870:
may increase the risk of death. 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. 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.
366:
866:
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. 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.
539:
838:, presumably from overactive inhibition of the fibrinolytic system, may occur at a higher rate, but until 2006 there was limited evidence for this association. Similarly, while biochemical measures of renal function were known to occasionally deteriorate, there was no evidence that this greatly influenced outcomes. A study performed in cardiac surgery patients reported in 2006 showed that there was indeed a risk of
29:
517:(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 The drug was temporarily withdrawn worldwide in 2007 after studies suggested that its use increased the risk of complications or death; this was confirmed by follow-up studies. Trasylol sales were suspended in May 2008, except for very restricted research use. In February 2012 the
985:, 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
869:
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
1908:
Kraut H, Bhargava N (1964). "Versuche zur
Isolierung des Kallikrein-Inaktivators aus Rinderlunge and seine Identifizierung mit dem Inaktivator aus Rinderparotis" [Experiments on the Isolation of the Kallikrein Inactivator. V. The Isolation of a Kallikrein Inactivator From the Bovine Lung and Its
977:
group at
Harvard. That study confirmed the then-surprising fact found in the NMR work 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
865:
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
741:
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.
978:
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.
918:
Aprotinin can be labelled with fluorescein isothiocyanate. The conjugate retains its antiproteolytic and carbohydrate-binding properties and has been used as a fluorescent histochemical reagent for staining glycoconjugates (mucosubstances) that are rich in uronic or sialic acids.
713:
The amino acid sequence for bovine BPTI is RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRA KRNNF KSAED CMRTC GGA. 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
2065:
Huber R, Kukla D, Bode W, Schwager P, Bartels K, Deisenhofer J, Steigemann W (October 1974). "Structure of the complex formed by bovine trypsin and bovine pancreatic trypsin inhibitor. II. Crystallographic refinement at 1.9 A resolution".
752:. 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.
800:
In cardiac surgery with a high risk of significant blood loss, aprotinin significantly reduced bleeding, mortality and hospital stay. Beneficial effects were also reported in high-risk orthopedic surgery. In
931:
in 1930. and independently as a trypsin inhibitor from bovine pancreas in 1936. It was purified from bovine lung in 1964. As it inhibits pancreatic enzymes, it was initially used in the treatment for
1489:
Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, et al. (February 2007). "Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery".
1078:
2136:
Havel TF, Wüthrich K (March 1985). "An evaluation of the combined use of nuclear magnetic resonance and distance geometry for the determination of protein conformations in solution".
521:(EMA) scientific committee reverted its previous standpoint regarding aprotinin, and has recommended that the suspension be lifted. Nordic became distributor of aprotinin in 2012.
2014:
Huber R, Kukla D, Rühlmann A, Epp O, Formanek H (August 1970). "The basic trypsin inhibitor of bovine pancreas. I. Structure analysis and conformation of the polypeptide chain".
965:
Because it is a small, stable protein whose structure had been determined at high resolution by 1975, it was the first macromolecule of scientific interest to be simulated using
109:
832:(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.
950:, and it's substrate-like interaction mode deciphered in the context of the bovine trypsin complex in 1974. It later also became famous being the first protein to have its
436:
1053:
955:
1241:
Kassell B, Radicevic M, Ansfield MJ, Laskowski M (January 1965). "The basic trypsin inhibitor of bovine pancreas. IV. The linear sequence of the 58 amino acids".
702:
types arranged in a chain 58 residues long that folds into a stable, compact tertiary structure of the 'small SS-rich" type, containing 3 disulfides, a twisted
613:
601:
49:
648:
2101:
Wagner G, Wüthrich K (March 1982). "Sequential resonance assignments in protein 1H nuclear magnetic resonance spectra. Basic pancreatic trypsin inhibitor".
2256:
Wüthrich K, Wagner G (February 1975). "NMR investigations of the dynamics of the aromatic amino acid residues in the basic pancreatic trypsin inhibitor".
2451:
543:
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.
1357:"Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials"
2764:
1082:
1987:
Tice DA, Worth MH, Clauss RH, Reed GH (July 1964). "The
Inhibition of Trasylol of Fibrinolytic Activity Associated With Cardiovascular Operations".
935:, in which destruction of the gland by its own enzymes is thought to be part of the pathogenesis. Its use in major surgery commenced in the 1960s.
792:. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis.
877:, found that mortality was increased by 32 and 64%, respectively. One study found an increased risk in need for dialysis and revascularisation.
1549:
1944:
Nugent FW, Warren KW, Jonasson H, Garciadeparedes G (November 1964). "Early
Experience With Trasylol in the Treatment of Acute Pancreatitis".
892:
Small amounts of aprotinin can be added to tubes of drawn blood to enable laboratory measurement of certain rapidly degraded proteins such as
2308:
1217:
1615:
1789:
Kiernan JA, Stoddart RW (1973). "Fluorescent-labelled aprotinin: a new reagent for the histochemical detection of acid mucosubstances".
