BACKGROUND Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed “radical cure”). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax . METHODS This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of prima-quine once daily for 14 days (129 patients). The primary outcome was the Kaplan– Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia. RESULTS In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention. CONCLUSIONS Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmith-Kline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167.)

BACKGROUND Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed “radical cure.” METHODS We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin. RESULTS A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, −4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96). CONCLUSIONS Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123.)

In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae), the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae), respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae), all presented significant in vitro inhibition (more active than quinine and chloroquine) of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.Key words: neosergeolide -ellipticine -aspidocarpine -4-nerolidylcatechol -Pothomorphe peltata -Picrolemma spruceiAspidosperma spp.Malaria is the main cause of economic loss and high morbidity in the world today and continues to be endemic to tropical regions such as the Amazon. In the Brazilian Amazon, 1.6 million positive plates (thick smears) in a total of 8 million diagnostic tests for malaria were registered from January 2004 to February 2007 (Ministério da Saúde, Sivep-Malaria 2007). The lack of an effective vaccine and the increasing expansion of strains of Plasmodium falciparum presenting resistance towards commonly used, low-cost antimalarials make control of this disease difficult (Olliaro & Bloland 2001, Wellens & Plowe 2001, Vieira et al. 2001, Gonzales et al. 2003, Alecrim et al. 2006. As a result, the World Health Organization (WHO 1978(WHO , 1995 has been promoting research on natural product based drugs for treatment of disease and many plant species have been evaluated for antimalarial activity (Weniger et al. 2004). In these studies, emphasis has been on the discovery of lead compounds for drug development (Gundidza & Chinyanganya 1999). The rational search for active substances in medicinal plants is a very promising and cost-effective strategy for antimalarial drug discovery. This approach benefits from the accumulated knowledge of the curing capacity of plants possessed by inhabitants of malaria endemic regions and permits the extensive evaluation of natural products derived from these sources (Campbell et al. 1997, 1998, Brandão et al. 1992, 1997, Krettli et al. 2001, Andrade-Neto et al. 2004a.This triage of useful and effective plants is at the heart of traditional medicinal knowledge and is an extremely important source of therapeutic compounds in use today. Important semi-synthetic, low-cost, highly effective antimalarial drugs such as the quinolines (chloroquine, mefloquine, primaquine, etc.) and artemisinin derivatives (sodium artesunate, arteether, artemether, etc.) owe their initial discovery to the isolation and structural identi...

Plasmodium vivax parasites with chloroquine resistance (CQR) are already circulating in the BrazilianAmazon. Complete single-nucleotide polymorphism (SNP) analyses of coding and noncoding sequences of the pvmdr1 and pvcrt-o genes revealed no associations with CQR, even if some mutations had not been randomly selected. In addition, striking differences in the topologies and numbers of SNPs in these transporter genes between P. vivax and P. falciparum reinforce the idea that mechanisms other than mutations may explain this virulent phenotype in P. vivax.Plasmodium vivax is the most widely distributed human malaria parasite, causing approximately 80 to 300 million clinical cases of malaria each year (17). Numerous factors indicate that this burden will increase due to the emergence and spread of chloroquine-resistant parasites (3, 17).More than 50% of the malaria cases in Latin America occur in Brazil, and P. vivax predominates as the causative agent (16,21). Notably, failures of chloroquine treatment of P. vivax malaria in the Brazilian Amazon city of Manaus have been reported recently (1). The local confirmation of the presence of active P. vivax parasites resisting chloroquine at the proposed minimal effective concentration in plasma for sensitive strains is a public health concern deserving attention.Point mutations in two digestive-vacuole membrane proteins of P. falciparum, the P. falciparum chloroquine resistance transporter (PfCRT) and multidrug resistance 1 protein (PfMDR1), have been associated with chloroquine resistance (CQR), albeit to different extents (2, 10). Orthologues of these proteins in P. vivax (P. vivax CRT-O [PvCRT-O] and PvMDR1) have been identified previously (6, 15, 18), and recently, pvmdr1 mutant alleles were suggested to be associated with both in vitro and in vivo CQR in Southeast Asia (6,20).Here, we report a single-nucleotide polymorphism (SNP) analysis of pvmdr1 and pvcrt-o genes in P. vivax isolates from chloroquine-treated patients with and without recrudescent disease in the Brazilian Amazon region. In addition to complete coding sequences, we analyzed sequences from 5Ј flanking regions and introns.Field isolates were collected during a 28-day in vivo chloroquine efficacy study conducted in the city of Manaus, Brazil (8). Plasmatic chloroquine levels in all volunteers were measured by high-performance liquid chromatography on day 3 to confirm adequate dosing and good absorption of the oral chloroquine intake (three doses of 10, 7.5, and 7.5 mg/kg of body weight in 150-mg tablet form at 24-h intervals). Clinical treatment failure was defined as the occurrence of a positive blood smear result (confirmed by PCR diagnostic analysis) on day 14, 21, or 28 and the presence of parasites in peripheral blood (collected on the same day as the positive blood smear) containing Ͼ10 ng/ml of chloroquine as determined by high-performance liquid chromatography (7). Measurements of chloroquine and its active metabolite desethylchloroquine in whole blood were not obtained, as plasma samples were c...