Human
African trypanosomiasis (HAT), or sleeping sickness, results from
infection with the protozoan parasites Trypanosoma brucei (T. b.) gambiense or T. b. rhodesiense 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 T. b. rhodesiense
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-β-
cyclodextrin and
melarsoprol randomly-methylated-β-
cyclodextrin. We found that these compounds retain trypanocidal properties in vitro 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.