1584:
881:
579:
2682:
2637:
198:
139:
1001:
One scientific study in rats reported that treatment with aprotinin prevents disruption of the blood–brain barrier during the
2774:
2444:
746:
1022:
1057:
862:) in which these risks were not documented. The same group updated their data in 2007 and demonstrated similar findings.
1861:"Isolation from beef pancreas of crystalline trypsinogen, trypsin, trypsin inhibitor, and an inhibitor trypsin compound"
1610:
1579:
813:
294:
2875:
2569:
1276:
Kassell B, Laskowski M (August 1965). "The basic trypsin inhibitor of bovine pancreas. V. The disulfide linkages".
2730:
2437:
2173:"Crystallographic Refinement of the Structure of Bovine Pancreatic Trypsin Inhibitor at 1.5 Angstroms Resolution"
518:
2579:
912:
247:
2326:"Increased permeability of blood-brain barrier is mediated by serine protease during Cryptococcus meningitis"
884:
transmission by aprotinin have been reported, although the drug was withdrawn in Italy due to fears of this.
2813:
2598:
1661:
Shaw AD, Stafford-Smith M, White WD, Phillips-Bute B, Swaminathan M, Milano C, et al. (February 2008).
594:
558:
97:
361:
904:
509:, the process that leads to the breakdown of blood clots. The aim in its use was to decrease the need for
343:
2545:
843:
802:
761:
238:
2365:
Bojkova D, Bechtel M, McLaughlin KM, McGreig JE, Klann K, Bellinghausen C, et al. (October 2020).
2214:
2023:
494:
228:
85:
2832:
839:
215:
1005:
infection. Another study in cell cultures suggests that the drug inhibits SARS-CoV-2 Replication.
2759:
2549:
2281:
2238:
2172:
2047:
1969:
1814:
1771:
1427:
970:
966:
939:
932:
67:
1637:
1605:
993:). BPTI was the cover image on a protein folding compendium volume by Thomas Creighton in 1992.
816:(CABG) surgery. In orthopedic surgery, a decrease of blood transfusions was likewise confirmed.
1575:"Early Communication about an Ongoing Safety Review Aprotinin Injection (marketed as Trasylol)"
1553:
2880:
2803:
2553:
2398:
2347:
2304:
2273:
2230:
2153:
2118:
2083:
2039:
1996:
1961:
1926:
1890:
1806:
1763:
1728:
1684:
1506:
1471:
1419:
1378:
1334:
1293:
1258:
1223:
1213:
1182:
1124:
951:
874:
586:
510:
154:
946:. It was one of the earliest protein crystal structures solved, in 1970 in the laboratory of
2788:
2735:
2388:
2378:
2337:
2265:
2222:
2187:
2145:
2110:
2075:
2031:
1953:
1918:
1880:
1872:
1841:
1798:
1755:
1718:
1674:
1498:
1461:
1409:
1398:"Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials"
1368:
1324:
1285:
1250:
1205:
1172:
1116:
900:
715:
695:
474:
378:
168:
2424:
303:
2808:
2565:
2561:
2557:
2473:
2460:
982:
943:
859:
765:
668:
224:
176:
1574:
1313:"Antifibrinolytics in orthotopic liver transplantation: current status and controversies"
2218:
2027:
365:
2393:
2366:
1885:
1860:
1525:
1414:
1397:
974:
855:
730:
538:
1209:
2869:
2708:
2703:
2661:
2503:
2269:
2149:
2114:
2079:
1957:
1289:
1254:
1002:
959:
928:
847:
809:
722:
in its name. (Because of the usual source organism, BPTI is sometimes referred to as
354:
2285:
1818:
1775:
1431:
618:
606:
2837:
2693:
2676:
2627:
2583:
2464:
2242:
2051:
1973:
1922:
947:
773:
506:
122:
117:
1746:
Stoddart RW, Kernan JA (March 1973). "Aprotinin, a carbohydrate-binding protein".
703:
1845:
59:
2852:
2754:
2745:
2698:
2688:
2623:
2541:
2526:
2478:
1373:
1356:
1120:
1029:
927:
Initially named "kallikrein inactivator", aprotinin was first isolated from cow
825:
737:
members of the chain (Cys5-Cys55, Cys14-Cys38 and Cys30-Cys51). The long, basic
707:
691:
678:
514:
182:
2797:
2749:
2671:
2666:
2656:
2618:
2594:
2191:
835:
828:(a severe allergic reaction) occurs at a rate of 1:200 in first-time use, but
789:
785:
781:
699:
642:
625:
490:
417:
278:
2342:
2325:
2205:
McCammon JA, Gelin BR, Karplus M (June 1977). "Dynamics of folded proteins".
