Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-25
1999-11-23
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514262, 514263, 514826, 514885, 514889, A61K 3155
Patent
active
059901039
DESCRIPTION:
BRIEF SUMMARY
The invention relates to pharmaceutical combination preparations for the treatment of immunological diseases in the broadest sense, which determine syndromes differing in their causes or symptoms. These combination preparations are determined by the pharmacological mechanisms of action on which the individual components are each based, and can be characterized by an concentration.
The activation of immunocompetent cells, which is the basis of any immune response, proceeds via the so-called signal chain: An extracellular stimulus (e.g. a toxin, an antigen or else complement, inflammation mediators, arachidonic acid derivatives or other metabolic products) reaches the cell as an "information carrier" and transfers the material information--usually via suitable receptors--to the target cell. This information is transmitted inside the cell to the nucleus via various intermediate stages within the signal chain, the nucleus reacts to this stimulus with proliferation and/or the formation of specific activators and the immune response is thus initiated in an appropriate way. However, the individual steps in this intracellular transmission of the information are still poorly understood, particularly as there are obviously different paths which can be followed within the cell in order to trigger an immune response. Thus, for example, depending on the type of receptor and the subunits coupled thereto (guanine nucleotide-binding proteins or "G proteins"), inositol triphosphate (IP.sub.3), diacylglycerol (DAG), phosphatidylcholine (PC) or phosphatidylinositol (PI) can be detected in the sequence, said compounds arising from a stimulus induced activation of phospholipase C or D and being associated with an increase in intracellular free Ca.sup.2+, while an activation of phospholipase A.sub.2 incurs the formation of arachidonic acid derivatives (prostaglandins, leukotrienes), which in turn can trigger their own stimulus via suitable receptors, with corresponding consequences. A second type of receptor is coupled via corresponding G proteins to adenylate cyclase (AC), the activation of which results in the formation of cyclic 3',5'-adenosine monophosphate (cAMP), while a third type seems to trigger effects which are again independent thereof (for survey see Roitt (ed.): Essential Immunology, Blackwell Scient. Publ. Oxford 1991, and Foreman, Fan (eds.). Textbook of Immunopharmacology, Blackwell Scient. Publ. Oxford 1994).
Both Ca.sup.2+ and cAMP are thus important information transmitters (second messenger) in signal transduction, although the processes subsequently taking place inside the cell are so complex that it is impossible to make a general prediction of the resulting cytobiological events. In any case the majority of downstream activation phenomena seem to depend on phosphorylation steps in the cell, which in turn are regulated via corresponding protein kinases or phosphatases. Particular mention may be made here of protein kinase C (PKC), whose activity is controlled via DAG and IP.sub.3 /Ca.sup.2+ in a concerted action, whereby the availability of intracellular free Ca.sup.2+ takes on a key role in the cascade of cell activation, irrespective of the fact that usually the Ca.sup.2+ /calmodulin complex subsequently mediates the Ca.sup.2+ effects (Hidaka et al.: Cell Calcium 13, 465-472 (1992); Kun et al.: Endocrin. Rev. 14, 40-58 (1993)). Phosphorylations do not have to lead to activations in every case, however, but can also induce inhibitory effects. Thus, for example, the cAMP-dependent protein kinase A (PKA) counter-acts cell activation in the way that really only the complex interplay of phosphorylation and dephosphorylation allows efficient regulation of cell activity and thereby makes it possible for the organism to react usefully to variable external influences (Sitkovsky et al.: Ann. NY Acad. Sci. 532, 350-358 (1988); Takayama et al.: J. Pharm. Sci. 78, 8-10 (1989)). One and the same substance can have both agonistic and antagonistic effects. Thus, for example, cAMP inhibits activation induced by interleu
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Mullner Stefan
Schonharting Martin
Zabel Peter
Hoechst Aktiengesllschaft
MacMillan Keith D.
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