Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria.

Autor: Leitgeb AM; Modus Therapeutics AB, Stockholm, Sweden., Charunwatthana P; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand., Rueangveerayut R; Mae Sot Hospital, Mae Sot, Thailand., Uthaisin C; Mae Ramat Hospital, Mae Ramat, Thailand., Silamut K; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand., Chotivanich K; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand., Sila P; Mae Ramat Hospital, Mae Ramat, Thailand., Moll K; Department of Microbiology, Tumor- and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Lee SJ; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Lindgren M; Modus Therapeutics AB, Stockholm, Sweden., Holmer E; Modus Therapeutics AB, Stockholm, Sweden., Färnert A; Department of Infectious Diseases, Karolinska University Hospital and Department Medicine Solna, Karolinska Institutet, Stockholm, Sweden., Kiwuwa MS; Department of Pediatrics, School of Medicine, Makerere University College of Health Sciences, and Department of Biochemistry, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda., Kristensen J; Modus Therapeutics AB, Stockholm, Sweden., Herder C; Modus Therapeutics AB, Stockholm, Sweden., Tarning J; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand., Wahlgren M; Department of Microbiology, Tumor- and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Dondorp AM; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2017 Dec 15; Vol. 12 (12), pp. e0188754. Date of Electronic Publication: 2017 Dec 15 (Print Publication: 2017).
DOI: 10.1371/journal.pone.0188754
Abstrakt: 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.
Trial Registration: ClinicalTrials.gov NCT01442168.
Databáze: MEDLINE
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