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Newly arrived refugees offer insights into malaria epidemiology in their countries of origin. We evaluated asymptomatic refugee children within 7 days of arrival in Uganda from South Sudan and the Democratic Republic of Congo (DRC) in 2022 for parasitemia, parasite species, and Plasmodium falciparum drug resistance markers. Asymptomatic P. falciparum infections were common in both populations. Coinfection with P. malariae was more common in DRC refugees. Prevalences of markers of aminoquinoline resistance (PfCRT K76T, PfMDR1 N86Y) were much higher in South Sudan refugees, of antifolate resistance (PfDHFR C59R and I164L, PfDHPS A437G, K540E, and A581G) much higher in DRC refugees, and of artemisinin partial resistance (ART-R; PfK13 C469Y and A675V) moderate in both populations. Prevalences of most mutations differed from those seen in Ugandans attending health centers near the refugee centers. Refugee evaluations yielded insights into varied malaria epidemiology and identified markers of ART-R in 2 previously little-studied countries., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

At a time when the world faces an emotional breakdown, crushing our dreams, if not, taking our lives, we realize that together we must fight the war against the COVID-19 outbreak even if almost the majority of the scientific community finds itself confined at home. Every day, we, scientists, listen to the latest news with its promises and announcements. Across the world, a surge of clinical trials trying to cure or slow down the coronavirus pandemic has been launched to bring hope instead of fear and despair. One first proposed clinical trial has drawn worldwide hype to the benefit of chloroquine (CQ), in the treatment of patients infected by the recently emerged deadly coronavirus (SARS-CoV-2). We should consider this information in light of the long-standing anti-inflammatory and anti-viral properties of CQ-related drugs. Yet, none of the articles promoting the use of CQ in the current pandemic evoked a possible molecular or cellular mechanism of action that could account for any efficacy. Here, given the interaction of viruses with macroautophagy (hereafter referred to as autophagy), a CQ-sensitive anti-viral safeguard pathway, we would like to discuss the pros, but also the cons concerning the current therapeutic options targeting this process.

India, a persistently significant contributor to the global malaria burden, rolled out several anti-malaria interventions at the national and state level to control and recently, to eliminate the disease. Odisha, the eastern Indian state with the highest malaria burden experienced substantial gains shown by various anti-malaria initiatives implemented under the National Vector-borne Disease Control Programme (NVBDCP). However, recalcitrant high-transmission "pockets" of malaria persist in hard-to-reach stretches of the state, characterised by limited access to routine malaria surveillance and the forested hilly topography favouring unbridled vector breeding. The prevalence of asymptomatic malaria in such pockets serves as perpetual malaria reservoir, thus hindering its elimination. Therefore, a project with the acronym DAMaN was initiated since 2017 by state NVBDCP, targeting locally identified high endemic 'pockets' in 23 districts. DAMaN comprised biennial mass screening and treatment, provisioning of long-lasting insecticidal net (LLIN) and behavioural change communication. Subsequently, to inform policy, assessment of DAMaN was conceived that aims to estimate the coverage of the various components of the project; the prevalence of malaria, even at sub-patent level especially among pregnant/lactating women and children; and its impact on malaria incidence. A survey of DAMaN beneficiaries will measure coverage; and knowledge and practices related to LLIN; along with collection of blood specimens from a probability sample. A multi-stage stratified clustered sample of 2228 households (~33% having pregnant/lactating women) will be selected from 6 DAMaN districts. Routine DAMaN project data (2017-2018) and NVBDCP data (2013-2018) will be extracted. Rapid Diagnostic Test, Polymerase Chain Reaction and blood smear microscopy will be conducted to detect malarial parasitemia. In addition to measuring DAMaN's coverage and malarial prevalence in DAMaN pockets, its impact will be estimated using pre-post differences and Interrupted Time Series analysis using 2017 as the "inflection" point. The assessment may help to validate the unique strategies employed by DAMaN., Competing Interests: The authors have declared that no competing interests exist.

Background: Plasmodium malariae is a widely spread but neglected human malaria parasite, which causes chronic infections. Studies on genetic polymorphisms of anti-malarial drug target genes in P. malariae are limited. Previous reports have shown polymorphisms in the P. malariae dihydrofolate reductase gene associated with pyrimethamine resistance and linked to pyrimethamine drug pressure. This study investigated polymorphisms of the P. malariae homologous genes, chloroquine resistant transporter and multidrug resistant 1, associated with chloroquine and mefloquine resistance in Plasmodium falciparum., Methods: The orthologous P. malariae crt and mdr1 genes were studied in 95 patients with P. malariae infection between 2002 and 2016 from Thailand (N = 51) and Myanmar (N = 44). Gene sequences were analysed using BioEdit, MEGA7, and DnaSP programs. Mutations and gene amplifications were compared with P. falciparum and Plasmodium vivax orthologous genes. Protein topology models derived from the observed pmcrt and pmmdr1 haplotypes were constructed and analysed using Phyre2, SWISS MODEL and Discovery Studio Visualization V 17.2., Results: Two non-synonymous mutations were observed in exon 2 (H53P, 40%) and exon 8 (E278D, 44%) of pmcrt. The topology model indicated that H53P and E278D were located outside of the transmembrane domain and were unlikely to affect protein function. Pmmdr1 was more diverse than pmcrt, with 10 non-synonymous and 3 synonymous mutations observed. Non-synonymous mutations were located in the parasite cytoplasmic site, transmembrane 11 and nucleotide binding domains 1 and 2. Polymorphisms conferring amino acid changes in the transmembrane and nucleotide binding domains were predicted to have some effect on PmMDR1 conformation, but were unlikely to affect protein function. All P. malariae parasites in this study contained a single copy of the mdr1 gene., Conclusions: The observed polymorphisms in pmcrt and pmmdr1 genes are unlikely to affect protein function and unlikely related to chloroquine drug pressure. Similarly, the absence of pmmdr1 copy number variation suggests limited mefloquine drug pressure on the P. malariae parasite population, despite its long time use in Thailand for the treatment of falciparum malaria.

Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world population is at risk of suffering from these diseases and many thousands die because of NTDs, to which we should add the sanitary, labor and social issues that hinder the economic development of these countries. Protozoan-borne diseases are responsible for more than one million deaths every year. Visceral leishmaniasis, Chagas disease or sleeping sickness are among the most lethal NTDs. Despite not being considered an NTD by the World Health Organization (WHO), malaria must be added to this sinister group. Malaria, caused by the apicomplexan parasite Plasmodium falciparum , is responsible for thousands of deaths each year. The treatment of this disease has been losing effectiveness year after year. Many of the medicines currently in use are obsolete due to their gradual loss of efficacy, their intrinsic toxicity and the emergence of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need for new drugs. Despite this, the scant interest shown by most of the stakeholders involved in the pharmaceutical industry makes our present therapeutic arsenal scarce, and until recently, the search for new drugs has not been seriously addressed. The sources of new drugs for these and other pathologies include natural products, synthetic molecules or repurposing drugs. The most frequent sources of natural products are microorganisms, e.g., bacteria, fungi, yeasts, algae and plants, which are able to synthesize many drugs that are currently in use (e.g. antimicrobials, antitumor, immunosuppressants, etc.). The marine environment is another well-established source of bioactive natural products, with recent applications against parasites, bacteria and other pathogens which affect humans and animals. Drug discovery techniques have rapidly advanced since the beginning of the millennium. The combination of novel techniques that include the genetic modification of pathogens, bioimaging and robotics has given rise to the standardization of High-Performance Screening platforms in the discovery of drugs. These advancements have accelerated the discovery of new chemical entities with antiparasitic effects. This review presents critical updates regarding the use of High-Throughput Screening (HTS) in the discovery of drugs for NTDs transmitted by protozoa, including malaria, and its application in the discovery of new drugs of marine origin., Competing Interests: The authors declare no conflict of interest.

In recent years, the research agenda to tackle global morbidity and mortality from malaria disease has shifted towards innovation, in the hope that efforts at the frontiers of scientific research may re-invigorate gains made towards eradication. Discovery of new antimalarial drugs with novel chemotypes or modes of action lie at the heart of these efforts. There is a particular interest in drug candidates that target stages of the malaria parasite lifecycle beyond the symptomatic asexual blood stages. This is especially important given the spectre of emerging drug resistance to all current frontline antimalarials. One approach gaining increased interest is the potential of designing novel drugs that target parasite passage from infected individual to feeding mosquito and back again. Action of such therapeutics is geared much more at the population level rather than just concerned with the infected individual. The search for novel drugs active against these stages has been helped by improvements to in vitro culture of transmission and pre-erythrocytic parasite lifecycle stages, robotic automation and high content imaging, methodologies that permit the high-throughput screening (HTS) of compound libraries for drug discovery. Here, we review recent advances in the antimalarial screening landscape, focussed on transmission blocking as a key aim for drug-treatment campaigns of the future., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Important strides have been made within the past decade toward malaria elimination in many regions, and with this progress, the feasibility of eradication is once again under discussion. If the ambitious goal of eradication is to be achieved by 2040, all species of Plasmodium infecting humans will need to be targeted with evidence-based and concerted interventions. In this perspective, the potential barriers to achieving global malaria elimination are discussed with respect to the related diversities in host, parasite, and vector populations. We argue that control strategies need to be reorientated from a sequential attack on each species, dominated by Plasmodium falciparum to one that targets all species in parallel. A set of research themes is proposed to mitigate the potential setbacks on the pathway to a malaria-free world.

Treatment recommendations for Plasmodium malariae and Plasmodium ovale malaria are largely based on anecdotal evidence. The aim of this prospective study, conducted in Gabon, was to systematically assess the efficacy and safety of artemether-lumefantrine for the treatment of patients with uncomplicated P. malariae or P. ovale species monoinfections or mixed Plasmodium infections. Patients with microscopically confirmed P. malariae , P. ovale , or mixed-species malaria with at least one of these two Plasmodium species were treated with an oral, fixed-dose combination of artemether-lumefantrine for 3 consecutive days. The primary endpoints were per-protocol PCR-corrected adequate clinical and parasitological response (ACPR) on days 28 and 42. Tolerability and safety were recorded throughout the follow-up period. Seventy-two participants (42 male and 30 female) were enrolled; 62.5% of them had PCR-corrected mixed Plasmodium infections. Per protocol, PCR-corrected ACPR rates were 96.6% (95% confidence interval [CI], 91.9 to 100) on day 28 and 94.2% (95% CI, 87.7 to 100) on day 42. Considering Plasmodium species independently from their coinfecting species, day 42 ACPR rates were 95.5% (95% CI, 89.0 to 100) for P. falciparum , 100% (exact CI, 84.6 to 100) for P. malariae , 100% (exact CI, 76.8 to 100) for P. ovale curtisi , and 90.9% (95% CI, 70.7 to 100) for P. ovale wallikeri Study drug-related adverse events were generally mild or moderate. In conclusion, this clinical trial demonstrated satisfying antimalarial activity of artemether-lumefantrine against P. ovale wallikeri , P. ovale curtisi , P. malariae , and mixed Plasmodium infections, with per-protocol efficacies of 90% to 100% and without evident tolerability or safety concerns. (This trial was registered in the clinical study database ClinicalTrials.gov under the identifier NCT02528279.)., (Copyright © 2018 American Society for Microbiology.)

Artemisinin resistance in Plasmodium falciparum, the agent of severe malaria, is currently a major obstacle to malaria control in Southeast Asia. A gene named "kelch13" has been associated with artemisinin resistance in P. falciparum The orthologue of the kelch gene in P. vivax was identified and a small number of mutations were found in previous studies. The kelch orthologues in the other two human malaria parasites, P. malariae and P. ovale, have not yet been studied. Therefore, in this study, the orthologous kelch genes of P. malariae, P. ovale wallikeri, and P. ovale curtisi were isolated and analyzed for the first time. The homologies of the kelch genes of P. malariae and P. ovale were 84.8% and 82.7%, respectively, compared to the gene in P. falciparum kelch polymorphisms were studied in 13 P. malariae and 5 P. ovale isolates from Thailand. There were 2 nonsynonymous mutations found in these samples. One mutation was P533L, which was found in 1 of 13 P. malariae isolates, and the other was K137R, found in 1 isolate of P. ovale wallikeri (n = 4). This result needs to be considered in the context of widespread artemisinin used within the region; their functional consequences for artemisinin sensitivity in P. malariae and P. ovale will need to be elucidated., (Copyright © 2016 Nakeesathit et al.)

