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Aprotinin

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Aprotinin
Clinical data
Other namestrasylol, bovine pancreatic trypsin inhibitor
Pregnancy
category
  • X
Dependence
liability		none
Routes of
administration		intravenous
ATC code
Legal status
Legal status
  • RX/POM
Pharmacokinetic data
Bioavailability100% (IV)
Identifiers
  • Aprotinin
CAS Number
PubChem CID
ECHA InfoCard100.029.983 Edit this at Wikidata
Chemical and physical data
FormulaC284H432N84O79S7
Molar mass6511.51 g·mol−1

Aprotinin, also known as bovine pancreatic trypsin inhibitor, BPTI (Trasylol, Bayer) is a protein, that is used as medication administered by 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 transfusions during surgery, as well as end-organ damage due to hypotension (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 The drug was temporarily withdrawn worldwide in 2007 after studies suggested that its use increased the risk of complications or death[1]; this was confirmed by follow-up studies. Trasylol was entirely and permanently withdrawn in May 2008 (except for very restricted research use).

Chemistry

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 acids arranged in a chain of 58 amino acid residues.[2][3]

Its amino acid sequence is RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRA KRNNF KSAED CMRTC GGA.[4]

The stability of the molecule is due to the 3 disulfide bonds linking the 6 cysteine members of the chain (Cys5-Cys55, Cys14-Cys38 and Cys30-Cys51).[5] The lysine (15)-alanine (16) sequence on this strongly basic polypeptide represents the active centre.

Aprotinin is the axiomic member of the protein family of Kunitz-type serine protease inhibitors.

It is one of the most thoroughly studied proteins in terms of structure and folding pathway. BPTI was one of the first proteins to have its structure solved by NMR spectroscopy.[citation needed] Nevertheless, its physiological function remains unknown.

Mechanism of action

Aprotinin inhibits several serine proteases, specifically trypsin, chymotrypsin and plasmin at a concentration of about 125,000 IU/ml, and kallikrein at 300,000 IU/ml[3]. Its action on kallikrein leads to the inhibition of the formation of factor XIIa. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis.[2]

Efficacy

In cardiac surgery with a high risk of significant blood loss, aprotinin significantly reduced bleeding, mortality and hospital stay[3]. Beneficial effects were also reported in high-risk orthopedic surgery.[3] In liver transplantation, initial reports of benefit were overshadowed by concerns about toxicity.[6]

In a meta-analysis performed in 2004, transfusion requirements decreased by 39% in coronary artery bypass graft (CABG) surgery.[7] In orthopedic surgery, a decrease of blood transfusions was likewise confirmed.[8]

Safety

There have been concerns about the safety of aprotinin[3]. 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.[3]

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.[3][7] Similarly, while biochemical measures of renal function were known to occasionally deteriorate, there was no evidence that this greatly influenced outcomes.[3] 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.[9] The study authors recommend older antifibrinolytics (such as tranexamic acid) in which these risks were not documented.[9] The same group updated their data in 2007 and demonstrated similar findings.[10]

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.[11] 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. [12]

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. [13] 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.[14] 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. [15]

Two studies published in early 2008, both comparing aprotinin with aminocaproic acid, found that mortality was increased by 32[16] and 64%[17], respectively. One study found an increased risk in need for dialysis and revascularisation.[17]

No cases of bovine spongiform encephalopathy transmission by aprotinin have been reported, although the drug was withdrawn in Italy due to fears of this.[3]

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 glucagon.

In cell biology aprotinin is used as an enzyme inhibitor to prevent protein degradation during lysis or homogenizaton of cells and tissues.

History

Initially named "kallikrein inactivator", aprotinin was first isolated from cow parotid glands in 1930.[18] and independently as "bovine pancreatic trypsin inhibitor" from cow pancreas in 1936.[19] It was purified from bovine lung in 1964.[20] 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.[21] Its use in major surgery commenced in the 1960s.[22]

Because it is a small, relatively stable protein whose structure had been accurately determined since 1975, it was the first macromolecule of scientific interest to be simulated using molecular dynamics computation, in 1977.[23]

