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Streptokinase

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Streptokinase C

Complex of Catalytic Domain of Human Plasmin and Streptokinase; structure derived from PDB file 1BML. Identifiers Symbol skc Entrez 8110746 PDB 1BML UniProt P00779 Other data EC number 3.4.24.29

Staphylokinase/Streptokinase family

Structure of staphylokinase, a plasminogen activator.


[1]

Symbol Pfam InterPro SCOP SUPERFAMILY

Identifiers Staphylokinase PF02821 IPR004093 2sak 2sak

[show]Available protein structures: Streptokinase (SK), a protein secreted by several species of streptococci can bind and activate human plasminogen. SK is used as an effective and inexpensive thrombolysis medication in some cases of myocardial infarction (heart attack)[2] and pulmonary embolism.[3] Streptokinase belongs to a group of medications known as fibrinolytics, and complexes of streptokinase with human plasminogen can hydrolytically activate other unbound plasminogen by activating through bond cleavage to produce plasmin. There are three domains to Streptokinase, denoted (residues 1150), (residues 151287), and (residues 288414). Each domain binds plasminogen, although none can activate plasminogen independently.[4]

Contents

1 Mechanism of action 2 Administration 3 Current research applications 4 Marketing 5 References

Mechanism of action

Proposed counterion for Asp740 is Lys698 create salt-bridge; structure derived from PDB file 1BML

Youtube Substrate Enzyme Mechanism Movie Plasmin is produced in the blood to break down fibrin, the major constituent of blood thrombi, therefore dissolving clots once they have fulfilled their purpose in stopping bleeding. Extra production of plasmin caused by streptokinase breaks down unwanted blood clots, for example, in the lungs (pulmonary embolism). The usual activation of Plasminogen (Plgn) is by proteolysis of the Arg561Val562 bond.[5] The amino group of Val562 then forms a salt-bridge with Asp740, which triggers a conformational change producing the active protease Plasmin (Pm). When (SK) is present, it binds to Plgn to form a complex (SK. Plgn) that converts substrate Plgn to Pm. Residues 159 of SK regulate its capacity to induce an active site in bound Pg by a nonproteolytic mechanism and to activate substrate Pg in a fibrin-independent manner. This complex subsequently rearranges to an active complex although the Arg561Val562 bond remains intact. Therefore another residue must substitute for the free amino group of Val562 and provide a counterion for Asp740 in this active complex.[6] Two candidates for this counterion have been suggested: Ile1 of streptokinase and Lys698 of Plgn. Deletion of Ile1 of SK markedly inhibits its capacity to induce an active site in plasminogen, which supports the hypothesis that establishment of a salt bridge between Ile1 of SK and Asp740 of plasminogen is necessary for SK to induce an active site in plasminogen by a nonproteolytic mechanism.[7] In contrast with the Ile1 substitutions, the Lys698 mutations also decreased the dissociation constant of the SK complex by 15 to 50 fold. These observations suggest that Lys698 is involved in formation of the initial SKPlgn complex.[8]

Administration
It is given intravenously as soon as possible after the onset of a heart attack to dissolve clots in the arteries of the heart wall. Thus it reduces the amount of damage to the heart muscle. As Streptokinase is a bacterial product, the body has the ability to build up an immunity to it. Therefore, it is recommended that this medication should not be used again after four days from the first administration, as it may not be as effective and can also cause an allergic reaction. For this reason, it is usually given only for a person's first heart attack. Further thrombotic events

could be treated with Tissue plasminogen activator (tPA). Overdose of streptokinase or tPA can be treated with aminocaproic acid. Laboratory findings in various platelet and coagulation disorders (V - T) Partial Prothrombin Bleeding Condition thromboplastin Platelet count time time time Vitamin K deficiency or Normal or mildly Prolonged Unaffected Unaffected warfarin prolonged Disseminated intravascular Prolonged Prolonged Prolonged Decreased coagulation Von Willebrand disease Unaffected Prolonged Prolonged Unaffected Hemophilia Unaffected Prolonged Unaffected Unaffected Aspirin Unaffected Unaffected Prolonged Unaffected Thrombocytopenia Unaffected Unaffected Prolonged Decreased Liver failure, early Prolonged Unaffected Unaffected Unaffected Liver failure, end-stage Prolonged Prolonged Prolonged Decreased Uremia Unaffected Unaffected Prolonged Unaffected Congenital afibrinogenemia Prolonged Prolonged Prolonged Unaffected Factor V deficiency Prolonged Prolonged Unaffected Unaffected Factor X deficiency as seen Prolonged Prolonged Unaffected Unaffected in amyloid purpura Glanzmann's thrombasthenia Unaffected Unaffected Prolonged Unaffected Decreased or Bernard-Soulier syndrome Unaffected Unaffected Prolonged unaffected Factor XII deficiency Unaffected Prolonged Unaffected Unaffected C1INH deficiency Unaffected Shortened Unaffected Unaffected

