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Drug repositioning as a route to anti-malarial drug discovery: preliminary investigation of the in vitro anti-malarial efficacy of emetine dihydrochloride hydrate.

Matthews H, Usman-Idris M, Khan F, Read M, Nirmalan N - Malar. J. (2013)

Bottom Line: The sum 50% fractional inhibitory concentration (∑FIC₅₀, ₉₀) of the interaction of emetine dihydrochloride hydrate and dihydroartemisinin against the K1 strains of P. falciparum ranged from 0.88-1.48.The results warrant further investigation of emetine dihydrochloride hydrate as a potential stand-alone anti-malarial option.The interaction between the drug and the current front line dihydroartemisinin ranged from additive to mildly antagonistic in the fixed drug ratios tested.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Environment and Life Sciences, University of Salford, M5 4WT, Salford, Manchester, UK. n.j.nirmalan@salford.ac.uk.

ABSTRACT

Background: Drug repurposing or repositioning refers to the usage of existing drugs in diseases other than those it was originally used for. For diseases like malaria, where there is an urgent need for active drug candidates, the strategy offers a route to significantly shorten the traditional drug development pipelines. Preliminary high-throughput screens on patent expired drug libraries have recently been carried out for Plasmodium falciparum. This study reports the systematic and objective further interrogation of selected compounds reported in these studies, to enable their repositioning as novel stand-alone anti-malarials or as combinatorial partners.

Methods: SYBR Green flow cytometry and micro-titre plate assays optimized in the laboratory were used to monitor drug susceptibility of in vitro cultures of P. falciparum K1 parasite strains. Previously described fixed-ratio methods were adopted to investigate drug interactions.

Results: Emetine dihydrochloride hydrate, an anti-protozoal drug previously used for intestinal and tissue amoebiasis was shown to have potent inhibitory properties (IC₅₀ doses of ~ 47 nM) in the multidrug resistant K1 strain of P. falciparum. The sum 50% fractional inhibitory concentration (∑FIC₅₀, ₉₀) of the interaction of emetine dihydrochloride hydrate and dihydroartemisinin against the K1 strains of P. falciparum ranged from 0.88-1.48.

Conclusion: The results warrant further investigation of emetine dihydrochloride hydrate as a potential stand-alone anti-malarial option. The interaction between the drug and the current front line dihydroartemisinin ranged from additive to mildly antagonistic in the fixed drug ratios tested.

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Related in: MedlinePlus

Isobolograms showing the interaction between dihydroartemisinin and emetine. The fixed ratio method was used to analyse the interaction between dihydroartemisinin and emetine dihydrochloride hydrate against trophozoite stage parasites. Treatments were set up in duplicate for 48 hours and analysed using the SYBR Green flow cytometer method. The FIC50(a) and FIC90(b) concentrations were determined and used to plot the isobologram.
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Figure 6: Isobolograms showing the interaction between dihydroartemisinin and emetine. The fixed ratio method was used to analyse the interaction between dihydroartemisinin and emetine dihydrochloride hydrate against trophozoite stage parasites. Treatments were set up in duplicate for 48 hours and analysed using the SYBR Green flow cytometer method. The FIC50(a) and FIC90(b) concentrations were determined and used to plot the isobologram.

Mentions: The FIC values for DHA at each ratio were then plotted against those calculated for emetine and the isobologram trends obtained are shown in Figure 6. The convex shape of the IC50 isobologram (Figure 6a) indicates an antagonistic interaction while the IC90 plot would suggest an additive interaction (Figure 6b).


Drug repositioning as a route to anti-malarial drug discovery: preliminary investigation of the in vitro anti-malarial efficacy of emetine dihydrochloride hydrate.

Matthews H, Usman-Idris M, Khan F, Read M, Nirmalan N - Malar. J. (2013)

Isobolograms showing the interaction between dihydroartemisinin and emetine. The fixed ratio method was used to analyse the interaction between dihydroartemisinin and emetine dihydrochloride hydrate against trophozoite stage parasites. Treatments were set up in duplicate for 48 hours and analysed using the SYBR Green flow cytometer method. The FIC50(a) and FIC90(b) concentrations were determined and used to plot the isobologram.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3852733&req=5

Figure 6: Isobolograms showing the interaction between dihydroartemisinin and emetine. The fixed ratio method was used to analyse the interaction between dihydroartemisinin and emetine dihydrochloride hydrate against trophozoite stage parasites. Treatments were set up in duplicate for 48 hours and analysed using the SYBR Green flow cytometer method. The FIC50(a) and FIC90(b) concentrations were determined and used to plot the isobologram.
Mentions: The FIC values for DHA at each ratio were then plotted against those calculated for emetine and the isobologram trends obtained are shown in Figure 6. The convex shape of the IC50 isobologram (Figure 6a) indicates an antagonistic interaction while the IC90 plot would suggest an additive interaction (Figure 6b).

Bottom Line: The sum 50% fractional inhibitory concentration (∑FIC₅₀, ₉₀) of the interaction of emetine dihydrochloride hydrate and dihydroartemisinin against the K1 strains of P. falciparum ranged from 0.88-1.48.The results warrant further investigation of emetine dihydrochloride hydrate as a potential stand-alone anti-malarial option.The interaction between the drug and the current front line dihydroartemisinin ranged from additive to mildly antagonistic in the fixed drug ratios tested.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Environment and Life Sciences, University of Salford, M5 4WT, Salford, Manchester, UK. n.j.nirmalan@salford.ac.uk.

ABSTRACT

Background: Drug repurposing or repositioning refers to the usage of existing drugs in diseases other than those it was originally used for. For diseases like malaria, where there is an urgent need for active drug candidates, the strategy offers a route to significantly shorten the traditional drug development pipelines. Preliminary high-throughput screens on patent expired drug libraries have recently been carried out for Plasmodium falciparum. This study reports the systematic and objective further interrogation of selected compounds reported in these studies, to enable their repositioning as novel stand-alone anti-malarials or as combinatorial partners.

Methods: SYBR Green flow cytometry and micro-titre plate assays optimized in the laboratory were used to monitor drug susceptibility of in vitro cultures of P. falciparum K1 parasite strains. Previously described fixed-ratio methods were adopted to investigate drug interactions.

Results: Emetine dihydrochloride hydrate, an anti-protozoal drug previously used for intestinal and tissue amoebiasis was shown to have potent inhibitory properties (IC₅₀ doses of ~ 47 nM) in the multidrug resistant K1 strain of P. falciparum. The sum 50% fractional inhibitory concentration (∑FIC₅₀, ₉₀) of the interaction of emetine dihydrochloride hydrate and dihydroartemisinin against the K1 strains of P. falciparum ranged from 0.88-1.48.

Conclusion: The results warrant further investigation of emetine dihydrochloride hydrate as a potential stand-alone anti-malarial option. The interaction between the drug and the current front line dihydroartemisinin ranged from additive to mildly antagonistic in the fixed drug ratios tested.

Show MeSH
Related in: MedlinePlus