Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-05-12
1997-07-08
Mosley, Terressa
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
435 695, 43525233, 43525411, 514247, 514257, 514259, 540582, 540600, 544292, A01N 4354
Patent
active
056461542
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition for inhibiting the formation or secretion of a tumor necrosis factor. More particularly, the present invention relates to a pharmaceutical composition inhibiting the formation or secretion of a tumor necrosis factor, which comprises a quinazoline compound or salts thereof as an effective ingredient and which is effective for the treatment of diseases including cachexia, sepsis and multiple organ failure wherein a tumor necrosis factor is considered to be involved in causing those diseases.
BACKGROUND ART
A tumor necrosis factor (hereinafter abbreviated as TNF) is a peptide of 157 amino acids, having a molecular weight of about 17,000. TNF is one of cytokines produced by various cells including macrophages.
Although TNF had been at first found as a cytokine showing a cytotoxic effect on tumor, subsequent studies have revealed that the activities of TNF are various, and not only limited to tumor cells but also extended to many other normal cells. Examples of such TNF activities include suppression of the lipoprotein lipase activity in adipocytes, expression of HLA antigen on blood endothelial cells and fibroblasts, interleukin-1 formation by fibroblasts or macrophages, activation of cytotoxic macrophages, suppression of CFU, formation of colony stimulating factor by fibroblasts, endothelial cells or some tumor cells, inhibition of the synthesis of proteoglycans and stimulation of their resorption in cartilage, activation of neutrophils and generation of superoxide, formation of procoagulant factor by blood endothelial cells, proliferation of fibroblasts, change in membrane potential of skeletal muscle, interferon .beta..sub.2 production by fibroblasts, and injury of blood endothelial cells. In these days, TNF has thus been recognized to be a cytokine which are involved broadly in vital protection through inflammation and immune response (Ann. Rev. Immunol., 10, 411 (1992)).
On the other hand, it has been found that continuous or excessive formation of TNF rather results in vigorous actions on normal cells to cause various diseases. It is also reported that TNF is known as cachectin which induces cachexia in cancer or infectious diseases which causes catabolic acceleration of total metabolism to lead to extreme wasting (B. Beutler, D. Greenwald, J. D. Hulmes et al., Nature, 316, 552-554 (1985), Kawakami, M., SEIKAGAKU (Biochemistry), 59, 1244-1247 (1987)).
An anti-TNF antibody is considered to be effective also for a septic shock (Starnes, H. F. Jr., Pearce, M. K., Tewari, A., Yim, J. H., Zou, J-C., Abrams, J. S., J. Immunol., 145, 4185-4191 (1990), Beutler, B., Milsark, I. W., Cerami, A. C., Science, 229, 869-871 (1985), Hinshaw, L. B., Tekamp-Olson, P., Chang, A. C. K. et al., Circ. Shock, 30, 279-292 (1990)).
An increased level of TNF is also observed in the synovial fluid or blood from patients with rheumatoid arthritis (Tetta, C., Camussi, G., Modena, V., Vittorio, C. D., Baglioni, C., Ann. Rheum. Dis., 49, 665-667 (1990)).
In addition, it is reported that there are many other diseases wherein a TNF level increase in blood, e.g., Kawasaki disease (Matsubara, T., Furukawa, S., Yabuta, K., Clin. Immunol. Immunopathol., 56, 29-36 (1990)); ulcerative colitis (Murch, S., Walker-Smith, J. A., Arch. Dis. Child, 66, 561 (1991)); Beh.cedilla.et disease (Akoglu, T., Direskeneli, H., Yazici, H., Lawrence, R., J. Rheumatol., 17, 1107-1108 (1990)); systemic lupus erythematosus (SLE) (Maury, C. P. J., Teppo, A-M., Arthritis Rheum., 32, 146-150 (1989)); graft versus host disease (GvHD) (J. Exp. Med., 175, 405-413 (1992)); multiple organ failure (Kawakami, M., Hayata, K., Medical Immunology, 20, 615-620 (1990)); malaria (Grau, G. E., Fajardo, L. F., Piguet, P. F., et al., Science, 237, 1210-1212 (1987)); acquired immune deficiency syndrome (AIDS) (Kawakami, M., Hayata K., Medical Immunology, 20, 615-620 (1990)); meningitis (Waage, A., Halstensen, A., Espevik, T., Lancet, I, 355-357 (1987)); fuluminant hepatitis (Sugano, K., KANZO (Liver),
REFERENCES:
patent: 3305553 (1967-02-01), Hoefle et al.
Fujiwara Norio
Irie Kenji
Ueda Yutaka
Mosley Terressa
Sumitomo Pharmaceuticals Co. Ltd.
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