Malaria recurrences after an initially successful therapy and malarial fever occurring a long time after infection are well-known problems in malariology. Currently, two distinct types of malaria recurrences are defined: recrudescence and relapse. A recrudescence is thought to originate from circulating Plasmodium blood stages which do not cause fever before a certain level of a microscopically detectable parasitemia is reached. Contrary, a relapse is thought to originate from quiescent intracellular hepatic parasite stages called hypnozoites. Recrudescences would typically occur in infections due to Plasmodium falciparum. Plasmodium knowlesi, and Plasmodium malariae, whereas relapses would be caused exclusively by Plasmodium vivax and Plasmodium ovale. This schematic view is, however, insufficiently supported by experimental evidence. For instance, hypnozoites of P. ovale have never been experimentally documented. On the other hand, the nonfinding of P. malariae hypnozoites turned into the proof for the nonexistence of P. malariae hypnozoites. Clinical relapse-type recurrences have been observed in both P. ovale and P. malariae infections, and decade-long incubation times have also been reported in P. falciparum infections. We propose a gradual hypothesis in accordance with the continuity concept of biological evolution: both, relapse and recrudescence may be potentially caused by all Plasmodium spp. We hypothesize that the difference between the various Plasmodium spp. is quantitative rather than qualitative: there are Plasmodium spp. which frequently cause relapses such as P. vivax, particularly the P.v. Chesson strain, species which cause relapses less frequently, such as P. ovale and sometimes P. malariae, and species which may exceptionally cause relapses such as P. falciparum. All species may cause recrudescences. As clinical consequences, we propose that 8-aminquinolines may be considered in a relapse-type recrudescence regardless of the causal Plasmodium sp., whereas primaquine relapse prevention might not be routinely indicated in malaria due to P. ovale.

Plasmodium malariae is widely distributed across the tropics, causing symptomatic malaria in humans with a 72-hour fever periodicity, and may present after latency periods lasting up to many decades. Delayed occurrence of symptoms is observed in humans using chemoprophylaxis, or patients having received therapies targeting P. falciparum intraerythrocytic asexual stages, but few investigators have addressed the biological basis of the ability of P. malariae to persist in the human host. To investigate these interesting features of P. malariae epidemiology, we assembled, here, an extensive case series of P. malariae malaria patients presenting in non-endemic China, Sweden, and the UK who returned from travel in endemic countries, mainly in Africa. Out of 378 evaluable P. malariae cases, 100 (26.2%) reported using at least partial chemoprophylaxis, resembling the pattern seen with the relapsing parasites P. ovale spp. and P. vivax. In contrast, for only 7.5% of imported UK cases of non-relapsing P. falciparum was any chemoprophylaxis use reported. Genotyping of parasites from six patients reporting use of atovaquone-proguanil chemoprophylaxis did not reveal mutations at codon 268 of the cytb locus of the P. malariae mitochondrial genome. While travellers with P. malariae malaria are significantly more likely to report prophylaxis use during endemic country travel than are those with P. falciparum infections, atovaquone-proguanil prophylaxis breakthrough was not associated with pmcytb mutations. These preliminary studies, together with consistent observations of the remarkable longevity of P. malariae, lead us to propose re-examination of the dogma that this species is not a relapsing parasite. Further studies are needed to investigate our favoured hypothesis, namely that P. malariae can initiate a latent hypnozoite developmental programme in the human hepatocyte: if validated this will explain the consistent observations of remarkable longevity of parasitism, even in the presence of antimalarial prophylaxis or treatment.

Background: Human population movement across country borders presents a real challenge for malaria control and elimination efforts in Cambodia and its neighbouring countries. To quantify Plasmodium infection among the border-crossing population, including asymptomatic and artemisinin resistant (AR) parasites, three official border crossing points, one from each of Cambodia's borders with Thailand, Laos and Vietnam, were selected for sampling., Methods and Findings: A total of 3206 participants (of 4110 approached) were recruited as they crossed the border, tested for malaria and interviewed. By real-time polymerase chain reaction (RT-PCR), 5.4% of all screened individuals were found to harbour Plasmodium parasites. The proportion was highest at the Laos border (11.5%). Overall there were 97 P. vivax (55.7%), 55 P. falciparum (31.6%), two P. malariae (1.1%) and 20 mixed infections (11.5%). Of identified infections, only 20% were febrile at the time of screening. Of the 24 P. falciparum samples where a further PCR was possible to assess AR, 15 (62.5%) had mutations in the K13 propeller domain gene, all from participants at the Laos border point. Malaria rapid diagnostic test (RDT) pLDH/HRP-2 identified a positivity rate of 3.2% overall and sensitivity compared to RT-PCR was very low (43.1%). Main individual risk factors for infection included sex, fever, being a forest-goer, poor knowledge of malaria prevention methods and previous malaria infection. Occupation, day of the week and time of crossing (morning vs. afternoon) also appeared to play an important role in predicting positive cases., Conclusions: This study offers a novel approach to identify asymptomatic infections and monitor AR parasite flow among mobile and migrant populations crossing the borders. Similar screening activities are recommended to identify other hot borders and characterise potential hot spots of AR. Targeted "customised" interventions and surveillance activities should be implemented in these sites to accelerate elimination efforts in the region.

