Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1993-10-07
1995-07-18
Schain, Howard E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530399, A61K 3827, A61K 3808, A61K 3800, C07K 1400
Patent
active
054341345
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to growth factors, related compounds, and their use in the prevention or treatment of disorders of the heart.
BACKGROUND ART
Insulin-like Growth Factor I (IGF-I) is a peptide present in plasma and other body fluids. It comprises 70 amino acids, including 3 disulphide bonds, and can stimulate growth of a wide range of cell types and it mediates the effects of growth hormone on skeletal growth. Human IGF-I has been purified from plasma and its complete amino acid sequence is established. Sequences with extensive homologies to human IGF-I are present in IGF-I purified from plasma of other species. IGF-I has both systemic and local effects and appears mostly associated with different specific binding proteins, four of which have been sequenced and are termed IGFBP1, IGFBP2, IGFBP3 and IGFBP4. These appear to modulate the biological functions and availability of IGF-I in both positive and negative manners. Analogues with changed affinities for the binding proteins have been produced and changes of biological activities related to sequence variation have been found. IGF-I appears to act mainly by interactions with the IGF-type 1 receptor exposed on the outer surface of plasma membranes in many different cell types. However, binding to IGF type 2- and insulin receptors also seems to be of importance. Because of the scarcity of purified plasma IGF-I there was a great necessity to develop methodology for the commercial scale production of IGF-I. Nowadays, such large scale production can readily be achieved by using recombinant DNA techniques. As a result of studies with preparations of recombinant IGF-I (rIGF-I), it has been demonstrated that rIGF-I promotes skeletal growth and skeletal muscle protein synthesis. Moreover, IGF-I is also effective for the treatment or prevention of catabolic states in patients (Swedish patent application SE 9002731-9) and improves the regeneration of transected periferal nerves (EP 0 308 386). It has previously been demonstrated in vitro that IGF-I also can promote actin synthesis in myocytes in culture (Florini, J. R., Muscle and Nerve 10 (1987)577-598) and contractility of neonatal rat cardiocytes in vitro (Vetter, U et al., Basic Res. Cardiol. 83 (1988)647-654). Prior art has, however, not extended these observations to the whole animal or to therapeutic usefulness.
SUMMARY OF THE INVENTION
In the first aspect of the present invention we have found that a specific biological action of IGF-I or its effective analogues when administered systemically to mammals, including man, is to selectively promote net protein synthesis in heart muscle, i.e. to an extent considerably greater than that seen in other tissues. In a second aspect, systemic administration of IGF-I or an effective analogue has by us been shown to markedly increase the stroke volume of the heart and thereby the cardiac output. Thus, IGF-I or an effective analogue, with or without coadministration of its binding proteins, is according to the present invention a suitable therapy for low cardiac output in man.
The invention discloses a method of preventing or treating cardiac disorders comprising administration of human IGF-I or effective analogues thereof, as well as the use of human IGF-I or effective analogues thereof for the manufacture of a medicament. The use is especially of interest for promotion of cardiac muscle protein synthesis and for treatment of cardiomyopathies, acute heart failure or acute insult including myocarditis or myocardial infarction.
Also disclosed are the uses for: prevention of cardiomyopathies following drug administration, inflammation, infection, sepsis or ischaemia, increasing the rate of recovery from cardiomyopathy, myocarditis, inflammation or myocardial ischaemia and infarction; improvement of cardiac output by increasing stroke volume and for treatment of myocardial infarction. The cardiac output can be reduced as a result of trauma, sepsis, myocardial infarction, surgery, cardiac inflammation or a combination thereof. Preferably hum
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Gluckman Peter
Skottner Anna
Pharmac IA AB
Schain Howard E.
Touzeau Phynn
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