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    • 专利摘要:
    The invention relates to biochemistry, and specifically to entomological proteins obtained by homogenization of drone brood brood and used for the normalization of the hormonal state and general well-being in women. Specifically, the invention relates to androgen donors for women. The composition for the treatment of androgen deficiency in women includes a bumblebee brood homogenate and can be made in the form of tablets, capsules or powder. The method for the treatment of androgen deficiency in women comprises daily intake of the composition for the treatment of androgen deficiency in women which comprises a homogenate of brood bumblebee in an amount of 10 mg to 600 mg. The invention increases the level of endogenous androgens, particularly in the blood of women.
    公开号:CH712460B1
    申请号:CH01177/17
    申请日:2016-03-10
    公开日:2020-02-14
    发明作者:Villorij Ivanovich Strukov；Vjacheslav Nikolaevich Trifonov；Julia Anatoljevna Elistratova；Konstantin Gennadievich Elistratov；Natalia Vyacheslavovna Kurus；Alexandr Viktorovich Fedorov；Evgeny Nikolaevich Krutyakov；Elena Stanislavovna Andreeva；Alla Nikolaevna Astafjeva；Tat'jana Anatol'evna Kupcova；Julija Gennad'evna Shherbakova；Natal'ja Mihajlovna Smirnova；Georgiy Maksimovich Elistratov
    申请人:Obshestvo S Ogranichennoj Otvetstvennostju Parafarm；
    IPC主号:
    专利说明:

    Description: The present invention relates to biochemistry, and specifically to entomological proteins obtained by homogenization of brood of bumblebees which are used for the normalization of the hormonal state and the general well-being perceived in women. Specifically, the invention relates to androgen donors for women.
    [0002] Androgen donors for women are obtained by homogenization of drone brood brood. The bumble bee brood is a mixture of developing larvae, pre-pupae and male bee pupae. Homogenization is carried out by homogenizers. Thus, a homogeneous mixture of proteins is obtained, including hormones and enzymes, fats, carbohydrates, oligonucleotides, nucleic acids and amino acids, vitamins, and macro and microelements.
    Any woman of childbearing age needs three sex hormones (estrogen, progestins, and androgens) for a normal life. Two of these hormones (estrogens and androgens) are especially necessary for a normal evolution of the aging process in postmenopausal women. One of the main causes of climacteria has been considered to be estrogen insufficiency which initiates climacteric processes without taking into account the causes of insufficient ovarian function. Therefore, to decrease climacteric disorders, estrogen replacement therapy is widely used. However, a number of researchers believe that androgens are of greater importance in postmenopausal disorders. To support this opinion, it should be noted that androgen receptors are possibly present in all organs and tissues of the female organism such as bone tissue, central nervous system, skin, blood vessels, adipose tissue, smooth and striated muscles.
    Androgen deficiency in women leads to a decrease in libido, a depressive state, a decrease in muscle mass, a decrease in bone mineral density, and a decrease in perceived well-being. Adequate androgen levels can play a vital role in metabolic, psychological, and sexual function in women.
    So far, the role of androgens in the female body has not been fully studied. The fact is established that androgens are necessary not only for the development of reproductive function, but also for the maintenance of normal hormonal state in various age periods since androgens are hormones - precursors of estrogen biosynthesis in women. The genomic and extra-genomic effects of androgens have been researched. The most peripheral organs and tissues such as bone tissue, mammary glands, sebaceous glands and hair follicles, skeletal muscles, adipose tissue, and genital glands have specific androgen receptors. In this way, androgens have various effects on bone mineral density, muscle mass and strength, distribution of fat tissue, mood, sexual desire, cognitive function, and perceived general well-being. Apart from the genomic mechanism, androgens can have extra-genomic effects, for example, on organs and tissues that contain an enzyme such as aromatase. These effects are provided by the conversion of androgens to estrogen. The normal level of testosterone in the blood in men is 300 to 1000 ng / dl; According to various authors, the level of testosterone in women is from 20 to 50 ng / dl to 10 to 120 ng / dl, that is to say, about 10 times less than in men [1-8] Since the biologically normal level of androgens in women is significantly lower than that in men, even a small disorder of androgenic metabolism formation can lead to androgenic insufficiency in women.
