Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-17
1999-08-03
Travers, Russell
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3135
Patent
active
059326107
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the use of pharmaceutical compositions for inhibiting the production or blocking the action of Tumor Necrosis Factor .alpha. (TNF-.alpha.), and for preventing or alleviating diseases and conditions associated with this cytokine, such as septic shock or cachexia. Said pharmaceutical compositions comprise as their active ingredient the stereospecific (+) enantiomers, having (3S,4S) configuration, of .DELTA.6-tetrahydrocannabinol (THC) type compounds of general formula (I), as defined hereinbelow. ##STR1##
BACKGROUND OF THE INVENTION
Tumor necrosis factor alpha (TNF-.alpha.) is a pleiotropic cytokine, which has been implicated in inflammatory and immunological responses, as well as in pathogenesis of endotoxic and septic shock (reviewed by Tracey and Cerami, Ann. Rev. Med. 45, 491-503, 1994; Glauser et al. Clin. Infect Dis. 18, suppl. 2, 205-216, 1994). TNF is one of several cytokines released mainly by mononuclear phagocytic cells in response to various stimuli. Though the role of cytokines in pathophysiological states has not been fully elucidated, it appears that TNF-.alpha. is a major mediator in the cascade of injury and morbidity.
Among the serious disease states related to the production of TNF-.alpha., a partial list includes the following: septic shock; endotoxic shock; cachexia syndromes associated with bacterial infections (e.g., tuberculosis, meningitis), viral infections (e.g., AIDS), parasite infections (e.g., malaria), and neoplastic disease; autoimmune disease, including some forms of arthritis (especially rheumatoid and degenerative forms); and adverse effects associated with treatment for the prevention of graft rejection.
Septic shock is an often lethal syndrome associated with the massive release of host cytokines due to stimuli present on, or released by, invasive micro-organisms. These invasive stimuli induce polyclonal stimulation of the infected host immune system, and include both lipopolysaccharide (LPS), an endotoxin that stimulates B-cells and macrophages, and superantigens which are exotoxins that stimulate T-cells.
Septic shock has been recognized generally as a consequence of gram-negative bacterial infection, but it is now clear that it can also result from infection with gram positive micro-organisms and probably also by fungi, viruses and parasites. The microorganism itself, its components or products trigger the host cells, especially the macrophages, to release inflammatory mediators such as TNF, thereby initiating a cascade of events leading to cachexia, sepsis syndrome and septic shock. TNF-.alpha. is a major mediator initiating septic shock, and therefore stands out as a potential therapeutic target (Lynn and Cohen, Clin. Infect. Dis. 20, 143-158, 1995)
Despite vast improvements in intensive care and antibiotic therapy, septic shock remains associated with a very high rate of mortality (30 to 90%). The poor prognosis for this syndrome is due to the fact that this severe complication of infection results in multiple organ failure, even when the actual infection itself is successfully treated. It is, therefore, apparent that effective therapies for this syndrome are an unmet medical need.
Various therapies have been suggested for the treatment of septic shock syndrome, but as yet none of these has proven to be clinically efficacious. Antibodies against TNF-.alpha. prevent the detrimental effects of superantigen (Miethke et al., J. Exp. Med. 175, 91-98, 1992) or LPS (Beutler et al., Science 229, 869-871, 1985). The use of anti-TNF antibodies to treat septic shock is disclosed for example in WO 92/16553 (Centocor Inc.). WO 92/01472 (Celltech Ltd.) discloses a multivalent immunoglobulin used to treat diseases associated with elevated cytokine levels. Various cytokines that inhibit TNF secretion can also reduce the toxicity of LPS action (Tzung et al., Eur. J. Immunol. 22, 3097-3101, 1992; Gerard et al., J. Exp. Med. 177, 547-550, 1993).
Soluble forms of the TNF binding protein (TBP) (Nophar et al. EMBO J., 9, 3269-32
REFERENCES:
patent: 5284867 (1994-02-01), Kloog et al.
patent: 5338753 (1994-08-01), Burstein et al.
Gallily Ruth
Mechoulam Raphael
Shohami Esther
Travers Russell
Yissum Research Development Co. of the Hebrew University
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