A Dose-Determining Trial of Heparinase-I (Neutralase™) for Heparin Neutralization in Coronary Artery Surgery

Heres, Edward K.; Horrow, Jay; Gravlee, G.P.; Tardiff, Barbara E.; Luber, John M.; Schneider, Joel E.; Barragry, T. P.; Broughton, Richard

doi:10.1097/00000539-200112000-00019

Cited by 31 publications

(14 citation statements)

References 14 publications

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“…Heparinase I, a specific enzyme that inactivates heparin, is another possible alternative to protamine (Michelsen et al 1996). Heres et al (2001) found that heparinase-I successfully restored activated coagulation time with no adverse hemodynamic events in patients undergoing coronary artery surgery with cardiopulmonary bypass in an open-label dose-determining trial. Finally, heparin-binding filters have been also considered as an alternative to protamine but additional human studies are needed to demonstrate the safety and efficacy of the method (Ma et al 1992).…”

Section: Discussionmentioning

confidence: 99%

Efficiency of Prostacyclin in the Treatment of Protamine-Mediated Right Ventricular Failure and Acute Pulmonary Hypertension

Öcal

Kiriş

Erdinç³

et al. 2005

Tohoku J. Exp. Med.

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[51][52][53][54][55][56][57][58] Protamine is used after cardiopulmonary bypass was stopped in order to reverse the anticoagulant effects of heparin administered during open-heart operations. Adverse hemodynamic responses to protamine are common, ranging from minor perturbations to cardiovascular collapse. The aim of the present study was to investigate whether a prostacyclin is effective in the treatment of protamine-mediated acute pulmonary hypertension and right ventricular failure in the perioperative period of isolated coronary artery bypass grafting (CABG) operations. In sixty-eight (1.78%) of 3800 patients who underwent isolated CABG, acute pulmonary hypertension and right ventricular failure developed during or following the protamine infusion. These 68 patients were included in the study and were randomized into two groups. Thirty-eight of the patients received prostaglandin I 2 (PGI 2 ), norepinephrine and dopamine (PGI 2 group), whereas 30 patients received nitroglycerin, norepinephrine and dopamine (control group). Hemodynamic data were recorded before and after the above drug combinations. The mean value of left ventricle ejection fraction significantly increased (p < 0.05) and mean values of central venous pressure, pulmonary artery systolic and diastolic pressure, pulmonary capillary wedge pressure and pulmonary vascular resistance significantly decreased (p < 0.05) in the PGI 2 group. The mean value of pulmonary capillary wedge pressure significantly decreased (p < 0.05) and the mean value of central venous pressure significantly increased (p < 0.05) in the control group. In conclusion, prostacyclin (PGI 2 ) is effective in the treatment of protamine-mediated acute pulmonary hypertension and right ventricular failure in the perioperative period in isolated CABG operations. This finding may be an important contribution to the treatment of severe protamine complications during open-heart operations.prostacyclin; protamine; heparin; pulmonary hypertension; right ventricular failure

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Section: Discussionmentioning

confidence: 99%

Efficiency of Prostacyclin in the Treatment of Protamine-Mediated Right Ventricular Failure and Acute Pulmonary Hypertension

Öcal

Kiriş

Erdinç³

et al. 2005

Tohoku J. Exp. Med.

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“…25f, 43 Early clinical trials demonstrated that a single intravenous injection of recombinant heparinase-I (Neutralase) could dose-dependently neutralize anticoagulant heparin in heart surgery patients. 44 However, later trials were terminated due to ineffectiveness and safety concerns. Endosulfatases are important enzymes that edit the sulfated domains of HS by removing the 6- O -sulfate groups.…”

Section: Targeting Heparan Sulfate-protein Interactionsmentioning

confidence: 99%

Targeting heparin and heparan sulfate protein interactions

2017

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Heparin and heparan sulfate glycosaminoglycans are long, linear polysaccharides that are made up of alternating dissacharide sequences of highly sulfated uronic acid and amino sugars. Unlike heparin, which is only found in mast cells, heparan sulfate is ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These negatively-charged carbohydrate chains play essential roles in important cellular functions such as cell growth, adhesion, angiogenesis, and blood coagulation. However, these biomolecules are also involved in pathophysiological conditions such as pathogen infection and human disease. This review discusses past and current methods for targeting these complex biomolecules as a novel therapeutic strategy to treating disorders such as cancer, neurodegenerative diseases, and infection.

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“…When given in doses up to 30 μg/ kg, heparinase I successfully neutralized heparin's anticoagulant effect in a dose-dependent fashion without significant adverse sequelae. Heres et al (2001) assessed the heparinneutralizing activity and safety profile of different doses of heparinase I in 49 patients undergoing coronary artery surgery. They found that heparinase I, 7 or 10 μg/kg, effectively restored the ACT after unfractionated heparin was given to patients undergoing CPB for coronary artery surgery.…”

Section: Heparin Antagonistmentioning

confidence: 99%

Microbial heparin/heparan sulphate lyases: potential and applications

Tripathi

Banga

Mishra

2012

Appl Microbiol Biotechnol

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Heparin/heparan sulphate glycosaminoglycans (HSGAGs) are composed of linear chains of 20-100 disaccharide units of N-acetylated D: -glucosamine α (1-4) linked to glucuronic acid. HSGAGs are widely distributed on the cell surface and extracellular cell matrix of virtually every mammalian cell type and play critical role in regulating numerous functions of blood vessel wall, blood coagulation, inflammation response and cell differentiation. These glycosaminoglycans present in this extracellular environment very significantly influence the blood coagulation system and cardiovascular functions. Recent studies have investigated the mechanism by which cancer causes thrombosis and emphasizes the importance of the coagulation system in angiogenesis and tumour metastasis. Heparan sulphate/heparin lyases or heparinases are a class of enzymes that are capable of specifically cleaving the (1-4) glycosidic linkages in heparin and heparan sulphate to generate biologically active oligosaccharides with substantially significant and distinct clinical, pharmaceutical and prophylactic/therapeutic applications. Bioavailability and pharmacokinetic behaviour and characteristics of these oligosaccharides vary significantly depending on the origin/nature of the substrate (heparin or heparan sulphate-like glycosaminoglycans), the source of enzyme and method of preparation. Various microorganisms are reported/patented to produce these enzymes with different properties. Heparinases are commercially used for the depolymerization of unfractionated heparin to produce low molecular weight heparins (LMWHs), an effective anticoagulant. Individual LMWHs are chemically different and unique and thus cannot be interchanged therapeutically. Heparinases and LMWHs are reported to control angiogenesis and metastasis also. This review catalogues the degradation of HSGAGs by microbial heparin/heparan sulphate lyases and their potential either specific to the enzymes or with the dual role for generation of oligosaccharides for a new generation of compounds, as shown by various laboratory or clinical studies.

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A Dose-Determining Trial of Heparinase-I (Neutralase™) for Heparin Neutralization in Coronary Artery Surgery

Abstract: Heparinase-I (Neutralase(TM)) successfully restored activated coagulation time with no adverse hemodynamic events in patients undergoing coronary artery surgery with cardiopulmonary bypass in an open-label dose-determining trial.

Cited by 31 publications

References 14 publications

Efficiency of Prostacyclin in the Treatment of Protamine-Mediated Right Ventricular Failure and Acute Pulmonary Hypertension

Efficiency of Prostacyclin in the Treatment of Protamine-Mediated Right Ventricular Failure and Acute Pulmonary Hypertension

Targeting heparin and heparan sulfate protein interactions

Microbial heparin/heparan sulphate lyases: potential and applications

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