Robert Mull

Efficacy and safety of CGP 56697 (artemether and benflumetol) compared with chloroquine to treat acute falciparum malaria in Tanzanian children aged 1–5 years

A randomized, open trial involving 260 Tanzanian children, aged 1–5 years, with acute Plasmodium falciparum malaria was conducted to evaluate the efficacy of the combination antimalarial CGP 56697 (artemether and benflumetol), and to compare it with chloroquine, the standard drug used for malaria treatment in the Kilombero area. Children who had received rescue medication within the first 48 h or had a negative slide at the same time were excluded. Seven‐day parasitological cure rates were 94% (95% CI 88–97.5) for CGP 56697 and 35.4% (95% CI 25.9–45.8) for chloroquine. Using the same definition, the 14‐day parasitological cure rates were 86.4% (95% CI 78.5–92.2) for CGP 56697 and 10.3% (95% CI 5.1–18.1) for chloroquine. Gametocytes were more effectively suppressed by CGP 56697 than by chloroquine. There were no major adverse events with either drug. CGP 56697 is highly efficacious against P. falciparum in this area of Tanzania. The study contributes to the discussion on treatment strategies, particularly whether chloroquine may still fulfil its role as first‐line drug in an area of high malaria transmission and very high levels of chloroquine resistance.

Multiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria

Multiple dose pharmacokinetics of artemether and dihydroartemisinin were investigated in chinese patients treated for malaria. They received over 2 days either 4 x 80 mg artemether orally (n = 48) or 4 x 80-480 mg co-artemether (n = 40), a combination of artemether and lumefantrine (benflumetol). Lag time = 0.48 h (mean), Cmax after first dose = 157 ng/ml, t(max) = 1.73 h and elimination half-life = 1.16 h. The lag and absorption times were 0.5 h longer for co-artemether compared with artemether. Dihydroartemisinin paralleled artemether pharmacokinetics. Artemether Cmax after the last dose was one-third of the Cmax after the first dose while, inversely, dihydroartemisinin Cmax increased over time. We suggest that auto-induction of gut mucosa enzymes and/or liver enzymes causes a time-dependent increase in first-pass metabolisation of artemether.

Distinction of recrudescences from new infections by pcr-rflp analysis in a comparative trial of cgp 56 697 and chloroquine in Tanzanian children.

Summary objective To test the efficacy of a new compound drug (CGP 56 697) against acute, uncomplicated falciparum malaria.

The comparative efficacy and tolerability of CGP 56697 (artemether + lumefantrine) versus halofantrine in the treatment of uncomplicated falciparum malaria in travellers returning from the Tropics to The Netherlands and France.

CGP 56697 (Riamet) is a new oral anti-malarial drug composed of artemether and lumefantrine (benflumetol) which combines the fast, short-acting artemether for rapid parasite clearance with the prolonged action of lumefantrine for intended radical cure. In this double-blind, comparative trial, the efficacy and tolerability of CGP 56697, given as a course of 4 x 4 tablets over 48 h, was compared to halofantrine, given as 3 x 2 tablets over 12 h with a second course 1 week later. Patients (mostly non-immune) with acute, uncomplicated Plasmodium falciparum infection were randomly assigned to either CGP 56697 (n = 51) or halofantrine (n = 52). CGP 56697 proved superior with respect to parasite clearance time (median 32 vs. 48 h, P < 0.001) and parasite reduction at 24 h (median 99.7 vs. 89.6%, P < 0.001) with a non-significant difference in resolution of fever (median 24 vs. 32 h, P = 0.835). However, a 28-day cure rate of 82% was observed for CGP 56697 and 100% for halofantrine. Significant QTc prolongations (> 30 ms) were seen 6-12 h after halofantrine intake but not after CGP 56697 intake. CGP 56697 is an effective, well-tolerated treatment for uncomplicated falciparum malaria but for this dosing regimen the recrudescence rate is unacceptablyhigh (18%). For travellers contracting malaria abroad, we propose a six-dose regimen of CGP 56697 over 3 days.

Dose-Finding Study of the Efficacy of Fixed-Combination Artemether/Lumefantrine for the Treatment of Multidrug-Resistant Plasmodium falciparum Malaria in Thailand

AbstractObjective: To investigate the efficacy and tolerability of three different regimens of the fixed combination artemether/lumefantrine (artemether/benflumetol) in patients with multidrug-resistant Plasmodium falciparum malaria. Design: Randomised, double-blind, dose-finding study. Setting: Two centres in Thailand (the Bangkok Hospital for Tropical Diseases and Mae-Sot Malaria Clinic). Patients and Interventions: 260 patients (aged between 14 and 60 years and weighing ≥35kg) with acute uncomplicated P. falciparum malaria were randomised to receive one of three regimens of the fixed combination artemether/lumefantrine (CGP 56697; one tablet contains artemether 20mg and lumefantrine 120mg). Regimen I: four tablets at 0, 8, 24 and 48 hours (n = 87); Regimen II: two tablets at 0, 8, 24 and 48 hours (n = 87); Regimen III: four tablets at 0, 8 and 24 hours (n = 86). Main Outcome Measures and Results: With only one exception, all patients in the three groups had a rapid initial response with comparable parasite clearance time (PCT) and fever clearance time (FCT). 19, 35 and 37 patients receiving regimen I, II and III, respectively, had recrudescence between days 7 and 28 (median 17 days). The cure rate of 79.5% with regimen I was significantly higher than that with the other two regimens (54.7 and 55.3% for regimen II and III, respectively; both p < 0.001). Six patients (two and four in regimens I and III) who had P. vivax malaria on admission were cleared, although reappearance of P. vivax was seen in all groups. Conclusions: The low cure rates obtained in this study suggest that these three regimens of artemether/lumefantrine may not be optimal for multidrug-resistant P. falciparum strains in Thailand. The highest dose combination used in this trial was well tolerated and more effective than the other regimens. There is therefore still room for the use of a higher dose regimen of this combination in the treatment of multidrug-resistant falciparum in Thailand.