2575:
2512:
2495:
1832:
Kraut H, Frey EK, Bauer E (1930). "Über die
Inaktivierung des kallikreins".
1606:"Information for Healthcare Professionals; Aprotinin (marketed as Trasylol)"
53:
2402:
2351:
2000:
1965:
1930:
1894:
1732:
1688:
1510:
1502:
1475:
1423:
1382:
1338:
1262:
1186:
805:, initial reports of benefit were overshadowed by concerns about toxicity.
2157:
2122:
2087:
2043:
1810:
1767:
1723:
1706:
1679:
1663:"The effect of aprotinin on outcome after coronary-artery bypass grafting"
1662:
1297:
1227:
1128:
505:, such as heart and liver surgery. Its main effect is the slowing down of
20:
2842:
2769:
2740:
2613:
2608:
2429:
2383:
2277:
2234:
1876:
1466:
1449:
1177:
1160:
893:
829:
734:
630:
498:
258:
981:
BPTI was important in the development of knowledge about the process of
267:
2035:
1802:
1759:
1200:
Richardson JS (1981). "The anatomy and taxonomy of protein structure".
989:(it was later discovered that the precursor sequence folds more easily
777:
769:
502:
478:
1909:
Identification With the
Inhibitor From the Bovine Parotid Gland].
1054:"European Medicines Agency recommends lifting suspension of aprotinin"
591:
28:
2821:
2420:
2226:
1526:"F.D.A. Says Bayer Failed to Reveal Drug Risk Study - New York Times"
1329:
1312:
1079:"The Nordic Group acquires rights to Trasylol® from Bayer HealthCare"
851:
749:
738:
574:
482:
334:
1707:"Aprotinin during coronary-artery bypass grafting and risk of death"
873:
Two studies published in early 2008, both comparing aprotinin with
323:
908:
458:
1550:"Facts & Comparisons: Trasylol Public Health Advisory Update"
1204:. Advances in Protein Chemistry. Vol. 34. pp. 167–339.
938:
BPTI is one of the most thoroughly studied proteins in terms of
812:
performed in 2004, transfusion requirements decreased by 39% in
314:
148:
2433:
1705:
Schneeweiss S, Seeger JD, Landon J, Walker AM (February 2008).
858:. The study authors recommend older antifibrinolytics (such as
942:, experimental and computational dynamics, mutagenesis, and
1355:
Sedrakyan A, Treasure T, Elefteriades JA (September 2004).
461:
and now Nordic Group pharmaceuticals), is a small protein
1028:(Press release). Trasylol.com. 2007-11-05. Archived from
1396:
Shiga T, Wajima Z, Inoue T, Sakamoto A (December 2005).
824:
There have been concerns about the safety of aprotinin.
1450:"The risk associated with aprotinin in cardiac surgery"
1056:. European Medicines Agency. 2012-02-17. Archived from
443:
1023:"Bayer Temporarily Suspends Global Trasylol Marketing"
2423:
online database for peptidases and their inhibitors:
2324:
Xu CY, Zhu HM, Wu JH, Wen H, Liu CJ (February 2014).
1911:
Hoppe-Seyler's Zeitschrift für Physiologische Chemie
745:
BPTI is the classic member of the protein family of
2787:
2723:
2647:
2525:
2494:
2487:
2472:
1278:
Biochemical and Biophysical Research Communications
1243:
Biochemical and Biophysical Research Communications
729:The high stability of the molecule is due to the 3
674:
664:
659:
641:
636:
624:
612:
600:
585:
573:
565:
553:
548:
531:
513:during surgery, as well as end-organ damage due to
416:
377:
372:
353:
333:
313:
293:
277:
257:
246:
237:
214:
189:
175:
167:
138:
133:
108:
96:
84:
66:
48:
40:
35:
1361:The Journal of Thoracic and Cardiovascular Surgery
690:Aprotinin is a monomeric (single-chain) globular
1448:Mangano DT, Tudor IC, Dietzel C (January 2006).
780:at a concentration of about 125,000 IU/ml, and
223:
2445:
2330:The Journal of International Medical Research
1700:
1698:
1107:Mannucci PM (July 1998). "Hemostatic drugs".
44:Trasylol, bovine pancreatic trypsin inhibitor
8:
1350:
1348:
788:leads to the inhibition of the formation of
19:
2367:"Aprotinin Inhibits SARS-CoV-2 Replication"
1161:"Perioperative systemic haemostatic agents"
694:derived from bovine lung tissue. It has a
160:In general: ℞ (Prescription only)
2491:
2484:
2452:
2438:
2430:
1443:
1441:
1102:
1100:
656:
537:
471:basic trypsin inhibitor of bovine pancreas
364:
2765:Tetragalacturonic acid hydroxymethylester
2392:
2382:
2341:
1884:
1722:
1678:
1465:
1413:
1372:
1328:
1176:
962:at the ETH in Zurich in the early 1980s.
