Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria

Abstract

Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine has led to the recent adoption of artemisinin-based combination therapies (ACTs) as the first line of treatment against malaria. ACTs comprise semisynthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs. These artemisinins are exceptionally potent against the pathogenic asexual blood stages of Plasmodium parasites and also act on the transmissible sexual stages. These combinations increase the rates of clinical and parasitological cures and decrease the selection pressure for the emergence of antimalarial resistance. This Review article discusses our current knowledge about the mode of action of ACTs, their pharmacological properties and the proposed mechanisms of drug resistance.Six decades ago, hopes of malaria eradication were raised by the discovery and implementation of chloroquine (CQ). The use of this highly effective, fast-acting and inexpensive 4-aminoquinoline, along with the potent insecticide dichlorodiphenyltrichloroethane (DDT), quickly proved successful in substantially reducing the incidence and severity of malaria worldwide. Initial successes were achieved primarily in regions with temperate climates and seasonal malaria transmission. However, in many parts of the world eradication efforts were effectively thwarted by multiple issues, including insecticide resistance in Anopheles mosquito vectors, high rates of Plasmodium parasite transmission, logistical hurdles to implementing DATABASES NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript control strategies, wars and population displacements, and a lack of sustained funding. Subsequently, resistance to CQ and the cost-effective replacement drug sulphadoxinepyrimethamine (SP) emerged in the most lethal human malarial pathogen, Plasmodium falciparum 1,2 . In some areas, the switch to either mefloquine (MFQ) or quinine resulted in the appearance of multidrug-resistant parasites, particularly in Southeast Asia 3 . The global consequence was a resurgence of malaria morbidity and mortality. With nearly 40% of the global population at risk, 300-660 million episodes of clinical P. falciparum malaria occur annually and there are an estimated one million deaths 4 . Most of these occur in sub-Saharan Africa (FIG. 1a), where rates of transmission can reach 1,500 mosquito-delivered parasite inoculations per individual per year 5 .Now there is hope that the tide may turn again with the implementation of artemisinin-based combination therapies (ACTs). Their success in treating CQ-and SP-resistant malaria has prompted the WHO to recommend ACTs as the preferred first-line antimalarials against P. falciparum malaria and has elicited substantial funding and logistical support from, among others, The Global Fund to Fight AIDS, Tuberculosis, and Malaria, The World Bank, Roll Back Malaria, the President's Malaria Initiative, the Medicines for Malaria Venture, and the Bill and Melinda Gates Foundation. ACTs have now been...

Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue

“…However, substantial inhibition of infectivity was observed at concentrations (330 nM) far below those levels achieved pharmacologically (mean peak plasma concentration in malaria patients was ∼11 μM, with a half-life of 4 or 5 d) (1,43). The reduction in oocyst numbers exceeded drug impact on exflagellation, suggesting that lumefantrine may impact the ac- …”

“…Encouragingly, in recent years, the global adoption of highly effective artemisinin-based combination therapies (ACTs) as first-line treatments and the distribution of long-lasting insecticide-treated bednets have helped reduce the prevalence of malaria in many endemic settings (1). This recent success contributed to the launch in 2007 of a new campaign of malaria eradication (2).…”

Factoring Quality Laboratory Diagnosis into the Malaria Control Agenda for Sub-Saharan Africa

“…Indiscriminate use of ACTs could create sufficient drug pressure that hastens development of resistant parasites, a situation that has begun to develop in Southeast Asia. [17][18][19] Furthermore, identifying febrile cases as having non-malarial causes provides opportunities to treat other potentially debilitating or fatal infections and also avoids unnecessary exposure to adverse events associated with ACTs. Therefore, laboratory-confirmed malaria is critical for appropriate management of malaria and other febrile diseases, maintaining the effectiveness of ACTs, and evaluating the effectiveness of interventions.…”

The growing pipeline of natural aminoacyl-tRNA synthetase inhibitors for malaria treatment

“…Although there are many effective agents, endoperoxides are the only drug class for which clinically significant resistance has not yet been reported. 4 The first generation endoperoxides includes artemisinin and several semisynthetic derivatives such as artemether, arteether, artesunate and artelinate. Unfortunately, endoperoxides are ineffective in the liver stage, and there are concerns that tolerance to artemisinins may be emerging in Cambodia.…”