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International Journal of Molecular... Jul 2023Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, APR was widely used as an antithrombotic and... (Review)
Review
Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, APR was widely used as an antithrombotic and anti-inflammatory drug in cardiac and noncardiac surgeries for reduction of bleeding and thus limiting the need for blood transfusion. The ability of APR to inhibit proteolytic activation of some viruses leads to its use as an antiviral drug for the prevention and treatment of acute respiratory virus infections. However, due to incompetent interpretation of several clinical trials followed by incredible controversy in the literature, the usage of APR was nearly stopped for a decade worldwide. In 2015-2020, after re-analysis of these clinical trials' data the restrictions in APR usage were lifted worldwide. This review discusses antiviral mechanisms of APR action and summarizes current knowledge and prospective regarding the use of APR treatment for diseases caused by RNA-containing viruses, including influenza and SARS-CoV-2 viruses, or as a part of combination antiviral treatment.
Topics: Humans; Aprotinin; SARS-CoV-2; Prospective Studies; COVID-19; Antiviral Agents; Respiration Disorders
PubMed: 37446350
DOI: 10.3390/ijms241311173 -
The Annals of Pharmacotherapy Apr 1996To review the clinical pharmacology of aprotinin in patients undergoing surgical procedures involving major blood loss, namely, coronary artery bypass graft (CABG). (Clinical Trial)
Clinical Trial Review
OBJECTIVE
To review the clinical pharmacology of aprotinin in patients undergoing surgical procedures involving major blood loss, namely, coronary artery bypass graft (CABG).
DATA SOURCES
A MEDLINE search was used to identify French- and English-language publications on aprotinin using the indexing terms aprotinin, cardiothoracic surgery, and hemorrhage. The MEDLINE search was supplemented by review of article bibliographies. Data also were obtained from the approved Canadian and US product labels.
STUDY SELECTIONS
All abstracts and uncontrolled and controlled clinical trials were reviewed.
DATA EXTRACTION
Study design, population, results, and safety information were retained. Efficacy conclusions were drawn from controlled trials.
DATA SYNTHESIS
Aprotinin, a serine protease inhibitor isolated from bovine lung tissue, decreases bleeding after cardiac surgery by mechanisms including antifibrinolytic activity and preservation of platelet function. Several trials have shown that aprotinin reduced blood loss and transfusion requirements in patients undergoing CABG. Its use in other surgical procedures involving major blood loss has been reported. Aprotinin is well tolerated, with minor allergic reactions being the most frequently reported adverse effect. Although unsubstantiated, the possibility that aprotinin could create a prothrombic state leading to early graft occlusion and formation of microthrombi in renal and coronary vasculatures is of concern.
CONCLUSIONS
Aprotinin is an effective hemostatic agent in CABG. Clear definitions of indications, dosing, safety, and repeated use remain to be investigated thoroughly.
Topics: Aprotinin; Coronary Artery Bypass; Drug Interactions; Hemostasis, Surgical; Hemostatics; Humans
PubMed: 8729892
DOI: 10.1177/106002809603000410 -
International Anesthesiology Clinics 2004
Review
Topics: Anticoagulants; Aprotinin; Blood Loss, Surgical; Cardiac Surgical Procedures; Hemostatics; Heparin; Humans
PubMed: 15577702
DOI: 10.1097/00004311-200404240-00009 -
The Annals of Thoracic Surgery Apr 1993Aprotinin is a nonspecific serine protease inhibitor extracted from bovine lung. It was first used during cardiopulmonary bypass to inhibit plasmin-induced complement... (Review)
Review
Aprotinin is a nonspecific serine protease inhibitor extracted from bovine lung. It was first used during cardiopulmonary bypass to inhibit plasmin-induced complement activation. By chance significant reductions of blood loss and blood requirements were noted in treated patients. Subsequent investigation showed improved hemostasis to result from protection of platelet adhesive receptors (Gp Ib) at the onset of cardiopulmonary bypass. Without aprotinin the contact system of plasma is massively activated on first passage through the cardiopulmonary bypass circuit. Activation of the intrinsic coagulation pathway causes thrombin formation, which impairs platelet adhesive function. Aprotinin blocks contact activation of the kallikrein system during cardiopulmonary bypass and in synergy with heparin prevents thrombin formation through inhibition of the intrinsic clotting cascade. It is likely that neither thrombin nor platelets become involved in the blood-foreign surface contact activation process