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At least 19 recordsLinked to original sources
PubMed1999

Low molecular weight protamine: a potential nontoxic heparin antagonist.

Protamine sulfate is the universal clinical antagonist to heparin and is used routinely after cardiovascular surgery to neutralize the anticoagulant function of heparin. Its clinical use, however, is associated with adverse effects including idiosyncratic fatal reactions. An examination of the mechanism of heparin neutralization and protamine toxicity suggests that the reversal of heparin anticoagulation may only require a small arginine-rich fragment of protamine to electrostatically dissociate antithrombin III from its binding to a specific pentasaccharide sequence in heparin. A review of literature indicates that chain-shortened peptide fragments derived from their parent proteins are normally accompanied with significantly reduced antigenicity and immunogenicity, which are two primary contributing factors to protamine-induced life-threatening toxic effects via an immunoglobulin-mediated pathway. Based on these observations, we propose our general hypothesis: if a chain-shortened low molecular weight protamine fragment containing the heparin-neutralizing domain could be derived directly from a native protamine, it could be a potent and nontoxic heparin antagonist. In this article, we present our experimental results to support the above hypothesis. LMWP fragments containing an intact arginine sequence and an average molecular weight of approximately 1.1 kDa were prepared successfully by enzymatic digestion of native protamine with thermolysin. In vitro studies demonstrated that such LMWP fragments completely neutralized the anticoagulant functions of heparin, based on the anti-Xa chromogenic assay and aPTT clotting time assay. Our in vivo results indicated that while administration of protamine to mice led to obvious production of antiprotamine antibodies, injection of LMWP did not elicit any detectable immunogenic responses. In addition, the LMWP fragments showed a significantly reduced antigenicity or, in other words, cross-reactivity towards the mice antiprotamine antibodies produced by the administration of protamine.

Animals↗
PubMedDate not supplied

[Effect of the synthetic heparin antagonist, conidine oligomer 25, on the synthesis of nucleic acids in regenerating liver cells].

Localization of 14C-conidine oligomer (the synthetic antagonist of heparin) and of polyelectrolyte complex heparin-conidine oligomer 25 was studied in cells of regenerating liver tissue within 20 hrs after partial hepatectomy in rats. Effects of heparin, conidine oligomer 25 and of their polyelectrolyte complex on synthesis of nucleic acids were studied. Conidine oligomer 25 penetrated from circulation into hepatocytes and subcellular organelles of regenerating liver cells and was localized mainly in cytosol (75-88%). In nuclei and mitochondria of the hepatocytes 14C-conidine oligomer 25 was mostly found in the fraction of low density of the organelles. Polyanion heparin, polycation conidine oligomer 25 and their polymeric complex impaired replication and transcription processes.

Animals↗
PubMed1995

Differential effects of a heparin antagonist (hexadimethrine) or chlorate on amphiregulin, basic fibroblast growth factor, and heparin-binding EGF-like growth factor activity.

Amphiregulin (AR) and heparin-binding EGF-like growth factor (HB-EGF) are two recently identified members of the EGF family. Both AR and HB-EGF share with EGF the ability to interact with the type-1 EGF receptor; however, AR and HB-EGF differ from EGF in that both of these mitogens bind to heparin while EGF does not. To determine whether interactions with heparin-like molecules on the cell surface influence binding of AR and HB-EGF with EGF receptors and the subsequent mitogenic activity exerted by these growth factors, murine AKR-2B and Balb/MK-2 cells were treated with either an inhibitor of proteoglycan sulfation (chlorate) or a heparin antagonist (hexadimethrine). As expected, neither treatment significantly altered the specific binding of 125I-EGF on AKR-2B cells. Interestingly, treatment with either chlorate or hexadimethrine inhibited the ability of AR to compete with 125I-EGF for cell surface binding and also attenuated AR-mediated DNA synthesis. Thus, as has been suggested for other heparin-binding growth factors such as basic fibroblast growth factor (bFGF), the interaction of AR with an EGF-binding receptor appears to be facilitated by interaction with cell-associated sulfated glycosaminoglycans or proteoglycans. Unexpectedly, however, neither chlorate nor hexadimethrine treatment caused an inhibition of HB-EGF-induced mitogenic activity. Chlorate treatment did not significantly alter the ability of HB-EGF to compete with 125I-EGF for cell surface binding sites, however, heparin and hexadimethrine reduced the ability of HB-EGF to compete for 125I-EGF binding. These results suggest that, in AKR-2B cells, HB-EGF may mediate its mitogenic response at least in part through a receptor which appears to be selective for HB-EGF and permits HB-EGF-mediated mitogenic responses in the presence of hexadimethrine or heparin. Finally, hexadimethrine inhibited the specific binding and mitogenic activity of bFGF, suggesting that this cationic polymer can function as an antagonist of heparin-binding mitogens other than AR.