    The 1 st International Conference on Androgen Insufficiency in Women (Princeton, USA, 2001) gave the definition of "androgen insufficiency" (AI) as a new diagnostic term characterizing the above disorder . The term "androgens" applies to C-19 steroids that are produced in both men and women in the gonads and adrenal glands. They include testosterone (T), dehydroepiandrosterone (DHAE), dehydroepiandrosterone sulfate (DHAES), androstenedione (A) and 5a-dihydrotestosterone (DHT). Regarding the Δ-androgens (delta-androgens) - DHEA and DHEAS, 70 to 80% of their total amount is produced by the adrenal glands, most of which is then converted into A, T, DHT, and estrogens. The androgenic steroids T and DHT are the most active biologically. Thus, the daily production of testosterone (T) in the body of healthy young women is approximately 300 pg, that is to say, 50% of the production in men. 98% of these hormones are linked to a protein such as globulin which binds sex steroids.
    Depending on the severity of the disorder, the following causes of AI in women are possible:
    1. Ovariectomy, chemotherapy, or radiotherapy. Thus, an oophorectomy leads to a sharp drop in estrogenic and androgenic levels in the first 24 hours after surgery.
    2. Adrenal insufficiency or adrenalectomy.
    3. Pituitary cause (hypopituitarism).
    4. Medicinal cause (taking corticosteroids, antiandrogenic drugs, or oral drugs for hormone replacement therapy).
    CH 712 460 B1
    5. Idiopathic cause.
    [0008] With the onset of menopause, the production of testosterone (T) gradually decreases. The decrease in androgen production begins as early as after the age of 30, and at the age of 70 it is about 20% of its rate at a young age.
    The diagnosis of ΓΙΑ includes the collection of psychosocial and medical history, objective examinations and laboratory tests. The diagnosis of ΓΙΑ can only be made if the estrogen level is normal. It applies to women of childbearing age with a normal menstrual cycle as well as to postmenopausal women who are receiving hormone replacement therapy (HRT). The detection of low androgen levels is an additional criterion for the diagnosis of ΓΙΑ. However, this latter sign as such cannot be considered as a basis for the diagnosis of ΓΙΑ in the absence of clinical signs. According to the Princeton Consensus statement on the definition, classification and estimation of androgen deficiency in women (2001), the level of testosterone (T) in the blood serum determined in the morning is recognized as the most reliable sign of ΓΙΑ. This criterion is an "absolute benchmark" in the diagnosis of androgen deficiency (AI) in women. Thus, the diagnosis of ΓΙΑ is rather complex. First, a doctor must be convinced that the characteristic symptoms of ΓΙΑ are not the result of estrogen deficiency. When estrogen levels are normal, characteristic symptoms of ΓΙΑ may thus be associated with one or more other somatic endocrine diseases such as hypo- or hyper-thyroidism, metabolic syndrome, vitamin D deficiency, chronic fatigue syndrome; chronic psychosocial stress at work and in the family, etc. Apart from low estrogen levels, low T levels can also be a cause of depression and reduced perceived well-being in women [1-8], [0010] When diagnosed with AI, exclude iatrogenic causes such as taking antidepressants, serotonin reuptake inhibitors, sedative drugs (barbiturates and benzodiazepines), antihypertensive drugs from the ß-blocker group (propranolol, atenolol, etc.), d calcium channel blockers (felodipine, isradipine), diuretics (spironolactone), hormonal drugs (estrogens, progestogens, antiandrogens, corticosteroids). Prolonged corticosteroid use during the treatment of rheumatoid arthritis or systemic lupus erythematosus, etc., also contributes to the development of ΓΙΑ. Alcohol and narcotic drugs also inhibit the production of testosterone (T).