Background: A better understanding of the effect of malaria control interventions on vector and parasite populations, acquired immunity, and burden of the disease is needed to guide strategies to eliminate malaria from highly endemic areas. We monitored and analysed the changes in malaria epidemiology in a village community in Senegal, west Africa, over 22 years., Methods: Between 1990 and 2012, we did a prospective longitudinal study of the inhabitants of Dielmo, Senegal, to identify all episodes of fever and investigate the relation between malaria host, vector, and parasite. Our study included daily medical surveillance with systematic parasite detection in individuals with fever. We measured parasite prevalence four times a year with cross-sectional surveys. We monitored malaria transmission monthly with night collection of mosquitoes. Malaria treatment changed over the years, from quinine (1990-94), to chloroquine (1995-2003), amodiaquine plus sulfadoxine-pyrimethamine (2003-06), and finally artesunate plus amodiaquine (2006-12). Insecticide-treated nets (ITNs) were introduced in 2008., Findings: We monitored 776 villagers aged 0-101 years for 2 378 150 person-days of follow-up. Entomological inoculation rate ranged from 142·5 infected bites per person per year in 1990 to 482·6 in 2000, and 7·6 in 2012. Parasite prevalence in children declined from 87% in 1990 to 0·3 % in 2012. In adults, it declined from 58% to 0·3%. We recorded 23 546 fever episodes during the study, including 8243 clinical attacks caused by Plasmodium falciparum, 290 by Plasmodium malariae, and 219 by Plasmodium ovale. Three deaths were directly attributable to malaria, and two to severe adverse events of antimalarial drugs. The incidence of malaria attacks ranged from 1·50 attacks per person-year in 1990 to 2·63 in 2000, and to only 0·046 in 2012. The greatest changes were associated with the replacement of chloroquine and the introduction of ITNs., Interpretation: Malaria control policies combining prompt treatment of clinical attacks and deployment of ITNs can nearly eliminate parasite carriage and greatly reduce the burden of malaria in populations exposed to intense perennial malaria transmission. The choice of drugs seems crucial. Rapid decline of clinical immunity allows rapid detection and treatment of novel infections and thus has a key role in sustaining effectiveness of combining artemisinin-based combination therapy and ITNs despite increasing pyrethroid resistance., Funding: Pasteur Institutes of Dakar and Paris, Institut de Recherche pour le Développement, and French Ministry of Cooperation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Quartan malaria due to Plasmodium malariae is commonly regarded as being preventable by current antimalarials. A case of P. malariae infection occurred in spite of previous treatment of Plasmodium falciparum malaria 4 months earlier with a full therapy course of intravenous quinine hydrochloride and oral doxycycline followed by artemether + lumefantrine. Since the patient was not anymore exposed to agents of malaria in the meantime, a new infection by P. malariae after therapy is unlikely. The present observation is difficult to explain by the current view on the origin of latent P. malariae infections and recurrences which are thought to arise from intra-erythrocytic development stages susceptible to common antimalarials. The most likely explanation of our observation is a delayed pre-erythrocytic development. The latency between infection by P. malariae and the quartan malaria fever attack might have been extended further by an initial subclinical circulation of a low number of intra-erythrocytic asexual parasites in the blood stream preceeding the clinical quartan malaria breakthrough.

Molecular investigations performed following the emergence of sulfadoxine-pyrimethamine (SP) resistance in Plasmodium falciparum have allowed the identification of the dihydrofolate reductase (DHFR) enzyme as the target of pyrimethamine. Although clinical cases of Plasmodium malariae are not usually treated with antifolate therapy, incorrect diagnosis and the high frequency of undetected mixed infections has probably exposed non-P. falciparum parasites to antifolate therapy in many areas. In this context, we aimed to assess the worldwide genetic diversity of the P. malariae dhfr gene in 123 samples collected in Africa and Asia, areas with different histories of SP use. Among the 10 polymorphic sites found, we have observed 7 new mutations (K55E, S58R, S59A, F168S, N194S, D207G, and T221A), which led us to describe 6 new DHFR proteins. All isolates from African countries were classified as wild type, while new mutations and haplotypes were recognized as exclusive to Madagascar (except for the double mutations at nucleotides 341 and 342 [S114N] found in one Cambodian isolate). Among these nonsynonymous mutations, two were likely related to pyrimethamine resistance: S58R (corresponding to C59R in P. falciparum and S58R in Plasmodium vivax; observed in one Malagasy sample) and S114N (corresponding to S108N in P. falciparum and S117N in P. vivax; observed in three Cambodian samples).

The status of chemotherapy as the main strategy in malaria control is rapidly being eroded by development of drug resistant Plasmodia, causing malaria to be dubbed a "re-emerging disease". To counter this misfortune, there is an urgent need to develop novel antimalarial drugs capable of delaying resistance, or circumventing it altogether. Mode of action of antimalarial drugs, inter alia, has a bearing on their useful therapeutic lives (UTLs), with single target drugs having short UTLs compared with drugs which possess pleiotropic action. Quinolines and artemisinins are the two classes of drugs with pleiotropic action and subsequently long UTLs. All other antimalarials are single-target drugs, and have been rendered ineffective within 1 to 5 years of their introduction for clinical use. This strongly underlines the need for development of new antimalarial therapies possessing long UTLs. The present review explores novel drug targets within the malaria parasite that may be exploited in the search for novel drugs that possess long and UTLs.

The rapid development by malaria parasites of resistance to almost all the chemotherapeutic agents so far used for their control means that constant efforts to develop new drugs are necessary. In this review, we propose that the exploration of protein-protein interactions as a new strategy to identify antimalarial drug targets is an attractive and a promising area of research. Nevertheless, one of the most important criteria is that the targeted gene should encode an essential protein within a complex that is able to affect parasite survival. Recently, our research on the biology of Plasmodium falciparum allowed us to identify the interaction of Protein Phosphatase type 1 and actin with two essential partners, PfLRR1 and PfLRR7 respectively, both of which belong to the Leucine Rich Repeat (LRR) protein family. LRR-containing proteins are composed of several consensus LRR motifs LXLXXNXL (where X is any amino acid) that provide sites for the assembly of protein interactions. The LRR combines structural versatility, adaptability and more importantly a high degree of interaction specificity. In addition, it has been shown that a single mutation in a particular LRR motif abolishes the protein-protein interaction and contributes to the expression of severe pathology in humans. This clearly infers that blocking the interaction related to 'hot spots' of LRR motifs can be considered as good targets to block parasite growth and development. Thus, the inhibition of protein-protein interactions by peptides, peptidomimetics or small-molecule inhibitors that interfere with binding domains can contribute to defining new potential drug targets.

The role of redox enzymes in establishing a microenvironment for parasite development is well characterized. Mimicking human glucose-6-phosphate dehydrogenase and glutathione reductase (GR) deficiencies by redox-cycling compounds thus represents a challenge to the design of new preclinical antiparasitic drug candidates. Schistosomes and malarial parasites feed on hemoglobin. Heme, the toxic prosthetic group of the protein, is not digested and represents a challenge to the redox metabolism of the parasites. Here, we report on old and new redox-cycling compounds--whose antiparasitic activities are related to their interference with (met)hemoglobin degradation and hematin crystallization. Three key-assays allowed probing and differentiating the mechanisms of drug actions. Inhibition of β-hematin was first compared to the heme binding as a possible mode of action. All tested ligands interact with the hematin π-π dimer with K(D) similar to those measured for the major antiparasitic drugs. No correlation between a high affinity for hematin and the capacity to prevent β-hematin formation was however deduced. Inhibition of β-hematin formation is consequently not the result of a single process but results from redox processes following electron transfers from the drugs to iron(III)-containing targets. The third experiment highlighted that several redox-active compounds (in their reduced forms) are able to efficiently reduce methemoglobin to hemoglobin in a GR/NADPH-coupled assay. A correlation between methemoglobin reduction and inhibition of β-hematin was shown, demonstrating that both processes are closely related. The ability of our redox-cyclers to trigger methemoglobin reduction therefore constitutes a critical step to understand the mechanism of action of our drug candidates.

Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches.

α-Lipoic acid (6,8-thioctic acid; LA) is a vital co-factor of α-ketoacid dehydrogenase complexes and the glycine cleavage system. In recent years it was shown that biosynthesis and salvage of LA in Plasmodium are necessary for the parasites to complete their complex life cycle. LA salvage requires two lipoic acid protein ligases (LplA1 and LplA2). LplA1 is confined to the mitochondrion while LplA2 is located in both the mitochondrion and the apicoplast. LplA1 exclusively uses salvaged LA and lipoylates α-ketoglutarate dehydrogenase, branched chain α-ketoacid dehydrogenase and the H-protein of the glycine cleavage system. LplA2 cannot compensate for the loss of LplA1 function during blood stage development suggesting a specific function for LplA2 that has yet to be elucidated. LA salvage is essential for the intra-erythrocytic and liver stage development of Plasmodium and thus offers great potential for future drug or vaccine development. LA biosynthesis, comprising octanoyl-acyl carrier protein (ACP) : protein N-octanoyltransferase (LipB) and lipoate synthase (LipA), is exclusively found in the apicoplast of Plasmodium where it generates LA de novo from octanoyl-ACP, provided by the type II fatty acid biosynthesis (FAS II) pathway also present in the organelle. LA is the co-factor of the acetyltransferase subunit of the apicoplast located pyruvate dehydrogenase (PDH), which generates acetyl-CoA, feeding into FAS II. LA biosynthesis is not vital for intra-erythrocytic development of Plasmodium, but the deletion of several genes encoding components of FAS II or PDH was detrimental for liver stage development of the parasites indirectly suggesting that the same applies to LA biosynthesis. These data provide strong evidence that LA salvage and biosynthesis are vital for different stages of Plasmodium development and offer potential for drug and vaccine design against malaria.

Histone deacetylases (HDACs) are important enzymes that effect post-translational modifications of proteins by altering the acetylation state of lysine residues. HDACs control epigenetic changes that trigger cell transformation and proliferation of transformed cells associated with many diseases. These enzymes are validated drug targets for some types of cancer and are promising therapeutic targets for a range of other diseases, including malaria. Annually, there are ~500 million clinical cases of malaria and ~0.8-1.2 million deaths. There is no licensed vaccine for preventing malaria, and parasites that cause malaria are becoming resistant to current drugs, necessitating the search for new therapies. HDAC inhibitors are emerging as a promising new class of antimalarial drugs with potent and selective action against Plasmodium parasites in vitro. Recent studies on the effects of HDAC inhibitors on the growth and development of P. falciparum have provided important new information on transcriptional regulation in malaria parasites and have validated the potential of this class of inhibitors for malaria therapy. To realise effective HDAC inhibitors for clinical trials, next generation inhibitors must not inhibit other human HDACs or proteins required for normal human physiology, be highly selective in killing parasites in vivo without killing normal host cells, and have improved bioavailability and pharmacokinetic profiles. This review summarizes current knowledge about malaria parasite HDACs and HDAC inhibitors with antimalarial properties, and provides insights for their development into new drugs for treatment of malaria.

Malaria is one of the major global health problems. About 500 million humans are infected each year, and 1 million, mostly African children, die from malaria annually. No vaccine is yet in sight, and those drugs that have previously served us well are now losing ground against the disease as parasites become resistant to our best compounds. The need for development of new antimalarials is now more urgent than ever. An exciting avenue for development of new drugs emerged recently when it was discovered that the malaria parasites have a previously unrecognized evolutionary history aligned to plants. These parasites contain a subcellular compartment--the apicoplast--which is homologous to the chloroplast of plants and algae, in which photosynthesis occurs. The malaria chloroplast (apicoplast) has lost photosynthesis but it retains many chloroplast pathways, which are otherwise unique to plants. These pathways obviously do not exist in the human host and there has been considerable excitement about using the apicoplast as a parasite-specific Achilles' Heel. We propose to review the current state of development of novel compounds directed against this emerging target of malaria parasites with emphasis on the chemistry.

We report a case of Plasmodium falciparum and Plasmodium malariae coinfection with associated failure of clinical response to artemether + lumefantrine therapy. This case highlights the need to consider co-infection in the setting of apparent treatment failure and the impact of mixed species infection upon host dynamics and clinical presentation. Recognition of malarial co-infection is clinically important for determining appropriate therapy and preventing disease sequelae., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

Reports of potential drug-resistant strains of Plasmodium malariae in western Indonesia raise concerns that chloroquine resistance may be emerging in P. malariae and P. ovale. In order to assess this, in vivo and in vitro efficacy studies were conducted in patients with monoinfection in Papua, Indonesia. Consecutive patients with uncomplicated malaria due to P. ovale or P. malariae were enrolled in a prospective clinical trial, provided with supervised chloroquine treatment, and followed for 28 days. Blood from patients with P. malariae or P. ovale parasitemia greater than 1,000 per microliter underwent in vitro antimalarial drug susceptibility testing using a modified schizont maturation assay. Of the 57 evaluable patients in the clinical study (P. malariae, n = 46; P. ovale, n = 11), none had recurrence with the same species during follow-up. The mean parasite reduction ratio at 48 h was 86 (95% confidence interval [CI], 57 to 114) for P. malariae and 150 (95% CI, 54 to 245) for P. ovale (P = 0.18). One patient infected with P. malariae, with 93% of parasites at the trophozoite stage, was still parasitemic on day 4. In vitro drug susceptibility assays were carried out successfully for 40 isolates (34 infected with P. malariae and 6 with P. ovale). The P. malariae infections at trophozoite stages had significantly higher chloroquine 50% effective concentrations (EC(50)s) (median, 127.9 nM [range, 7.9 to 2,980]) than those initially exposed at the ring stage (median, 14.0 nM [range, 3.5 to 27.0]; P = 0.01). The EC(50) for chloroquine in P. ovale was also higher in an isolate initially at the trophozoite stage (23.2 nM) than in the three isolates predominantly at ring stage (7.8 nM). Chloroquine retains adequate efficacy against P. ovale and P. malariae, but its marked stage specificity of action may account for reports of delayed parasite clearance times.

