RU2067001C1 - Method for reducing risk to acquire mammary gland carcinoma - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves prolonging follicular phase of menstrual cycle and its general duration. It is ensured by daily administering effective dose of melatonin also in combination, among others, with progesterone and/or estrogen. EFFECT: enhanced effectiveness of treatment. 13 cl

Description

 The invention is directed to a method for preventing the appearance of breast cancer in women. It was found that pharmacological administration of melatonin prevents the formation of 7,12-dimethylbenzanthracene (DMBA), which caused adenocardinoma in various species of rodents. It has also been found that women with estrogen receptors that are positive for breast cancer have a reduced nighttime concentration of melatonin (Tamarkeu et al. Science, 216: 1003-1005, 1982).

 It can be assumed that the introduction of pharmacological doses of melatonin will prevent the formation of cells in the breast tissue, which may appear during the menstrual cycle. It is theoretically possible that this formation, if it lasts for a long period of time, can lead to the development of a tumor and that the introduction of melatonin will stabilize cell growth, so that there will be a balanced number of cells in the breast tissue in each reproductive cycle.

 As indicated in the description, the term melatonin also encompasses melatonin analogs that exhibit an inhibitory effect when administered to women. Such melatonin analogs include 6-fluoromelatonin, 6-hydroxytryptamine, 5-methoxy indole and 6-methoxytryptamine. Other such melatonin analogs include the compounds described in US Pat. Nos. 4,087,444 and 4,614,807, cited in a bibliographic reference.

 Melatonin (or an analog of melatonin) is administered daily in doses sufficient to suppress the normal release of luteinizing hormone in women using melatonin and thus prevent ovulation.

 In general, melatonin is administered in amounts ranging from 2 to 1000 mg per day per 70 kg of body weight of women taking melatonin. Preferably, 30 to 500 mg of melatonin is administered daily.

 Melatonin can be administered every day during the female cycle. It was found, however, that the administration of melatonin for only one seven-day period in the cycle that immediately precedes the woman's normal day of ovulation is sufficient to achieve a contraceptive effect.

 Ovulation usually appears on the fourteenth day of the cycle or alternatively between the ninth and seventeenth day of the female cycle. This regimen is preferred for administration of melatonin. The type of regimen chosen may affect the amount of melatonin administered daily. The amount provided for each daily dosage may also vary from the chosen method of administration.

 Melatonin can be administered to women either orally, parenterally or in the form of an implant. Administration is most common if melatonin is prepared in an oral dosage form, such as capsules, tablets, suspensions or solutions. Capsules or tablets are preferred. Capsules can be prepared by mixing the compound with a pharmaceutically acceptable carrier and then filling the gelatin capsules with a mixture in accordance with the traditional procedure for preparing dosage forms.

 Alternatively, melatonin can be mixed with one or more lubricants, such as stearic acid or magnesium stearate, taste improvers, dispersants, including potato starch, alginic acid, binders such as gelatin and corn starch, and melatonin can be used to prepare tablets mixed with lactose, corn starch and sucrose and then compressed into tablets.

 Alternatively to oral administration, melatonin can be administered parenterally or in the form of a solid implant. For parenteral administration, melatonin is prepared in injectable doses of a solution or suspension of the hormone in a physiologically acceptable diluent with a pharmaceutical carrier. The carrier may include water or oil, and optionally also contain a surfactant or other pharmaceutically acceptable additive.

 Suitable oils include oils of animal, vegetable, petroleum and synthetic origin, including peanut, soybean, corn, sesame, castor and mineral oils. Preferred liquid carriers include water, saline, aqueous sugars, and glycols such as polyethylene glycol or polypropylene glycol.

 Melatonin can also be introduced in the form of an implant, which is prepared so that provides a prolonged release of melatonin. To prepare the implant, it is necessary to compress the melatonin into small cylinders and place them in a shell of a physiologically acceptable material, such as degrading in the body or a porous polymer in accordance with the traditional technology for producing grafts.

 In a preferred embodiment of the present invention, melatonin is administered in combination with a progestogen. A progestogen is added to induce cyclic bleeding similar to cyclic menstrual bleeding and to benefit from the administration of progestogens in traditional contraceptives.

 Any progestogenically active compound is useful for use as a progestogen component in the present invention. Suitable progestogens include progestogen and its derivatives. Currently preferred progestogens are norethinodrone (i.e. 19-nor-17α-ethynyl-17b-hydroxy-4-androsten-3-one) and norgestrel (13b-ethyl-17a-ethynyl-17b-oxygon-4-ene -3-he).

