Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-09
2001-04-24
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S255010, C514S357000, C514S523000, C514S825000
Reexamination Certificate
active
06221861
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to the use of an existing class of calcium blocking drugs, or calcium antagonists for the correction of an underlying metabolic abnormality responsible for calcium pyrophosphate crystal formation and the resulting development of one of the most recently recognized forms of crystal-induced arthritis from deposition of these crystals in the cartilage of major joints.
BACKGROUND OF THE INVENTION
The first two decades of the past half-century marked the first successful treatment in a preventive mode of the most anciently recognized form of crystal-induced arthritis—gouty arthritis, by simply reducing the supersaturated concentrations of serum urate to the normal range by use of new drugs that became available. (Seegmiller, J E., “Conquest of Gouty Arthritis” in
Landmark Advances in Rheumatology,
ed. McCarty, D J (Amer. Rheum. Assn., Atlanta, Ga.) pp. 89-101 (1985)). It may well serve as a model for similar success with the above new and as yet unpublished finding. An important difference is that the elevated pyrophosphate was first found inside, instead of outside, the cells (Lust, G., et al.
Arthritis Rheum
(1976) 19:479-487). Inorganic pyrophosphate (PPi) serves a number of different biological functions. In bone and growth plate cartilage, extracellular inorganic PPi provides a critical source of phosphate (Pi) for the physiologic deposition of calcium phosphate crystals during bone mineralization (Ali, Y., “Calcification of Cartilage” in
Cartilage: Structure, Function, Biochemistry,
ed. Hall, BK (Academic, New York), pp. 343-378 (1983); Oyajobi, B O, et al.,
J Bone Miner Res
(:1259-1266 (1944); Anderson, H C,
Rhem Dis Clin North Am
14:303-319 (1988), and Rosen et al., Arthritis & Rheumatism, 40:7 (July 1997)).
Although PPi is required for the induction of calcification (Russell, R G, et al.,
Calcif Tissue Res.
(1970) 6:183-196; Siegel, S A et al., (1983)
J Biol Chem
258:8601-8607), an excess of free PPi in relation to Pi suppresses mineralization by inhibiting hydroxyapatite crystal nucleation from amorphous calcium phosphate (Ali, Y., “Calcification of Cartilage” in
Cartilage: Structure, Function, Biochemistry,
ed. Hall, BK (Academic, New York), pp. 343-378 (1983); Oyajobi, B O, et al.,
J Bone Miner Res
(:1259-1266 (1944); Anderson, H C,
Rhem Dis Clin North Am
14:303-319 (1988), and Rosen et al., Arthritis & Rheumatism, 40:7 (July 1997)). Chondrocytes in articular cartilage have the unique ability to constitutively elaborate extracellular PPi in large amounts (Rosenthal, A K et al. (1993)
Arthritis Rheum.
36:539-542; Derfus, B A et al.,
Arthritis Rheum
35:231-240 (1992)), which helps to suppress mineralization of the avascular cartilage matrix (Poole, A R (1992) in
Arthritis and Allied Conditions,
eds., McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 335-345).
PPi elaboration is governed by the balance between PPi formation and degradation (Rachow, J W and Ryan, L M (1988)
Rheum Dis Clin North Am
14:289-302). PPi generation is a byproduct of many synthetic reactions in the cell (Rachow, J W and Ryan, L M (1988)
Rheum Dis Clin North Am
14:289-302) and is a direct product of enzymes that have nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity. PPi degradation is affected by several inorganic pyrophosphatases, including alkaline phosphatase. (Rachow, J W and Ryan, L M (1988)
Rheum Dis Clin North Am
14:289-302, Rasmussen, H. (1983) in
The Metabolic Basis of Inherited Disease,
eds. Stanbury, H., et al., (McGraw-Hill, New York), pp. 1497-1507).
