Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-08-19
2004-09-07
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S825000, C530S324000, C530S399000
Reexamination Certificate
active
06787518
ABSTRACT:
TECHNICAL FIELD
This invention relates to drugs having either preventive or therapeutic effect on osteoarthritis and other diseases that involve the destruction and degeneration of the articular cartilage tissue.
BACKGROUND ART
Osteoarthritis involves the collapse of the articular cartilage surface and the resulting growth of new cartilage at the articular margins, joint deformity and loss of compliance, which are eventually manifested as the inflammation of the synovial membrane of the joint. Osteoarthritis is divided into two types, primary and secondary. Secondary osteoarthritis has predisposing causes such as trauma and infection that lead to the degeneration of cartilage but no predisposing cause can be identified in primary osteoarthritis. The principal lesion of osteoarthritis is the degeneration of articular cartilage and it may be attributable to the endogenous degeneration of articular cartilage and the mechanical stress on the joint; however, the mechanism of its etiology remains unknown in many aspects. Two major pathological phenomena occur in osteoarthritis. In one case, accelerated calcification of subchondral bone causes narrowing of joint fissures and destruction of the bone tissue (Bollet, A. J., Arthritis Rheum. 12, 152-163, 1969); in the other case, synovial inflammation causes either destruction or degeneration of the cartilaginous tissue (Huskisson, R. C. et al., Ann. Rheum. Dis. 38, 423-428, 1979; Campion, G. V. et al., Seimnars in Arthritis and Rheumatism 17, 232-245, 1988).
In inflammatory osteoarthritis, an observable decrease of proteoglycans (a matrix component of cartilaginous tissue) occurs due to such substances as IL-1 produced as from the synovial tissue (Tyler, J. A., Biochem. J. 225, 493-507, 1985); in addition, the production of proteoglycans by chondrocytes is suppressed (Ratcliffe, A., Biochem. J. 238, 571-580, 1986). As a result, the cartilage matrix would decrease (Pettipher, E. R. et al., Proc. Natl. Acad. Sci. USA 83, 8749-8753, 1986) to cause gradual loss of the articular cartilage layer.
The cartilage in the Joint tissue is classified as a permanent cartilage which is strictly distinguished from a grown cartilage which plays an important role in skeletal growth. Grown chondrocytes typically occurring in epiphysial cartilage plate go through the stages of growth, differentiation and calcification until they are replaced by bone, whereupon they fulfill their physiological function. In contrast, articular cartilage cells do not normally become calcified; this is because environmentally, calcification is strongly restrained from occurring in articular cartilage cells and because it is not calcified, the articular cartilage retains elasticity to thereby serve as a load-bearing cushion and assure high mobility at the joint. However, the elasticity of the articular cartilage surface is known to decrease in osteoarthritis (Myers, E. R. et al., Trans. Orthop. Res. USA 231, 1986). This is believed to be attributable to the rupturing of collagen fibers in the cartilaginous tissue (Stockwell, R. A. et al., J. Anat. 136, 425-439, 1982). The mechanism by which calcification is suppressed in the articular cartilage is not clear but calcification does take place when isolated articular cartilage cells are cultivated. Most probably, the strong suppressor of calcification of articular cartilage exists within the matrix surrounding the chondrocytes (Iwamoto, M. et al, J. Biol. Chem. 266, 461-467, 1991; Pacifici, M. et al., Exp. Cell Res. 192, 266-270, 1991).
