A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria |
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Authors: | William MR Matshe Lesego L Tshweu Sindisiwe Mvango Zamani ED Cele Avashnee S Chetty Lynne A Pilcher Ibukun M Famuyide Lyndy J McGaw Dale Taylor Liezl Gibhard Gregory S Basarab Mohammed O Balogun |
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Institution: | 1. Bio-Polymer Modification and Therapeutics Laboratory, Centre for Nanostructures and Advanced Materials, CSIR, Pretoria, 0001 South Africa;2. Department of Chemistry, University of Pretoria, Lynnwood Road, Hatfield, Pretoria, 0002 South Africa;3. Phytomedicine Programme, Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort, Pretoria, 0110 South Africa;4. Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, 7701 South Africa |
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Abstract: | Uncomplicated malaria is effectively treated with oral artemisinin-based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for uncomplicated due to the nonavailability of a water-soluble partner drug for the artemisinin, artesunate. The currently available treatment is a two-part regimen split into an intravenous artesunate followed by the conventional oral ACT . In a novel application of polymer therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to a carrier polymer to create a new water-soluble chemical entity suitable for intravenous administration in a clinically relevant formulation . The conjugate is characterized by spectroscopic and analytical techniques, and the aqueous solubility of lumefantrine is determined to have increased by three orders of magnitude. Pharmacokinetic studies in mice indicate that there is a significant plasma release of lumefantrine and production its metabolite desbutyl-lumefantrine (area under the curve of metabolite is ≈10% that of the parent). In a Plasmodium falciparum malaria mouse model, parasitemia clearance is 50% higher than that of reference unconjugated lumefantrine. The polymer-lumefantrine shows potential for entering the clinic to meet the need for a one-course combination treatment for severe malaria. |
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Keywords: | artemisinin-based combination therapy drug delivery infectious disease lumefantrine nanomedicine polymer therapeutics severe malaria |
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