Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-07-21
2001-10-30
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06310098
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods of treating symptoms of hormonal variation, including hot flashes, treating fever, and treating nausea and emesis.
BACKGROUND OF THE INVENTION
Hot flashes or flushing occur commonly in menopausal women. This is characterized by a sudden onset of warmth in the face and neck and often progressing to the chest. Such an episode generally lasts several minutes and is evidenced by a visible flushing of the skin. Often such episodes are accompanied by sweating, dizziness, nausea, palpitations and diaphoresis. Such symptoms can disrupt sleep and interfere with the quality of life. Although the cause of hot flashes are not completely understood, they are thought to be a disorder of thermoregulation resulting from a transient lowering of the hypothalamic temperature regulatory set point (Kronenberg et al., “Thermoregulatory Physiology of Menopausal Hot Flashes: A Review,”
Can. J. Physiol. Pharmacol.,
65:1312-1324 (1987)). In post-menopausal woman, the cause of such hot flashes is believed to be a consequence of declining estrogen levels. Thus, it is not surprising that hot flashes also occur in a high percentage of women taking the anti-estrogen drug tamoxifen.
Men may also have hot flashes following androgen-deprivation therapy (from bilateral orchiectomy or treatment with a gonadotrophin-releasing-hormone agonist) for metastatic prostate cancer.
Although estrogen replacement therapy is the most direct and effective treatment for hot flashes in women, there are women in whom such therapy is contraindicated, i.e., women with breast cancer or a strong family history of breast cancer, a history of clotting, severe migraine, or who are averse to taking the drug.
In these women, there are alternative medications to prevent or treat the serious consequences of menopause, such as osteoporosis and raised serum lipid levels. Included in this category are the selective estrogen-receptor modulators (SERMs), such as raloxifene (see U.S. Pat. No. 5,534,526 to Cullinan), which selectively bind to and activate the estrogen receptors of some tissues such as bone, and block the receptors of others, i.e., breast and uterus. In so doing, they lack the negative impact that prolonged estrogen therapy may have on these organs. However, in contrast to estrogen, SERMs are not as effective in preventing hot flashes.
Other than estrogen-replacement therapy, there are no effective means to alleviate hot flashes. Low dose oral megestrol acetate, a progestational agent, was shown to reduce the frequency of hot flashes in both men and women in a short term study (Loprinzi et al., “Megestrol Acetate for the Prevention of Hot Flashes,”
N. Engl. J. Med.
331:347-351 (1994)). However, chronic adrenal insufficiency can be a side effect of low dose megestrol acetate when taken long term. Transdermal clonidine, a centrally active &agr;-agonist, had only a moderate effect on the frequency and severity of hot flashes in tamoxifen-treated women (Goldberg et al., “Transdermal Clonidine for Ameliorating Tamoxifen-induced Hot Flashes,”
J. Clin. Onc.
12:155-158 (1994)).
Accordingly, there is a need for an alternative method of treating symptoms of hormonal variation, including hot flashes, which overcomes the deficiencies in the relevant art.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to a method of treating hot flashes in a patient which is carried out by providing a compound which binds an &agr;
2
&dgr; subunit of a voltage-gated calcium channel and administering the compound to a patient experiencing hot flashes under conditions effective to treat the hot flashes.
Another aspect of the present invention relates to a method for treating a symptom of hormonal variation in a patient which is carried out by providing a compound which binds an &agr;
2
&dgr; subunit of a voltage-gated calcium channel and administering the compound to a patient experiencing a symptom of hormonal variation under conditions effective to treat the symptom of hormonal variation.
Yet another aspect of the present invention relates to a method of treating fever in a patient which is carried out by providing a compound which binds an &agr;
2
&dgr; subunit of a voltage-gated calcium channel and administering the compound to a patient experiencing a fever under conditions effective to treat the fever.
A further aspect of the present invention relates to a method of treating nausea and emesis in a patient which is carried out by providing a compound which binds an &agr;
2
&dgr; subunit of a voltage-gated calcium channel and administering the compound to a patient experiencing nausea and emesis under conditions effective to treat the nausea and emesis.
The present invention provides an improved treatment for symptoms of hormonal variation, including hot flashes, which can be significantly uncomfortable and seriously affect one's quality of life. Compounds which are active at the &agr;
2
&dgr; subunit of a voltage-gated calcium channel can be administered in a manner which is effective to reduce or substantially eliminate the occurrence or severity of hot flashes. In addition, the therapeutic use of such compounds as anti-pyretic and anti-emetic agents is also contemplated. According to preferred aspects of the present invention, two known compounds—gabapentin and pregabalin—can be administered to effect such treatments. Moreover, because gabapentin is well tolerated, its use according to the presently claimed invention is not believed to raise any new health concerns.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention relates to a method of treating hot flashes in a patient which is carried out by providing a compound which binds an &agr;
2
&dgr; subunit of a voltage-gated calcium channel (“VGCC”) and administering the compound to a patient experiencing hot flashes under conditions effective to treat the hot flashes.
Another aspect of the present invention relates to a method for treating a symptom of hormonal variation in a patient which is carried out by providing a compound which binds an &agr;
2
&dgr; subunit of a VGCC and administering the compound to a patient under conditions effective to treat the symptom of hormonal variations. A symptom of hormonal variation which is readily treated according to the present invention includes, but is not limited to, hot flashes.
Suitable compounds which are active at the &agr;
2
&dgr; subunit of VGCC include, without limitation, &ggr;-aminobutyric acid (“GABA”) analogs as well as pharmaceutically acceptable salts thereof. Suitable salts can be prepared according to known techniques.
GABA analogs are compounds which are derived from or based on GABA. GABA analogs are either readily available or readily synthesized using methodologies known to those of skill in the art. Exemplary GABA analogs and their salts have been described in U.S. Pat. No. 4,024,175 to Satzinger et al., U.S. Pat. No. 5,563,175 to Silverman et al., Bryans et al., “Identification of Novel Ligands for the Gabapentin Binding Site on the &agr;
2
&dgr; Subunit of a Calcium Channel and Their Evaluation as Anticonvulsant Agents,”
J. Med. Chem.
41:1838-1845 (1998), and Bryans et al., “3-Substituted GABA Analogs with Central Nervous System Activity: A Review,”
Med. Res. Rev.
19:149-177 (1999), which are hereby incorporated by reference. GABA analogs which are preferred for use according to the methods of the present invention include, without limitation, gabapentin and pregabalin.
Gabapentin, (1-aminomethyl)cyclohexaneacetic acid, is a GABA analog which has been used previously in the treatment of epilepsy, neurogenic pain, restless legs syndrome, essential tremor, bipolar disorder, and migraine (Magnus, “Nonepileptic Uses of Gabapentin,”
Epilepsia,
40:S66-S72 (1999), which is hereby incorporated by reference). Gabapentin has been shown to bind to a single site in the brain with high affinity, the &agr;
2
&dgr; subunit of VGCC (Bryans et al., “3-Substituted GABA Analogs with Central Nervous System Activity: A Review,”
Henley III Raymond
Nixon & Peabody LLP
University of Rochester
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