Use of growth hormone in low dose

Details Use of growth hormone in low dose Use of growth hormone in low dose

2001-03-13

2004-02-24

Eyler, Yvonne (Department: 1647)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S866000, C514S909000, C930S120000

Reexamination Certificate

active

06696414

ABSTRACT:

The present invention relates to treatment of patients in need of increasing insulin sensitivity by administration of growth hormone or analogues thereof, preferably human growth hormone, in a low dose and the use of growth hormone or analogues thereof, preferably human growth hormone, for the manufacturing of a medicament useful for increasing insulin sensitivity in low dose therapy.
BACKGROUND
Human Growth Hormone, hGH, is a protein consisting of a single chain of 191 amino acids. The molecule is cross-linked by two disulfide bridges and the monomeric form has a molecular weight 22 kDa. hGH preparations have been prepared from human pituitaries, but nowadays the products on the market are produced by recombinant methods, rhGH. Two types of therapeutically useful recombinant hGH preparations are present on the market: the recombinant hGH, e.g. Genotropin®, Pharmacia AB, and an analogue of the recombinant hGH with an additional methionine residue at the N-terminal end, e.g. Somatonorm®. hGH is used to stimulate linear growth in patients with hypopituitary dwarfism or Turner's syndrome but other indications have also been suggested.
Growth hormone therapy is used in children to promote growth and in adults to improve muscle strength, reduce fat mass and improve metabolic profiles, which could predispose to cardiovascular disease. In contrast to the growth promoting effects of growth hormone, the metabolic effects have been less often studied, yet they may be very important to the risk-benefit assessment of GH therapy in adults.
GH therapy is known to counter insulin actions and is contra-indicated for individuals with diabetes mellitus.
At present GH therapy in adults is monitored using serum IGF-I levels, but it is possible that it is the metabolic effects which are more relevant to improvements in symptomatology and disease risk profiles and there is a need to develop ways of formally assessing these responses.
PRIOR ART
Growth hormone replacement supplementation to hypophysectomized rats has been shown to improve glucose uptake in the diaphragm muscle, see Diabetes, 1962, Vol. 11 (3), pp. 171-178. By contrast, pharmacological treatment with GH, resulting in supra-physiological circulating levels of the hormone, is known to produce a decrease in total body glucose uptake and disposal as well as a blunted metabolic response to insulin (i.e. insulin resistance) in skeletal muscle, see Hettiarachchi M et al., Diabetes 45(4):415-21, 1996. However, in tissues which are metabolically markedly different from the muscle, like adipose tissue, GH could induce glucose up-take, as reported in Endocrinology, 1996, Vol. 137(11), pp. 4650-5 M Ridderstr{dot over (a)}le et al.
Koller J et al, Acta Chirurgiae Plasticae, (1998) 40/3 (76-78) disclose the growth hormone effect in burn treatment. rhGH was administered at daily doses of 0.52 i.u./kg starting on day 19 post-burn for 15 consecutive days. It is stated that the treatment was well tolerated except for mild insulin resistance.
Initial studies of GH replacement in hypopituitary adults used high daily GH doses (0.07 IU/kg BW; ~3 IU/m2; ~5 IU/day) based on experience in children (Salomon F et al.
NEJM
1989; 321: 1797-1803.). However, these studies were associated with an increased incidence of side-effects (mainly salt and water retention), which usually resolved on reduction in dosage. In sequential studies using half this dose (0.035 IU/kg BW; ~1.5 IU/m2; ~2.5 IU/day), the incidence of side-effects decreased significantly (Mardh G, et al.
Endocrinol Metab
1995; 2: 11-16). This is also in agreement with using lower doses in adults than in children as physiological GH production decreases with ageing (Iranmanesh A et al.
J Clin Endocrinol Metab
1991; 73: 1081-1088.). Rosenfalck et al recently demonstrated the beneficial effects of a relatively low dose of GH replacement therapy (mean dose of 1.6 IU/day) in GH-deficient adults on body composition with an increase in lean body mass and a reduction in body fat. In spite of these favourable changes, a deterioration in insulin sensitivity was observed with a quarter of the patients developing impaired glucose tolerance (Rosenfalck A M, et al
J Clin Endocrinol Metab
2000; 11: 4173-4181). In 1998, the Growth Hormone Research Society recommended that GH replacement was commenced at a low dose (0.45-0.9 IU/day), and increased gradually on the basis of biochemical and clinical response at intervals greater than 1 month (Carroll P V et al.
J Clin Endocrinol Metab
1998; 83; 382-395.). Murray et al recently demonstrated that baseline serum IGF-I SD is the only determinant required for optimal GH replacement therapy in GH-deficient adults (Murray R D et al.
Clinical Endocrinology
2000; 52: 537-542.).
WO9409813 discloses a method for treating obesity by the administration of GH and IGF-I. The dose of GH should be at least 0.01 mg/kg/day.
WO9532991 discloses the combined administration of human growth hormone and dehydroepiandrosterone to regenerate human thymus to allow intra-thymic transplantation to eliminate organ and tissue rejection. The hyperinsulinaemia side effects of growth hormone are thereby eliminated e.g. hyperinsulinaemia in children, i.e. no elevation in blood levels of insulin are observed.
In WO97/38709 obese subjects have been treated with GH to find the potential for growth hormone to reduce central obesity.
The subjects treated had a body mass index between 25 and 35 kg/m
2
, an IGF-I less that 160 &mgr;g/L (low normal) and a waist hip ratio of more that 0.95. The study was performed for 9 months with the administration of rhGH. The daily rhGH dose was 0.0095 mg/kg (0.20 IU/kg body weight/week), administrated subcutaneously before bedtime.
Lipoprotein lipase (LPL) activity and Glucose disposal rate (GDR) were observed in this study.
The patients in WO97/38709 are obese and rhGH was given for 9 months. No conclusion can be drawn from this study for treatment of normal individuals with low dose GH treatment.
WO9901151 relates to a therapy involving administration of human growth hormone for improving cellular function in the heart challenged by insulin resistance and thereby treating or protecting the heart from complications derivable from this condition. Only complications resulting from insulin resistance in the heart are mentioned.
In none of these references has a low dose of growth hormone been given to normal subjects and no conclusion regarding insulin sensitivity can be drawn from the earlier reported findings.


REFERENCES:
patent: 4670393 (1987-06-01), Seeburg
patent: 5079345 (1992-01-01), Becker et al.
patent: 5597709 (1997-01-01), Rossen et al.
patent: 0534568 (1993-03-01), None
patent: WO 9004788 (1990-05-01), None
patent: WO 9005185 (1990-05-01), None
patent: WO 9409813 (1994-05-01), None
patent: WO 9709060 (1997-03-01), None
patent: WO 9738709 (1997-10-01), None
patent: WO 9901151 (1999-01-01), None

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