Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-12-15
2001-11-06
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S725000
Reexamination Certificate
active
06313168
ABSTRACT:
BACKGROUND OF THE INVENTION
Articular cartilage is a unique tissue present in the joints in the limbs, trunk and cervical region. The tissue is composed of articular chondrocytes and an abundant extracellular matrix that contains several well characterized macromolecules, including proteoglycan aggregates, hyaluronic acid, link protein and type II collagen fibrils. The chondrocytes are responsible for the synthesis, deposition and maintenance of the matrix components. The proteoglycan aggregates are large supramolecular structures that bind large quantities of water molecules and ions and provide the tissue with bioelasticity. The collagen fibrils form a three dimensional network that is able to withstand tensile and shear forces and provides the tissue with tensile strength. Together, the proteoglycan aggregates and collagen fibrils are responsible for a fundamental biomechanical property of articular cartilage, resilience. This property allows the tissue to undergo reversible changes in shape and volume that result from physical forces acting on the joints during movement, and thus permit normal functioning of the joints. Under normal healthy circumstances, articular chondrocytes remain active and phenotypically stable throughout life; in turn, this allows articular cartilage to maintain its structural and organization characteristics and to perform its biomechanical roles in the joints throughout life.
Endochondral ossification is the process by which the cartilaginous skeletal elements present in the embryo and growing organism are replaced by definitive bone elements. The process starts in the second half of embryogenesis and is concluded at the end of puberty when skeletal growth ceases. Endochondral ossification is a highly-regulated multistep process that involves several distinct steps of chondrocyte maturation and is best appreciable in long bone growth plates in the limbs. During endochondral ossification, resting immature chondrocytes first undergo a phase of rapid cell proliferation. The cells then withdraw from the cell cycle and enter a phase of active matrix production. Matrix components synthesized at this step are typical cartilage matrix macromolecules, including proteoglycans (aggrecan), type II collagen, link protein and hyaluronan. The postmitotic matrix-synthesizing cells then begin to enlarge in size and change from flat to oval-round in shape. This step is called the pre-hypertrophic stage and is characterized by synthesis of new proteins, including the signaling factor Indian hedgehog. The cells continue to enlarge and advance to their ultimate stage of maturation, the hypertrophic stage. The biosynthetic repertoire of hypertrophic chondrocytes changes dramatically, and the cells initiate production of various new proteins including: metalloproteases, type X collagen, alkaline phosphatase and annexin V-rich matrix vesicles. As they undergo these changes in biosynthesis, the hypertrophic chondrocytes also begin synthesis of bone-characteristic type I and III collagens and deposit apatite crystals in the matrix, thus transforming hypertrophic cartilage into a bone-like tissue. Finally, they undergo apoptosis. As a result, the tissue becomes amenable to invasion by bone and bone marrow precursor cells, which then proceed to remove the hypertrophic tissue and replace it with definitive bone tissue.
A large number of studies have been carried out during the last several years to identify and characterize the mechanisms regulating endochondral ossification. Interest in these mechanisms reflects the fact that defects in endochondral ossification are associated, and probably cause, congenital and acquired conditions of skeletogenesis (Jacenko et al.,
J. Rheumatol
. 22:39-41 (1995)). Interestingly, several molecules have been shown to have a negative role in endochondral ossification and to limit the rates at which chondrocytes progress from the immature to the hypertrophic stage. These molecules include fibroblast growth factor-2 (FGF-2), fibroblast growth factor receptor-3 (FGF-R3), parathyroid-related protein (PTH-rP), and Indian hedgehog (IHH) (Coffin, et al.,
Mol. Biol. Cell
, 6:1861-1873 (1995); Colvin et al.,
Nature Genet
., 12:390-397 (1996); Vortkamp et al.,
Science
, 273:613-622 (1996)). However, very few positive factors have been identified to date, which would have the critical role of counteracting the negative factors and allow the endochondral process to advance and reach its conclusion.
Pathologies associated with bone growth include osteoarthritis. Osteoarthritis is a degenerative disease of the joints that causes progressive loss of articular tissue. The disease, for which presently no cure or effective treatment exists, affects over 10% of the population over 60 years of age. Osteoarthritis is probably initiated by a number of factors, including mechanical insults derived from life-long use of the joints. Once articular cartilage is damaged, the disease progresses and numerous changes occur in the cells and matrix. At sites most affected by the disease, the articular chondrocytes can reinitiate proliferation and begin to acquire abnormal phenotypic traits. These include synthesis of type I and III collagens, cell hypertrophy, type X collagen synthesis, alkaline phosphatase activity increased proteolytic activity and even matrix mineralization (Hamerman,
New Engl. J. Med
. 320, 1322-1330 (1989); Nerlich, et al.,
Vichows Archiv. B. Cell Pathol
. 63, 249-255 (1993); von der Mark, K. et al.,
Acta Orthop. Scand
. 266, 125-129 (1995)). At the same time, while synthesis of proteoglycans increases, net proteoglycan content decreases because of increased matrix degradation by metalloproteases and other degradative enzymes. There are also reports that the articular chondrocytes can display signs of cellular degeneration and apoptosis. Once the articular cells disappear and the matrix degenerates, the tissue is replaced by non-fimctional scar tissue or even bony tissue.
Thus, a need exists for effective therapeutic methods for the treatment of cartilage and bone pathologies, including bone growth related diseases such as osteoarthritis.
SUMMARY OF THE INVENTION
The present invention provides a method for treating a cartilage or bone pathology comprising administering a therapeutically effective amount of a retinoid receptor antagonist. According to one preferred embodiment, the retinoid receptor antagonist is an RAR receptor antagonist, and preferably an RAR&agr;&bgr;&ggr; receptor antagonist.
The present invention further provides a method for treating a cartilage or bone pathology comprising antagonizing RAR&ggr; receptors associated with the pathology.
In a further embodiment, the present invention provides a method for ameliorating the symptoms associated with cartilage and bone pathologies comprising administering a therapeutically effective amount of a retinoid receptor antagonist.
The invention additionally provides a method for treating a cartilage or bone pathology comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a retinoid receptor antagonist and a pharmaceutically acceptable carrier or excipient.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of treating cartilage and bone pathologies, including bone growth related diseases, comprising the use of retinoid receptor antagonists. Bone growth related diseases include those involving pathological ossification such as osteoarthritis, multiple cartilaginous exostoses and osteoblastic tumors including osteoid osteoma, osteosarcoma and osteoma; and osteitis deformans (see generally,
Pathological Basis of Disease
, Robbins, et al. W. B. Saunders Co. (1979)). At the molecular level retinoids exert their biological effects through two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which belong to the superfamily of steroid/thyroidlvitamin D3 nuclear receptors.
RARs and RXRs are ligand-dependent transcription factors which regulate gene expression in at least two
Chandraratna Roshantha A.
Pacifici Maurizio
Allergan Sales Inc.
Fay Zohreh
LandOfFree
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