Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1993-03-17
2000-03-07
Eisenschenk, Frank C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 514 21, 530324, 530303, 530399, 435 691, A61K 3800, A61K 3818
Patent
active
060340592
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
1. Technical Field
This invention relates to a method and a product for the treatment or prevention of the catabolic state in patients, involving the administration of insulin-like growth factor 1 (IGF-1).
2. Background Art
IGF-1 is a peptide belonging to the somatomedin family. It is comprised of 70 amino acids, including 3 disulphide bonds. Its amino acid sequence is known. IGF-1 is normally found in the circulation bound to at least two different classes of binding proteins (ca 150.000 D) and the low molecular weight binding protein (ca 30.000 D). IGF-1 is mitogenic in cell lines (i.e in vitro) and has been shown to stimulate growth in growth hormone (GH) deficient animals.
The IGF-1 concentration is in plasma (blood), at least partly, regulated by GH but also by other hormones, such as thyroxine, and by the nutritional status.
A wide variety of clinical conditions can lead to loss of weight and muscle in patients and in particular to protein depletion. Examples of possible causes are burns, multiple trauma, sepsis, major surgery and maligant tumours. In some cases, patients cannot be fed orally at all (e.g in the case of gastrointestinal surgery) or only at an inadequate caloric level. In other instances nutrients taken orally cannot be absorbed or cannot be absorbed with normal efficiency via the gastro-intestinal tract. In such cases intravenous feeding must be utilised but it is difficult or sometimes impossible to supply normal caloric requirements by the intravenous route. There is also a risk for liquid overload.
In such circumstances there is a need to be able to treat or prevent a catabolic state whilst supplying the patient with a diet that, to the extent that it is utilised by the body, is inadequate to meet his/her normal caloric requirements. Such a diet is referred to herein as a "hypocaloric diet".
It has been suggested (International Patent Application WO 87/04074) that protein accretion or nitrogen retention can be promoted in the case of a hypocaloric diet by the administration of growth hormone (GH). It is thought that any beneficial effect resulting from the administration of GH may be derived from an increased level of IGF-1 in the bloodstream that has been observed in some cases. On the other hand, there is conflicting evidence both from human and ovine studies where administration of GH did not bring about any IGF-1 response. In any event, not all classes of patients are able to respond to the administration of GH by an increase in IGF-1 levels. Indeed, relative GH resistance is frequently seen in catabolic states.
Moreover, very young children particularly those less than one year of age do not have the necessary GH receptors and in severely-starved adults the GH receptor function is impaired or the receptors are reduced in number so that administration of GH in such cases is ineffective or only effective in greatly increased (i.e pharmacological) quantities. High doses of GH are undesirable as they can lead to hyperglycaemia and in any event the drug is expensive. Futhermore, in the case of adults, it is not always easy to determine whether a given patient will be able to respond to the treatment with GH or not.
It has also been suggested that treatment with certain analogues of IGF-1 can lead to increased growth rates in animals (International Patent Application WO 87/01038, WO 89/05822). It was postulated that the use of analogues having certain amino acid residues absent from the N-terminus would reduce the degree of binding to the IGF-1 binding proteins. This was based on the assumption that only free (i.e unbound) IGF-1 has the desired anti-catabolic activity. On the other hand, it has been suggested that freely-circulating IGF-1 may be responsible for the known tendency of that material to cause undesirable hypoglycaemia. In fact, the prevailing opinion was that systemically administered IGF-1 could not be used therapeutically for that reason. However, we now believe that the bound forms of IGF-1 may be responsible for the desired anabolic effects.
SUMMARY O
REFERENCES:
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Fryklund Linda
Gluckman Peter
Skottner Anna
Blackburn Robert P.
Chiron Corporation
Eisenschenk Frank C.
Guth Joseph H.
Spruill W. Murray
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