infected either intraperitoneally with metacestodes or orally with eggs, oral treatment with mefloquine led to a significant reduction of parasite growth compared to the standard treatment with albendazole. However, mefloquine was not acting parasiticidally. Assessment of mefloquine plasma concentrations in treated mice showed that levels were reached which are close to serum concentrations that are achieved in humans during long-term malaria prophylaxis. Mefloquine might be applied in human AE patients as a salvage treatment. Future studies should focus on other repurposed anti-infective compounds (MMV665807, niclosamide, atovaquone), which showed stronger in vitro activity against E. multilocularis than mefloquine.

Long-Term Prophylaxis and Pharmacokinetic Evaluation of Intramuscular Nano- and Microparticle Decoquinate in Mice Infected with P. berghei Sporozoites.

Decoquinate nanoparticle and microparticle suspended in an oily vehicle to retard drug release are evaluated for long-term malaria prophylaxis. Pharmacokinetic studies in normal animals and antimalarial efficacy in liver stage malaria mice were conducted at various single intramuscular-decoquinate doses for 2, 4, 6, or 8 weeks prior to infection with P. berghei sporozoites. The liver stage efficacy evaluation was monitored by using an in vivo imaging system. Full causal prophylaxis was shown in mice with a single intramuscular dose at 120 mg/kg of nanoparticle decoquinate (0.43 μm) for 2-3 weeks and with microparticle decoquinate (8.31 μm) injected 8 weeks earlier than inoculation. The time above MIC of 1,375 hr observed with the microparticle formulation provided a 2.2-fold longer drug exposure than with the nanoparticle formulation (624 hr). The prophylactic effect of the microparticle formulation observed in mice was shown to be 3-4 times longer than the nanoparticle decoquinate formulation.

Safety, Tolerability, and Compliance with Long-Term Antimalarial Chemoprophylaxis in American Soldiers in Afghanistan.

Long-term antimalarial chemoprophylaxis is currently used by deployed U.S. military personnel. Previous small, short-term efficacy studies have shown variable rates of side effects among patients taking various forms of chemoprophylaxis, though reliable safety and tolerability data on long-term use are limited. We conducted a survey of troops returning to Fort Drum, NY following a 12-month deployment to Operation Enduring Freedom, Afghanistan from 2006 to 2007. Of the 2,351 respondents, 95% reported taking at least one form of prophylaxis during their deployment, and 90% were deployed for > 10 months. Compliance with daily doxycycline was poor (60%) compared with 80% with weekly mefloquine (MQ). Adverse events (AEs) were reported by approximately 30% with both MQ and doxycycline, with 10% discontinuing doxycycline compared with 4% of MQ users. Only 6% and 31% of soldiers reported use of bed nets and skin repellents, respectively. Compliance with long-term malaria prophylaxis was poor, and there were substantial tolerability issues based on these anonymous survey results, though fewer with MQ than doxycycline. Given few long-term antimalarial chemoprophylaxis options, there is an unmet medical need for new antimalarials safe for long-term use.

The hyper-reactive malarial splenomegaly: a systematic review of the literature.

BackgroundThe hyper-reactive malarial splenomegaly syndrome (HMS) is a leading cause of massive splenomegaly in malaria-endemic countries. HMS is caused by a chronic antigenic stimulation derived from the malaria parasite. Classic Fakunle’s major criteria for case definition are: persistent gross splenomegaly, elevated anti-malarial antibodies, IgM titre >2 SD above the local mean value and favourable response to long-term malaria prophylaxis. The syndrome is fatal if left untreated. The aim of this study is to systematically review the literature about HMS, particularly focussing on case definition, epidemiology and management.MethodsThe search strategy was based on the following database sources: Pubmed, EmBase, Scopus. Search was done in March, 2014 and limited to English, Spanish, Italian, French, and Portuguese.ResultsPapers detected were 149, of which 89 were included. Splenomegaly was variably defined and the criterion of increased IgM was not always respected. The highest prevalence was reported in Papua New Guinea (up to 80%). In different African countries, 31 to 76% of all splenomegalies were caused by HMS. Fatality rate reached 36% in three years. The most frequent anti-malarial treatments administered were weekly chloroquine or daily proguanil from a minimum of one month to lifelong. In non-endemic countries, a few authors opted for a single, short anti-malarial treatment. All treated patients with no further exposure improved. Cases not completely fulfilling Fakunle’s criteria and therefore untreated, subsequently evolved into HMS. It seems thus appropriate to treat incomplete or ‘early’ HMS, too.ConclusionsFor patients not re-exposed to endemic areas, a short course of treatment is sufficient, showing that eradicating the infection is sufficient to cure HMS. Longer (probably lifelong) courses, or intermittent treatments, are required for those who remain exposed. Splenectomy, associated with high mortality, should be strictly limited to cases not responding to medical treatment.

