Enantiospecific antitrypanosomal in vitro activity of eflornithine.

Mikael Boberg,Rasmus Jansson-Löfmark,Monica Cal,Michael Ashton,Pascal Mäser,Marcel Kaiser

doi:10.1371/journal.pntd.0009583

Abstract

The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. The study compared the in vitro antitrypanosomal activity of the two enantiomers with the racemic mixture against three Trypanosoma brucei gambiense strains. Antitrypanosomal in vitro activity at varying drug concentrations was analysed by non-linear mixed effects modelling. For all three strains, L-eflornithine was more potent than D-eflornithine. Estimated 50% inhibitory concentrations of the three strains combined were 9.1 μM (95% confidence interval [8.1; 10]), 5.5 μM [4.5; 6.6], and 50 μM [42; 57] for racemic eflornithine, L-eflornithine and D-eflornithine, respectively. The higher in vitro potency of L-eflornithine warrants further studies to assess its potential for improving the treatment of late-stage Gambian human African trypanosomiasis.

Highlights

The neglected tropical disease human African trypanosomiasis (HAT), known as sleeping sickness, is fatal unless treated
One of the treatments for the late stage–i.e. when parasites have invaded the central nervous system–of Gambian human African trypanosomiasis is the drug eflornithine, which is dosed as 50:50 racemic mixture of the two enantiomers L-eflornithine and D-eflornithine
This study showed that L-eflornithine was better than D-eflornithine at inhibiting the growth of parasites in vitro

Summary

Introduction

The neglected tropical disease human African trypanosomiasis (HAT), known as sleeping sickness, is fatal unless treated. Eflornithine, included in the World Health Organization (WHO) model list of essential medicines [3], is dosed intravenously, commonly together with oral nifurtimox, to treat the late stage of Gambian HAT [4,5,6,7], which account for 98% of the total HAT cases [8]. Clinical trials with oral racemic eflornithine have failed to achieve sufficiently high systemic exposure, most likely due to poor bioavailability at maximum tolerated oral dose [9,10]. This study aimed to investigate the antitrypanosomal in vitro activities of racemic eflornithine, L-eflornithine and D-eflornithine against three Trypanosoma brucei (T.b.) gambiense strains to support whether a future late-stage Gambian HAT treatment with a potentially more active enantiomer would be feasible or not

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