Amphiregulin↗
PubMed1986

In vitro neutralization of heparin in plasma prior to the activated partial thromboplastin time test: an assessment of four heparin antagonists and two anion exchange resins.

This study was carried out to investigate the effects on the activated partial thromboplastin time test (APTT) when heparin in plasma was neutralized with protamine, Polybrene(R), poly-DL-lysine, or heparin neutralizing activity (HNA) extracted from platelets; or removed by means of the anion exchange resins TEAE cellulose or ECTEOLA cellulose. The effect on the APTT of adding the polycations protamine, Polybrene or poly-DL-lysine to citrated plasma was examined. The formation of heparin/polycation complexes was studied by means of their light scattering properties. The low yields of platelet HNA obtained excluded this from practical use as an in vitro heparin antagonist. ECTEOLA cellulose was unable to remove plasma heparin at levels as low as 1 U/ml by the technique employed. TEAE cellulose was able to efficiently remove at least 40 U of heparin from 1 ml of plasma but also caused a non-specific prolongation of the APTT. The polycations protamine, Polybrene, and poly-DL-lysine, possessed clot promoting activity at low concentrations and acted as anticoagulants in their own right at higher concentrations. At a plasma heparin concentration of 4 U/ml, protamine was the most efficient neutralizer of heparin, while at 10 U/ml, Polybrene was the most effective in this respect. It was concluded that care must be taken in the interpretation of the APTT after heparin neutralization or removal as heparin antagonist induced non-specific effects may be present.

Anion Exchange Resins↗
PubMed2003

Human antithrombin III-derived heparin-binding peptide, a novel heparin antagonist.

In the blood coagulation cascade, human antithrombin III (hAT III) acts as an inhibitor of serine proteases such as thrombin and factor Xa, and this anticoagulatory glycoprotein requires the binding of heparin for its activation. In this study, we synthesized the polypeptides corresponding to the proposed heparin-binding sites including the (41-49), (286-301) and (123-139) regions of hAT III, and examined their interactions with heparin by means of physicochemical and biochemical methods. All the synthetic peptides had a high affinity toward heparin, evidenced by the fact that they were eluted from a heparin-agarose column at the high salt concentration range of 520-700 mM. In addition, hAT III (123-139) attenuated the effect of heparin on the activation of hAT III, whereas other HBPs did not, suggesting that only hAT III (123-139) could interact with the active site of heparin. On the basis of these results, we prepared novel hAT III (123-139)-related derivatives as potent heparin antagonist candidates, and examined the influence of several modifications on their activity in vitro. The results provided new findings about the structure-activity relationship of hAT III (123-139), and led us to the successful development of a potent antagonist for heparin.

Anticoagulants↗
PubMed1999

Development of heparin antagonists with focused biological activity.

