CiNii 図書 - Fibrinolytics and antifibrinolytics

Disturbances of haemostasis and thromboembolic disorders still constitute a great problem in clinical practice. Increasing insight into the mechanism of blood coagula- tion has led to more effective therapy and prophylaxis. Particularly, the understand- ing of the biochemistry of fibrinolysis has provided possibilities for the pharma- cological interference of these processes, which has resulted in effective haemostatic agents and useful antithrombotic ones. The development of antifibrinolytics for interfering with pathological fibrinolytic processes is nearly complete and has led to the development of drugs essential to the therapy of hyperfibrinolytic bleeding. The search for fibrinolytics for dissolving intravascular thrombi has led to highly effective compounds. This development is still under way and promising results are hoped. Spontaneous dissolution of blood clots is a phenomenon which was described a century ago. First investigations of this process assured that there is in the organism a system capable of removing the fibrin which is formed during blood coagulation after it has fulfilled its physiological function. This fibrinolytic system is specifically adapted to the degradation of insoluble fibrin into soluble degradation products. In the past 30 years, thorough investigation of this system has clarified the fibrinolytic process, its physiological role and its meaning as a pathogenetic principle. A good knowledge of these processes is required for an understanding of the effects and side effects of fibrinolytics and antifibrinolytics, which comprise the basis of methods for the detection of fibrinolytic processes in the organism and of the control of therapy with these drugs.

The Fibrinolytic Process.- Biochemistry of the Factors of the Fibrinolytic System.- A. Factors of the Fibrinolytic System.- I. Plasminogen - Plasmin.- 1. Plasminogen.- 2. Plasmin.- II. Plasminogen Activators.- 1. Activators in Body Fluids.- a) Blood Activator.- b) Urine Activator (Urokinase).- c) Activators from Other Body Fluids.- 2. Tissue Activators.- 3. Bacterial Activators.- a) Streptokinase.- b) Staphylokinase.- III. Inhibitors.- B. Mechanisms of the Fibrinolytic Process.- I. Plasmin Formation (Plasminogen Activation).- II. Formation of Activator (Mechanism of Action of Streptokinase).- III. Fibrin Dissolution.- Final Remarks.- References.- Fibrinogen and Fibrin Formation.- A. Physico-chemical Properties of Fibrinogen.- B. Biochemical Properties of Fibrinogen.- I. Subunits and Prosthetic Groups.- II. The Primary Structure.- 1. CNBr-Fragments.- 2. Disulphide Bridges.- 3. Plasmin Fragments.- III. The Antigenic Structure of Fibrinogen and the Location of Epitopes and Other Structural Elements.- C. Fibrin - The Ordered Structure of Fibrinogen.- I. Release of Fibrinopeptides.- II. Polymerization of Fibrin Monomers.- III. Stabilizing of the Fibrin Polymer.- D. Fibrinogen in Health and Disease.- References.- Fibrinogen and Fibrin Degradation Products.- A. Degradation of the Fibrinogen Molecule.- I. Degradation by Thrombin.- II. Degradation by Plasmin.- III. Degradation by Both Plasmin and Thrombin.- IV. Degradation by Other Enzymes.- 1. Thrombin-like Enzymes.- 2. Pancreatic Proteases.- 3. Proteases from Other Sources.- B. Biological Activities.- I. Products of Thrombin Action.- 1. Fibrin Monomer.