    The mechanisms of the androgenic effect of the above-mentioned causes can be induced by the decrease in the production of androstenedione (A) and T in the ovaries, by competitive inhibition of 5a-reductase - enzyme which provides the conversion of T in DHT in the skin, and by reducing the production of DHAES. The most potent androgens are cyproterone acetate, dienogest, and Chlormadinone acetate.
    The treatment for ΓΙΑ is not yet developed. In Russia and most countries around the world, there is no officially approved drug for androgen replacement therapy in women with AI. Thus, the treatment of such patients is associated with certain difficulties. The presence of "residual" derivatives of 19-nor-steroids with a slight androgenic effect is used in combination with HRT drugs in the treatment of women with AI in the perimenopausal (Climonorm, Trisequence) and postmenopausal (Kliogest) age. , Tibolone). If patients with post-oophorectomy syndrome, even with the elimination of the uterus, have expressed sexual disturbances, severe astheno-depressive syndrome, it is better to use combination drugs. Properly chosen HRT has a combined beneficial effect on psycho-vegetative disorders and metabolic processes, prevents changes in body proportions, improves social adjustment and quality of life in general. However, wide use of HRT, especially at an advanced age, is limited by a number of contraindications such as impaired liver function, tendency to thrombosis and thrombophlebitis, hyperplastic processes in the uterus and the mammary glands. In addition, HRT increases the risk of breast cancer by 30 to 50%.
    Currently, testosterone-based drugs are also used in the form of injections, implants, patches and gels. However, all of these drugs are dangerous in the treatment of ΓΙΑ in women. There are often side effects such as obesity, acne, body and facial hair growth, weight gain, voice severity, angry outbursts, and aggression.
    The prior art does not disclose recommendations for the treatment of Γ AI which would be based on results of large randomized placebo-controlled clinical trials.
    The main androgens in blood serum in women with a normal menstrual cycle are testosterone and dihydrotestosterone. Dehydroepiandrosterone (DHAE), dehydroepiandrosterone sulfate (DHAES), and androstenedione are considered prohormones since they can manifest their androgenic effects only when they are converted to testosterone. The body of a healthy woman of childbearing age produces 300 pg of testosterone per day (that is, 5% of the daily production for men). As we age, women experience a significant decrease in the levels of all androgens. Also, the average levels of total and free testosterone, androstenedione, and DHAE in women at the age of 45 are 50%, at the age of 60 - about 30%, at the age 70 - 10% of these hormones in women aged 20 [4], On
    CH 712 460 B1 the basis of what has been described above, Kalinchenko S. et al. [5] thinks that researching the role of androgens in women has great significance.
    [0016] In world practice, there is a great deal of experience in the use of estrogen replacement therapy. However, there is mounting evidence that it is often impossible to improve quality of life without correcting age-related androgen deficiency. Widespread use of HRT, especially at an advanced age, is limited by a number of contraindications such as impaired liver function, tendency to thrombosis and thrombophlebitis, hyperplastic processes in the uterus and mammary glands. In addition, HRT increases the risk of breast cancer by 30 to 50%.
    In connection with what has been described above, the search for new methods of treating age-related ΓΙΑ is extremely important. Since the use of natural hormones - estrogens and androgens - has a number of disadvantages, it has been suggested to use plant hormones. Also, produced in the United States, "Citracal plus Vitamin D" contains genistein - soy hormone (analog of female sex hormones) - as a substrate for the synthesis of endogenous hormones. The authors of the claimed invention have developed new technologies in the treatment of ΓΙΑ with the use of drone brood brood as a donor of sex hormones, including testosterone, in women.
    From the prior art, there is known a composition comprising brood of drones and Potentina alba (RU 2 425 593, 10.08.2011). Based on this patent, the effect of the drone brood on the male organism is well studied. The effect of the bumblebee brood on the male organism has been explained by the stimulation of testicular function to produce endogenous testosterone.
