Aprotinin

Identification

Summary

Aprotinin is a serine protease inhibitor used to reduce the risk for perioperative blood loss and the need for blood transfusion in high-risk patients during cardiopulmonary bypass for coronary artery bypass graft surgery.

Brand Names
Artiss, Tisseel, Trasylol
Generic Name
Aprotinin
DrugBank Accession Number
DB06692
Background

Aprotinin is a protein-based drug that is also known as bovine pancreatic trypsin inhibitor (BPTI). Since it demonstrates the capacity to slow fibrinolysis, it has been employed to reduce bleeding during complex surgery such as heart and liver surgery. For this use, it is typically administered by injection. The goal of using of aprotinin was subsequently to minimize end-organ damage resulting from hypotension due to blood loss in surgery and to reduce the necessity for blood transfusions during surgery. Nevertheless, the drug was formally withdrawn worldwide in May of 2008 after studies confirmed that its use enhanced the risk of complications or death. The substance is consequently made available only for very restricted research use.

Type
Biotech
Groups
Approved, Investigational, Withdrawn
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Structure
Db06692
Protein Chemical Formula
C284H432N84O79S7
Protein Average Weight
6511.439 Da
Sequences
>Aprotinin (bovine pancreatic trypsin inhibitor)
RPDFCLEPPYTGPCKARIIRYFYNAKAGLCQTFVYGGCRAKRNNFKSAEDCMRTCGGA
Download FASTA Format
Synonyms
  • Aprotinin
  • Aprotinin (bovine)
  • Aprotinin biosynthetic
  • Aprotinin bovine
  • Aprotinin concentrated solution
  • Aprotinina
  • Aprotinine
  • Aprotininum
  • Bovine aprotinin
  • Bovine pancreatic trypsin inhibitor
  • BPTI
  • Fibrinolysis inhibitor
  • Trypsin inhibitor, pancreatic basic
External IDs
  • 232-994-9
  • Bayer A 128
  • Bayer-A-128
  • BAYERA-128
  • RIKER 52G
  • Riker-52G
  • RP 9921
  • RP-9921

Pharmacology

Indication

For prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.

Pharmacology
Reduce drug development failure rates
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Associated Therapies
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Aprotinin is a broad spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators [e.g., kallikrein, plasmin] results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation. Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b). The effects of aprotinin use in CPB involves a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding.

Mechanism of action

Aprotinin inhibits serine proteases including trypsin, chymotrypsin and plasmin at a concentration of about 125,000 IU/mL, and kallikrein at 300,000 IU/mL. The inhibition of kallikrein inhibits formation of factor XIIa. This inhibits the intrinsic pathway of coagulation and fibrinolysis. Inhibition of plasmin also slows fibrinolysis.

TargetActionsOrganism
UTrypsin-1Not AvailableHumans
UChymotrypsinogen BNot AvailableHumans
UPlasminogenNot AvailableHumans
UKallikrein-1Not AvailableHumans
Absorption

100% (IV)

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Aprotinin is slowly degraded by lysosomal enzymes.

Route of elimination

Following a single IV dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of the dose.

Half-life

Following this distribution phase, a plasma half-life of about 150 minutes is observed. At later time points, (i.e., beyond 5 hours after dosing) there is a terminal elimination phase with a half-life of about 10 hours.