Background: Previous data from our laboratory suggest that gonadally intact C57BL/6 male mice are more likely than their female counterparts to die from Plasmodium chabaudi infection, to recover more slowly from weight loss and hematocrit loss, and to have reduced interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) responses. Removal of the ovaries, and hence, the primary production of sex steroids in females, reverses these differences., Objective: We hypothesized that sex differences in response to P chabaudi may be mediated by differential synthesis of IFN-gamma and IL-10 that is influenced by estrogen, progesterone, or both., Methods: C57BL/6 female mice (n = 200; n = 10/time point/treatment/experiment) were ovariectomized and implanted with a 21-day controlled-release pellet containing either 0.1 mg of 17beta-estradiol (E(2)), 10 mg of progesterone (P(4)), 0.1 mg of E(2) plus 10 mg of P(4), or cholesterol (placebo). Females were inoculated with 10(6)P chabaudi-infected erythrocytes. Body mass, body temperature, hematocrit, parasitemia, cytokine production, and antibody responses were monitored 0, 3, 5, 7, 10, 14, and 21 days postinoculation., Results: Administration of E(2), either alone or in combination with P(4), mitigated infection-induced weight loss, hematocrit loss, and hypothermia, compared with females receiving placebo pellets (P < 0.05 in each case). Hormone treatment did not affect levels of parasitemia. Females administered E(2) alone or in combination with P(4) produced 4 to 7 times higher IFN-gamma and IL-10 during peak parasitemia than did females implanted with pellets containing either P(4) alone or placebo (P < 0.05 in each case). Exposure to E(2), either alone or in combination with P(4), increased anti-P chabaudi immunoglobulin G (IgG1) responses and the ratio of IgG1 to IgG2c (P < 0.05 in each case)., Conclusion: This animal study suggests that physiological levels of estrogen, rather than progesterone, enhance immunity and, possibly, protect females from disease symptoms during malaria infection.

We report the results of clinical studies carried out at six sites in Madagascar, between January and October 2006. The aims were (i) to update our knowledge of the burden of Plasmodium malariae infection and (ii) to assess the therapeutic efficacy of chloroquine for uncomplicated quartan malaria. Our findings confirm that P. malariae is the third leading cause of malaria, accounting for 1.1% of all malarial infections. They also demonstrate that chloroquine-currently recommended for the home management of presumed malaria in children under the age of five years and commonly used by adults-remains highly effective in patients with uncomplicated P. malariae infection.

We conducted a community-randomized controlled trial in an area of moderate malaria transmission in the Amazon region, southern Venezuela, home of the Yanomami indigenous ethnic group. The aim was to compare the malaria incidence rate in villages with lambdacyhalothrin-treated hammock nets (ITHN) or with placebo-treated hammock nets (PTHN). In both arms of the study, intensive surveillance for early case detection was maintained and prompt malaria treatment was administered. Baseline data were collected before the intervention and a population of around 924 Yanomami was followed for 2 years. Despite the recent introduction of nets in the Yanomami villages and the adverse natural conditions in the area, the nets were accepted enthusiastically by the study population, used conscientiously and looked after carefully. The malaria incidence rate per thousand person-years at risk was 114.6 in the IHTN group and 186.8 in the PTHN group. The adjusted rate ratios indicated that ITHN prevent 56% [IRR: 0.44, 95% confidence interval (CI): 52-59%] of new malaria cases. ITHN reduced the prevalence of parasitaemia by 83% [relative risks (RR): 0.17, 95% CI: 47-100%], according to a cross-sectional survey carried out during the high transmission season. The prevalence of splenomegaly and anaemia was too low to detect any possible reduction as a result of ITHN. The main conclusion of the present study is that ITHN can reduce malaria incidence in the area and it is the most feasible method for malaria control in a forested area where indigenous villages are scattered over a large territory. This is the first community-level epidemiological trial to show that ITHN are highly effective against malaria transmitted by Anopheles darlingi.

Liver function tests were performed in 61 vivax, 54 malariae and 15 ovale malaria patients who were admitted to Bangkok Hospital for Tropical Diseases between 2001 and 2004. The objective of the study was to evaluate changes in hepatic biochemical indices before and after treatment with artemisinin derivatives. On admission and prior to treatment, hepatic dysfunction was found among the 3 groups. Serum liver function tests and physical examinations were performed weekly during the 28-day follow-up period. Initially elevated serum bilirubin and diminished albumin returned to normal within 2 weeks of treatment. Serum alkaline phosphatase and aminotransferases returned to within normal limits within 3 weeks. We conclude that patients with Plasmodium vivax, P. malariae and P. ovale infections had slightly elevated serum bilirubin, aminotransferase and alkaline phosphatase levels, and hypoalbuminemia. These minor abnormalities returned to normal within a few weeks after treatment with therapies based on artemisinin derivatives.

Artemisinin-based combination treatments (ACTs) are seen as an important tool in the global effort to roll back malaria. With parasite resistance to chloroquine increasing rapidly in many parts of the world, there is greater recognition of the need for a globally coordinated strategy to ensure that artemisinins are not used as monotherapy, which has the potential to cut short their useful therapeutic life. We find that even a partial subsidy could delay the emergence of resistance and that a delay in implementing a subsidy for ACTs could facilitate the emergence of resistance and lower the economic value of ACTs.

