Aprotinin inhibition

Lottenberg R., Sjak-Shie N., Fazleabas A. T Roberts R. M. Aprotinin inhibits urokinase but not tissue-type plasminogen activator. Thromb Res 1988 49,549-56. 

A plasmin inhibitor such as aprotinin used for blood collection, while effective in inhibiting activation of plasminogen by urokinase, is ineffective against the ac-... 

Serine protease inhibitor that inhibits trypsin, chymotrypsin, kallikrein, and plasmin Binding is reversible, with most aprotinin-protease complexes dissociating at pH>10or <3 Peptidase inhibitor... 

Aprotinin is a polypeptide consisting of a chain of 58 amino acid residues, which inhibits stoichiometrically the activity of several proteolytic enzymes such as chymotrypsin, kallikrein, plasmin, and trypsin. Aprotinin is obtained from bovine tissues and purified by a suitable process. It is stored as a bulk solution or lyophilized powder. The amount of two related substances des-Ala-des-Gly-aprotinin and des-Ala-aprotinin is determined by CZE with a 100% analysis. The relative migration times are 0.98 for des-Ala-des-Gly-aprotinin and 0.99 for des-Ala-aprotinin, and the specified limits are 8.0 and 7.5%, respectively. 

Proteases occurring in the epithelial lining fluids are another source of variability in protein absorption from the lung. In the epithelial lining fluids proteases and peptidases do occur. Inhibition of proteases and peptidases with substances such as bacitracin or aprotinin might improve the bioavailability of proteins. For example bacitracin was shown to increase insulin bioavailability by a factor of 6.8 [3]. 

Inactivation of the fibrinolytic system can be achieved by plasmin inhibitors, such as -aminocaproic acid, p-aminomethylbenzoic acid (PAMBA), tranexamic acid, and aprotinin, which also inhibits other proteases. 

Cardiopulmonary bypass, with extracorporeal circulation during cardiac artery bypass graft or heart valve replacement surgery, causes transient hemostatic defects in blood cells and perioperative bleeding. The protease inhibitor aprotinin (Trasylol) inhibits kalhkrein (coagulation phase) and plasmin (hbrinolysis) and protects platelets from mechanical injury. The overall effect after infusion is a decrease in bleeding. 

The synthesis of kinins can be inhibited with the kallikrein inhibitor aprotinin. Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin. Conversely, the actions of kinins can be enhanced with ACE inhibitors, which block the degradation of the peptides. Indeed, as noted above, inhibition of bradykinin metabolism by ACE inhibitors contributes significantly to their antihypertensive action. 

Aprotinin is a polypeptide consisting of 58 amino acid residues derived from bovine lung tissues and shows inhibitory activity toward various proteolytic enzymes including chymo-trypsin, kallikrein, plasmin, and trypsin. It was also one of the first enzyme inhibitors used as an auxiliary agent for oral (poly)peptide administration. The co-administration of aprotinin led to an increased bioavailability of peptide and protein drugs [5,44,45], The Bowman-Birk inhibitor (71 amino acids, 8 kDa) and the Kunitz trypsin inhibitor (184 amino acids, 21 kDa) belong to the soybean trypsin inhibitors. Both are known to inhibit trypsin, chymotrypsin, and elastase, whereas carboxypeptidase A and B cannot be inhibited [7,46],... 

There is evidence that protein structures are also responsible for cell cohesion in nonpalmo-plantar stratum corneum. When punch biopsies of normal human gluteal skin were incubated in a buffer containing a mixture of the zwitterionic surfactant /V,/V,-dimethyldodecylamine and the anionic surfactant sodium dodecyl sulfate,11 there was dissociation of cells in the stratum corneum but not in the rest of the epidermis. The cell dissociation took place only in the presence of EDTA and was inhibited by the serine protease inhibitor aprotinin.12 Suzuki et al.13,14 presented evidence that spontaneous cell dissociation in nonpalmo-plantar stratum corneum could be inhibited by a combination of inhibitors of trypsin-like and chymotrypsin-like enzymes. Thus, nonpalmo-plantar stratum corneum contains endogenous proteases that mediate cell dissociation. 

During inflammation, degranulation of immune cells releases serine proteases that pass through and bind to the capillary wall. Increased levels of Bik suppress these immune cell proteases and protect the extracellular matrix in arterial walls and connective tissue [4]. Bik inhibits phagocytic destruction of cells. Bik has been shown to inhibit elastases, granzymes A and K [4, 57], Mast cell tryptases (J3- and a-tetrameric forms with a molecular weight of 134 kDa) are resistant to aprotinin [58]. Lymphocytes serine esterase TL2 is not inhibited by Bik [59]. 

Brinkmann T, Schaefers J, Guertler L, Kido H, Niwa Y, Katunuma N, et al. Inhibition of tryptase TL2 from human T4+ lymphocytes and inhibition of HIV-1 replication in H9 cells by recombinant aprotinin and bikunin homologs. J Protein Chem 1997 16 651-660. 

Day JRS, Punjabi PP, Randi AM, Haskard DO, Landis RC, Taylor KM. Clinical inhibition of the seven-transmembrane thrombin receptor (PARI) by intravenous aprotinin during cardiothoracic surgery. Circulation 2004 110 2597-2600. 

MEROPS identifies Kunitz-type inhibitors as families 12 and 13, yet they seem to have developed separately in evolutionary history. Families 12 and 13 are referred to as Kunitz-A and Kunitz-P for their origin from animals and plants, respectively. Aprotinin, also known as bovine pancreatic trypsin inhibitor, was one of the first protease inhibitors identified and isolated by Kraut and coworkers in 1930. The 12 family is considerably more homogenous and thought to inhibit only S1 peptidases. In contrast, the 13 family is split into two phylogenetic groups, 13A and 13B, both of which typically inhibit SI peptidases, yet members of the I3A family can also potentially inhibit the A1 family aspartyl proteases and the Cl family cysteine proteases. The first structure of an 13 inhibitor was the... 

Aprotinin is not effective after oral administration, but is administered intravenously as a loading dose followed by a continuous infusion. Its activity is expressed as kallikrein inactivation units (KIU). The conventional (Munich) dose regimen consists of an initial 2 x 10 KIU bolus, a similar initial dose to prime the bypass machine, and then 0.5 x 10 KIU/ hour by continuous infusion thereafter. The half-life of aprotinin is about 2 hours. Plasma concentrations of 125 KlU/ml are necessary to inhibit plasmin, but a... 

Aprotinin has a high affinity for renal tissue 80-90% is stored in the proximal tubule cells after 4 hours and is excreted over 12-24 hours (2). It has been hjrpothesized that aprotinin causes reversible overload of tubular reabsorption, resulting in transient renal dysfunction (2). It has also been postulated that aprotinin has a direct toxic effect on the proximal tubule cells or alters intrarenal blood flow, through inhibition of renin and kaUikrein activity (2). 

Pharmacological inhibition of the key enzymes responsible for the consecutive activation of cascade of reactions, including aprotinin, tranexamic acid, aminocapron acid, Cl-esterase inhibitor, antioxidants, and free radical scavengers are also under evaluation to improve hemocompatibility. Research into the modification of surfaces with integrin (receptors that link cellular components to extracellular matrix proteins) fragments, such as peptides with RGD amino acid sequence, has been conducted to increase hemocompatibility and biocompatibility. Further research into the improvement of device... 

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