Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-02-11
2001-09-18
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S320000
Reexamination Certificate
active
06291483
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
It is essential for a host that its immune system be responsive to foreign entities especially disease causing pathogens. However, under certain conditions or in specific situations, the immune response may need to be selectively regulated or suppressed. These situations are generally encountered before, during or after organ or bone marrow transplants or to control or treat autoimmune disorders. There are also situations where an uncontrolled immune response triggered by a pathogen or a product could be deleterious for the host, as for example, in the case of septic shock syndrome. The prophylaxis and/or treatment of all such clinical manifestations requires the use of immunosuppressive drugs which can selectively inhibit T cell and/or macrophage responses to specific challenges.
2. Description of the Related Art
In recent years the number of organ transplants including allogenic bone marrow transplants have increased considerably due to their use as a therapeutic option for, inter alia, hematologic, immunologic and malignant disorders. Transplant of bone marrow has led to an immunological complication known as Graft-vs-Host disease (GVHD), where immunologically competent cells of the graft cause damage to the recipient host. This effect is primarily mediated by T lymphocytes (Grebe and Streilein, 1976). Basically, the Major Histocompatibility Complex (MHC) antigens present on all tissue provide the immunological identity to an individual which helps the immune system distinguish between self and non-self so that the immune system can destroy foreign invaders while preserving normal healthy tissue. When MHC bearing tissue is transferred from one individual to another via for example, an organ transplant, it is recognized by the T cell of the recipient as foreign which leads to rejection of tissue in a Host-vs.-Graft (HVG) reaction. However, when MHC bearing immunocompetent cells are transferred from a normal individual to an immunocompromised host (e.g. bone marrow transplant), the grafted immunocompetent cells (mainly T lymphocytes) recognize the differences in host MHC complex and initiate a Graft-vs.-Host reaction leading to GVHD. GVHD is an immunopathophysiologic process with two consecutive phases: the afferent phase, where the recipient tissue first activates the T lymphocytes from the donor and in the second phase (i.e. the effector phase), activated donor cells then secrete inflammatory cytokines, including IL-2 (interleukin 2), IFN-g (interferon g) and TNF-a (tumor necrosing factor a) and recruit additional cells and focus attack on recipient targets. The main targets include the skin, gastrointestinal tract, liver and lymphoid organs (Ferrara and Deeg, 1991). Acute GVHD occurs in approximately 50% of patients who receive bone marrow transplants and is a primary or contributory cause of death in 15-45% of the 50% of the patients who develop GVHD after bone marrow transplant. The post-transplant period is also associated with immune dysfunction due to use of prior ablative radio/chemo therapy to suppress the recipient's lymphoid system (especially mature T lymphocytes) and to allow engraftment of a donor organ (e.g. bone marrow). This in turn often results in severe infections, which are also a major cause of morbidity and mortality in transplant patients. Therapeutic strategy in such situations requires a selective suppression of alloreactivity of T cells and protection against opportunistic infections.
MACROPHAGE RESPONSE TO ENDOTOXINS
While macrophages play an important role in elimination of microbial infections, their response to microbial products (endotoxins) could lead to a pathological situation known as septic shock syndrome (Lynn and Golenbock 1992). Ironically, the same mediators and effector molecules which are involved in microbiocidal activity of macrophages, if produced in excess, lead to septic shock. Endotoxins, lipopolysaccharides (LPS) released by disintegrating bacteria activate macrophages to produce tumor necrosis factor (TNF-a), which in turn initiates a cascade of inflammatory reactions including activation of the complement system, enhanced expression of adhesion molecules on the endothelial lining of the blood vessels, activation of neutrophils and production of reactive oxygen intermediates (ROI) (Galanos and Freudenberg, 1993). Activation of complement results in the release of factors which act as chemotactic and activation signals for neutrophils. Expression of adhesion molecules causes adherence of neutrophils to the endothelial lining of blood capillaries. These changes lead to extravasion of activated neutrophils and tissue damage due to release of ROIs. Widespread tissue damage ultimately results in multiorgan dysfunction and septic shock. Therapeutic strategy under such circumstances requires reduction of production of TNF-a by macrophages in response to microbial endotoxin or suppression of TNF-a induced effects on the target cells.
Strategies for immunosuppressive therapy are generally aimed at interfering with different stages of T cell activation. Extensive work has been carried out to identify new immunosuppressive drugs which can selectively block T cell activation. However. currently available immunosuppressive therapies are inadequate because they exhibit limited efficacy, modest selectivity, considerable toxicity and are generally very costly.
A) GRAFT-VS-HOST DISEASE (or rejection of organ transplant):
Methotrexate has been widely used for prophylaxis of GVHD in humans (Thomas et al. 1975), although its efficacy is still controversial. The most commonly used drug of choice has been cyclosporin (Tutschka et al. 1979; Powels et al. 1980). However, a review by the International Bone Marrow Transplant Registry failed to indicate a benefit of cyclosporin over methotrexate (Bortin, 1985). Alternative approaches to prevent GVHD include treatment of donor bone marrow in vitro with antithymocyte globulin, monoclonal antibodies or lectins to deplete T lymphocyctes.
Treatment of established acute GVHD has been unsatisfactory. A variety of agents including corticosteroids, antithymocyte globulin, cyclosporin, and azathioprine have been used without convincing evidence of improvement in survival (Doney et al. 1981; Kendra et al., 1981; Kersey et al., 1983; Sullivan 1983; Kennedy et al. 1985). The problem is that the approaches used to treat GVHD further exacerbate the severe immune suppression making the host vulnerable to opportunistic infections leading to a decrease in survival.
Other immunosuppressive agents that are currently undergoing clinical trials include, FK-506, rapamycin, RS-61443, mizoribine, deoxyspergualin and brequinar sodium, etc. FK-506, like cyclosporin, is derived from fungal sources. The immunosuppressive effects of both cyclosporin and FK-506 block early events of T cell activation via similar mechanisms. They act by forming a heterodimeric complex with their respective cytoplasmic receptor proteins (i.e. cyclophilin and FK-binding protein) which inhibit phosphatase activity of calcinurin thereby inhibiting expression of nuclear regulatory proteins and T-cell activation genes (Schreiber, 1992). Corticosteroids are known to be immunosuppressive and are used for a variety of inflammatory diseases. These steroids inhibit T cell proliferation, T cell dependent immunity and cytokine gene expression (Knudsen et al., 1987, Zanker et al., 1990, Arya et al., 1984). The anti-metabolite azothioprine is a thioguanine derivative of 6-mercaptopurine (Elion, 1967) and it acts as a purine antagonist and functions as an anti-proliferative agent. Rapamycin is also a macrolide like FK-506, but it inhibits T cell response to IL-2 rather than signal transduction for T cell activation (Morris, 1992). RS-61443, the semi-synthetic derivative of the fungal antibiotic, mycophenolic acid, has been found to inhibit allograft rejection in experimental animals (Morris and Wang, 1991). Mizoribine, a imidazole nucleoside, blocks the purine biosynthetic pathway and inhibits mitogen stim
Dhawan Suman
Upadhyay Shakti N.
Jones Dwayne C.
Ladas & Parry
National Institute of Immunology
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