Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-02-19
2002-03-05
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S108000, C514S109000, C514S182000
Reexamination Certificate
active
06352970
ABSTRACT:
BACKGROUND OF INVENTION
This invention relates to the use of leptin and leptin mimetics to augment bone mass including the prevention and treatment of skeletal disorders such as osteoporosis in vertebrates, e.g., mammals, including humans.
Osteoporosis is a systemic skeletal disorder, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecast to increase three-fold over the next 60 years, and one study estimates that there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
In addition to hip fractures numbering approximately 250,000/year in the U.S., approximately, 20-25 million women and an increasing number of men have detectable vertebral fractures. Hip fracture is associated with a 12% mortality rate within the first two years and with a 30% rate of patients requiring nursing home care after the fracture. While this is already significant, the economic and medical consequences of convalescence due to slow or imperfect healing of these bone fractures is expected to increase, due to the aging of the general population.
There are currently two main types of pharmaceutical therapy for the treatment of osteoporosis and skeletal fractures. The first is the use of anti-resorptive compounds to inhibit the resorption of bone tissue and therefore prevent bone loss and reduce the incidence of skeletal fractures.
Estrogen is an example of an anti-resorptive agent. It is known that estrogen prevents post-menopausal bone loss and reduces skeletal fractures. However, estrogen fails to restore bone to the established osteoporotic skeleton. Furthermore, long-term estrogen therapy, however, has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment. The significant undesirable effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis.
A second type of pharmaceutical therapy for the treatment of osteoporosis and bone fractures is the use of anabolic agents to promote bone formation and increase bone mass. This class of agents is expected to restore bone to the established osteoporotic skeleton by stimulating osteoblastic bone formation. Currently, such pharmaceutical therapy is not available for established osteoporotic patents.
Leptin, a product of the obese gene, is a 16 kDa protein. Leptin is produced by mature adipocytes and is secreted in plasma. Leptin has been reported to increase lean body mass (Friedman et al., UK Patent Application No. GB 2292382 and Pelleymounter et al., International Patent Application Publication Number WO97/18833) and decrease fat body mass (Halaas et al., Science 269:543-546, 1995). Further, a leptin receptor, OB-R, has been identified and cloned (Tartaglia et al., Cell 83:1263-1271, 1995). Further, leptin has been disclosed to stimulate cortical bone formation in ob/ob mice (Liu et al., Americal Society for Bone and Mineral Research, 19th Annual Meeting, Sep. 10-14, 1997, Cincinati, Ohio).
Skeletal disorders are highly prevalent diseases caused by nutrition deficiency, sex steroid deficiency, aging, trauma or other factors. All approved therapies and clinically advanced candidates including calcitonin, estrogen replacement therapy, bisphosphonates and tissue selective estrogen agonists act to prevent bone loss by inhibiting bone resorption, but these agents cannot restore bone mass. Thus, there is significant medical need for agents that would increase bone mass and strength above a critical threshold in established osteoporotic patients, fractured patients, and other skeletal disorder patients.
SUMMARY OF THE INVENTION
This invention is directed to methods for augmenting bone mass and preventing bone loss in a vertebrate, e.g., a mammal (including humans) comprising administering to said vertebrate, e.g., a mammal, a therapeutically effective amount of leptin or a leptin mimetic.
This invention is also directed to methods for treating a vertebrate, e.g. a mammal (including a human being) having a condition which presents with low bone mass comprising administering to said vertebrate, e.g., mammal, having a condition which presents with low bone mass a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, prosthetic ingrowth, or inducing vertebral synostosis in a vertebrate, e.g. a mammal (including a human being) by administering to said vertebrate, e.g., mammal, suffering from or susceptible to osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, prosthetic ingrowth or vertebral synostosis a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., mammal, suffering from or susceptible to osteoporosis a therapeutically effective amount of a leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating osteotomy bone loss in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., a mammal, suffering from or susceptible to an osteotomy bone loss a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating alveolar bone loss in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., mammal, suffering from or susceptible to an alveolar bone loss a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating bone loss associated with periodontitis in a vertebrate, e.g., a mammal (including a human being) by administering to said vertebrate, suffering from or susceptible to bone loss associated with periodontitis a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating childhood idiopathic bone loss in a child by administering to a child suffering from or susceptible to childhood idiopathic bone loss a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating “secondary osteoporosis”, which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, suffering from or susceptible to “secondary osteoporosis” a therapeutically effective amount of leptin or a leptin mimetic.
Yet another aspect of this invention is directed to methods for treating glucocorticoid-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, suffering from or susceptible to glucocorticoid-induced osteoporosis a therapeutically effective amount of leptin or a leptin mimetic.
Yet
Ke HuaZhu
Steppan Claire M.
Swick Andrew Gordon
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