Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-05-17
2004-03-09
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S544000, C514S570000, C514S621000, C514S622000, C514S679000, C514S733000, C514S736000, C560S051000, C560S057000, C562S459000, C562S468000, C564S169000, C564S171000, C568S325000, C568S744000
Reexamination Certificate
active
06703421
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel drugs for prevention and treatment of myocarditis, dilated cardiomyopathy and heart failure.
BACKGROUND ART
Myocarditis is sometimes the result of infection by a virus or bacterium or a stimulus response to drugs or the like, and sometimes an autoimmunity, and it includes a group of diseases provoked by cardiomyopathy due to inflammation of cardiac muscle. A kind of myocarditis is chronic due to repeated aggravation and amelioration of the inflammation or continuous inflammation, eventually progressing to dilated cardiomyopathy.
The typical pathology of dilated cardiomyopathy includes dilation of the ventricle and contraction deficiency, and heart failure symptoms appear in 75-95% of patients, often with complications of arrhythmic death (sudden death) or thrombosis and embolism during the course of the disease. It is an intractable disease with a mortality rate of approximately fifty percent within 5 years of onset, and it accounts for half of the heart transplant patients in Europe and the U.S. It is therefore important to promptly achieve amelioration of acute myocarditis from the acute stage to prevent it from becoming chronic or intractable (Junkanki NOW, Vol.6, “Cardiomyopathy and Myocarditis”, Nankodo Publishing).
No successful therapy has yet been established for this disease, and no effective therapeutic agent has been provided. It is ardently desired, therefore, to develop a drug that can suppress the necrosis of cardiac muscle cells and infiltration of inflammatory cells in myocarditis, in order to inhibit increase in heart weight and lead to improved survival rates.
Although the cause of myocarditis has not been thoroughly elucidated, reports of viral genes in cardiac muscle biopsy tissue from acute stage myocarditis and dilated cardiomyopathy patients suggest a viral infection link in almost all cases (Junkanki NOW, Vol.6, “Cardiomyopathy and Myocarditis”, Nankodo Publishing).
Nitric oxide (NO) is biosynthesized from L-arginine as the substrate by NO synthase (NOs). Currently three isozymes of NOS have been found (Moncada, S. and Higgs, A. (1993) N. Eng. J. Med. 329: 2002-2012). Expression of inducible NOS (iNOs) is induced in various types of tissues and cells by endotoxins and cytokines (Forstermann U, et al. (1995) Biochem. Pharmacol. 50, 1321-1332).
Marked increase in NO production has been reported in myocarditis, dilated cardiomyopathy and heart failure patients (De Belder A J, et al. (1993) Lancet 341, 84-85; Habib F M, et al. (1996) Lancet 347, 1151-1155; Haywood G A, et al. (1994) Circulation 93, 1087-1094). Also, arginine derivatives and aminoguanidine, which are known as iNOS enzyme inhibitors, have been reported to exhibit a pharmacological effect in diseased animal models (Moncada S and Higgs E A (1995) PASEB J. 9, 1319-1330).
Thus, excess NO produced as a result of induced iNOS expression is implicated as a cause of myocarditis, dilated cardiomyopathy and heart failure.
In addition, tumor mecrosis factor (TNF)-&agr;, a cytokine produced from several kinds of cells including rmacrophages, is believed to be an important mediator of inflammation (Vassalli, P. (1992) Annu. Rev. Immunol. 10: 411-452). There is growing evidence that the excessive production of TNF-&agr; damages normal cells and causes various pathosis (Muto, Y., et. al. (1988) Lancet 2: 72-74, Sharief, M. K. and Hentges, R. (1991) N. Engl. J. Med. 325: 467-472). Increase of TNF-&agr; levels in the blood, like NO, has also been found in myocarditis, dilated cardiomyopathy and heart failure patients (Matsumori A, et al. (1994) Br. Heart J. 72, 561-566, Levine B, et al. (1990) N. Engl. J. Med. 323, 236-241). Antibodies for TNF-&agr; have been demonstrated to be effective in animal models of myocarditis (Yamada T, et al. (1994) Circulation 89, 846-851).
Such findings have shown that excess production of TNF-&agr; leads to and exacerbates myocarditis, dilated cardiomyopathy and heart failure, and it is therefore necessary to inhibit production of TNF-&agr; as well as NO.
