Thrombolytic enzyme

Enzymes Thrombolytic agents, digestive aids, debriding agents (i.e. cleansing of wounds)... 

Monoclonal antibodies for in vivo use Cytokines (e.g. interferons and interleukins) Therapeutic enzymes Thrombolytic agents Hormones Growth factors Additional miscellaneous proteins Blood Blood proteins (e.g. albumin and blood factors) Vaccines Cell- and tissue-based products Gene therapy products Antitoxins, venoms and antivenins Allenergic extracts... 

Coronary thrombosis History, ECG, enzymes Thrombolytics, oxygen, nitroglycerin, heparin, aspirin, morphine... 

Therapeutic enzymes have a broad variety of specific uses, ie, as oncolytics, thrombolytics, or replacements for inherited deficiencies. Additionally, there is a growing group of miscellaneous enzymes of diverse function. 

Thrombolytic Enzymes. Although atherosclerosis and the accompanying vascular wall defects are ultimately responsible for such diseases as acute pulmonary embolism, arterial occlusion, and myocardial infarction, the lack of blood flow caused by a fibrin clot directly results in tissue injury and in the clinical symptoms of these devastating diseases (54). Thrombolytic enzyme therapy removes the fibrin clot by dissolution, and has shown promise in the treatment of a number of thrombo-occlusive diseases (60). 

Streptokinase has an initial plasma half-life (/ 2 of 18 min, and a P half-life of 83 min (73) it is well recognized that the thrombolytic efficacy of the enzyme decreases as the age of the thrombus increases thus, thrombolysis is significantly decreased when therapy is initiated more than three hours after an occlusion (74). 

Several clinical trials have been conducted with streptokinase adrninistered either intravenously or by direct infusion into a catheterized coronary artery. The results from 33 randomized trials conducted between 1959 and 1984 have been examined (75), and show a significant decrease in mortaUty rate (15.4%) in enzyme-treated patients vs matched controls (19.2%). These results correlate well with an ItaUan study encompassing 11,806 patients (76), in which the overall reduction in mortaUty was 19% in the streptokinase-treated group, ie, 1.5 million units adrninistered intravenously, compared with placebo-treated controls. The trial also shows that a delay in the initiation of treatment over six hours after the onset of symptoms nullifies any benefit from this type of thrombolytic therapy. Conversely, patients treated within one hour from the onset of symptoms had a remarkable decrease in mortaUty (47%). The benefits of streptokinase therapy, especially in the latter group of patients, was stiU evident in a one-year foUow-up (77). In addition to reducing mortahty rate, there was an improvement in left ventricular function and a reduction in the size of infarction. Thus early treatment with streptokinase is essential. 

The thrombolytic efficacy of streptokinase treatment may be compromised by the presence of antibodies to the enzyme in the patient s blood. 

Anistreplase has a considerably longer a half-life than streptokinase, ie, 90 min compared to 20 min (87,88). Moreover, it does not require prolonged infusion to achieve its thrombolytic effects. Anistreplase was found to be highly effective after a single intravenous dose of 30 units over a 5-min period compared to a 60-min infusion of 1.5 million units of streptokinase (89—94). In direct comparative studies, anistreplase was as effective as intracoronary (95,96) and intravenously (96—100) adrninistered streptokinase. In a randomized, double-blind, placebo-controUed study (AIMS trial) with 1004 patients given this modified enzyme, the 30-day mortaUty rate was 12.2% for patients receiving placebo, compared to 6.4% for patients who received 30 units of anistreplase intravenously within six hours of the onset of symptoms (101). 

Although the exact action of the thrombolytic dragp is slightly different, these drugs break down fibrin clots by converting plasminogen to plasmin (fibrinolysin). Plasmin is an enzyme that breaks down the fibrin of a blood clot. This reopens blood vessels after their occlusion and prevents tissue necrosis. 

Peng, Y., Yang, X., and Zhang, Y. 2005. Microbial fibrinolytic enzymes an overview of source, production, properties and thrombolytic activity in vivo. Applied Microbiology and Biotechnology 69(2), 126-132. 

Thrombolytic agents are proteolytic enzymes that enhance the conversion of plasminogen to plasmin, which subsequently degrades the fibrin matrix. 

Cytokines, growth factors, enzymes, immunomodulators, and thrombolytics... 

Although most of the enzyme-based drugs are inhibitors of enzymes, a number of enzyme preparations have also been developed as drugs for the treatment of a number of diseases. The development of enzymes as therapeutics has been made easier due to the advances in biotechnology. Most successful example of enzyme therapy includes various preparations of plasminogen activators (thrombolytic or fibrinolytic agents) such as a bacterial protein streptokinase and two plasminogen activators... 

Aheplase Recombinant [tPA] (Activase) [Plasminogen ActlVator/ThrombolytlC Enzyme] Uses AMI, PE, acute ischemic stroke, CV cath occlusion Action Thrombolytic binds fibrin in thrombus, initiates fibrinolysis Dose AMI 15 mg IV over 1-2 min, then 0.75 mg kg (max 50 mg) over 30 min, then 0.5 mg/kg over next 60 min (max 35 mg) (ECC 2005) Stroke 0.09 mg/kg IV over 1 min, then 0.81 mg/kg max 90 mg) inf over 60 min... 

Mechanism of Action A tissue plasminogen activator that activates the fibrinolytic system by directly cleaving plasminogen to generate plasmin, an enzyme that degrades the fibrin ot the thrombus. Therapeutic Effect Exerts CV-thrombolytic action. Pharmacokinetics Rapidlycleared from plasma. Eliminated primarilyby the liverand kidney. Haif-Hfe 13-16 min. 

Anistreplase (anisoylated plasminogen streptokinase activator complex APSAC) consists of a complex of purified human plasminogen and bacterial streptokinase that has been acylated to protect the enzyme s active site. When administered, the acyl group spontaneously hydrolyzes, freeing the activated streptokinase-proactivator complex. This product (recently discontinued in the USA) allows for rapid intravenous injection, greater clot selectivity (ie, more activity on plasminogen associated with clots than on free plasminogen in the blood), and more thrombolytic activity. 

Myocardial infarction -thrombolytic therapy [ENZYME APPLICATIONS - THERAPEUTIC] (Vol 9)... 

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