Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-05-18
2001-08-28
Carlson, Karen Cochrane (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S009100, C514S014800, C514S554000, C530S317000, C530S327000, C560S019000
Reexamination Certificate
active
06281244
ABSTRACT:
The present invention relates to a new use of glycine alone or in combination with other therapeutic agents.
It is known to use a medicament or nutritional formulation comprising glycine, alanine or serine as an active ingredient to minimize or prevent the metabolic effects of a wide range of disease states or conditions induced by elevated tumor necrosis factor (TNF) levels.
It has now been found that glycine is indicated to prevent or treat acute or chronic graft rejection. Thus the invention provides:
1.1. A method of preventing or treating non TNF-induced transplant rejection in a recipient of organ or tissue transplant, e.g. heart, lung, combined heart-lung, trachea, bowel, liver, kidney or pancreatic transplants, comprising the step of administering to said recipient a therapeutically effective amount of glycine, in free form or in pharmaceutically acceptable salt form;
1.2. A method of preventing or treating manifestations of chronic rejection in a recipient of organ or tissue transplant, e.g. heart, lung, combined heart-lung, trachea, liver, bowel, kidney or pancreatic transplants, comprising the step of administering to said recipient a therapeutically effective amount of glycine, in free form or in pharmaceutically acceptable salt form;
Chronic rejection is considered as a multifactorial process in which not only the immune reaction towards the graft but also the response of the blood vessel wall in the grafted organ to injury plays a role. The variant of chronic rejection with the worst prognosis is an arteriosclerosis-like alteration, also called transplant vasculopathy graft vessel disease. This vascular lesion is characterized by migration and proliferation of smooth muscle cells. It appears to progress also through repetitive endothelial injury induced amongst others by host antibody or antigen-antibody complexes, through intimal proliferation and thickening, smooth muscle cell hypertrophy repair, and finally to gradual luminal obliteration. Also so-called non-immunological factors like hypertension, hyperlipidemia, hypercholesterolemia etc. play a role.
2. A pharmaceutical composition or nutritional formulation for use in any method as defined hereinabove comprising glycine, in free form or in pharmaceutically acceptable salt form, together with a pharmaceutically acceptable diluent or carrier therefor.
In a series of further specific or alternative embodiments, the present invention also provides:
3.1. Use of glycine, in free form or in pharmaceutically acceptable salt form, in combination with an immunosuppressant or immunomodulating agent or a mixture thereof, in a method as defined hereinafter under 1.1 or 1.2;
3.2. Use of glycine, in free form or in pharmaceutically acceptable salt form, in the preparation of a medicament or nutritional formulation for a combined use with an immunosuppressant or immunomodulating agent or a mixture thereof, in a method as defined hereinafter under 1.1 or 1.2;
4.1. A method of preventing or treating non TNF-induced transplant rejection in a recipient of organ or tissue transplant, e.g. heart, lung, combined heart-lung, trachea, liver, bowel, kidney or pancreatic transplants, comprising the step of administering to said recipient glycine, in free form or in pharmaceutically acceptable salt form, and an immunosuppressant or immunomodulating agent or a mixture thereof, in a therapeutically effective amount;
4.2. A method of preventing or treating manifestations of chronic rejection in a recipient of organ or tissue transplant, e.g. heart, lung, combined heart-lung, trachea, liver, bowel, kidney or pancreatic transplants, comprising the step of administering to said recipient glycine, in free form or in pharmaceutically acceptable salt form, and an immunosuppressant or immunomodulating agent or a mixture thereof, in a therapeutically effective amount;
5.1. A pharmaceutical composition or nutritional formulation for use in any method as defined hereinabove comprising glycine, in free form or in pharmaceutically acceptable salt form, in combination with an immunosuppressant or immunomodulating agent or a mixture thereof.
5.2. A kit or package for use in any method as defined hereinabove, said kit or package including a pharmaceutical composition or nutritional formulation comprising glycine in free form or in pharmaceutically acceptable salt form and a pharmaceutical composition comprising an immunosuppressant or immunomodulating agent, together with instructions to use.
According to a preferred embodiment of the invention, glycine is indicated optionally in combination with an immunosuppressant or immunomodulating agent for preventing or treating manifestations of chronic rejection.
According to the invention, glycine is conveniently employed in free amino acid form, in the form of glycine precursors, in particular alanine or serine, likewise in free amino acid form, in pharmaceutically acceptable salt form of said amino acids, or in form of mixtures of said amino acids and/or pharmaceutically acceptable salts thereof. Glycine is preferably used in free amino acid form, in pharmaceutically acceptable salt form or in the form of a mixture of glycine in free amino acid form with glycine in pharmaceutically acceptable salt form; most preferably glycine is in free amino acid form. Glycine may also be used in the form of a dipeptide according to the invention. Suitable salts include e.g. mineral or organic acid salts of the amino residue, and alkali or organic salts of the carboxylic acid residue.
Daily dosages of glycine required in treating or preventing diseases and conditions according to the invention will vary depending upon, for example, the host, the mode of administration, the severity of the condition to be treated and the optionally used (concomitantly, separately or in sequence) immunosuppressant or immunomodulating agent. A preferred daily dosage of glycine is about 1 to 80 g, preferably, 1 to 60 g, particularly preferred 15 to 30 g. It may also be administered to the patient in an amount such that its concentration in the patients'plasma is elevated to between 0.5 and 2.0 mM, preferably from 1.0 to 2.0 mM, although concentrations higher than this may be used. Suitable examples of immunosuppressants or immunomodulating agents include e.g. cyclosporins, rapamycins or ascomycins or their immunosuppressive analogs, e.g. Cyclosporin A, Cyclosporin G, FK-506, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin; corticosteroids; cyclophosphamide; azathioprine; methotrexate; brequinar; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine; immunosuppressive antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, or CD 58 or their ligands; or other immunomodulatory compounds, e.e. CTLA4 lg.
Where giycine is administered in conjunction, i.e. sequentially, separately or concomitantly, with other immunosuppressive or immunomodulating therapy, e.g. as hereinabove specified, dosage of the co-administered immunosuppressant or immunomodulating agent will of course vary depending on the type of co-drug employed, e.g. whether it is a cyclosporin or an immunosuppressive antibody, on the specific drug employed, on the condition being treated, and so forth. According to the invention, glycine may also be administered in conjunction with a combination of immunosuppressants/immunomodulating agents, e.g. Cyclosporin A/ Steroids/Azathioprine or mycophenolate mofetil.
Glycine may be administered to the patient enterally or parenterally. The enteral administration route is preferred; particularly contemplated enteral administration routes are oral and/or tube feeding such as nasal feeding, particularly oral feeding. The medicament or nutritional formulation is conveniently administered in the form of an aqueous liquid. The medicament or nutritional formulation in a form suitable for enteral application is accordingly preferably aqueous or in powder form, whereby the powder is conveniently added to water prior to use. For use in tube feeding, the amount o
Cook Nigel Scott
Schneider Heinz
Thurman Ronald G.
Carlson Karen Cochrane
Gupta Anish
Novartis Nutrition AG
Pfeiffer Hesna J.
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