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 s...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5731734?pdf=render |
| _version_ | 1819053694655660032 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Anna M Leitgeb |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-21T12:39:48Z |
| format | Article |
| id | doaj.art-a32e41f6da174193bb80624bd9ade0f3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T12:39:48Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a32e41f6da174193bb80624bd9ade0f32022-12-21T19:03:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-011212e018875410.1371/journal.pone.0188754Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria.Anna M LeitgebPrakaykaew CharunwatthanaRonnatrai RueangveerayutChirapong UthaisinKamolrat SilamutKesinee ChotivanichPatima SilaKirsten MollSue J LeeMaria LindgrenErik HolmerAnna FärnertMpungu S KiwuwaJens KristensenChristina HerderJoel TarningMats WahlgrenArjen M DondorpSEVERE 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.http://europepmc.org/articles/PMC5731734?pdf=render |
| spellingShingle | 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 Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC5731734?pdf=render |
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