Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-12-02
2004-11-02
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S025000, C514S054000, C514S886000, C514S887000, C536S001110, C536S004100, C536S008000
Reexamination Certificate
active
06812215
ABSTRACT:
The present invention relates, e.g., to compositions and pharmaceutical compositions for the treatment and/or prevention of osteoporosis and/or inflammatory joint diseases, methods of treating and/or preventing osteoporosis and/or inflammatory joint diseases and the use of the aforementioned composition for the treatment and/or prevention of osteoporosis and/or inflammatory joint diseases.
BACKGROUND OF THE INVENTION
Osteoporosis (gr: osteon bone; poros hole) is described in general terms as a reduction in bone density with retention of a normal chemical composition. More specifically, osteoporosis is a generalized, progressive diminution of bone density, i.e. bone mass per unit volume, causing skeletal weakness, although the ratio of mineral to organic elements is unchanged. 30 to 40% of the skeletal mass must be lost in order to reliably diagnose osteoporosis by radiology. Contemporary medicine distinguishes between primary and secondary osteoporosis (The Merck Manual of Diagnosis and Therapy, 17th ed., 1999). Primary osteoporosis includes idiopathic osteoporosis, rare but occurring in children and young adults; postmenopausal osteoporosis, occurring between the ages of 50 and 75; and involutional or senile osteoporosis associated with the normal process of aging. It is characterized by a predominant osteoclast activity and a disruption of the feedback mechanism between the serum calcium level and the parathyroid hormone (PTH) secretion. It occurs mainly uniformly throughout the whole skeleton. Secondary osteoporosis, accounting for less than 5% of all osteoporosis cases, includes endocrine dysfunctions. It starts mostly at the main skeleton and progresses centrifugally. Osteoporosis is characterized by pain in the respective bones, diffuse back pain, vertebral body collapse, pathological fractures, in particular, fracture of the neck of the femur. The goal of the management of all types of osteoporosis is therefore to decrease pain, to prevent fractures and to maintain the body functions.
Osteoporosis is a common clinical feature and common complication in patients affected with chronic inflammatory diseases with joint manifestations. These include rheumatoid arthritis (RA), Juvenile Rheumatoid Arthritis (JRA), psoriatic arthritis, Reiter's syndrome (reactive arthritis), Crohn's disease, ulcerative colitis, sarcoidosis (Orcel, P.; Cohen-Solal, M.; de Vernejoul, M. C., and Kuntz, D. [Bone demineralization and cytokines]. Rev Rhum Mal Osteoartic. 1992 September; 59(6 Pt 2):16S-22S; Brown, J. H. and Deluca, S. A. The radiology of rheumatoid arthritis. Am Fam Physician. 1995 Oct; 52(5):1372-80; De Vos, M.; De Keyser, F.; Mielants, H.; Cuvelier, C., and Veys, E. Review article: bone and joint diseases in inflammatory bowel disease. Aliment Pharmacol Ther. 1998 May; 12(5):397-404; Falcini, F.; Trapani, S.; Civinini, R.; Capone, A.; Ermini, M., and Bartolozzi, G. The primary role of steroids on the osteoporosis in juvenile rheumatoid patients evaluated by dual energy X-ray absorptiometry. J Endocrinol Invest. 1996 March; 19(3):165-9; Scutellari, P. N. and Orzincolo, C. Rheumatoid arthritis: sequences. Eur J Radiol. 1998 May; 27 Suppl 1:S31-8).
Rheumatoid arthritis is associated with a decrease in bone mass (Cortet, B.; Flipo, R. M.; Blanckaert, F.; Duquesnoy, B.; Marchandise, X., and Delcambre, B. Evaluation of bone mineral density in patients with rheumatoid arthritis. Influence of disease activity and glucocorticoid therapy. Rev Rhum Engl Ed. 1997 July-Sep. 30, 1997; 64(7-9):451-8). Typical changes of an inflammatory arthritis include juxta-articular osteoporosis, cartilage loss, and cortical or marginal bone erosions (Lawson, J. P. and Steere, A. C. Lyme arthritis: radiologic findings. Radiology. 1985 January; 154(1):37-43; Grassi, W.; De Angelis, R.; Lamanna, G., and Cervini, C. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998 May; 27 Suppl 1:S18-24).
