Partially N-desulfated heparin as a non-anticoagulant heparin: some physico-chemical and biological properties.
A partially N-desulfated preparation of heparin (UFH) obtained by thermally inactivating heparinic acid for 24 hours at 50 degrees C (TIHA) was examined for its physico-chemical and biological properties in vitro and in vivo. TIHA has a molecular weight of 14,700 and 27% remaining N-sulfate groups (UFH = 17,500; 100% N-sulfate groups). TIHA has no anticoagulant activity measurable by conventional amidolytic or clotting tests. However, in a rabbit stasis-induced thrombosis model and using two different thrombogenic stimuli (Feiba and PCC(Konyne)/RVV), TIHA afforded a dose-dependent (1.0-2.5 mg/kg) protection sufficient to impair thrombosis (UFH: fully effective at 0.13 mg/kg). TIHA did not produce any bleeding at supramaximal antithrombotic dosage in a rat tail bleeding and a rabbit ear blood loss model and it did not augment ADP-induced aggregation of platelets. In contrast, a completely N-desulfated derivative of UFH (Inoue and Nagasawa, Carbohydr. Res. 46, 87-95, 1976) also lacking measurable in vitro activity was completely inactive in vivo. The results in this study suggest that TIHA may be considered as a non-anticoagulant heparin still retaining antithrombotic activity and also with lower haemorrhagic effect than UFH.
Sache
E
E
Sanofi-Recherche, Institut Choay, Paris, France.
Maillard
M
M
Malazzi
P
P
Bertrand
H
H
D000244:Adenosine Diphosphate / Q000502:physiology; D000818:Animals; D000925:Anticoagulants; D055598:Chemical Phenomena; D002621:Chemistry; D005343:Fibrinolytic Agents; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D010504:Periodic Acid; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D000925:Anticoagulants; D005343:Fibrinolytic Agents; C044153:heparin, N-desulfated; D010504:Periodic Acid; D000244:Adenosine Diphosphate; D006493:Heparin