Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1998-02-02
2000-08-22
Naff, David M.
Drug, bio-affecting and body treating compositions
Lymphokine
4242821, 435170, 4352531, 435863, A61K 4500, C12N 100, C12N 120, C12P 104
Patent
active
061068225
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND
1. Field of the Invention
The present invention relates to second messengers which mimic the action of insulin and other mammalian growth factors and hormones.
2. Related Art
Non insulin-dependent diabetes mellitus is one of the most common metabolic disorders in the industrial world. Associated with the disorder are dyslipidemias, atherosclerosis, hypertension, cardiovascular disorders and renal dysfunction. Obesity constitutes the greatest risk factor for the disease. Two physiological defects that lead to the development of diabetes are tissue resistance to the effects of insulin and altered secretion of insulin.
In order for new treatments of this disorder to be developed it is necessary to understand the specifics of the insulin signalling pathways and other signalling pathways which may interfere with insulin action. It has recently been demonstrated that low molecular weight phosphorylated inositolglycans (IPGs), are released upon insulin stimulation in a tissue-specific manner. These compounds are in the family of phosphoglycokines (PGK), defined as biologically active low molecular weight compounds containing phosphorylated carbohydrates. The tissue-derived IPGs mediate some of the actions of insulin. Such insulin-mimetics have therapeutic potential in that they could:
(i) substitute for insulin either as a parenteral or oral treatment in patients with diabetes where the primary pathology relates either to decreased synthesis (type I diabetes) or lack of bioavailable insulin (defects in conversion of proinsulin to insulin or in the formation of anti-insulin antibodies).
(ii) be used to treat patients with tissue insulin resistance, which is seen in many cases of adult onset or type II diabetes.
(iii) be used to treat or prevent complications of diabetes including dyslipidemias, atherosclerosis, hypertension, cardiovascular disorders and renal dysfunction. It has further been found that the IPGs are able to cross the blood brain barrier and affect cerebral glucose and energy metabolism. Since insulin itself has limited ability to cross the blood brain barrier, release of the compounds into the circulation following insulin stimulation may be crucial in the control of energy metabolism in the brain. In clinical trials, tissue-derived IPGs have been shown to be effective in reversing age-associated memory loss and in providing a protective effect under cerebral hypoxic conditions.
As detailed below, the inositolphosphoglycan second messenger signal transduction effect has also been shown to be functionally relevant for the signalling of other growth factors, including fibroblast growth factor (important in wound healing), transforming growth factor .beta. (important in autoimmunity) and hepatocyte growth factor (also known as scatter factor), that together with other growth factors, is important for the regeneration of liver tissue following damage by infection, alcohol abuse, drug sensitivity, or autoimmunity.
SUMMARY OF THE INVENTION
The present invention provides a valuable source of phosphoglycokines (PGK) which mimic the activity of the tissue-derived IPGs, which are otherwise not readily available. Only very small quantities of the IPGs can be isolated from mammalian tissues. Since the IPGs are non-protein in composition, they cannot be produced by recombinant DNA technology. Synthetic chemistry approaches are complicated by the current lack of structural details of the tissue-derived IPGs and the complications associated with oligosaccharide syntheses.
Immunotherapy with M. Vaccae
We have previously described the use of antigenic and/or immuno regulatory material derived from Mycobacterium vaccae in the treatment of tuberculosis (see, for example, British Patent No. 2156673 and U.S. Pat. No. 4,724,144). In our International Patent Application No. PCT/GB90/01169 (publication No. WO91/01751), we have described the use of the same material for immunoprophylactic treatment against AIDS, i.e. for increasing the period between infection by HIV and development of AIDS.
Mycobacterium
REFERENCES:
Chemical Abstracts, vol. 120, No. 25, Jun. 20, 1994 Columbus, Ohio, US; abstract No. 315887v, T W Rademacher et al.; "inositolphosphoglycan second messengers" p. 106; XP002006591 see abstract & Braz. J. Med. Biol. Res., vol. 27, No. 2, 1994, pp. 327-341.
Chemical Abstracts, vol. 123, No. 23, Dec. 4, 1995 Columbus, Ohio, US; abstract No. 312104p, R Hernandez-Pando et al.: "Adrenal changes in murine pulmonar tuberculosis; a clue to pathogenesis?" p. 724; XP002006592 see abstract & FEMS Immunol. Med. Microbiol., vol. 12, No. 1, 1995, pp. 63-72.
Caro Hugo N.
Rademacher Thomas W.
Rook Graham A. W.
Naff David M.
University College of London
Ware Deborah K.
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