Mode of action of artemether lumefantrine (COARTEM): The sole, fixed, oral ADCC and its role in combatting multidrug resistance

Lumefantrine binds to hemin produced during hemoglobin breakdown, preventing detoxification to crystalline malaria pigment (hemozoin). During the same process, the perOXide group in artemether binds to heme and releases toxic free-radicals. Resistance to both lumefantrine and artemether depends on expression of a multidrug-resistance protein PGH-1. This shared resistance mechanism is responsible for potentiation between the components of coartemether. Sensitivity to lumefantrine and artemether is determined by mutations in PGH-1 associated with chloroquine-resistance, but if mutated PGH-1 is over-expressed, resistance to all three drugs may be seen. In Africa and S.America, where PGH-1 is not generally found amplified, but chloroquine-resistance is widespread, resistance to either component of coartemether is expected to be rare. This feature should be maintained especially where chloroquine is still in regular use. In areas of S.E.Asia where chloroquine and mefloquine are widely used, both wild type and mutated PGH-1 are present and amplified. To combat the consequent low-level resistance to the combination, higher treatment doses of co-artemether are required. The advantage of co-artemether as opposed to artesunate/mefloquine is seen in the shorter half-life of lumefantrine, allowing less time for resistance to be selected, and in co-artemether's better tolerability. The selection of chloroquine-sensitivity determinants by co-artemether, and of co-artemethersensitivity determinants by chloroquine suggests a possible strategy for resistance prevention in Africa and S. America, which may be enhanced by probable effects of artemether on transmissibility of gametocytes.