- 2. Fibrinopeptide A and B (FpA, FpB).- II. Products of Plasmin Action.- 1. Clottability.- 2. Anticlotting Activity.- a) Inhibition of Thrombin.- b) Inhibition of Fibrin Polymerization.- c) Inhibition of Thromboplastin Generation.- 3. Interference of FDP with Platelet Function.- 4. Effects on Smooth Muscle, Heart and Permeability of Biological Membranes.- 5. Stimulation of Fibrinogen Biosynthesis.- 6. Other Effects.- C. Immunologic Properties of FDP.- D. Detection and Quantitation of FDP.- I. Immunologic Assays.- II. Radioimmunoassay.- III. Staphylococcal Clumping Test (SC).- IV. Thrombin and Reptilase Time.- V. Detection of Soluble Fibrin Complexes.- VI. Practical Value.- E. The Role of FDP in Clinical Practice.- References.- The Measurement of Fibrinolytic Activities.- A. Methods for Measuring the Spontaneous Fibrinolytic Activity of Blood.- I. Whole Blood Lysis Test.- II. Euglobulin Clot Lysis Test.- III. Dilute Clot Lysis Time Methods.- 1. Dilute Whole Blood Clot Lysis Time.- 2. Schneider's Test.- IV. Fibrin Plate Method.- V. Determination of Fibrin/Fibrinogen Degradation Products (FDP).- 1. Tanned Red Cell Hemagglutination Inhibition Immunoassay (TRCHII).- 2. Latex Agglutination Tests.- 3. Immunochemical Method According to Nilehn.- a) Malignant Diseases.- b) Renal Diseases.- c) Conditions Associated with Abnormal Proteolysis.- 4. Radioimmunoassay for Determination of FDP.- B. Fibrinolytic Response to Stimuli, with Special References to Venous Occlusion Test.- C. The Fibrin Slide Method (Todd's Method).- D. Release of Fibrinolytic Agents from Tissue Cultures ("Culture with Clot" Plasmin.- 1. Plasminogen.- 2. Plasmin.- II. Plasminogen Activators.- 1. Activators in Body Fluids.- a) Blood Activator.- b) Urine Activator (Urokinase).- c) Activators from Other Body Fluids.- 2. Tissue Activators.- 3. Bacterial Activators.- a) Streptokinase.- b) Staphylokinase.- III. Inhibitors.- B. Mechanisms of the Fibrinolytic Process.- I. Plasmin Formation (Plasminogen Activation).- II. Formation of Activator (Mechanism of Action of Streptokinase).- III. Fibrin Dissolution.- Final Remarks.- References.- Fibrinogen and Fibrin Formation.- A. Physico-chemical Properties of Fibrinogen.- B. Biochemical Properties of Fibrinogen.- I. Subunits and Prosthetic Groups.- II. The Primary Structure.- 1. CNBr-Fragments.- 2. Disulphide Bridges.- 3. Plasmin Fragments.- III. The Antigenic Structure of Fibrinogen and the Location of Epitopes and Other Structural Elements.- C. Fibrin - The Ordered Structure of Fibrinogen.- I. Release of Fibrinopeptides.- II. Polymerization of Fibrin Monomers.- III. Stabilizing of the Fibrin Polymer.- D. Fibrinogen in Health and Disease.- References.- Fibrinogen and Fibrin Degradation Products.- A. Degradation of the Fibrinogen Molecule.- I. Degradation by Thrombin.- II. Degradation by Plasmin.- III. Degradation by Both Plasmin and Thrombin.- IV. Degradation by Other Enzymes.- 1. Thrombin-like Enzymes.- 2. Pancreatic Proteases.- 3. Proteases from Other Sources.- B. Biological Activities.- I. Products of Thrombin Action.- 1. Fibrin Monomer.- 2. Fibrinopeptide A and B (FpA, FpB).- II. Products of Plasmin Action.- 1. Clottability.- 2. Anticlotting Activity.- a) Inhibition of Thrombin.- b) Inhibition of Fibrin Polymerization.- c) Inhibition of Thromboplastin Generation.- 3. Interference of FDP with Platelet Function.