Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-04-02
2003-09-02
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000
Reexamination Certificate
active
06613758
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a treatment for slowing or preventing the progression of osteoporosis in surgically or chemically castrated prostatic cancer patients.
BACKGROUND OF THE INVENTION
Osteoporosis is generally the occurrence of a reduction in the quantity of bone, or the atrophy of skeletal tissue. This disorder is evidenced by a decrease in bone density throughout the body. Although the mechanism of osteoporosis is not entirely understood, it is believed that there is an imbalance between bone production and bone resorption, resulting in net bone resorption or breakdown. The condition can begin to occur as early as age 30. The process is typically more rapid in postmenopausal women than in men. Bone loss in males can be recognized at about 65 years of age. A significant bone loss is seen in men at about 80 years of age, and is accompanied by increased hip, spine and wrist fractures.
Surgical and chemical (e.g., LH-RH agonists) castration are widely used for the treatment of patients with prostate cancer. A number of side effects occur as a result of such therapy. Impotence and the occurrence of hot flashes are among the more distressing side effects to patients.
A less noted side effect of surgical or chemical castration is osteoporosis. It has been reported that orchiectomy for prostate cancer is often followed by severe osteoporosis (Daniell, H. W., J. Urol. 157:439-444, 1997). Castration of man and many animal species retards skeletal growth and development. Orchiectomy in rats can cause osteoporosis detectable from within two to four months. (Winks and Felts, Calcif. Tissue Res. 32:77-82 (1980); Verhas et al., Calcif. Tissue Res. 39:74-77 (1986)).
Unlike the evident side effects of orchiectomy or LH-RH agonist treatment, the pronounced onset of osteoporosis can be insidious since the risk of osteoporetic fracture increases rapidly. Moreover, these patients are preoccupied with adjusting to their treatment and addressing basic quality of life issues rather than taking measures to deter bone loss. Because of pain or their overall condition, many of these patients are not up to exercising, for instance.
It is thought that the sudden reduction in androgen levels effected by surgical castration or medical castration (e.g., LH-RH agonist treatment) in these men causes or is an important factor contributing to the degree of bone loss that can occur. (Daniell, H. W. J. Urol. 157:439-444, 1997). The correlation between the reduction in levels of adrenal estrogen in women during the menopause and the onset of osteoporosis is well known. In both sexes, the clinical situation can be described as an acquired gonadal insufficiency. Furthermore, it has been suggested that androgens increase the synthesis of bone matrix. Studies in animals have shown that testosterone administration increases the overall quantity of bone. (Silberberg and Silberberg, 1971; see Finkelstein et al., Ann. Int. Med. 106:354-361, 1987).
Estrogen replacement therapy has been the therapy of choice for osteoporosis in post-menopausal women. For men, estrogens may be effective to treat osteoporosis, but at the risk of gynecomastia and increased cardiovascular morbidity.
U.S. Pat. No. 5,541,172 to Labrie et al. addresses methods of treatment of diseases responsive to activation of the androgen receptor. The patent indicates methods for prevention and therapy of breast and endometical cancer, as well as osteoporosis. An androgenic steroid is administered such that circulating serum levels are maintained at low concentrations of between 1.0 and 50.0 nanomoles per liter. This cumulative dose is provided by administering the steroid within a sustained release formulation to avoid fluctuating blood levels.
Also discussed by the Labrie et al. patent are contentions that some synthetic progestins possess, in addition to their progesterone-like activity, varying degrees of androgenic activity. Labrie et al. indicate that progestins frequently have a high affinity for the androgen receptor at the low plasma concentrations mentioned. The patent reports on the use of medroxyprogesterone acetate and megestrol acetate. It also indicates that certain synthetic progestins or anabolic steroids including, for example, nor-testosterone, ethisterone and cyproterone acetate, possess androgenic activity at low concentrations in the in vitro system of human breast cancer ZR-75-1 cells.
The Labrie et al. patent advises assessing the specific interactions of a compound at the indicated concentrations with the androgen receptors, including estrogen, progesterone and glucocorticoid-mediated activities. At low concentrations, the compounds of interest to Labrie et al. do not interact with the glucocortioid receptor. Thus, masculinizing side effects of androgens in the treatment of women can be avoided. The patent further advises evaluating by in vitro assay the effects of a potential compound on the various receptors indicated in ZR-75-1 human breast cancer cells. The focus of the patent on the treatment of women who have diseases responsive to activation of the androgen receptor, particularly estrogen-dependent diseases, is apparent.
U.S. Pat. No. 5,567,695 to Labrie is related to the above discussed Labrie et al. patent and similarly reports a method for preventing osteoporosis. An androgenic steroid having a Ki of less than 2×10
−8
M for the androgen receptor and having a receptor-mediated inhibitory effect on the growth of human breast cancer ZR-75-1 cells is used, where the dosage is sufficiently low to maintain a cumulative androgenic steroid serum concentration below 50 nanomoles per liter. Similar to the above Labrie et al. patent, the compounds are indicated to have the special property of potent androgenic activity at these low blood concentrations, while exhibiting little glucocorticoid activity, and therefore, they produce no visible masculinizing effects.
It has been suggested that progestational agents can potentiate bone mineralization, although the definitive effect of progesterone on bone is apparently not known. (Loprinzi, et al., N. Engl. J. Med. (1994) 331:347-352).
Cyproterone acetate (“CPA”) is disclosed in U.S. Pat. No. 3,234,093, which is incorporated herein by reference. CPA, a synthetic 21-carbon hydroxyprogesterone derivative, is a steroidal antiandrogenic agent that inhibits the action of adrenal and testicular androgens on prostatic cells, resulting in total androgen blockade. Additionally, due to the antigonadotropic effects of its progestogenic activity, CPA causes a centrally mediated reduction in testicular secretion of androgens. The progestational activity of CPA is considered relatively weak. (Goldenberg, S. L. et al., Pharmanual 1994, Current Perspectives on the Expanding Role of Androcur,® Pharma Libri Publishers Inc., at p. 21).
CPA is approved for use in many countries throughout Europe, Asia, Australia, South America and Canada. It is used as a component of oral contraceptives and in the treatment of acne, seborrhea, hirsutism, precocious puberty, hypersexuality and in the treatment of prostate cancer. The pharmaceutical preparations Androcur®, Cyprostat®, Diane® and Dianette® are CPA-based products. Manufacturers of these products include Schering AG, Berlin, Germany and Berlex, Canada.
Since 1966, CPA has been used in combination with bilateral orchiectomy to achieve total androgen blockade in the treatment of prostate cancer. CPA has also been administered as monotherapy for prostate cancer. The potent antiandrogenic activity of CPA is “cancerocidal” to prostate cancer cells. Dosages of 250-300 mg/day are used to bring about a complete anti-androgenic blockade. Dosages prescribed are usually 200-300 mg/day, divided into 2-3 doses. After orchiectomy a lower daily dose of 100-200 mg may be recommended. In a study reported in 1972 by Bracci and DiSilvero (discussed in Goldenberg, S. L. et al., Pharmanual 1994, Current Perspectives on the Expanding Role of Androcur,® Pharma Libri Publishers Inc., p. 23-24), CPA was administered at 100 mg/day or more with o
Barr Laboratories, Inc.
Chadbourne & Parke LLP
Gersh Kathleen
Goldberg Jerome D.
Waddell Mark E.
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