Artemisinin-Resistant Plasmodium falciparum Malaria

Abstract

For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins -the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs) -the first-line treatments for malaria -are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in-vitro, genomics, and transcriptomics studies in SEA have defined invivo and in-vitro phenotypes of artemisinin resistance; identified its causal genetic determinant; explored its molecular mechanism; and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's 'K13' gene; is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins; and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent; test whether new combinations of currently-available drugs cure ACT failures; and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to Sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest. (1). Reducing this disease burden continues to rely heavily on the availability and proper use of effective antimalarial drugs. Artemisinin and its derivatives [artesunate, artemether, dihydroartemisinin (DHA)], referred to collectively as artemisinins, are sesquiterpene lactones with potent activity against nearly all blood stages of Plasmodium falciparum parasites. These include asexual stages (rings, trophozoites, schizonts), which cause the clinical manifestations of malaria, and sexual stages (immature gametocytes), which give rise to the mature gametocytes that transmit infection through Anopheles mosquitoes to other humans. These blood stages, but not others [merozoites, which invade red blood cells (RBCs), and mature gametocytes], are susceptible to artemisinins because they actively digest hemoglobin as they develop within RBCs. It is believed that the hemeassociated iron released from this process cleaves the endoperoxide moiety of artemisinins, thereby forming the reactive oxygen species that target nucleophilic groups in parasite proteins and lipids. In an unbiased chemical proteomics analysis (2), Wang et al. found that artemisinin covalentl...

Molecular Detection of Residual Parasitemia after Pyronaridine–Artesunate or Artemether–Lumefantrine Treatment of Uncomplicated Plasmodium falciparum Malaria in Kenyan Children

“…Artemisinin-based combination therapies (ACTs) are firstline treatment of uncomplicated Plasmodium falciparum malaria in many African countries, where they show excellent cure rates despite concerns about increasing resistance in Southeast Asia. 1,2 Artemisinin resistance is characterized by delayed parasite clearance and associated with point mutations in the P. falciparum kelch protein gene on chromosome 13 (K13). 1,3 Even though the polymorphisms related to P. falciparum artemisinin resistance in Southeast Asia are not prevalent in sub-Saharan Africa, several (other) K13 coding polymorphisms circulate in African countries.…”

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“…46 The pro-oxidant activity of artemisinin is simply too potent and rapid for wild-type parasites to combat and survive. 47 Clinical studies demonstrated increased ROS production in patients with essential hypertension, renovascular hypertension, malignant hypertension. 48…”

<p>Effects of Surface Characteristics of Polymeric Nanocapsules on the Pharmacokinetics and Efficacy of Antimalarial Quinine</p>

“…1 Malaria treatment should be curative in order to prevent disease progression, relapse (due to the survival of erythrocytic forms in hepatocytes), malarial transmission, and the development of drug resistance. 2,3 Current treatments are hampered by the emergence of parasites with resistance to antimalarial drugs, such as chloroquine, [4][5][6] leading to the utilization of concomitant drugs to increase antimalarial efficacy, such as quinine (QN) plus doxycycline or tetracycline; however, this requires a 7-day course and is poorly tolerated, due to serious side effects caused as cardiotoxicity and the development of cinchonism syndrome. 6,7 Moreover, the high doses required for i.v.…”