Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Patent
1991-09-18
1993-08-17
Nucker, Christine M.
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
424 9463, 424 9464, A61K 4500, A61K 3748, A61K 3754, A61K 3762
Patent
active
052367053
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to fibrin degradation or breakdown (which may be referred to as fibrinolysis), and compositions and methods for the treatment of pathological conditions associated with fibrin deposition.
Fibrin plays a crucial role in haemostasis and wound healing, and is laid down in the human and animal body as a result of a complex series of biochemical reactions. Notwithstanding these crucial functions of fibrin, fibrin formation is also a common event in many pathological conditions and inflammatory lesions. For example, fibrin deposition is associated with atherosclerosis, rheumatoid arthritis, glomerulonephritis, systemic lupus erythematosis, myocardial infarcts, pulmonary embolism, deep vein thrombosis, autoimmune neuropathies, granulomatous disease, parasitic infections and allograft rejection. Metastases, or so called "secondary" tumours, have been linked with thromboembolism phenomona. The abundant fibrin deposited around some solid tumours in the stroma may serve as a cocoon that hinders lymphocytes, macrophages and other inflammatory cells from reaching tumours.
Fibrin deposition may also be associated with renal disease and hypertrophic scars and keloids. Fibrous adhesions are also a significant problem in post-operative surgery.
Urokinase and tPA (tissue plasminogen activator) are plasminogen activators (PA's) which have previously been used both experimentally and clinically to effect fibrin lysis, and in particular, the lysis or degradation of fibrin clots. Whilst effective in degrading fibrin, these molecules have attendant disadvantages. Urokinase activates plasminogen to give plasmin independently of the presence of fibrin (unlike tPA), and thus large amounts must be administered to effect fibrinolysis, this being expensive and causing unwanted bleeding. tPA has a short half life in vivo, and thus large quantities have to be administered over a long period of time, resulting in unwanted bleeding and expense.
It has now surprisingly been found that the lymphokine, interleukin-4 (IL-4), activates both human and animal cells to produce plasminogen activators, which results in fibrin degradation. Also, IL-4 inhibits the procoagulant activity of human monocytes resulting in decreased fibrin formation at the monocyte surface.
IL-4 is a lymphokine, which exhibits both B cell and T cell growth factor activities (published Australian Patent Application No. 67334/87). This lymphokine also exhibits suppressive activity, as it supresses human monocyte production of the cytokines lL-1, TNF, and suppression of PGE.sub.2.
IL-4 has been purified to homogeneity, and the gene encoding this protein has been cloned allowing IL-4 to be produced in large amounts by recombinant DNA technology, as described in published Australian Patent Application No. 67334/87, in the name Schering-Biotech Corporation. IL-4 (human) is commercially available from a number of suppliers.
On the basis of IL-4's activity in suppressing cytokine production, it was most surprising that IL-4 was effective in stimulating plasminogen activator (PA) production, notably, t-PA and urokinase, by appropriate target cells.
In accordance with the present invention, there is provided a method for degrading fibrin deposits and preventing such deposits associated with pathological conditions or which may lead to such conditions, which comprises administering to a subject in need of such treatment a therapeutically effective amount of IL-4 or a derivative thereof possessing IL-4 activity, optionally in association with one or more pharmaceutically acceptable carriers or excipients.
Pathological conditions which may be treated in accordance with the invention are those which are caused wholly or at least in part by fibrin deposition. These include deep vein thrombosis, pulmonary embolism, renal disease, hypertrophic keloid scars, coronary infarction, metastasis, inflammation, disseminated intravascular coagulation, atherosclerosis, rheumatoid arthritis, glomerulonephritis, systematic lupus eryttematosis, autoimmune neuropathies, gra
Hamilton John A.
Hart Prudence H.
Dreger Walter H.
Koh Choon P.
Nucker Christine M.
The University of Melbourne
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