    Therefore, the use of brood bee brood for stimulating the production of testosterone in the female organism does not seem obvious, especially with regard to postmenopausal women because it is not obvious which organ in the female body needs to be stimulated to produce testosterone.
    We know from the prior art that androgens are produced in women either by the adrenal cortex or by the ovaries. As for postmenopausal women, the second route of testosterone synthesis can be excluded because of the overall decrease in ovarian function. With regard to the first route of synthesis of androgens, the adrenal glands produce androstenedione, dehydroepiandrosterone (DHAE), and 11-β-hydroxy-androstenedione which, as is known, are precursors of testosterone (Filippovich Yu.B. Biochemical basis of human life. Moscow: Vlados, 2005. P. 336).
    The authors of the invention assumed that the production of testosterone in the female organism is ensured by the liver which disintegrates entomological testosterone up to the level of human testosterone.
    But regardless of the route of synthesis of testosterone in the female organism, it is not possible to draw parallels with routes of synthesis of this hormone in the male organism. So, as we know, all steroids are lipid compounds that are poorly soluble in water. Therefore, they are present in the blood mainly in the bound state with blood plasma proteins. Only a small part of these compounds is in free form. These are just free steroids that have high biological activity: they penetrate the membrane of target cells. The precursor of steroids is cholesterol which converts progesterone in the cells of the adrenal cortex. Progesterone, in turn, can be converted to corticosteroids, androgens, and estrogens (Liubimova Z.V Age physiology. Part 1. Moscow: Vlados, 2004. P. 105). One of the dietary recommendations for increasing testosterone levels in men usually includes increasing the consumption of cholesterol, for example, eggs. However, this recommendation is unacceptable to women because it can lead to an increase in estrogen or corticosteroid levels. It is known from the prior art that the same stimuli on the internal secretory glands of men and women have different effects on the synthesis of hormones. Thus, follicle-stimulating hormone (FSH) secreted by the pituitary gland causes estrogen production in women and testosterone production in men, respectively (Gurovets GV Age anatomy and physiology. Moscow: Vlados, 2013. P. 215). Thus, despite the fact that the effect of the bumblebee brood as a stimulator of testosterone production in men is known from the prior art, it is necessary to take into account the differences in the functioning of the endocrine system in men and in women. Therefore, it is not easy to expect that substances that influence the central links controlling testosterone synthesis in men (Theory and practice of apitherapy. Moscow, 2007) have the same effect on the female organism. In addition, the same substances that regulate the secretion of testosterone from the testes in men cannot be expected to stimulate the secretion of testosterone in women.
    The present invention is based on the unexpected discovery that the drone brood has an androgenotropic effect on the female organism.
    The technical result of the claimed group of inventions consists of an increase in the level of endogenous androgens in the blood in women, especially testosterone.
    Previously, the authors of the claimed invention have reported that the drone brood is a donor of various kinds of sex hormones (estradiol, progesterone, and testosterone) both in men and in women (UK 2 498 811,20.11.2013; RU 2 412 616, 27.02.2011). However, at that time, we did not know which
    CH 712 460 B1 sex hormones for women, the bumblebee brood was donor, that is to say that the publications cited did not give any data which indicates that the bumblebee brood can increase the rate of testosterone in the blood in women. Based on the prior art, it would be reasonable to expect that it would lead to an increase in estradiol or progesterone levels in women. Although various sources mention a pronounced gonadotropic effect which stimulates the activity of the gonads, it is known that a homogenate of drone brood is a stimulator of the central regulatory mechanisms of the secretion of male sex hormones (androgens) which also restores biochemical characteristics of the testes (concentration of testosterone in the blood and that of fructose in the fluid of the seminal vesicles), the prostate gland, and sperm production. The use of bumblebee brood is effective against male sexual dysfunction, male infertility, and decreased sexual desire. Taking a bumblebee brood homogenate stimulates ovarian function in women, restores hormonal status and reproductive function. Thus, it is known from the prior art that a homogenate of drone brood stimulates androgen production in men and estrogen production in women.
