Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-10
2002-08-13
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S291000, C514S011400
Reexamination Certificate
active
06432968
ABSTRACT:
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 nitogen) 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 &ggr;-interferon) and in this way start the cellular immune response. T-cell-independant B cell-dependent mechanisms (e.g. the humoral immune response via certain antibodies) cannot be inhibited, however, under the therapeutically achievable CysA concentrations. The immuno-suppression 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
2+
/calmodulin/calcineurin system is inhibited by CysA, which joins intracellularly with a protein called “cyclophilino” 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 al.: J. Rheumattl. 19 (1992), 997), so that by critical benefit-risk assessment an otherwise advantageous CysA medication in many cases has to be sacrificed.
Xanthines have already been taken by people for many hundreds of years in the form of aqueous extracts, and the stimulating as well as diuretic properties of tea or coffee are generally known. About 70 years ago, theophylline was then introduced into medicine as a pure substance for the treatment of pulmonary complaints (e.g. asthma attack), followed 50 years later by pentoxifylline (POF), which is employed for the treatment of peripheral and cerebral circulatory disorders (Ward A. et al.: Drugs 34 (1987), 50-97). The latter xanthine derivative, which clearly differs from theophylline due to its extensive lack of central and cardiac effects, in the following was subject of in-depth investigations on its mechanism of action, in the course of which also effects on the immune system have been detected. Thus, for example, it was already found at the start of the '80s that POF significantly prolonged the survival rate of heart and kidney transplants in the rat model, although these findings, at that time, have primarily been attributed to improved circulatory phenomena (Kostakis A. J. et al.: IRCS 8 (1980), 15; Kostakis A. J. et al.: IRCS Med. Sci. 10 (1982), 77-78). Only later was it recognized that POF—together with other representatives of the xanthine family—interacts with the immunologically important cytokine network. This is not only true for tumor necrosis factor (TNF), which plays a central role in a number of very different disorders and whose formation is inhibited on the transcriptional level by POF (Strieter R. M. et al.: Biochem. Biophys. Res. Commun. 155 (1988), 1230-1236), but also for other cytokines such as IL-2 or IFN&ggr; (Rieneck K. et al.: Immunol. Lett. 37 (1993), 131-138; Thanhäuser A. et al.: Immunology 80 (1993), 151-156; Tilg H. et al.: Transplantation 56 (1993), 196-201). Since, in addition antiproliferative effects of POF also became known in the meantime (Singer J. W. et al.: Bone Marrow Transplant. 10 (1992), 19-25), it is not astonishing that today certain immunomodulatory properties are ascribed to POF, which have already given rise to speculations about an extension of its present applications (Zabel P. et al.: Immun. Infect. Dis. 3 (1993), 175-180).
As far as the mechanism of action of xanthines is concerned, the cAMP system may play a predominant role. cAMP (cyclic 3′,5′-adenosine monophosphate) is a “second messenger” and able to control the activity state of the cell: the higher the intracellular cAMP level, the less activated the cell. The height of the cAMP level may generally be affected by two different mechanisms: increase in formation by adenylate cyclase (AC) or inhibition of degradation by phosphodi-esterase(s) (PDE). Xanthines from the POF series are prone to both of these possibilities, i.e. directly via inhibition of PDE and indirectly via stimulation of the release of prostaglandins, which themselves stimulate AC's. Actually, the increase in intracellular cAMP level due to xanthine action—with all its consequences—is not restricted to T-lymphocytes, however, but is also found in other immunocompetent cells such as monocytes or granulocytes, which in the former leads to the inhibition of TNF synthesis (Strieter R. M. et al.: Diochem, Biophys. Res. Commun. 155 (1988), 1230-1236) but in the latter suppresses the “metabolic burst” (=oxygen free radical formation and release of lytic enzymes from the granules for bacterial infection defence (Hammerschmidt D. E. et al.: J. Lab. Clin. Med. 112 (1988), 254-263)), both reactions of which—intravasally induced—being able to cause massive complications in the microcirculation. This mechanism, which in the various representatives of the xanthine family may differ markedly (Semmler J. et al.: Immunology 78 (1993), 520-525), indeed leads to very selective interventions in the cytokine network (the formation of IL-1, for example, is nearly not affecte
Gebert Ulrich
Schönharting Martin
Waer Mark
Aventis Pharma Deutschland GmbH
Heller Ehrman White & McAuliffe LLP
Travers Russell
LandOfFree
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