- 4. Effects on Smooth Muscle, Heart and Permeability of Biological Membranes.- 5. Stimulation of Fibrinogen Biosynthesis.- 6. Other Effects.- C. Immunologic Properties of FDP.- D. Detection and Quantitation of FDP.- I. Immunologic Assays.- II. Radioimmunoassay.- III. Staphylococcal Clumping Test (SC).- IV. Thrombin and Reptilase Time.- V. Detection of Soluble Fibrin Complexes.- VI. Practical Value.- E. The Role of FDP in Clinical Practice.- References.- The Measurement of Fibrinolytic Activities.- A. Methods for Measuring the Spontaneous Fibrinolytic Activity of Blood.- I. Whole Blood Lysis Test.- II. Euglobulin Clot Lysis Test.- III. Dilute Clot Lysis Time Methods.- 1. Dilute Whole Blood Clot Lysis Time.- 2. Schneider's Test.- IV. Fibrin Plate Method.- V. Determination of Fibrin/Fibrinogen Degradation Products (FDP).- 1. Tanned Red Cell Hemagglutination Inhibition Immunoassay (TRCHII).- 2. Latex Agglutination Tests.- 3. Immunochemical Method According to Nilehn.- a) Malignant Diseases.- b) Renal Diseases.- c) Conditions Associated with Abnormal Proteolysis.- 4. Radioimmunoassay for Determination of FDP.- B. Fibrinolytic Response to Stimuli, with Special References to Venous Occlusion Test.- C. The Fibrin Slide Method (Todd's Method).- D. Release of Fibrinolytic Agents from Tissue Cultures ("Culture with Clot" The Ordered Structure of Fibrinogen.- I. Release of Fibrinopeptides.- II. Polymerization of Fibrin Monomers.- III. Stabilizing of the Fibrin Polymer.- D. Fibrinogen in Health and Disease.- References.- Fibrinogen and Fibrin Degradation Products.- A. Degradation of the Fibrinogen Molecule.- I. Degradation by Thrombin.- II. Degradation by Plasmin.- III. Degradation by Both Plasmin and Thrombin.- IV. Degradation by Other Enzymes.- 1. Thrombin-like Enzymes.- 2. Pancreatic Proteases.- 3. Proteases from Other Sources.- B. Biological Activities.- I. Products of Thrombin Action.- 1. Fibrin Monomer.- 2. Fibrinopeptide A and B (FpA, FpB).- II. Products of Plasmin Action.- 1. Clottability.- 2. Anticlotting Activity.- a) Inhibition of Thrombin.- b) Inhibition of Fibrin Polymerization.- c) Inhibition of Thromboplastin Generation.- 3. Interference of FDP with Platelet Function.- 4. Effects on Smooth Muscle, Heart and Permeability of Biological Membranes.- 5. Stimulation of Fibrinogen Biosynthesis.- 6. Other Effects.- C. Immunologic Properties of FDP.- D. Detection and Quantitation of FDP.- I. Immunologic Assays.- II. Radioimmunoassay.- III. Staphylococcal Clumping Test (SC).- IV. Thrombin and Reptilase Time.- V. Detection of Soluble Fibrin Complexes.- VI. Practical Value.- E. The Role of FDP in Clinical Practice.- References.- The Measurement of Fibrinolytic Activities.- A. Methods for Measuring the Spontaneous Fibrinolytic Activity of Blood.- I. Whole Blood Lysis Test.- II. Euglobulin Clot Lysis Test.- III. Dilute Clot Lysis Time Methods.- 1. Dilute Whole Blood Clot Lysis Time.- 2. Schneider's Test.- IV. Fibrin Plate Method.- V. Determination of Fibrin/Fibrinogen Degradation Products (FDP).- 1. Tanned Red Cell Hemagglutination Inhibition Immunoassay (TRCHII).- 2. Latex Agglutination Tests.- 3. Immunochemical Method According to Nilehn.- a) Malignant Diseases.- b) Renal Diseases.- c) Conditions Associated with Abnormal Proteolysis.- 4. Radioimmunoassay for Determination of FDP.- B. Fibrinolytic Response to Stimuli, with Special References to Venous Occlusion Test.