There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
<!--Non–Guideline-Supported Use (Adult)-->
|offLabelAdultNoGuideSupport======Condition1=====
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
<!--Pediatric Indications and Dosage-->
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
|fdaLIADPed======Condition1=====
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
<!--Off-Label Use and Dosage (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
|offLabelPedGuideSupport======Condition1=====
* Developed by:
* Class of Recommendation:
* Strength of Evidence:
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Non–Guideline-Supported Use (Pediatric)-->
|offLabelPedNoGuideSupport======Condition1=====
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Contraindications-->
|contraindications=* Condition1
<!--Warnings-->
|warnings=* Description
====Precautions====
* Description
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Postmarketing Experience-->
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Drug Interactions-->
|drugInteractions=* Drug
:* Description
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
<!--Administration and Monitoring-->
|administration=* Oral
* Intravenous
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description
<!--IV Compatibility-->
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
<!--Overdosage-->
|overdose====Acute Overdose===
====Signs and Symptoms====
* Description
====Management====
* Description
'''Aprotinin''', also known as '''bovine pancreatic trypsin inhibitor, BPTI''' (Trasylol®, [[Bayer]]) is a protein, that is used as [[medication]] administered by [[Injection (medicine)|injection]] to reduce [[bleeding]] during complex [[surgery]], such as heart and liver surgery. Its main effect is the slowing down of [[fibrinolysis]], the process that leads to the breakdown of blood clots. The aim in its use is to decrease the need for [[blood transfusion]]s during surgery, as well as end-organ damage due to [[hypotension]] (low blood pressure) as a result of marked blood loss.
===Chronic Overdose===
==Chemistry==
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
Aprotinin is a monomeric (single-chain) globular [[polypeptide]] derived from bovine lung tissue; it has a [[molecular weight]] of 6512 and consists of 16 different [[amino acid]]s arranged in a chain of 58 amino acid residues.<ref name=Mannucci>Mannucci PM. Hemostatic drugs. ''N Engl J Med'' 1998;339:245-53. PMID 9673304.</ref><ref name=Mahdy>Mahdy AM, Webster NR. Perioperative systemic haemostatic agents. ''Br J Anaesth'' 2004;93:842-58. PMID 15277296.</ref>.
Its amino acid sequence is RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRA KRNNF KSAED CMRTC GGA.<ref>Kassell B, Radicevic M, Ansfield MJ, Laskowski Sr M. The basic trypsin inhibitor of bovine pancreas IV. The linear sequence of the 58 amino acids. ''Biochem Biophys Res Commun'' 1965;18:255-8. PMID 14282026.</ref>
<!--Pharmacology-->
The stability of the molecule is due to the 3 [[disulfide bond]]s linking the 6 [[cysteine]] members of the chain (Cys5-Cys55, Cys14-Cys38 and Cys30-Cys51).<ref>Kassell B, Laskowski M Sr. The basic trypsin inhibitor of bovine pancreas. V. The disulfide linkages. ''Biochem Biophys Res Commun'' 1965;20:463-8. PMID 5860161.</ref> The [[lysine]] (15)-[[alanine]] (16) sequence on this strongly basic polypeptide represents the active centre.
<!--Drug box 2-->
|drugBox=<!--Mechanism of Action-->
|mechAction=*
Aprotinin is the [[axiom]]ic member of the protein family of Kunitz-type [[serine protease inhibitor]]s.
<!--Structure-->
|structure=*
It is one of the most thoroughly studied proteins in terms of structure and [[protein folding|folding pathway]]. BPTI was one of the first proteins to have its [[protein structure|structure]] solved by [[protein nuclear magnetic resonance spectroscopy|NMR spectroscopy]]. Nevertheless, its physiological function remains unknown.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
==Mechanism of action==
<!--Pharmacodynamics-->
Aprotinin inhibits several [[serine protease]]s, specifically [[trypsin]], [[chymotrypsin]] and [[plasmin]] at a concentration of about 125,000 IU/ml, and [[kallikrein]] at 300,000 IU/ml<ref name=Mahdy/>. Its action on [[kallikrein]] leads to the inhibition of the formation of [[factor XII]]a. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis<ref name=Mannucci/>.
