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Revision as of 11:23, 17 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 475995814 of page Aprotinin for the Chem/Drugbox validation project (updated: 'ChEMBL').		Latest revision as of 18:35, 20 July 2024 edit Teaktl17 (talk | contribs)Extended confirmed users18,082 editsm →Chemistry: +wl
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			{{Short description|Antifibrinolytic molecule}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
			{{Infobox drug
	{{Drugbox
	| Verifiedfields = changed		| Verifiedfields = changed
	| verifiedrevid = 447556430		| verifiedrevid = 477350259
	| IUPAC_name = Aprotinin		| IUPAC_name = Aprotinin
	| image = Aprotinin.png		| image = Aprotinin.png
	| width = 181		| width = 181
			<!--Clinical data -->
			| tradename =
	<!--Clinical data-->
	| tradename =
	| Drugs.com = {{drugs.com|monograph|aprotinin}}		| Drugs.com = {{drugs.com|monograph|aprotinin}}
	| pregnancy_category = X		| pregnancy_category = X
	| legal_status = RX/POM		| legal_UK = POM
			| legal_status = Rx-only
	| dependency_liability = None		| dependency_liability = None
	| routes_of_administration = Intravenous		| routes_of_administration = Intravenous
			<!--Pharmacokinetic data -->
	<!--Pharmacokinetic data-->
	| bioavailability = 100% (])		| bioavailability = 100% (])
	| protein_bound =		| protein_bound =
	| metabolism =		| metabolism =
	| elimination_half-life =		| elimination_half-life =
	| excretion =		| excretion =
			<!--Identifiers -->
	<!--Identifiers-->
	| CASNo_Ref = {{cascite|correct|CAS}}
	| CAS_number_Ref = {{cascite|correct|??}}		| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 9087-70-1		| CAS_number = 9087-70-1
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	| ATC_prefix = B02		| ATC_prefix = B02
	| ATC_suffix = AB01		| ATC_suffix = AB01
	| PubChem =		| PubChem =
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank = DB06692		| DrugBank = DB06692
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	| KEGG = D02971		| KEGG = D02971
	| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
	| ChemSpiderID = NA		| ChemSpiderID = none
	| ChEMBL_Ref = {{ebicite|changed|EBI}}		| ChEMBL_Ref = {{ebicite|changed|EBI}}
	| ChEMBL = <!-- blanked - oldvalue: 1201619 -->		| ChEMBL = 1201619
			| IUPHAR_ligand = 6570
	| chemical_formula =
			<!--Chemical data -->
	| C=284 | H=432 | N=84 | O=79 | S=7
			| chemical_formula =
	| molecular_weight = 6511.51 g/mol
			| C=284 | H=432 | N=84 | O=79 | S=7
	| synonyms = Trasylol, bovine pancreatic trypsin inhibitor		| synonyms = Trasylol, bovine pancreatic trypsin inhibitor
	}}		}}
			The drug '''aprotinin''' (Trasylol, previously ] and now Nordic Group pharmaceuticals), is a small protein '''bovine pancreatic trypsin inhibitor''' ('''BPTI'''), or '''basic trypsin inhibitor of bovine pancreas''', which is an ] molecule that inhibits ] and related proteolytic ]s. Under the trade name '''Trasylol''', aprotinin was used as a ] administered by ] to reduce ] during complex ], such as heart and liver surgery. Its main effect is the slowing down of ], the process that leads to the breakdown of blood clots. The aim in its use was to decrease the need for ]s during surgery, as well as end-organ damage due to ] (low blood pressure) as a result of marked blood loss. The drug was temporarily withdrawn worldwide in 2007 after studies suggested that its use increased the risk of complications or death;<ref>{{cite press release|title=Bayer Temporarily Suspends Global Trasylol Marketing |publisher=Trasylol.com |date=2007-11-05 |url=http://www.trasylol.com/Trasylol_11_05_07.pdf |access-date=2007-12-03 |archive-url=https://web.archive.org/web/20110717091728/http://www.trasylol.com/Trasylol_11_05_07.pdf |archive-date=2011-07-17 }}</ref> this was confirmed by follow-up studies. Trasylol sales were suspended in May 2008, except for very restricted research use. In February 2012 the ] (EMA) scientific committee reverted its previous standpoint regarding aprotinin, and has recommended that the suspension be lifted.