naphthoquinones and Malaria--Vivax

In a recent trial of artemisinin-naphthoquine (artemisinin-NQ) and artemether-lumefantrine (AM-LM) therapy in young children from Papua New Guinea (PNG), there were no treatment failures in artemisinin-NQ-treated children with Plasmodium falciparum or Plasmodium vivax compared with 2.2% and 30.0%, respectively, in AM-LM-treated children during 42 days of follow-up. To determine whether, consistent with the long elimination half-life of NQ, this difference in efficacy would be more durable, clinical episodes of malaria were assessed in a subset of trial patients followed for six months post-treatment.. For children completing trial procedures and who were assessable at six months, all within-trial and subsequent clinical malaria episodes were ascertained, the latter by clinic attendances and/or review of hand-held health records. Presentations with non-malarial illness were also recorded. Differences between allocated treatments for pre-specified endpoints were determined using Kaplan-Meier survival analysis.. Of 247 children who were followed to Day 42, 176 (71.3%) were included in the present sub-study, 87 allocated to AM-LM and 89 to artemisinin-NQ. Twenty children in the AM-LM group (32.8%) had a first episode of clinical malaria within six months compared with 10 (16.4%) in the artemisinin-NQ group (P = 0.033, log rank test). The median (interquartile range) time to first episode of clinical malaria was 64 (50-146) vs 116 (77-130) days, respectively (P = 0.20). There were no between-group differences in the incidence of first presentation with non-malarial illness (P = 0.31).. The greater effectiveness of artemisinin-NQ over conventional AM-LM extends to at least six months post-treatment for clinical malaria but not non-malarial illness.. Australian New Zealand Clinical Trials Registry ACTRN12610000913077 .

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Half-Life; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Papua New Guinea; Plasmodium falciparum; Plasmodium vivax; Treatment Outcome

Plasmodium vivax is the main malaria parasite in China, and China is now making efforts to eliminate malaria by 2020. Radical cure of vivax malaria is one of challenges for malaria elimination. The purpose is to evaluate the efficacy and safety of artemisinin-naphthoquine (ANQ) versus chloroquine-primaquine (CQ-PQ) in treatment of vivax malaria in Yunnan Province, China.. An open-label randomized and non-inferiority design, eligible patients with monoinfections of P. vivax were randomly assigned to receive either a total target dose of ANQ 24.5 mg/kg (naphthoquine 7 mg/kg and artemisinin 17.5 mg/kg), once a day for three days, or a total CQ dose of 24 mg base/kg, once a day for three days plus a PQ dose of 0.45 mg base/kg/day, once a day for eight days. Patients were followed up for one year. The difference in efficacy between ANQ and CQ-PQ was compared via Wilson's test.. By day 42, the number of patients free of recurrence was 125 (98.4%; 95% Confidence interval, 94.4-99.8%) for ANQ arm and 123 (96.1%; 95%CI, 91.1-98.7%) for CQ-PQ, and non-significant (P = 0.4496). By day 365, the number was 101 (79.5%; 95%CI, 71.8-85.9%) for ANQ and 106 (82.8%; 95%CI, 75.1-88.9%) for CQ-PQ, and non-significant (P = 0.610). So the proportions of patients free of recurrence had no significant difference between ANQ and CQ-PQ groups by day 28, 42 and 365; compared with CQ-PQ, the side effect of ANQ was mild.. ANQ is non-inferior to CQ-PQ in terms of patients free of recurrence, and safer than CQ-PQ.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Artemisinins; Child; Child, Preschool; China; Chloroquine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Malaria, Vivax; Male; Middle Aged; Naphthoquinones; Plasmodium vivax; Primaquine; Treatment Outcome; Young Adult

The increasing prevalence of resistance to antimalarial drugs reduces options for malaria prophylaxis. Atovaquone/proguanil (Malarone; GlaxoSmithKline) has been >95% effective in preventing Plasmodium falciparum malaria in lifelong residents of areas of holoendemicity, but data from persons without clinical immunity or who are at risk for Plasmodium vivax malaria have not been described. We conducted a randomized, double-blinded study involving 297 people from areas of nonendemicity in Indonesia who migrated to Papua (where malaria is endemic) < or =26 months before the study period. Subjects received prophylaxis with 1 Malarone tablet (250 mg of atovaquone and 100 mg of proguanil hydrochloride; n=148) or placebo (n=149) per day for 20 weeks. Hematologic and clinical chemistry values did not change significantly. The protective efficacy of atovaquone/proguanil was 84% (95% confidence interval [CI], 44%-95%) for P. vivax malaria, 96% (95% CI, 72%-99%) for P. falciparum malaria, and 93% (95% CI, 77%-98%) overall. Atovaquone/proguanil was well tolerated, safe, and effective for the prevention of drug-resistant P. vivax and P. falciparum malaria in individuals without prior malaria exposure who migrated to Papua, Indonesia.

