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Primaquine, an 8-aminoquinoline, is a relatively unknown and underutilized drug in French-speaking African countries. It acts against the liver stage parasites of all human malaria species, asexual blood stages of Plasmodium vivax and, to a lesser degree, Plasmodium falciparum; P. falciparum mature gametocytes, and P. vivax and Plasmodium ovale hypnozoites. Gastrointestinal disturbances are its most common side effects. The clinical utility of primaquine is limited due to its hematological side effects in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency and other contraindications (pregnant woman, breastfeeding woman, infants less than 6 months old). In the light of the recent recommendations of the World Health Organization (WHO), we propose to examine how primaquine can be used in French-speaking Africa to improve malaria control and move towards malaria elimination. Two indications supported by the WHO are of relevance in Africa. First, artemisinin-based combination therapies and primaquine given as a single low dose (0.25 mg base/kg) are effective to kill asexual and sexual parasites of P. falciparum, are well-tolerated, and have very little risk even in mild to moderate G6PD-deficient patients. This strategy may be helpful to contain transmission in an area in Africa where P. falciparum malaria incidence has decreased considerably. There is an ethical concern in administering primaquine as a gametocytocide as it does not confer any direct benefit to the treated patient. However, the single low-dose primaquine is most likely associated with very low risk for adverse hematological effects, and WHO recommends its use even without prior G6PD testing. In our opinion, clinical studies including G6PD test should be conducted to assess the safety of low-dose primaquine in African patients. Second, primaquine is effective and necessary for radical treatment of P. vivax and P. ovale, but the standard 14-day treatment (0.25-0.5 mg base/kg/day) is not recommended in patients with G6PD deficiency. Prior G6PD testing is required before prescribing primaquine for radical treatment. The use of primaquine for radical treatment in patients without contraindications does not raise any major ethical problem since the probability of relapse in patients who do not receive anti-hypnozoite treatment can be relatively high and each relapse can cause or aggravate anemia, especially in children. In our opinion, patients with mild or moderate G6PD deficiency should not be treated with primaquine at present. Further clinical studies are necessary to define the role of this drug for radical treatment in G6PD-deficient African patients. Without primaquine, the eventual elimination of P. vivax and P. ovale malaria appears to be very difficult. Updated epidemiological data on G6PD, Duffy antigen, and the current distribution of and burden due to P. vivax and P. ovale are required for a rational use of primaquine in the African continent. Moreover, clinical studies on primaquine are required in Africa.

We studied the proportion of malaria-infected patients among febrile outpatients in nine health centres selected in relation to their geo-climatic location and the level of malaria transmission in order to establish a reliable database on malaria-associated morbidity and Plasmodium species in three epidemiological strata in Mauritania. Blood samples were collected from a total of 7368 febrile individuals (1603 in sahelian zone, 3023 in sahelian-saharan transition zone, and 2742 in Saharan zone) to examine thin and thick blood smears between August 2010 and July 2011. The proportion of malaria-infected patients was 9.1% (672/7368). Depending on the season, the proportion varied from 16.3% (494/3021), 5.5% (157/2850), to 1.4% (21/1497) during the humid season (July-October), cool dry season (December-March), and hot dry season (April-June), respectively. Febrile patients in the sahelian-Saharan transition zone were most affected by malaria, with 65.6% (441/672) smear-positive cases. P. vivax occurred most frequently (61.6%, 414/672). P. falciparum, P. ovale, and P. malariae accounted for 32.4% (218/672), 5.2% (35/672), and 0.8% (5/672) of smear-positive cases, respectively. These data may contribute to improving our knowledge on malaria in Mauritania, which may in turn help develop control strategies and improved monitoring in each geo-climatic zone.

During the surveys on antimalarial drug efficacy carried out from 2003 to 2006, we systematically checked the presence of Plasmodium falciparum in patients consulting in two health centres located in the south of Brazzaville. The first centre is situated in the urban zone; the second, in the semi rural area. The objective of this survey was to determine the prevalence of malaria-infected patients among the consulting patients and the prevalence of symptomatic patients with acute malaria attacks based on the parasitic density. Patients with parasites were assigned to one of the 5 following classifications: <2000, > or =2000, <5000, > or =5000 and > or =10,000 asexual parasites/microl of blood. Based on the threshold of parasite density 10,000 asexual parasites/microl, 10% and 24% of febrile patients in Tenrikyo and Madibou health centres were diagnosed as cases of malaria, respectively; 13.6% and 26.8% of patients under 5 years old consulting in these two health centres had malaria attacks. If the threshold of parasite density is lowered to 2000 asexual parasites/microl for patients > or =15 years old, 8% and 14% of adults in Tenrikyo and Madibou had malaria attacks, respectively The malaria burden was higher in the periphery of the city of Brazzaville than in the urbanized central districts. The Madibou health centre located in semi rural zone receives twice as many malaria cases for consultation than Tenrikyo located in the urban zone.

