Extending the spectrum of antimalarial treatment: Artemisinin combinations for the treatment of rare Plasmodium species infections and the development of dyes as antimalarials

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URI: http://hdl.handle.net/10900/74719
Dokumentart: PhDThesis
Date: 2017
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Kremsner, Peter G. (Prof. Dr.)
Day of Oral Examination: 2016-11-11
DDC Classifikation: 570 - Life sciences; biology
610 - Medicine and health
Keywords: Malaria , Arzneimittel , Farbe
License: http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en
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Malaria, an infectious disease caused by a parasite of the genus Plasmodium, was responsible for about 198 Million cases and 584 000 deaths in 2013, mainly in Sub-Saharan Africa. The first line treatment for uncomplicated Plasmodium falciparum infections are artemisinin combination therapies (ACTs). Although the efficacy of ACTs against P. falciparum has been well documented, there is only anecdotal evidence of efficacy of ACTs against other human Plasmodium species because chloroquine is still recommended and commonly used. However, in highly endemic regions non-falciparum species can occur together with P. falciparum and, moreover, exact microscopic species identification and detection of residual parasites is usually not possible in those settings. Availability of broadly acting drugs would ease clinical management of suspected non-falciparum and mixed infections. This thesis presents data on the efficacy of artemether-lumefantrine (AL), a widely used ACT, against uncomplicated non-falciparum or mixed-species malaria in Lambaréné, Gabon and assesses the performance of microscopy in an African routine laboratory setting. Forty patients presenting with uncomplicated malaria caused by P. malariae, P. ovale or a mixed infection (including P. falciparum) were treated with a three days AL regimen and were followed up to 28 days after start of the treatment. All evaluable patients presented an adequate clinical and parasitological response. All adverse events were mild or moderate and resolved by the end of the follow-up. The parasitological cure rate was 100% and the drug was well tolerated. These findings support the use of AL for the treatment of uncomplicated malaria in Gabon, even when non-falciparum or mixed infections are suspected. Microscopic identification of Plasmodium species other than P. falciparum did not perform well. From 39 samples microscopically determined as non-falciparum or mixed infection, only 19 were confirmed by PCR. This might be due to the very low parasitaemia found in most cases and underlines the need for the development of broadly acting antimalarials. The second part of this thesis reports on the in vitro activity of fluorescent dyes against cultured malaria parasites. The emergence of resistance against most of the drugs in current use urges the development of new antimalarial compounds. Since x several antimicrobials were derived from molecular modification of synthetic dyes, which often have a broad spectrum of activity, screening of dyes may represent an interesting strategy to identify novel antimalarial lead structures. The original motivation to screen fluorescent dyes in Plasmodium were in vivo labeling experiments. Here, a remarkably high antiparasitic activity was noted for some compounds. Hence, the activity of fourteen fluorescent dyes was systematically investigated by in vitro growth assays using the two laboratory P. falciparum strains 3D7 and Dd2. Five had an activity comparable to the control drug chloroquine and were not cytotoxic against human HeLa cells (Rhodamine B, MitoTracker Red, and DiOC6, Hoechst33342, SYTO 9). Rhodamine B and DiOC6 were further tested in a mouse model but DiOC6 was toxic and Rhodamine B, although less toxic, did not lead to a notable reduction of parasitaemia. Despite of this, this pilot experiment shows that pre-screening for staining properties may be an interesting way to build highly efficient pathogen-specific compound libraries. There is a need for broadly acting antimalarial drugs. This requirement includes multi-stage activity as well as activity against different parasite species. AL showed high in vivo activity against different Plasmodium species, but does not act against pre-erythrocytic stages (sporozoites and infected hepatocytes) and reduces gametocytes only modestly. Dyes are a group of chemically heterogeneous compounds that may extent the spectrum of activity. In fact, the dye methylene blue was shown to meet many of the requirements. Investigation of larger dye libraries may result in highly interesting novel antimalarial compounds and may lead to the development of novel, broadly acting drugs.

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