Hirudin: Difference between revisions

Latest revision as of 04:17, 3 February 2014

Desirudin
IPRIVASK^® FDA Package Insert
Indications and Usage
Dosage and Administration
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
Nonclinical Toxicology
Clinical Studies
How Supplied/Storage and Handling
Labels and Packages
Clinical Trials
ClinicalTrials.gov

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]

Overview

Iprivask® (desirudin for injection) is a specific inhibitor of human thrombin. It has a protein structure that is similar to that ofHirudin, the naturally occurring anticoagulant present in the peripharyngeal glands in the medicinal leech, Hirudo medicinalis. Hirudin is a single polypeptide chain of 65 amino acids residues and contains three disulfide bridges. Desirudin has a chemical formula of C287H440N80O110S6 with a molecular weight of 6963.52. Desirudin, which is expressed in yeast (Saccharomyces cerevisiae,strain TR 1456) by recombinant DNA technology differs from the naturalHirudin by lack of a sulfate group on Tyr-63. The biological activity of desirudin is determined through a chromogenic assay which measures the ability of desirudin to inhibit the hydrolysis of a chromogenic peptidic substrate by thrombin in comparison to a desirudin standard. One vial of desirudin contains 15.75 mg desirudin corresponding to approximately 315,000 antithrombin units (ATU) or 20,000 ATU per milligram of desirudin with reference to the WHO International Standard (prepared 1991) for alphathrombin.

US Brand Names

IPRIVASK

FDA Package Insert

Mechanism of Action

Desirudin is a selective inhibitor of free circulating and clot-bound thrombin. The anticoagulant properties of desirudin are demonstrated by its ability to prolong the clotting time of human plasma. One molecule of desirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected. Activated partial thromboplastin time (aPTT) is a measure of the anticoagulant activity of desirudin and increases in a dose-dependent fashion. The pharmacodynamic effect of desirudin on proteolytic activity of thrombin was assessed as an increase in aPTT. A mean peak aPTT prolongation of about 1.38 times baseline value (range 0.58 to 3.41) was observed following subcutaneous b.i.d. injections of 15 mg desirudin. Thrombin time (TT) frequently exceeds 200 seconds even at low plasma concentrations of desirudin, which renders this test unsuitable for routine monitoring of Iprivask therapy. At therapeutic serum concentrations, desirudin has no effect on other enzymes of the hemostatic system such as factors IXa, Xa, kallikrein, plasmin, tissue plasminogen activator, or activated protein C. In addition, it does not display any effect on other serine proteases, such as the digestive enzymes trypsin, chymotrypsin, or on complement activation by the classical or alternative pathways.

