Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-02-16
2004-03-09
Brumback, Brenda (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S800000, C530S313000, C530S328000
Reexamination Certificate
active
06703367
ABSTRACT:
BACKGROUND OF THE INVENTION
Menopausal women frequently experience a variety of symptoms which have been attributed to estrogen deprivation due to ovarian failure. Occurring in up to 85% of menopausal women, the most common and most characteristic symptom of menopause is an episodic disturbance consisting of sudden flashing and perspiration, referred to as the“hot flash.” Vasomotor hot flashes are also the most frequent side effect associated with the anti estrogen drug Tamoxifen, used in the treatment of breast cancer. Non-hormonal related causes of hot flashes also exist even though they are not very common. One example is a deficiency or low, level of alcohol dehydrogenase. People with such deficiency may, be particularly prone to flushing with alcohol intake. Other rare causes of hot flashes include carcinoid syndrome or pheochromocytoma.
Although hot flashes are most commonly treated by estrogen replacement therapy (orally, transdermally, or via an implant), some women cannot tolerate estrogen treatment. In addition, estrogen is usually not recommended for women with hormonally, sensitive cancers (e.g. breast cancer). Other options have been studied for the treatment of hot flashes, including steroids, alpha-adrenergic agonists, and beta-blockers, with varying degree of success. Progestins, like Megestrol acetate and Medroxyprgesterone, have been shown to reduce hot flashes to 25-85% and 75-100% respectively, but the long-term effects of progestin therapy have not been studied. It is possible that side effects like thromboembolic disorders, edema, weight gain, lipid changes, and death due to cardiovascular disease make the use of this treatment unattractive.
Central nor adrenergic activity is believed to play a a role in the initiation of hot flashes. Therefore, agents that inhibit the release of nor epinephrine have also been used to ameliorate hot flashes. CLONIDINE™ (administered transdermally) reduced the frequency and severity of hot flashes due to Tamoxifen, but the results for orally administered clonidine varied. Side effects associated with the clonidine treatment included drowsiness, constipation, orthostatic hypotension, dry mouth, headache, nausea, fatigue, and decreased libido. Medthyldopa was shown to decrease hot flashes by 30% but it was associated with fatigue, weakness, dizziness, and nausea. Mixed reports exist for the use of Naproxen beta-blockers. VERALIPRIDE™ and NAXOLONE™.
Gynaecomastia is the development of excess breast tissue in the male. There may be a physiological (puberty, aging) or a pathological (drugs, tumors, liver and renal failure, hormonal imbalances) basis to it. Whatever the aetiology, the ultimate cause of gynaecomastia is an increase in the estrogen: testosterone ratio. Surgical correction (mastectomy) is a common method of treatment, although a rather costly one. Recently, liposuction has also been used as a method of treatment. This method, however, does not completely cure true gynaecomastia, because it removes fat rather than breast tissue. Anti-estrogens have also been tried. Tamoxifen and DANAZOL™ have been shown to reduce gynaecomastia in approximately 70% of middle aged men (Parker L N et al. Metabolism, 1986, 35: 705-8. Jones D J et al, Ann Roy Coll Surg, 1990, 72:286-8). CLOMIPHENE™ proved to be unsuccessful and was associated with adverse side-effects (Ploudre P V et al, Am. J. Dis. Child., 1983, 137: 1080-2).
Accordingly, treatment methods are needed for patients suffering from hot flashes or gynaecomastia, which are effective and will not result in adverse side-effects.
SUMMARY OF THE INVENTION
This invention provides effective treatments for inhibiting hot flashes or gynaecomastia in subjects suffering from these disorders. In general, the treatment methods of the invention involve administering an LHRH antagonist to a subject suffering from, or at risk for suffering from, hot flashes or gynaecomastia such that the hot flashes or gynaecomastia are inhibited in the subject.
Thus, one aspect of the invention features a method of inhibiting hot flashes in a subject by administering an LHRH antagonist to the subject such that hot flashes are inhibited in the subject. In another embodiment, the invention provides a method of treating a subject for hot flashes in which a subject in need of treatment for hot flashes is first selected for treatment and then an LHRH antagonist is administered to the subject such that the subject is treated for hot flashes. The subject in need of treatment for hot flashes can be a subject currently suffering from hot flashes or a subject that is at risk for suffering from hot flashes. In an especially preferred embodiment, the invention provides a method of treating a subject for menopause-related hot flashes. In this method, a subject in need of treatment for menopause-related hot flashes is selected and an LHRH antagonist is administered to the subject such that the subject is treated for menopause-related hot flashes. The subject in need of treatment for menopause-related hot flashes can be a subject currently suffering from menopause-related hot flashes or a subject at risk for suffering from menopause-related hot flashes. In addition to treatment for menopause-related hot flashes, the methods of the invention can be used to treat hot flashes that result from other disorder or treatments, such as hot flashes that are the result of prostate cancer treatment, tamoxifen acetate treatment, alcohol dehydrogenase deficiency or carcinoid syndrome/pheochromocytoma.
Another aspect of the invention pertains to a method of inhibiting gynaecomastia in a subject by administering an LHRH antagonist to the subject such that gynaecomastia is inhibited in the subject. In another embodiment, the invention provides a method of treating a subject for gynaecomastia in which a subject in need of treatment for gynaecomastia is first selected for treatment and then an LHRH antagonist is administered to the subject such that the subject is treated for gynaecomastia. The subject in need of treatment for gynaecomastia can be a subject currently suffering from gynaecomastia or a subject that is at risk for suffering from gynaecomastia. In a preferred embodiment, gynaecomastia in the subject is the result of a hormonal balance.
Any LHRH antagonist that effectively inhibits the activity of the LHRH-R receptor can be used in the methods of the invention. However, in a particularly preferred embodiment, the LHRH antagonist has the structure: Ac-D-Nal
1
, 4-Cl-D-Phe
2
, D-Pal
3
, N-Me-Tyr
5
, D-Asn
6
, Lys(iPr)
8
, D-Ala
10
-LHRH (referred to herein as PPI-149).
In another preferred embodiment of the invention, the subject is a mammal, e.g., most preferably a human.
In yet another preferred embodiment, the LHRH antagonist is administered to the subject by a parenteral route, preferably by injection, most preferably by intramuscular or subcutaneous/intradermal injection.
In still another preferred embodiment, the LHRH antagonist is administered to the subject in a pharmaceutically acceptable formulation. The pharmaceutically acceptable formulation can be a dispersion system. For example, the formulation can be lipid-based (e.g., a liposome formulation) or polymer-based (e.g., a polymeric microsphere). In a particularly preferred embodiment, the formulation comprises the LHRH antagonist in an insoluble complex with an anionic carrier macromolecule (e.g., carboxymethylcellulose).
In preferred embodiments, the LHRH antagonist is administered at, for example, a dosage of about 15-300 &mgr;g/kg/day, 15-200 &mgr;g/kg/day or 15-100 &mgr;g/kg/day. The LHRH antagonist can be administered continuously using a sustained-release formulation, e.g., a formulation in an osmotic pump or a formulation that allows for slow-release of the LHRH antagonist into the tissue of the subject. For sustained treatment of a subject, the LHRH antagonist can be administered to the subject for at least one month, preferably three and more months and even more preferably six months. To achieve sustained treatment for extended periods of time, it may be ne
Brumback Brenda
DeConti, Jr. Giulio A.
Gupta Anish
Laccotripe-Zacharakis Maria
Lahive & Cockfield LLP
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