 Other progestogens include chlormadione acetate (i.e. 6-chloro-17-hydroxypregna-4,6-diene-3,20-dione acetate), norethinodrel (17a-ethynyl-17-hydroxyestr-5 (10) -en) , medroxyprogesterone acetate (17a-acetoxy-6a-methylpregna-4-ene-3,20-dione), megestrol acetate (17a-acetoxy-6-methylpregna-4,6-diene-3,20-dione), linestrenol (17a ethynyl-17b-hydroxyestr-4-en), hingestron (3-cyclopentyloxy-pregna-3,5-diene-20-one), norethindrone acetate (17b-acetoxy-17a-ethynyl-estr-4-en-3- he), ethynodiol acetate (13b, 17b-diacetoxy-17a-ethynyl-estr-4-en), dimethisterone (17b-hydroxy-6a-methyl-17- (1-propynyl) -androst-4-en-3-one ) and levonorgestrel.

 Several administration regimens are suitable for taking a combination of melatonin and a progestogen. For example, based on a 28-day cycle, melatonin and a progestogen can be administered for 21 days, followed by melatonin without progestogen for seven days. In a second regimen, melatonin and a progestogen are administered for 21 days and then the administration of both compounds is stopped for about seven days.

 In a third drug administration regimen, melatonin is administered for approximately 5-14 days, followed by administration of the progestogen for approximately 7-14 days, in order to obtain a total of about 21 days. Neither melatonin nor a progestogen are administered in the remaining seven days of the cycle. The fourth regimen includes the introduction of a placebo for the first five days, then the introduction of melatonin for about 3-7 days, followed by the administration of a progestogen up to twenty-one days of medication. Again, neither melatonin nor a progestogen is administered on the remaining seven days of the cycle.

 In another administration regimen, the progestogen is taken for 21 days. Melatonin is administered in combination with a progestogen for 1-7 days (preferably 3-5 days) of the menstrual cycle just before the normal day of ovulation of the woman using the medication.

 After 21 days, the progestogen is not administered for approximately seven days. As noted above, traditional doses of only one progestogen for 21-28 days did not have an effective contraceptive effect. The addition of melatonin eliminates the inefficiency of administering a single progestogen.

 The progestogen component of these contraceptives is usually administered in an amount of 7.5 to 2500 micrograms per day, preferably in the range of 7.5 to 600 micrograms per day. Most preferably, the progestogen is administered in an amount of 7.5 to 250 micrograms per day. The actual amount of progestogen administered in each daily dose will depend on the particular progestogen chosen, its relative effectiveness and the chosen route of administration. For example, with smaller amounts of a more active progestogen, you can achieve the same result as with large quantities of a less active progestogen.

 As noted above, the amount of progestogen may also vary depending on the route of administration, and lower doses are usually required with an implant or with an intravenous injection than with an oral administration.

 In any of the above regimens, on the days when melatonin and a progestogen are administered, both active components are usually mixed and administered together, although they can also be administered separately.

 In an alternative embodiment of the present invention, a small amount of estrogen can be added to any regimen for the administration of melatonin or melatonin and a progestogen. Estrogen can be added, if desired, to stabilize melatonin by preventing latent ovulation, which can occur if melatonin is administered in the absence of estrogen.

 Any conventional estrogen can be used as a suitable component of the contraceptive compositions of the present invention. The following compounds are currently preferred estrogen: ethinyl estradiol (i.e. 17a-ethynyl-3,17b-dioxestra-1,3,5 (10) -triene) and mestranol (17a-ethynyl-17b-hydroxy-3-methoxy estra-1,3,5 (10) -trien).

 Other suitable estrogens include estradiol (3,17b-dioxi-estra-1,3,5 (10) -triene, estriol (3, 16a, 17b-trioxy-estra-1,3,5 (10) -triene), estrone (3-hydroxy-estra-1,3,5 (10) -trien-17-one), diethylstilbestrol, chinestradiol (3-cyclopentyloxy-16a, 17b-dioxestra-1,3,5 (10-triene) and estrone sulfate .

 Estrogen can be administered daily for 21 days from a 28-day cycle in any dosage regimen described above, but it is preferably administered before the normal day of ovulation. In general, estrogen is administered in an amount of from 2 to 100 μg per day, and preferably in the range of 10 to 50 μg per day. As with the progestogen, the actual amount of estrogen used in the daily dose will depend on the particular estrogen chosen and its relative activity.

 Ethinyl estradiol, for example, has twice as high activity as Mestranol. Due to the negative side effects caused by estrogen, it is advisable to use the minimum amounts of estrogen necessary to stabilize the melatonin used. Estrogen can be mixed with melatonin and / or a progestogen in any of the drug regimens mentioned above.

