title: Relative neutralization of the biological actions of sulfaminoheparosans (K5 derivatives) and heparins by protamine sulfate.
abstract: Biosynthetic, semisynthetic, and synthetic analogues of heparins are currently developed as substitute antithrombotic agents for heparin. Sulfaminoheparosan (SAH) represents a bacterial polysaccharide (K5)-derived antithrombotic polymer from which pharmacologically active products with varying molecular weights (5-25 kDa) can be derived. These agents have been shown to exhibit pharmacologic effects comparable to heparins. The objective of this investigation is to determine the relative neutralization profile of various SAH derivatives, also called as bioheparins, by protamine sulfate. Four SAH fractions with varying molecular weights (20, 9, 7, and 6 kDa), a low molecular weight heparin (LMWH), tinzaparin, and unfractionated heparin (UFH) were supplemented to normal human pool plasma over a concentration range of 6.2 to 100 microg/mL. A fixed amount of protamine sulfate at 25 microg/mL (final concentration) was supplemented to determine the neutralization profile by performing tests such as prothrombin time (PT), activated partial thromboplastin time (APTT), Heptest, prothrombin-induced clotting time (PiCT), and amidolytic anti-Xa and anti-IIa assays. Protamine sulfate produced varying degrees of neutralization of all bioheparin fractions in the clotting assays. In the amidolytic anti-IIa assay relatively stronger inhibition was noted for all agents than inhibition of FXa. On a cumulative basis the neutralization profile of SAHs was comparable with heparins. These results suggest that the anticoagulant activities of SAH derivatives can be antagonized by protamine sulfate. These studies warrant further in vivo investigation to validate the relative neutralization profile of sulfaminoheparosans.
authors.affiliation: Department of Pharmacology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Maddineni
authors.forename: Debra A
authors.initials: DA
authors.lastname: Hoppensteadt
authors.forename: Umberto
authors.initials: U
authors.lastname: Cornelli
authors.forename: Marco
authors.initials: M
authors.lastname: Manoni
authors.forename: Jawed
authors.initials: J
authors.lastname: Fareed
mesh_terms: D016667:Bacterial Capsules; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005343:Fibrinolytic Agents; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006494:Heparin Antagonists / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D008970:Molecular Weight; D011135:Polysaccharides, Bacterial / Q000187:drug effects* / Q000494:pharmacology; D011479:Protamines / Q000494:pharmacology*; D017186:Titrimetry
chemical_list: D005343:Fibrinolytic Agents; D006494:Heparin Antagonists; D006495:Heparin, Low-Molecular-Weight; D011135:Polysaccharides, Bacterial; D011479:Protamines; C050673:capsular polysaccharide K5; D006493:Heparin