Current research applications


Streptokinase may find a use in helping to prevent postoperative adhesions, a common complication of surgery, especially abdominal surgery (appendectomy, gall stones, hysterectomy, etc.) One study using animal models (rats) found that when used with a PHBV membrane drug-delivery system, it was 90 percent effective in preventing adhesions.[9]

Marketing
It is marketed in Chile as Streptase by Alpes Selection, under license of ZLB Behring from Marburg, Germany. Available in Viet Nam under the name Mutose. Available in Cuba, Venezuela, Ecuador and other Latin American countries under the trademark Heberkinasa, commercialized by Heber

Biotech, Havana, Cuba. Available in India under the name STPase by Cadila Pharmaceuticals Limited.

Streptokinase
Pronunciation: STREP-toe-KIN-ace Class: Thrombolytic enzyme Trade Names: Streptase - Powder for Injection 250,000 units - Powder for Injection 750,000 units - Powder for Injection 1,500,000 units
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Pharmacology
Converts plasminogen to the enzyme plasmin, which aids in dissolution of blood clots.

Pharmacokinetics
Metabolism

No metabolites identified.
Elimination

Streptokinase is cleared by the liver. The t is approximately 23 min (for activator complex).

Indications and Usage


Acute MI, lysis of intracoronary thrombi, improvement of ventricular function, and reduction of mortality associated with acute MI (IV or intracoronary route); reduction of infarct size and CHF associated with acute MI (IV); lysis of objectively diagnosed (eg, angiography) pulmonary emboli (involving obstruction of blood flow to a lobe or multiple segments, with or without unstable hemodynamics); lysis of objectively diagnosed (eg, ascending venography), acute,

extensive thrombi of the deep veins (eg, those involving the popliteal vessels); lysis of acute arterial thrombi and emboli; alternative to surgical revision for clearing totally or partially occluded arteriovenous cannulae when acceptable flow cannot be achieved.

Contraindications
Active internal bleeding; recent cerebrovascular accident (within 2 mo); intracranial or intraspinal surgery; intracranial neoplasm; severe uncontrolled hypertension.

Dosage and Administration


Acute Evolving Transmural MI Adults

IV infusion Administer as soon as possible after symptom onset (greatest benefit when administered within 4 h, but benefit has been reported up to 24 h). Infuse a total dose of 1,500,000 units within 60 min. Intracoronary infusion Administer 20,000 units by bolus followed by 2000 units/min for 60 min (total dose, 140,000 units).
Pulmonary Embolism, Deep Vein Thrombosis (DVT), Arterial Thrombosis, or Embolism Adults

IV infusion Administer as soon as possible after onset of thrombolic event, preferably within 7 days. A loading dose of 250,000 units infused into a peripheral vein over 30 minutes has been found appropriate in over 90% of patients. If thrombin time or any parameter of lysis after 4 h of therapy is not significantly different from the normal control level, discontinue streptokinase because excessive resistance is present. Dose and duration of therapy (following the loading dose of 250,000 units/30 min): pulmonary embolism 100,000 units/h for 24 h (72 h if concurrent DVT is suspected); DVT 100,000 units/h for 72 h; arterial thrombosis or embolism 100,000 units/h for 24 to 72 h.
Arteriovenous Cannulae Occlusion

Slowly instill 250,000 in 2 mL of solution into each occluded limb of the cannula. Clamp off cannula limb(s) for 2 h. Closely observe patient for adverse effects. After treatment, aspirate contents of infused cannula limb(s) and flush with saline before reconnecting cannula.

Storage/Stability
Store unopened vials at controlled room temperature (59 to 86F). Use reconstituted solution immediately or within 8 h if stored at 36 to 46F. Discard any unused solution.
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Drug Interactions
Anticoagulants, agents that alter platelet function (eg, aspirin, other NSAIDs, dipyridamole), other thrombolytic agents, agents that alter coagulation

May increase the risk of bleeding.


Incompatibility

Do not add other medication to the streptokinase container.


Laboratory Test Interactions

Will cause marked decreases in plasminogen and fibrinogen levels and increases in thrombin time, activated partial thromboplastin time, and prothrombin time, which usually normalize within 12 to 24 h.

Adverse Reactions
Cardiovascular

Hypotension (sometimes severe).


Hematologic

Bleeding (major and minor).


Respiratory

Respiratory depression.

Miscellaneous

Allergic reactions (eg, fever and shivering, urticaria, itching, flushing, nausea, headache, musculoskeletal pain); anaphylactic and anaphylactoid reactions (ranging from minor breathing difficulty to bronchospasm, periorbital swelling or angioneurotic edema); transient elevations of serum transaminases; back pain.