|PD=There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
==Efficacy==
<!--Pharmacokinetics-->
In cardiac surgery with a high risk of significant blood loss, aprotinin significantly reduced bleeding, mortality and hospital stay<ref name=Mahdy/>. Beneficial effects were also reported in high-risk orthopedic surgery<ref name=Mahdy/>. In [[liver transplantation]], initial reports of benefit were overshadowed by concerns about toxicity<ref name=Xia>Xia VW, Steadman RH. Antifibrinolytics in orthotopic liver transplantation: current status and controversies. ''Liver Transpl'' 2005;11:10-8. PMID 15690531.</ref>.
|PK=There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.
In a [[meta-analysis]] performed in 2004, transfusion requirements decreased by 39% in [[coronary artery bypass graft]] (CABG) surgery<ref name=Sedrakyan>Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. ''J Thorac Cardiovasc Surg'' 2004;128:442-8. PMID 15354106.</ref>. In orthopedic surgery, a decrease of blood transfusions was likewise confirmed<ref name=Shiga>Shiga T, Wajima Z, Inoue T, Sakamoto A. Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials. ''Anesth Analg'' 2005;101:1602-7. PMID 16301226.</ref>.
<!--Nonclinical Toxicology-->
|nonClinToxic=There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
==Safety==
<!--Clinical Studies-->
There have been concerns about the safety of aprotinin<ref name=Mahdy/>. [[Anaphylaxis]] (a severe allergic reaction) occurs at a rate of 1:200 in first-time use, but [[serology]] (measuring antibodies against aprotinin in the blood) is not carried out in practice to predict anaphylaxis risk because the correct interpretation of these tests is difficult.<ref name=Mahdy/>
|clinicalStudies=There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.
[[Thrombosis]], presumably from overactive inhibition of the fibrinolytic system, may occur at a higher rate, but until 2006 there was limited evidence for this association<ref name=Mahdy/><ref name=Sedrakyan/>. Similarly, while biochemical measures of renal function were known to occasionally deteriorate, there was no evidence that this greatly influenced outcomes<ref name=Mahdy/>. A study performed in cardiac surgery patients reported in 2006 showed that there was indeed a risk of [[acute renal failure]], [[myocardial infarction]] and [[heart failure]], as well as [[stroke]] and [[encephalopathy]]<ref name=Mangano>Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. ''N Engl J Med'' 2006;354:353-65. PMID 16436767.</ref> The study authors recommend older antifibrinolytics (such as [[tranexamic acid]]) in which these risks were not documented<ref name=Mangano/>. The same group updated their data in 2007 and demonstrated similar findings.<ref>{{cite journal |author=Mangano D, Miao Y, Vuylsteke A, Tudor I, Juneja R, Filipescu D, Hoeft A, Fontes M, Hillel Z, Ott E, Titov T, Dietzel C, Levin J |title=Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery |journal=JAMA |volume=297 |issue=5 |pages=471-9 |year=2007 |pmid=17284697}}</ref>
<!--How Supplied-->
|howSupplied=*
|packLabel=<!--Patient Counseling Information-->
|fdaPatientInfo=There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
In September 2006, Bayer A.G. was faulted by the FDA for not revealing during testimony the existence of a commissioned retrospective study of 67,000 patients, 30,000 of whom received Trasylol and the rest other anti-fibrinolytics. The study concluded Trasylol carried greater risks. The FDA was alerted to the study by one of the researchers involved. Although the FDA issued a statement of concern they did not change their recommendation that the drug may benefit certain subpopulations of patients.<ref> Gardiner Harris. F.D.A. says Bayer Failed to Reveal Drug Risk Study. New York Times; September 30, 2006</ref> In a Public Health Advisory Update dated October 3, 2006, the FDA recommended that "physicians consider limiting Trasylol use to those situations in which the clinical benefit of reduced blood loss is necessary to medical management and outweighs the potential risks" and carefully monitor patients. <ref> [http://factsandcomparisons.com/News/ArticlePage.aspx?id=7387 Trasylol Public Health Advisory Update]; October 3, 2006</ref>
<!--Precautions with Alcohol-->
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
On October 29, 2006 the Food and Drug Administration issued a warning that aprotinin may have serious kidney and cardiovascular toxicity. The producer, Bayer, reported to the FDA that additional observation studies showed that it may increase the chance for death, serious kidney damage, congestive heart failure and strokes. FDA warned clinicians to consider limiting use to those situations where the clinical benefit of reduced blood loss is essential to medical management and outweighs the potential risks.<ref>{{cite web | url = http://www.fda.gov/cder/drug/InfoSheets/HCP/aprotininHCP.htm | title = Information for Healthcare Professionals; Aprotinin (marketed as Trasylol) | accessdate = 2006-10-30 | author = U.S. Food and Drug Administration }}</ref>
<!--Brand Names-->
|brandNames=* ®<ref>{{Cite web | title = | url = }}</ref>
No cases of [[bovine spongiform encephalopathy]] transmission by aprotinin have been reported, although the drug was withdrawn in Italy due to fears of this <ref name=Mahdy/>.