Compliance with long-term malaria prophylaxis in British expatriates

There were 219 million cases of malaria with 600,000 deaths in 2010. Current UK guidance recommends malaria chemoprophylaxis for travellers to malaria endemic areas. Despite proven efficacy, compliance amongst long-term travellers with prophylaxis and personal protective strategies is sub-optimal. This survey assesses compliance rates amongst Foreign and Commonwealth Office employees on placement in malaria endemic areas and establishes the rationale for their decisions. A Survey Monkey questionnaire was circulated to Foreign and Commonwealth Office employees on long-term placement in endemic areas. This ascertained background knowledge of malaria, compliance with prevention strategies and the rationale for decisions made. The response rate was 56.5% (327 of 579); responses showed a good knowledge of malaria. 59% of respondents continued their prophylaxis for 0-3 months only. No pregnant women reported compliance of greater than 95%. More than half of the individuals with a compliance of <25% cited concerns about long term safety. 39.5% of respondents reported significant side-effects to chemoprophylaxis. 12.8% reported contracting malaria. Despite being well informed, poor adherence was reported, especially amongst pregnant respondents. The majority of individuals ceased medication within three months. Concern regarding the safety of long-term medication was the major barrier. Suggestions are made regarding optimisation of compliance or alternative strategies.

Population Pharmacokinetics of Tafenoquine during Malaria Prophylaxis in Healthy Subjects

The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (K(a)), clearance (CL/F), and volume of distribution (V/F) were 0.243 h(-1), 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military deployment.

Long-Term Malaria Prophylaxis for Travelers

Long-term malaria prophylaxis is hampered by a lack of standardization and compliance. Advice should be individually optimized to achieve a high degree of protection and compliance. Individual risk assessment takes into consideration the duration of stay in the endemic area, the individual exposure, the seasonal transmission rates, and the drug-resistance situation. Methods for prevention of exposure may help reduce the reliance on chemoprophylactic drugs. Exposure-prevention methods may be combined with standby treatment in lower transmission areas if the traveler has been trained to take the antimalarials appropriately. Although suitable for long-term use, chloroquine and chloroquine-proguanil cannot be used as prophylaxis owing to high resistance rates in most endemic regions. Mefloquine is suitable for most malaria-endemic regions, although its use is restricted by neuropsychiatric side effects, particularly in women. Doxycycline is also appropriate; experience with long-term malaria prophylaxis is available for up to 6 months. The use ofatovaquone-proguanil is restricted to 28 days in some countries, but clinical studies indicate that its use is suitable for at least 20 weeks. Primaquine is also effective for chemoprophylaxis; experience is limited to 1 year of protection against falciparum and vivax malaria. When giving individual recommendations to a traveler, special considerations for backpackers, expatriates, and frequent travelers may apply.

Comparison of whole blood and serum levels of mefloquine and its carboxylic acid metabolite.

