Evaluation of a stable 5-F prostacyclin analogue as an antithrombotic agent in haemodialysis.
Prostacyclin has been used as a substitute for heparin in renal dialysis because of its potent antiplatelet activity and its short half-life. However, it is difficult to use because of its instability in neutral buffer and its hypotensive activity at antithrombotic doses. SC-39902, a 5-F prostacyclin analogue, has an ED50 of 17.7 micrograms/kg i.v. against ADP-induced thrombocytopenia in rats. The ED25 for hypotensive activity is 7.0 micrograms/kg i.v. The therapeutic index (blood pressure ED25/antiplatelet ED50) of 0.40 is 3.6 times better than that of PGI2 (0.11). SC-39902 supports clot-free dialysis in dogs at 4.0 micrograms/kg/min (ED100 for dialysis) with a 26% change in blood pressure at the 100% effective dose as compared with 0.052 microgram/kg/min required for PGI2 with a 32% change in blood pressure. The authors conclude that SC-39902 will provide the desirable antiplatelet/antithrombotic activities of PGI2 without instability and buffer incompatability problems. However, at the ED100 for dialysis, SC-39902 does have haemodynamic activity and, thus, a therapeutic index which is greater than four times that of PGI2 in rats is required for a PGI2 analogue to have less hypotensive activity during dialysis.
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D011464:Epoprostenol / Q000008:administration & dosage / Q000494:pharmacology / Q000031:analogs & derivatives; D005343:Fibrinolytic Agents; D008297:Male; D051381:Rats; D006435:Renal Dialysis
D005343:Fibrinolytic Agents; C049451:SC 39902; D011464:Epoprostenol