The de-sequestering capacity of sevuparin in <i>P</i>. <i>falciparum</i> infected patients.

<p>A total of 44 patients were included in the efficacy part of the trial and were treated with oral atovaquone/proguanil with or without adjunctive treatment in the form of short i.v. infusions of sevuparin. The numbers of trophozoite and schizont IEs were estimated in the peripheral blood samples on thin and thick films that were taken at time points 0, 1, 2, 3, 4, 6, 8, 10, and 11 h and thereafter every 6 h until two consecutive blood samples were parasite negative. The relative numbers were calculated from the number of trophozoite and schizont IEs at one time point related to the baseline number of trophozoite and schizont IEs at time point 0 h (immediately prior to the first dose of sevuparin), and the mean was measured based on all subjects in one group. The red dotted line represents the sevuparin treated patients, and the blue line represents the control patients. Logarithmic y- axis is used. Significantly (p<0.05) higher numbers of trophozoite and schizont IEs were found in the sevuparin treated patients at time point 1 h (p = 0.0322). In a, the relative numbers (mean ± SD) of trophozoite and schizont parasites in the two study groups up to H30 are presented. In b, the detailed relative changes in the number of trophozoite and schizont parasites (mean ± SD) during the first 12 hours after the first injection of sevuparin are shown. In c, individual effects of sevuparin on the number of trophozoites and schizont parasites per patient is shown. The grey arrows indicate the periodic sevuparin infusions.</p

Sevuparin lowers the relative mean number of ring-stage IEs after a single sevuparin infusion in <i>P</i>. <i>falciparum</i> infected patients.

<p>A total of 44 patients were included in the efficacy part of the trial (part 2) and were treated with oral atovaquone/proguanil with or without adjunctive treatment in the form of i.v. infusions of sevuparin. The relative numbers were calculated from the number of ring IEs at one time point related to the baseline value of ring IEs at time point 0 h (immediately prior to the first dose of sevuparin), and the mean was measured based on all subjects in one group. a, The mean relative numbers (mean ± SD) of ring stage parasites in the two study groups from 0 h to 30 h. The numbers of ring-stage IEs were estimated in peripheral blood samples on thin and thick films that were taken at time points 0, 1, 2, 3, 4, 6, 8, 10, and 11 h and thereafter every 6 h until two consecutive blood samples were parasite negative. The red dotted line represents the patients treated with sevuparin (3 mg/kg) and oral atovaquone/proguanil, and the blue line represents the control patients who were given only oral atovaquone/proguanil, a logarithmic y-axis is used. Significantly lower levels of ring stage IEs were found in the sevuparin treated patients at time points 1 h (p = 0.0223), 2 h (p = 0.0246), 3 h (p = 0.0027), 4 h (p = 0.0278), and 6 h (p = 0.0346). (An outlier appears in the data but does not drive the difference as the statistical significant difference between the two groups remains even if data from this patient is excluded from the analysis since the tests used are non-parametric which are thus very robust against divergent.) b, Detailed mean relative changes in the number (mean ± SD) of ring stage parasites during the first 12 hours after the first injection of sevuparin. c, Numbers of ring-stage IEs levels in the individual patients. Oragne arrow indicate an outlier. Grey arrows indicate the short i.v. sevuparin infusions over five minutes.</p

Sevuparin inhibits merozoite invasion of <i>P</i>. <i>falciparum</i> clones, strains and fresh isolates <i>in vitro</i> at low concentrations, independently of parasite origin or phenotype.

<p>The invasion blocking capacity of sevuparin in 34 <i>in vitro</i> propagated <i>P</i>. <i>falciparum</i> isolates expressed as IC50. The inhibitory capacity of sevuparin was titrated in double dilution steps between 0.125 μg/mL and 1 mg sevuparin/mL culture. Ten laboratory isolates were either sensitive (3D7, 3D7PG12, Dd2, HB3) or resistant (R29, TM180, TM284, F32, 7G8, FCR3S1.2) to chloroquine. Three parasites of the W2mef background carried disrupted genes for EBA 140, EBA 175 or EBA 181 (EBA-KO). W2mef is a cloned line of parasites derived from the Indochina III-CDC strain. Of the fresh primary isolates 11 were from Ugandan children with either severe (dot) or uncomplicated (square) malaria and six isolates were from adults infected in Ethiopia/Eritrea, Kenya or Niger. Four Cambodian isolates were sensitive or resistant to artemisinin (red-circled square; IPC-4884, Pursut, artemisinin resistant (RSA 0-3h: 6,5%) and IPC 4912 artemisinin resistant (red circled square; RSA 0–3 h: 49%). ICP 5188 Rattanakiri and IPC 3663 Pailin were artemisinin sensitive (square).</p

Study design of phase I/II study in patients with uncomplicated <i>falciparum</i> malaria-TSM02.

<p>a, Overview of study design and dosing regimen for all patients in part 1. b, Overview of study design and dosing regimen for patients in part 2 randomized to the anti-malarial regimen (atovaquone and proguanil) alone or sevuparin plus anti-malarial regimen (atovaquone/proguanil).</p

Anticoagulant activity of sevuparin.

<p>Anticoagulant activity of sevuparin.</p