- C. The Fibrin Slide Method (Todd's Method).- D. Release of Fibrinolytic Agents from Tissue Cultures ("Culture with Clot" Method).- References.- Activators of Fibrinolysis.- Biochemistry of Streptokinase.- A. Assays of Streptokinase Activity.- I. Clot Lysis Assay.- II. Lysine Methyl Ester Assay.- III. Casein Assay.- IV. NPGB Burst Assay.- B. Preparation of Streptokinase.- I. Preparation of High Purity Streptokinase.- II. Affinity Column Preparation of Streptokinase*.- C. Physical Properties of Streptokinase.- D. Mechanism of Streptokinase Activity.- References.- Pharmacology of Streptokinase.- A. Characteristics and Requirements for Pharmacological Examination.- I. Selection of Experimental Animals.- II. Formation of Plasminogen Activator.- III. Formation of AntiStreptokinase.- IV. Formation of Pyrogenic Substances.- B. Toxicity.- C. Pharmacodynamics.- I. Fibrinolytic Effect.- II. Effects on Smooth Muscle, Heart and Circulation.- D. Pharmacokinetics.- I. Native Streptokinase.- II. Radiolabeled Streptokinase.- E. Thrombolytic Effect.- F. Clinical Pharmacology.- References.- Clinical Use of Streptokinase.- A. Fundamentals of Clinical Use.- I. Thrombolytic Effect.- II. Effect on Hemostasis.- III. Immunologic Reactions.- IV. Influence on Kinin Formation.- B. Therapeutic Use.- I. Indications.- II. Contraindications.- III. Administration.- IV. Dosage.- 1. Initial Dose.- 2. Maintenance Dose.- 3. Special Dosage Schemes.- V. Control of Therapy.- VI. Side-Effects.- C. Results of Therapy.- I. Venous Thrombosis.- 1. Thrombosis of Deep Veins.- 2. Thrombosis of Veins of Organs.- 3. Priapism.- 4. Special Forms of Venous Thrombosis.- II. Pulmonary Embolism.- III. Arterial Thrombosis and Embolism.- 1. Acute Occlusion.- 2. Chronic Occlusion.- IV. Ischemic Heart Disease.- V. Thrombosis and Embolism of Retinal Vessels.- VI. Thrombosis of the Microvasculature.- VII. Other Fields of Application.- References.- Urokinase.- A. Origin of Urokinase.- I. Urokinase as Excreted Blood Activator.- II. Urokinase Produced in the Ureters and Bladder.- III. Urokinase Produced in the Kidneys.- IV. Comparison of Urokinase with Other Activators.- V. Urokinase from Tissue Cultures.- B. Physiology and Pathophysiology.- C. Purification and Isolation of Urokinase.- D. Biochemical Properties of Urokinase.- I. Characterization.- II. Urokinase and Plasminogen Activation.- III. Esterolytic and Amidolytic Activity of Urokinase.- IV. Inhibition of Urokinase.- V. Determination of Urokinase Activity and Units.- E. Experimental Pharmacology.- I. Urokinase Preparation for Thrombolysis.- II. Experimental Thrombolysis.- F. Clinical Use of Urokinase.- I. General Aspects.- II. Thrombolysis with Urokinase.- 1. Preliminary Investigations.- 2. Urokinase in Pulmonary Embolism.- 3. Urokinase in Myocardial Infarction.- 4. Urokinase in Cerebral Vascular Disease.- 5. Urokinase in Peripheral Thrombosis.- 6. Urokinase in Ophthalmology.- 7. Local Use of Urokinase.- III. Urokinase as Diagnostic Tool.- G. Conclusion.- References.- Synthetic Fibrinolytic Agents. Induction of Fibrinolytic Activity In Vitro.- Historical Remarks.- A. Methods for the In Vitro Assessment of Fibrinolysis-Inducing Capacity of Synthetic Organic Compounds.- I. Rotating Standard Clot.- II. Hanging Clot.- III. Plasma Clot.- B. Mechanism of Action.- I. Diffusion into Clots.- II. Adsorption onto Fibrin.