HKline.Lotharius et al. Malaria Journal 2014, 13:143 http://www.malariajournal.com/content
HKline.Lotharius et al. Malaria Journal 2014, 13:143 http://www.malariajournal.com/content/13/1/Page 11 ofA) Day 5, 48 h after the first doseVehicle UK-112,214 (100 mg/kg) UK-112,214 (300 mg/kg)TER 119 PETER 119 PETER 119 PESYTO-SYTO-TE0370_G7N3D5_SYTO.TE0370_G8N1D5_SYTO.TE0370_G9N3D5_SYTO.SYTO-B) PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26577270 Day 7, 96 h after the first doseVehicle UK-112,214 (100 mg/kg) UK-112,214 (300 mg/kg)TER 119 PETER 119 PETER 119 PESYTO-SYTO-100TE0370_G7N3D7_SYTO.TE0370_G8N1D7_SYTO.TE0370_G9N3D7_SYTO.SYTO-Figure 5 The effect of UK-112,214 treatment on Plasmodium falciparum Pf3D70087/N9 in vivo at (A) Day 5 and (B) Day 7. Photomicrographs of FPS-ZM1 clinical trials peripheral blood smears stained with Giemsa. Lower panels show flow cytometry dot plots from samples of peripheral blood stained with TER-119Phycoerythrine (marker of murine erythrocytes) and SYTO-16 (nucleic acid dye). Dots inside the polygonal region represent P. falciparum-infected human erythrocytes. Study performed by GlaxoSmithKline.and CE-245677). These compounds were of particular interest as they are essential throughout all stages of the Plasmodium spp. lifecycle [40,41]. Many protein kinaseinhibitors have been registered or investigated, primarily for the treatment of cancer, although these drugs have known toxicities that have discouraged their use inLotharius et al. Malaria Journal 2014, 13:143 http://www.malariajournal.com/content/13/1/Page 12 ofABFigure 6 Therapeutic efficacy of A) lestaurtinib (CEP-701) and B) CEP-1347 against Plasmodium falciparum Pf3D70087/N9. Parasitaemia in peripheral blood of mice obtained from day 3 to day 7 after infection, data for vehicle-treated animals are denoted by triangles. Data are presented as mean of three mice ?SE for log10 [ parasitaemia] except in plot A, where groups labelled with symbols had two mice (*) or one mouse () at the end of the experiment. Study performed by GlaxoSmithKline.malaria. Antiretroviral protease inhibitors were also of interest and tested in this study, though they had relatively poor in vitro activity. Previous data showed moderate in vitro activity of saquinavir, nevirapine, ritonavir, nelfinavir, amprenavir, and indinavir at clinically relevant concentrations [46]. However, a recent clinical study in HIV-infected women from malaria-endemic regions of sub-Saharan Africa showed no effect of antiretroviral treatment on the incidence of malaria [47]. Among the licensed products that were active in vitro, none of the compounds were progressed to the in PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/27486068 vivo model, mainly because of their unfavourable pharmacokinetic and/or safety profile for use as an oral anti-malarial. However, the scope of this study did not include speculation about the clinical safety and pharmacokinetics that might be discovered should clinical studies in malaria be conducted. In fact, a number of these compounds have been investigated further in malaria. Methotrexate has good activity against P. falciparum and Plasmodium vivaxin vitro, although poor activity in vivo against murine malaria species [48-50]. The assumed toxicity of methotrexate and other anticancer drugs when used in short-course, low-dose therapy has been questioned [51]. However, a recent clinical study of methotrexate in healthy volunteers failed to achieve sufficient drug exposures for effective malaria therapy [52]. Methylene blue has also been investigated clinically for malaria, although it is slow acting and there are potential haemolytic effects of this compound in glucose-6-phosphate dehydrogenase-de.