MXPA97006964A - Use of 8,9-dehydroestrone as a estrogen with neutral effects on the levels of prolact - Google Patents

Abstract

This invention provides a method for providing estrogen therapy or supplementation in a mammal in need thereof, wherein an elevation in prolactin levels concomitant with said estrogenic supplementation in the mammal is undesirable, which comprises administering an effective amount of the , 9-dehistrone or a pharmaceutically acceptable salt of 3-sulfate ester to said mammal

Description

USE OF 8,9-DEHYDROESTRONE AS A ESTROGEN WITH NEUTRAL EFFECTS ON THE LEVELS OF PROLACTIN BACKGROUND OF THE INVENTION The use of estrogenic compositions of natural origin of substantial purity and low toxicity such as PREMARIN (conjugated equine estrogens) has become a preferred medical treatment for alleviating the symptoms of menopausal syndrome, osteoporosis / osteopenia in women with estrogen deficiency and in other disorders related to hormones. The estrogenic components of estrogenic compositions of natural origin have generally been identified as esters of estrone sulphate, equilin, equilenin, 17-β-estradiol, dihydroequilenin and 17-β-dihydroequilenin (US Patent No. US 2,834,712). Concomitant with the administration of estrogen, elevated levels of prolactin can be observed. Prolactin is mainly responsible for milk production during lactation, but it also has a wide variety of actions in humans. Excessive secretion of this hormone leads to amenorrhea and galactorrhea in women, REF: 25543 and galactorrhea in men treated with estrogen. In addition, the elevation of prolactin has been associated with difficulties in conceiving pregnancies and abnormalities of menstrual function. 8, 9-dehydroestrone is a compound known to be useful as an intermediate in the synthetic production of estrone by isomerization to unsaturation 9,11 (US Patent No. 3,394,169) and as an intermediate in the production of 3-cyclopentyloxy-17 derivatives -ethyltin of the hormone (US Patent No. US 3,649,621). In addition, it is known that 8, 9-dehydroestrone possesses estrogenic activity and decreases blood lipid levels (US Patent No. US 3,391,169). The alkali metal salts of 8,9-dehydroestrone, the 8,9-dehydroestrone-3-sulfate ester and its alkali metal salts, and its use in estrogen replacement therapy, in atherosclerosis and in senile osteoporosis, are discloses in U.S. Patent Nos. 5,210,081 and 5,288,717.

DESCRIPTION OF THE INVENTION This invention provides a method for the provision of an estrogenic therapy or supplement in a mammal in need thereof, wherein an elevation in prolactin levels, concomitant with estrogen supplementation in said mammal, which comprises administering an amount is undesirable. effective 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester to said mammal. More particularly, the administration of 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester is useful in infertility therapies where an increase in prolactin levels is observed when estrogenic substances are administered, it is undesirable since the elevation of prolactin makes conception more difficult. For example, 8,9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester can be used to prime or prepare the endometrium during the preimplantation period in women undergoing embryo donation during in vitro fertilization and transfer of embryos. Such women, who generally would not have ovarian function or artificially suppressed ovarian function, typically suffer several weeks of estrogen therapy during these artificial cycles. In such circumstances, 8,9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester, could be administered from day one of the cycle to the end of the cycle, in order to cause a proliferative endo-trcial change, and then maintain the luteal change after the addition of progesterone and oocyte transfer, which occurs approximately in the intermediate stage of the cycle. A second use for 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester, in the treatment of infertility, is its use in the treatment of cervical mucus hostility. In this use, the cervical mucus becomes more favorable to the penetration of sperm by the beneficial effects of treatment with estrogen. Estrogen creates a thinner cervical mucus with a slightly higher pH. Estrogen therapy also increases the size of the cervical mucus in the womb, allowing sperm penetration to occur. Elevated levels of prolactin, associated with typical estrogenic administration, however, can create collateral menstrual changes and other changes, and thus may negate the beneficial effects of estrogenic administration. Since the administration of 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester does not cause an increase in prolactin levels, such treatment may not suffer from the deleterious effects of concomitant elevation in the levels of prolactin When administered for such use, 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester, could typically be administered from several days before, until approximately the time when ovulation will occur in women who ovulate normally. . The administration of 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester is also useful in the treatment of amenorrhea, other ovulatory disorders, and osteopenia, which frequently accompany hyperprolactinemia. Hyperprolactinemia can be caused by the presence of pituitary microprolactinomas, or it can be idiopathic in nature. In amenorrheic hyperprolactinemic women, mean estradiol levels are often comparable to the levels of estradiol observed in menopausal women, causing such women to be in a state of absolute or relative deficiency of estrogen. In other women, the presence of estradiol levels in the early follicular phase, in combination with elevated prolactin levels, is associated with amenorrhea. These women lack the elevation in serum estradiol levels typically seen in the middle ovulatory and luteal follicular phase of the cycle. Progressive osteopenia often also develops in these women as a result of their estrogen deficiency [Klibans i, A., MGH Neuroendocrine Clinical Center Bulletin, Issue 2 (1994; obtained from http://neurosurgery.mgh.harvard.edu/e-f-941.htm]. It has also been suggested that elevations of serum prolactin contribute to osteopenia in young hyperprolactinemic women. In addition, 8,9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester is useful in patients who are or are susceptible to hyperprolactinemia, or who have galactorrhea as an estrogen in oral contraceptives, for replacement therapy. of hormones, in the treatment of young high adolescents, in male-to-female transsexuals, and in other disease states or conditions in which estrogenic administration might be of benefit, but an elevation of prolactin levels might be undesirable.

