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The restriction of its medicinal use was due to side effects of nausea and vomiting following oral administration and dose-dependent cardiotoxicity at the higher doses required for use as a tissue amoebicide. The natural product anti-protozoal drug (derived from the root of Carapichea ipecacuanha), was widely used in the treatment of hepatic and intestinal amoebiasis until it was replaced in the 1980s by the safer drug, metronidazole. falciparum isolates showed ED 50 values of 47 nM (44.9–49.2) for emetine dihydrochloride. SYBR Green fluorescence flow-cytometric analysis of K1 P. We recently reported the findings of a repositioning screen on selected leads from FDA-approved compound libraries, which identified the anti-amoebic drug emetine dihydrochloride to have potent antimalarial efficacy. However, the lack of a standardised definition for synergy has resulted in confusion and conflict in the field, leading to many unsubstantiated claims of synergistic potential. Thus, it follows that the methods used to analyse drug interactions have been evaluated extensively and owe their origins to these disciplines. The values of combination therapy, namely: (i) better therapeutic efficacy, (ii) the potential to impede or delay the onset of resistance, (iii) dose reduction, whilst maintaining potency, and avoiding adverse effects, and (iv) the potential for selective synergism or toxic antagonism, were realised much sooner for diseases like cancer, AIDS and tuberculosis.
#CALCUSYN V2 FREE#
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 V2 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.