302:
1748:Histochemie. Histochemistry. Histochimie
899:In cell biology aprotinin is used as an
698:of 6512 Da and consists of 16 different
1202:Advances in Protein Chemistry Volume 34
1154:
1152:
1150:
1148:
1146:
1144:
1142:
1140:
1138:
1014:
266:
203:
1159:Mahdy AM, Webster NR (December 2004).
1081:. The Nordic Group B.V. Archived from
528:
355:
18:
342:
58:
7:
2171:Deisenhofer J, Steigemann W (1975).
1989:Surgery, Gynecology & Obstetrics
1638:"Bayer Withdraws Heart Surgery Drug"
1311:Xia VW, Steadman RH (January 2005).
121:
1859:Kunitz M, Northrop JH (July 1936).
1711:The New England Journal of Medicine
1667:The New England Journal of Medicine
1454:The New England Journal of Medicine
1109:The New England Journal of Medicine
532:Bovine pancreatic trypsin inhibitor
463:bovine pancreatic trypsin inhibitor
322:
1415:10.1213/01.ANE.0000180767.50529.45
14:
2640:(II, VII, IX, X, protein C and S)
1865:The Journal of General Physiology
1958:10.1097/00007611-196411000-00012
882:bovine spongiform encephalopathy
784:at 300,000 IU/ml. Its action on
395:
389:
27:
2683:thrombopoietin receptor agonist
2638:Prothrombin complex concentrate
1618:from the original on 2006-10-10
1587:from the original on 2007-10-30
726:pancreatic trypsin inhibitor.)
2775:Hemostatic Powder Spray TC-325
1923:10.1515/bchm2.1964.338.1-2.231
1165:British Journal of Anaesthesia
407:
401:
383:
1:
1834:Hoppe-Seyler's Z Physiol Chem
1210:10.1016/S0065-3233(08)60520-3
2270:10.1016/0014-5793(75)80504-7
2150:10.1016/0022-2836(85)90346-8
2138:Journal of Molecular Biology
2115:10.1016/0022-2836(82)90009-2
2103:Journal of Molecular Biology
2080:10.1016/0022-2836(74)90163-6
2068:Journal of Molecular Biology
1846:10.1515/bchm2.1930.192.1-3.1
1611:Food and Drug Administration
1580:Food and Drug Administration
1290:10.1016/0006-291X(65)90601-7
1255:10.1016/0006-291X(65)90749-7
814:coronary artery bypass graft
1374:10.1016/j.jtcvs.2004.03.041
1121:10.1056/NEJM199807233390407
2897:
2570:Valoctocogene roxaparvovec
750:serine protease inhibitors
489:, aprotinin was used as a
373:Chemical and physical data
2731:Absorbable gelatin sponge
2192:10.1107/S0567740875002415
718:, which accounts for the
655:
559:Bos taurus (domestic cow)
536:
519:European Medicines Agency
433:
194:
26:
16:Antifibrinolytic molecule
2580:Fidanacogene elaparvovec
2343:10.1177/0300060513504365
2180:Acta Crystallographica B
1946:Southern Medical Journal
1402:Anesthesia and Analgesia
973:and Bruce Gelin, in the
969:computation, in 1977 by
756:Mechanism of drug action
481:and related proteolytic
2814:Aminomethylbenzoic acid
2016:Die Naturwissenschaften
1636:Harris G (2007-11-05).
1524:Harris G (2006-09-30).
958:, in the laboratory of
485:. Under the trade name
477:molecule that inhibits
1503:10.1001/jama.297.5.471
915:of cells and tissues.
457:(Trasylol, previously
2546:Damoctocog alfa pegol
2299:Creighton TE (1992).
1724:10.1056/NEJMoa0707571
1680:10.1056/NEJMoa0707768
1317:Liver Transplantation
844:myocardial infarction
803:liver transplantation
762:competitive inhibitor
2384:10.3390/cells9112377
1877:10.1085/jgp.19.6.991
1467:10.1056/NEJMoa051379
649:13: 75.02 - 75.03 Mb
2219:1977Natur.267..585M
2028:1970NW.....57..389H
903:to prevent protein
840:acute renal failure
157:(Prescription only)
23:
2760:Oxidized cellulose
2550:Efanesoctocog alfa
2036:10.1007/BF00599976
1803:10.1007/BF00304309
1760:10.1007/BF00306299
1642:The New York Times
1530:The New York Times
1178:10.1093/bja/aeh227
1085:on 1 February 2014
971:J. Andrew McCammon
967:molecular dynamics
940:structural biology
933:acute pancreatitis
511:blood transfusions
2876:Antifibrinolytics
2863:
2862:
2833:Alfa1 antitrypsin
2804:Aminocaproic acid
2789:Antifibrinolytics
2783:
2782:
2719:
2718:
2554:Efmoroctocog alfa
2504:Phytomenadione (K
2310:978-0-7167-7027-5
2303:. W. H. Freeman.