- III. Suppression of Antiplasmin and Antiactivator Activity.- C. Synergism of Action Between Synthetic Fibrinolytic Compounds, the Natural Plasminogen Activators and Proteolytic Enzymes.- I. Synergism with Urokinase.- II. Synergism with Streptokinase.- III. Synergism with the Endogenous Plasminogen Activator.- IV. Synergism with Proteolytic Enzymes.- V. Synergism Among Synthetic Fibrinolytic Compounds.- D. Structure-Activity Relationship of Synthetic Fibrinolytic Compounds.- E. Binding of Synthetic Fibrinolytic Compounds to Albumin.- F. Enhancement by Hydrazine and Cobra Venom Factor of the Fibrinolytic Activity Induced by Synthetic Compounds In Vitro.- G. Induction of Fibrinolytic Activity In Vitro and In Vivo.- H. Effect of Synthetic Fibrinolytic Agents on Thrombocytes, Erythrocytes and some Clotting Factors.- References.- Indirect Fibrinolytic Agents.- A. Neurotransmitters and Autacoids.- I. Sympathomimetic Amines.- 1. Adrenaline.- a) Pharmacological Aspects.- b) Clinical Aspects.- 2. Noradrenaline.- 3. Phenylephrine.- 4. Dopamine.- 5. ? and ? Adrenoceptor Stimulating and Blocking Agents.- a) Clinical Aspects.- b) Pharmacological Aspects.- II. Cholinomimetics and Cholinolytics.- 1. Acetylcholine.- 2. Atropine.- 3. Nicotine.- III. Biogenic Amines.- 1. Serotonin.- a) Pharmacological Aspects.- b) Clinical Aspects.- 2. Histamine.- a) Biochemical Aspects.- b) Pharmacological Aspects.- c) Clinical Aspects.- IV. Biogenic Peptides.- 1. Hypotensive Polypeptides.- 2. Hypertensive Polypeptides.- B. Hormones.- I. Pituitary Hormones.- 1. Anterior Pituitary Hormones.- 2. Posterior Pituitary Hormones.- II. Steroid Hormones.- 1. Nonanabolic Steroids.- 2. Anabolic Steroids.- a) Male Sexual Hormones.- ?) Pharmacological Aspects.- ?) Clinical Aspects.- b) Female Sexual Hormones.- III. Thyroid Hormones.- IV. Insulin.- 1. Clinical Aspects.- 2. Pharmacological Aspects.- V. Antidiabetic Drugs.- 1. Sulfonylureas.- 2. Biguanides.- a) Phenformin.- b) Metformin.- c) Buformin.- VI. Combination of Biguanides and Anabolic Steroids.- 1. Combination Phenformin-Ethylestrenol.- 2. Combination Phenformin-Stanozolol.- 3. Combination Metformin-Ethylestrenol.- C. Anticoagulants and Related Compounds.- I. Heparin.- II. Heparinoids.- III. Oral Anticoagulants.- IV. Clofibrate.- D. Vasodilators.- E. Diuretic Drugs.- F. Anti-Inflammatory Drugs.- G. Pyrogens.- H. Miscellaneous Drugs.- I. Antibiotics.- II. Monoamine Oxidase Inhibitors.- III. Amino Acids and Derivatives.- IV. Chemical Emulsifying and Dispersing Substances.- V. Vegetable Extracts.- VI. Animal Extracts.- Conclusion.- References.- Fibrinolytically Active Enzymes.- Plasmin.- A. Plasminogen, the Zymogen Precursor of Plasmin.- I. Preparation.- II. Physical and Chemical Properties.- III. Primary Structure of Human Plasminogen.- 1. NH2-Terminus (Glu1-Lys77).- 2. Heavy (A) Chain (Lys78-Arg561).- 3. Light (B) Chain (Val561-Asn790, or Val1-Asn230).- IV. Activation of Human Plasminogen.- 1. Mechanism.- 2. Kinetics.- B. Plasmin.- I. Preparation.- II. Physical and Chemical Properties.- III. Nomenclature.- IV. Assay Methods.- V. Kinetic Parameters.- C. Human Plasmin-Derived Heavy (A) and Light (B) Chains.- D. Equimolar Plasminogen-Streptokinase, Plasmin-Streptokinase, and Plasmin-Derived Light (B) Chain-Streptokinase Complexes.- I. Preparation.- II. Plasminogen Activator Activity.- E. Limited Proteolysis of Protein Substrates.- References.