<ref name=EMA2012>{{cite web | title=European Medicines Agency recommends lifting suspension of aprotinin | url=http://www.ema.europa.eu/ema/pages/news_and_events/news/2012/02/news_detail_001447.jsp | publisher=European Medicines Agency | date=2012-02-17 | access-date=2012-02-22 | archive-date=2014-02-18 | archive-url=https://web.archive.org/web/20140218215114/http://www.ema.europa.eu/ema/pages/news_and_events/news/2012/02/news_detail_001447.jsp }}</ref> Nordic became distributor of aprotinin in 2012.<ref>{{cite web|title=The Nordic Group acquires rights to Trasylol® from Bayer HealthCare |url=http://www.nordicpharmagroup.com/art-4-4-38-the-nordic-group-acquires-rights-to-trasylol-from-bayer-healthcare.html |publisher=The Nordic Group B.V. |access-date=28 January 2014 |archive-url=https://web.archive.org/web/20140201214751/http://www.nordicpharmagroup.com/art-4-4-38-the-nordic-group-acquires-rights-to-trasylol-from-bayer-healthcare.html |archive-date=1 February 2014 }}</ref>
			==Chemistry==
			{{Infobox nonhuman protein
			| Name = Bovine pancreatic trypsin inhibitor
			| image = BPTI_seq_ribbon_sticks.jpg
			| width =
			| caption = BPTI sequence, with its folded 3D structure represented by a ribbon for the secondary structure and a stick model (gray) for the backbone and sidechains.
			| Organism = Bos taurus (domestic cow)
			| TaxID = 9913
			| Symbol = PTI
			| AltSymbols =
			| IUPHAR_id =
			| ATC_prefix =
			| ATC_suffix =
			| ATC_supplemental =
			| CAS_number =
			| CAS_supplemental =
			| DrugBank =
			| EntrezGene = 404172
			| HGNCid =
			| OMIM =
			| PDB = 4PTI
			| PDB_supplemental =
			| RefSeqmRNA = NM_001001554
			| RefSeqProtein = NP_001001554
			| UniProt = P00974
			| ECnumber =
			| Chromosome = 13
			| EntrezChromosome = NC_007311
			| GenLoc_start = 75024552
			| GenLoc_end = 75030832
			}}
			Aprotinin is a monomeric (single-chain) globular ] derived from bovine lung tissue. It has a ] of 6512 Da and consists of 16 different ] types arranged in a chain 58 residues long<ref name=Mannucci>{{cite journal | vauthors = Mannucci PM | title = Hemostatic drugs | journal = The New England Journal of Medicine | volume = 339 | issue = 4 | pages = 245–53 | date = July 1998 | pmid = 9673304 | doi = 10.1056/NEJM199807233390407 }}</ref><ref name=Mahdy>{{cite journal | vauthors = Mahdy AM, Webster NR | title = Perioperative systemic haemostatic agents | journal = British Journal of Anaesthesia | volume = 93 | issue = 6 | pages = 842–58 | date = December 2004 | pmid = 15277296 | doi = 10.1093/bja/aeh227 | doi-access = free }}</ref> that folds into a stable, compact tertiary structure of the 'small SS-rich" type, containing 3 disulfides, a twisted ] and a C-terminal ].<ref>{{cite book | vauthors = Richardson JS | title = Advances in Protein Chemistry Volume 34 | chapter = The anatomy and taxonomy of protein structure | volume = 34 | pages = 167–339 | year = 1981 | pmid = 7020376 | doi = 10.1016/S0065-3233(08)60520-3 | isbn = 978-0-12-034234-1 | series = Advances in Protein Chemistry }}</ref>
			The amino acid sequence for bovine BPTI is RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRA KRNNF KSAED CMRTC GGA.<ref>{{cite journal | vauthors = Kassell B, Radicevic M, Ansfield MJ, Laskowski M | title = The basic trypsin inhibitor of bovine pancreas. IV. The linear sequence of the 58 amino acids | journal = Biochemical and Biophysical Research Communications | volume = 18 | issue = 2 | pages = 255–8 | date = January 1965 | pmid = 14282026 | doi = 10.1016/0006-291X(65)90749-7 }}</ref> There are 10 positively charged lysine (K) and arginine (R) side chains and only 4 negative aspartate (D) and glutamates (E), making the protein strongly ], which accounts for the ''basic'' in its name. (Because of the usual source organism, BPTI is sometimes referred to as ''bovine'' pancreatic trypsin inhibitor.){{citation needed|date=December 2021}}
