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

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...

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Autores principales: Leitgeb, Anna M., Charunwatthana, Prakaykaew, Rueangveerayut, Ronnatrai, Uthaisin, Chirapong, Silamut, Kamolrat, Chotivanich, Kesinee, Sila, Patima, Moll, Kirsten, Lee, Sue J., Lindgren, Maria, Holmer, Erik, Färnert, Anna, Kiwuwa, Mpungu S., Kristensen, Jens, Herder, Christina, Tarning, Joel, Wahlgren, Mats, Dondorp, Arjen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731734/
https://www.ncbi.nlm.nih.gov/pubmed/29244851
http://dx.doi.org/10.1371/journal.pone.0188754
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author Leitgeb, Anna M.
Charunwatthana, Prakaykaew
Rueangveerayut, Ronnatrai
Uthaisin, Chirapong
Silamut, Kamolrat
Chotivanich, Kesinee
Sila, Patima
Moll, Kirsten
Lee, Sue J.
Lindgren, Maria
Holmer, Erik
Färnert, Anna
Kiwuwa, Mpungu S.
Kristensen, Jens
Herder, Christina
Tarning, Joel
Wahlgren, Mats
Dondorp, Arjen M.
author_facet Leitgeb, Anna M.
Charunwatthana, Prakaykaew
Rueangveerayut, Ronnatrai
Uthaisin, Chirapong
Silamut, Kamolrat
Chotivanich, Kesinee
Sila, Patima
Moll, Kirsten
Lee, Sue J.
Lindgren, Maria
Holmer, Erik
Färnert, Anna
Kiwuwa, Mpungu S.
Kristensen, Jens
Herder, Christina
Tarning, Joel
Wahlgren, Mats
Dondorp, Arjen M.
author_sort Leitgeb, Anna M.
collection PubMed
description 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
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spelling pubmed-57317342017-12-22 Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria Leitgeb, Anna M. Charunwatthana, Prakaykaew Rueangveerayut, Ronnatrai Uthaisin, Chirapong Silamut, Kamolrat Chotivanich, Kesinee Sila, Patima Moll, Kirsten Lee, Sue J. Lindgren, Maria Holmer, Erik Färnert, Anna Kiwuwa, Mpungu S. Kristensen, Jens Herder, Christina Tarning, Joel Wahlgren, Mats Dondorp, Arjen M. PLoS One Research Article 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 Public Library of Science 2017-12-15 /pmc/articles/PMC5731734/ /pubmed/29244851 http://dx.doi.org/10.1371/journal.pone.0188754 Text en © 2017 Leitgeb et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Leitgeb, Anna M.
Charunwatthana, Prakaykaew
Rueangveerayut, Ronnatrai
Uthaisin, Chirapong
Silamut, Kamolrat
Chotivanich, Kesinee
Sila, Patima
Moll, Kirsten
Lee, Sue J.
Lindgren, Maria
Holmer, Erik
Färnert, Anna
Kiwuwa, Mpungu S.
Kristensen, Jens
Herder, Christina
Tarning, Joel
Wahlgren, Mats
Dondorp, Arjen M.
Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria
title Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria
title_full Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria
title_fullStr Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria
title_full_unstemmed Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria
title_short Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria
title_sort inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with plasmodium falciparum malaria
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731734/
https://www.ncbi.nlm.nih.gov/pubmed/29244851
http://dx.doi.org/10.1371/journal.pone.0188754
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