 In an alternative regimen, estrogen is administered at the beginning of the female cycle for about 5-13 days, followed by melatonin for 1-7 days (preferably 3-5 days) until the normal day of ovulation, then a progestogen is administered for about 21 days of treatment.

 In another embodiment of the present invention, melatonin may be administered as a “morning ofter” pill, either alone or in combination with estrogen and / or progestogen. In this embodiment, melatonin is administered at a daily dose of about 100 mg and up to 10,000 mg, preferably at a dose of at least 2,000 mg, over a 1-5 day post-conus period. If melatonin is administered in combination with a progestogen and / or estrogen, then the progestogen is administered in a daily amount in the range of 10 to 20 mg and estrogen is administered in a daily dose in the range of 2.5 to 25 mg.

 In a preferred embodiment of this invention, the contraceptives of the invention are administered in an oral dosage form, preferably in the form of pills or capsules. Pills or capsules may be packaged in any manner suitable for quick preparation and use. Preferably they are packaged in the form of a pharmaceutical kit or package in which the daily unit dosage forms are located, or arranged in an alternating sequence that allows the woman taking the medication to take the appropriate dosage form at the appropriate time of her reproductive cycle.

 Suitable kits or packages include a set of plastic vials containing individual pills, or 21 or 28 pills, depending on the chosen dosage regimen, in a flexible plastic sheath. The bubbles are enclosed in a plastic shell, which can be broken and the pill released when squeezing the bubble. On the first day of medication, which is usually the first day after the bleeding stops from the last menstrual period, the first pill in the sequence, whether it contains a contraceptive or a placebo, is removed from its individual package and taken.

 The next pill in the sequence is taken the next day and continues until the packaging is empty. The next packing begins on the seventh day of the next female cycle. Appropriate clarifications and instructions can be attached to the packaged kit for guidance and guidance to users on the use of oral contraceptives.

 As noted above, it has also been found that the administration of melatonin in amounts taken in the above schemes may be effective in preventing breast cancer. This finding is an important advantage for women of childbearing age who are taking melatonin or compositions according to the invention containing melatonin as a contraceptive.

 In addition, melatonin and compositions containing melatonin can be administered to postmenopausal women as a way to prevent breast cancer. Melatonin is preferably administered to postmenopausal women in a daily dose of 2 to 1000 mg, as described above. Progestogen and / or estrogen can be combined with melatonin and administered in amounts and according to the schemes described above to prevent the appearance of breast cancer.

 Breast cancer is a very common disease in today's society; in industrialized countries, approximately 1 out of every 10 women develop breast cancer.

 Studies have shown that the development of certain types of cancer is associated with various external factors. The link between smoking and lung cancer, for example, is clearly shown. Diet can affect the risk of developing other forms of cancer, such as colon cancer, and the effects of chemical carcinogens can increase the risk of developing other cancers. On the contrary, the development of breast cancer is not associated with the presence of such "external" factors.

 A number of breast cancer researchers have suggested that breast cancer is associated with endogenous endocrine imbalance. Various theories based on that platform have suggested that breast cancer development may occur due to ovarian dysfunction, pituitary dysfunction, adrenal disorder, hypothalamic dysfunction, cone-shaped disorder, and combinations thereof.

 Researchers found certain parameters or factors that were generally accepted as determining a high risk of developing breast cancer. For example, it has been shown that factors are a number of reproductive changes. Some studies have determined that the later the age at which a woman has her first full-term pregnancy, for example, the higher the risk of breast cancer.

 In addition, the earlier the onset of the first menstruation and the later the age at which menopause occurs, the higher the risk. Also among women in postmenopausal age, completeness is associated with an increased risk. It is postulated that this is due to the higher rate of conversion of androstenedione to estrone in tissues of obese women and lower levels of sex hormone-binding globulin in obese women compared to incomplete women (see Kelsey JL and GS Berkowitz, Cancer Research, 48: 5615 -5623, 1988).

 Recently, one of the researchers suggested that the age of a woman during her first full-term pregnancy alone cannot be a risk factor, but rather a reflection of the hormonal phenomena preceding the first pregnancy. This theory suggests that a large number of normal menstrual cycles, especially before the first full-term pregnancy, increases the risk of breast cancer (see Olsson H. Acta Oncologia, 28: 849, 1989). Other researchers have found that breast cancer patients often have normal menstrual cycles.