References

  1. ^ "Bayer Temporarily Suspends Global Trasylol Marketing" (PDF) (Press release). Trasylol.com. 2007-11-05. Retrieved 2007-12-03.
  2. ^ a b Mannucci PM (1998). "Hemostatic drugs". N. Engl. J. Med. 339 (4): 245–53. doi:10.1056/NEJM199807233390407. PMID 9673304.
  3. ^ a b c d e f g h i Mahdy AM, Webster NR (2004). "Perioperative systemic haemostatic agents". British journal of anaesthesia. 93 (6): 842–58. doi:10.1093/bja/aeh227. PMID 15277296.
  4. ^ Kassell B, Radicevic M, Ansfield MJ, Laskowski M (1965). "The basic trypsin inhibitor of bovine pancreas. IV. The linear sequence of the 58 amino acids". Biochem. Biophys. Res. Commun. 18: 255–8. doi:10.1016/0006-291X(65)90749-7. PMID 14282026.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Kassell B, Laskowski M (1965). "The basic trypsin inhibitor of bovine pancreas. V. The disulfide linkages". Biochem. Biophys. Res. Commun. 20 (4): 463–8. doi:10.1016/0006-291X(65)90601-7. PMID 5860161.
  6. ^ Xia VW, Steadman RH (2005). "Antifibrinolytics in orthotopic liver transplantation: current status and controversies". Liver Transpl. 11 (1): 10–8. doi:10.1002/lt.20275. PMID 15690531.
  7. ^ a b Sedrakyan A, Treasure T, Elefteriades JA (2004). "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. 128 (3): 442–8. doi:10.1016/j.jtcvs.2004.03.041. PMID 15354106.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Shiga T, Wajima Z, Inoue T, Sakamoto A (2005). "Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials". Anesth. Analg. 101 (6): 1602–7. doi:10.1213/01.ANE.0000180767.50529.45. PMID 16301226.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b Mangano DT, Tudor IC, Dietzel C (2006). "The risk associated with aprotinin in cardiac surgery". N. Engl. J. Med. 354 (4): 353–65. doi:10.1056/NEJMoa051379. PMID 16436767.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ 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 (2007). "Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery". JAMA. 297 (5): 471–9. doi:10.1001/jama.297.5.471. PMID 17284697.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Gardiner Harris. "F.D.A. Says Bayer Failed to Reveal Drug Risk Study - New York Times". Retrieved 2007-11-05.
  12. ^ "Facts & Comparisons: Trasylol Public Health Advisory Update". Retrieved 2007-11-05.
  13. ^ U.S. Food and Drug Administration. "Early Communication about an Ongoing Safety Review Aprotinin Injection (marketed as Trasylol)". Retrieved 2007-10-28.
  14. ^ U.S. Food and Drug Administration. "Information for Healthcare Professionals; Aprotinin (marketed as Trasylol)". Retrieved 2006-10-30.
  15. ^ Gardiner Harris. "Bayer Withdraws Heart Surgery Drug". Retrieved 2007-11-05.
  16. ^ Shaw AD, Stafford-Smith M, White WD; et al. (2008). "N Engl J Med". New England Journal of Medicine. 358 (8): 784–793. doi:10.1056/NEJMoa0707768. PMID 18287601. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  17. ^ a b Schneewiss S, Seeger JD, Landon J, Walker AM (2008). "Aprotinin during coronary-artery bypass grafting and risk of death". N Engl J Med. 358 (8): 771–783. doi:10.1056/NEJMoa0707571. PMID 18287600.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Kraut H, Frey EK, Bauer E (1930). "Über die Inaktivierung des kallikreins". Hoppe-Seyler's Z Physiol Chem (in German). 192: 1–21.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Kunitz M, Northrup J (1936). "Isolation from beef pancreas of crystalline trypsinogen, trypsin, trypsin inhibitor, and an inhibitor trypsin compound". J Gen Physiol. 19: 991–1007. doi:10.1085/jgp.19.6.991.
  20. ^ Kraut H, Bhargava N (1964). "Versuche zur Isolierung des Kallikrein-Inaktivators aus Rinderlunge and seine Identifizierung mit dem Inaktivator aus Rinderparotis". Hoppe-Seyler's Z. Physiol. Chem. (in German). 338: 231–7. PMID 14330402.
  21. ^ Nugent FW, Warren KW, Jonasson H, Garciadeparedes G (1964). "Early experience with trasylol in the treatment of acute pancreatitis". South. Med. J. 57: 1317–21. PMID 14195953.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Tice DA, Worth Jr MH, Clauss RH, Reed GH (1964). "The inhibition of trasylol of fibrinolytic activity associated with cardiovascular operations". Surgery, gynecology & obstetrics. 119: 71–4. PMID 14179354.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ McCammon JA, Gelin BR, Karplus M (1977). "Dynamics of folded proteins". Nature. 267 (5612): 585–90. doi:10.1038/267585a0. PMID 301613.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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