Topics: Adolescent; Adult; Animals; Antimalarials; Atovaquone; Chemoprevention; Child; Double-Blind Method; Female; Humans; Indonesia; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Naphthoquinones; Patient Compliance; Plasmodium falciparum; Plasmodium vivax; Proguanil; Transients and Migrants; Treatment Outcome

Thirty-eight of 295 subjects participating in a randomized, double-blind, placebo-controlled trial of the efficacy of daily administration of atovaquone/proguanil for malaria prevention developed malaria at some time during the 20-week prophylaxis period. These subjects (3 atovaquone/proguanil recipients and 35 placebo recipients) were treated with 4 tablets of atovaquone/proguanil per day for 3 days. Atovaquone/proguanil provided safe, well-tolerated, and effective therapy for uncomplicated malaria in nonimmune Indonesians.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Atovaquone; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Humans; Indonesia; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Naphthoquinones; Plasmodium falciparum; Plasmodium vivax; Proguanil; Treatment Outcome

A recent randomized trial showed that artemisinin-naphthoquine (AN) was non-inferior to artemether-lumefantrine (AL) for falciparum malaria and superior for vivax malaria in young Papua New Guinean children. The aim of this study was to compare the cost-effectiveness of these two regimens.. An incremental cost-effectiveness analysis was performed using data from 231 children with Plasmodium falciparum and/or Plasmodium vivax infections in an open-label, randomized, parallel-group trial. Recruited children were randomized 1:1 to receive once daily AN for 3 days with water or twice daily AL for 3 days given with fat. World Health Organisation (WHO) definitions were used to determine clinical/parasitological outcomes. The cost of transport between the home and clinic, plus direct health-care costs, served as a basis for determining each regimen's incremental cost per incremental treatment success relative to AL by Day 42 and its cost per life year saved.. In the usual care setting, AN was more effective for the treatment of uncomplicated malaria in children aged 0.5-5.9 years. AL and AN were equally efficacious for the treatment of falciparum malaria, however AN had increased anti-malarial treatment costs per patient of $10.46, compared with AL. AN was the most effective regimen for treatment of vivax malaria, but had increased treatment costs of $14.83 per treatment success compared with AL.. Whilst AN has superior overall efficacy for the treatment of uncomplicated malaria in PNG children, AL was the less costly regimen. An indicative extrapolation estimated the cost per life year saved by using AN instead of AL to treat uncomplicated malaria to be $12,165 for girls and $12,469 for boys (discounted), which means AN may not be cost-effective and affordable for PNG at current cost. However, AN may become acceptable should it become WHO prequalified and/or should donated/subsidized drug supply become available.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Cost-Benefit Analysis; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Papua New Guinea; Randomized Controlled Trials as Topic; Treatment Outcome

Quantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated Plasmodium falciparum and/or Plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral P. falciparum gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/μl for artemether-lumefantrine and 61/μl for artemisinin-naphthoquine (P < 0.001). The median time for P. falciparum gametocyte density to fall to <2.5/μl (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (P < 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days; P < 0.001) and had a longer median P. falciparum gametocyte carriage time per individual (20 versus 13 days; P < 0.001). Clearance of P. vivax gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed P. vivax gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential P. falciparum transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses P. vivax recurrence and consequent gametocytemia.

Topics: Antimalarials; Artemether; Artemisinins; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Half-Life; Humans; Kinetics; Lumefantrine; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Plasmodium falciparum

