Tolerance and Biological Activity of Pentosan Polysulfate After Intramuscular or Subcutaneous Administration for Ten Days in Human Volunteers

Summary

This study reports on the tolerance and the pharmacological activity of pentosan polysulfate (PPS) administered to healthy volunteers for 10 days. Three groups of 10 subjects received either one daily injections of 100 mg of PPS by I. M. route (group I), or two daily injection of 50 mg of PPS by I. M. or S. C. route (groups II and III, respectively). In each group two random subjects received a placebo for the 10 days; on day 0, each subject was injected by a placebo. Clinical tolerance was checked by a daily physical examination; biological tolerance was assessed comparing the results of the main biochemical and haematological constants measured before starting the treatment (day 0) and 12 or 24 h after the end of the treatment (day 11). The pharmacological activity was measured on serial samples taken before treatment and between 1 and 6 h after the drug injection on days 1, 3 and 10; the results were compared to those obtained on day 0. Clinical tolerance was good. The biological side effects concern the transaminase levels and the platelet counts. An increase above the upper normal limit was observed in 18/i4 and 3/24 for alanine and aspartic transaminase respectively. The mean platelet reduction ranged between 24 and 34% according to the groups. The drug injection induced a slight Quick time (PT) prolongation, no significant alteration of factors II, VII-X, V levels and of thrombin clotting time. The activated partial thromboplastin time (APTT) was significantly prolonged and there was a weak but significant circulating anti-Xa activity. The fibrinolytic activity was enhanced without increase in the tissue plasminogen activator antigen level. These pharmacological effects were at their maximum between 2 and 4 h after the drug injection and returned to the pre-injection equilibrium between 4 and 6 h except for circulating anti-Xa activity; these effects remained unchanged all over the 10-day therapeutic period. The comparison between group I and II indicates that the PT and APTT effects are dose-dependent while the anti-Xa and the profibrinolytic effects are not; the comparison between group II and III indicates that the S. C. and I. M. route are bioequivalent.

Key words

Heparinoid - Pentosan polysulfate - Hemoclar

• References

• 1 Joffe S. Drug prevention of postoperative deep vein thrombosis. A comparative study of calcium heparinate and sodium pentosan polysulfate. Arch Surg 1976; 111: 07-40
• 2 Bergqvist E, Efsing HO, Hallböök T, Lindblad B. Prevention of postoperative thromboembolic complications. A prospective comparison between Dextran 70, Dihydroergotamin-heparin and a sulphated polysaccharid. Acta Chir Scand 1980; 146: 559-568
• 3 Bergqvist D, Ljungner H. A comparative study of Dextran 70 and a sulphated polysaccharide in the prevention of postoperative thromboembolic complications. Br J Surg 1981; 68: 449-451
• 4 Soria C, Soria J, Ryckewaert JJ, Holmer E, Caen JP. Anticoagulant activities of a pentosane polysulfate: comparison with standard heparin and a fraction of low molecular weight heparin. Thromb Res 1980; 19: 455-463
• 5 Fischer AM, Barrowcliffe TW, Thomas DP. A comparison of pentosan polysulfate (SP 54) and heparin. I: mechanism of action on blood coagulation. Thromb Haemostas 1982; 47: 104-108
• 6 Vinazzer H, Haas S, Stemberger A. Influence on the clotting mechanism of sodium pentosan polysulfate (SP 54) in comparison to commercial beef lung sodium heparin. Thromb Res 1980; 20: 57-68
• 7 Scully MF, Kakkar VV. Identification of heparin cofactor II as the principal plasma cofactor for the antithrombin activity of pentosan polysulfate (SP 54). Thromb Res 1984; 36: 187-194
• 8 Sié P, Fernandez F, Ofusu F. The relative importance of AT III and HC II for the anticoagulant effect of heparin, dermatan sulfate (DS) and pentosan polysulfate (PPS). Thromb Haemostas 1985 54. 204 (Abstr)
• 9 Wagenvoord R, Hendrix H, Soria C, Hemker HC. Determination of the non-antithrombin III dependent inhibitor sites of pentosan polysulphate in the blood coagulation. First International Symposium upon pentosan polysulphate. Paris 1985 (Abstract book)
• 10 Vinazzer H, Stemberger A, Haas S, Blümel G. Influence of heparin of different heparin fraction and of a low molecular weight heparin-like substance of the mechanism of fibrinolysis. Thromb Res 1982; 27: 341-352
• 11 Fischer AM, Merton RE, Marsh NA, Williams S, Gaffney PJ, Barrowcliffe TW, Thomas DP. A comparison of pentosan polysulfate and heparin II: effects of subcuteneous injection. Thromb Haemostas 1982; 47: 109-113
• 12 Williams SP, Barrowcliffe TW. The effects of post-heparin plasma lipases on anti-Xa clotting activity. Thromb Res 1985; 37: 371-377
• 13 Caen J, Larrieu MJ, Samama M. L’hémostase: methodes d’explora-tion et Diagnostic pratique. L’expansion Scientifique edit Paris 1975
• 14 Kluft C. Occurrence of C-inactivator and other proteinase inhibitors in euglobulin fractions and their influence on fibrinolytic activity. Haemostasis 1976; 5: 136-146
• 15 Haverkate F, Brakman P. Fibrin plate assay. In Progress in Chemical Fibrinolysis and Thrombolysis Davidson JF, Samama M, Desnoyers PC. (Eds.) Vol. 1 151-159 Amsterdam 1975
• 16 Sonnenblick M, Oren A, Jacobson W. Hyper-transaminasemia with heparin therapy. Br Med J 1975; 3: 77
• 17 Dukes GE, Sanders SW, Russo J, Swenson E, Burnakis TG, Saffle JR, Warden GD. Transaminases elevations in patients receiving bovine or porcine heparin. Ann Intern med 1984; 100: 646-650
• 18 King DJ, Kelton JG. Heparin-associated thrombocytopenia. Ann Intern Med 1984; 100: 535-540
• 19 Dunn F, Soria J, Soria C, Thomaidis A, Tobelem G, Caen JP. Fibrinogen binding on human platelets. Influences of different hepa-rins and of pentosan polysulfate. Thromb Res 1983; 29: 141-148
• 20 Rosing DR, Brakman P, Redwood DR, Goldstein E, Beiser GD, Astrup T, Epstein SE. Blood fibrinolytic activity in man. Diurnal variation and the response to varying intensities of exercise. Circul Res 1970; 27: 171-184
• 21 Cepelak V, Barcal R, Cepe La Koua M, Mayer O. Circadian rhythm of fibrinolysis. Progress in chemical fibrinolysis and thrombolysis Davidson JF, Rowan RM, Samama MM, Desnoyers PC. (eds.) Vol. 3 571-578 Raven Press; New-York: 1978
• 22 Juhan-Vague I. Contribution à l’étude de l’activateur tissulaire du plasminogène; dosage radioimmunologique; étude des différentes formes moléculaires plasmatiques; mise en évidence d’un inhibiteur spécifique. Thèse de doctorat en biologie humaine, Université de Paris VII 1984: 74