Abstract
Heparins extracted from different animal sources have been conventionally considered effective anticoagulant and antithrombotic agents despite of their pharmacological dissimilarities. We performed herein a systematic analysis on the physicochemical properties, disaccharide composition, in vitro anticoagulant potency and in vivo antithrombotic and bleeding effects of several batches of pharmaceutical grade heparins obtained from porcine intestine, bovine intestine and bovine lung. Each of these three heparin types unambiguously presented differences in their chemical structures, physicochemical properties and/or haemostatic effects. We also prepared derivatives of these heparins with similar molecular weight differing exclusively in their disaccharide composition. The derivatives from porcine intestinal and bovine lung heparins were structurally more similar with each other and hence presented close anticoagulant activities whereas the derivative from bovine intestinal heparin had a higher proportion of 6-desulfated α-glucosamine units and about half anticoagulant activity. Our findings reasonably indicate that pharmaceutical preparations of heparin from different animal sources constitute distinct drugs, thus requiring specific regulatory rules and therapeutic evaluations.
Highlights
The current production of heparin mostly based on a single animal source and concentrated in a single country raises a “supply insecurity”, which lead the FDA – USA to evaluate the reintroduction of lung or intestine bovine heparins[8]
The proportion of these units in the heparin polymer directly relates to the tissue used for its extraction, notably: the proportion of N-acetylated α-D-glucosamine residues is lower in bovine lung heparin[9] and the amount of 6-sulfated α-D-glucosamine units is significantly lower in bovine than in porcine intestinal heparin[10,11]
The objective of the present study was to answer two essential questions involving the production and therapeutic use of heparin: (1) Are heparins obtained from different sources distinct drugs? (2) Which are the analytical thresholds separating these distinct heparins? To answer these questions, we undertook a systematic analysis on physicochemical properties, disaccharide composition, in vitro anticoagulant activity and in vivo antithrombotic and bleeding effects of pharmaceutical heparins obtained from porcine intestine (HP-I), bovine intestine (HB-I) and bovine lung (HB-L)
Summary
The current production of heparin mostly based on a single animal source and concentrated in a single country raises a “supply insecurity”, which lead the FDA – USA to evaluate the reintroduction of lung or intestine bovine heparins[8]. Other minority units found in the molecule are non-sulfated α-L-iduronic acid, α-D-glucosamine N-acetylated or N, 3, 6-trisulfated, and β-D-glucuronic acid residues (not epimerized to α-L-iduronic acid) The proportion of these units in the heparin polymer directly relates to the tissue used for its extraction, notably: the proportion of N-acetylated α-D-glucosamine residues is lower in bovine lung heparin[9] and the amount of 6-sulfated α-D-glucosamine units is significantly lower in bovine than in porcine intestinal heparin[10,11]. In addition to these structural differences, heparins obtained from different sources differ in their average molecular weight[9]. Our findings allowed us to clarify many aspects of these questions concerning the pharmacological features of heparins produced from different animal sources
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