			The high stability of the molecule is due to the 3 ]s linking the 6 ] members of the chain (Cys5-Cys55, Cys14-Cys38 and Cys30-Cys51).<ref>{{cite journal | vauthors = Kassell B, Laskowski M | title = The basic trypsin inhibitor of bovine pancreas. V. The disulfide linkages | journal = Biochemical and Biophysical Research Communications | volume = 20 | issue = 4 | pages = 463–8 | date = August 1965 | pmid = 5860161 | doi = 10.1016/0006-291X(65)90601-7 }}</ref> The long, basic ] 15 side chain on the exposed loop (at top left in the image) binds very tightly in the specificity pocket at the active site of trypsin and inhibits its enzymatic action. BPTI is synthesized as a longer, precursor sequence, which folds up and then is cleaved into the mature sequence given above.{{citation needed|date=December 2021}}
			BPTI is the classic member of the protein family of ] ]. Its physiological functions include the protective inhibition of the major digestive enzyme trypsin when small amounts are produced, by cleavage of the trypsinogen precursor during storage in the pancreas.{{citation needed|date=December 2021}}
			==Mechanism of drug action==
			Aprotinin is a ] of several ]s, specifically ], ] and ] at a concentration of about 125,000 IU/ml, and ] at 300,000 IU/ml.<ref name=Mahdy/> Its action on ] leads to the inhibition of the formation of ]a. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis.<ref name=Mannucci/>
			==Drug efficacy==
			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 ], initial reports of benefit were overshadowed by concerns about toxicity.<ref name=Xia>{{cite journal | vauthors = Xia VW, Steadman RH | title = Antifibrinolytics in orthotopic liver transplantation: current status and controversies | journal = Liver Transplantation | volume = 11 | issue = 1 | pages = 10–8 | date = January 2005 | pmid = 15690531 | doi = 10.1002/lt.20275 | doi-access = free }}</ref>
			In a ] performed in 2004, transfusion requirements decreased by 39% in ] (CABG) surgery.<ref name=Sedrakyan>{{cite journal | vauthors = Sedrakyan A, Treasure T, Elefteriades JA | title = Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials | journal = The Journal of Thoracic and Cardiovascular Surgery | volume = 128 | issue = 3 | pages = 442–8 | date = September 2004 | pmid = 15354106 | doi = 10.1016/j.jtcvs.2004.03.041 | doi-access = free }}</ref> In orthopedic surgery, a decrease of blood transfusions was likewise confirmed.<ref name=Shiga>{{cite journal | vauthors = Shiga T, Wajima Z, Inoue T, Sakamoto A | s2cid = 33762135 | title = Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials | journal = Anesthesia and Analgesia | volume = 101 | issue = 6 | pages = 1602–7 | date = December 2005 | pmid = 16301226 | doi = 10.1213/01.ANE.0000180767.50529.45 | doi-access = free }}</ref>
			==Drug safety==
			There have been concerns about the safety of aprotinin.<ref name=Mahdy/> ] (a severe allergic reaction) occurs at a rate of 1:200 in first-time use, but ] (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/>
			], 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 ], ] and ], as well as ] and ].<ref name=Mangano>{{cite journal | vauthors = Mangano DT, Tudor IC, Dietzel C | title = The risk associated with aprotinin in cardiac surgery | journal = The New England Journal of Medicine | volume = 354 | issue = 4 | pages = 353–65 | date = January 2006 | pmid = 16436767 | doi = 10.1056/NEJMoa051379 | doi-access = free }}</ref> The study authors recommend older antifibrinolytics (such as ]) 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 | vauthors = Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, Hoeft A, Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J | display-authors = 6 | title = Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery | journal = JAMA | volume = 297 | issue = 5 | pages = 471–9 | date = February 2007 | pmid = 17284697 | doi = 10.1001/jama.297.5.471 | doi-access = }}</ref>
			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 aprotinin and the rest other anti-fibrinolytics. The study concluded aprotinin 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>{{cite news | vauthors = Harris G |url=https://www.nytimes.com/2006/09/30/health/30fda.html |title=F.D.A. Says Bayer Failed to Reveal Drug Risk Study - New York Times |access-date=2007-11-05 |work=The New York Times | date=2006-09-30}}</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>{{cite web |url=http://factsandcomparisons.com/News/ArticlePage.aspx?id=7387 |title=Facts & Comparisons: Trasylol Public Health Advisory Update |access-date=2007-11-05 |archive-date=2012-07-22 |archive-url=https://web.archive.org/web/20120722234427/http://www.factsandcomparisons.com/trade-show-event-schedule.aspx |url-status=dead }}</ref>