Heparin, a complex glycosaminoglycan, has long been used to temporarily render the blood incoagulable during extracorporeal circulation, cardiovascular surgery, and other arterial interventions. But bleeding complications are especially common when the arterial tree is violated, occurring in as many as 10-15% of cases. For cardiovascular surgery and many related interventions, protamine has long been the standard antagonist when acute and complete neutralization of heparin s anticoagulant effect is necessary. Protamine s efficacy is related in part to its total net cationic charge, but unfortunately so is its toxicity. For these reasons, there is renewed interest in developing heparin antagonists which will replace the use of protamine. At Commonwealth Biotechnologies, Inc., we have used a rationale design approach for the preparation of a family of low molecular weight helix peptides which bind heparin with high affinity. For each of the new compounds, we have assessed their ability to bind heparin using isothermal titration calorimetry and circular dichroism spectrometry and have examined potential complexes formed with the anticoagulant pentasaccharide unit of heparin using molecular modeling techniques. The biological potencies of these compounds were assessed in ex vivo experiments where their ability to compete with antithrombin for binding heparin was determined. The best of the compounds, designated HepArrestTM, is highly effective in reversing heparin-mediated and HepArrest is a safer drug than protamine because of reduced adverse hemodynamic side effects compared with those associated with protamine. HepArrest binds low molecular weight heparins and causes reversal of anticoagulation by low molecular weight heparins, as determined by activated partial thromboplastin time, thrombin time, or factor Xa neutralization assays. These highly promising preclinical results indicate that HepArrest is a novel heparin neutralizing agent that may well fill a substantial unmet need for vascular surgeons and cardiac anesthesiologists who perform coronary artery bypass grafts and several other major vascular surgeries, as well as for cardiologists and interventional radiologists.

Animals↗
PubMed2001

Heparin antagonists are potent inhibitors of mast cell tryptase.

Tryptase may be a key mediator in mast cell-mediated inflammatory reactions. When mast cells are activated, they release large amounts of these tetrameric trypsin-like serine proteases. Tryptase is present in a macromolecular complex with heparin proteoglycan where the interaction with heparin is known to be essential for maintaining enzymatic activity. Recent investigations have shown that tryptase has potent proinflammatory activity, and inhibitors of tryptase have been shown to modulate allergic reactions in vivo. Many of the tryptase inhibitors investigated previously are directed against the active site. In the present study we have investigated an alternative approach for tryptase regulation. We show that the heparin antagonists Polybrene and protamine are potent inhibitors of both human lung tryptase and of recombinant mouse tryptase (mouse mast cell protease 6). Protamine inhibited tryptase in a competitive manner whereas Polybrene showed noncompetitive inhibition kinetics. Treatment of tetrameric, active tryptase with Polybrene caused dissociation into monomers, accompanied by complete loss of enzymatic activity. The present report thus suggests that heparin antagonists potentially may be used in treatment of mast cell-mediated diseases such as asthma.

Animals↗
PubMed2003

A less toxic heparin antagonist--low molecular weight protamine.

A new thirteen amino acid peptide, named low molecular weight protamine (LMWP), was obtained through the enzymatic digestion of native protamine. Both in vitro and in vivo results showed that LMWP fully maintained the heparin neutralization function of protamine but had much lower immunogenicity and antigenicity. Unlike protamine, neither LMWP nor LMWP/heparin complexes caused significant blood platelet aggregation in rats. These results suggest that LMWP can be used as a substitute for protamine for developing a new generation of nontoxic heparin antagonists.

Animals↗
PubMed1996

IP3 receptor antagonist heparin uncompetitively inhibits [3H](+)-SKF-10047 binding to sigma receptors.

Interaction of sigma receptors with intracellular Ca2+ channel blocker and modulators was examined. Ryanodine and inositol 1,4,5-trisphosphate (IP3) did not inhibit [3H](+)-N-allylnormetazocine ([3H](+)-SKF-10047) binding to sigma receptors from either brain microsomal fractions or liver membrane extracts of the rat. However, the IP3 receptor antagonist heparin inhibited [3H](+)-SKF-10047 to sigma receptors in an uncompetitive manner with a Ki of 93 microM. These results suggest that sigma receptors may bear some relationship with IP3 receptor associated proteins or channels.

Animals↗
PubMedDate not supplied

[Synthesis and pharmacokinetic characteristics of 14CH3-polymethacryloyl lupinine--a heparin antagonist].

The quaternary salt of 1-14C-polymetacryloyl lupinine with a specific activity of 1 microCi/mM has been synthesized. It has been shown that intravenous injection of the polymer after heparin administration leads to uneven distribution of the label in the organs. The most intensive reduction of the label was observed in the kidneys. During 10 days, 85% of the label is eliminated from the body with urine and feces (76 and 9% respectively).

Alkaloids↗