Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-06
2002-06-11
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S201000
Reexamination Certificate
active
06403613
ABSTRACT:
BACKGROUND OF THE INVENTION
Tumor necrosis factor-&agr;, or TNF&agr;, is a cytokine which is released primarily by mononuclear phagocytes in response to a number immunostimulators. It is a key proinflammatory cytokine in the inflammation cascade causing the production and/or release of other cytokines and agents. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen during acute infections and shock states. Excessive or unregulated TNF&agr; production thus has been implicated in a number of disease conditions. These include endotoxemia and/or toxic shock syndrome {Tracey et al.,
Nature
330, 662-664 (1987) and Hinshaw et al.,
Circ. Shock
30, 279-292 (1990)}; cachexia {Dezube et al.,
Lancet,
335 (8690), 662 (1990)} and Adult Respiratory Distress Syndrome (ARDS) where TNF&agr; concentration in excess of 12,000 pg/mL have been detected in pulmonary aspirates from ARDS patients {Millar et al.,
Lancet
2(8665), 712-714 (1989)}. Systemic infusion of recombinant TNF&agr; also resulted in changes typically seen in ARDS {Ferrai-Baliviera et al.,
Arch. Surg.
124(12), 1400-1405 (1989)}.
TNF&agr; appears to be involved in bone resorption diseases, including arthritis. When activated, leukocytes will produce bone-resorption, an activity to which the data suggest TNF&agr; contributes. {Bertolini et al.,
Nature
319, 516-518 (1986) and Johnson et al,
Endocrinology
124(3), 1424-1427 (1989).} TNF&agr; also has been shown to stimulate bone resorption and inhibit bone formation in vitro and in vivo through stimulation of osteoclast formation and activation combined with inhibition of osteoblast function. Although TNF&agr; may be involved in many bone resorption diseases, including arthritis, the most compelling link with disease is the association between production of TNF&agr; by tumor or host tissues and malignancy associated hypercalcemia {
Calci. Tissue Int.
(
US
) 46(Suppl.), S3-10 (1990)}. In Graft versus Host Reaction, increased serum TNF&agr; levels have been associated with major complication following acute allogenic bone marrow transplants {Holler et al.,
Blood,
75(4), 1011-1016 (1990)}.
Cerebral malaria is a lethal hyperacute neurological syndrome associated with high blood levels of TNF&agr; and the most severe complication occurring in malaria patients. Levels of serum TNF&agr; correlated directly with the severity of disease and the prognosis in patients with acute malaria attacks {Grau et al.,
N. Engl. J. Med.
320(24), 1586-1591 (1989)}.
Macrophage-induced angiogenesis is known to be mediated by TNF&agr;. Leibovich et al. {
Nature,
329, 630-632 (1987)} showed TNF&agr; induces in vivo capillary blood vessel formation in the rat cornea and the developing chick chorioallantoic membranes at very low doses and suggest TNF&agr; is a candidate for inducing angiogenesis in inflammation, wound repair, and tumor growth. TNF&agr; production also has been associated with cancerous conditions, particularly induced tumors {Ching et al.,
Brit. J. Cancer,
(1955) 72, 339-343, and Koch,
Progress in Medicinal Chemistry,
22, 166-242 (1985)}.
TNF&agr; also plays a role in the area of chronic pulmonary inflammatory diseases. The deposition of silica particles leads to silicosis, a disease of progressive respiratory failure caused by a fibrotic reaction. Antibody to TNF&agr; completely blocked the silica-induced lung fibrosis in mice {Pignet et al.,
Nature,
344, 245-247 (1990)}. High levels of TNF&agr; production (in the serum and in isolated macrophages) have been demonstrated in animal models of silica and asbestos induced fibrosis {Bissonnette et al.,
Inflammation
13(3), 329-339 (1989)}. Alveolar macrophages from pulmonary sarcoidosis patients have also been found to spontaneously release massive quantities of TNF&agr; as compared with macrophages from normal donors {Baughman et al.,
J. Lab. Clin. Med.
115(1), 36-42 (1990)}.
TNF&agr; is also implicated in the inflammatory response which follows reperfusion, called reperfusion injury, and is a major cause of tissue damage after loss of blood flow {Vedder et al.,
PNAS
87, 2643-2646 (1990)}. TNF&agr; also alters the properties of endothelial cells and has various pro-coagulant activities, such as producing an increase in tissue factor pro-coagulant activity and suppression of the anticoagulant protein C pathway as well as down-regulating the expression of thrombomodulin {Sherry et al.,
J. Cell Biol.
107, 1269-1277 (1988)}. TNF&agr; has pro-inflammatory activities which together with its early production (during the initial stage of an inflammatory event) make it a likely mediator of tissue injury in several important disorders including but not limited to, myocardial infarction, stroke and circulatory shock. Of specific importance may be TNF&agr;-induced expression of adhesion molecules, such as intercellular adhesion molecule (ICAM) or endothelial leukocyte adhesion molecule (ELAM) on endothelial cells {Munro et al.,
Am. J. Path.
135(1), 121-132 (1989)}.
TNF&agr; blockage with monoclonal anti-TNF&agr; antibodies has been shown to be beneficial in rheumatoid arthritis {Elliot et al.,
Int. J. Pharmac.
1995 17(2), 141-145}. High levels of TNF&agr; are associated with Crohn's disease {von Dullemen et al.,
Gastroenterology,
1995 109(1), 129-135} and clinical benefit has been achieved with TNF&agr; antibody treatment.
Moreover, it now is known that TNF&agr; is a potent activator of retrovirus replication including activation of HIV-1. {Duh et al.,
Proc. Nat. Acad. Sci.
86, 5974-5978 (1989); Poll et al.,
Proc. Nat. Acad. Sci.
87, 782-785 (1990); Monto et al.,
Blood
79, 2670 (1990); Clouse et al.,
J. Immunol.
142, 431-438 (1989); Poll et al.,
AIDS Res. Hum. Retrovirus,
191-197 (1992)}. AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Other viruses, such as HIV-1, HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication. Cytokines, specifically TNF&agr;, are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by prevention or inhibition of cytokine production, notably TNF&agr;, in an HIV-infected individual assists in limiting the maintenance of T lymphocyte caused by HIV infection.
Monocytes, macrophages, and related cells, such as kupffer and glial cells, also have been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. {Rosenberg et al.,
The Immunopathogenesis of HIV Infection,
Advances in Immunology, 57 (1989)}. Cytokines, such as TNF&agr;, have been shown to activate HIV replication in monocytes and/or macrophages {Poli et al.,
Proc. Natl. Acad. Sci.,
87, 782-784 (1990)}, therefore, prevention or inhibition of cytokine production or activity aids in limiting HIV progression for T cells. Additional studies have identified TNF&agr; as a common factor in the activation of HIV in vitro and has provided a clear mechanism of action via a nuclear regulatory protein found in
Man Hon-Wah
Muller George W.
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