Protamine sulfate neutralization of the anticoagulant activity of Aprosulate, a synthetic sulfated lactobionic acid amide.
Aprosulate or lactobionic acid is a highly sulfated analogue of heparin which is currently undergoing clinical trials in Europe as a potential antithrombotic drug. Aprosulate exerts a strong anticoagulant effect in plasma as a result of its interaction with heparin cofactor II. In this study, the ability of protamine sulfate to neutralize the anticoagulant activity of Aprosulate was investigated. In vitro, ex vivo, and in vivo coagulation studies were performed using various clotting assays such as the APTT, Heptest, and thrombin time as a measure of the anticoagulant activity of Aprosulate. In the first study, protamine sulfate when administered in vitro to plasma samples containing various concentrations of Aprosulate was found to effectively neutralize the anticoagulant activity of the Aprosulate in both normal human and normal monkey plasma systems. However, the relative index of neutralization of Aprosulate was assay dependent. Protamine sulfate was also found to antagonize the anticoagulant effects of Aprosulate in an ex vivo study. The ex vivo supplementation of protamine sulfate to plasma samples collected at various time intervals following the subcutaneous administration of Aprosulate to a group of primates completely neutralized the anticoagulant activity of the Aprosulate. In a third in vivo study, protamine sulfate when injected intravenously into the bloodstream of a group of primate was found to completely neutralize the anticoagulant effects of a previously administered dosage of Aprosulate. The results of these three studies clearly suggest that protamine sulfate can be used to effectively neutralize the anticoagulant activity of Aprosulate.
Loyola University Medical Center, Stritch School of Medicine, Maywood, IL 60153.
R
R
Kijowski
D
D
Hoppensteadt
W
W
Jeske
J
J
Fareed
D000818:Animals; D000925:Anticoagulants / Q000037:antagonists & inhibitors*; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D002240:Carbohydrate Sequence; D004187:Disaccharides / Q000037:antagonists & inhibitors*; D000882:Haplorhini / Q000097:blood; D006801:Humans; D008969:Molecular Sequence Data; D011479:Protamines / Q000494:pharmacology*
D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D004187:Disaccharides; D011479:Protamines; C005608:lactobionic acid; C069690:aprosulate