Low molecular weight dextran sulfate is well tolerated in humans and increases endogenous expression of islet protective hepatocyte growth factor.
BACKGROUND
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.


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=150 s) were back at APTT-levels below 75 s 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.


CONCLUSIONS
At doses that maintain APTT at up to 150 s 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.
Schmidt
Peter
P
TikoMed AB, Dag Hammarskjölds väg 10A, SE-751 83 Uppsala, Sweden. peter.schmidt@tikomed.com
Magnusson
Caroline
C
Lundgren
Torbjörn
T
Korsgren
Olle
O
Nilsson
Bo
B
D000328:Adult; D016264:Dextran Sulfate / Q000627:therapeutic use*; D005260:Female; D005786:Gene Expression Regulation; D006470:Hemorrhage / Q000517:prevention & control; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D008970:Molecular Weight; D010314:Partial Thromboplastin Time; D010976:Platelet Count; D013997:Time Factors
D036341:Intercellular Signaling Peptides and Proteins; D017228:Hepatocyte Growth Factor; D016264:Dextran Sulfate