Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-06
2004-10-12
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...
C514S365000, C514S609000
Reexamination Certificate
active
06803375
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to chemical compositions, preparations and methods for medical treatment and more particularly to the use of certain substituted triarylmethane compounds for immunosuppressive treatment of autoimmune disorders or inflammatory diseases, or the treatment or prevention of transplant rejection or graft-versus-host disease in mammalian patients.
BACKGROUND OF THE INVENTION
Organ transplantation has become routine in many parts of the world. Transplants of liver, kidney, heart, lung and pancreas, are now regularly performed as treatment for end-stage organ disease. The outcomes of organ transplant procedures have progressively improved with the development of refinements in tissue typing, surgical techniques, and more effective immunosuppressive treatments. However, rejection of transplanted organs remains a major problem. T-lymphocytes play a central role in the immune response and they are responsible, in large measure, for the rejection of many transplanted organs. They are also responsible for the so-called graft-versus host disease in which transplanted bone marrow cells recognize and destroy MHC-mismatched host tissues. Accordingly, drugs such as cyclosporin and FK506 that suppress T-cell immunity are used to prevent transplant rejection and graft-versus-host disease. Unfortunately, these T-cell inhibiting drugs are toxic, with liver and renal toxicities limiting their use.
Autoimmune diseases encompass a whole spectrum of clinical disorders wherein a patient's immune system mistakenly attacks self, targeting the cells, tissues, and organs of the patient's own body. The following are some examples of autoimmune diseases, categorized with respect to the target organ that is principally affected by each such disease:
Nervous System:
Multiple sclerosis
Myasthenia gravis
Autoimmune neuropathies
such as Guillain-Barré
Autoimmune uveitis
Blood:
Autoimmune hemolytic anemia
Pernicious anemia
Autoimmune thrombocytopenia
Vascular:
Temporal arteritis
Anti-phospholipid syndrome
Vasculitides such as
Wegener's granulomatosis
Behcet's disease
Skin:
Psoriasis
Dermatitis herpetiformis
Pemphigus vulgaris
Vitiligo
Gastrointestinal Tract:
Crohn's Disease
Ulcerative colitis
Primary biliary cirrhosis
Autoimmune hepatitis
Endocrine:
Type 1 diabetes mellitus
Addison's Disease
Grave's Disease
Hashimoto's thyroiditis
Autoimmune oophoritis and
orchitis
Multiple Organs and/or
Musculoskeletal System:
Rheumatoid arthritis
Systemic lupus erythematosus
Scleroderma
Polymyositis, dermatomyositis
Spondyloarthropathies such as
ankylosing spondylitis
Sjogren's syndrome
Irrespective of the particular organ(s) affected, T-lymphocytes are believed to contribute to the development of autoimmune diseases. The currently available therapies for these diseases are largely unsatisfactory and typically involve the use of glucocorticoids (e.g. methylprednisolone, prednisone), non-steroidal anti-inflammatory agents, gold salts, methotrexate, antimalarials, and other immunosuppressants such as cyclosporin and FK-506.
Thus, the search for additional immunosuppressive agents for preventing transplant rejection and for the treatment of autoimmune and inflammatory disorders occupies considerable attention in the pharmaceutical industry. Since cytokines such as interferon-gamma and tumor necrosis factor-alpha play a critical role in transplant rejection and in the pathophysiology of autoimmune disorders, much effort has been invested in the development of agents that suppress their production, secretion and/or end-organ effect.
There is an excellent track record of treating nervous and cardiovascular disorders with ion channel modulators—either openers or blockers. Ion channel blockers as a general class, represent the major therapeutic agents for treatment of stroke, epilepsy and arrhythmias. Since ion channels play a major role in the T-cell immune response, these channels may represent attractive targets for pharmaceutical immunomodulation.
