Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-02-12
2001-06-05
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06242415
ABSTRACT:
1.0 FIELD OF THE INVENTION
Methods and compositions are described for the use of purified melanin to treat disease in animals and man. The disclosed melanin compositions are particularly useful for regulating cytokine production by mammalian and human cells both in vitro and in vivo.
2.0 BACKGROUND OF THE INVENTION
Tumor necrosis factor-alpha (TNF-&agr;) is a 17-kd polypeptide released primarily by macrophages. Generally, TNF-&agr; is not present in measurable quantity in sera from healthy individuals; but appears rapidly in response to immunostimulators (Beutler and Cerami,
Adv. Immunol.
42:213-232, 1988). At physiological concentrations, TNF-&agr; limits the growth and spread of invasive pathogens. However, excessive or uncontrolled production of this cytokine contributes to the pathogenesis of number of disease conditions.
TNF-&agr;, acting alone and/or in concert with other mediators, evokes a potentially fatal syndrome of irreversible cardiovascular collapse (shock) and critical organ failure (Beutler, Science 229:869-871, 1985; Tracy et al., Nature 330:662-664, 1987; Waag et al.,
Lancet
1:355-357, 1987). Additionally, TNF-&agr; acting in concert or in synergy with the interleukins IL-1 and IL-6 contributes to the development of wasting syndrome (cachexia) (Grunfeld, et al.,
Am. J. Clin. Nutr.
55:455-460, 1992; Grunfeld and Feingold,
N. Engl. J. Med.
327:329-337, 1992).
For example, the experimental administration of supernatants from endotoxin-stimulated macrophages produced severe weight loss in rodents (Cerami et al.,
Immunol. Lett.
11:173-177, 1985). Moreover, nude mice implanted with genetically engineered tumor cells that secreted either TNF-&agr; (Rouzer and Cerami,
Mol. Biochem. Parasitol.
2:31-38, 1980) or IL-6 (Black et al.,
Endocrinology
128:2657-2659, 1991) became progressively anorectic and wasted. Administering TNF-&agr;, IL-1, and IL-6 increases plasma triglycerides in rodents by boosting hepatic lipogenesis and very-low-density lipoprotein production leading to futile cycling of fatty acid/triglyceride and eventually wasting (Feingold and Grunfeld,
J. Clin. Invest.
80:184-190, 1987; Grunfeld et al.,
Cancer Res.
50:4233-4238, 1990; Feingold, et al.,
Arterioscler. Thromb. Vasc. Biol.
11:495-500, 1991).
Cytokines also boost the levels of key catabolic hormones; alter glucose and amino acid metabolism; and have profound effect on food intake. In experimental animals, TNF-&agr; decreases gastric motility and consequently leads to retention of food (Patten et al.,
J. Clin. Invest.
80:1587-1596, 1987), and IL-1 induces continuous anorexia by indirectly affecting the hypothalamic appetite center (Hellerstein et al.,
J. Clin. Invest.
84:228-235, 1989). In humans, wasting syndrome is often associated with cancer and a variety of infectious diseases including, but not limited to tuberculosis and AIDS.
In addition to progressive weight loss, many patients experience anorexia (reduced appetite), nausea, muscle weakness, and anemia (Lawson et al.,
Lancet
2:1-5, 1982; Grunfeld and Feingold,
New Engl. J. Med.
237:329-337, 1992). Although cachexia may involve anorexia, usually the degree of lean body mass lost in cachexia associated with cancer and infectious disease cannot be explained by reduced caloric intake (Spiegelman and Hotamisligil,
Cell
73:625-627, 1993).
Cachexia is considered as a detrimental end point because, apart from directly effecting patient survival, the progressive weight loss and anemia usually restrict the ability of cachectic patients to tolerate aggressive therapy (Dewy et al.,
Am. J. Med.
69:491-497, 1980).
The prevalence of cachexia makes this syndrome a significant medical problem. Taken together, these results provide a mechanistic basis for considering the use of melanin, an agent that interferes with the synthesis/release of IL-1, IL-6 and TNF-&agr;, for managing wasting in patients.
TNF-&agr; can also induce adult respiratory distress syndrome (ARDS), a severe consequence of gram-negative sepsis in humans (Shaby et al., In:
Pathophysiology of Endotoxin,
J. B. Hinshaw, ed. Amsterdam: Elsevier, pp. 105-128, 1985). TNF-&agr; concentrations in excess of 12,000 pg/ml were detected in pulmonary aspirates from ARDS patients (Millar et al.,
Lancet
2:712-714, 1989). This cytokine is also known to increase the adherence of polymorphonuclear leukocytes to endothelial cells (Gamble et al.,
Proc. Natl. Acad. Sci., U.S.A.
