Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-06-29
1999-01-19
Achutamurthy, Ponnathapura
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514885, 530351, 530868, 536 6, 424 851, A01N 4316, C07K 14525, A61K 3170, C08B 3710
Patent
active
058613820
DESCRIPTION:
BRIEF SUMMARY
1. FIELD OF THE INVENTION
The present invention relates to substances, their compositions, and methods for the regulation of cytokine activity, for instance, the up regulation or down regulation of Tumor Necrosis Factor alpha (TNF-.alpha.) activity. In particular, substances and pharmaceutically acceptable compositions are disclosed which, when administered to a host in effective amounts, either inhibit or augment the secretion of active TNF-.alpha. by host cells. It is thought that the secretion of active cytokines, for example TNF-.alpha., by the host's immune effector cells (e.g., the host's activated macrophages) may be regulated by the methods of the present invention.
The present invention also relates to methods for the prevention and/or treatment of pathological processes or, conversely, the initiation of a beneficial immune system-related response involving the induction of cytokine production, secretion, and/or activity. Selected compositions of the present invention comprise an effective low dosage of a low molecular weight heparin (LMWH) to be administered at intervals of up to between five to eight days. Still other compositions include substances comprising carboxylated and/or sulphate oligosaccharides in substantially purified form obtained from a variety of primary sources including chromatographic separation and purification of LMWHs, enzymatically degraded heparin and enzymatically degraded extracellular matrix (DECM).
Individually, the substances, compositions containing same, and pharmaceutical compositions especially suited for parenteral, oral, or topical administration, inhibit or augment TNF-.alpha. secretion by resting T cells and/or macrophages in vitro in response to activation by immune effector cell activators, including, but not limited to, T cell-specific antigens, T cell mitogens, macrophage activators, residual extracellular matrix (RECM), fibronectin, laminin or the like. In vivo data, showing inhibition of experimental delayed type hypersensitivity (DTH), are also presented in further support of the in vitro results.
2. BACKGROUND OF THE INVENTION
2.1. Tumor Necrosis Factor Alpha
TNF-.alpha., a cytokine produced by monocytes (macrophages) and T lymphocytes, is a key element in the cascade of factors that produce the inflammatory response and has many pleiotropic effects as a major orchestrator of disease states (Beutler, B. and Cerami, A., Ann. Rev. Immunol. (1989) 7:625-655).
The biologic effects of TNF-.alpha. depend on its concentration and site of production: at low concentrations, TNF-.alpha. may produce desirable homeostatic and defense functions, but at high concentrations, systemically or in certain tissues, TNF-.alpha. can synergize with other cytokines, notably interleukin-1 (IL-1) to aggravate many inflammatory responses.
The following activities have been shown to be induced by TNF-.alpha. (together with IL-1); fever, slow-wave sleep, hemodynamic shock, increased production of acute phase proteins, decreased production of albumin, activation of vascular endothelial cells, increased expression of major histocompatibility complex (MHC) molecules, decreased lipoprotein lipase, decreased cytochrome P450, decreased plasma zinc and iron, fibroblast proliferation, increased synovial cell collagenase, increased cyclo-oxygenase activity, activation of T cells and B cells, and induction of secretion of the cytokines, TNF-.alpha. itself, IL-1, IL-6, and IL-8. Indeed, studies have shown that the physiological effects of these cytokines are interrelated (Philip, R. and Epstein, L. B., Nature (1986) 323(6083):86-89; Wallach, D. et al., J. Immunol. (1988) 140(9):2994-2999).
How TNF-.alpha. exerts its effects is not known in detail, but many of the effects are thought to be related to the ability of TNF-.alpha. to stimulate cells to produce prostaglandins and leukotrienes from arachidonic acid of the cell membrane.
TNF-.alpha., as a result of its pleiotropic effects, has been implicated in a variety of pathologic states in many different organs of the body. In blood ve
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Cahalon Liora
Cohen Irun R.
Lider Ofer
Margalit Raanan
Shoseyov Oded
Achutamurthy Ponnathapura
Ponnaluri Padmashri
Yeda Research and Development Co. Ltd.
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