Malaria Combination Therapies: Advantages and Shortcomings

Abstract

Drug combination therapies have been devised to delay the development and spread of resistant malaria parasites. However, poor design often leads to ineffective combinations. Here, the properties of various drug combinations are reviewed in relationship to drug resistance and their pharmacokinetic compatibility.

The Impact of Pharmacokinetic Mismatched Antimalarial Drug Combinations on the Emergence and Spread of Drug Resistant Parasites

“…All currently used combinations of artemisinins have mismatched drug elimination rates, and the pharmacokinetic half-life differences between the short-lived artemisinins and the longlived quinolines such as piperaquine and mefloquine is a cause for concern regarding the longterm development and spread of drug resistance [8]. The elimination half-life of artemisinins ranges from 0.4-2.6 hours, but the elimination half-life of quinolines range from 4 days-2 months.…”

“…Accordingly, there is an extended period when SP and MQ are "unprotected" given the short half-life of AS (Table 1) [32][33][34]. This sort of mismatched PK profile occurs with other combinations such as AL, AS-AQ, DP, and the combination of atovaquone-proguanil used in Asia and Africa [8,35]. Artemisinin derivatives are protected from the rapid development of resistance as these drugs circulates in the presence of a much more long-lived partner, but the long-lived partner is not protected by the artemisinins [36].…”

“…By administering drugs with short half-lives, the exposure of drug to parasites is limited and the pressure to select for drug tolerance and resistance is minimized. However, as recently discussed, administration of PK mismatched antimalarial drug combinations does not significantly impact the spread of resistance, and administration of PK mismatched ACTs have a known risk of jeopardizing the efficacy of partner drugs where resistance has not yet been widely observed [7,8]. Although PK matching has been required by the FDA for new anti-infective drug combinations, simply matching halflives has not been considered sufficient [9].…”

Novel Endoperoxide-Based Transmission-Blocking Antimalarials with Liver- and Blood-Schizontocidal Activities

“…For this reason, the WHO recommends that P. falciparum malaria should be treated with artemisinin (ART, 1)-based combination therapies (ACT), in which the ART-based component is combined with a second, longer-acting agent. 1, 3 Artemisinin and its derivatives are potent blood schizontocides, acting rapidly against parasitic forms that invade erythrocytes and cause disease symptoms. 4 The ultimate goal of eradicating malaria will benefit greatly from a drug that eliminates all life cycle stages of parasites.…”

“…27−29 Reductive amination of 7 with PQ and NaBH-(AcO) 3 gave compound 5 in moderate yield. Hybrid 12 was synthesized by reductive amination of tetraoxane 11 with PQ and NaBH(AcO) 3 . 30 The 1,2,4-trioxane-based hybrid 16, the amine counterpart of the previously reported amide 17, was prepared as outlined in Scheme 2.…”