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

J. Rodgers, A. Jones, S. Gibaud, B. Bradley, C. McCabe, M. P. Barrett, G. Gettinby, P. G. E. Kennedy

Research output: Contribution to journalArticle

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Abstract

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.
Original languageEnglish
Article numbere1308
Number of pages10
JournalPLOS Neglected Tropical Diseases
Volume5
Issue number9
DOIs
Publication statusPublished - 6 Sep 2011

Fingerprint

Melarsoprol
African Trypanosomiasis
Cyclodextrins
Central Nervous System
Trypanosoma brucei rhodesiense
Therapeutics
Parasites
Infection
Trypanosoma brucei gambiense
Protozoan Infections
Parasite Load
Arsenicals
Drug Therapy
Propylene Glycol
Trypanosoma brucei brucei
Africa South of the Sahara
Brain Diseases
Blood-Brain Barrier
Pharmaceutical Preparations
Solubility

Keywords

  • bioavailability
  • risk-factors
  • pharmaceutical applications
  • sleeping sickness
  • brain
  • chemotherapy
  • brucei-gambiense
  • issues
  • central-nervous-system
  • beta-cyclodextrin

Cite this

Rodgers, J. ; Jones, A. ; Gibaud, S. ; Bradley, B. ; McCabe, C. ; Barrett, M. P. ; Gettinby, G. ; Kennedy, P. G. E. / Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human african trypanosomiasis. In: PLOS Neglected Tropical Diseases. 2011 ; Vol. 5, No. 9.
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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.; Kennedy, P. G. E.

In: PLOS Neglected Tropical Diseases, Vol. 5, No. 9, e1308, 06.09.2011.

Research output: Contribution to journalArticle

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T1 - Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human african trypanosomiasis

AU - Rodgers, J.

AU - Jones, A.

AU - Gibaud, S.

AU - Bradley, B.

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AU - Barrett, M. P.

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AU - Kennedy, P. G. E.

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