Artemisinin-naphthoquine (ART-NQ) is a fixed-dose coformulated antimalarial therapy recommended as a single-dose treatment and marketed in Papua New Guinea among other tropical countries. We conducted a tolerability, safety, and efficacy study of ART-NQ for Papua New Guinean children aged 5 to 12 years with uncomplicated malaria, comparing single-dose ART-NQ (15 and 6 mg/kg of body weight) given with water (group 1; n = 15), single-dose ART-NQ (22 and 9 mg/kg) given with milk (group 2; n = 17), or two daily doses of 22 and 9 mg/kg given with water (group 3; n = 16). Of the 48 children (45 with Plasmodium falciparum malaria, 2 with Plasmodium vivax malaria, and 1 with mixed-species malaria), 2 in group 2 did not attend all follow-up assessments. All regimens were well tolerated, with no serious adverse events. There were no clinically significant changes in pulse, blood pressure, rate-corrected electrocardiographic QT, routine biochemistry/hematology, or hearing after treatment. Fever clearance was prompt. Mean 50% parasite clearance times were 4, 4, and 5 h for groups 1, 2, and 3, respectively. One group 1 patient had PCR-confirmed P. falciparum recrudescence at day 23; four had PCR-confirmed P. falciparum reinfections on day 28 or 42; and three had P. vivax infections detected on day 42. The only recurrent parasitemia in groups 2 and 3 occurred in a group 2 child who developed a P. vivax infection on day 42. Day 14 gametocyte positivity levels were 20%, 27%, and 9% in groups 1, 2, and 3, respectively. The lower single ART-NQ dose was associated with relatively frequent recurrence of parasitemia, but the prolonged gametocytemia in all three groups has implications for the transmission of malaria.

Topics: Antimalarials; Artemisinins; Blood Pressure; Child; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Female; Follow-Up Studies; Hearing; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Papua New Guinea; Recurrence; Treatment Outcome

Artemisinin-naphthoquine (ART-NQ) is a coformulated antimalarial therapy marketed as a single-dose treatment in Papua New Guinea and other tropical countries. To build on limited knowledge of the pharmacokinetic properties of the components, especially the tetra-aminoquinoline NQ, we studied ART-NQ disposition in Papua New Guinea children aged 5 to 12 years with uncomplicated malaria, comparing a single dose (15 and 6 mg/kg of body weight) administered with water (group 1; n = 13), a single dose (22 and 9 mg/kg) with milk (group 2) (n = 17), and two daily doses of 22 and 9 mg/kg with water (group 3; n = 16). The plasma NQ concentration was assayed by high-performance liquid chromatography, and the plasma ART concentration was assayed using liquid chromatography-mass spectrometry. Population-based multicompartment pharmacokinetic models for NQ and ART were developed. NQ disposition was best characterized by a three-compartment model with a mean absorption half-life (t(1/2)) of 1.0 h and predicted median maximum plasma concentrations that ranged as high as 57 μg/liter after the second dose in group 3. The mean NQ elimination t(1/2) was 22.8 days; clearance relative to bioavailability (CL/F) was 1.1 liters/h/kg; and volume at steady state relative to bioavailability (V(ss)/F) was 710 liters/kg. Administration of NQ with fat (8.5 g; 615 kJ) versus water was associated with 25% increased bioavailability. ART disposition was best characterized by a two-compartment model with a mean CL/F (4.1 liters/h/kg) and V/F (21 liters/kg) similar to those of previous studies. There was a 77% reduction in the bioavailability of the second ART dose (group 3). NQ has pharmacokinetic properties that confirm its potential as an artemisinin partner drug for treatment of uncomplicated pediatric malaria.

Topics: Antimalarials; Artemisinins; Biological Availability; Child; Chromatography, High Pressure Liquid; Chromatography, Liquid; Drug Administration Schedule; Female; Follow-Up Studies; Half-Life; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Mass Spectrometry; Naphthoquinones; Papua New Guinea; Plasmodium falciparum; Plasmodium vivax

Artemisinin-based combination therapies (ACTs) have been adopted as the first line of treatment against malaria in nearly all malaria-endemic countries, mainly as a result of Plasmodium falciparum infection, as this species of malaria parasite has developed resistance to most of the available non-artemisinin antimalarial drugs. Artemisinin-naphthoquine (ART-NQ, also named as ARCO™; Kunming Pharmaceuticals, Kunming, China) is one of the several currently available ACTs that show a promising approach to dealing with drug-resistant malaria rather than monotherapies. Unlike other ACTs, ART-NQ requires either a single-dose treatment or a two-dose treatment within 24 h against uncomplicated P. falciparum malaria; however, this was mainly validated in adults rather than children. Batty et al. performed the first pharmacokinetic study of ART-NQ combination therapy for uncomplicated pediatric malaria, and the authors' results are described and discussed below.

Topics: Antimalarials; Artemisinins; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Malaria, Vivax; Naphthoquinones; Papua New Guinea; Plasmodium falciparum; Plasmodium vivax; Treatment Outcome

After a trip to Zambia, a previously healthy adult traveler presented with a prolonged illness characterized by low-grade fevers and fatigue. Although malaria smears and antibody tests results for Plasmodium species were negative, a diagnosis of malaria was ultimately determined by polymerase chain reaction (PCR) amplification and species-specific nucleic acid hybridization techniques. The patient was successfully treated and cured. Clinical use of PCR technology may facilitate the identification of cases of smear-negative malaria, which up to the present time, have been difficult to diagnose.

