Pharmacologic profile of the antithrombotic and bleeding actions of sulfated lactobionic acid amides.
1. The introduced bis-lactobionic acid amides represent a new group of synthetic polyanions with a molecular weight of 2387 to 2514d. The compounds are homogeneous and chemically defined. 2. The in vitro blood coagulation parameters (APTT, Heptest, anti-Xa, thrombin time, and anti-IIa) are only marginally altered by these compounds. 3. In a rat model of venous thrombosis using endothelial damage as the thrombogenic stimulus, the antithrombotic activity of the bis-lactobionic acid amides was shown in a dose- and time-dependent manner. 4. LW 10082 and LW 10121 prolong the bleeding time at dosages about 10 times less than that of heparin. The safety/efficacy index appears to be wider for these compounds than for heparin. 5. In subchronic toxicologic studies in rats, LW 10082 was well tolerated up to a dosage of 100 mg/kg body weight. 6. The anticoagulant and antithrombotic activities of the bis-lactobionic acid amides decrease gradually with the increasing number of methylene groups in the alkylene chain.
Raake
W
W
Department of Pharmacology, Luitpold-Werk, München, Germany.
Klauser
R J
RJ
Meinetsberger
E
E
Zeller
P
P
Elling
H
H
D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001760:Bleeding Time; D004187:Disaccharides / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000494:pharmacology / Q000633:toxicity; D007601:Jugular Veins / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013464:Sulfuric Acids / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D013927:Thrombosis / Q000188:drug therapy*
D000577:Amides; D000925:Anticoagulants; D004187:Disaccharides; D005343:Fibrinolytic Agents; D013464:Sulfuric Acids; D006493:Heparin