Limits...
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.

Show MeSH

Related in: MedlinePlus

In vitro stage specific effects of dihydroartemisinin and emetine against P. falciparum.  Trophozoite stage parasites were treated with IC50 DHA and IC50 emetine either alone or in combination for a 24, 48 and 72 hour time course. The percentage of multinuclear cells as a proportion of the total parasitaemia was recorded for each condition at each time point. The total parasitaemia is indicated by the numbers above bars.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: In vitro stage specific effects of dihydroartemisinin and emetine against P. falciparum. Trophozoite stage parasites were treated with IC50 DHA and IC50 emetine either alone or in combination for a 24, 48 and 72 hour time course. The percentage of multinuclear cells as a proportion of the total parasitaemia was recorded for each condition at each time point. The total parasitaemia is indicated by the numbers above bars.

Mentions: The results of the stage-specific analysis of DHA and emetine revealed variations in parasite progression pattern during the course of drug treatment. For DHA treated samples, progress into the multinucleated schizont form imitate that of the untreated control samples. However, emetine treated samples show a reversal of the pattern, representing a delay in parasite development. The combined effect of the drugs appears to display a true amalgamation of the two (Figure 7). It is also noteworthy that the overall parasitaemia of the combination is consistently lower throughout the course of drug than either of the individual component drugs.


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)

In vitro stage specific effects of dihydroartemisinin and emetine against P. falciparum.  Trophozoite stage parasites were treated with IC50 DHA and IC50 emetine either alone or in combination for a 24, 48 and 72 hour time course. The percentage of multinuclear cells as a proportion of the total parasitaemia was recorded for each condition at each time point. The total parasitaemia is indicated by the numbers above bars.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: In vitro stage specific effects of dihydroartemisinin and emetine against P. falciparum. Trophozoite stage parasites were treated with IC50 DHA and IC50 emetine either alone or in combination for a 24, 48 and 72 hour time course. The percentage of multinuclear cells as a proportion of the total parasitaemia was recorded for each condition at each time point. The total parasitaemia is indicated by the numbers above bars.
Mentions: The results of the stage-specific analysis of DHA and emetine revealed variations in parasite progression pattern during the course of drug treatment. For DHA treated samples, progress into the multinucleated schizont form imitate that of the untreated control samples. However, emetine treated samples show a reversal of the pattern, representing a delay in parasite development. The combined effect of the drugs appears to display a true amalgamation of the two (Figure 7). It is also noteworthy that the overall parasitaemia of the combination is consistently lower throughout the course of drug than either of the individual component drugs.

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