A review of the effects of artemether-lumefantrine on gametocyte carriage and disease transmission

Abstract

While significant advances have been made in the prevention and treatment of malaria in recent years, these successes continue to fall short of the World Health Organization (WHO) goals for malaria control and elimination. For elimination strategies to be effective, limited disease transmission, achieved through rapid reduction in the infectious parasite reservoir and decreased gametocyte carriage, will be critical. Artemisinin-based combination therapy (ACT) forms the cornerstone of WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria, and in combination with other effective interventions will undoubtedly play a vital role in elimination programmes. The gametocytocidal properties of artemisinins are a bonus attribute; there is epidemiological evidence of reductions in malaria incidence and transmission in African regions since the introduction of these agents. Many studies and analyses have specifically investigated the effects of the ACT, artemether-lumefantrine (AL) on gametocyte carriage. In this systematic review of 62 articles published between 1998 and January 2014, the effects of AL on gametocyte carriage and malaria transmission are compared with other artemisinin-based anti-malarials and non-ACT. The impact of AL treatment of asymptomatic carriers on population gametocyte carriage, and the potential future role of AL in malaria elimination initiatives are also considered. Despite the inherent difficulties in comparing data from a range of different studies that also utilized different diagnostic approaches to assess baseline gametocyte counts, the gametocytocidal effect of AL was proportionately consistent across the studies reviewed, suggesting that AL will continue to play a vital role in the treatment of malaria and contribute to clearing the path towards malaria elimination. However, the specific place of AL is the subject of much ongoing research and will undoubtedly be dependent on different demographic and geographical scenarios. Utilizing ACT, such as AL, within malaria elimination strategies is also associated with a number of other challenges, such as balancing potential increased use of ACT (e g, treatment of asymptomatic carriers and home-based treatment) with rational use and avoidance of drug resistance development.

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

“…Alternatively, the effects of artemisinin on stage III and IV sequestered gametocytes about to be released into the circulation at study entry may have been relatively weak. Consistent with this hypothesis, other clinical studies have shown that artemether has greater gametocytocidal effects than other artemisinin drugs (14). In addition, there was evidence that artemisinin-naphthoquine-treated children became gametocytemic more rapidly in the gametocyte density model (with a shorter 1/f), while the average time that an individual carried gametocytes was longer in the artemisinin-naphthoquine group than in the artemether-lumefantrine group.…”

“…In vitro experiments suggest that artemether is less potent than other endoperoxide compounds, including artemisinin itself, in exflagellation assays (11,12). However, in comparative clinical studies, artemether-based artemisinin combination therapies (ACTs) are at least as effective at reducing posttreatment gametocytemia as artesunate-or dihydroartemisinin (DHA)-based ACTs (13,14). With the development of these semisynthetic derivatives that have more advantageous pharmacological profiles, artemisinin itself has not been incorporated as part of commonly used ACTs, but the first in vivo studies showing gametocytocidal activity involved artemisinin (15).…”

Systematic development of optimized SNEDDS of artemether with improved biopharmaceutical and antimalarial potential

“…Similar responses were observed in several other reports (Lin et al, 1997;Mohd Ridzuan et al, 2006;Aditya et al, 2012). The implications on the current treatment therapy may require adjuvant drug therapy to overcome the parasitemia load in the erythrocytic phase of the malaria parasite (Makanga et al, 2011;Aditya et al, 2012;Makanga, 2014).…”

“…Pharmacologically, it is a gametocidal agent found to be highly effective against malaria caused by multidrug-resistant Plasmodium falciparum (Tran et al, 1996;Van Hensbroek et al, 1996;Makanga, 2014). Being a BCS class II drug, it exhibits poor solubility and high lipophilicity (log p of 3.8), and undergoes extensive hepatic first-pass effect and metabolism by CYP3A4 isozymes, leading eventually to its low oral bioavailability (i.e.,545%) (Van Hensbroek et al, 1996;Grace et al, 1999).…”

New developments in anti-malarial target candidate and product profiles

“…However, a male stage V gametocyte marker is similarly required to properly interpret the potential of a compound, particularly since, from in vitro data, the majority of mechanisms appear to predominantly impact only male gametocytes [151]. Understanding the duration of exposure that is required will also be a critical factor here; artemether incapacitates gametocytes in culture [152], and an analysis of 62 studies concluded that artemether–lumefantrine has consistent gametocytocidal effects [153–155]. …”