Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-01
2001-06-19
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S406000, C514S473000
Reexamination Certificate
active
06248745
ABSTRACT:
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-&agr; (TNF&agr;) or interferon gamma (INF&ggr;), 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. Pharmacol.,
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 stiudies 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,
Lancet,
1993, 341, 465), psoriasis (Rowe A. et al,
Lancet,
1994, 344, 1371; Bruch-Gerharz D. et al,
J. Exp. Med.,
1996, 184, 2007) and asthma (Hamid, Q. et al,
Lancet,
1993, 342, 1510; Barnes J. and Liew F. Y.,
Immunol. Today,
1995, 16, 128) and iNOS is implicated as a major pathological factor in these chronic inflammatory diseases. Thus, there is considerable evidence that inhibition of excessive NO production by iNOS will be anti-inflammatory. Since the production of NO from eNOS and nNOS is involved in normal physiology, it is important that any NOS inhibitor used therapeutically for treating inflammation is selective for iNOS. Such an inhibitor will inhibit the excessive production of NO by iNOS without effecting the modulation of blood pressure produced by NO production from eNOS or the non-adrenergic non-cholinergic neuronal transmission produced by NO from nNOS.
The recent discovery of an inducible isoform of cyclooxygenase (COX-2) has provided a specific target for inhibition of inflammatory prostaglandin synthesis while leaving the physiological actions of prostaglandins formed by constitutive cyclooxygenase (COX-1) intact (Fu et al,
J. Biol. Chem.,
1989, 265, 16740; DeWitt D.,
Biophys. Acta,
1991, 1083, 121; Masferrer J. L. and Seibert,
Receptor,
1994, 94, 17). Prostaglandins play an important role in inflammation, for example in both the pain and swelling associated with arthritis. The commonly used cyclooxygenase inhibitors or non-steroid anti-inflamrnmatory drugs (NSAIDs) are non-selective in that they reduce prostaglandins involved in inflammatory pain and swelling but also inhibit the physiological prostaglandin formation which is required particularly for maintenance of gastrointestinal integrity. A number of selective COX-2 inhibitors have been described which are anti-inflammatory in a variety of animal models but which, unlike non-selective COX inhibitors, do not produce gastrointestinal pathology.
Since both INOS and COX-2 inhibitors are selective for the enzyme isoforms induced in inflammation which produce NO and prostaglandins respectively, and will not effect the constitutive enzymes involved in normal physiology, the combination will have a substantially reduced level of adverse side effects associated with NSAIDs and also anti-inflammatory glucocorticoids, which inhibit the induction of both enzymes (Radomski M. V. et al,
Proc. Natl. Acad. Sci. USA,
1990, 87, 10043; Masferrer J. L. et al,
J. Clin. Invest.,
1990, 86, 1375).
Compounds that selectively inhibit COX-2 have been described in U.S. Pat. Nos. 5,380,738; 5,344,991; 5,466,823; 5,434,178; 5,474,995; 5,510,368; 5,521,207 and 5,604,260.
Compounds that selectively inhibit iNOS have been described in U.S. Pat. Nos. 5,132,453 and 5,273,875.
Combination therapies of NSAIDs with other drugs targeted at different mechanisms are known in the art. A combination of the analgesic diflunisal and an antispasmodic compound has been described (Basmajian
J., Spine,
1989, 14, 438). Also, a combination of ibuprofen with an antispasmodic to reduce morning stiffness in primary fibromyaglia syndrome (Fossaluzza V. and DeVita S.,
Int. J. Clin. Pharm. Res.,
1992, 12, 99) and a combination of tetracycline with flurbiprofen for the treatment of rheumatoid arthritis (Greenwald R. et al,
J. Rheumatol.,
1992, 19, 927) are known.
However, COX-2 inhibitors (and other NSAIDs) do not have complete efficacy and do not completely overcome the inflammatory condition being treated, even at optimal doses. There is therefore a need to improve the efficacy of COX-2 inhibitors. It has now been found that the efficacy of a COX-2 inhibitor can be improved if it is combined with a iNOS inhibitor, and as a result inflammatory diseases may be treated with a combination of an iNOS inhibitor and a COX-2 inhibitor. Although it has been said that some of the inflammatory actions of iNOS are dependent on the secondary activation of COX and an increase in prostaglandin formation (Salvemini D. et
Hamley Peter
Tinker Alan
Astrazeneca AB
Jarvis William R. A.
Nixon & Vanderhye
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