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

Abstract 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.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 29244851
OWN - NLM
STAT- In-Process
LR  - 20171224
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 12
DP  - 2017
TI  - Inhibition of merozoite invasion and transient de-sequestration by sevuparin in
      humans with Plasmodium falciparum malaria.
PG  - e0188754
LID - 10.1371/journal.pone.0188754 [doi]
AB  - 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.
FAU - Leitgeb, Anna M
AU  - Leitgeb AM
AUID- ORCID: http://orcid.org/0000-0002-8091-6961
AD  - Modus Therapeutics AB, Stockholm, Sweden.
FAU - Charunwatthana, Prakaykaew
AU  - Charunwatthana P
AD  - Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
FAU - Rueangveerayut, Ronnatrai
AU  - Rueangveerayut R
AD  - Mae Sot Hospital, Mae Sot, Thailand.
FAU - Uthaisin, Chirapong
AU  - Uthaisin C
AD  - Mae Ramat Hospital, Mae Ramat, Thailand.
FAU - Silamut, Kamolrat
AU  - Silamut K
AD  - Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
FAU - Chotivanich, Kesinee
AU  - Chotivanich K
AD  - Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
FAU - Sila, Patima
AU  - Sila P
AD  - Mae Ramat Hospital, Mae Ramat, Thailand.
FAU - Moll, Kirsten
AU  - Moll K
AD  - Department of Microbiology, Tumor- and Cell Biology, Karolinska Institutet,
      Stockholm, Sweden.
FAU - Lee, Sue J
AU  - Lee SJ
AD  - Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
AD  - Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Lindgren, Maria
AU  - Lindgren M
AD  - Modus Therapeutics AB, Stockholm, Sweden.
FAU - Holmer, Erik
AU  - Holmer E
AD  - Modus Therapeutics AB, Stockholm, Sweden.
FAU - Farnert, Anna
AU  - Farnert A
AD  - Department of Infectious Diseases, Karolinska University Hospital and Department 
      Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
FAU - Kiwuwa, Mpungu S
AU  - Kiwuwa MS
AD  - 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.
FAU - Kristensen, Jens
AU  - Kristensen J
AD  - Modus Therapeutics AB, Stockholm, Sweden.
FAU - Herder, Christina
AU  - Herder C
AD  - Modus Therapeutics AB, Stockholm, Sweden.
FAU - Tarning, Joel
AU  - Tarning J
AD  - Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
FAU - Wahlgren, Mats
AU  - Wahlgren M
AD  - Department of Microbiology, Tumor- and Cell Biology, Karolinska Institutet,
      Stockholm, Sweden.
FAU - Dondorp, Arjen M
AU  - Dondorp AM
AD  - Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
AD  - Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20171215
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
PMC - PMC5731734
EDAT- 2017/12/16 06:00
MHDA- 2017/12/16 06:00
CRDT- 2017/12/16 06:00
PHST- 2017/04/07 00:00 [received]
PHST- 2017/11/03 00:00 [accepted]
PHST- 2017/12/16 06:00 [entrez]
PHST- 2017/12/16 06:00 [pubmed]
PHST- 2017/12/16 06:00 [medline]
AID - 10.1371/journal.pone.0188754 [doi]
AID - PONE-D-17-13474 [pii]
PST - epublish
SO  - PLoS One. 2017 Dec 15;12(12):e0188754. doi: 10.1371/journal.pone.0188754.
      eCollection 2017.