- Fungal Proteases.- A. Proteases from Aspergillus oryzae.- I. Isolation, Purification and Chemical Characteristics.- 1. Aspergillin O.- 2. Protease I, Brinase, Brinastrase.- a) Preparation of Crude Enzyme.- b) Determination of Proteolytic Activity.- c) Differential Analysis of Proteases.- d) Separation of Proteases.- e) Properties of Proteases.- 3. CA-7, Brinase, Brinolase.- a) Preparation of Crude Enzyme.- b) Purification of Enzyme.- c) Determination of Fibrinolytic Activity.- d) Characterization of Purified Enzyme.- 4. Comparison of Swedish and Canadian Enzymes.- II. Biological and Pharmacologic Properties.- 1. Inhibition by Plasma and Serum.- 2. Pharmacokinetics.- 3. Proteolysis.- a) Fibrin.- b) Fibrinogen.- c) Other Natural Proteins and Synthetic Substrates.- 4. Hemostasis.- a) Coagulation.- b) Platelet Function.- 5. Physicochemical Effects.- 6. Kininogenesis.- 7. Antigenicity.- 8. Toxicity.- III. Experimental Thrombolysis.- 1. In Vitro Experiments.- 2. In Vivo Experiments.- a) Systemic Administration.- b) Local Administration.- IV. Other Experimental Proteolytic Uses.- 1. Tissue Culture.- 2. Enzymatic Zonulysis in Ophthalmology.- V. Clinical Thrombolysis.- 1. Systemic Infusion.- 2. Local Perfusion.- a) Cannula Declotting.- b) Intra-arterial Instillation.- c) Intra-articular Instillation.- VI. Other Clinical Uses.- 1. Inhibition of Platelet Aggregation.- 2. Chemotherapy of Malignant Disease.- VII. Clinical Control of Therapy.- 1. Brinase-Inhibitor Assay.- 2. Protease Resistance Test.- 3. Photometric Determination of Inhibitors on Chromogenic Substrate.- 4. Photometric Determination of Inhibitors on Azocollagen Substrate.- 5. Critique of Tests.- B. Protease from Aspergillus ochraceus.- I. Isolation, Purification and Chemical Characteristics.- 1. Preparation of Crude Enzyme.- 2. Purification of Enzyme.- 3. Characterization of Purified Enzyme.- II. Biological and Pharmacologic Properties.- 1. Inhibition.- 2. Proteolysis.- a) Fibrin and Fibrinogen.- b) Other Natural Proteins.- 3. Hemostasis.- a) Coagulation.- b) Platelet Function.- 4. Toxicity.- III. Experimental Thrombolysis.- 1. In Vitro Experiments.- 2. In Vivo Experiments.- a) Systemic Administration.- b) Local Administration.- IV. Other Experimental Uses.- V. Clinical Thrombolysis.- 1. Coagulation.- 2. Determination of Dosage.- 3. Therapeutic Use.- C. Protease from Trichothecium roseum.- I. Isolation and Purification.- II. Biological Properties.- 1. Fibrinolysis.- 2. Thrombolysis.- D. Protease from Armillaria mellea.- I. Isolation, Purification and Chemical Characteristics.- II. Biological Properties.- References.- Defibrinogenation with Thrombin-like Snake Venom Enzymes.- A. Introduction.- I. Specific Defibrinogenation.- II. Occurrence of Thrombin-like Enzymes in Snake Venoms.- III. Nomenclature.- B. Characterization of Ancrod and Batroxobin.- I. Physicochemical Properties.- 1. Ancrod.- 2. Batroxobin.- II. Enzymatic Properties.- 1. Specificity.- 2. Activators and Inactivators.- 3. Stability.- III. Immunochemical Properties.- IV. Assay Methods.- 1. Assay on Human Plasma.- 2. Assay on Fibrinogen.- 3. In Vivo Activity Test on Mice.- C. Pharmacologic Properties of Ancrod and Batroxobin.- I. Toxicity.- 1. Mice.- 2. Rat.- 3. Rabbit.- 4. Cat.- 5. Dog.- 6. Monkey (Yellow-Faced Baboon).- 7. Pigeon.- II. Teratology.- III. Absorption and Metabolic Transformation of Ancrod and Batroxobin.