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Title: Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria
Authors: Anna M. Leitgeb
Prakaykaew Charunwatthana
Ronnatrai Rueangveerayut
Chirapong Uthaisin
Kamolrat Silamut
Kesinee Chotivanich
Patima Sila
Kirsten Moll
Sue J. Lee
Maria Lindgren
Erik Holmer
Anna Färnert
Mpungu S. Kiwuwa
Jens Kristensen
Christina Herder
Joel Tarning
Mats Wahlgren
Arjen M. Dondorp
Modus Therapeutics AB
Mahidol University
Mae Sot General Hospital
Mae Ramat Hospital
Karolinska University Hospital
Nuffield Department of Clinical Medicine
Makerere University
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Dec-2017
Citation: PLoS ONE. Vol.12, No.12 (2017)
Abstract: © 2017 Leitgeb et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Severe malaria Even with the best available treatment, the mortality from severe Plasmodium falciparum malaria remains high. Typical features at death are high parasite loads and obstructed micro- vasculature. Infected erythrocytes (IE) containing mature parasites bind to the host receptor heparan sulfate, which is also an important receptor for merozoite invasion. To block merozoite invasion has not previously been proposed as an adjunctive therapeutic approach but it may preclude the early expansion of an infection that else leads to exacerbated sequestration and death. Sevuparin in phase I study The drug sevuparin was developed from heparin because heparan sulfate and heparin are nearly identical, so the rationale was that sevuparin would act as a decoy receptor during malaria infection. A phase I study was performed in healthy male volunteers and sevuparin was found safe and well tolerated. Sevuparin in phase I/II clinical study A phase I/II clinical study was performed in which sevuparin was administered via short intravenous infusions to malaria patients with uncomplicated malaria who were also receiving atovaquone/proguanil treatment. This was a Phase I/II, randomized, open label, active control, parallel assignment study. Sevuparin was safe and well tolerated in the malaria patients. The mean relative numbers of ring-stage IEs decreased after a single sevuparin infusion and mature parasite IEs appeared transiently in the circulation. The effects observed on numbers of merozoites and throphozoites in the circulation, were detected already one hour after the first sevuparin injection. Here we report the development of a candidate drug named sevuparin that both blocks merozoite invasion and transiently de-sequesters IE in humans with P. falciparum malaria.
ISSN: 19326203
Appears in Collections:Scopus 2016-2017

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