Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-09-27
2003-06-17
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S063000, C558S156000, C558S161000, C562S013000
Reexamination Certificate
active
06579860
ABSTRACT:
This application is a 371 of PCT/JP99/03346 filed Jun. 23, 1999, now WO00/38693 Jun. 7, 2000.
TECHNICAL FIELD
The present invention relates to an interleukin-6 production inhibitor or thrombocytosis inhibitor, which contains one of methanebisphosphonic acid derivatives, and esters, salts, and hydrates thereof, as active components.
BACKGROUND ART
Cytokine is a generic name for a group of humoral factors performing main intercellular information communication, particularly in the immune response, hematopoietic reactions, and inflammation reactions. Many cytokines have been identified and functions thereof have been analyzed. As a result, it has been clarified that the action of a cytokine affects various biological functions, such as development, differentiation, and maintaining homeostasis, and that abnormally high cytokine production is deeply related to many diseases.
In particular, regarding interleukin-6, cDNA thereof was isolated in 1986 as a B-cell differentiation factor which induces final differentiation of B cells into antibody producing cells [Hirano T. et al., Nature, 324, 73-76(1986)]. Interleukin-6 is secreted from immunocytes, such as T cells, B cells, and macrophages, and various other cells, such as, fibroblasts, vascular endothelial cells, keratinocytes, and renal mesangial cells, and it is known that this exerts effects on the immune system, such as B-cell differentiation, and T cell activation and differentiation [Hirano T. et al., Immunol. Today, 11, pp. 443-449 (1990)]. In addition, interleukin-6 is deeply related to hematopoietic systems, for example, proliferating hematopoietic cells in cooperation with interleukin-3 [Ikebuchi K. et al., Proc. Natl. Acad. Sci., 84, pp. 9035-9039 (1987)]; promoting maturation of megakaryocyte and inducing an increase in platelet, as a platelet hematopoietic factor [Ikebuch K. et al., Proc. Natl. Acad. Sci., 86, pp. 5953-5957 (1989)]; and promoting differentiation of osteoclast-like multinucleated cells [Kurihara H. et al., J. Immunol., 144, pp. 4226-4230 (1990)]. Moreover, this exhibits a significant variety of functions, for example, the induction of acute phase proteins such as a 2-macroglobulin and CRP [Woloski BMR. et al., Proc. Natl. Acad. Sci., 82, pp. 1443-1447 (1985)], and participating in proliferation and differentiation of nerve cells [Hirano T. et al., Immunol. Today, 11, pp. 443-449 (1990)].
Although interleukin-6 is multi-functional factor, as described above, it has been clarified that excess production thereof is deeply related to onset, progression, and maintenance of various diseases.
For example, increased expression of messenger RNA for interleukin-6 in bone marrow of postmenopausal osteoporosis patients is reported [Raston S. H., J. Bone Miner. Res., 9, pp. 883-890 (1994)].
Moreover, the association with autoimmune diseases is reported; for example, large amounts of interleukin-6 are detected in synovial fluid and culture supernatant of synovial tissue from rheumatoid arthritis patients [Hirano T. et al., Eur. J. Immunol., 18, pp. 1797-1801 (1988)], and in systemic lupus erythematosus, production of interleukin-6 from B cells is promoted, and thus the B cells are activated by the autocrine system [Umland SP. et al., J. Immunol., 142, pp. 1528-1535 (1989)].
In addition, in multiple myeloma, interleukin-6 functions as a growth factor in myeloma proliferation [Kawano M. et al., Nature, 322, pp. 83-85 (1988); Klein B. et al., Blood, 73, pp. 517-526 (1989); Zhang X G., J. Exp. Med., 179, pp. 1337-1342 (1994); and Nishimoto N. et al., J. Exp. Med., 179, pp. 1343-1347 (1994)]. In multiple myeloma patients, interleukin-6 is considered to be produced in excess in osteoblast and stromal cells [Barille S., Blood, 86, pp. 3151-3159 (1995); and Caligaris-Capio F. et al., Blood, 77, pp. 2688-2693 (1991)].
In atrial myxoma patients, a large amount of interleukin-6 is produced in tumor cells [Kanda T. et al., Inter. J. Cardiol., 45, pp. 144-146 (1994)].