<!--Look-Alike Drug Names-->
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref>
==In vitro use==
<!--Drug Shortage Status-->
Small amounts of aprotinin can be added to tubes of drawn blood to enable laboratory measurement of certain rapidly degraded proteins such as [[glucagon]].
|drugShortage=
In cell biology aprotinin is used as a enzyme [[inhibitor]] to prevent protein [[degradation]] during [[lysis]] or homogenizaton of cells and tissues.
}}
{{PillImage
|fileName=No image.jpg
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{{LabelImage
|fileName={{PAGENAME}}11.png
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{{LabelImage
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<!--Pill Image-->
==History==
Initially named "kallikrein inactivator", aprotinin was first isolated from cow [[parotid gland]]s in 1928<ref>Kraut H, Frey EK, Bauer E. ''Z Physiol Chem'' 1928;175:97-114.</ref> and independently as "bovine pancreatic trypsin inhibitor" from cow pancreas in 1936.<ref>Kunitz M, Northrup J. Isolation from beef pancreas of crystalline trypsinogen, trypsin, trypsin inhibitor, and an inhibitor trypsin compound. ''J Gen Physiol'' 1936;19:991-1007. [http://www.jgp.org/cgi/reprint/19/6/991 PDF].</ref> It was purified from bovine lung in 1964.<ref>Kraut H, Bhargava N. Versuche zur Isolierung des Kallikrein-Inaktivators aus Rinderlunge and seine Identifizierung mit dem Inaktivator aus Rinderparotis. ''Z Physiol Chem'' 1964;328:231-7. PMID 14330402.</ref> As it inhibits pancreatic enzymes, it was initially used in the treatment for [[acute pancreatitis]], in which destruction of the gland by its own enzymes is thought to be part of the pathogenesis.<ref>Nugent FW, Warren KW, Jonasson H, Garciadeparedes G. Early experience with trasylol in the treatment of acute pancreatitis. ''South Med J'' 1964;57:1317-21. PMID 14195953.</ref> Its use in major surgery commenced in the 1960s.<ref>Tice DA, Worth Jr MH, Clauss RH, Reed GH. The inhibition of trasylol of fibrinolytic activity associated with cardiovascular operations. ''Surg Gynecol Obstet'' 1964;119:71-4. PMID 14179354.</ref>
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Black Box Warning
ConditionName:
See full prescribing information for complete Boxed Warning.
ConditionName:
Content
Overview
Aprotinin is a {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Condition1
Dosing Information
Dosage
Condition2
Dosing Information
Dosage
Condition3
Dosing Information
Dosage
Condition4
Dosing Information
Dosage
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Aprotinin in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aprotinin in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Aprotinin in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Aprotinin in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aprotinin in pediatric patients.
Contraindications
Condition1
Warnings
ConditionName:
See full prescribing information for complete Boxed Warning.
ConditionName:
Content
Description
Precautions
Description
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Aprotinin in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Aprotinin in the drug label.
