Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-01-13
2002-07-16
Berch, Mark (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S266400, C544S264000, C544S277000, C546S118000
Reexamination Certificate
active
06420373
ABSTRACT:
BACKGROUND OF THE INVENTION
Autoimmune and inflammatory diseases affect more than fifty million Americans. As a result of basic research in molecular and cellular immunology over the last ten to fifteen years, approaches to diagnosing, treating and preventing these immunological based diseases has been changed forever. By dissecting the individual components of the immune system, those cells, receptors and mediators which are critical to the initiation and progression of immune responses have been, and continue to be, elucidated. Crystallographic analysis of proteins encoded in the major histocompatability complex, identification of an antigen-specific T cell receptor, and development of a basic understanding of the complex cytokine network have all contributed to a revolution in immunology. Equipped with this new and fundamental information about basic immune mechanisms, selective and rational approaches to the treatment of inflammatory and autoimmune disease can now be developed.
Until the last decade, treatment of immunological based disorders were treated exclusively with nonspecific immunosuppressive agents. These included a variety of drugs, such as corticosteroids, antimalarials, methotrexate, azathioprine, and treatments such as total lymphoid irradiation. Although some of these approaches may affect one component of the immune response more than another, they remain nonspecific in their actions and treatment frequently is complicated by serious side effects. It would be very useful to discover and develop new drugs which are immune cell selective or mediator specific and which interfere with processes critical to the initiation, progression, and maintenance of the acute and chronic inflammatory processes associated with certain immunological based diseases.
The two most important cells of the immune response in the autoimmune and inflammatory processes are the T lymphocyte and the monocyte/macrophage.
The T cell is critical to all antigen driven cellular immune responses. There are at least two major subpopulations of T cells: T helper (CD4
+
) and T cytotoxic (CD8
+
). T cells recognize antigen via a unique membrane receptor: the T cell antigen receptor (TCR). The TCR can recognize antigen only in association with cell surface proteins known as major histocompatibility complex (MHC) molecules. In response to antigen presented by MHC class II molecules, T helper cells secrete a variety of soluble factors, collectively known as lymphokines. Lymphokines play an essential role in the activation, differentiation, and expansion of all the cells of the immune response. In contrast to the T helper cell, the T cytotoxic cell responds to antigen in the context of MHC class I molecules. Cytotoxic T lymphocytes, once activated, can eliminate cells displaying a specific antigen derived from a virus, tumor cell, or foreign tissue graft.
Mononuclear phagocytic macrophages are widely distributed throughout the body and display great structural and functional heterogeneity. Macrophages are derived from circulating monocytes which migrate into extravascular tissues. The migration of peripheral blood monocytes involves adherence to the endothelium, migration between endothelial cells, and subsequently movement through subendothelial structures. Adherence of monocytes to endothelium involves high molecular weight glycoproteins, such as lymphocyte function-associates antigen 1 (LFA-1; CDlla/CD18), which interacts with intercellular adhesion molecule-1 (ICAM-1; CD54) present on vascular endothelial cells. Monocytes and macrophages produce a variety of pro-inflammatory mediators (cytokines), such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF). These cytokines have numerous effects on many cells within and outside the immune system, such as promoting activation, differentiation, expansion, or apoptosis. In addition, cytokines such as IL-1 increase the expression of adhesion molecules like ICAM-1 and greatly facilitate monocyte migration to the inflammatory site. Furthermore, the monocyte/macrophage is one of the major types of antigen presenting cells required for T helper cell activation.
During the last decade, an understanding of immunopathological reactions has greatly evolved as a result of the characterization of cytokines and interleukins which regulate interactions between cells of the immune system and other nonimmune tissues and cells such as endothelial cells, fibroblasts and adipocytes. A major cytokine increasingly recognized as a central mediator in a wide spectrum of physiologic and immune functions is macrophage-derived Tumor Necrosis Factor-&agr;, also known as TNF-&agr;, or Cachectin. TNF-&agr; has been found to mediate effects as diverse as tumoricidal activity, wasting and weight loss associated with chronic disease, promotion of cartilage erosion and the destruction of joints in rheumatoid arthritis, and the recruitment of cells to participate more effectively in the host's response to an invasive agent. In addition, an increasingly large body of evidence indicates that TNF-A serves as the proximal mediator in the evolution of septic shock.
The biological function of TNF-&agr; extends well beyond its initial discovery as a mediator of tumor necrosis. It is increasingly realized that the interacting milieu of host cytokines existing locally and systemically is an extremely important network that dictates the pathogenesis of many immune and inflammatory diseases. TNF-&agr; appears to play a critically important role in this regard because of its ability to activate a wide range of cell types in order to promote production of several key cytokines (e.g. IL-1&bgr;, IL-1&agr; and IL-6), bioactive eicosanoids, and platelet activating factor (PAF).
Enhanced synthesis and release of cytokines has been observed during many acute and chronic inflammatory processes, and it is increasingly realized that in many cases, overproduction of TNF-&agr; is a major contributor to inflammation, cellular injury, and cell death associated with various immunological based diseases.
There is now evidence to indicate that TNF-&agr; is a primary mediator of septic shock. TNF-&agr;, along with other cytokines, triggers inflammatory and metabolic responses attributed to sepsis and septic shock including adult respiratory distress syndrome (ARDS), fever, and disseminated intravascular coagulation. ARDS is characterized by increased pulmonary capillary permeability resulting in noncardiogenic pulmonary edema, decreased lung compliance and decreased lung volume. Although ARDS is frequently associated with sepsis, it also occurs as a result of smoke inhalation, pancreatitis and long-bone fractures.
Patients infected with the human immunodeficiency virus (HIV) enter a long period of clinical latency prior to developing clinically apparent disease. HIV infects T cells as well as monocytes and macrophages, and activation of latent or marginally active HIV infected cells may be promoted in part by cytokines, including TNF-&agr;. TNF-&agr; has also been implicated in the pathogenesis of fever, cachexia (wasting syndrome), and
Myobacterium tuberculosis
infections in patients with acquired immunodeficiency syndrome (AIDS).
Cytokines, including TNF-&agr;, are known to play an important role in the pathogenic processes of inflammatory bowel disease. Ulcerative colitis and Crohn's disease are two common forms of inflammatory bowel disease.
Complex patterns of interacting cytokines, including TNF-&agr;, and products of arachidonic acid metabolism produced locally in the central nervous system have been implicated in contributing to adverse sequelae of bacterial meningitis.
Rheumatoid arthritis is a heterogenous, systemic disease of unknown etiology, and persons with rheumatoid arthritis typically develop inflammation of joint synovium (synovitis). Clinical symptoms become apparent with progression of synovitis due to production and release of cytokines from activated macrophages along with activation of T lymphocytes, angiogenesis, and attraction of neutrophils
Borcherding David R.
Edwards III Carl K.
Munson H. Randall
Berch Mark
Darkas Paul R.
Merrell Pharmaceuticals Inc.
Payne T. Helen
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