Other differences can be found between the calcifying chondrocytes and the articular artilage cells. The calcifying cartilage hash alkaline phosphatase activity (Robinson, R., Biochem. J. 17, 286-293; 1923; Ali, S. Y., in “Cartilage” (B. K. Hall, ed.), Vol. 1, pp. 343-378, Academic Press, New York) whereas only a hundredth of that activity is exhibited by the articular cartilage tissue (Iwamoto, M. et al., J. Biol. Chem. 266, 461-467, 1991). The cartilage matrix contains type X collagen and this occurs in a calcified cartilaginous tissue (Capasso, O. et al., Exp. Cell Res., 142, 197-206, 1982) but its occurrence is limited in the articular cartilage. It has been suggested that these markers are associated with the calcification of chondrocytes (Kato, Y. et al., Proc. Natl. Acad. Sci. USA 85, 9552-9556, 1988; Kwan, A. P. L. et al., J. Cell Biol. 109, 1849-1856, 1989). In osteoarthritis, articular cartilage cells have a higher alkaline phosphatase activity than normal articular cartilage cells (Mokondjimobe, E. et al., 39, 759-762, 1991) and it has been found in a study using human articular cartilage tissue that an osteoarthritic tissue has a higher alkaline phosphatase activity (Einhorn, T. A. et al., J. Orthop. Res. 3, 160-169, 1985). Similarly, the occurrence of type X collagen has been shown to be high in the cartilaginous tissue from patients with osteoarthritis (Hoyland, J. A. et al., Bone Miner. 15, 151-164, 1991). Based on these findings, it is speculated that the calcification of the cartilaginous tissue or subchondral bone in osteoarthritis is attributable to changes in the characters of articular cartilage cells, namely, the production of alkaline phosphatase and the occurrence of type X collagen.
The currently practised therapeutic regimens against osteoarthritis are no more than nosotropic or indirect as exemplified by preservative therapy, administration of anti-inflammatory agents or hyaluronic acid, and surgical treatments and there is no established therapeutic approach that may well be described as being “etiotropic”.
The purpose of the invention is to provide medicines which serve not only as preventives of osteoarthritis and other diseases that involve the destruction and degeneration of the articular cartilage tissue but also as etiotropic and direct therapeutics of such diseases.
DISCLOSURE OF INVENTION
Briefly, the present invention relates to preventives or therapeutics of diseases that involve the destruction and degeneration of the articular cartilage tissue, said preventives and therapeutics containing a PTH related peptide (PTHrP) or a PTHrP derived substance as an effective ingredient.
The parathyroid hormone related peptide (PTHrP) to be used in the invention embraces native PTHrP, PTHrP created by genetic engineering techniques and chemically synthesized PTHrP and may be exemplified by human, bovine and porcine PTHrP that are composed of 141 amino acids, with human PTHrP being preferred. The term “PTHrP derived substance” means partial peptides of the above-listed PTHrPs, as well as peptides that are obtained by partial modification of constituent amino acids of the PTHrP or partial peptides thereof through substitution, deletion or addition and which have the same activity. Examples of partial peptides of PTHrP include 1-34PTHrP, 1-84PTHrP, 3-141PTHrP, 7-141PTHrP, 35-141PTHrP, 85-141PTHrP, 107-141PTHrP, 107-140PTHrP, 1-87PTHrP, 3-87PTHrP, 7-87PTHrP, 1-111PTHrP, 3-111PTHrP and 7-111PTHrP, with human 1-34PTHrP and human 1-84PTHrP being preferred.
The 1-34PTHrP designates a partial peptide of PTHrP which is composed of 34 amino acids as counted from the N terminus of PTHrP. The number of amino acid residues to be substituted, deleted or added is not limited to any particular value as long as the activity intended by the present invention is retained. Diseases that involve the destruction and degeneration of the articular cartilage tissue include osteoarthritis and rheumatoid arthritis, with osteoarthritis being preferred.
As already mentioned, type X collagen and alkaline phosphatase are known to be critical substances that occur during calcification of cartilage or subchondral bone and suppressing the occurrence of type X collagen and the production of alkaline phosphatase is effective for the purpose of ameliorating osteoarthritis. Other findings on osteoarthritis are the lowering of the ability of articular cartilage cells to synthesize the matrix and the deformity of cartilaginous tissue by matrix decomposition; in view of this, a preferred therapeutic of osteoarthr
Iwamoto Masahiro
Kato Yukio
Koike Tatsuya
Browdy and Neimark , P.L.L.C.
Saunders David
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