References

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+|[[File:Desirudin01.jpg|thumb|900px|center]]
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 ==Overview==
-'''Hirudin''' is a naturally occurring [[peptide]] in the [[salivary gland]]s of medicinal [[leech]]es (such as ''[[Hirudo medicinalis]]'') that has a blood [[anticoagulant]] property. This is fundamental for the leeches’ alimentary habit of hematophagy, since it keeps the blood flowing after the initial [[phlebotomy]] performed by the worm on the host’s skin.
-==Structure==
+Iprivask® (desirudin for injection) is a specific inhibitor of human thrombin. It has a protein structure that is similar to that of[[Hirudin]], the naturally occurring anticoagulant present in the peripharyngeal glands in the medicinal leech, Hirudo medicinalis. [[Hirudin]] is a single polypeptide chain of 65 amino acids residues and contains three disulfide bridges. Desirudin has a chemical formula of C287H440N80O110S6 with a molecular weight of 6963.52. Desirudin, which is expressed in yeast (Saccharomyces cerevisiae,strain TR 1456) by recombinant DNA technology differs from the natural[[Hirudin]] by lack of a sulfate group on Tyr-63. The biological activity of desirudin is determined through a chromogenic assay which measures the ability of desirudin to inhibit the hydrolysis of a chromogenic peptidic substrate by thrombin in comparison to a desirudin standard. One vial of desirudin contains 15.75 mg desirudin corresponding to approximately 315,000 antithrombin units (ATU) or 20,000 ATU per milligram of desirudin with reference to the WHO International Standard (prepared 1991) for alphathrombin.
-In 1884, the British physiologist John Berry Haycraft discovered that the leech secreted a powerful anticoagulant, which he named hirudin, though it was not isolated until the 1950s, nor its structure fully determined until 1976. Full length, hirudin is made up of 65 amino acids. These amino acids are organised into a compact N-terminal domain containing three [[disulfide bonds]] and a C-terminal domain which is completely disordered, when the protein is [[protein complex| un-complexed]] in solution.<ref>{{cite journal | author = Folkers PJM, Clore GM. ''et al''. | title = Solution structure of recombinant hirudin and the Lys-47-Glu mutant: a nuclear magnetic resonance and hybrid distance geometry-dynamical simulated annealing study | journal = Biochemistry | year=1989 | volume=28 | pages=2601-2617 | issue=6 | id = PMID 2567183}}</ref><ref>{{cite journal | author = Haruyama H. and Wuthrich K. | title = Conformation of recombinant desulfatohirudin in aqueous solution determined by nuclear magnetic resonance | journal = Biochemistry | year=1989 | volume=28 | pages=4301-4312 | issue=10 | id = PMID 2765488}}</ref> Natural hirudin contains a mixture of various [[protein isoform| isoforms]] of the protein. However, [[recombinant]] techniques can be used to produce [[homogeneous]] preparations of hirudin.<ref name=Rydell>{{cite journal | author = Rydell TJ, Tulinsky A. ''et al''. | title = Refined structure of the Hirudin-Thrombin complex | journal = J. Mol. Biol. | year=1991 | volume=221 | pages=583-601 | issue=2 | id = PMID 1920434}}</ref>
+==Category==
-==Biological activity==
+Anticoagulants:Direct thrombin (II) inhibitors
-A key event in the final stages of [[blood coagulation]] is the conversion of [[fibrinogen]] into [[fibrin]] by the [[serine protease]] enzyme [[thrombin]].<ref>{{cite journal | author = Fenton JW 2nd, Ofosu SA ''et al''. | title = Thrombin and antithrombotics | journal = Semin Thromb Hemost | year=1998 | volume=24 | pages=87-91 | issue=2 | id = PMID 9579630}}</ref> Thrombin is produced from [[prothrombin]], by the action of an enzyme, prothrombinase, in the final states of coagulation. Fibrin is then cross linked by factor XIII to form a [[blood clot]]. The principal [[Enzyme inhibitor| inhibitor]] of [[thrombin]] in normal blood circulation is [[antithrombin III]].<ref name=Rydell/> Similar to [[antithrombin III]], the anticoagulatant activity of hirudin is based on its ability to inhibit the pro-coagulant activity of [[thrombin]].
+==US Brand Names==
-Hirudin is the most potent natural inhibitor of thrombin. Unlike [[antithrombin III]] hirudin binds to and inhibits only the activity of thrombin forms with a specific activity on fibrinogen.<ref name=Rydell/> Therefore, hirudin prevents or dissolves the formation of clots and [[thrombus|thrombi]] (i.e. it has a [[thrombolysis|thrombolytic activity]]), and has therapeutic value in [[blood diseases|blood coagulation disorder]]s, in the treatment of [[skin]] [[hematoma]]s and of superficial [[varicose vein]]s, either as an injectable or a topical application cream. In some aspects, hirudin has advantages over more commonly used anticoagulants and thrombolytics, such as [[heparin]], as it does not interfere with the biological activity of other serum proteins and can also act on [[protein complex| complexed]] thrombin.
+IPRIVASK
+==FDA Package Insert==
-It is difficult to extract large amounts of hirudin from natural sources, so a method for producing and purifying this protein using [[recombinant]] [[biotechnology]] has been developed. This has led to the development and marketing of a number of hirudin based anticoagulant pharmaceutical products such as [[lepirudin]] (Refludan®) and [[Desirudin]] (Revasc/Iprivask®). Several other [[direct thrombin inhibitor]]s are derived chemically from hirudin.
+'''| [[Desirudin indications and usage|Indications and Usage]]'''
+'''| [[Desirudin dosage and administration|Dosage and Administration]]'''
+'''| [[Desirudin contraindications|Contraindications]]'''
+'''| [[Desirudin warnings and precautions|Warnings and Precautions]]'''
+'''| [[Desirudin adverse reactions|Adverse Reactions]]'''
+'''| [[Desirudin drug interactions|Drug Interactions]]'''
+'''| [[Desirudin use in specific populations|Use in Specific Populations]]'''
+'''| [[Desirudin overdosage|Overdosage]]'''
+'''| [[Desirudin description|Description]]'''
+'''| [[Desirudin clinical pharmacology|Clinical Pharmacology]]'''
+'''| [[Desirudin nonclinical toxicology|Nonclinical Toxicology]]'''
+'''| [[Desirudin clinical studies|Clinical Studies]]'''
+'''| [[Desirudin how supplied storage and handling|How Supplied/Storage and Handling]]'''
+'''| [[Desirudin labels and packages|Labels and Packages]]'''
+==Mechanism of Action==
+Desirudin is a selective inhibitor of free circulating and clot-bound thrombin. The anticoagulant properties of desirudin are demonstrated by its ability to prolong the clotting time of human plasma. One molecule of desirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected. Activated partial thromboplastin time (aPTT) is a measure of the anticoagulant activity of desirudin and increases in a dose-dependent fashion. The pharmacodynamic effect of desirudin on proteolytic activity of thrombin was assessed as an increase in aPTT. A mean peak aPTT prolongation of about 1.38 times baseline value (range 0.58 to 3.41) was observed following subcutaneous b.i.d. injections of 15 mg desirudin. Thrombin time (TT) frequently exceeds 200 seconds even at low plasma concentrations of desirudin, which renders this test unsuitable for routine monitoring of Iprivask therapy. At therapeutic serum concentrations, desirudin has no effect on other enzymes of the hemostatic system such as factors IXa, Xa, kallikrein, plasmin, tissue plasminogen activator, or activated protein C. In addition, it does not display any effect on other serine proteases, such as the digestive enzymes trypsin, chymotrypsin, or on complement activation by the classical or alternative pathways.
 ==References==
-{{reflist}}
-==See also==
+{{Reflist|2}}
-* [http://www.leechesturkey.com Supplier of Hirudo Medicinalis TURKEY]
-*[[Hirudotherapy]]
 {{Antithrombotics}}
-{{SIB}}
+[[Category:Direct thrombin (II) inhibitors]]
 [[Category:Anticoagulants]]
-[[Category:Peptides]]
+[[Category:Cardiovascular Drugs]]
-[[Category:Hematology]]
-[[Category:Drugs]]
-[[de:Hirudin]]
-[[es:Hirudina]]
-[[fr:Hirudine]]
-[[nl:Hirudine]]
-[[pl:Hirudyna]]
-[[pt:Hirudina]]
-[[sl:Hirudin]]
-[[fi:Hirudiini]]
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