The ideal partner drugs for malaria treatment should have matching pharmacokinetics, synergise against drug-resistant strains, be free of significant side-effects, be relatively inexpensive and have no other antimicrobial activity. This strategy delays resistance acquisition and thereby prolongs the shelf-life of the valuable cohort of current drugs. Due to the limited number of chemotherapies available, not least because the development of two novel compounds is doubly challenging, candidates are usually combined with existing treatments. The prioritisation of combinatorial regimes over monotherapy in malaria has meant that the analysis of drug interactions has become an increasingly important part of the drug development pipeline. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil).
#Calcusyn for windows software
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.