Resistance of Plasmodium falciparum (Pf) and P. vivax (Pv) to standard antimalarials is widespread in Papua New Guinea (PNG). The objective of the study was to assess the rate of clinical treatment failure (TF) and parasite resistance to amodiaquine (AQ), chloroquine (CQ) and quinine+sulfadoxine/pyrimethamine (Q+SP) for malaria in a rural health centre of the East Sepik Province. 179 patients presenting with symptoms and signs of malaria and with Pf (144 patients), Pv (18 patients), P. malariae (Pm) (7 patients) or mixed infection (10 patients) were included. 86 were treated with AQ, 88 with CQ and 5 with Q+SP. 21/179 patients (12%) were not cured or had a recrudescence of symptoms associated with parasitaemia in the 28 days following treatment, 14% after AQ, 10% after CQ and 0% after Q+SP. The proportion of TF was higher (17%) when the analysis population included only the 108 subjects who had a complete follow-up, especially for failure with Pf following AQ treatment (26%). During the 28 days of follow-up, RII or RIII level of resistance in Pf was detected in 55% of the subjects treated with amodiaquine, 30% of those treated with chloroquine and 0% of those treated with quinine+SP. Of the Pv or Pm parasites only one Pv was found to be RII resistant to CQ in the 28-day test. In vitro resistance of Pf to CQ was higher than to AQ (50% versus 27% of 36 parasite samples that grew successfully). The level of TF and parasitological resistance to standard antimalarial drugs was lower in this area than in urban settings, where drugs are more easily available. AQ performed less well than CQ but the difference is likely to be due to the age of the users, ie, their level of immunity, AQ being the first-line drug for young children. These results provided support for the recent change in the policy for the standard treatment of uncomplicated malaria in PNG from AQ or CQ to the combination of AQ+SP or CQ+SP, a recommendation aimed at slowing down the spread of multidrug resistance.

Malaria caused by Plasmodium parasites kills approximately 1-3 million people and causes disease in 300-500 million people annually throughout the world. The current approaches to curtail this disease include vector control, vaccination, immunotherapy and chemotherapy. The vector control is achieved by reducing vector density, interrupting their life cycle, and creating a barrier between the human host and mosquitoes. A number of vaccine candidates are being clinically tried and R&D effort in this direction is coming in a big way. Currently there are only limited safe drugs for the treatment of this disease, however, reports of emerging resistance against existing drugs warrant the introduction of new drugs, which are unlikely to come from pharmaceutical industries because of limited commercial opportunities. One of the most important current approaches to develop new drugs involves the synthesis of chemical libraries and evaluate them against most validated biochemical targets of malarial parasite. Although a number of such targets in antimalarial drug development are known today, yet only validated and selective biochemical targets including mitochondrial transport, glycolic pathway, folate pathway, proteases and heme metabolism, apicoplast metabolism, glycophospatidyl inositol, lipid metabolism (glycerophospholipids), peptidyl deformylase and oxidative stress in parasite-infected erythrocytes have been discussed here. The well known antimalarial drugs and different drug combinations for the treatment of malaria are also briefly reviewed. A survey of the recently discovered new molecules active against malaria has also been narrated. Lastly, the future of malaria chemotherapy and new directions emerging from literature has been elucidated.

Resistance of Plasmodium falciparum to chloroquine has been reported in several countries. Other anti-malarial drugs in use are expensive and not readily accessible to most people in malaria endemic countries. This has led to renewed interest in the development of herbal medicines that have the potential to treat malaria with little or no side effects. This study obtained a preliminary information on the safety and effectiveness of a plant decoction (AM-1), used in treating malaria. The AM-1 is formulated from Jatropha curcas, Gossypium hirsutum, Physalis angulata and Delonix regia. Patients with suspected malaria attending a herbal clinic were enrolled in the study on voluntary basis. They were hospitalized for treatment, clinical observation, biochemical and haematological monitoring, and parasite clearance while on AM-1. In addition male and female Sprague Dawley rats were used to evaluate the acute and subchronic toxicity effects of AM-1. The AM-1 eliminated malaria parasites (Plasmodium falciparum and Plasmodium malarie) from the peripheral blood of patients with malaria. In addition the AM-1 did not show any undesired effects in the patients as well as in laboratory rats. The AM-1, however, showed differential effect on the activities of selected cytochrome P450 isozymes (7-pentoxyresorufin-O-depentylation, 7-ethoxyresorufin-O-deethylation and p-nitrophenol hydroxylase) in relation to sex of the laboratory rats. These results indicate that AM-1 could be used to treat malaria. However, it could precipitate interactions with other drugs via their biotransformation and elimination. The obtained data warrant further studies in a large number of malaria subjects with monitoring for possible drug interactions., (Copyright 2003 John Wiley & Sons, Ltd.)

In Austria, between 1990 and 2000, 924 travel related malaria cases were reported (mean = 84/year). No significant decreasing or increasing trends were observed. P. falciparum (n=517; 55.9%) accounted for the highest number of cases followed by P. vivax or ovale (n=321; 34.7%) and P. malariae (n=29; 2.2%). Most infections were contracted in highly endemic malaria regions (n=686; 74.2%) and most cases were reported from the largest counties: Vienna (n=336, 36.4%), Styria (n=156, 16.8%), and Lower Austria (n=151, 16.3%). Overall, 12 deaths occurred, most were caused by P. falciparum (n=9, 75%; case fatality rate: 1.9%). Data on chemoprophylaxis was available for 752 cases (81.4%) but only half of them (n=367, 48.8%) gave detailed information on the drug used. Data on compliance were obtained for only 45.4% of the cases, with only about 60% of patients completing the full course of prophylaxis.

This study evaluated the efficacy and safety of a 3-day course of artesunate (4 mg/kg/day) for asymptomatic Plasmodium malariae infections. The parasitological cure rates on days 7 and 56 in the group treated with artesunate were 100% and 83%, respectively, compared with no cure in the placebo group (P < 0.0001).

A retrospective examination was made of archival data on the response of Plasmodium malariae infections in humans to chloroquine. The clearance time for P. malariae was longer than that for P. falciparum and P. vivax. Of 100 P. malariae-infected patients treated with 1,500 mg of chloroquine given over 3 days, 15 had detectable parasites for 7 days, 4 for 10 days, and 1 for 15 days after treatment. Of 17 patients treated intramuscularly with 450 mg of dihydrochloroquine, parasites persisted in 1 patient for 11 days. Of patients with chloroquine-sensitive P. falciparum. 44 cleared parasites by 6 days after treatment; 37 patients with P. vivax infections cleared parasites by day 5. The confirmation of chloroquine resistance may depend on the adaptation of isolates to nonhuman primates in which controlled drug trials can be made.