1219:978-0-12-034234-1
875:aminocaproic acid
706:and a C-terminal
688:
687:
684:
683:
451:
450:
152:
2888:
2736:Calcium alginate
2492:
2485:
2474:Antihemorrhagics
2461:Antihemorrhagics
2454:
2447:
2440:
2431:
2407:
2406:
2396:
2386:
2362:
2356:
2355:
2345:
2321:
2315:
2314:
2296:
2290:
2289:
2253:
2247:
2246:
2227:10.1038/267585a0
2213:(5612): 585–90.
2202:
2196:
2195:
2177:
2168:
2162:
2161:
2133:
2127:
2126:
2098:
2092:
2091:
2062:
2056:
2055:
2011:
2005:
2004:
1984:
1978:
1977:
1941:
1935:
1934:
1905:
1899:
1898:
1888:
1856:
1850:
1849:
1829:
1823:
1822:
1786:
1780:
1779:
1743:
1737:
1736:
1726:
1702:
1693:
1692:
1682:
1658:
1652:
1651:
1649:
1648:
1633:
1627:
1626:
1624:
1623:
1602:
1596:
1595:
1593:
1592:
1571:
1565:
1564:
1562:
1561:
1552:. Archived from
1546:
1540:
1539:
1537:
1536:
1521:
1515:
1514:
1486:
1480:
1479:
1469:
1445:
1436:
1435:
1417:
1393:
1387:
1386:
1376:
1352:
1343:
1342:
1332:
1330:10.1002/lt.20275
1308:
1302:
1301:
1273:
1267:
1266:
1238:
1232:
1231:
1197:
1191:
1190:
1180:
1156:
1133:
1132:
1104:
1095:
1094:
1092:
1090:
1075:
1069:
1068:
1066:
1065:
1050:
1044:
1043:
1041:
1040:
1034:
1027:
1019:
997:Current findings
956:NMR spectroscopy
901:enzyme inhibitor
766:serine proteases
696:molecular weight
657:
561:
541:
529:
493:administered by
475:antifibrinolytic
447:
446:
439:
428:
426:
409:
403:
397:
391:
385:
368:
357:
346:
326:
306:
270:
250:
227:
150:
147:
125:
62:
31:
24:
22:
2896:
2895:
2891:
2890:
2889:
2887:
2886:
2885:
2866:
2865:
2864:
2859:
2809:Tranexamic acid
2779:
2715:
2649:
2643:
2566:Turoctocog alfa
2562:Susoctocog alfa
2558:Moroctocog alfa
2528:
2521:
2516:
2507:
2476:
2468:
2458:
2416:
2411:
2410:
2364:
2363:
2359:
2323:
2322:
2318:
2311:
2301:Protein Folding
2298:
2297:
2293:
2255:
2254:
2250:
2204:
2203:
2199:
2175:
2170:
2169:
2165:
2135:
2134:
2130:
2100:
2099:
2095:
2064:
2063:
2059:
2013:
2012:
2008:
1986:
1985:
1981:
1952:(11): 1317–21.
1943:
1942:
1938:
1907:
1906:
1902:
1871:(6): 991–1007.
1858:
1857:
1853:
1831:
1830:
1826:
1788:
1787:
1783:
1745:
1744:
1740:
1704:
1703:
1696:
1660:
1659:
1655:
1646:
1644:
1635:
1634:
1630:
1621:
1619:
1604:
1603:
1599:
1590:
1588:
1573:
1572:
1568:
1559:
1557:
1548:
1547:
1543:
1534:
1532:
1523:
1522:
1518:
1488:
1487:
1483:
1447:
1446:
1439:
1395:
1394:
1390:
1354:
1353:
1346:
1310:
1309:
1305:
1275:
1274:
1270:
1240:
1239:
1235:
1220:
1199:
1198:
1194:
1158:
1157:
1136:
1106:
1105:
1098:
1088:
1086:
1077:
1076:
1072:
1063:
1061:
1052:
1051:
1047:
1038:
1036:
1032:
1025:
1021:
1020:
1016:
1011:
999:
983:protein folding
944:folding pathway
925:
890:
860:tranexamic acid
822:
798:
768:, specifically
760:Aprotinin is a
758:
731:disulfide bonds
595:More structures
557:
544:
527:
501:during complex
442:
440:
437:(what is this?)
