Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1997-07-21
1999-12-07
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514886, 514895, A61K 3120
Patent
active
059984767
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new polyunsaturated fatty acids having antimalarial activity and/or neutrophil stimulatory activity. In addition, certain of the new polyunsaturated fatty acids depress cytokine activity.
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 M M Preface In: Stevenson M M, 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.
Neutrophil/macrophage stimulatory agents may have application in the treatment of other infections including Candida sp, Trypanosoma. Schistosomiasis, Tuberculosis, viruses eg herpes, Sindbis viris. Legionella. Listeriosis, Pneumocystsis. Pseudomonas. They would also be useful as adjunct therapy in immunocompromised individuals including those undergoing cancer chemotherapy, transplant recipients and burns patients. In addition, others, so called normal individuals may also be treated, eg. the aged, children under 2, alcoholics, who are known to have poor phagocytic cell activity.
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 or otherwise. Septic shock is an illustration of a disease involving systemic 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.alpha.).
Chronic administration of TNF 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. Nature. 42. 1179-1182). TNF levels have been measured in patients with cancer and chronic disease associated with cachexia.
TNF.alpha. has been implicated 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 and in the serum of patients with rheumatoid 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 he 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).
Elevated pro-inflammatory cytokine levels have further been implicated in causing the pathology and tissue destruction in rheumatoid arthritis, multiple sclerosis (MS) and Crohns disease. Experimentally, anti-bodies which neutralise the activity of cytokine producing cells (eg antibodies aga
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Ferrante Antonio
Poulos Alfred
Rathjen Deborah Ann
Schober Paul Adam
Sleigh Merilyn Joy
Peptide Technology Limited
Weddington Kevin E.
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