Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Tolerability, Safety, and Preliminary Efficacy Study

Abstract

dArtemisinin-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.

Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia

“…The standard dose of ARCO, which contains 50 mg of naphthoquine and 125 mg of artemisinin per tablet to be given as a single dose of 8 tablets for adults, is equivalent in naphthoquine content to the 800 mg NQAZ treatment tested in this study. Two studies on ARCO that were conducted in Papua New Guinea did not show safety concerns in children (30,31). Although future studies involving larger populations are still needed, these results collectively indicate that NQAZ has an overall good safety profile.…”

Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Pharmacokinetic Study

“…Efficacy against asexual parasite forms over 42 days of follow-up for groups 2 and 3 was 100%, but prolonged gametocyte carriage was observed in some patients (7). The latter observation, together with concerns regarding the emergence of artemisinin resistance in areas of endemicity with a history of subtherapeutic drug use (17), the implication that higher individual pediatric doses than those recommended by the manufacturer can be used, and the safety of the two-dose ART-NQ regimen employed for group 3 (7), supports an argument for a 3-day ART-NQ regimen in line with WHO recommendations for all artemisinin combination therapies (54).…”

“…Using either a weight-based equation (28) (7). The regimens used for groups 2 and 3 (means, 9.0 and 9.5 mg/kg NQ per dose) were based on the manufacturer's recommendations of 6.5 to 9.5 mg/kg for children weighing as much as 40 kg (33,38), doses that still fall short of the allometrically scaled dose of Ն10 mg/kg.…”

“…Full details of the studies have been provided in a separate report (7). In brief, children aged 5 to 10 years who presented with an axillary temperature of Ͼ37.5°C or a history of fever in the previous 24 h and who were slide positive for malaria (Ͼ1,000 asexual P. falciparum parasites/l of whole blood or Ͼ250 Plasmodium vivax parasites/l) were eligible provided that they had no complications or concomitant illness, no prior treatment with study drugs, and no history of allergy to ART or aminoquinoline drugs.…”

Malaria-Infected Mice Live Until at Least Day 30 after a New Artemisinin-Derived Thioacetal Thiocarbonate Combined with Mefloquine Are Administered Together in a Single, Low, Oral Dose

“…22,23,24 To overcome such non-adherence to a repeated dosing regimen, curing malaria patients with a single oral dose of drug is a very important goal. 2526,27,28,29 Toward that goal, we have reported that malaria-infected mice are cured by a single, oral, 6 mg/kg dose of several new artemisinin derivatives combined with 18 mg/kg of mefloquine hydrochloride. 30,31 …”