			On October 25, 2007, the FDA issued a statement regarding the "Blood conservation using antifibrinolytics" (BART) randomized trial in a cardiac surgery population. The preliminary findings suggest that, compared to other antifibrinolytic drugs (epsilon-aminocaproic acid and tranexamic acid) aprotinin may increase the risk of death.<ref>{{cite web|url=https://www.fda.gov/cder/drug/early_comm/aprotinin.htm |title=Early Communication about an Ongoing Safety Review Aprotinin Injection (marketed as Trasylol) |access-date=2007-10-28 |website=] |archive-url=https://web.archive.org/web/20071030053834/https://www.fda.gov/cder/drug/early_comm/aprotinin.htm |archive-date=2007-10-30 |url-status=live }}</ref> 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=https://www.fda.gov/cder/drug/InfoSheets/HCP/aprotininHCP.htm |title=Information for Healthcare Professionals; Aprotinin (marketed as Trasylol) |access-date=2006-10-30 |website=] |archive-url=https://web.archive.org/web/20061010033920/https://www.fda.gov/cder/drug/InfoSheets/HCP/aprotininHCP.htm |archive-date=2006-10-10 |url-status=live }}</ref> On November 5, 2007, Bayer announced that it was withdrawing Aprotinin because of a Canadian study that showed it increased the risk of death when used to prevent bleeding during heart surgery.<ref>{{cite news | url = https://www.nytimes.com/2007/11/05/health/05cnd-bayer.html?hp | title = Bayer Withdraws Heart Surgery Drug | access-date = 2007-11-05 | vauthors = Harris G | work=The New York Times | date=2007-11-05}}</ref>
			Two studies published in early 2008, both comparing aprotinin with ], found that mortality was increased by 32<ref>{{cite journal | vauthors = Shaw AD, Stafford-Smith M, White WD, Phillips-Bute B, Swaminathan M, Milano C, Welsby IJ, Aronson S, Mathew JP, Peterson ED, Newman MF | display-authors = 6 | title = The effect of aprotinin on outcome after coronary-artery bypass grafting | journal = The New England Journal of Medicine | volume = 358 | issue = 8 | pages = 784–93 | date = February 2008 | pmid = 18287601 | doi = 10.1056/NEJMoa0707768 | doi-access = free }}</ref> and 64%,<ref name=Schneewiss>{{cite journal | vauthors = Schneeweiss S, Seeger JD, Landon J, Walker AM | title = Aprotinin during coronary-artery bypass grafting and risk of death | journal = The New England Journal of Medicine | volume = 358 | issue = 8 | pages = 771–83 | date = February 2008 | pmid = 18287600 | doi = 10.1056/NEJMoa0707571 | doi-access = free }}</ref> respectively. One study found an increased risk in need for dialysis and revascularisation.<ref name=Schneewiss/>
			No cases of ] transmission by aprotinin have been reported, although the drug was withdrawn in Italy due to fears of this.<ref name=Mahdy/>
			==In vitro use==
			Small amounts of aprotinin can be added to tubes of drawn blood to enable laboratory measurement of certain rapidly degraded proteins such as ].{{citation needed|date=December 2021}}
			In cell biology aprotinin is used as an ] to prevent protein ] during ] or ] of cells and tissues.{{citation needed|date=December 2021}}
			Aprotinin can be labelled with fluorescein isothiocyanate. The conjugate retains its antiproteolytic and carbohydrate-binding properties<ref>{{cite journal | vauthors = Stoddart RW, Kernan JA | s2cid = 44549220 | title = Aprotinin, a carbohydrate-binding protein | journal = Histochemie. Histochemistry. Histochimie | volume = 34 | issue = 4 | pages = 275–80 | date = March 1973 | pmid = 4266832 | doi = 10.1007/BF00306299 }}</ref> and has been used as a fluorescent histochemical reagent for staining glycoconjugates (mucosubstances) that are rich in uronic or sialic acids.<ref>{{cite journal | vauthors = Kiernan JA, Stoddart RW | title = Fluorescent-labelled aprotinin: a new reagent for the histochemical detection of acid mucosubstances | journal = Histochemistry | volume = 34 | issue = 1 | pages = 77–84 | year = 1973 | pmid = 4119444 | doi = 10.1007/BF00304309 | s2cid = 32032724 }}</ref>
