Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations

Autor: Holly Matthews, Maryam Idris-Usman, May Rajab, Niroshini Nirmalan, Jon Deakin
Rok vydání: 2016
Předmět:
0301 basic medicine
Plasmodium
lcsh:Medicine
Pharmacology
Medicine and Health Sciences
Drug Interactions
Artemisinin
Malaria
Falciparum
lcsh:Science
media_common
Protozoans
Multidisciplinary
Drug discovery
Pharmaceutics
Malarial Parasites
Drugs
Chloroquine
Drug Synergism
Artemisinins
Drug Combinations
Proguanil
Drug Therapy
Combination
Atovaquone
medicine.drug
Research Article
Drug
Combination therapy
media_common.quotation_subject
Emetine
030106 microbiology
Emetine Hydrochloride
Plasmodium falciparum
Drug-Drug Interactions
03 medical and health sciences
Antimalarials
Drug Therapy
Parasite Groups
medicine
Parasitic Diseases
Potency
Humans
business.industry
lcsh:R
Organisms
Computational Biology
Biology and Life Sciences
Tropical Diseases
Parasitic Protozoans
Malaria
030104 developmental biology
lcsh:Q
Parasitology
business
Apicomplexa
Zdroj: PLoS ONE
PLoS ONE, Vol 12, Iss 3, p e0173303 (2017)
ISSN: 1932-6203
Popis: The widespread introduction of artemisinin-based combination therapy has contributed to\ud recent reductions in malaria mortality. Combination therapies have a range of advantages,\ud including synergism, toxicity reduction, and delaying the onset of resistance acquisition.\ud Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of\ud effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we\ud have previously employed drug-repositioning to identify the anti-amoebic drug, emetine\ud dihydrochloride hydrate, as a potential candidate for repositioned use against malaria.\ud Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with\ud its anti-amoebic potency (ED50 26±32 uM), practical use of the compound has been limited\ud by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner\ud drug would present an opportunity for dose-reduction, thus increasing the therapeutic window.\ud The lack of reliable and standardised methodology to enable the in vitro definition of\ud synergistic potential for antimalarials is a major drawback. Here we use isobologram and\ud combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define\ud drug interactivity in an objective, automated manner. The method, based on the median\ud effect principle proposed by Chou and Talalay, was initially validated for antimalarial application\ud using the known synergistic combination (atovaquone-proguanil). The combination was\ud used to further understand the relationship between SYBR Green viability and cytocidal versus\ud cytostatic effects of drugs at higher levels of inhibition. We report here the use of the\ud optimised Chou Talalay method to define synergistic antimalarial drug interactivity between\ud emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential\ud route to harness the nanomolar antimalarial efficacy of this affordable natural product.
Databáze: OpenAIRE
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