In Castleman's syndrome, a large amount of interleukin-6 is produced in hypertrophic lymph nodes and the interleukin-6 concentration in the serum is correlated to lymphadenia, hypergammaglobulinemia, and acute phase protein levels in serum [Yoshizaki K. et. al., Blood, 74, pp. 1360-1367 (1989)].
Furthermore, the correlation between the interleukin-6 and the cachexia occurring in the inflammatory reaction and tumors is reported [Oldenburg H S. et al., Eur. J. Immunol., 23, pp. 1889-1894 (1993)], [Yasumoto K. et al., Cancer Res., 55, pp. 921-927 (1995)], and the strong correlation between the interleukin-6 and the hypercalcemia due to tumors and the like is also disclosed [Strassmann G. et al., Cytokine, 5, pp. 463-468 (1993)].
Urine from primary glomerulonephritis patients has high interleukin-6 activity compared to that of healthy humans, and the interleukin-6 acts as a growth factor for renal mesangial cells [Horii Y. et al., J. Immunol, 143, pp. 3949-3955 (1989)]. Also, the activity of interleukin-6 is enhanced in serum and urine in Kawasaki's disease patients [Ueno Y. et al., Clin. Exp. Immunol, 76, pp. 337-342 (1989)].
The interleukin-6 concentration in the serum of psoriatic patients is significantly increased and expression of messenger RNA and protein of interleukin-6 are enhanced at the lesion sites [Grossman R M., et al., Proc. Natl. Acad. Sci. USA, 86, pp. 6367-6371 (1989)].
Platelet, the increasing production thereof is induced by interleukin-6, is one of blood components, which play a primary role in hemostasis mechanism, and the platelets are produced from megakaryocytes which are precursor cells in myeloid tissue. Megakaryocytes are classified into megakaryoblasts, promegakaryocytes, megakaryocytes, and platelet-producing megakaryocytes in the maturation process thereof. In the production process of the platelets, various humoral factors, that is, platelet producing factors, are related, and subtle balance therebetween maintains a constant number of platelets in blood. Examples of known platelet producing factors are interleukin-3, interleukin-7, interleukin-11, leukemia inhibitory factor (LIF), erythropoietin, and thrombopoietin.
In healthy humans, the number of platelets in peripheral blood is maintained constant by the action of the above humoral factors. When an imbalance of humoral factors occurs or an abnormallity in hematopoietic stem cells occurs for any reason, the number of the platelets in the peripheral blood increases abnormally, resulting in a state called thrombocytosis. The thrombocytosis includes primary thrombocythemia, secondary thrombocytosis, reactive thrombocytosis, and the like. The thrombocytosis involves persistently increasing platelets; thrombosis, such as peripheral ischemia and transient cerebral ischemia; and hemorrhagic diseases, such as peliosis, subcutaneous bleeding, nasal bleeding, bloody stool, gingival bleeding, and intracranial bleeding, and sometimes induces serious symptoms, such as large artery infarctions, e.g., myocardial infarction and brain infarction.
The origin of the primary thrombocythemia is clonal abnormalities in precursor cells of platelets in the myeloid tissue. Medulla depression therapies using alkylating agents such as busulphan are frequently performed for primary thrombocythemia, and the onset of carcinoma due to long-term administration of the alkylating agents is reported. Also, platelet activity reduction therapies using Aspirin or the like has been performed, and side effects, such as aggravation of hemorrhagic diseases, are also reported. Thus, no satisfactory method of treatment is established.
The reactive thrombocytosis is secondary thrombocytosis accompanying underlying diseases, such as tumors, iron deficiency, bleeding, acute inflammatory diseases, chronic inflammatory diseases, such as rheumatoid arthritis, ulcerative colitis, and osteomyelitis, and osteoporosis. Although the d
Funaba Yuriko
Ito Masatoshi
Koike Junzo
Okazaki Seiji
Tanahashi Masahiko
Aulakh Charanjit S.
Schnader Harrison Segal & Lewis LLP
Toray Industries Inc.
LandOfFree
Interleukin-6 production inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Interleukin-6 production inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Interleukin-6 production inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3101524