Amino acid compositions and use thereof in immunosuppression

Details Amino acid compositions and use thereof in immunosuppression Amino acid compositions and use thereof in immunosuppression

1999-02-01

2001-03-20

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S561000

Reexamination Certificate

active

06204244

ABSTRACT:

The present invention relates to the use of glycine in the preparation of a medicament or nutritional formulation which may be therapeutically administered to patients to prophylactically and/or therapeutically treat renal dysfunction induced by substances belonging to the classes of cyclosporins and/or ascomycins.
Cyclosporins comprise a class of structurally distinct, cyclic, polyN-methylated undecapeptides, generally possessing immunosuppressive, anti-inflammatory, anti-viral and/or anti-parasitic activity, each to a greater or lesser degree. The first of the cyclosporins to be identified was the fungal metabolite Cyclosporin A, or Ciclosporin, and its structure is given in The Merck Index, 11th Edition; Merck & Co., Inc.; Rahway, N.J., U.S.A. (1989) under listing 2759. Later cyclosporins to be identified are cyclosporins B, C, D and G which are also listed in The Merck Index under listing 2759. A large number of synthetic analogues are also known and representative examples are disclosed in EP 296 123, EP 484 281, and GB 2222770. Cyclosporin A and its structurally similar analogues and derivatives as well as metabolites thereof are generally referred to as “cyclosporins” for the purposes of this specification.
Ascomycins, of which FK-506 is the best known, are another class of generally immunosuppressive substances, also referred to as macrolide immunosuppressants. FK-506 is a macrolide immunosuppressant that is produced by
Streptomyces tsukubaensis
No. 9993. The structure of FK-506 is given in the appendix to The Merck Index, supra, as item A5. A large number of related compounds which retain the basic structure and immunological properties of FK-506 are also known. These compounds are described in various publications, for example EP 184162, EP 315973, EP 323042, EP 423714, EP 427680, EP 465426, EP 474126, WO 91/13889, WO 91/19495, EP 484935, EP 532088, EP 532089, WO 93/5059 and the like. Ascomycin, FK-506 and their structurally similar analogues and derivatives as well as metabolites thereof are termed collectively “ascomycins” in this specification.
Due to their extremely useful pharmaceutical properties, cyclosporins (Cyclosporins A and G in particular) and ascomycins (e.g., FK-506) have wide application in, for example the prevention of transplant rejection, in the treatment of auto-immune diseases such as rheumatoid arthritis and psoriasis, and also in the treatment of multi-drug-resistance. Cyclosporins and ascomycins also have certain side effects, the most notable being renal dysfunction, in particular nephrotoxicity, especially at higher doses. Nephrotoxicity is characterized by diminished renal blood flow and glomerular filtration with corresponding elevations in serum creatinine, alkaline phosphatase and urea as well as proximal cell swelling and necrosis and infiltration of macrophages. In some studies, hypoxia has been shown to damage proximal tubules rather selectively, and a decrease in blood flow could lead to hypoxia. Evidence has been presented implicating intracellular calcium in this pathology, and calcium channel blockers are effective in minimizing injury. However, Ca
++
channel blockers cannot be given without impunity. Accordingly, there is currently no known useful therapy for this important side effect on the kidney.
It has now surprisingly been found that glycine is suitable for prophylactic and/or therapeutic treatment of renal dysfunction induced by cyclosporins or ascomycins.
In accordance with the invention it has more particularly been found that dietary glycine inhibits and/or ameliorates one of the major side effects of chronic cyclosporin A administration-nephrotoxicity. Glycine prevents the decrease in glomerular filtration rate. Glycine also prevents the elevation in serum creatinine and urea, and tends to minimize the elevation in alkaline phosphatase due to cyclosporin A. The swelling and necrosis of proximal tubules and macrophage infiltration are also all prevented by dietary glycine. Thus, it is clear that glycine has a major protective action on nephrotoxicity due to cyclosporin A.


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