434:
424:
422:
412:
406:
400:
394:
388:
349:
329:
309:
289:
273:
253:
233:
210:
207:
202:
201:
177:Bioavailability
169:Pharmacokinetic
163:
129:
99:
87:
80:
69:
17:
12:
11:
5:
2894:
2892:
2884:
2883:
2878:
2868:
2867:
2861:
2860:
2858:
2857:
2856:
2855:
2847:
2846:
2845:
2840:
2835:
2830:
2818:
2817:
2816:
2811:
2806:
2793:
2791:
2785:
2784:
2781:
2780:
2778:
2777:
2772:
2767:
2762:
2757:
2752:
2743:
2738:
2733:
2727:
2725:
2721:
2720:
2717:
2716:
2714:
2713:
2712:
2711:
2706:
2701:
2696:
2691:
2679:
2674:
2669:
2664:
2659:
2653:
2651:
2645:
2644:
2642:
2641:
2631:
2630:
2621:
2616:
2611:
2602:
2601:
2588:
2587:
2573:
2539:
2533:
2531:
2523:
2522:
2520:
2519:
2514:
2510:
2505:
2500:
2498:
2489:
2482:
2470:
2469:
2459:
2457:
2456:
2449:
2442:
2434:
2428:
2427:
2415:
2414:External links
2412:
2409:
2408:
2357:
2316:
2309:
2291:
2248:
2197:
2163:
2128:
2093:
2057:
2006:
1979:
1936:
1900:
1851:
1824:
1791:Histochemistry
1781:
1738:
1694:
1653:
1628:
1597:
1566:
1541:
1516:
1481:
1437:
1388:
1344:
1303:
1268:
1233:
1218:
1192:
1134:
1096:
1070:
1045:
1013:
1012:
1010:
1007:
998:
995:
954:determined by
929:parotid glands
924:
921:
913:homogenization
889:
886:
856:encephalopathy
821:
818:
797:
794:
757:
754:
733:linking the 6
686:
685:
682:
681:
676:
672:
671:
666:
662:
661:
653:
652:
645:
639:
638:
634:
633:
628:
622:
621:
616:
610:
609:
604:
598:
597:
589:
583:
582:
577:
571:
570:
567:
563:
562:
555:
551:
550:
546:
545:
542:
534:
533:
526:
523:
473:, which is an
449:
448:
431:
430:
420:
414:
413:
410:
404:
398:
392:
386:
381:
375:
374:
370:
369:
359:
351:
350:
348:
347:
339:
337:
331:
330:
328:
327:
319:
317:
311:
310:
308:
307:
299:
297:
291:
290:
288:
287:
283:
281:
275:
274:
272:
271:
263:
261:
255:
254:
252:
251:
243:
241:
235:
234:
232:
231:
220:
218:
212:
211:
209:
208:
205:
197:
196:
195:
192:
191:
187:
186:
179:
173:
172:
165:
164:
162:
161:
158:
144:
142:
136:
135:
131:
130:
128:
127:
114:
112:
106:
105:
102:
100:administration
94:
93:
90:
82:
81:
79:
78:
74:
72:
64:
63:
56:
46:
45:
42:
38:
37:
33:
32:
15:
13:
10:
9:
6:
4:
3:
2:
2893:
2882:
2879:
2877:
2874:
2873:
2871:
2854:
2851:
2850:
2848:
2844:
2841:
2839:
2836:
2834:
2831:
2829:
2826:
2825:
2824:
2823:
2819:
2815:
2812:
2810:
2807:
2805:
2802:
2801:
2800:
2799:
2795:
2794:
2792:
2790:
2786:
2776:
2773:
2771:
2768:
2766:
2763:
2761:
2758:
2756:
2753:
2751:
2747:
2744:
2742:
2739:
2737:
2734:
2732:
2729:
2728:
2726:
2722:
2710:
2709:Rafutrombopag
2707:
2705:
2704:Lusutrombopag
2702:
2700:
2697:
2695:
2692:
2690:
2687:
2686:
2685:
2684:
2680:
2678:
2675:
2673:
2670:
2668:
2665:
2663:
2662:Carbazochrome
2660:
2658:
2655:
2654:
2652:
2646:
2639:
2636:
2635:combinations:
2633:
2632:
2629:
2625:
2622:
2620:
2617:
2615:
2612:
2610:
2607:
2604:
2603:
2600:
2596:
2593:
2590:
2589:
2585:
2581:
2577:
2574:
2571:
2567:
2563:
2559:
2555:
2551:
2547:
2543:
2540:
2538:
2535:
2534:
2532:
2530:
2524:
2518:
2511:
2509:
2502:
2501:
2499:
2497:
2493:
2490:
2486:
2483:
2480:
2475:
2471:
2466:
2462:
2455:
2450:
2448:
2443:
2441:
2436:
2435:
2432:
2426:
2422:
2418:
2417:
2413:
2404:
2400:
2395:
2390:
2385:
2380:
2376:
2372:
2368:
2361:
2358:
2353:
2349:
2344:
2339:
2335:
2331:
2327:
2320:
2317:
2312:
2306:
2302:
2295:
2292:
2287:
2283:
2279:
2275:
2271:
2267:
2263:
2259:
2252:
2249:
2244:
2240:
2236:
2232:
2228:
2224:
2220:
2216:
2212:
2208:
2201:
2198:
2193:
2189:
2185:
2181:
2174:
2167:
2164:
2159:
2155:
2151:
2147:
2144:(2): 281–94.
