Modified polyunsaturated fatty acids

Details Modified polyunsaturated fatty acids Modified polyunsaturated fatty acids

1997-05-29

2002-04-23

Carr, Deborah D. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S154000, C554S213000, C554S223000, C554S224000, C514S558000, C514S560000, C514S885000, C514S895000

Reexamination Certificate

active

06376688

ABSTRACT:

This application is a 371 of PCT/AU95/00677 filed Oct. 13, 1995.
The present invention relates to new polyunsaturated fatty acids having antimalarial activity and/or neutrophil stimulatory activity. The present invention further relates to a group of modified polyunsaturated fatty acids which have the ability to suppress cytokine production and cytokine action. Such fatty acids have enhanced stability when compared to naturally occurring polyunsaturated fatty acids. The present invention further relates to compositions including the polyunsaturated fatty acids as the active ingredient and methods of anti-malarial, anti-infective of anti-inflammatory treatment or prevention involving the administration of this composition.
BACKGROUND OF THE INVENTION
Over half of the world's population is at risk from malaria, with about 500 million acute infections and approximately 1 million deaths recorded each year. (Tropical Diseases Progress in International Research, 1987-1988. Ninth Programme Report, UNDP/World Bank/WHO, Geneva, 43-49: Stevenson MM Preface In: Stevenson MM. Ed. Malaria: Host responses to Infection, CRC Press, Inc). The use of antimalarial drugs is associated with major problems because of increased resistance and toxic side-effects. Most currently used antimalarials are unsuitable for use in children (most at risk of potentially fatal cerebral malaria), pregnant women and the aged.
Inflammation may be 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 of otherwise. 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 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 pro-inflammatory cytokines such as tumour necrosis factor alpha [TNF&agr;]. Cachexia, which is characteristic of chronic exposure to TNF or interleukin-6, is a common symptom of advanced malignancy and severe infection. It is characterised by abnormal protein and glucose metabolism and body wasting. Chronic administration of TNF IL-1 in mice, rats and/or humans cause 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, 1989J. Exp. Med. 170, 1627, Moldawer et al. Am. J. Phusiol., 254 G450-G456, 1988: Fong et am. Am. J Physiol, 256, R659-R665 (1989): McCarthy et al. Am. J. Clin. Nature, 42, 1179-1182, 1982). TNF levels have been measured in patients with cancer and chronic disease associated with cachexia.
TNF&agr; and IL-1, with their common functional activities such as pyrogenicity, somnogenicity and being mediators of inflammation, have been implicated in the pathology of other diseases associated with chronic inflammation apart from toxic shock and cancer-related cachexia. TNF has been detected in synovial fluid in patients with both rheumatoid and reactive arthritis and in the serum of patients with rheumatoid arthritis (Saxne et en. 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 en. 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 lebvels of TNF have been reported in malaria patients (Scuderi et al. 1986, Lancet 2, 1364-1365).
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and is the commonest chronic neutroligical 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, 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 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. Anti-T cell agents such as anti-CD4 treatment are effective. Such agents inhibit the proliferation of T-cells.
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. Both TNF&agr; (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 activators 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 least palliation for short periods of time.
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 autoimmune 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 autoimmune 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 “Autoimmune 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

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