The 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester is also useful in the treatment of men in need of estrogenic therapy without inducing galactorrhea. Pharmaceutically acceptable salts of the 8,9-dehydroestrone 3-sulfate ester include, but are not limited to, alkali metal salts, alkaline earth metal salts, ammonium salts, alkylamine salts containing 1 to 6 carbon atoms. carbon or dialkylamine salts containing from 1 to 6 carbon atoms in each alkyl group. The estrogenicity of the sodium salt of the ester 8, 9-dehydrostrone-3-sulfate was described in U.S. Patent Nos. 5,210,081 and 5,288,717, which are incorporated by reference herein. The neutral effect of 8,9-dehydroestrone and the pharmaceutically acceptable salts of its 3-sulfate ester on prolactin levels were established in a standard in vivo pharmaceutical test procedure described below. Ovariectomized female Sprague-Dawley rats (OVX) weighing 150-200 grams were maintained in a light cycle: 12 hours dark: 12 hours with food and water available ad libitum. The animals were treated as follows, two to three weeks after the ovariectomy. The animals were divided into treatment groups and received either the sodium salt of the ester 8, 9-dehydrostrone-3-sulfate (20 or 100 μg in distilled water), the sodium salt of estrone sulfate (20 or 100 μg in distilled water), or distilled water vehicle (control group) subcutaneously once a day for three days, and then once more 8 hours before slaughter. The animals were sacrificed on the fourth day and the prolactin levels were measured by radioimmunoassay. The following table summarizes the results that were obtained.

EFFECTS ON THE PROLACTINE LEVELS Group Prolactin levels (ng / ml) Control 14.29 ± 3.20 Oestrone sulfate - 20 μg 48.47 ± 7.04 Oestrone sulfate - 100 μg 244.87 ± 70.01 sulphate of 8.9-9.47 ± 1.96 dehydroestrone - 20 μg sulfate 8.9- 6.77 ± 2.97 dehydrostrone - 100 μg These results show that estrone sulfate, a typical estrogen, significantly raised prolactin levels 3 times and 17 times when administered at 20 μg and 100 μg, respectively, while the sodium salt of 8,9-dehydroestrone-3 ester -sulfate did not produce elevation of prolactin levels at any dose level, demonstrating that 8, 9-dehydrostrone, contrary to other estrogens, has a neutral effect on prolactin levels. Based on these results, 8,9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester, could be useful to provide estrogen therapy or supplementation when an increase in prolactin levels is concomitant with such supplementation. estrogenic The 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester can be formulated pure or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, by the chosen route of administration and by the conventional pharmacological practice. The pharmaceutical carrier can be solid or liquid.

A solid carrier includes one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents; this can also be an encapsulation material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting point waxes and ion exchange resins. Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can also be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives such as the above, for example, cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, eg, glycols ) and its derivatives, lecithins and oils (for example fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for the pressurized compositions may be halogenated hydrocarbon or another pharmaceutically acceptable propellant. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester can be administered orally either in the form of liquid or solid composition. The 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester can also be administered as a subdermal implant. The 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester can be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the antioxidants of this invention can be formulated in an aqueous or partially aqueous solution, which can then be used in the form of an aerosol. The compounds of this invention can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier which is inert to the active compound, which is not toxic to the skin, and which allows the distribution of the agent for systemic absorption into the bloodstream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels and occluding devices.The creams and ointments can be liquid or semi-solid viscous emulsions of either oil-in-water or water-in-oil type. Absorbent powders dispersed in hydrophilic petrolatum or petrolatum containing the active ingredient may also be appropriate A variety of occluder devices may be used to release the active ingredient into the bloodstream, such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient.Other occluder devices are known in the literature.In addition, 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester, can be employed as a solution, cream, or lotion by formulation with pharmaceutically acceptable carriers containing 0.1-5%, preferably 2%, of active compound, which can be administered to a mycotic-affected area. The dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, the projected daily doses of the active compound could be from 0.02 μg / kg to 500 μg / kg. The treatment will generally be initiated with small doses lower than the optimum dose of the compound. After this the dose is increased until the optimum effect is reached under the circumstances; The precise doses for oral, parenteral, nasal or intrabronchial administration will be determined by the doctor who administers it, based on the experience with the individual subject treated. Preferably, the pharmaceutical composition is in the form of a unit dose, for example, tablets or capsules. In such a form, the composition is subdivided into a unit dose containing appropriate quantities of the active ingredient; the unit dosage forms may be packaged compositions, for example, packaged powders, flasks, ampoules, pre-filled syringes or sacks containing liquids. The unit dosage form may be, for example, a capsule or a tablet, or it may be in an appropriate number of any such compositions in package form.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (7)

R E I V I N D I C A C I O N S

1. The use of 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester for the preparation of a medicament for estrogen therapy or a supplementation in a mammal in need thereof, wherein an elevation is undesirable in prolactin levels, with constituents with estrogen supplementation in said mammal.

2. The use of 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester for the preparation of a medicament for the provision of estrogen therapy in the treatment of infertility in a mammal in need thereof.

3. The use of 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester for the preparation of a medicament for the treatment of ovulatory disorders in a mammal having hyperprolactinemia.

4. The use according to claim 3, wherein the ovulatory disorder is amenorrhea.

5. The use of 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester for the preparation of a medicament for the treatment of osteopenia in a mammal having hyperprolactinemia.

6. The use of 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester for the preparation of a medicament for the provision of estrogen therapy or supplementation in a mammal susceptible to developing hyperprolactinemia.

7. The use of 8, 9-dehydrostrone or a pharmaceutically acceptable salt of its 3-sulfate ester for the preparation of a medicament for the provision of estrogen therapy or supplementation in a mammal having galactorrhea.