Because of the widespread presence of chloroquine-resistant Plasmodium falciparum malaria, mefloquine is now the recommended drug of choice for long-term malaria prophylaxis in these areas. Although several studies have compared plasma and whole blood concentrations of either mefloquine or its carboxylic acid metabolite, we report the first comparison of serum and whole blood levels in 86 Dutch marines taking 250 mg of mefloquine weekly for 18 weeks while deployed in western Cambodia. All samples were taken during steady-state and at 42-48 hr after the most recent dose. The concentration of mefloquine in serum (mean = 979 ng/ml) was significantly greater than in whole blood (mean = 788 ng/ml) (P < 0.00001, by paired t-test) with an overall mean ratio of 1.28. The concentration of the metabolite in serum (mean = 3,039 ng/ml) was also significantly greater than in whole blood (mean = 1,390 ng/ml) (P < 0.00001, by paired t-test) with an overall mean ratio of 2.25. These findings are similar to previous reports of plasma-to-whole blood levels. Furthermore, we report that the within-individual ratios of the metabolite concentration to the mefloquine concentration were also found to be significantly different in serum (3.79; P < 0.00001, by paired t-test) and in whole blood (2.02; P < 0.00001, by paired t-test). Appropriate attention must be given to these differences when comparing serum and whole blood concentrations of either mefloquine or its metabolite to avoid misinterpretation of their respective levels. Also, the determination of the relative mefloquine ratios in various blood fluids, as well as the documentation of the metabolite levels and their ratios, is critical to the appropriate interpretation of both chemoprophylaxis and chemotherapy, especially in the presence of resistant strains.

Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. Need for a better dosing regimen

Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. Need for a better dosing regimen

Effectiveness and Tolerance of Long-term Malaria Prophylaxis With Mefloquine

To measure the effectiveness and tolerance of long-term malaria prophylaxis with mefloquine, the incidence of Plasmodium falciparum malaria and of adverse reactions was compared in Peace Corps volunteers in West Africa who took mefloquine every 2 weeks and in volunteers who took chloroquine phosphate weekly. Mefloquine was only 63% more effective than chloroquine; the monthly incidence of P falciparum infections was one case per 100 volunteers who took mefloquine and 2.7 cases per 100 volunteers who took chloroquine. Using daily proguanil (chloroguanide) hydrochloride in addition to chloroquine did not provide additional protection. All mefloquine prophylaxis failures occurred during the second week of the every-2-weeks dosing regimen in volunteers who had used mefloquine for more than 2 months. Blood concentrations of mefloquine were lower during the second week of the alternate-week regimen than during the first week, suggesting that blood levels are too low during the second week to suppress parasitemia. No serious adverse reactions were observed. The results indicate that a dosing regimen of 250 mg of mefloquine weekly should be considered for travelers to areas with chloroquine-resistant P falciparum malaria.

Tolerability of long-term malaria prophylaxis with the combination mefloquine + sulfadoxine + pyrimethamine (Fansimef ®): results of a double blind field trial versus chloroquine in Nigeria

A randomized double blind study in long term malaria chemoprophylaxis was performed to compare the tolerability of Fansimef ® (1 tablet containing 250 mg mefloquine + 500 mg sulfadoxine + 25 mg pyrimethamine per week) with chloroquine (300 mg per week). 211 Austrian industrial workers and their families in Warri, Nigeria, participated in this study; 101 received Fansimef ® and 110 chloroquine for 3–18 months (mean 41 weeks). Prophylaxis was discontinued because of adverse effects in 7 volunteers in the Fansimef ® group (mainly insomnia, palpitations, dizziness, nausea and headache) and in 2 volunteers of the chloroquine group (headache and loss of hair in one volunteer, nausea, dizziness and vomiting in the other). Most of the adverse effects could be due to the mefloquine component. A few minor complaints of burning eyes, nausea and gastric pain were reported in both groups. Laboratory checks performed at 3-monthly intervals showed a slight, transient and clinically irrelevant (but statistically significant) increase of serum glutamic-oxalacetic transaminase and γ-glutamyl transpeptidase at month 3 in the Fansimef ® group. An attack of acute Plasmodium falciparum malaria occurred in one volunteer 6 weeks after discontinuation of prophylaxis with Fansimef ®. Antibodies against blood stage parasites could be demonstrated by the indirect immunofluorescence test at different stages of the study, indicating that these two antimalarials are not causal prophylactic agents.