Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-01
2003-01-14
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06506785
ABSTRACT:
The present invention relates to the use of carprofen in mammals as a means of treating and preventing cartilage and subchondral bone injury and loss in the inflamed joints of such mammals. Such damage to the cartilage and subchondral bone is a natural sequelae of the process of osteoarthritis and its aftermath when it occurs in the mammal. The ability of carprofen to achieve this unexpected result is referred to as “chondroprotection”.
BACKGROUND OF THE INVENTION
Carprofen has been used heretofore as a COX-2 selective non-steroidal anti-inflammatory drug (NSAID) whose activity was based at least in part on the potent and selective inhibition of the inducible cyclooxygenase II (COX-2) isoenzyme. Such activity does not, however, exclude the possibility that carprofen, like other NSAIDs, possesses inhibitory activity with respect to the enzymes involved in the lipoxygenase pathway, or that it is active against the suppression, recruitment and migration of inflammatory cells and the release of enzymes and oxygen derived free radicals from such cells. While all of these activities would be understood in the art to have obvious relevance to the treatment of rheumatoid arthritis (RA), they would not be as clearly relevant to the treatment of osteoarthritis (OA). In fact, some NSAIDs are known to exacerbate the progress of OA and some pathologic cartilaginous and bone changes result from overuse of impaired joints as the result of NSAID-induced analgesia. This phenomenon is referred to as analgesic arthropathy.
OA has a complex multifactorial causality and considerable variability in its clinical expression, but synovial inflammation appears to be a key component of OA. Further, as a result of communication between synovial cells and cartilage cells (chondrocytes), synovial injury can stimulate the disaggregation of proteoglycans (PGs) and activated synovial cells produce an abundance of soluble factors, e.g., interleukin-1 (IL-1), tumor necrosis factor-&agr; (TNF-&agr;), and prostaglandins, which can induce loss of articular cartilage. Direct injury to chondrocytes also stimulates matrix matelloprotease (MMP) activity, e.g., collagenases, stromelysins and gelatinases, and the production of various inflammatory mediators. In any event, decreased functionality of joint articular cartilage is fundamental to the pathogenesis of OA. Depletion of the PGs from the tissues of OA joints subjects the chondrocytes and cells of the subchondral bone and synovium to abnormal mechanical stresses because of the resilience which the PGs confer on cartilage.
Cartilage is basically a PG aggregate comprising a protein-carbohydrate complex whose filamentous structure is built from a single, long hyaluronic acid molecule to which extended core proteins are bonded noncovalently. These protein chains, in turn, have chondroitin sulfate and keratin sulfate chains bound to them covalently through serine side chains. Hyaluronic acid, chondroitin sulfate and keratin sulfate are all examples of glycosaminoglycans (GAGs), i.e., polysaccharides comprising polymers of repeating disaccharide units in which one of the sugars is either N-acetylgalactosamine or N-acetylglucosamine. In cartilage the PG structure binds collagen and helps to hold the collagen fibers in a tight, strong network. Collagen fibers, in turn, are formed from the basic tropocollagen molecule, which is a triple helix of three polypeptide chains, each about 1000 residues in length.
Metabolic processes continuously occur in any given joint that are necessary for its repair and normalization subsequent to its being subjected to an insult such as a traumatic injury. Accordingly, in order for a compound to be an acceptable chondroprotective agent it must first of all be capable of sustaining such chondrocyte metabolic activity, i.e., of not inhibiting or interfering with the cellular replication and biosynthesis of matrix components which are part of the healing process. In this regard, the artisan will recognize that many NSAIDs display a marked inhibitory action on the biosynthesis of the principal components of the extracellular matrix. At the same time an acceptable chondroprotective agent must be capable of counteracting the degradative action of mediators such as various cytokines, prostaglandins and proteinases on the cartilage. Accordingly, it has been accepted in the art that potential chondroprotective drugs should be evaluated both as to their positive effects on anabolic pathways as well as to their ability to inhibit catabolic processes. Catabolic events which have typically been monitored include, inter alia, the release and inhibition of matrix degrading enzymes, effects on prostaglandin and leukotriene biosynthesis, and the ability of the test drug to inhibit IL-1 mediated degradation of articular cartilage. Anabolic events which have been studied have commonly included the ability of a test drug to stimulate the synthesis of protein, collagen, PGs, and hyaluronic acid (HA).
While the term “chondroprotective agent” as used herein will be understood to refer to those compounds whose chief site of action is the cartilage, it will also be appreciated that such chondroprotective agents may also possess anti-inflammatory action with regard to the synovium, may positively impact the biosynthesis of cells in subchondral bone and other connective tissues such as synovial fibroblasts, and may mediate inflammatory cell migration so as to impede the inflammatory process.
The present invention is applicable to all mammals generally because of the significant extent to which their shared evolution and embryogenic congruity produce similar cells, tissues and organ systems with homologous genetic codes that express comparable protein entities which operate in equivalent metabolic pathways. Mammals of all types are included within the scope of the present invention, since even the rarest of these may be held in captivity in a zoological institution and require the therapy provided by the present invention. It is preferred, however, that the present invention be directed to more numerous and economically significant species such as cats, dogs, cattle and bison, horses, pigs, sheep and goats. Some of these species are more susceptible or prone to problems of articular cartilage degeneration and loss than others. Thus, the therapy provided by the present invention is especially directed to cats, dogs and horses.
DESCRIPTION OF THE STATE OF THE ART
Commercial preparations which have been examined heretofore as potential chondroprotective agents include tiaprofenic acid, diclofenac sodium, tribenoside, pentosan polysulfate sodium, Arteparon® (a trademark of Luitpold-Werk, Munich, Germany), and Rumalon® (a trademark of Robapharm Limited, Basel, Switzerland). The diverse structures of these agents may be demonstrated or explained in the following manner:
None of the above-described compounds would in any way suggest carprofen and the carprofen derivatives used in the methods of treatment of the present invention.
Lust, G.; Williams, A. J.; Burton-Wurster, N.; Beck, K. A.; and Rubin, G.; “Effects of Intramuscular Administration of Glycosaminoglycan Polysulfates on Signs of Incipient Hip Dysplasia in Growing Pups”,
American Joumal of Veterinary Research,
53(10), 1992, 1836-1843, treated growing pups susceptible to hip dysplasia with GAG polysulfates available as Adequan® from Luitpold-Werk, Munich, Germany. Hip joints were examined radiographically and intra-articular tissues were evaluated macroscopically and biochemically. Lust et al. concluded that although there was a significant reduction of cartilage fibronectin content, the proteoglycan content and the observed joint pathologic score means were not statistically different between control and treated pups. An earlier study using the same drug was noted that had reported reduction in cartilage degeneration, inhibition of proteases, and promotion of proteoglycan formation in stifles of dogs when cruciate ligaments had been resected to create an unstable stifle, with subsequent development of osteoarthri
Evans Nigel A.
Kilroy Carolyn R.
Lundy Kristin M.
Pelletier Jean-Pierre
Ricketts Anthony P.
Criares Theodore J.
Ginsburg Paul H.
Kohn & Associates PLLC
Ling Lorraine B.
Pfizer Inc.
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