lumefantrine and chlorproguanil

Topics: Amodiaquine; Antimalarials; Artemether; Artemisinins; Artesunate; Chloroquine; Dapsone; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Mefloquine; Proguanil; Pyrimethamine; Sesquiterpenes; Sulfadoxine

Chlorproguanil-dapsone-artesunate (CDA) was developed as an affordable, simple, fixed-dose artemisinin-based combination therapy for use in Africa. This trial was a randomized parallel-group, double-blind, double-dummy study to compare CDA and artemether-lumefantrine (AL) efficacy in uncomplicated Plasmodium falciparum malaria and further define the CDA safety profile, particularly its hematological safety in glucose-6-phosphate dehydrogenase (G6PD) -deficient patients.. The trial was conducted at medical centers at 11 sites in five African countries between June 2006 and August 2007. 1372 patients (> or =1 to <15 years old, median age 3 years) with acute uncomplicated P. falciparum malaria were randomized (2:1) to receive CDA 2/2.5/4 mg/kg once daily for three days (N = 914) or six-doses of AL over three days (N = 458). Non-inferiority of CDA versus AL for efficacy was evaluated in the Day 28 per-protocol (PP) population using parasitological cure (polymerase chain reaction [PCR]-corrected). Cure rates were 94.1% (703/747) for CDA and 97.4% (369/379) for AL (treatment difference -3.3%, 95%CI -5.6, -0.9). CDA was non-inferior to AL, but there was simultaneous superiority of AL (upper 95%CI limit <0). Adequate clinical and parasitological response at Day 28 (uncorrected for reinfection) was 79% (604/765) with CDA and 83% (315/381) with AL. In patients with a G6PD-deficient genotype (94/603 [16%] hemizygous males, 22/598 [4%] homozygous females), CDA had the propensity to cause severe and clinically concerning hemoglobin decreases: the mean hemoglobin nadir was 75 g/L (95%CI 71, 79) at Day 7 versus 97 g/L (95%CI 91, 102) for AL. There were three deaths, unrelated to study medication (two with CDA, one with AL).. Although parasitologically effective at Day 28, the hemolytic potential of CDA in G6PD-deficient patients makes it unsuitable for use in a public health setting in Africa.. ClinicalTrials.Gov NCT00344006.

Topics: Adolescent; Africa; Antimalarials; Artemisinins; Artesunate; Child; Dapsone; Double-Blind Method; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Patient Compliance; Proguanil; Treatment Outcome

Artesunate+amodiaquine (AS+AQ) and artemether-lumefantrine (AL) are now the most frequently recommended first line treatments for uncomplicated malaria in Africa. Artesunate+chlorproguanil-dapsone (AS+CD) was a potential alternative for treatment of uncomplicated malaria. A comparison of the efficacy and safety of these three drug combinations was necessary to make evidence based drug treatment policies.. Five hundred and thirty-four, glucose-6-phosphate dehydrogenase (G6PD) normal children were randomised in blocks of 15 to the AS+AQ, AL or AS+CD groups. Administration of study drugs was supervised by project staff and the children were followed up at r home on days 1,2,3,7,14 and 28 post treatment. Parasitological and clinical failures and adverse events were compared between the study groups.. In a per-protocol analysis, the parasitological and clinical failure rate at day 28 post treatment (PCF28) was lower in the AS+AQ group compared to the AL or AS+CD groups (corrected for re-infections: 6.6% vs 13.8% and 13.8% respectively, p = 0.08; uncorrected: 14.6% vs 27.6% and 28.1% respectively, p = 0.005). In the intention to treat analysis, the rate of early treatment failure was high in all three groups (AS+AQ 13.3%; AL 15.2%; and AS+CD 9.3%, p = 0.2) primarily due to vomiting. However, the PCF28 corrected for re-infection was lower, though not significantly, in the AS+AQ group compared to the AL or the AS+CD groups (AS+AQ 18.3%; AL 24.2%; AS+CD 20.8%, p = 0.4) The incidence of adverse events was comparable between the groups.. AS+AQ is an appropriate first line treatment for uncomplicated malaria in Ghana and possibly in the neighbouring countries in West Africa. The effectiveness of AL in routine programme conditions needs to be studied further in West Africa.. ClinicalTrials.gov NCT00119145.

Topics: Amodiaquine; Antimalarials; Artemether; Artemisinins; Artesunate; Child; Child, Preschool; Dapsone; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Male; Polymerase Chain Reaction; Proguanil; Treatment Outcome

Combination drug therapy for malaria is recommended both to prevent and to overcome drug resistance. Drug combinations developed for use in Asia are being deployed in Africa, where higher rates of malaria affect the therapeutic and public health objectives of malaria chemotherapy as well as drug safety. Rational consideration of drug mechanisms, pharmacokinetics (PK), pharmacodynamics (PD), and malaria epidemiology should result in more effective combination regimens that retain therapeutic and prophylactic efficacy in the face of resistance.

Topics: Amodiaquine; Antimalarials; Artemether; Artemisinins; Artesunate; Chloroquine; Dapsone; Drug Design; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Global Health; Half-Life; Humans; Lumefantrine; Malaria; Mefloquine; Pregnancy; Pregnancy Complications, Infectious; Proguanil; Pyrimethamine; Quinine; Sesquiterpenes; Sulfadoxine