Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis

Rodgers, J. , Jones, A., Gibaud, S., Bradley, B., McCabe, C. , Barrett, M. P. , Gettinby, G. and Kennedy, P. G.E. (2011) Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis. PLoS Neglected Tropical Diseases, 5(9), e1308. (doi: 10.1371/journal.pntd.0001308)



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Human African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites <i>Trypanosoma brucei</i> (<i>T.b.</i>) <i>gambiense</i> or <i>T.b.rhodesiense</i> and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage <i>T.b.rhodesiense</i> infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-͎-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties <i>in vitro</i> and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Kennedy, Professor Peter and Bradley, Mrs Barbara and McCabe, Dr Chris and Barrett, Professor Michael and Rodgers, Dr Jean
Authors: Rodgers, J., Jones, A., Gibaud, S., Bradley, B., McCabe, C., Barrett, M. P., Gettinby, G., and Kennedy, P. G.E.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:PLoS Neglected Tropical Diseases
Publisher:Public Library of Science
ISSN (Online):1935-2735
Published Online:06 September 2011
Copyright Holders:Copyright © 2011 The Authors
First Published:First published in PLoS Neglected Tropical Diseases 5(9):e1308
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
443321Combination chemotherapy of human African trypanosomiasis - the potential of drug synergism and the blood-brain barrierPeter KennedyMedical Research Council (MRC)G0601059Institute of Infection Immunity and Inflammation