Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-03-15
1998-08-18
Hutzell, Paula K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530324, 53038712, 4241851, A61K 3800, C07K 1400
Patent
active
057958599
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a group of peptides which have the ability to abrogate TNF toxicity and/or LPS toxicity. The present invention further relates to compositions including this peptide as the active ingredient and methods of anti-inflammatory treatment involving the administration of this composition.
BACKGROUND OF THE INVENTION
Many of the clinical features of septicemic shock induced by Gram-negative bacteria which have lipopolysaccharide (LPS) in their cell walls may be reproduced in animals by the administration of LPS. This induces 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 (TN ). Many of the effects of LPS injection or indeed of Gram-negative bacteria can be reproduced by TNE. Thus, mice injected with recombinant human TNF develop piloerection of the hair (ruffling), diarrhoea, a withdrawn, unkempt appearance and die if sufficient amounts are given.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 revealed severe leukostatsis in the lungs, haemorraghic necrosis in the adrenals, pancreas and other organs and tubular necrosis of the kidneys. All 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, enhanced antimicrobiocidal and anti-tumour activity (Klebanoff et al., 1986 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 regulation of the expression of thrombomodulin (Stern and Nawroth, 1986 J Exp Med 163, 740).
TNF, a product of activated macrophages produced in response to infection and malignancy, was first identified as a serum factor in LPS treated mice which caused the haemorraghic necrosis of transplantable tumours in murine models and was cytoxoic for tumour cells in culture (Carswell et al., 1975 PNAS 72, 3666; Helson et al., 1975 Nature 258, 731). Cachexia is a common symptom of advanced malignancy and severe infection. It is characterised by abnormal lipid metabolism with hypertriglyceridemia, abnormal protein and glucose metabolism and body wasting. Chronic administration of TNF (also known as cachectin in the early literature) to mice causes anorexia, weight loss and depletion of body lipid and protein within 7 to 10 days (Cerami et al., 1985 Iununol Lett 11, 173, Fong et al., 1989 J Exp Med 170, 1627). These effects were reduced by concurrent administration of antibodies against TNF. Although TNF has been measured in the serum of patients with cancer and chronic disease associated with cachexia the results are inconclusive since large differences in TNF levels have been reported. These may be due to 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.alpha., as a mediator of inflammation, has been implicated in the pathology of other diseases apart from toxic shock and cancer-related cachexia. TNF has been measured 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 the pathogenesis of graft versus host disease in skin and gut following allogeneic marrow tr
REFERENCES:
patent: 4508728 (1985-04-01), Nagai et al.
patent: 4717716 (1988-01-01), Nagai et al.
patent: 5118500 (1992-06-01), Hanel et al.
patent: 5436154 (1995-07-01), Barbanti et al.
**S.H. Socher et al. "Antibodies against amino acids 1,15 . . . " Proceedings of the National Academy of Sciences of the USA, vol. 84 No. 24 Dec. 1987, pp. 8755-9308.
Merck Manual, Fifteenth Edition. Merck & Co., Rahway, NJ (1987). see p. 1120.
Grigg Geoffrey W.
Mack Philip O.
Rathjen Deborah A.
Widmer Fred
Hutzell Paula K.
Peptide Technology Limited
Prickril Benet
LandOfFree
Peptide which abrogates TNF and/or LPS toxicity does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Peptide which abrogates TNF and/or LPS toxicity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Peptide which abrogates TNF and/or LPS toxicity will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1114732