EFFECTS OF PENTOSAN POLYSULPHATE (EXMLRON) ON FIBRINOLYSIS

Abstract

Decreased fibrinolytic capacity is thought to be an important ccnponent in the pathqgenesis of different thrombotic states. There is a need for agents improving the fibrinolytic capacity, especially perorally (p.o.) active drugs. Since long the semi-synthetic heparinoid Pentosan Polysulphate (PPS) has been shown to have a stimulating effect on fibrinlysis when given parenterally. Alsop.o. administered drug has been claimedto improve fibrinolysis. However, the degree of gastrointestinal resorption has not been thoroughly assessed and the mechanism behind the effect of PPS cn fibrinolysis is not known.8 healthy male volcnteers and 14 patients with a history of venous thrombosis were studied. Before and after administration of PPS blood samples were taken and plasminogen activator activity (tPA-act), antigen (tPA-ag) and plasminogen activator inhibitor (PAI) were determined. The volonteers were given 50 ng PPS i.v. and blood was sanpled before and after 30 minutes. In a second experiment they received 400 rrg PPS p.o. follwed by blood sarrpling after 2 hours. They also received 400 ng of PPS daily p.o. for 25 days. The patient group were given 500 ng PPS p.o. 8 a.m. and blood was collected 6 hours later. To exclude influence of diumal variation blood was also taken 2 p.m. the day before. The plasma level of PPS after p.o. administration was determined by a sensitive modified radioassay for heparin.30 minutes after i.v. injection of PPS PAI was essentially unchanged, tPA-ac-tivity was slightly increased but tPA-ag showed a strongly significant decrease. 400 ng PPS p.o. resulted in an increase in tPA-ag after 2 hours. 400 ng PPS durirg 25 days resulted in a significant decrease of PAI with no charges in tPA-act and tPA-ag. 500 ng FEB given as a single dose in the morning did not cause greater charges of PAI than expected from the diumal variation. The uptake of PPS following p.o. administration is lav with a bioavailability of only 0,5 − 1 %.The low bioavailability of p.o. adninistrered PPS suggest that some of the ad-vantagous effects of PPS on fibrinolysis migjnt be caused through local effects in the intestine. The strong decrease of tPA-ag without significant changes in the other parameters may reflect an accelerated elimination of tPA-PAI-ccnplex. The mechanism of the inproved fibrinlysis following adninistration of PPS is still unsettled but our resluts may indicate that PPS initially facilitates the elimination of the tPA-PAI complex with a secondary increase of the tPA-ag. The tPA-ag may bind to PAI with a secondary decrease of the active component of this inhibitor. However, a more direct effect of PPS cn PAI cannot be excluded.