Aprotinin

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Pancreatic trypsin inhibitor ( Bos taurus )
Pancreatic trypsin inhibitor (Bos taurus)

Existing structural data: s. UniProt

Mass / length primary structure 58 amino acids
Identifier
External IDs
Drug information
ATC code B02 AB01
Drug class Protease inhibitor
Inhibitor classification
MEROPS I02.001

Aprotinin (pancreatic trypsin inhibitor) is a natural polypeptide and a protease inhibitor .

The aprotinin from domestic cattle is used in human medicine to reduce the tendency to bleed. Aprotinin is z. Administered in open heart surgery or liver surgery to reduce blood loss and minimize the need for blood transfusions. In November 2007 it was temporarily withdrawn from the market worldwide due to indications of increased side effects.

It is extracted from the lung tissue of cows and was discovered in the 1930s and patented by Bayer in 1959 . Aprotinin consists of 58 amino acids . Aprotinin is a protease inhibitor , the main action of which is to inhibit the serine protease plasmin , which slows down the breakdown of clotted blood ( fibrinolysis ).

Side effects

In January 2006, the New England Journal of Medicine published the results of an observational study that aprotinin was associated with an increased rate of postoperative kidney failure .

An advisory committee of the American health authority FDA has the above. Report reviewed in September 2006 and concluded that aprotinin is a safe and effective drug for preventing blood loss in open heart surgery. A week after the September 2006 meeting, the New York Times reported on aprotinin that Bayer had not fully provided the information.

After further testing, a new risk assessment was carried out, which continued to allow use under certain conditions. On November 5, 2007, Bayer temporarily stopped marketing the product worldwide. With the marketing stop, Bayer followed an order from the Federal Institute for Drugs and Medical Devices and recommendations from the US FDA .

In February 2008, The Lancet published a study that assessed the use of aprotinin as safe for certain surgical methods (on-pump), but not for other methods (off-pump).

Also in February 2008, the New England Journal of Medicine published two further studies that showed increased mortality after coronary artery bypass surgery when using aprotinin .

Following the publication of the results of the Canadian BART study (Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population - The BART Study) on May 14, 2008, Bayer withdrew all remaining Trasylol stocks from the market. Until the company has made a final decision, Trasylol will initially only be available to patients under strict conditions agreed with the authorities.

In July 2012 Bayer announced in a press release that the company had sold the worldwide distribution rights outside the United States to the Nordic Pharma Group. As early as February 2012, the European Medicines Agency (EMA) recommended lifting the sales ban because the study results on the basis of which the drug was withdrawn from the market a few years ago were flawed. Sales of the product in Canada had already been re-opened in September 2011. A final decision by the European Commission is expected at the end of this year, but it usually follows the recommendations of the Medicines Agency. On November 11, 2013 a partial re-approval for use in cardiac surgery was granted subject to conditions.

In vitro use

Aprotinin is a protease inhibitor common in molecular biology and biochemistry , which is used in particular for cell disruption and protein purification. Aprotinin inhibits kallikrein , plasmin, trypsin , chymotrypsin and various intracellular serine proteases. Aprotinin is a competitive inhibitor that blocks the active site of the enzymes by forming stable complexes. The reversible bond is unstable in acidic and basic environments. Aprotinin was discovered in 1930 by Kraut et al. and first isolated in 1936 by Kunitz and Northrup.

Trade names

Monopreparations

Trasylol (A, CH)

Combination preparations

Artiss (A), Beriplast (D, A, CH), Tachocomp (A), Tisseel (A), Tissucol (D, CH)

Individual evidence

  1. ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals . 11th edition, 1989
  2. ↑ UniProt P00974
  3. ↑ Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprrotinin in cardiac surgery. N Engl J Med. 2006; 354 ​​(4): 353-65 Link to journal PMID 16436767
  4. ↑ FDA statement of September 29, 2006
  5. ↑ FDA News of December 15, 2006
  6. ↑ A. Thiele: Defense against the dangers of drugs / aprotinin-containing drugs for intravenous use. Federal Institute for Pharmaceuticals and Medical Products. November 5, 2007, accessed on February 13, 2017 (PDF; 56 kB).
  7. ↑ FDA press release of November 5, 2007
  8. ↑ Abstract from The Lancet
  9. ↑ Schneeweiss, Sebastian et al .: Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death . In: N Engl J Med . No. 358 , 2008, p. 771-783 , doi : 10.1056 / NEJMoa0707571 .
  10. ↑ Shaw, Andrew D: The Effect of Aprotinin on Outcome after Coronary-Artery Bypass Grafting . In: N Engl J Med . No. 358 , 2008, p. 784-793 , doi : 10.1056 / NEJMoa0707768 .
  11. ^ Dean A. Fergusson et al .: A Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery . In: N Engl J Med . No. 358 , 2008, p. 2319-2331 , doi : 10.1056 / NEJMoa0802395 .
  12. ↑ FDA news of May 14, 2008
  13. ↑ Bayer sells rights to the controversial drug Trasylol. Reuters Germany, July 13, 2012, accessed February 13, 2017 .
  14. ↑ Singbartl G., Singbartl K., Todt H., Schindler E., Martin K., Tassani-Prell P. (2016) Antifibrinolytics – tranexamic acid and aprotinin. In: Singbartl G., Singbartl K. (eds) Transfusion-associated pharmacotherapy. Springer, Berlin, Heidelberg. ISBN 978-3-662-47258-3 . Pp. 71-170.
  15. ↑ Aprotinin at Sigma-Aldrich (PDF file)
  16. ↑ ES Zyznar: A rationale for the application of trasylol as a protease inhibitor in radioimmunoassay. In: Life sciences. Volume 28, Number 17, April 1981, pp. 1861-1866, PMID 6166824 (Review).
  17. ↑ H. Kraut, EK Frey, E. Werle: About the inactivation of the kallikreins. (VI. Communication about this circulatory hormone.). In: Hoppe-Seyler's magazine for physiological chemistry. 192, 1930, p. 1, doi: 10.1515 / bchm2.1930.192.1-3.1 .
  18. ^ M. Kunitz, JH Northrop: ISOLATION FROM BEEF PANCREAS OF CRYSTALLINE TRYPSINOGEN, TRYPSIN, A TRYPSIN INHIBITOR, AND AN INHIBITOR-TRYPSIN COMPOUND. In: The Journal of general physiology. Volume 19, Number 6, July 1936, pp. 991-1007, PMID 19872978 , PMC 2141477 (free full text).
  19. ↑ Red List online, as of September 2009
  20. ↑ AM comp. d. Switzerland, as of September 2009
  21. ↑ AGES-PharmMed, as of September 2009

literature