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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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Representative dose response curves for dihydroartemisinin (a) and emetine (b). Parasites were treated at trophozoite stage and analysed at 48 hours using the SYBR Green flow cytometer method. IC50 values calculated from at least three independent experiments are also displayed.
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Figure 5: Representative dose response curves for dihydroartemisinin (a) and emetine (b). Parasites were treated at trophozoite stage and analysed at 48 hours using the SYBR Green flow cytometer method. IC50 values calculated from at least three independent experiments are also displayed.

Mentions: Emetine dihydrochloride hydrate was reported to have an IC50 value of 1 nM on the drug sensitive 3D7 P. falciparum parasite strains. Preliminary screening panels from our experiments showed effective parasite suppression for the drug, both alone and in combination with DHA. Dose response curves were determined for both drugs using K1 resistant isolates and IC50 values of 47 ± 2.1 nM and 2.6 ± 0.41 nM established for emetine dihydrochloride hydrate and DHA, respectively (Figure 5).


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)

Representative dose response curves for dihydroartemisinin (a) and emetine (b). Parasites were treated at trophozoite stage and analysed at 48 hours using the SYBR Green flow cytometer method. IC50 values calculated from at least three independent experiments are also displayed.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Representative dose response curves for dihydroartemisinin (a) and emetine (b). Parasites were treated at trophozoite stage and analysed at 48 hours using the SYBR Green flow cytometer method. IC50 values calculated from at least three independent experiments are also displayed.
Mentions: Emetine dihydrochloride hydrate was reported to have an IC50 value of 1 nM on the drug sensitive 3D7 P. falciparum parasite strains. Preliminary screening panels from our experiments showed effective parasite suppression for the drug, both alone and in combination with DHA. Dose response curves were determined for both drugs using K1 resistant isolates and IC50 values of 47 ± 2.1 nM and 2.6 ± 0.41 nM established for emetine dihydrochloride hydrate and DHA, respectively (Figure 5).

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