Combination preparation, containing cyclosporin A or FK506 or ra

Details Combination preparation, containing cyclosporin A or FK506 or ra Combination preparation, containing cyclosporin A or FK506 or ra

1997-04-03

2000-04-04

Geist, Gary

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen bonded directly to ring carbon of the purine ring...

C07D47328

Patent

active

060463287

DESCRIPTION:

BRIEF SUMMARY
Cyclosporin A (CysA) is a cyclic undecapeptide which is obtained from a fungus (CAS No. 59865-13-3; U.S. Pat. No. 3,737,433). Its immunosuppressive effect has been known since 1972, but nevertheless it still took about 10 years until CysA found its way into the treatment of the acute rejection reaction of transplants (Borel, J. F.: Cyclosporine. In: Dale, M., Foreman, J. C., Fan, T. P. D. (eds.): Textbook of Immunology (3rd ed.). Blackwell Scient. Publ. Oxford 1994, pp 320-329). Today, as a result of its outstanding properties, CysA can no longer be overlooked in immunosuppression, even if its use is accompanied by a number of sometimes serious side effects.
The immunosuppressive action of CysA is very selective and concentrates on T-cell-dependent mechanisms. CysA inhibits the proliferation of T-lymphocytes, which normally respond to a proliferative stimulus (produced e.g. by antigen or mitogen) with cell replication and cell differentiation but also the release of lymphokines (e.g. various interleukins such as IL-2, IL-3 and IL-4, but also .gamma.-interferon) and in this way start the cellular immune response. T-cell-independent B cell-dependent mechanisms (e.g. the humoral immune response via certain antibodies) cannot be inhibited, however, under the therapeutically achievable CysA concentrations. The immunosuppression produced by CysA is completely reversible after removing or washing out the substance (Thomson, A. W. (ed.): Cyclosporin: Mode of Action and Clinical Applications. Kluwer Acad. Publ. Dordrecht 1989), which points to the fact that it is not a general lymphocytotoxic reaction which we are dealing with here, instead the release of IL-2 by T-helper cells primarily appears to be inhibited, which brings about a blockade of secondary immunological reactions. In this case the expression of the IL-2 gene represents the biochemical response of the T-helper cell to an immunological stimulus, which is fed from the cell membrane into the nucleus in the course of a "signal chain". Although the individual biochemical chain constituents and their sequence have not yet been elucidated in detail, the activation and translocation of a cytosolic "nuclear factor" (NF-AT=nuclear factor of activated T cells) can be assumed as an important step which then causes the transcription of the IL-2 gene in the nucleus. This activation of NF-AT which is controlled by the Ca.sup.2+ /calmodulin/calcineurin system is inhibited by CysA, which joins intracellularly with a protein called "cyclophilin" to give a complex (Handschumacher, R. E. et al.: Science 226 (1984), 544-546), with the result that despite the presence of an immunological stimulus no IL-2 is formed which, however, is of crucial importance for the further course of the cellular immune response (inter alia for the formation of cytotoxic T-cells).
This immunosuppressive action appears CysA to be suitable not only for allogeneic transplantations, but also for autoimmune disorders of different manifestation. In fact, numerous respective therapeutic attempts have been undertaken, from rheumatoid arthritis through psoriasis up to juvenile diabetes (Schindler, R. (ed.): Cyclosporin in Autoimmune Diseases. Springer Verlag Berlin 1985; Thomson, A. W. et al.: Br. Med. J. 302 (1991), 4-5). Despite various successful results, however, CysA has not been able to establish itself as the drug of choice in these indications, the reason for this being exclusively to be sought in the toxicity of this substance. In the first place, its marked nephrotoxicity which in some cases is irreversible has to be mentioned here, but also other phenomena such as high blood pressure, nausea, diarrhoea, tremor, tingling or gingival hypertrophy (Palestine, A. R. et al.: Am. J. Med. 77 (1984), 652-656) represent complications to be taken seriously, which usually cannot be avoided even with systematic checking of the serum level. At the same time--as with any effective immunosuppression--opportunistic infections additionally have to be considered (Dawson, T. et at.: J. Rheumatol. 19 (1992), 997

REFERENCES:
Bruserud, Oeystein, The additive of ceratin drugs on the cyclosporin A inhibition of human T-cell proliferation, APMIS 98(12) 1070-6, Dec. 1990.

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