Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-11
2002-07-30
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S488000, C514S601000, C435S366000, C548S252000, C548S254000, C549S071000, C568S030000
Reexamination Certificate
active
06426359
ABSTRACT:
BACKGROUND OF INVENTION
This invention relates to the use of EP2 receptor subtype selective prostaglandin E2 agonists to augment bone mass including the prevention and treatment of skeletal disorders in 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 are expected to restore bone to the established osteoporotic skeleton. There are a variety of natural prostaglandins (e.g., PGE, PGD and PGF) that are implicated in skeletal metabolism. PGE2 has been reported to stimulate bone formation, increase bone mass and bone strength in animal models of osteoporosis when administered locally or systemically. However, there are severe side effects which are associated with PGE2 such as diarrhea, gastrointestinal bleeding, decreased food consumption, dehydration, weight loss and decreased physical activity. Accordingly, PGE2 has not found widespread use in humans because of these side effects.
Recently, four different subtypes of PGE2 receptors (EP1, EP2, EP3 and EP4) have been cloned (Funk, C. D., et al.,
Cloning and Expression of a cDNA for the Human Prostaglandin E Receptor EP
1
Subtype,
Journal of Biological Chemistry, vol. 268, No. 35, pp. 26767-26772, 1993; Regan, J. W., et al.,
Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmacologically Defined EP
2
Subtype,
Molecular Pharmacology, vol. 46, pp. 213-220, 1994; Yang, J., et al.,
Cloning and Expression of the EP
3-
Subtype of Human Receptors for Prostaglandin E
2, Biochemical Biophysical Research Communication, vol. 198, pp. 999-1006, 1994; Bastien, L., et al., Cloning,
Functional Expression and Characterization of the Human Prostaglandin E
2
Receptor EP
2
Subtype,
Journal Biological Chemistry, vol. 269, pp. 11873-11877, 1994). J. Bone Miner. Res. 1996, 11(supp.):S174 discussed the different subtyes of the PGE2 receptors. However, it is unclear whether one or more or these PGE2 receptor subtypes is selectively associated with bone anabolism of PGE2.
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 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 anabolic 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 a method for augmenting bone mass and preventing bone loss in a mammal (including humans) comprising selectively agonizing, one of the prostaglandin E
2
receptor subtypes, the EP2 receptor subtype by administering to a mammal a therapeutically effective amount of a selective EP2 receptor subtype agonist.
This invention is also directed to a method for treating (e.g., preventing) a mammal having a condition which presents with low bone mass comprising selectively agonizing the EP2 receptor subtype by administering to a mammal having a condition which presents with low bone mass a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to methods for treating (e.g., preventing) osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, prosthetic ingrowth, or inducing vertebral synostosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, prosthetic ingrowth or vertebral synostosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) osteoporosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from osteoporosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) osteotomy bone loss in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from an osteotomy bone loss a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) alveolar bone loss in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from an alveolar bone loss a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) bone loss associated with periodontitis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from bone loss associated with periodontitis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) childhood idiopathic bone loss in a child b
Cameron Kimberly O.
Ke Hua Z.
Lefker Bruce A.
Rosati Robert L
Thompson David D.
Benson Gregg C.
Munchhof Martha G.
Pfizer Inc.
Richardson Peter C.
Solola T. A.
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