Peptide T and related peptides in the treatment of inflammation,

Details Peptide T and related peptides in the treatment of inflammation, Peptide T and related peptides in the treatment of inflammation,

1995-02-24

1998-05-26

Cain, Edward J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

A61K 3710

Patent

active

057564493

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB93/00649, filed Mar. 29, 1993.
The present invention relates, broadly, to the treatment of 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 chromatic 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-.alpha.). Mice injected with recombinant human TNF develop piloerection of the hair (ruffling), diarrhoea and a withdrawn and unkempt appearance followed by death if sufficient amounts are given.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, haemorraphic 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 nuetralizing 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 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-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 tumours in murine models and was cytotoxic for 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, is a common symptom of advanced malignancy and severe infection. It is characterised 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 inconclusive 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-.alpha. and IL-1, with their comm

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