The early stages of T-cell activation may be conceptually separated into pre-Ca
++
and post-Ca
++
events (Cahalan and Chandy 1997
, Curr. Opin. Biotechnol
. 8: 749). Following engagement of antigen with the T-cell antigen-receptor, activation of tyrosine kinases and the generation of inositol 1,4,5-triphosphate leads to the influx of Ca
++
through store-operated calcium channels (also known as Calcium-Release Activated Calcium or CRAC channels) and the rise of cytoplasmic Ca
2+
concentration (Cahalan and Chandy 1997
, Curr. Opin. Biotechnol
. 8: 749; Kerschbaum and Cahalan 1999
, Science
283: 836; Kerschbaum and Cahalan 1998
; J. Gen. Physiol
. 111: 521). The rise in Ca
++
activates the phosphatase calcineurin, which then dephosphorylates a cytoplasmically localized transcription factor (N-FAT) enabling it to accumulate in the nucleus and bind to a promoter element of the interleukin-2 gene. Along with parallel events involving the activation of protein kinase C and ras, gene transcription leads to lymphokine secretion and to lymphocyte proliferation. Some genes require long-lasting Ca
++
signals while others require only a transient rise of Ca
++
. Furthermore, Ca
++
immobilization of the T-cell at the site of antigen presentation helps to cement the interaction between T-cell and the antigen-presenting cell and thereby facilitate local signaling between the cells (Negulescu 1996
, Immunity
4:421).
Ion channels underlie the Ca
++
signal of T-lymphocytes. Ca
++
ions move across the plasma membrane through a channel termed the store-operated Ca
++
channel or the CRAC channel which is activated by depletion of internal calcium stores like the endoplasmic reticulum (Cahalan and Chandy 1997
, Curr. Opin. Biotechnol
. 8: 749). Two distinct types of potassium channels indirectly determine the driving force of calcium entry through the store-operated Ca
2+
channel (Cahalan and Chandy 1997, Curr. Opin. Biotechnol. 8: 749). The first is the voltage-gated Kv1.3 channel (Cahalan 1985
, J. Physiol
. 385: 197; Grissmer 1990
, Proc. Natl. Acad. Sci USA
87: 9411; Verheugen 1995
, J. Gen. Physiol
. 105: 765; Aiyar 1996
, J. Biol. Chem
. 271: 31013; Cahalan and Chandy 1997, Curr. Opin. Biotechnol. 8: 749) and the second is the intermediate-conductance calcium-activated potassium channel, IKCa1 (Grissmer 1993
, J. Gen. Physiol
. 102: 601; Fanger 1999
J. Biol. Chem
. 274: 5746; Rauer 1999
, J. Biol. Chem
. 274: 21885) which is also known as IK1 (VanDorpe 1998, J. Biol. Chem. 273: 21542), hSK4 (Joiner 1997
, Proc. Natl. Acad. Sci. USA
94: 11013; Khanna 1999, J. Biol. Chem. 274: 14838) and hKCa4 (Lodgson 1997
, J. Biol. Chem
. 272: 32723; Ghanshani 1998
, Genomics
51: 160). When these potassium channels open, the resulting efflux of K
+
hyperpolarizes the membrane, which in turn accentuates the entry of Ca
++
, which is absolutely required for downstream activation events (Cahalan and Chandy 1997
, Curr. Opin Biotechnol
. 8: 749). Blockers of the Kv1.3 and IKCa1 channels suppress human T-cell activation, when applied independently, and produce greater suppression when applied together (DeCoursey 1984, Nature 307: 465; Chandy
J. Exp. Med
. 160: 369; (Koo 1997
, J. Immunol
. 158: 5120; Nguyen 1995
, Mol. Pharmacol
. 50: 1672; Hanson 1999
, Br. J. Pharmacol
. 126: 1707; Kalman 1998
, J. Biol. Chem
. 278: 32697; Khanna 1999
, J. Biol. Chem
. 274:14838; Jensen 1999
; Proc. Natl. Acad. Sci. USA
96: 10917). One mechanism for the immunosuppression by K
+
channel blockers is via membrane depolarization, which reduces Ca
++
entry through CRAC channels in the T-cell membrane, which in turn leads to suppression of calcium-dependent signaling events during human T-cell activation (Cahalan and Chandy 1997
, Curr. Opin. Biotechnol
. 8: 749; Koo 1999
, Cell. Immunol
. 197: 99).
Clotrimazole, a non-selective inhibitor of IKCa1, suppresses mitogen-stimulated T-cell activ
Chandy K. George
Wulff Heike
Buyan Robert D.
Stout, Uxa Buyan & Mullins, LLP
The Regents of the University of California
Travers Russell
LandOfFree
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