Topics: Adult; Animals; Antimalarials; Atovaquone; Drug Therapy, Combination; Eye Infections, Parasitic; Female; Humans; Malaria, Vivax; Naphthoquinones; Plasmodium vivax; Polymerase Chain Reaction; Proguanil; Travel; Treatment Outcome; Zambia

To report a case of severe chloroquine toxicity in the presence of high-grade chloroquine-resistant Plasmodium vivax.. A febrile 36-year-old seaman from Mumbai (Bombay) was prescribed >5 times the usual dose of chloroquine for malaria diagnosed empirically onboard ship. His fever resolved, but he developed symptoms consistent with those of chloroquine toxicity. Fever recurred 30 days after his initial presentation, and blood smear-positive vivax malaria was diagnosed. A serum chloroquine concentration at this time (91 micro g/L) was above that considered effective for chloroquine-sensitive P. vivax (>15 micro g/L). The patient responded to atovaquone plus proguanil followed by primaquine.. The patient was given chloroquine by his captain in a dosage regimen appropriate for quinine (2 tablets 3 times daily for 7 d). Pharmacokinetic modeling suggested that the patient's initial over-treatment was as reported and that the predicted maximum serum concentration of chloroquine (902 micro g/L) was within the range seen in fatal chloroquine overdose.. Chloroquine-resistant vivax malaria is increasingly widespread, and transmission can occur within large tropical population centers. For drugs with a narrow therapeutic index such as chloroquine, recommended dosing regimens should be respected, and adequate information sources must be available where such drugs are dispensed by untrained personnel.

Topics: Adult; Animals; Antimalarials; Atovaquone; Chloroquine; Drug Overdose; Humans; Malaria, Vivax; Male; Naphthoquinones; Plasmodium vivax; Primaquine; Proguanil

To bring military medical problems concerning malaria to the attention of the Defence Medical Services.. Seven military medical problems related to malaria are illustrated by cases referred for secondary assessment over the past five years. Each is discussed in relation to published data.. The cases of failure of various kinds of chemoprophylaxis, diagnosis and treatment of malaria may represent just a fraction of the magnitude of the overall problem but in the absence of reliable published military medical statistics concerning malaria cases, the situation is unclear.. Present experience suggests there are a number of persisting problems affecting the military population in relation to malaria. Only publication of reliable statistics will define their magnitude. Interim remedies are proposed whose cost-effectiveness remains to be established.

Topics: Adult; Animals; Antimalarials; Atovaquone; Chloroquine; Drug Combinations; Global Health; Humans; Kenya; Malaria, Falciparum; Malaria, Vivax; Male; Mefloquine; Military Medicine; Military Personnel; Naphthoquinones; Patient Compliance; Plasmodium falciparum; Plasmodium vivax; Proguanil; Sierra Leone; Treatment Failure; Treatment Outcome; United Kingdom

1. The radical cure of human malaria caused by Plasmodium vivax requires two drugs, i.e., a blood schizontocide such as chloroquine to clear the circulating parasites, and primaquine aimed at the liver stages (hyponozoites) responsible for the late relapses of this parasite. Primaquine is unique as a radical curative drug but is highly toxic. The only useful model currently available for screening drugs to replace primaquine is Plasmodium cynomolgi-induced malaria in Rhesus monkeys. Because of the limited availability and cost of these animals, the development of non-primate models for such screening would be of considerable value. 2. We used a drug-screening assay for the liver stage malaria parasite based on the ability of such drugs to stop development of gametocytes in the mosquito vector. The inhibition of the sporogonic cycle of malaria in the mosquito by primaquine (15 mg/kg) was confirmed here and used for re-evaluation of the gametocyte method. 3. We observed that the level of parasitemia in the untreated control chicken used to infect mosquitos was a crucial factor affecting the subsequent development of sporogony. Thus, parasitemia was carefully controlled in the studies involving oocyst development. Parasitemias lower than 6% at the beginning of the experiment and increasing were found to be most appropriate for the production of the infectious gametocytes during a period of 8 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aedes; Animals; Brazil; Chickens; Disease Models, Animal; Drug Evaluation, Preclinical; Liver; Malaria, Vivax; Naphthoquinones; Plant Extracts; Plants, Medicinal; Plasmodium gallinaceum

Topics: Humans; Malaria; Malaria, Vivax; Male; Naphthoquinones