9002-01-1

Therapeutic Function

Enzyme

Biochem/physiol Actions

DKK1 (dickkopf WNT signaling pathway inhibitor 1) functions as a pure inhibitor of Wnt signaling, and was identified as an essential factor for head induction during early Xenopus embryogenesis by suppressing Wnt signaling. In skin, this protein plays a role in determining the pigmentation pattern of the human hand. In colon cancer cells, this protein is inactivated by CpG island promoter hypermethylation. Mesenchymal stem cells (MSCs) have an anti-proliferative effect on cancer cells, as they secrete DKK1 which blocks Wnt signaling.

Mechanism of action

Streptokinase is a protein purified from culture broths of group C β-hemolytic streptococci bacteria. Streptokinase contains a single polypeptide chain of 414-amino-acid residues with a molecular weight of 47 kDa. Streptokinase by itself has no intrinsic enzymatic activity. To be active, it must bind with plasminogen to form an activator complex (1:1 complex). This complex then acts to convert uncomplexed plasminogen to the active fibrinolytic enzyme, plasmin. The streptokinase/plasminogen complex not only degrades fibrin clots but also catalyzes the breakdown of fibrinogen and factors V and VII. As a result, streptokinase is considered to be a fibrinnonspecific drug.

Pharmacokinetics

Unfortunately, the half-life of the activator complex is less than 30 minutes, which frequently is too short to completely lyse a thrombus. Anistreplase (APSAC; Eminase) is a 1:1 streptokinase/lysineplasminogen complex that has been acylated with an anisoyl group at the active-site serine within the lysine-plasminogen. Anistreplase is inactive as such, but following complexation with fibrin, the anisoyl group is slowly cleaved, exposing the active site and, thus, leading to degradation of fibrin. The pro-drug nature of anistreplase exhibits an improved pharmacokinetic profile, with anistreplase acting as a semiselective lysis agent at the clot site. The inactivity of the circulating anistreplase also allows this drug to be given as a very rapid intravenous infusion (typically, 30 U over 3–5 minutes). Tissue reperfusion following anistreplase therapy compares favorably to streptokinase because of the extended half-life (90 minutes).

Side effects

Because it is a foreign protein, streptokinase is associated with significant hypersensitivity reactions. Most people have, at some point in their lives, had a streptococcal infection and, therefore, have developed circulating antistreptococcal antibodies. These antibodies frequently are active against streptokinase as well. The response of the streptokinase to these antibodies can vary widely, from inactivation of the fibrinolytic properties of the protein to rash, fever, and rarely, anaphylaxis. Significant allergic reactions to streptokinase occur in approximately 3% of patients.

Veterinary Drugs and Treatments

Streptokinase may be useful for the adjunctive treatment of serious thromboses. The use of thrombolytics (streptokinase, t-PA) in cats is controversial.

Drug interactions

Potentially hazardous interactions with other drugs Anticoagulants should not be given with streptokinase. Heparin infusions should be stopped 4 hours before streptokinase infusion. If this is not possible, protamine sulphate should be used to neutralise the heparin; heparin infusions can be restarted 4 hours post streptokinase infusion followed by oral anticoagulants.

Metabolism

A small proportion of the dose is bound to antistreptokinase antibodies and metabolised with a half-life of 18 minutes, whilst most of it forms the streptokinaseplasminogen activator complex and is biotransformed with a half-life of about 80 minutes.

General Description

Streptokinase (Kabikinase, Streptase)is a catabolic 47,000-d protein secreted by group Cβ-hemolyticstreptococci. It is a protein with no intrinsic enzymaticactivity. Streptokinase activates plasminogen toplasmin, a proteolytic enzyme that hydrolyzes fibrin andpromotes the dissolution of thrombi. Plasminogen is activatedwhen streptokinase forms a 1:1 stoichiometric complexwith it. Allergic reactions to streptokinase occur commonlybecause of antibody formation in individuals treatedwith it. Furthermore, the antibodies inactivate streptokinaseand reduce its ability to prolong thrombin time.Streptokinase is indicated for acute myocardial infarction,for local perfusion of an occluded vessel, and before angiography,by intravenous, intra-arterial, and intracoronaryadministration, respectively.