 Other important risk indicators are age, height, weight, country of origin, dietary factors, and family history of breast cancer. More precisely, among the demographic layers, the spread of cancer increases with age, although life expectancy in Western countries is greater among women of higher social classes than among women in lower social classes, among women who have never been married, compared to women, who were married, among women living in the northern United States, compared to women in the southern United States, among white women compared to black. A summary of all risk factors is given in Table 1-1 in "Diagnosis and Management of Breast Cancer" by M.E. Lippman, A.S. Lichfer and P.N. Danforth, publishes by W. R. Saunders Company, 1988, Philadelpfia, PA.

 From the foregoing, it seems that there is a direct correlation between the existence of a large number of ovulatory cycles that do not end in pregnancy and a predisposition to the development of breast cancer. That is, there is a direct link between the modern lifestyle and the increased prevalence of breast cancer. In the past, when more women had more children and usually started having babies at an earlier age and breast-fed their children, the spread of breast cancer was much lower. Such women had long periods without ovulation: both during pregnancy and breastfeeding, the woman does not ovulate.

 The use of modern estrogen / progestogen oral contraceptives is known to significantly reduce the risk of ovarian and uterine cancer. Thus, it seems that the risk of these types of cancer is reduced by reducing the number of ovulatory cycles that do not end in pregnancy.

 Modern oral contraceptives, however, do not provide protection against the risk of breast cancer. In fact, there is evidence that estrogen / progestogen contraceptives can actually increase the risk of breast cancer, although the data are controversial and controversial.

 In each ovulatory cycle, hormones are stimulated to prepare the mammary gland, at least the growth of the epithelium of the mammary gland, for pregnancy and subsequent lactation. For each cycle that does not result in pregnancy, this cell growth remains in the mammary gland without a complete cycle of cell differentiation from recruitment to lactation.

 A similar cycle in the endometrium of the uterus leads less often to cancer, since the uterus has a menstrual mechanism, which eliminates these excess cell populations in the absence of pregnancy. Menstrual blood leaches these excess tissue from the uterus. The breast, however, does not have such a protective mechanism that involves the removal of excess tissue.

 Cellular neoplasm or cell groups that remain in the breast after each ovulation can be stimulated to further growth. Over the years, anaplasia and metaplasia can occur and transform these cells into breast cancer.

 Women, and not other female mammals, have shown this cyclic recruitment of cells in the breast, as other mammals have long periods of endogenous contraception, that is, they are seasonal producers. Endogenous contraception of other mammals is achieved due to the function of neutroendocrine glands, especially due to the pineal gland and the hormone melatonin. In humans, the melatonin impulse that regulates seasonal reproduction is lost during evolution.

 Thus, the present invention relates to the administration of melatonin, optionally in combination with estrogen and / or a progestogen, in order to reduce the number of ovulations that a woman has, and thus limit the cyclic formation of cells in the breast, which can lead to the development of breast cancer through repeated ovulatory cycles.

 The application describes a number of modes and methods of administration. Melatonin and, if desired, a progestogen and / or estrogen can be administered orally, parenterally or as an implant. Melatonin can be administered in a daily dose of from about 2 to about 100 mg. A progestogen can be administered in an amount ranging from about 7.5 mg to about 2500 μg per day, and estrogen can be administered in a daily dose of from about 2 μg to about 100 μg.

 The application sets out a number of specific regimens to achieve contraception, but, as explained above, the obstruction of ovulation is a mechanism for the prevention of breast cancer.

 Each of the proposed modes related to the introduction of a composition for contraceptive action may be useful for the prevention of breast cancer. By providing a wide range of regimens and the number of active components of the compositions, an individual physician will be able to determine the most effective dose and regimen for each patient. Thus, the amount of hormones administered can be kept at the lowest level necessary to achieve the desired goal.

 The present invention is further described and explained in the following examples, which are presented for informational purposes, but not to limit the scope of the invention.

 Example 1

 The contraceptive effectiveness of melatonin was studied in patient S.B. born September 21, 1950. The concentration of luteinizing hormone, follicle-stimulating hormone, progestogen and estradiol in her blood was determined for each day of her cycle, averaged over five consecutive cycles. This patient had normal pre-ovulation fluctuations of the luteinizing hormone and a peak of follicle-stimulating hormone, accompanied by a post-ovulation increase in progesterone.

 In each of the three cycles, the patient received intravenously 300 mg of melatonin in physiological glucose in saline from the ninth day of her cycle for six consecutive days.

 The introduction of melatonin leads to suppression of the normal pre-ovulatory release of luteinizing hormone in the patient. These data also indicate that there is minimal suppression of follicle-stimulating hormone and pre-ovulation estradiol and a significant decrease in progestogen levels. Suppression of luteinizing hormone is a sufficient indication that the patient did not ovulate in any of the three months in which melatonin was administered.