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
PathwayCategory
Aprotinin Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcebutololAprotinin may increase the bradycardic activities of Acebutolol.
AcetylcholineThe risk or severity of adverse effects can be increased when Aprotinin is combined with Acetylcholine.
AclidiniumAprotinin may increase the neuromuscular blocking activities of Aclidinium.
Albutrepenonacog alfaAprotinin may increase the thrombogenic activities of Albutrepenonacog alfa.
Alpha-1-proteinase inhibitorAlpha-1-proteinase inhibitor may increase the thrombogenic activities of Aprotinin.
AlteplaseThe therapeutic efficacy of Alteplase can be decreased when used in combination with Aprotinin.
AmantadineThe therapeutic efficacy of Amantadine can be decreased when used in combination with Aprotinin.
AmifampridineThe risk or severity of adverse effects can be increased when Aprotinin is combined with Amifampridine.
Aminocaproic acidAminocaproic acid may increase the thrombogenic activities of Aprotinin.
AmitriptylineThe therapeutic efficacy of Amitriptyline can be decreased when used in combination with Aprotinin.
Interactions
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TrasylolSolution2000000 1/200mLIntravenousBayer Pharmaceuticals Corporation1993-12-292008-05-22US flag
TrasylolSolution10000 unit / mLIntravenousNordic Group Bv1997-12-15Not applicableCanada flag
TrasylolSolution1000000 1/100mLIntravenousBayer Pharmaceuticals Corporation1993-12-292008-05-22US flag
Trasylol Inj 10000 Kiu/mlLiquid100000 unit / ampIntravenousMiles Inc. Pharmaceutical Division1981-12-311998-09-25Canada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ArtissAprotinin (3000 kiu / mL) + Calcium chloride (40 mcmol / mL) + Fibrinogen human (125 mg / mL) + Human thrombin (4 unit / mL)SolutionTopicalBaxter Laboratories2011-12-18Not applicableCanada flag
ARTISS 10 ML ÇÖZELTİ İÇEREN KULLANIMA HAZIR ENJEKTOR, 1 ADETAprotinin (3000 KIU/ml) + Calcium chloride dihydrate (40 mcmol/ml) + Fibrinogen human (91 mg/ml) + Thrombin (4 IU/ml)SolutionTopicalBAXTER TURKEY RENAL HİZMETLER A.Ş.2020-08-14Not applicableTurkey flag
ARTISS 2 ML ÇÖZELTİ İÇEREN KULLANIMA HAZIR ENJEKTOR, 1 ADETAprotinin (3000 KIU/ml) + Calcium chloride dihydrate (40 mcmol/ml) + Fibrinogen human (91 mg/ml) + Thrombin (4 IU/ml)SolutionTopicalBAXTER TURKEY RENAL HİZMETLER A.Ş.2020-08-14Not applicableTurkey flag
ARTISS 4 ML ÇÖZELTİ İÇEREN KULLANIMA HAZIR ENJEKTOR, 1 ADETAprotinin (3000 KIU/ml) + Calcium chloride dihydrate (40 mcmol/ml) + Fibrinogen human (91 mg/ml) + Thrombin (4 IU/ml)SolutionTopicalBAXTER TURKEY RENAL HİZMETLER A.Ş.2020-08-14Not applicableTurkey flag
BERIPLAST-P COMBI SET 1 ML TROMBİN ÇÖZELTİSİ VE 1 ML FİBRİNOJEN ÇÖZELTİSİ İÇEREN FİBRİN YAPIŞTIRICIAprotinin (1000 KIU/ml) + Antihemophilic factor human (60 IU/ml) + Calcium chloride dihydrate (5.9 mg/ml) + Fibrinogen human (90 mg/ml) + Thrombin (500 IU/ml)SolutionCSL BEHRİNG BİYOTERAPİ İLAÇ DIŞ TİC. A.Ş.2020-08-14Not applicableTurkey flag
BERIPLAST-P COMBI SET 3 ML TROMBİN ÇÖZELTİSİ VE 1 ML FİBRİNOJEN ÇÖZELTİSİ İÇEREN FİBRİN YAPIŞTIRICIAprotinin (1000 KIU/ml) + Antihemophilic factor human (60 IU/ml) + Calcium chloride dihydrate (5.9 mg/ml) + Fibrinogen human (90 mg/ml) + Thrombin (500 IU/ml)SolutionCSL BEHRİNG BİYOTERAPİ İLAÇ DIŞ TİC. A.Ş.2020-08-14Not applicableTurkey flag
TİSSE İNTERNASYONEL SAĞ. ÜR. İTH. İHR. PAZ. SAN. VE TİC. LTD. ŞTİ.EL LYO 1 ML TROMBIN ÇÖZELTİSİ VE 1 ML FIBRINOJEN ÇÖZELTİSİ ICEREN IKI BILESENLI FIBRIN YAPISTIRICI, SET 1 (2 İĞNE+2 ENJEKTÖR) VE SET 2 (2 İĞNE +2 ENJEKTÖR+1 ENJEKTÖR KLİPSİ+2 BİRLEŞTİRME PARÇASI+ 4 APLİKASYON İĞNESİAprotinin (3000 KIU/mL) + Calcium chloride (40 µmol/mL) + Fibrinogen human (91 mg/mL) + Thrombin (500 IU/mL)Kit; SolutionECZACIBAŞI-BAXTER HASTANE ÜRÜNLERİ SAN.VE TİC. A.Ş.2020-08-142017-11-02Turkey flag
TisseelAprotinin (3000 kiu / mL) + Calcium chloride (40 mcmol / mL) + Fibrinogen human (125 mg / mL) + Human thrombin (500 unit / mL)SolutionTopicalBaxter Laboratories2011-06-20Not applicableCanada flag
TisseelAprotinin (3000 kiu / mL) + Calcium chloride (40 mcmol / mL) + Fibrinogen human (125 mg / mL) + Human thrombin (500 unit / mL)KitTopicalBaxter Laboratories2011-12-14Not applicableCanada flag
TISSEEL 10 ML ÇÖZELTİ İÇEREN KULLANIMA HAZIR ENJEKTÖR 1 ADETAprotinin (3000 KIU/mL) + Calcium chloride (40 µmol/mL) + Fibrinogen human (91 mg/mL) + Thrombin (500 IU/mL)Kit; SolutionBAXTER TURKEY RENAL HİZMETLER A.Ş.2020-08-14Not applicableTurkey flag

