Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. Despite its 1000-fold increase in in vitro antimalarial potency (ED 50 47 nM) compared with its anti-amoebic potency (ED 50 26–32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality.
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