Use of IGF-1

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai

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A61K 3805, A61K 3806, C07K 500

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active

054666708

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BRIEF SUMMARY
The present invention relates to the use of insulin-like growth factor (IGF-I) for the manufacture of a medicament for treatment of Type 1 diabetes mellitus (IDDM), the medicament comprising a subcutaneous dose to achieve an IGF-I serum level characteristic for healthy individuals, especially in children, adolescents and young adults. Evidence for the efficacy of such treatment is presented in adolescents with insulin dependent Type 1 diabetes mellitus.


BACKGROUND

Human IGF-I (hIGF-I) is a peptide present in plasma and other body fluids. It has been purified from human plasma and the complete amino acid sequence is known. The primary sequence comprises 70 amino acids, including 3 disulphide bonds. Moreover, purified IGF-I:s from plasma of other species show extensive sequence homologies to hIGF-I.
hIGF-I can stimulate growth of a wide range of cell types. It has both systemic and local effects and is present in the circulation mainly associated with different binding proteins, six of which are sequenced (IGFBP1-6). The binding proteins appear to modulate the biological functions and availability of IGF-I variably. IGF-I analogues with changed biological activities seemingly related to changes of affinities to the binding proteins have been produced. IGF-I appears to act mainly through the IGF-type 1 receptor exposed on the outer surface of many different cell types. However, the relative specificity of action may vary at the cell level, for example, due to varying influence of binding proteins. The structures of the IGF-I and insulin receptors are closely homologous, but binding of IGF-I and insulin show only limited cross-reactivity.
Because of the scarcity of purified plasma hIGF-I, there was a great need to develop methodology for a commercial scale production. Nowadays such large scale production of hIGF-I can readily be achieved by using recombinant DNA techniques.
IGF-I is primarily involved in mediating the somatogenic effects of growth hormone (GH). As a result of studies with preparations of recombinant DNA derived hIGF-I, it has been demonstrated that it promotes skeletal growth and skeletal muscle protein synthesis. Moreover, hIGF-I is also effective for the treatment or prevention of catabolic states (WO 92/03154)).
In WO 91/12018 (Ballard et al.) the therapeutic use of IGF-I, or a peptide analogue thereof, for gastrointestinal disease or the treatment of the shortened gut after surgery was disclosed.
It has also been found that IGF-I improves the regeneration of transected periferal nerves (EP 308 386) and it has previously been demonstrated in vitro that IGF-I promotes actin synthesis in myocytes in culture (Florini, J. R., Muscle and Nerve, 10 (1987) 577-598), and contractility of neonatal rat cardiocytes (Vetter, U. et al., Basic Res. Cardiol. 83 (1988) 647-654.
Large doses of hIGF-I do lower blood glucose in non-diabetic animals and humans (Zapf J. et al. J Clin-Invest, Jun Vol:77(6) (1986) 1768-75 and Guler H-P et al, N Engl. J. Med, 317 (1987) 137-140). In these studies the hypoglycaemic effect of hIGF-I was around 1.5-7% of that of insulin. Recent studies in the depancreatised dog demonstrated that as an agent for lowering blood glucose hIGF-I was 8-11% as potent as insulin (Giacca A. et al., Diabetes, 39 (1990) 340-347). However, these studies also demonstrated that the metabolic effects of IGF-I may be quite distinct from those of insulin. The glucose lowering effects of IGF-I were largely mediated by increased glucose uptake, while glucose production rates remained unchanged. One explanation for this observation might be the relative paucity of IGF-I receptors in adult liver (Caro J. F. et al., J. Clin. Invest, 81 (1988) 976-981). It is likely that the effects of IGF-I are largely mediated through muscle. Similar distinctions in the distribution of receptors may explain the less potent antilipolytic effects of IGF-I as compared to insulin in vitro (Bolinder et al, J. Clin. Endocrinol. Metab, 65, (1987) 732-737) and in vivo (Zapf J. et al. 1986, Guler H-P et al. 1987, Giacca A et a

REFERENCES:
Diabetologia, vol. 34, 1991, E. J. Schoenle, et al., "Recombinant human insulin-like growth factor I (rhIGF I) reduced hyperglycaemia in patients with extreme insulin resistance" pp. 675-679.
Trends in Endocrinology and Metabolism, Volume, May 1990 (6), E. Rudolf Froesch, et al., "Therapeutic Potential of Insulinlike Growth Factor I" pp. 254-260.
Diabetes, vol. 40, Apr. 1991, Luciano Rossetti, et al., "Metabolic Effects of IGF-I in Diabetic Rats" pp. 444-448.
Chemical Abstracts, vol. 114, No. 114, 15 Apr. 1991 (15.Apr.1991), (Columbus, Ohio, USA), Jacob, Ralph J., et al., "Metabolic effects of IGF-I and insulin in spontaneously diabetic BB/w rats" p. 109, The Abstract No. 136379k.
Amiel, S. A. et al., (1986) N. Engl. J. Med. 315, 215-219, Impaired insulin action in puberty.
Guler, H. P. et al. (1987) N. Engl. J. Med. 317, 137-140 Short term metabolic effects of recombinant human insulin.

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