			==History==
			Initially named "kallikrein inactivator", aprotinin was first isolated from cow ]s in 1930.<ref>{{cite journal|doi=10.1515/bchm2.1930.192.1-3.1|year=1930|vauthors=Kraut H, Frey EK, Bauer E |title=Über die Inaktivierung des kallikreins | language=de|journal=Hoppe-Seyler's Z Physiol Chem|volume=192|pages=1–21}}</ref> and independently as a trypsin inhibitor from bovine pancreas in 1936.<ref>{{cite journal | vauthors = Kunitz M, Northrop JH | title = Isolation from beef pancreas of crystalline trypsinogen, trypsin, trypsin inhibitor, and an inhibitor trypsin compound | journal = The Journal of General Physiology | volume = 19 | issue = 6 | pages = 991–1007 | date = July 1936 | pmid = 19872978 | pmc = 2141477 | doi = 10.1085/jgp.19.6.991 }}</ref> It was purified from bovine lung in 1964.<ref>{{cite journal | vauthors = Kraut H, Bhargava N |title=Versuche zur Isolierung des Kallikrein-Inaktivators aus Rinderlunge and seine Identifizierung mit dem Inaktivator aus Rinderparotis | trans-title = Experiments on the Isolation of the Kallikrein Inactivator. V. The Isolation of a Kallikrein Inactivator From the Bovine Lung and Its Identification With the Inhibitor From the Bovine Parotid Gland | language = de | journal = Hoppe-Seyler's Zeitschrift für Physiologische Chemie | volume = 338 | pages = 231–7 | year = 1964 | pmid = 14330402 | doi = 10.1515/bchm2.1964.338.1-2.231 }}</ref> As it inhibits pancreatic enzymes, it was initially used in the treatment for ], in which destruction of the gland by its own enzymes is thought to be part of the pathogenesis.<ref>{{cite journal | vauthors = Nugent FW, Warren KW, Jonasson H, Garciadeparedes G | title = Early Experience With Trasylol in the Treatment of Acute Pancreatitis | journal = Southern Medical Journal | volume = 57 | issue = 11 | pages = 1317–21 | date = November 1964 | pmid = 14195953 | doi = 10.1097/00007611-196411000-00012 | s2cid = 5286289 }}</ref> Its use in major surgery commenced in the 1960s.<ref>{{cite journal | vauthors = Tice DA, Worth MH, Clauss RH, Reed GH | title = The Inhibition of Trasylol of Fibrinolytic Activity Associated With Cardiovascular Operations | journal = Surgery, Gynecology & Obstetrics | volume = 119 | pages = 71–4 | date = July 1964 | pmid = 14179354 }}</ref>
			BPTI is one of the most thoroughly studied proteins in terms of ], experimental and computational dynamics, mutagenesis, and ]. It was one of the earliest protein crystal structures solved, in 1970 in the laboratory of ],<ref>{{cite journal | vauthors = Huber R, Kukla D, Rühlmann A, Epp O, Formanek H | s2cid = 6261274 | title = The basic trypsin inhibitor of bovine pancreas. I. Structure analysis and conformation of the polypeptide chain | journal = Die Naturwissenschaften | volume = 57 | issue = 8 | pages = 389–92 | date = August 1970 | pmid = 5447861 | doi = 10.1007/BF00599976 | bibcode = 1970NW.....57..389H }}</ref> and it's substrate-like interaction mode deciphered in the context of the bovine trypsin complex in 1974.<ref>{{cite journal | vauthors = Huber R, Kukla D, Bode W, Schwager P, Bartels K, Deisenhofer J, Steigemann W | title = Structure of the complex formed by bovine trypsin and bovine pancreatic trypsin inhibitor. II. Crystallographic refinement at 1.9 A resolution | journal = Journal of Molecular Biology | volume = 89 | issue = 1 | pages = 73–101 | date = October 1974 | pmid = 4475115 | doi = 10.1016/0022-2836(74)90163-6 }}</ref> It later also became famous being the first protein to have its ] determined by ], in the laboratory of ] at the ETH in Zurich in the early 1980s.<ref>{{cite journal | vauthors = Wagner G, Wüthrich K | title = Sequential resonance assignments in protein 1H nuclear magnetic resonance spectra. Basic pancreatic trypsin inhibitor | journal = Journal of Molecular Biology | volume = 155 | issue = 3 | pages = 347–66 | date = March 1982 | pmid = 6176717 | doi = 10.1016/0022-2836(82)90009-2 }}</ref><ref>{{cite journal | vauthors = Havel TF, Wüthrich K | title = An evaluation of the combined use of nuclear magnetic resonance and distance geometry for the determination of protein conformations in solution | journal = Journal of Molecular Biology | volume = 182 | issue = 2 | pages = 281–94 | date = March 1985 | pmid = 2582141 | doi = 10.1016/0022-2836(85)90346-8 }}</ref>