 Example 2

 The concentration of luteinizing hormone, follicle-stimulating hormone, progesterone and estradiol in the patient's plasma was measured daily for three menstrual cycles. The average concentration of each hormone for each day of the cycle was determined. The average peak concentration of the patient's luteinizing hormone was 295 ng / ml and the average peak concentration of follicle-stimulating hormone was 410 ng / ml. The average progesterone level at the peak of its cycle phase was 14.5 ng / ml and the average concentration of estradiol peak was 0.6 ng / ml. The peak of the patient's luteinizing hormone appeared on the fifteenth day of her cycle.

The patient was injected intravenously with 500 mg of melatonin in glucose in physiological saline every day from 7 to 12 days of its cycle. The concentration of four hormones in the patient's plasma was measured during this cycle, as before. The introduction of melatonin has been found to affect hormone concentrations as follows:
peak plasma luteinizing hormone concentration was 110 ng / ml;
follicle-stimulating hormone 295 ng / ml;
estradiol 0.4 ng / ml and
progesterone 0.3 ng / ml.

 These data indicate that the patient did not ovulate during this cycle; studies have shown that a peak concentration of luteinizing hormone of at least 250 ng / ml is necessary for ovulation to occur.

 Example 3

 A woman with a normal menstrual cycle of 28 days with 3-5 days of moderate menstrual bleeding (± 50 ml blood loss) received intravenous injections of 350 mg of melatonin in glucose in saline for seven consecutive days, starting on the 8th day of her cycle. At 14–28 days of her cycle, she was given orally 0.75 mg of norethiniron per day. The concentrations of luteinizing hormone, follicle-stimulating hormone, progesterone and estradiol in the blood were measured daily during its cycle. Ovulation did not occur during this cycle (peak plasma luteinizing hormone concentration was 115 ng / ml). A minimum blood loss of ± 15 ml was observed.

 Example 4

 A woman with a normal menstrual cycle of 30 days (ovulation on the twelfth day) received an intravenous injection of 200 mg of melatonin in glucose in saline every 7-10 days of her cycle. Ovulation did not occur in this cycle, although the level of luteinizing hormone in the blood was not found to be uniformly suppressed, but rather fluctuated between 50 and 180 ng during the cycle. The concentration of follicle-stimulating hormone in plasma during this cycle was normal for her, progesterone was somewhat suppressed, and the concentration of estradiol in plasma during the cycle was normal.

 Example 5

 In a clinical study, five women were given melatonin in gelatin capsules. Melatonin was administered in a daily dose in the range of 30-1000 mg. A preliminary assessment shows satisfactory absorption of melatonin from the gastrointestinal tract without adverse side effects (such as diarrhea or vomiting).

Claims (13)

 1. A method of reducing the risk of breast cancer, characterized in that it includes daily administration of melatonin in an amount sufficient to increase the duration of the total menstrual cycle and its follicular phase.  2. The method according to claim 1, characterized in that melatonin is administered in a daily dose of from 2 to 1000 mg per 70 kg of woman’s body weight.  3. The method according to claim 1, characterized in that melatonin is administered in combination with a progestogen.  4. The method according to claim 3, characterized in that melatonin is administered in a daily dose of from 2 to 1000 mg per 70 kg of body weight, and the progestogen in a daily dose of from 7.5 to 2500 μg.  5. The method according to claim 3, characterized in that the progestogen is selected from the group comprising norethindrone, norgestrel, chlormadinone acetate, norethinodrel, medroxyprogesterone acetate, megesterol acetate, linestrenol, hingestron, norethindrone acetate, ethinodiol acetate, levonorgestrel and dimethisterone.  6. The method according to claim 1, characterized in that melatonin is administered in combination with estrogen.  7. The method according to claim 5, characterized in that the daily dose of melatonin is from 2 to 1000 mg per 70 kg of body weight of women, and estrogen from 2 to 100 μg.  8. The method according to claim 1, characterized in that melatonin is administered in combination with a progestogen and estrogen.  9. The method according to claim 8, characterized in that the daily dose of melatonin is from 2 to 1000 mg per 70 kg of body weight, a progestogen from 7.5 to 2500 μg and estrogen from 2 to 100 μg.  10. The method according to p. 6 or 8, characterized in that the estrogen is selected from the group comprising ethinyl estradiol, mestranol, estradiol, estrone, estriol, diethylstilbestrol, quinestradiol, estrone sulfate.  11. The method according to claim 1, characterized in that melatonin is administered by intravenous injection.  12. The method according to claim 1, characterized in that melatonin is administered orally.  13. The method according to claim 1, characterized in that melatonin is administered in the form of an implant.