2143:
2139:
2132:
2129:
2124:
2120:
2116:
2112:
2109:(3): 347–66.
2108:
2104:
2097:
2094:
2089:
2085:
2081:
2077:
2074:(1): 73–101.
2073:
2069:
2061:
2058:
2053:
2049:
2045:
2041:
2037:
2033:
2029:
2025:
2022:(8): 389–92.
2021:
2017:
2010:
2007:
2002:
1998:
1994:
1990:
1983:
1980:
1975:
1971:
1967:
1963:
1959:
1955:
1951:
1947:
1940:
1937:
1932:
1928:
1924:
1920:
1916:
1913:(in German).
1912:
1904:
1901:
1896:
1892:
1887:
1882:
1878:
1874:
1870:
1866:
1862:
1855:
1852:
1847:
1843:
1839:
1836:(in German).
1835:
1828:
1825:
1820:
1816:
1812:
1808:
1804:
1800:
1796:
1792:
1785:
1782:
1777:
1773:
1769:
1765:
1761:
1757:
1754:(4): 275–80.
1753:
1749:
1742:
1739:
1734:
1730:
1725:
1720:
1717:(8): 771–83.
1716:
1712:
1708:
1701:
1699:
1695:
1690:
1686:
1681:
1676:
1673:(8): 784–93.
1672:
1668:
1664:
1657:
1654:
1643:
1639:
1632:
1629:
1617:
1613:
1612:
1607:
1601:
1598:
1586:
1582:
1581:
1576:
1570:
1567:
1556:on 2012-07-22
1555:
1551:
1545:
1542:
1531:
1527:
1520:
1517:
1512:
1508:
1504:
1500:
1496:
1492:
1485:
1482:
1477:
1473:
1468:
1463:
1460:(4): 353–65.
1459:
1455:
1451:
1444:
1442:
1438:
1433:
1429:
1425:
1421:
1416:
1411:
1408:(6): 1602–7.
1407:
1403:
1399:
1392:
1389:
1384:
1380:
1375:
1370:
1366:
1362:
1358:
1351:
1349:
1345:
1340:
1336:
1331:
1326:
1322:
1318:
1314:
1307:
1304:
1299:
1295:
1291:
1287:
1283:
1279:
1272:
1269:
1264:
1260:
1256:
1252:
1248:
1244:
1237:
1234:
1229:
1225:
1221:
1215:
1211:
1207:
1203:
1196:
1193:
1188:
1184:
1179:
1174:
1171:(6): 842–58.
1170:
1166:
1162:
1155:
1153:
1151:
1149:
1147:
1145:
1143:
1141:
1139:
1135:
1130:
1126:
1122:
1118:
1115:(4): 245–53.
1114:
1110:
1103:
1101:
1097:
1084:
1080:
1074:
1071:
1060:on 2014-02-18
1059:
1055:
1049:
1046:
1035:on 2011-07-17
1031:
1024:
1018:
1015:
1008:
1006:
1004:
1003:C. neoformans
996:
994:
992:
988:
984:
979:
976:
972:
968:
963:
961:
960:Kurt Wuthrich
957:
953:
949:
945:
941:
936:
934:
930:
922:
920:
916:
914:
910:
906:
902:
897:
895:
887:
885:
883:
878:
876:
871:
867:
863:
861:
857:
853:
850:, as well as
849:
848:heart failure
845:
841:
837:
833:
831:
827:
819:
817:
815:
811:
810:meta-analysis
806:
804:
796:Drug efficacy
795:
793:
791:
787:
783:
779:
775:
771:
767:
763:
755:
753:
751:
748:
743:
740:
736:
732:
727:
725:
721:
717:
711:
709:
705:
701:
697:
693:
680:
677:
673:
670:
667:
663:
658:
654:
651:
650:
646:
644:
640:
635:
632:
629:
627:
623:
620:
617:
615:
614:RefSeq (Prot)
611:
608:
605:
603:
602:RefSeq (mRNA)
599:
596:
593:
590:
588:
584:
581:
578:
576:
572:
568:
564:
560:
556:
552:
547:
540:
535:
530:
524:
522:
520:
516:
512:
508:
504:
500:
496:
492:
488:
484:
480:
476:
472:
468:
464:
460:
456:
445:
438:
432:
421:
419:
415:
382:
380:
376:
371:
367:
363:
360:
358:
356:ECHA InfoCard
352:
345:
344:ChEMBL1201619
341:
340:
338:
336:
332:
325:
321:
320:
318:
316:
312:
305:
301:
300:
298:
296:
292:
285:
284:
282:
280:
276:
269:
265:
264:
262:
260:
256:
249:
245:
244:
242:
240:
236:
230:
226:
222:
221:
219:
217:
213:
204:
200:
193:
188:
184:
180:
178:
174:
170:
166:
159:
156:
146:
145:
143:
141:
137:
132:
124:
119:
116:
115:
113:
111:
107:
103:
101:
95:
91:
89:
83:
76:
75:
73:
71:
65:
61:
57:
55:
51:
47:
43:
39:
36:Clinical data
34:
30:
25:
2838:C1-inhibitor
2827:
2820:
2796:
2694:Avatrombopag
2681:
2677:Fostamatinib
2634:
2628:Catridecacog
2619:I/Fibrinogen
2605:
2599:Eptacog alfa
2591:
2584:Nonacog alfa
2536:
2513:Menadione (K
2377:(11): 2377.
