The pharmacokinetics and pharmacodynamics of dermatan sulphate MF701 during haemodialysis for chronic renal failure.

Abstract

Single i.v. bolus doses of dermatan sulphate MF701 were administered before the onset of haemodialysis to patients with chronic renal failure, to prevent clotting in the extracorporeal circuit. Six patients received 2 mg kg‐1; six were given 2.5 and 3 mg kg‐1; 13 received 4.5 and 6 mg kg‐1. Plasma MF701 concentrations (chromogenic assay), activated partial thromboplastin time (APTT) and plasma markers of coagulation and platelet activation (TAT and beta‐TG) were measured over 4 or 8 h from the onset of dialysis. The disposition of MF701 was described by a monoexponential function. C(0) and AUC values increased proportionally with dose. Volumes of distribution (approximately 4 l) were dose‐independent. Half‐lives showed a non significant increase with dose (from 2.2 to 3.1 h) and were 2.5‐3 times longer than those reported for healthy subjects. There was a significant correlation between plasma MF701 concentration and its effects in prolonging APTT and suppressing TAT and beta‐TG generation during dialysis.

Galactosaminoglycans: Medical Applications and Drawbacks

“…The results showed that DS is less hemorrhagic than heparin at equivalent antithrombotic doses [114]. Due to its reduced hemorrhagic potential, DS has been proposed as a safer alternative than heparin for use during hemodialysis in patients with renal impairment [131].…”

Effect of Dermatan Sulphate on Activated Partial Thromboplastin Time Determined with Different Reagents

“…The dermatan sulphate con centration range tested approximated with some excess that of drug plasma levels mea sured in humans given MF701 intravenously, as a bolus and/or as an infusion [8][9][10][11]17], At plasma concentrations below 10 pg/ml, such as those generated by intramuscular prophy lactic doses of MF701 [3], APTT response is only barely detectable [3,5,7], APTT response was linearly related to der matan sulphate concentration with all the re agents over the entire concentration range tested. This is a basic prerequisite for the practical application of APTT to ex vivo mon itoring of dermatan sulphate treatment.…”

“…Activated partial thromboplastin time (APTT) has been shown to be responsive to dermatan sulphate both in vitro and ex vivo in human subjects treated with this agent, a prolongation of clotting time becoming appar ent for dermatan concentrations greater than approximately 5 pg/ml [2,[7][8][9][10][11], Beyond this threshold, APTT response was found to be related to dermatan sulphate plasma concen tration added in vitro [2,7,8] or measured ex vivo [8][9][10][11] with a specifically developed, sen sitive chromogenic substrate assay [12], Thrombin clotting time performed with hu man thrombin appeared to be slightly more sensitive to dermatan sulphate than APTT, but it also showed a narrower useful range and a wider intrinsic variability [7,9,10].…”