Regulation of NTPPPH activity, and of other factors that modulate elaboration of extracellular PPi in cartilage and bone, appears critical not only to physiologic mineralization, but also to the development of certain disorders of pathologic mineralization (Anderson, H C,
Rhem Dis Clin North Am
14:303-319 (1988). One example is a prevalent disease of the elderly known as idiopathic chondrocalcinosis. In this disease, the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in articular cartilage is strongly linked to substantial increases in NTPPPH activity and PPi concentration (Tenenbaum, J. et al., (1981)
Arthritis Rheum
24:492-500; Ryan, L M and McCarty, D J (1992) in
Arthritis and Allied Conditions,
eds., McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 1835-1856; Jones, A C, et al., (1992)
Semin Arthritis Rheum
22:188-202).
In addition, a 2-3-fold increase in intracellular PPi has been found in cartilage cells, fibroblasts, and lymphoblasts cultured from chondrocalcinosis patients (Lust, G. et al., (1976)
Arthritis Rheum
19:479-487; Lust, G., et al., (1981)
Science
214:809-810; Ryan, L M, et al. (1986)
J Clin Invest
77:1689-1693). The capacity of CPPD crystals to activate an inflammatory response can promote acute and chronic inflammatory synovitis and cartilage degeneration (Ryan, L M and McCarty, D J (1992) in
Arthritis and Allied Conditions,
eds., McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 1835-1856; Terkeltaub, R. (1992) in
Arthritis and Allied Conditions,
eds. McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 1819-1833). Moreover, the presence of CPPD crystal deposition commonly complicates prior articular injury and is an adverse prognostic factor in osteoarthritis (Ryan, L M and McCarty, D J (1992) in
Arthritis and Allied Conditions,
eds., McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 1835-1856; Sokoloff, L. & Varma, A A (1988)
Arthritis Rheum
31:750-756).
“Pseudogout” was the term first used to describe the clinical syndrome of acute gout-like arthritis associated with the presence of crystals of calcium pyrophosphate dihydrate in synovial fluid (McCarty, D J et al., I. Clinical aspects.
Ann Intern Med
56:711 (1962). Also, see Seegmiller, J E, “Gout and Pyrophosphate Gout (Chondrocalcinosis,”) in
Principles of Geriatric Medicine and Gerontology,
Third Edition, 1994, Hazzard, W., et al., eds., McGraw-Hill, Inc., pp. 987-994). Subsequent studies showed this gout-like presentation to be just one aspect of the far larger range of clinical presentations of patients showing radiologic evidence of a characteristic pattern of calcification within the joints, which is called “chondrocalcinosis” (Zitnan, D., and Sitaj, D.,
Cesk Radiol
14:27 (1960)) and more precisely designated as “calcium pyrophosphate dihydrate crystal deposition disease” (CPDD) (Ryan, L M, and McCarty, D J, “Calcium Pyrophosphate Crystal Deposition Disease: Pseudogout: Articular Chondrocalcinosis,” in McCarty, D J (ed):
Arthritis and Allied Conditions: A Textbook of Rheumatology,
10th ed., Philadelphia, Lea & Febiger, 1985, p. 1515). Since these multiple names for the same basic pathological process are confusing to both students and professionals, a subcommittee of the American College of Rheumatology has recommended the name “pyrophosphate gout” as being a more specific and simple designation for naming this disorder in a whole family of pathological states that would include apatite gout, cholesterol gout, and oxalate gout, with the prototype, urate gout, being referred to simply as “gout.” (Simkin, P A,
JAMA
260:1285 (1988)).
Pyrophosphate gout shows similarities to gouty arthritis in that it is a crystal-induced arthritis with intermittent acute attacks associated with appearance of crystals within phagocytes in the joint fluid and a consequent acute inflammatory reaction (Ryan, L M, and McCarty, D J, “Calcium Pyrophosphate Crystal Deposition Disease: Pseudogout: Articular Chondrocalcinosis,” in McCarty, D J (ed):
Arthritis and Allied Conditions: A Textbook of Rheumatology,
10th ed., Philadelphia, Lea & Febiger, 1985, p. 1515; McCarty, D J, et al, (1962), Ann Intern Med 56:711). The overall incidence of pyrophosphate gout increases markedly in later years of life. It is seldom seen in patients below age 50 except in familial forms of the disease. However, X-ray evidence of the disease has been found in some 44 percent of patients over age
Krass Frederick
Mandel & Adriano
The Regents of the University of California
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