Joint inflammation exerts both local and systemic effects on skeletal tissues. Three forms of bone disease (bone loss) have been described in rheumatoid arthritis, namely: focal bone loss affecting the immediate subchondral bone and bone at the joint margins; periarticular osteopenia adjacent to inflamed joints; and generalized osteoporosis involving the axial and appendicular skeleton (Goldring, S. R. and Gravallese, E. M. Mechanisms of bone loss in inflammatory arthritis: diagnosis and therapeutic implications. Arthritis Res. 2000; 2(1):33-7).
During chronic inflammatory joint diseases, such as rheumatoid arthritis, synovial cells produce large amounts of cytokines leading to increased local bone resorption and juxta-articular bone destructions (Orcel, P.; Cohen-Solal, M.; de Vernejoul, M. C., and Kuntz, D. [Bone demineralization and cytokines]. Rev Rhum Mal Osteoartic. 1992 September; 59(6 Pt 2):16S-22S).
The cause of osteoporosis has not been fully clarified. According to one theory, osteoporosis is a calcium dysfunction and the use of calcium supplements has been widely suggested. However, so far, no reossification of the osteoporotic bone after calcium therapy could be demonstrated.
U.S. Pat. No. 5,478,579 describes a method for inducing and enhancing the absorption of calcium into mammalian bone tissue in order to treat metabolic calcium deficiencies in bone tissue, in particular osteoporosis. It was found that ossification of mammalian bone tissue could be enhanced by orally administering to a patient an effective dose of calcium in combination with a flavonol aglycone glycoside. It is believed that the flavonol aglycone glycoside affords an advantageous function through a chelation delivery system. Flavonols possess a benzene ring structure having available bonds to function as a chelate. Therefore, flavonols, due to their particular molecular structure, are capable of holding and delivering certain minerals, including calcium, to mammalian bone tissue. Also bone tissue would naturally absorb flavonol glycosides from the blood stream. It is further disclosed that the combination of the flavonol aglycone glycoside and calcium leads to an increased bone mineral density which would not have been obtainable through the use of simple calcium supplements.
Furthermore, quercetin, which is a related bioflavonoid and differs from the aforementioned flavonol compounds in that it does not contain the glycoside residue, has been shown to inhibit tumor necrosis factor-&agr; induced expression of interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in cultured human synovial cells. It was therefore suggested that quercetin can be used in the treatment of rheumatoid arthritis which is an autoimmune disorder that involves inflammation mainly in synovial tissues of joints (Sato et al., The Journal of Rheumatology, 1997; 24:9, p. 1680). In addition, the relation between interleukins and cytokines and metabolic bone diseases was studied (Pumarino et al., Rev Med Chile 1996; 124: p. 48). It could be shown that interleukin 1, 6 and 11, transforming growth factor and tumor necrosis factor stimulate osteoclast mediated bone resorption. Interleukin 1 is the most potent bone resorption agent. Although the role of interleukin 1, 6, 11 and the tumor necrosis factors is not quite clear, they appear to have a depressing effect on bone formation.
Cohen et al. (Israel Journal of Medical Sciences, 17, 1981, p. 1123) investigated the cause of an increased crystallinity index in bone tissue found in iliac crest bone samples from postmenopausal osteoporotic women by chemical analysis. The percentage of crystallinity should be regarded as an index that assumes that mature bone is only apatitic and this provides a measure of crystal size and perfection. It could be demonstrated by Cohen et al. that osteoporotic women have low total body magnesium stores. It could also be shown that magnesium exerts its action as a crystal poison in the nucleation and growth of apatite and its precrystalline intermediate. Therefore, osteoporotic bone, i.e. bone mineral with a lower magnesium content, has larger a
Buchholz Herwig
Meduski Jerzy
McIntosh III Traviss C.
Merck Patent Gesellschaft mit beschränkter Haftung
Millen White Zelano & Branigan P.C.
Wilson James O.
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