Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-04-12
2001-07-17
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S627000, C514S826000, C514S861000, C514S863000, C514S885000, C514S903000
Reexamination Certificate
active
06262119
ABSTRACT:
The present invention relates to methods of treatment of a variety of disease states involving the use of new polyunsaturated fatty acids which include at least one &bgr; oxa, &bgr; thia, &ggr; oxa or &ggr; thia substitution and/or which includes an amino acid. The disease states include multiple sclerosis, rheumatoid conditions, and other T-cell mediated diseases; allergic conditions such as asthma, allergic rhinitis, contact hypersensitivity; transplant rejection and graft vs. host disease and conditions where arachidonic acid metabolites are formed.
BACKGROUND OF THE INVENTION
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 usually affects multiple areas of white matter in the central nervous system (CNS), most frequently, the preventricual white matter, brain stem, 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 lymphocytes, plasma cells and macrophages into the lesion. This is followed by astrocyte gliosis and the attempts of demyelination by oligodendrocytes. The plaque is surrounded by lymphocytes.
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 auto-immunity and genetic predisposition, both of which may play a role in he actual development of disease. Both TNF&bgr; (lymphotoxin) and TNF&agr; are thought to play a role in the pathophysiology.
Multiple immunological abnormalities are reproducibly found in patients in the acute stage of the disease. The synthesis of immunoglobulins, 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 the disease.
Various stressors known to activate the immune system such as viral infection or surgery can also produce an exacerbation of MS. Other activator such as &ggr;-interferon produce similar effects when administered. In addition, immunosuppressive anti-inflammatory therapy with corticosteroids for example, can produce modest remission or at lease 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 auto-immune response against neuronal tissue.
Myelopathy, a disorder of the spinal cord, can have many different aetiologies, most of which are mediated by inflammation, including the following:
Neurosyphillis;
b
12
or folate deficiency;
sarcoidosis;
transverse myelitis;
arachidonitis;
cervical spondylitis;
motor neuron disease;
neurofibromatosis;
spinal cord compression from tumour, disc or arthritis;
lupus erythematosus of the spinal cord; and
viral encephalomyelitis
Chronic inflammation or, as more commonly known, chronic immune system activation occurs in response to persistent antigen whose origin may be exogenous or may result from an auto-immune state. Such chronic inflammation results in local tissue destruction and depending upon the type of inflammation can result in systemic effects due to the sustained production of inflammatory mediators. Such inflammatory mediators include the cytokines which are soluble mediators produced by activated lymphocytes and macrophages and effect cellular communication and physiological response. Chronic immune activation can occur as a result of infectious disease, such as chronic fatigue syndrome or toxic shock syndrome or through auto-immune mechanisms resulting in such conditions as rheumatoid arthritis, inflammatory bowel disease, Crohns Disease and other diseases such as graft versus host disease.
Rheumatoid arthritis (Marrow et al, I “Auto-immune Rheumatic Disease”,
Blackwell Scientific Publ.
Oxford, UK, Chapter 4 pp148-207 (1987) is a disease characterised by chronic inflammation and erosion of joints that may affect up to 3% of the population, including children. Symptoms of rheumatoid arthritis include morning stiffness, swelling and pain upon motion in at lease one joint and joint swelling. Non-specific symptoms including lethargy, anorexia and weakness as well as fever and lymphadenopathy (characteristic of immune activation) may antedate joint involvement. Extr&agr;-articular manifestations of rheumatoid arthritis include vasculitis, cataracts, uveitis, interstitial fibrosis, pericarditis and myocarditis, peripheral neuropathy, myeloid deposits, chronic anaemia and subcutaneous and pulmonary nodules.
Genetic factors and infectious agents including bacteria, fungi, mycoplasmas and viruses have been associated with the development of rheumatoid arthritis. Mild rheumatoid arthritis may be treated with non-steroidal anti-inflammatory drugs while severe cases require systemic corticosteroids, anti-metabolites or cytotoxic agents. Experimentally, anti-CD4 monoclonal antibodies and anti-TNF&agr; antibodies have been used to treat rheumatoid arthritis (Horneff et al, Cytokine 3 266-267 (1991); Horneff et al, Arth. Rheum. 34 129-140 (1991) and Shoenfeld et al, Clin. Exp. Rheum. 9. 663-673 (1991), Williams et al, 1992 PNAS 89, 9784).
Arthritis is the most common manifestation of systemic lupus erythematosus (SLE) and is classically the symptom for which the patient seeks medical attention. SLE is a set of clinical disorders involving multiple organ systems and characterised by the production of auto-antibodies and immune complexes. The immune complexes are deposited in various organs eg kidney, gastrointestinal tract and the resultant inflammation and tissue injury cause cell and organ dysfunction. B cell hyper-reactivity and production of auto-antibodies is an attributed imbalance between CD8 and CD4 T cells and altered cytokine production including increased production of interleukini 1, interleukin 2 and interferon &ggr;. Azathioprine is commonly used in management of the disease.
Systemic sclerosis (scleroderma) is characterised by thickening and fibrosis of the skin and by distinctive forms of internal organ involvement. (Claman, H. N., 1989, JAMA 262: 1206). The skin thickening of scieroderma is due to the accumulation of collagen in the lower dermis. The immobility of the skin is caused by replacement of the subcutaneous tissue with fibrous bands. Dermal fibroblasts obtained from involved skin accumulated types I, III and IV collagen, fibronectin and glycosaminoglycan. This is a secondary response to factors released by other cells. T-helper cells are demonstrable in involved skin. Elevated levels of serum IL-2 and IL-2 receptor are present and correlate with clinical progression of the disease (Kahaleh et al, 1989. Ann. Itern. Med. 110:446). This suggests a role for lymphokines that either stimulate collagen biosynthesis in fibroblasts or stimulate other cells such as monocytes or mast cells to produce such factors. Human chronic graft vs host disease is associated with a similar dermal fibrotic change. Interferon &ggr; is known to stimulate collagen accumulation by systemic scleroderma fibroblasts.
Polymyositis is a chronic inflamniatory disease of skeletal muscle, characterised by symmetric weakness of proximal limb girdle muscles and muscles of the trunk, neck and pharynx. A characteristic rash may also be present (Hochberg et al, 1986, Semin Arthritis Rheum 15:168). Peripheral blood lymphocytes from patients with polyin-yositis produce lymphokines cytotoxic to foetal muscle cells in vitro. In addition, the proportion of activated lymphocytes is increased particularly in muscle
Easton Christopher John
Ferrante Antonio
Pitt Michael Joseph
Poulos Alfred
Rathjen Deborah Ann
Krass Frederick
Nixon & Vanderhye
Peptide Technology Limited
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