Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-10-20
2001-07-24
Davenport, Avis M. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S015800, C514S016700, C514S017400, C530S300000, C530S322000, C530S328000, C530S329000, C424S185100
Reexamination Certificate
active
06265374
ABSTRACT:
The present invention relates, broadly to the treatment or prevention of inflammation, whether caused by bacteria, viruses and/or other infective agents, opportunistic infections (which may be consequent on an immunodepressed state, for example resulting from cancer or therapy, particularly cytotoxic drug therapy or radiotherapy) autoimmunity or otherwise. In particular embodiments, the invention relates to the prevention or treatment of neurodegenerative or demyelinating diseases such as HTLV-1-associated myelopathy (HAM), multiple sclerosis (MS) and symptoms or diseases in humans which are associated with chronic immune activation. The invention also relates to pharmaceutical compositions useful in such treatment and/or prevention and to certain active peptides per se.
Septic shock is an illustration of a disease involving inflammation. Many of the clinical features of Gram-negative septic shock may be reproduced in animals by the administration of lipopolysaccharide (LPS). The administration of LPS to animals can prompt severe metabolic and physiological changes which can lead to death. Associated with the injection of LPS is the extensive production of tumour necrosis factor alpha (TNF-&agr;). Mice injected with recombinant human TNF develop piloerection of the hair (ruffling), diarrhoea and a withdrawn and unkept appearance, followed by death if sufficient amounts are given. Rats treated with TNF become hypotensive, tachypneic and die of sudden respiratory arrest (Tracey et al. 1986
Science
234, 470). Severe acidosis, marked haemoconcentration and biphasic changes in blood glucose concentration were also observed.
Histopathology of such rats revealed severe leukostatsis in the lungs, haemorraghic necrosis in the adrenals, pancreas and other organs and tubular necrosis of the kidneys. All of these changes were prevented if the animals were pretreated with a neutralizing monoclonal antibody against TNF.
The massive accumulation of neutrophils in the lungs of TNF-treated animals reflects the activation of neutrophils by TNF. TNF causes neutrophil degranulation, respiratory burst as well as enhanced neutrophil antimicrobacterial and anti-tumor activity (Klebanoff et al, 1996
, J. Immunol.
136, 4220; Tsujimoto et al, 1986
Biochem. Biophys. Res. Commun.
137, 1094). Endothelial cells are also an important target for the expression of TNF toxicity. TNF diminishes the anticoagulant potential of the endothelium, inducing procoagulant activity and down-regulating the expression of thrombomodulin (Stern and Nawroth, 1986
J. Exp. Med.
163, 740).
TNF is a product of activated macrophages and is produced in response to infection and malignancy. It was first discovered in LPS-treated mice as a serum factor which caused the haemorraghic necrosis of transplanted tumour cells in culture (Carswell et al, 1975 PNAS 72, 3666; Helson et al, 1975
, Nature
258, 731). Cachexia, which is characteristic of chronic exposure to TNF, it a common symptom of advanced malignancy and severe infection. It is characterized by abnormal lipid metabolism with hypertriglyceridaemia., abnormal protein and glucose metabolism and body wasting. Chronic administration of TNF and IL-1 in mice, rats and/or humans causes anorexia, weight loss and depletion of body lipid and protein within 7 to 10 days (Cerami et al, 1985
, Immunol. Lett.
11, 173; Fong et al, 1989
J. Exp. Med.
170, 1627, Moldawer et al,
Am. J. Physiol.,
254 G450-G456, 1988; Fong et al,
Am. J. Physiol
. 256 R659-R665 (1989); McCarthy et al,
Am. J. Clin. Nutr.
42 1179-1182, 1982). TNF levels have been measured in patients with cancer and chronic disease associated with cachexia. The results are inclusive since large differences in TNF levels have been reported. These may have been explicable by the short half-life of TNF (6 minutes), differences in TNF serum binding protein or true differences in TNF levels in chronic disease states.
TNF-&agr; and IL-1, with their common functional activities such as pyrogenicity, somnogenicity and being mediators of inflammation, have been impacted in the pathology of other diseases associated with chronic inflammation. apart form toxic shock and cancer-related cachexia. TNF has been detected in synovial fluid in patients with both rheumatoid and reactive arthritis (Saxne et al, 1988
, Arthrit. Rheumat.
31, 1041). Raised levels of TNF have been detected in renal transplant patients during acute rejection episodes (Maury and Teppo 1987
, J. Exp. Med.
166, 1132). In animals, TNF has been shown to be involved in the pathogenesis of graft-versus-host disease in skin and gut following allogenic marrow transplantation.
Administration of a rabbit anti-murine TNF antibody was shown to prevent the histological changes associated with graft-versus-host disease and to reduce mortality (Piquet et al, 1987
, J. Exp. Med.
166, 1220). TNF has also been shown to contribute significantly to the pathology of malaria (Clark et al, 1987
, Am. J. Pathol.
129, 192-199). Further, elevated serum levels of TNF have been reported in malaria patients (Scuderi et al, 1986,
Lancet
2, 1364-1365).
Multiple sclerosis (MS) is generally considered by many authorities to be a chronic inflammatory disease.
Both MS and HTLV-1 associated myelopathy (HAM) affect the central and the peripheral nervous systems and both may present clinically as a myelopathy affecting both the spinal nerves and the spinal myelinated nerve fibres.
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and is the commonest chronic neurological disease of young adults. The incidence of MS and its pattern of distribution have been unchanged for decades. The disease remains essentially untreatable.
MS has always been regarded as a disease of the temperate zones and has a prevalence in the northern United States, Canada and Europe of 1:1000. The disease has a gender predilection of 1.5:1 (female:male).
MS usually affects multiple areas of white matter in the central nervous system (CNS), most frequently, the perventricular white matter, brainstem, spinal cord and the optic nerves. The primary process destroys myelin sheaths and eventually kills oligodendrocytes creating the characteristic plaque of MS.
The early development of the plaque is characterised by the development of perivascular inflammation followed by the migration of lumpnocytes, plasma cells and macrophages into the lesion. This is followed by astrocyte gloisis and the attempts of remyelination by oligodendrocytes. The plaque is surrounded by lumphocytes.
Although the aetiology of MS is still unknown, the focus of research efforts that have led to plausible hypotheses have been those of immune dysregulation including autoimmunity and genetic predisposition, both of which may play a role in the actual development of disease.
Multiple immunological abnormalities are reproducibly found in patients in the acute stage of the disease. The synthesis of immunoglobins, although normal in the periphery, is increased in the central nervous system and the antibodies produced have a characteristic banding pattern. The antigenic specificity of these antibodies is not known and it is unclear whether they have a role to play in the progression of disease.
Various stressors known to activate the immune system such as viral infection or surgery can also produce an exacerbation of MS. Other activators such as &ggr;-interferon produce similar effects when administered. In addition, immunosuppresive anti-inflammatory therapy with corticosteroids for example, can produce modest remission or at least palliation for short periods of time, although this therapy is controversial.
Lymphocyte reactivity against two neuronal antigens myelin basic protein and proteolipid has been demonstrated. Although not proven, this activity would form the basis for an autoimmune response against neuronal tissue.
The discovery of the neurotropic capacity of HTLV-1 in patients form Martinique with tropical spastic paraparesis (TSP) and in Japan with chronic myleopathy, has demonstrated HTLV-1 as the common aet
Andersen Anders Jorgen
Aston Roger
Carlen Peter Louis
Doob Penelope Reed
MacFadden Douglas Kevin
Advanced Immuni T, Inc.
Coleman Sudol Sapone P.C.
Davenport Avis M.
Sapone William J.
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