Four airport malaria cases have been observed in the vicinity of the Roissy-Charles-de-Gaulle International Airport, Paris, France. These cases were geographically very close to each other and clustered in a short period of time during the summer of 1999. The phenotype and genotype of the Plasmodium falciparum isolates obtained from these patients were determined in order to know whether a single mosquito could have infected more than one subject. The genomic characterisation of isolates was performed using the polymorphic markers merozoite surface protein 1 (Msp 1) and merozoite surface protein 2 (Msp 2) genes, the kappa and omega repeats domains of cg2 and the dihydrofolate reductase (DHFR) genotypes. Results showed identical genotypes for isolates 1, 2 and 4 whereas the genotype of isolate 3 differed at one locus. The molecular analysis was consistent with the hypothesis that all patients could have been bitten by the same mosquito and that patient 3, may have received a different clone and an additional species. In vitro susceptibility data did not confirm or rule out this hypothesis because isolates had the same profile of susceptibility to the tested drugs.

Malaria is a worldwide epidemic causing high morbidity and mortality especially in children younger than 5 years. In France the incidence of pediatric malaria has constantly increased up to 1500 cases in the last two years, due to Plasmodium falciparum in more than 80% of cases. According to current recommendations, any patient with clinical suspicion or confirmed diagnosis of malaria must be hospitalized for treatment. Halofantrine is the most widely used antimalarial for treatment of uncomplicated P. falciparum malaria in children. However due to halofontrine-related cardiotoxicity some teams recommend mefloquine as the first-line drug despite disadvantages related to its poorly adapted formulation and adverse gastrointestinal effects in young children. Treatment of malaria involving other plasmodium species is still based on chloroquine. Likewise the World Health Organization continues to recommend chloroquine as the first-line agent for uncomplicated malaria in endemic zones with moderate chloroquine resistance. Amodiaquin or sulfadoxine-pyrimethamine combination may be used either in case of failure or as first-line agents in zones with high chloroquine resistance. In case of multiple resistance, quinine may be used alone or in association with an antimicrobial. Other drug therapies such as combinations using artemisinine derivatives have been shown to be highly effective for control of clinical symptoms and parasitemia. Widespread use of these therapies to prevent the appearance and extension of resistance is now undergoing evaluation.

Background: Safe and effective antimalarial drugs are needed for treatment and prophylaxis of malaria. The combination of atovaquone and proguanil hydrochloride is a new antimalarial drug combination that has recently become available in many countries., Methods: Data were reviewed from nonclinical studies evaluating the microbiology, secondary pharmacology, pharmacokinetics, and toxicology of atovaquone and proguanil hydrochloride., Results: Atovaquone is highly active against asexual erythrocytic stages of Plasmodium falciparum in vitro (IC50 0.7-6 nM) and in animal models. Proguanil per se has only weak antimalarial activity in vitro (IC50 2.4-19 microM), and its effectiveness depends on the active metabolite cycloguanil (IC50 0.5-2.5 nM). The combination of atovaquone and proguanil is synergistic in vitro. Both drugs also have activity against gametocytes and pre-erythrocytic (hepatic) stages of malaria parasites. Atovaquone is a ubiquinone antagonist that inhibits mitochondrial electron transport and collapses mitochondrial membrane potential. The proguanil metabolite cycloguanil is a dihydrofolate reductase inhibitor, but the mode of action of proguanil is unknown. In screening evaluations of secondary pharmacology, neither atovaquone nor proguanil had activity that adversely affected gastrointestinal, cardiovascular, or central or autonomic nervous system functions at clinically relevant concentrations. After oral administration, atovaquone exposure is extensive in rats but limited in dogs, while proguanil and cycloguanil exposure is extensive in dogs but limited in rats. In both species, toxicity was related to proguanil exposure, the principal manifestations being salivation, emesis, and loss of body weight. Neither atovaquone nor proguanil was teratogenic or mutagenic. An increased incidence of hepatic adenomas and adenocarcinomas was seen in mice, but not rats, after lifetime exposure to atovaquone, and appears to be related to species-specific differences in hepatic enzymatic activity. No additional toxicity was evident in animals treated with the combination of atovaquone and proguanil hydrochloride compared to those treated with either drug alone., Conclusion: Nonclinical studies of atovaquone and proguanil hydrochloride supported the clinical development of this combination for treatment and prophylaxis of malaria.

French medical practitioners have at their disposal several antimalarial drugs for giving chemoprophylaxis to people travelling to a malaria endemic country or treating an imported malaria case in a patient. The choice depends on the contre-indications and indications of each drug, essentially subordinated to the presence and level of Plasmodium falciparum chemosensitivity in the visited area. For prevention, chloroquine alone can be taken in the areas where P. falciparum is absent or not chloroquine resistant; elsewhere, the choice between chloroquine/proguanil or mefloquine depends on knowing the prevalence and level of falciparum chloroquine resistance in these areas. For treatment, the only indications of chloroquine are imported malaria cases either due to P. vivax, P. ovale or P. malariae, or caused by P. falciparum contracted in one of the rare countries where the species is still sensitive to chloroquine. For uncomplicated falciparum malaria cases acquired in a chemoresistance area, mefloquine, halofantrine, sulfadoxine-pyrimethamine or oral quinine is selected, depending on the observed chemoprophylaxis, the contra-indications and the suspicion of chemoresistance type. Whatever the provenance area, P. falciparum in a patient with one or several serious symptoms or possibly profuse vomiting is treated by intravenous quinine, associated with tetracycline if the patient comes from an area known for a low quinine sensitivity of this species. The spectrum of falciparum malaria treatment has recently broadened to include new drugs such as artemisinin, artemether or atovaquone/proguanil, the latter being as yet unauthorized in France.

Thirty-five pregnant women with Plasmodium falciparum parasitaemia were treated with chloroquine 25 mg/kg body weight over 3 days. They were followed up in vivo by use of a modified 14-day WHO extended field test. In vitro sensitivity of the parasite isolates to chloroquine was assessed by using the WHO microtest method. All pregnant women were aparasitaemic by day 7 and there was no parasite reappearance throughout the 14-day observation period. The mean parasite clearance time (MPCT) was 3.2 +/- 1.4 days. Eleven parasite isolates obtained from the women were highly susceptible to chloroquine in vitro. The effective drug concentration that gave 99% parasite growth inhibition (EC 99) was 0.36 mumol/l.