Interleukin (IL)-1&bgr; also increases markedly in the blood of acute myocarditis patients, and a good correlation has been found between IL-1&bgr; expression in chronic stage cardiac muscle and the heart/body weight ratio and extent of cardiac tissue fibrosis, in animal models of myocarditis (Shioi T, et al. (1996) Circulation 94, 2930-2937), while it has also been reported that administration of IL-1&bgr; to animals provokes cardiomyopathy or myocarditis (Lane J R, et al. (1992) J. Exp. Med. 175, 1123-1129; Japanese Unexamined Patent Publication No. 10-273445), thus also implicating IL-1&bgr; as one of these pathogenesis.
No therapeutic agents for cardiomyopathy or myocarditis have been reported that improve survival rates, but antibody that inhibits binding of the selectin an adhesion molecule, is being studied (Japanese Unexamined Patent Publication No. 10-273445).
Thus, iNOS, inflammatory cytokines such as TNF-&agr;, IL-1&bgr;, etc. and adhesion molecules have all been implicated in myocarditis, dilated cardiomyopathy and heart failure (Habib F M, et al. (1996) Lancet 347, 1151-1155). However, numerous other causatory inflammatory mediators have been found (Matsumori A (1997) Jpn. Circ. J. 61, 275-291), and the fact that these pathological factors cannot be specified to a single mediator has complicated efforts to develop effective treatment agents. Given this current situation, there are doubts against the effectiveness of treatment or prevention using, for example, antibodies that recognize one antigen or substances that inhibit binding of adhesion molecules such as selecting. Therefore, there is a desire for low molecular compounds that, instead of suppressing only expression of specific inflammatory mediators, can broadly inhibit production and expression of proteins implicated as causes of inflammation.
NF-&kgr;B is a protein that regulates gene expression and is one of the so-called transcription factors. When normal cells are stimulated with an inflammatory cytokine such as IL-1&bgr; and TNF-&agr;, a lipopolysaccharide, or ultraviolet rays, NF-&kgr;B translocates from the cytoplasm into the nucleus where they bind to specific nucleotide sequences on the genomic DNA and thereby become involved in the expression of various genes (Blackwell, T. S. and Christman, J. W. (1997) Am. J. Respir. Cell Mol. Biol. 17: 3-9).
Although the genes coding for iNOS, inflammatory cytokines such TNF-&agr; and IL-1&bgr; and adhesion molecules such as P selectin are completely distinct genes, in the expression regulatory regions of these genomic genes, there are consensus regions to which NF-&kgr;B binds, and activation of NF-&kgr;B has been shown to be important for expression of all of these proteins (Ghosh S, et al. (1998) Annu. Rev. Immunol. 16, 225-260).
Many genes that are involved in immunological inflammatory reactions under expression control by NF-&kgr;B are recognized, including inflammatory cytokines such as IL-6 and IL-8, as well as cell adhesion molecules such as ICAM-1, VCAM-1 and ELAM-1 or the like (Collins, T., et al. (1995) Faseb. J. 9: 899-909). Furthermore, it is known that inflammatory cytokines, when bound to receptors, transduce NF-&kgr;B-activating signals via various routes, and this fact is believed to be cause that further aggravates inflammation. Thus, the activation of NF-&kgr;B in inflammation is understood as an pathogenesis and aggravating factor of diseases (Baeuerle, P. A. and Baichwal., V. R. (1997) Adv. Immunol. 65: 111-137).
NF-&kgr;B inhibitors are characterized by inhibiting expression of iNOS, TNF-&agr; and IL-1&bgr; at the genetic level in cells and tissues, thereby suppressing production of two or more among the inflammation mediators such as NO, TNF-&agr; and IL-1&bgr; at once with a single agent, and they are expected to exhibit therapeutic effects against various diseases (Lee J C (1994) Ann. Report Med. Chem. 29, 235-244).
For example, the compound BAY11-7083, which has an inhibitory effect on NF-&kgr;B, is reported to exhibit an effect i
Matsumori Akira
Nunokawa Yoichi
Berch Mark L.
Burns Doane Swecker & Mathis L.L.P.
Daiichi Suntory Pharma Co., Ltd.
McKenzie Tom
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