82:8667-8671, 1985). Increased adherence of activated granulocytes in the microvasculature of the lungs and upper respiratory tract is one of the major causes of pulmonary vascular injury in ARDS. Of note, expression of intracellular adhesion molecule (ICAM), and endothelial leukocyte adhesion molecule (ELAM) on endothelial cells is either induced or enhanced by cytokines such as TNF-&agr; or IL-1 (Munre et al.,
Am. J. Pathol.
135:121-132, 1989), a phenomenon which results in the augmentation of cell binding.
TNF-&agr;, IL-1 and IL-6 also play a major role in the pathology of rheumatoid arthritis (Saklatvala.,
Nature
322:547-549, 1986; Miossec.
Clin. Rheumatol.
5:305-308, 1987; Lupia et al.
Eur. J. Immunol.,
26: 1690-1694, 1996). Synovial fluids from patients with rheumatoid arthritis contain TNF-&agr; (Saxne et al.,
Arthritis Rheumatism
31:1041-1132, 1989) and IL-6 (Guerne et al.,
J. Clin. Invest.
83:585-592, 1989). Current evidence suggests that immune complexes may stimulate monocytes to secrete TNF-&agr; (Visser et al.,
Am. J. Pathol.
134:1-6, 1989) and IL-1 (Chantry et al.,
Eur. J. Immunol.
19:189-192, 1989). TNF-&agr; and IL-1 in turn stimulates production of proteases and prostaglandins by synoviocytes and bone resorption by osteoclasts (Miossec,
Clin. Rheumatol.
5:305-308, 1987; Dayer et al.,
J. Exp. Med.
162:2163-2168, 1985; Saklatvala,
Nature
322:547-549, 1986). Moreover, the presence of TNF-&agr; and IL-1 in rheumatoid joints may act together to perpetuate synovitis by stimulating IL-6 synthesis which, if found in close proximity to plasma cells, may lead to autoantibody production. IL-6 is spontaneously produced by synoviocytes and high levels of IL-6 are present in synovial fluids from patients with inflammatory arthropathies (Guerne et al.,
J. Clin. Invest.
83:585-592, 1989).
Cerebral malaria is a lethal hyperacute neurological syndrome and prognosis of some malaria patients which has been associated with threshold levels of serum TNF-&agr; (Grau et al.,
Science
237:1210-1212, 1987; Clark et al.
Am. J. Pathol.,
129:192-199, 1987; Grau et al.,
New Engl. J. Med
320:1586-1591, 1989; Kwiatkowski et al.,
Lancet
336:1201-1204, 1990; McGuire et al.
Nature
371-510, 1994). Similarly, in Graft versus Host Reactions, increases in TNF-&agr; concentration have been associated with major complications (Holler et al.,
Blood
75:1011-1016, 1990).
TNF-&agr; alone, or in synergy with either IL-1 or IL-6, enhances replication of HIV-1 in latently infected T cells and monocytes (Folks et al.,
Science
238:800-802, 1987; Folk et al.,
Proc. Natl. Acad. Sci. U.S.A.
86:2365-2368, 1989; Poli et al.,
J. Exp. Med.
172:151-158, 1990; Poli et al.,
Proc. Natl. Acad. Sci. U.S.A.
91:108-112, 1994). TNF-&agr; is a strong inducer of NF-&kgr;&bgr;, a transcriptional factor used by HIV (Nobel and Baltimore,
N. Engl. J. Med.
234:308-317, 1987; Duh et al.,
Proc. Natl. Acad. Sci. U.S.A.
86:5974-5978, 1989). Moreover, synthesis of TNF-&agr;, IL-1, and IL-6 are upregulated as a consequence of HIV infection (Folks et al.,
Science
238:800-802, 1987; Nakajima et al.,
J. Inmunol.
142:531-536, 1989). Serum and cerebrospinal fluid of patients with AIDS contain increased levels of TNF-&agr;, IL-1, and IL-6 (Lahdevirta et al.,
Am. J. Med.
85:289-291, 1988; Emille et al.,
J. Clin. Invest.
86:148-159, 1990; Breen et al.,
J. Immunol.
144:480-484, 1990).
The apoptotic neuronal loss occurring in HIV-1 encephalitis is associated with TNF-&agr; (DeSimone et al.,
Immunol. Today
17:256-258, 1996). In addition, TNF-&agr; has been implicated in AIDS associated cachexia (Wright et al.,
J
Criares Theodore J.
Halluin Albert P.
Howrey Simon Arnold & White , LLP
SRI - International
Whiting Adam K.
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