			Because it is a small, stable protein whose structure had been determined at high resolution by 1975,<ref>{{cite journal | vauthors = Deisenhofer J, Steigemann W |title= Crystallographic Refinement of the Structure of Bovine Pancreatic Trypsin Inhibitor at 1.5 Angstroms Resolution |year=1975 |journal=Acta Crystallographica B |volume=31 |pages=238 |doi=10.1107/S0567740875002415 |url=http://journals.iucr.org/b/issues/1975/01/00/a11880/a11880.pdf }}</ref> it was the first macromolecule of scientific interest to be simulated using ] computation, in 1977 by ] and Bruce Gelin, in the ] group at Harvard.<ref>{{cite journal | vauthors = McCammon JA, Gelin BR, Karplus M | s2cid = 4222220 | title = Dynamics of folded proteins | journal = Nature | volume = 267 | issue = 5612 | pages = 585–90 | date = June 1977 | pmid = 301613 | doi = 10.1038/267585a0 | bibcode = 1977Natur.267..585M }}</ref> That study confirmed the then-surprising fact found in the NMR work<ref>{{cite journal | vauthors = Wüthrich K, Wagner G | title = NMR investigations of the dynamics of the aromatic amino acid residues in the basic pancreatic trypsin inhibitor | journal = FEBS Letters | volume = 50 | issue = 2 | pages = 265–8 | date = February 1975 | pmid = 234403 | doi = 10.1016/0014-5793(75)80504-7 | s2cid = 46084481 | doi-access = }}</ref> that even well-packed aromatic sidechains in the interior of a stable protein can flip over rather rapidly (microsecond to millisecond time scale). Rate constants were determined by NMR for the hydrogen exchange of individual peptide NH groups along the chain, ranging from too fast to measure on the most exposed surface to many months for the most buried hydrogen-bonded groups in the center of the β sheet, and those values also correlate fairly well with degree of motion seen in the dynamics simulations.
			BPTI was important in the development of knowledge about the process of ], the self-assembly of a polypeptide chain into a specific arrangement in 3D. The problem of achieving the correct pairings among the 6 Cys sidechains was shown to be especially difficult for the two buried, close-together SS near the BPTI chain termini, requiring a non-native intermediate for folding the mature sequence ''in vitro'' (it was later discovered that the precursor sequence folds more easily ''in vivo''). BPTI was the cover image on a protein folding compendium volume by Thomas Creighton in 1992.<ref>{{cite book | vauthors = Creighton TE |title= Protein Folding |year= 1992 |publisher= W. H. Freeman |isbn=978-0-7167-7027-5 }}</ref>
			==Current findings==
			One scientific study in rats reported that treatment with aprotinin prevents disruption of the blood–brain barrier during the ] infection.<ref name=" pmid = 24398759 ">{{cite journal | vauthors = Xu CY, Zhu HM, Wu JH, Wen H, Liu CJ | title = Increased permeability of blood-brain barrier is mediated by serine protease during Cryptococcus meningitis | journal = The Journal of International Medical Research | volume = 42 | issue = 1 | pages = 85–92 | date = February 2014 | pmid = 24398759 | doi = 10.1177/0300060513504365 | doi-access = free }}</ref> Another study in cell cultures suggests that the drug inhibits SARS-CoV-2 Replication.<ref name="BojkovaBechtel2020">{{cite journal | vauthors = Bojkova D, Bechtel M, McLaughlin KM, McGreig JE, Klann K, Bellinghausen C, Rohde G, Jonigk D, Braubach P, Ciesek S, Münch C, Wass MN, Michaelis M, Cinatl J | display-authors = 6 | title = Aprotinin Inhibits SARS-CoV-2 Replication | journal = Cells | volume = 9 | issue = 11 | pages = 2377 | date = October 2020 | pmid = 33143316 | pmc = 7692688 | doi = 10.3390/cells9112377 | doi-access = free }}</ref>
			== References ==
			{{Reflist}}
			== External links ==
			* The ] online database for peptidases and their inhibitors:
			{{Antihemorrhagics}}
			{{Authority control}}
			]
			]