Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-10-26
2000-04-04
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142335, 5142338, 5142352, 514300, 514301, 514307, 514309, 514310, A61K 3147, A61K 4506
Patent
active
060461918
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the co-administration of an inhibitor of induced nitric oxide synthase and an inhibitor of cyclooxygenase-2 for the treatment of inflammation and inflammatory disorders, such as arthritis, inflammatory bowel disease and CNS inflammatory disorders.
The excessive production of nitric oxide (NO) has been implicated in immune and inflammatory responses and as an important and novel mechanism in the pathology of a variety of chronic inflammatory diseases (Moncada S. et al, Pharmacol. Rev., 1991, 43, 109). The role of NO, as either a beneficial physiological mediator, or as pathological cytotoxic radical, is largely determined by the level and extent of synthesis. Under physiological conditions only low levels of NO are required for effector functions, whereas excessive NO production may be detrimental and pathological.
The synthesis of NO from the semi-essential amino acid L-arginine is catalysed by three different enzyme isoforms: endothelial NOS (eNOS) and neuronal NOS (nNOS) are constitutively expressed, calcium dependent enzymes and play a major role in normal physiology. The third major NOS isoform, inducible NOS (iNOS) is not expressed under physiological conditions but requires induction. Inflammatory stimuli, such as endotoxin and the cytokines interleukin-1 (IL-1), tumour necrosis factor-.alpha. (TNF.alpha.) or interferon gamma (INF.gamma.), induce de novo formation of a calcium independent NOS in a variety of cells, including epithelial cells, macrophages and neutrophils. The inducible NOS (iNOS) produces much greater amounts of NO for longer periods compared to the constitutive enzymes.
There is considerable evidence for an important role for iNOS in inflammation. The excessive NO production following induction of NO synthase plays an important role in the vascular permeability in intestinal inflammation produced by endotoxin. Inhibitors of iNOS attenuate the increase in plasma leakage (Boughton-Smith N. K. et al, Eur. J. Phannacol., 1990, 191, 485). Inhibitors of iNOS reduce plasma leakage produced in zymosan peritonitis and by carrageenan in the rat paw and air pouch, in which there are increases in iNOS activity (Ialenti A., Eur. J Pharmacol., 1992, 211, 177; Salvamini D. et al, J. Clin. Invest., 1995, 96, 301; Salvemini D. et al, Br. J. Pharmacol., 1996, 118, 829; Boughton-Smith N. K. and Ghelani A., Inflamm. Res., 1995, Suppl. 2, S149). In rat adjuvant arthritis there are increases in plasma nitrite and NO production by peritoneal macrophages and immunoreactive iNOS is localised to synovial tissue. Paw swelling, loss in weight gain, synovial inflammation and cartilage degradation are reduced by the non-selective NOS inhibitors L-NAME and L-NMMA (Ialenti A. et al, Br. J. Pharmacol., 1993, 110, 701; Stefanovic-Racic M., Arthritis and Rheumatism, 1994, 37, 1062; Stefanovic-Racic M. et al, Rheumatol., 1995, 22, 1922). Inhibitors of NOS also have beneficial effects in a rat model of arthritis induced by streptococcal cell wall (McCartney-Frances N., J. Exp. Med., 1993, 178, 749) and in the spontaneous arthritis and nephritis produced in MLR lpr/lpr mice, in which there is also evidence of iNOS induction (Weinberg J. B., J Exp. Med., 1994, 179, 651). There are also increases in NOS activity in animal models of inflammatory bowel disease and an inhibitor of NOS ameliorates guinea-pig model ileitis (Boughton-Smith N. K. et al, Agents and Actions, 1994, 41, 223; Miller M. J. S., J. Pharmacol. Exp. Ther., 1993, 264, 11).
In clinical studies there are increases in the production of NO and in iNOS expression in a variety of chronic inflammatory diseases, such as rheumatoid and osteoarthritis (Farrell A. J. et al, Ann Rheum. Dis., 1992, 51, 1219; Grabowski P. S. et al, Arth. & Rheum., 1996, 39, 643; Stichtenoth D. O. et al, Ann of the Rheumatic Diseases, 1995, 54, 820; McInnes I. B. et al, J. Exp. Med., 1996, 184, 1519), inflammatory bowel disease (Boughton-Smith N. K. et al, Lancet, 1993, 342, 338; Lundberg J. O. N. et al, Lancet, 1994, 344, 1673; Middleton S. J. et al, Lanc
REFERENCES:
J. Med. Chem., vol. 40, 1997, Lazer et al, "Effect of Structural Modification of Enol-Carboxamide-type Nonsteroidal Antiinflammatory Drugs on COX-2/COX-1 Selectivity", pp. 980-989, Apr. 1997.
Hamley Peter
Tinker Alan
Astra Pharmaceuticals Ltd.
Krass Frederick
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