Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-01-18
2002-04-09
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S473000, C514S027000
Reexamination Certificate
active
06369107
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions for use in the treatment of osteoarthritis (OA).
BACKGROUND OF THE INVENTION
Many drugs are known for the treatment of osteoarthritis, but in general their effectiveness is low, especially if side-effects are to be avoided. A known drug of this type is diclofenac sodium.
In normal articular cartilage (human as well as murine), monoamine oxidase in chondrocytes can be found located precisely in mitochondria. During the development of the natural disease in mice, these granules become larger and apparently burst, the monoamine oxidase (MAO) activity becomes distributed through the cytoplasm of the chondrocytes and even into the surrounding matrix. This was described by Chambers et al, Int. J. Exp. Path. 73:115-123 (1992), who related the MAO activity in the medial as against that in the (normal) lateral cartilage in untreated mice and in those treated with diclofenac.
The presumption from these findings was as follows: when circulating pharmacologically-active amines, such as adrenalin, enter normal chondrocytes they are detoxified by the MAO inside the mitochondria. Such detoxification requires both the close association of the MAO with the coenzyme FAD (flavine adenine dinucleotide) and the close presence of a peroxidase to remove the H
2
O
2
generated by the MAO activity. When the MAO occurs in the matrix of the cartilage, it is unlikely to be functional, because (i) it may have been disrupted from its coenzyme (FAD), and (ii) if it were to be operative, it would be generating H
2
O
2
which would be damaging to the matrix.
When diclofenac sodium was given to mice, there was a marked improvement in the localisation of the MAO in the potentially osteoarthritic cartilage. There was no sign of activity in the general cytoplasm or in the matrix.
It was suggested that the diclofenac molecule might become split to yield monoamines which would be a weak substrate for the relevant enzyme, and act as competitive inhibitors of the MAO activity. However, diclofenac sodium did not stop the development of OA in these mice.
Diclofenac sodium is related to fenamic acid. Derivatives of fenamic acid have been used as anti-inflammatory agents, particularly influencing the cyclooxygenase and/or 5-lipoxygenase systems; see U.S. Pat. No. 5,114,958.
SUMMARY OF THE INVENTION
The present invention is based on the postulate that two influences are involved in the development of OA: a cellular and an extracellular factor. The first is improved by, for example, diclofenac sodium or another compound having the same effect; the second, namely oedema of the matrix, is improved by, for example, tribenoside or another compound having the same effect. Whether or not the postulate is correct, it has been found experimentally that administration of diclofenac resulted in at least 9/10 mice having severe OA, but that a combination of the two drugs has resulted in 7/9 mice having no sign of OA.
A composition according to the present invention comprises compounds that respectively act on the chondrocytes and that reduce the water content of the chondrocyte matrix. These compounds can be given simultaneously or sequentially, for the prevention or treatment of OA.
REFERENCES:
patent: 4464376 (1984-08-01), Sunshine et al.
patent: 6034122 (2000-03-01), Chayen et al.
patent: 36 14 278 (1986-10-01), None
patent: 0 433 817 (1991-06-01), None
D.A. Kalbhen, “Arthrosis: medication and cartilagenous degeneration,” Le Concours Medical, vol. 108, No. 38, pp. 3273-3277, 1986.
Daniel Burkhardt et al., “Laboratory Evaluation of Antiarthritic Drugs as Potential Chondroprotective Agents,” Seminars in Arthritis and Rheumatism, col. 17. No. 2, supp. 1, pp. 3-34, Nov. 1987.
M.G. Chamber et al., “Chondrocytic monomine oxidase activity in the development of natural murine osteoarthritis,” Int. J. Exp. Path., 73, 115-123, 1992.
J. Chayen et al., “Modulation of Murine Osteoarthritis,” Cel Biochemistry and Function, vol. 14, pp. 57-61, 1996.
CA:98949; Kalbhen et al. (1983).
Bitensky Lucille
Chayen Joseph
Kagan Martin Roy
Jagoe Donna
Kagan Martin Roy
Krass Frederick
KS Biomedix Ltd.
Oliff & Berridg,e PLC
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