in aprotinin-treated patients. The fact that the hemostatic process is affected from the very beginning of cardiopulmonary bypass is substantiated by the fact that low-dose aprotinin therapy (2 x 10(6) KIU aprotinin added to the pump prime) leads to the same preservative effect on Gp Ib receptors and blood loss as continuous high-dose infusion (6 x 10(6) KIU) throughout the whole surgical procedure. In the presence of heparin aprotinin prolongs the activated clotting time and the in vitro activated partial thromboplastin time. This has important implications for heparin dosage. An inhibitory effect on the endothelial cell anticoagulant function may also have consequences during hypothermic low flow and circulatory arrest states.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Aprotinin; Cardiopulmonary Bypass; Hemostasis; Humans; Kidney
PubMed: 7682054
DOI: 10.1016/0003-4975(93)90149-c -
Current Opinion in Anaesthesiology Feb 2009The nonspecific protease inhibitor aprotinin has been used successfully to reduce bleeding in cardiac surgery. Recent investigations have questioned its safety, and... (Review)
Review
PURPOSE OF REVIEW
The nonspecific protease inhibitor aprotinin has been used successfully to reduce bleeding in cardiac surgery. Recent investigations have questioned its safety, and aprotinin has finally been withdrawn from marketing after a large prospective study demonstrated a trend toward higher mortality.
RECENT FINDINGS
The initial studies of Karkouti and Mangano provoked a considerable number of large-scale investigations focusing on the safety issues of aprotinin. These studies were of retrospective nature and used sophisticated statistical methods to overcome a possible selection bias. Recently, aprotinin was predominantly used in patients with a higher risk of bleeding, which hampers a retrospective comparison with patients without the drug. This review summarizes the diverging results of these studies.
SUMMARY
It remains a matter of speculation whether the quality and results of published data justify the withdrawal of aprotinin; however, one has to accept that this drug is no longer available. It is clear from the aprotinin story that there are no effective instruments to control the safety and clinical efficacy of a drug after its regulatory approval. This highlights the urgent need for independent clinical safety studies after the formal registration of a drug.
Topics: Antifibrinolytic Agents; Aprotinin; Blood Loss, Surgical; Cardiac Surgical Procedures; Hemostatics; Humans; Randomized Controlled Trials as Topic
PubMed: 19295302
DOI: 10.1097/ACO.0b013e32831c833f -
Anaesthesia Jan 2015There is a considerable difference between the mechanism of action of the lysine analogues, tranexamic acid and epsilon-aminocaproic acid, and the serine protease... (Review)
Review
There is a considerable difference between the mechanism of action of the lysine analogues, tranexamic acid and epsilon-aminocaproic acid, and the serine protease inhibitor aprotinin. Aprotinin acts to inactivate free plasmin, but with little effect on bound plasmin, whereas the lysine analogues are designed to prevent excessive plasmin formation by fitting into plasminogen's lysine-binding site to prevent the binding of plasminogen to fibrin. Aprotinin is associated with a reduction in bleeding and transfusion requirements following major surgery, and has a dose-response profile, compared with no dose-response effect in the one study investigating tranexamic acid in cardiac surgical patients. Following its withdrawal in 2007, which is explained in detail in this review, the regulators have now licensed aprotinin for myocardial revascularisation only, which is relatively low-risk for bleeding.
Topics: Animals; Aprotinin; Hemorrhage; Hemostatics; Humans; Tranexamic Acid
PubMed: 25440394
DOI: 10.1111/anae.12907 -
The Annals of Thoracic Surgery Jul 1999Early experience with aprotinin in deep hypothermic circulatory arrest (DHCA) raised alarm about hazards associated with its use. Based on what little is known about... (Review)
Review
Early experience with aprotinin in deep hypothermic circulatory arrest (DHCA) raised alarm about hazards associated with its use. Based on what little is known about possible mechanistic interactions between hypothermia, stasis, and aprotinin, there is no evidence that aprotinin becomes unusually hazardous in DHCA. Excessive mortality and complication rates have only been reported in clinical series in which the adequacy of heparinization is questionable. Benefits associated with use of aprotinin in DHCA have been inconsistently demonstrated. The only prospective, randomized series showed significant reduction in blood loss and transfusion requirements. Use of aprotinin in DHCA should be based on the same considerations applied in other cardiothoracic procedures.
