Advances In The Pharmacology And Clinical Use Of Aprotinin

Aprotinin is a natural,broad-spectrum,nonspecific serine proteinase inhibitor consisting of fifty-eight amino acids residue arranged in a single polypeptide chain, cross-linked by three disulfide bridges and having a molecular mass of 6512 Daltons. It is isolated from bovine lung tissue. It has no effect by p.o, and is usually used by iv or put in pump prime. After iv, aprotinin will distribute immediately into the whole extracellular fluid and its half-life time is about 2 hours. Aprotinin can't pass through the normal blood-brain barrier and only a few parts of it passes through the placental barrier. Aprotinin is metabolized in the kidney and excreted from the urine.Aprotinin acts in a number of interrelated ways to provide an antifibrinolytic effect, inhibit contact activation, reduce platelet dysfunction and attenuate the inflammatory response. For coagulation and fibrinolysis system, aprotinin inhibits the activity of several proteolytic enzymes such as plasmin, thrombin, trypsin, kallikre and blood coagulation factors IV-XII, and reduces FDP and D-dimer formation. In platelets, aprotinin reduces glycoprotein loss (e.g.,GpIb, GpIIb/IIIa receptors), and there is a direct effect on platelet adhesion and accumulation. Meanwhile, aprotinin will increase the Von Willebrard molecule level produced by the vascular endoth-elial cell.For granulocyte and complement system, aprotinin may prevents the leukocyte transmigration, neutrophil activation, degranulation, and especially the generation and release of inflammatory cytokines of neutrophils and macrophages, such as tumor necrosis factor-alpha(TNF-a), interleukin-lbeta(IL-1B), interleukin-6(IL-6), interleukin-8(IL-8) and MACF, and increases the release of interleukin-lO(IL-lO). In the same time, aprotinin also inhibits the activation of complement system to release inflammatory mediators (e.g, C3a,C5a, and sC5b-9 )The development of a systemic inflammatory response associated with cardiopulmonary bypass(CPB) can lead to ischemia-reperfusion injury.Ischemia-reperfusion injury, a complex process involving the generation and release of inflammatory cytokines, the accumulation and infiltration of neutrophils and macrophages, the release of oxygen free radicals, the activation of proteases and generation of nitric oxide (NO), may result in myocardial dysfunction and possible injury to other major organs- ranging from mild organ dysfunction to multisystem organ failure. Its complications include coagulation disorders (bleeding diathesis, hyperfibrinolysis) from platelet defects and plasmin activation, as well as pulmonary dysfunction from neutrophil sequestration and degranulation. Diverse injuries are a consequence of multiple inflammatory mediators (complement, kinins, kallikrein, cytokines). Both plasmin and kallikrein amplify the inflammatory response by activating components of the contact activation system. Data indicate that aprotinin may not only reduce blood loss and transfusion requirements in CPB, but also inhibit kallikrein and plasmin, resulting in suppression of multiple systems involved in the inflammatory response and provide protection from ischemia-reperfusion injury. Specifically, inhibition of factor XII, bradykinin, C5a, neutrophil integral expression, elastase activity, and airway nitric oxide production areobserved. In conclusion, evidence indicates that aprotinin attenuates the systemic inflammatory response associated with CPB. For myocardial tissue, aprotinin may reduce the release of cardiac troponin I and diminish postischemic myocardial contractile dysfunction. In lung ischemia-reperfusion injury , it has been shown that aprotinin makes the pulmonary alveolus endoth-elial cell-II keep integrated in function and structures. It can also improve the arterial oxygenation and maintain the lung compliance in the early reperfusion period and offer protection of the pulmonary function. It has been reported that aprotinin may reduce the blood concentration of IL-8, IL-6, MDA,TNF-a, and SlOObeta protein ,and it might be useful to reduce postoperative cerebral damage in patients undergoing cardiac surgery with CPB.Although aprotinin is metabolizd in the kidney, it is indicated that the use of aprotinin can not increase the risk of postoperative renal dysfunction. Up to now, there was also no evidence of hepatic dysfunction in patients receiving aprotinin.Because aprotinin may provide actions such as an antifibrinolytic effect, protection from ischemia-reperfusion injury., reduction of platelet dysfunction and attenuation of inflammatory response to CPB, it has been widely used in patients with an increased risk of bleeding, especially in cardiac surgery with CPB, major orthopedic surgery, organ transplantion, repeat surgery and other fields. In many surgery, aprotinin can significantly reduce the postoperative blood Ioss(40%-80%) and the requirement for allogenic blood transfusions (70%-100%). Generally, aprotinin has dose-dependent effects on coagulation, fibrinolytic and inflammatory variables. The full-Hammersmith(high dose) of aprotinin is 2xlO6 KIU intravenous infusion in loading dose,2xl06 KIU in pump prime, and 5xlO5 KlU/h intravenous continuous infusion. In clinical use, the dose of aprotinin must be calculated on either the patient's weight or their body surface area, and added an appropriate dose in the prime of the cardiopulmonary bypass circuit, to achieve a plasma concentration of aprotinin (200 KIU/mL to 400 KIU/mL). Clinical trials indicated that aprotinin binds directly to the fibrinolytic plasmin at the lower plasmin-inhibiting dose (plasma concentration, 137 KIU/mL),and the inflammatory mediator, kallikrein, using the higher kallikrein-inhibiting dose (plasma concentration, >250 KIU/mL). In the pediatric heart surgery, evidence showed the inflammatory response is attenuated by high-dose aprotinin, leading to a reduction in inotropic support, earlier extubation, a tendency toward reduced post-operative blood loss and a shorten hospital stay.Besides its conservation of blood effects, aprotinin reduces vasoactive medication use and results in an improvement hemodynamic stability during orthotopic liver transplantion(OLT), and provides protection from liver ischemia-reperfusion injury. In patients undergoing total hip replacement surgery, aprotinin also decreases the incidence of deep venous thrombosis. The topical efficacy of aprotinin has been documented in several studies.Clinical data indicated that aprotinin is generally well tolerated. No severe side effects of aprotinin were registered. Anaphylactic reactions, thrombosis and prolonging of the activated clotting time (ACT) are commonly seen. The incidence of hepersensitivity reactions reported in the literature range from 0.1 to 0.6% of patients receiving aprotinin for the first time.There were no plenty of evidences of severe allergy in re-use cases.To keep allergy from happening, routine skin test is necessary before aprotinin used.The results of original reports, indicating that aprotinin therapy might decrease early vein graft occlusion and increase thrombosis rates, have not been supported by recent studies which were specifically designed to investigate the effects of aprotinin on graft patency in patients undergoing routine coronary artery bypass grafting(CABG). Clinical evidence to date supports that aprotinin may be beneficial to decrease the incidence of perioperative myocardial infarction or pulmonary embolism in CABG.When aprotinin is used during CPB, there is a prolongation of ACT, which is used to monitor heparinization. This results showed that when kaolin was used as the contact activator, the intrinsic clotting system was also inhibited by aprotinin. So, we suggest that the patientswhich ACT is over 750 seconds use aprotinin during CPB.Overall, aprotinin is a safe, effective medicine, and will have a wonderful future in clinical use.