The prevalence of point mutations associated with resistance to sulfadoxine and pyrimethamine was determined by sequencing the fragments of genes encoding dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr), respectively in 59 isolates collected during 2002-2003 in São Tomé and Príncipe to develop an early warning system of drug-resistant P. falciparum. Almost all isolates (57 of 59, 97%) were dhfr mutant. The majority of the isolates (43 of 59, 73%; 16 with mixed alleles) carried the triple dhfr mutations (lle-51/Arg-59/Asn-108). The presence of dhps mutations were only limited to positions 436 and 437. The pure mutant codon Gly-437 was present in 39 out of 59 isolates (66%), in association with Ser-436 (n=34) or Ala-436 (n=5). Mixed isolates displayed different combinations of 436 (Ser, Ala ou Phe) and 437 (Gly with or without Ala) alleles. None of the isolates carried mutant 540, 581 or 613 codons. A total of 39 isolates (66%) were characterized as quadruple mutants (i.e. triple dhfr mutations + Gly-437 dhps mutant allele). Monitoring the possible emergence of isolates carrying multiple dhfr and dhps mutations, in particular codon Glu-540, may be used as an early warning system which indicates a decrease in sulfadoxine-pyrimethamine efficacy.

The malaria, deadly parasite infection in its severe form, is widely spread in tropical zone where it rages in an endemic way. The emergence and the extension of Plasmodium resistance contributed to increase the morbidity and the mortality of this pathology in children under 5 years old. Facing the extend of this phenomenon, a monitoring of the expansion of the chemosensitivity proves to be necessary. The goal of the present study was to assess the sulfadoxine-pyrimethamine (S-P) efficacy according to the in vivo test WHO protocol of 14 days-follow-up. Children are treated to the S-P at the rate of 1/2 tablet per 10 kg of body weight in unique dose, then controls are done days 3, 7 and 14. At the end of this work, 179 on 475 subjects were effectively carriers of asexual parasites. So, the general plasmodic index and Plasmodium falciparum rate infection were respectively 37.7% and 100%. Among the 89 children followed until J14, those aged of 13 to 24 months represented 38% of the population of children suffering from Plasmodium malaria, against 7% of those aged between 49 and 59 months. In terms of therapeutic efficacy, 76.4% of adequate clinical and parasitological response (ACR) have been reached against 23.6% of therapeutic failure (TF).

The in vitro activity of proguanil, cycloguanil (active metabolite of proguanil), pyrimethamine, and chloroquine was determined for 14 isolates of Plasmodium falciparum and the chloroquine-resistant W2 clone. In vitro assays were performed by using different types of RPMI 1640 culture medium and incubation period. The use of the standard RPMI medium or RPMI medium containing low concentrations of folate and para-aminobenzoic acid increases the 50% inhibitory concentrations of cycloguanil and pyrimethamine, as compared with the use of folate- and para-aminobenzoic acid-free RPMI medium. The concentrations of folate and para-aminobenzoic acid did not affect the in vitro activity of proguanil and chloroquine. However, prolongation of the incubation period from 42 to 66 hours decreased the 50% inhibitory concentrations of all test compounds. The weak antagonism in vitro between chloroquine and proguanil or cycloguanil does not seem to have any repercussion on the in vivo efficacy of chloroquine-proguanil combination.

The National Reference Centre for Malaria Chemosusceptibility (CNRCP) and the Tropical Medicine Institute of the Health Department for the Army (IMTSSA) monitor the chemosusceptibility of falciparum malaria introduced in France. In 1995, 353 isolates of P. falciparum are sent to the CNRCP and IMTSSA from malaria cases presenting in 49 civil and military hospitals distributed all over the french country. The patients are mostly Africans living in France and have mainly stayed in West Africa. Half of them did not take any chemoprophylaxis and a quarter took only chloroquine more or less regularly. The curative treatment, when known, is halofantrine alone in 52% of cases and quinine alone in 28% of cases. Three halofantrine failures are reported including 1 incorrect regimen and 4 quinine failures including 3 incorrect regimens. In 1995, in vitro resistance of P. falciparum isolates imported in France to the chemoprophylactic and therapeutic drugs is not worsening. In vitro quinine resistance is rare (1/108), mefloquine resistance (2/20) and halofantrine resistance (12/211) are limited, cycloguanil resistance (42/185) is stable and chloroquine resistance (84/230) is even decreasing (less selective pressure in Africa?).

The in vitro drug sensitivity of three dihydrofolate reductase inhibitors (pyrimethamine, cycloguanil, trimethoprim) was determined against 29 strains and isolates of Plasmodium falciparum by an isotopic semi-microtest. Trimethoprim is less active than pyrimethamine or cycloguanil and its activity is correlated with that of two other inhibitors, suggesting cross-resistance in vitro among the dihydrofolate reductase inhibitors.

Resistance to pyrimethamine and proguanil is due to a single point mutation in the gene that codes for dihydrofolate reductase. A single mutation gives rise to resistance to only one of the drugs. Resistance to both drugs results from several mutations. Chloroquine resistance phenotype is due to a rapid efflux of the drug from the parasite's digestive vacuole. This efflux is associated with a transmembrane permeability glycoprotein, or P-gp, which is similar to the protein implicated in the multidrug resistant phenotype of some cancer cells. However, one or several other poorly understood major gene(s) may be involved. Drugs which can inhibit the supposed affinity of P-gp for chloroquine are under study.