Topics: Aprotinin; Blood Loss, Surgical; Blood Transfusion; Heart Arrest, Induced; Hemostasis; Hemostatics; Humans; Hypothermia, Induced
PubMed: 10421168
DOI: 10.1016/s0003-4975(99)00518-4 -
Expert Review of Cardiovascular Therapy Mar 2006Aprotinin is a naturally occurring serine protease inhibitor that is being used with increasing frequency in cardiac surgery and beyond to reduce blood loss and the need... (Review)
Review
Aprotinin is a naturally occurring serine protease inhibitor that is being used with increasing frequency in cardiac surgery and beyond to reduce blood loss and the need for perioperative blood transfusion. Through inhibition of serine proteases such as plasmin, aprotinin significantly reduces fibrinolysis, thereby aiding hemostasis during surgical procedures. In addition, aprotinin interacts with other factors in the coagulation and fibrinolytic cascade, creating a hemostatic balance, without increasing the risk of thrombosis. These proven benefits are supplemented by the anti-inflammatory properties of aprotinin, which may help curb some of the deleterious effects of cardiopulmonary bypass. This article will review the discovery of aprotinin, its mechanism of action, dosing and adverse effects, and highlight the major recent trials demonstrating its efficacy.
Topics: Animals; Aprotinin; Blood Loss, Surgical; Cardiac Surgical Procedures; Clinical Trials as Topic; Drug Costs; Drug Monitoring; Hemostatics; Humans; Serine Proteinase Inhibitors
PubMed: 16509811
DOI: 10.1586/14779072.4.2.151 -
British Journal of Anaesthesia Dec 1994
Topics: Aprotinin; Blood Coagulation; Blood Platelets; Endothelium, Vascular; Hemostasis; Humans; Randomized Controlled Trials as Topic; Thrombosis
PubMed: 7533511
DOI: 10.1093/bja/73.6.734 -
Drugs Jun 1995Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) experience transient haemostatic defects as a result of adverse changes to their blood components,... (Review)
Review
Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) experience transient haemostatic defects as a result of adverse changes to their blood components, blood cells and specific coagulation proteins. Aprotinin is a naturally occurring serine protease inhibitor isolated from bovine lung tissue which inhibits kallikrein and plasmin. A high dose aprotinin regimen (aprotinin 280mg loading dose over 20 to 30 minutes after anaesthesia induction followed by 70 mg/h for the duration of the operation and 280mg added to the priming fluid of the CPB circuit) has been used during CPB in order to reduce perioperative bleeding. Recent clinical trials confirm the efficacy of high dose aprotinin in reducing blood loss and transfusion requirements associated with primary cardiac procedures such as coronary artery bypass graft (CABG) or heart valve replacement surgery. High dose aprotinin is also effective in procedures known to possess a high risk for excessive blood loss, such as repeat CABG or heart valve replacement surgery, cardiac surgery in patients with infective endocarditis, or in patients receiving aspirin (acetylsalicylic acid) before surgery. Studies indicate that low dose aprotinin (280mg added to CPB pump prime fluid) is effective in reducing blood loss and transfusion requirements in patients undergoing primary CABG surgery. Additionally, low dose aprotinin regimens (both 280mg added to CPB pump prime fluid and 50% of the high dose regimen) have shown some benefit in repeat CABG surgery; however, more studies are needed to confirm these results. Data from clinical trials indicate that aprotinin is well tolerated. The types and incidences of adverse events reported with aprotinin therapy are generally consistent with those associated with major cardiac surgery, and are not significantly different from those observed in control groups. A trend towards lower graft patency rates, detected by ultrafast computerised tomography (CT), has been observed in aprotinin recipients in 2 US trials. These differences did not reach statistical significance and should be interpreted with caution since the ability of ultrafast CT to determine graft patency has not been validated. Mildly elevated plasma creatinine levels are more commonly observed in aprotinin-treated patients; these changes are transient in the majority of patients. Both high dose and low dose aprotinin regimens (280mg added to CPB pump prime fluid or 50% of the high dose regimen) have reduced blood loss and transfusion requirements in patients undergoing primary and repeat cardiac surgery. The role of aprotinin in paediatric cardiac surgery needs further clarification, while well-designed studies comparing aprotinin with other agents which inhibit fibrinolysis are also awaited with interest.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Aprotinin; Blood Loss, Surgical; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Hemostatics; Humans
PubMed: 7543841
DOI: 10.2165/00003495-199549060-00008