A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria.

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.

Effects of the antimalarial lumefantrine on Lemna minor, Raphidocelis subcapitata and Chlorella vulgaris.

Lumefantrine is used to treat uncomplicated malaria caused by pure or mixed Plasmodium falciparum infections and as a prophylactic against recrudescence following artemether therapy. However, the pharmaceutical is released into the aquatic environment from industrial effluents, hospital discharges, and human excretion. This study assessed the effects of lumefantrine on the growth and physiological responses of the microalgae Chlorella vulgaris and Raphidocelis subcapitata (formerly known as Selenastrum capricornutum and Pseudokirchneriella subcapitata) and the aquatic macrophyte Lemna minor. The microalgae and macrophyte were exposed to 200-10000 µg l-1 and 16-10000 µg l-1 lumefantrine, respectively. Lumefantrine had a variable effect on the growth of the aquatic plants investigated. There was a decline in the growth of R. subcapitata and L. minor post-exposure to the drug. Contrarily, there was stimulation in the growth of Chlorella vulgaris. All experimental plants had a significant increase in lipid peroxidation, which was accompanied by an increase in malondialdehyde content. Peroxidase activity of L. minor increased only at low lumefantrine concentrations, while the opposite occurred at higher levels of the drug. Incubation in lumefantrine contaminated medium significantly up-regulated the activity of R. subcapitata cultures. Glutathione S-transferase of L. minor exposed to lumefantrine treatments had substantially higher activities than the controls. Our findings suggest lumefantrine could have adverse but variable effects on the growth and physiology of the studied aquatic plants.