Categories

ATC Codes
B02AB01 — Aprotinin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
04XPW8C0FL
CAS number
9087-70-1

References

Synthesis Reference

Marion Steinbuch, Jacques Chabbat, Olivier Taby, "Process for preparation of activated protein C by immobilized aprotinin chromatography." U.S. Patent US5198534, issued February, 1985.

US5198534
General References
  1. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [Article]
KEGG Drug
D02971
PubChem Substance
347910361
RxNav
353110
ChEMBL
CHEMBL1201619
Therapeutic Targets Database
DAP000185
PharmGKB
PA448472
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Aprotinin
FDA label
Download (108 KB)
MSDS
Download (19.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentControl of Local Bleeding in Patients Undergoing Prostatectomy1
3CompletedPreventionSurgical Blood Loss1
3CompletedTreatmentHemostasis in Participants Receiving Peripheral Vascular Expanded Polytetrafluoroethylene (ePTFE) Graft Prostheses1
3TerminatedPreventionPostoperative Hemorrhages / Surgical Blood Loss1
3TerminatedTreatmentPostoperative Hemorrhages / Surgical Blood Loss1
3TerminatedTreatmentSurgical Blood Loss1
3Unknown StatusPreventionAllogeneic Blood Transfusions / Aortic Valve Replacement / Bleeding and Cardiac Surgery / Coronary Artery Bypass Grafting (CABG)1
2CompletedTreatmentDura Defects / Pathological Processes in the Posterior Fossa1
2CompletedTreatmentFacial Rhytidectomy (Face-lift)1
2Unknown StatusTreatmentBile Leak / Common Bile Duct Gallstones / Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Baxter International Inc.
  • Bayer Healthcare
Dosage Forms
FormRouteStrength
SolutionTopical
Solution
PowderTopical
Powder, for solutionTopical
KitTopical
Kit; solution
PowderSoft tissue
SolutionIntravenous10000 unit / mL
SolutionIntravenous1000000 1/100mL
SolutionIntravenous2000000 1/200mL
SolutionIntravenous
LiquidIntravenous100000 unit / amp
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)>100 °CNot Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific Function
Has activity against the synthetic substrates Boc-Phe-Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val-Pro-Arg-Mec. The single-chain form is more active than the two-chain form aga...
Gene Name
PRSS1
Uniprot ID
P07477
Uniprot Name
Trypsin-1
Molecular Weight
26557.88 Da
References
  1. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific Function
Not Available
Gene Name
CTRB1
Uniprot ID
P17538
Uniprot Name
Chymotrypsinogen B
Molecular Weight
27869.74 Da
References
  1. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type peptidase activity
Specific Function
Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In...
Gene Name
PLG
Uniprot ID
P00747
Uniprot Name
Plasminogen
Molecular Weight
90568.415 Da
References
  1. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific Function
Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.
Gene Name
KLK1
Uniprot ID
P06870
Uniprot Name
Kallikrein-1
Molecular Weight
28889.425 Da
References
  1. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Aronson JK (2016). Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions (16th ed.). Amsterdam : Elsevier Science. [ISBN:9780444537164]

Drug created on February 12, 2009 16:44 / Updated on September 28, 2021 07:54