Use of insulin and IGF-1

Details Use of insulin and IGF-1 Use of insulin and IGF-1

1996-12-18

1998-05-26

Tsang, Cecilia J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 4, 514 21, 514 3, 530303, 530306, A61K 3800, A61K 3140

Patent

active

057564639

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of a combination of insulin and Insulin-like Growth Factor (IGF-I) for the manufacture of a medicament for counteracting a decrease in nitrogen balance and for counteracting a decrease in protein synthesis. The medicament can be used in the treatment of catabolism, to increase in body protein, and in protein synthesis.
The invention also relates to a method for counteracting a decrease in nitrogen balance and counteracting a decrease in protein synthesis.


INTRODUCTION

It is well recognised that the protein catabolism normally observed during different states of critical illness is influenced by hormones such as glucagon, catecholamines and glucocorticoids (Alberti et al. 1980; Smith & Williamson 1983; Bessey & Lowe 1993).
Glucocorticoids have been associated with a decrease in protein synthesis and an increase in protein catabolism (Kayall et al. 1978; Simmons et al. 1984) and also with an increase in the excretion of nitrogen in urine (Long et al. 1940; Sapir et al. 1977). These effects are probably partly mediated via a decrease in growth hormone secretion (Trainer et al. 1991) but could also be the result of direct action of glucocorticoids on the tissue level (Baron et al. 1992), therewith also interfering with the local production of insulin like growth factor I (McCarthy et al. 1990) and antagonising the action of insulin (Horber et al. 1991). Because of the strong catabolic effects exerted by glucocorticoids these substances have either been used alone (Tomas et al. 1992) or in combination with other catabolic hormones (Bessey & Lowe 1993) to produce models in which the effects of agents that have an anticipated potential of reversing protein catabolism can be studied. Previous studies on rats have demonstrated that the catabolic action of glucocorticoid analogues, such as dexamethasone, can be counteracted by recombinant human insulin-like growth factor I (rhIGF-I) and its analogues (Tomas et al. 1992). The effect of recombinant human growth hormone (rhGH), however, appears more variable and some studies carried out on growing rats have shown that this hormone is inefficient in reversing glucocorticoid induced catabolism (Ortoft et al 1993), whereas studies in humans have pointed to positive effects (Horber & Hammond 1990).
Not only rhIGF-I and rhGH but also insulin have individually been shown to ameliorate protein catabolism (Woolfson et al. 1979 ).
In WO 9110348 there is claimed a method for restoring normal growth, weight gain and lean body mass of mammal with glucocorticoid excess by administering IGF-I.
The potency of the combination of GH and IGF-I in terms of improving nitrogen balance is suggested by Clemmons et al, Horm Res., 40 (1-3), 62-67, 1993 and Genn et al, Biochem. Arch., 5(1), 53-59, 1989 discloses the anabolic effect of insulin and IGF-II.
Fuller S. J. et al, Biochem Soc Trans 19(3), 1991, p.277S describes the stimulation of cardiac protein synthesis after treatment with insulin and IGF. The experiments have been performed in vitro with freshly isolated cardiac myocytes.
Umpleby A. M. et al Europ J Clin Invenst 24(5), 1994, p.337-344, reports on effects on protein metabolismus after treatment with insulin and IGF on dogs which have been starved overnight. No medicaments for counteracting decrease in nitrogen balance have been disclosed in these documents.


THE INVENTION

The invention thus relates to the use of a combination of insulin and IGF-I in the manufacture of a medicament for counteracting a decrease in nitrogen balance and for counteracting a decrease in protein synthesis. The invention can be applied in the treatment of protein catabolism caused by glucocortoid excess and the medicament can be used for patients that suffer from cardiac diseases.
The ratio of IGF-I and insulin in the medicament could be in a range of 30:1 to 2:1 based on molecular weight, preferably in a range of less than 10:1 and more preferably in a range of less than 8:1. IGF-I is preferably administered in a dose of 20 to 500 microgram/kg and insulin is p

REFERENCES:
patent: 4988675 (1991-01-01), Froesch et al.
patent: 5128320 (1992-07-01), Hahn et al.
patent: 5434134 (1995-07-01), Gluck et al.
European Journal of Clinical Investigation, vol. 24, No. 5, May 1994, A.M. Umpleby et al. Effects of insulin-like growth factor-I (IGF-L), insulin and combined IGF-I-insulin infusions on protein metabolism in dogs, p. 344.
Biochemical Society Transactions, vol. 19, No. 3, 2775 1991, Stephen J. Fuller et al, Stimulation of cardiac protein synthesis by insulin-like growth.
The New England Journal of Medicine, 4 Jan. 1979, Anthony M. J. Woolfson et al. Insulin to inhibit protein catabolism after injury, pp. 14-17.

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