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

• Published in: PloS one Vol. 12; no. 12; p. e0188754
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15-12-2017; Public Library of Science (PLoS)
• Subjects: Active control; Administration, Oral; Adolescent; Adult; Aged; Anticoagulants; Antimalarials; Antimalarials - blood; Antimalarials - pharmacokinetics; Antimalarials - pharmacology; Area Under Curve; Atovaquone; Atovaquone - blood; Atovaquone - pharmacokinetics; Atovaquone - pharmacology; Binding sites; Binding, Competitive; Biology and Life Sciences; Care and treatment; Dosage and administration; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Erythrocytes; Erythrocytes - drug effects; Erythrocytes - parasitology; Female; Health aspects; Health sciences; Heparan sulfate; Heparin; Heparin - analogs & derivatives; Heparin - blood; Heparin - pharmacokinetics; Heparin - pharmacology; Heparitin Sulfate - chemistry; Heparitin Sulfate - metabolism; Hospitals; Humans; Infections; Infusions, Intravenous; Intravenous administration; Malaria; Malaria, Falciparum - blood; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Male; Medicin och hälsovetenskap; Medicine; Medicine and Health Sciences; Merozoites; Merozoites - drug effects; Merozoites - physiology; Middle Aged; Molecular weight; Parasite Load; Parasitemia - blood; Parasitemia - drug therapy; Parasitemia - parasitology; Parasites; Patients; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - physiology; Proguanil; Proguanil - blood; Proguanil - pharmacokinetics; Proguanil - pharmacology; Red blood cells; Severity of Illness Index; Studies; Sulfates; Vector-borne diseases; Thailand; Bangkok Thailand
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0188754

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.
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.
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.
ClinicalTrials.gov NCT01442168.