cgp-56697 and halofantrine

Co-artemether (Coartem, Riamet) is a tablet containing 20 mg artemether and 120 mg lumefantrine for treatment of falciparum malaria. Lumefantrine has some chemical similarities to halofantrine (Halfan), an antimalarial known for QTc prolongation. Effects on the QTc interval of fed single oral doses of 500 mg halofantrine and 80/480 mg co-artemether were compared in 13 healthy males in a randomized double-blind crossover study. Electrocardiograms (ECGs) were recorded from 48 hours before dosing until 48 hours thereafter. The maximum QTc interval (QTc = QT/square root(RR)) was compared before and after treatment and between treatments, fitting a general linear model. Drug plasma concentrations were determined concomitantly. After halofantrine, all participants showed an increase in the QTc interval; the mean maximum increase was 28 ms. The length of the QTc interval was positively correlated to halofantrine exposure. The QTc interval remained unchanged after co-artemether. The difference between treatments was statistically significant. In conclusion, halofantrine caused a significant, exposure-dependent increase in the QTc interval. No such effect was seen with co-artemether.

Topics: Administration, Oral; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Cross-Over Studies; Double-Blind Method; Drug Combinations; Electrocardiography; Ethanolamines; Fluorenes; Heart; Heart Rate; Humans; Long QT Syndrome; Male; Phenanthrenes; Sesquiterpenes

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.

Topics: Adolescent; Adult; Africa; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fluorenes; France; Humans; Malaria, Falciparum; Male; Middle Aged; Netherlands; Parasite Egg Count; Phenanthrenes; Plasmodium falciparum; Sesquiterpenes; Time Factors; Travel; Tropical Climate

Analysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring of Plasmodium falciparum drug resistance in the field. Here we genotype Pfcrt and Pfdmr1 of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively introduced and mefloquine was abandoned. Gene sequencing showed fixation of the 7G8-type Pfcrt SMVNT resistance haplotype and near fixation of the NYCDY Pfdmr1 haplotype. Pfdmr1 gene copy number correlated with 50% inhibitory concentrations of mefloquine and halofantrine (r = 0.64 and 0.47, respectively, n = 547); its temporal changes paralleled changes in in vitro mefloquine susceptibility. However, the molecular parameters studied did not account for the regained in vitro susceptibility to chloroquine and showed a poor correlation with susceptibility to artemether, lumefantrine, or quinine. Identification of novel markers of resistance to these antimalarials is needed in this South American area.

Topics: Aminoquinolines; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chloroquine; Drug Combinations; Drug Resistance; Ethanolamines; Evolution, Molecular; Fluorenes; French Guiana; Gene Dosage; Haplotypes; Humans; Inhibitory Concentration 50; Longitudinal Studies; Malaria, Falciparum; Mefloquine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Practice Guidelines as Topic; Protozoan Proteins; Quinine

Artemether, artemether-lumefantrine, or coartem and halofantrine are alternative antimalarial drugs to chloroquine. Their efficacy and potential to delay drug resistance in falciparum malaria had led to their increased use. Although these drugs have proven to be well tolerated, there are adverse effects associated with them. This study was designed to examine the toxic potential of acute administration of these drugs in rats. Twenty-four rats were divided into four groups: group I (control) received distilled water; group II received artemether for 5 days with an initial dose of 3.2 g/kg body weight on day 1 and 1.6 mg/kg body weight on days 2-5; group III received coartem (27 mg/kg body weight/day) for 3 days, which was divided into two equal portions per day; and group IV received halofantrine (24 mg/kg body weight/day) in three equal portions. Administration of artemether, coartem and halofantrine caused significant decrease (P < 0.05) in reduced glutathione levels in the liver by 29%, 21% and 26%, respectively. In contrast, there were no significant differences (P > 0.05) in the kidney glutathione levels. Furthermore, artemether, coartem and halofantrine decreased the liver- and kidney-enzymatic antioxidant status of the animals. Precisely, artemether, coartem and halofantrine decreased liver superoxide dismutase and catalase activities by 45%, 50% and 57%; and 20%, 29% and 23%, respectively. While the kidney catalase activities were decreased by 41%, 28% and 30%, respectively, the drugs however did not produce significant effect (P > 0.05) on the kidney superoxide dismutase activities. In addition, artemether, coartem and halofantrine decreased the hepatic levels of glutathione S-transferase by 64%, 51% and 53%, respectively. Administration of artemether, coartem and halofantrine significantly increased (P < 0.05) liver and kidney lipid peroxidation levels by 67%, 50% and 81%; and 58%, 43% and 31%, respectively. This indicates that the liver is considerably more affected than the kidneys. Similarly, halofantrine treatment caused significant elevation (P < 0.05) in the levels of serum creatinine, aspartate and alanine aminotransferases and blood urea nitrogen by 73%, 66%, 61% and 63%, respectively. These data indicate that oral administration of artemether, coartem and halofantrine has adverse effects on both enzymic and non-enzymatic antioxidant status of the animals.

Topics: Administration, Oral; Alanine Transaminase; Animals; Antimalarials; Antioxidants; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Aspartate Aminotransferases; Bilirubin; Biomarkers; Blood Urea Nitrogen; Catalase; Creatinine; Drug Combinations; Ethanolamines; Fluorenes; Glutathione; Glutathione Transferase; Intubation, Gastrointestinal; Kidney; Lipid Peroxidation; Liver; Male; Phenanthrenes; Rats; Rats, Wistar; Superoxide Dismutase; Time Factors