Use of fumaric acid derivatives in transplant medicine

Details Use of fumaric acid derivatives in transplant medicine Use of fumaric acid derivatives in transplant medicine

2000-12-08

2002-03-19

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S557000

Reexamination Certificate

active

06359003

ABSTRACT:

The present invention relates to the use of certain fumaric acid monoalkyl esters either in the form of salts thereof or as the free acid, alone or in combination with a dialkyl fumarate, for preparing pharmaceutical compositions for use in transplantation medicine. In particular, it relates to the use of said pharmaceutical preparations containing fumaric acid alkyl esters for treating, alleviating or suppressing rejection of the transplant by the recipient, i.e. host-versus-graft reaction.
Transplantations are tissue or organ transplantations, i.e. the transfer of tissue such as cornea, skin, bones (bone chips), vessels or fasciae, of organs such as kidney, heart, liver, lung, pancreas or intestine, or of individual cells such as islet cells, &agr;-cells and liver cells, the kidney having the greatest significance as a transplanted organ.
According to the degree of relationship between the donor and the recipient we differentiate between auto-transplantation (transfer to another part of the body of the same individual), iso-transplantation (transfer to another, genetically identical individual) or allogenic transplantation (transfer to another individual of the same species). Depending on the site of origin and transplantation, we further differentiate between homotopic transplantation (transfer to the same site) and heterotopic transplantation (transfer to a different site). The above-mentioned transplantations play an important role in modern medicine.
A major problem in transplantation medicine is graft rejection after transplantation of the tissue, organ or cell by immunological defence reactions of the recipient. Such a graft rejection is also called host-versus-graft reaction. The immunological defence reaction of the organism against the heteroprotein often results in rejection or dissolution of the grafts. By using modern immunosuppressive agents, the most important representatives of which are the cyclosporines, especially cyclosporine A, a significant improvement in the results of transplantations was achieved over the last few years. At present, the one-year survival rate is about 60% for liver transplantations, about 80% for heart transplantations and over 90% for kidney transplantations.
In host-versus-graft reactions, different stages may be distinguished. Depending on the degree of difference between the recipient and the donor, this reaction takes place at different speeds so that we speak of a an acute, sub-acute or chronic reaction. Acute rejection processes are accompanied by the irreversible loss of the transplant (necrotisation) as a result of arteriitis or arteriolitis within 48 hours and cannot be influenced by the administration of drugs. The subacute rejection reaction becomes manifest as a rejection crisis from day 12 to month 4 with reversible functional disorders as a result of a transplant vasculopathy. Finally, the loss of function of the transplant as a result of vascular changes such as obliterating arteriopathy, which proceeds over weeks or years and can practically not be influenced by drugs, is termed a chronic rejection reaction.
To avoid such rejection reactions, i.e. the host-versus-graft reaction, transplantation medicine essentially makes use of immunosuppression, i.e. a weakening of the normal immunoresponse. For this purpose, anti-lymphocyte sera are often used in combination with corticosteroids and so-called anti-metabolites, e.g. purine analogues such as 6-mercaptopurine and thioguanine which affect the nucleic acid and protein synthesis and thus prevent cell division and proliferation. This leads to suppression of the production of antibodies and the cellular immune response. The immunosuppressive agents used for therapy are substances which suppress or weaken the immunoreaction in the body either specifically or non-specifically. Non-specific immunosuppressive agents are cytostatic agents such as, for example, alkylating agents or antimetabolites. In addition, active ingredients are known which cause at least partial specific immunosuppression, such as corticosteroids, antisera, antibodies FK-506, tacrolimus, mycophenolatemofetil and primarily cyclosporines such as cyclosporine A.
The danger in using immunosuppressive agents lies in weakening the body's defence against infectious diseases and the increased risk of malignant diseases. Therefore, it is the object of the invention to provide a pharmaceutical preparation to be employed in transplantation medicine which may be used to treat, especially to suppress, weaken and/or alleviate host-versus-graft reactions but does not have the above disadvantage.
The object of the invention is achieved by using certain fumaric acid monoalkyl esters as salts with mono- or bivalent cations or in the form of the free acid, either alone or in combination with a dialkyl fumarate for preparing pharmaceutical compositions to be used in transplantation medicine. The subject matter of the invention is characterised in detail in the claims. The compositions according to the invention do not contain free fumaric acid per se.
It is known that pharmaceutical preparations which, upon biological degradation after administration, enter into the citric acid cycle or are part thereof gain increasing therapeutic significance—especially when given in high dosages—since they can alleviate or heal diseases caused cryptogenetically.
Fumaric acid, for example, inhibits the growth of the Ehrlich ascites tumour in mice, reduces the toxic effects of mitomycin C and aflatoxin [K. Kuroda, M. Akao, Biochem. Pharmacol. 29, 2839-2844 (1980)/Gann. 72, 777-782 (1981)/Cancer Res. 36, 1900-1903, (1976)] and displays a anti-psoriatic and anti-microbial activity [C. N. Huhtsnen, J. Food Sci. 48, 1574 (1983)/M. N. Islam, U.S. Pat. No. 4,346,118 dated Aug. 24, 1982/C.A. 97, 161317b (1982)].
When administered parenterally, transdermally and especially perorally, high dosages of fumaric acids or its derivatives known so far such as dihydroxyl fumaric acid, fumaramide and fumaronitrile have such unacceptably severe side effects and high toxicity [P. Holland, R. G. White, Brit. Dermatol. 85, 259-263 (1971)/M. Hagedorn, K. W. Kalkoff, G. Kiefer, D. Baron. J. Hug, J. Petres, Arch. Derm. Res. 254, 67-73 (1975)] that, in most cases, such a therapy had to be abandoned in the past.
European Patent Application 0 188 749 already describes fumaric acid derivatives and pharmaceutical compositions containing the same for the treatment of psoriasis. Pharmaceutical compositions for the treatment of psoriasis containing a mixture of fumaric acid and other fumaric acid derivatives are known from DE-A-25 30 372. The content of free fumaric acid is obligatory for these medicaments.
DE-A-26 21 214 describes medicaments containing the fumaric acid monoethyl ester and its mineral salts as active ingredient for the treatment of psoriasis. The publication “Hautarzt (Dermatologist) (1987) 279-285” discusses the use of fumaric acid monoethyl ester salts. Pharmaceutical compositions containing a mixture of fumaric acid monoalkyl ester salts and a fumaric acid diester for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn are known from EP 0 312 697 B1.
Surprisingly, it has now been found that fumaric acid-C
1
-C
5
-monoalkylester(s) in the form of a salt thereof with mono- or bivalent cations, preferably in the form of calcium, magnesium, zinc or iron salts or lithium, sodium or potassium salts, or in the form of free acid, either alone or in combination with a di-C
1
-C
5
-alkyl-fumarate are advantageous for preparing a pharmaceu-tical composition for use in transplantation medicine. Compositions containing such fumaric acid C
1-5
-monoalkyl esters surprisingly permit a positive modulation of the immune system in host-versus-graft reactions.
The invention preferably uses pharmaceutical compositions containing one or more compounds from the group consisting of calcium, magnesium, zinc and iron salts or lithium, sodium or potassium salts of fumaric acid monoalkyl esters of the g

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