- IV. Effect of Ancrod and Batroxobin on Fibrinogen Metabolism.- 1. Fibrinogen Depletion.- 2. Fibrinogen Removal.- V. Effect of Ancrod and Batroxobin on the Plasminogen Metabolism.- VI. Effect of Ancrod and Batroxobin on Hemostatic and Coagulation Parameters.- 1. The Hemostatic Function in the Defibrinogenated State.- 2. Effects of Ancrod and Batroxobin on Platelets.- 3. Effect of Ancrod and Batroxobin on Plasma Coagulation Factors.- VII. Effect of Ancrod and Batroxobin on Wound Healing.- VIII. Effect of Ancrod and Batroxobin on Hemorheology.- D. Preclinical Trials.- I. Antithrombotic Effect of Ancrod and Batroxobin.- II. Defibrinogenation and Transplant Rejection.- III. Defibrinogenation and Tumor Growth.- E. Clinical Experience.- I. Dose-Response Studies.- II. Laboratory Monitoring.- III. Exploratory Clinical Trials.- IV. Comparative Clinical Trials.- V. Immunologic Resistance to Ancrod and Batroxobin.- VI. Side-Effects.- References.- Antifibrinolytics.- Naturally Occurring Inhibitors of Fibrinolysis.- A. Endogenous Inhibitors.- I. Inhibitors from Plasma.- II. Inhibitors from Blood Platelets.- III. Inhibitors from Other Body Fluids and Tissues.- B. Animal Inhibitors.- I. Aprotinin.- 1. Chemistry.- 2. Mechanism of Action.- 3. Determination of Activity, Standardization.- 4. Experimental Pharmacology.- a) Toxicity.- b) Pharmacokinetics.- c) Antifibrinolytic Action.- 5. Clinical Pharmacology.- a) Pharmacokinetics.- b) Therapeutic Use.- ?) Indications.- ?) Side-Effects.- ?) Doses.- II. Miscellaneous Inhibitors.- C. Plant Inhibitors.- References.- Synthetic Inhibitors of Fibrinolysis.- A. Chemistry.- I. ?-Aminocaproic Acid.- II. Cyclic Aminocarboxylic Acids.- III. Derivatives of Benzamidine.- IV. Other Synthetic Inhibitors of Fibrinolysis.- B. Mode of Action.- I. Influence on the Activation of Plasminogen.- II. Influence on Plasmin.- 1. Inhibition of Proteolytic and Esterolytic Activity.- 2. Inhibition of Fibrinolytic Activity.- III. Influence on Other Enzymes.- IV. Physico-Chemical Effects.- C. Assay Methods.- I. Chemical Methods.- II. Biological Methods.- D. Experimental Pharmacology.- I. Toxicity.- II. Side-Effects.- III. Pharmacokinetics.- 1. EACA.- 2. PAMBA.- 3. AMCA.- 4. EACA and PAMBA Derivatives.- IV. Antifibrinolytic Action.- 1. Prevention of Experimental Fibrinolysis.- 2. Hemostatic Effect.- 3. Other Effects Connected with the Inhibition of Fibrinolysis.- 4. Combination with Naturally Occurring Inhibitors.- E. Clinical Pharmacology.- I. Pharmacokinetics.- 1. EACA.- 2. PAMBA.- 3. PAMBA Derivatives.- 4. AMCA.- II. Therapeutic Uses.- 1. Mode of Action.- 2. Side-Effects.- 3. Contraindications.- 4. Indications.- a) Bleeding after Operations on Activator-Rich Organs.- b) Bleeding in the Region of the Oral, Nasal and Pharyngeal Mucosa.- c) Bleeding in the Gastrointestinal Tract.- d) Bleeding in the Urinary Tract.- e) Uterine Bleeding.- f) Bleeding in Obstetrical Complications.- g) Subarachnoidal Bleeding.- h) Bleeding in Carcinoma and Leukemia.- i) Extracorporeal Circulation.- k) Control of Therapeutic Fibrinolysis.- l) Bleeding of Unknown Etiology.- m) Thrombocytopenia and Hemophilia.- n) Wound Healing.- o) Allergic Reactions.- 5. Administration and Dosage.- References.- Author Index.

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Fibrinolytics and antifibrinolytics

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