Low Molecular Weight Dextran Sulfate Is Well Tolerated in Humans and Increases Endogenous Expression of Islet Protective Hepatocyte Growth Factor

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Abstract

Introduction.

Low molecular weight dextran sulfate (LMW-DS) is a strong candidate to prevent early islet graft destruction caused by the instant blood-mediated inflammatory reaction. Pharmacokinetics, safety, tolerability, and the effect on endogenous release of various growth factors were studied in humans.

Materials and Methods.

Thirty healthy volunteers were given LMW-DS as a combined bolus and 20 min intravenous infusion followed by a continuous intravenous infusion for 5 hr to reach different predetermined target-activated partial thromboplastin times (APTT) in five study groups. Monitoring of APTT was used to estimate and control the plasma concentration. Safety, including hemostasis parameters, was evaluated before proceeding to a higher target APTT-level. Plasma was collected continuously during the infusion and was analyzed for additional safety markers and the presence of six different growth factors.

Results.

Predetermined target APTT levels were reached and kept for 5 hr without extensive dose corrections. After the 5 hr 20 min of LMW-DS infusion, the subjects in the highest dose group (target APTT=150s) were back at APTT-levels below 75s within 60 min. Plasma levels of hepatocyte growth factor were increased 100-fold within 20 min of infusion start and persisted more than 8 hr in the two highest dose groups.

Conclusion.

At doses that maintain APTT at up to 150s for 5 hrs 20 min, LMW-DS could be safely infused without affecting the platelet count or revealing other signs of increased bleeding risk. The observed endogenous release of islet protective hepatocyte growth factor could be an additional beneficial effect of LMW-DS during the first critical hours after transplantation.

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