2374:
2370:
2360:
2336:(1): 85–92.
2333:
2329:
2319:
2300:
2294:
2264:(2): 265–8.
2261:
2258:FEBS Letters
2257:
2251:
2210:
2206:
2200:
2183:
2179:
2166:
2141:
2137:
2131:
2106:
2102:
2096:
2071:
2067:
2060:
2019:
2015:
2009:
1992:
1988:
1982:
1949:
1945:
1939:
1914:
1910:
1903:
1868:
1864:
1854:
1837:
1833:
1827:
1797:(1): 77–84.
1794:
1790:
1784:
1751:
1747:
1741:
1714:
1710:
1670:
1666:
1656:
1645:. Retrieved
1641:
1631:
1620:. Retrieved
1609:
1600:
1589:. Retrieved
1578:
1569:
1558:. Retrieved
1554:the original
1544:
1533:. Retrieved
1529:
1519:
1497:(5): 471–9.
1494:
1490:
1484:
1457:
1453:
1405:
1401:
1391:
1367:(3): 442–8.
1364:
1360:
1320:
1316:
1306:
1284:(4): 463–8.
1281:
1277:
1271:
1249:(2): 255–8.
1246:
1242:
1236:
1201:
1195:
1168:
1164:
1112:
1108:
1087:. Retrieved
1083:the original
1073:
1062:. Retrieved
1058:the original
1048:
1037:. Retrieved
1030:the original
1017:
1000:
990:
986:
980:
964:
948:Robert Huber
937:
926:
917:
898:
891:
888:In vitro use
880:No cases of
879:
872:
868:
864:
834:
823:
807:
799:
774:chymotrypsin
759:
744:
728:
723:
719:
712:
689:
647:
619:NP_001001554
607:NM_001001554
507:fibrinolysis
486:
470:
466:
462:
454:
452:
441:
435:
140:Legal status
134:Legal status
2853:Ulinastatin
2798:amino acids
2755:Fibrin glue
2746:Epinephrine
2699:Eltrombopag
2689:Romiplostim
2614:II/Thrombin
2527:Coagulation
2479:coagulation
1323:(1): 10–8.
905:degradation
826:Anaphylaxis
820:Drug safety
790:factor XIIa
764:of several
747:Kunitz-type
692:polypeptide
669:Swiss-model
549:Identifiers
515:hypotension
429: g·mol
362:100.029.983
190:Identifiers
183:intravenous
104:Intravenous
41:Other names
2870:Categories
2750:adrenalone
2672:Etamsylate
2667:Concizumab
2657:Batroxobin
2592:extrinsic:
2537:intrinsic:
1647:2007-11-05
1622:2006-10-30
1591:2007-10-28
1560:2007-11-05
1535:2007-11-05
1089:28 January
1064:2012-02-22
1039:2007-12-03
1009:References
836:Thrombosis
786:kallikrein
782:kallikrein
700:amino acid
665:Structures
660:Search for
643:Chromosome
637:Other data
497:to reduce
491:medication
418:Molar mass
304:04XPW8C0FL
279:ChemSpider
239:IUPHAR/BPS
216:CAS Number
199:IUPAC name
86:Dependence
2849:unsorted
2828:Aprotinin
2496:Vitamin K
1917:: 231–7.
952:structure
704:β-hairpin
525:Chemistry
495:injection
455:aprotinin
453:The drug
229:9004-04-0
225:9087-70-1
206:Aprotinin
98:Routes of
88:liability
68:Pregnancy
60:Monograph
54:Drugs.com
21:Aprotinin
2881:Proteins
2843:Camostat
2770:Thrombin
2741:Collagen
2650:systemic
2488:Systemic
2403:33143316
2352:24398759
2286:46084481
2001:14179354
1995:: 71–4.
1966:14195953
1931:14330402
1895:19872978
1840:: 1–21.
1819:32032724
1776:44549220
1733:18287600
1689:18287601
1616:Archived
1585:Archived
1511:17284697
1476:16436767
1432:33762135
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