    The publications cited relate to decisions related to the treatment of osteoporosis. It is known from the prior art that osteoporosis in women can be estradiol dependent. To sum it all up, the authors conclude that the analysis of the prior art did not disclose any decision that would lead to the claimed technical result - the increase in the level of endogenous androgens in the blood in women, especially testosterone - when using biologically active substances, especially brood of drones. It has been discovered that the effect of entomological testosterone differs significantly from that of exogenous, for example, the effect of testosterone propionate, the use of which is deleterious for the health of women (masculinization , acne, voice severity, excessive body hair growth, male pattern baldness, clitoral development, and thrombophlebitis).
    Given the fact that the liver converts testosterone propionate to estrogen, it would be logical to assume that entomological testosterone is converted by the liver into human testosterone.
    The closest analog to the claimed group of inventions is the decision disclosed in documents EA14 932,29.04.2011. The above decision discloses a method of treating conditions associated with decreased androgen levels in women, including the use of selective androgen receptor modulators. The authors created the composition based on a bumblebee brood homogenate produced in the form of powder, tablets or capsules.
    The authors conducted a study to investigate the effects of the composition created on the hormonal state of women with androgen deficiency.
    Materials and processes. From 2009 to March 2013, 72 women aged 49 to 85 were examined. The criteria for inclusion in the study were: women with hormonal and clinical confirmed androgen deficiency.
    The research included an objective examination, general clinical laboratory tests as well as hormonal tests - determination of the levels of total testosterone, of globulin, of globulin binding the sex hormones (SHBG). The hormonal tests were carried out by an immunochimioluminescent process on the “Immulite 2000” device.
    All the women tested were divided into 2 comparative groups according to the degree and severity of the disease: the 1st group (38 women) received the claimed composition orally - one tablet in the morning and in the evening (one tablet contained 100 mg of bumblebee brood) for 3 months 3 times a year. The 2 nd group (control) (34 women) received placebo - twice a day on the same regimen as in the 1 st group.
    The statistical analysis of the data received was carried out using the StatSoft software package, Windows XP. The quantitative characteristics were described by the mean and the standard deviations. The data are presented in the format: Μ ± m where Μ is the arithmetic mean and m is the standard deviation. The differences were considered statistically significant at the significance level p <0.05.
    Results After the end of the trial, in the group of women who received the claimed composition, an improvement in mood was observed, an increase in activity, an increase in muscle strength, a decrease in dysuretic disorders and osteoporotic activity.
    In the control group of women who received the placebo, no effect was observed which was present in the 1st group.
    Analysis of the hormonal characteristics revealed that the total testosterone level in the women of the two groups tested before treatment was:
    1st group: 1.1 ± 0.4 nmol / l;
    2 nd group: 1.2 ± 0.5 nmol / l (p <0.5),
    CH 712 460 B1 with reference values for this process of 1.7 to 3.4 nmol / l. The sex hormone binding globulin (SHBG) levels in the 1 st and 2 nd groups before treatment were 64.3 ± 2.6 nmol / l and 62.8 ± 2.9 nmol / l (p <0 , 05), respectively. After 9 months of treatment with the claimed composition, 29 patients in the group of 37 women reported an improvement. When estimating laboratory characteristics, an increase in total testosterone levels in blood serum was noted from 1.1 ± 0.4 nmol / l to 2.5 ± 0.6 nmol / l (p < 0.05), SHBG from 64.3 ± 2.6 to 115.0 ± 5.9 nmol / l (p <0.05). In the 2nd group that received placebo, none of the patients showed any positive change in testosterone levels and increasing SHBG.
    The results of this research clearly demonstrate that taking the claimed composition normalizes the level of androgens in women. It leads to an improvement in general well-being, to the disappearance or reduction of the clinical symptoms of ΓΙΑ. This effect can be obtained when taking the claimed composition in an amount of 10 mg to 600 mg per day.
    The data received show that the aging process is accompanied by a decrease in the hormonal state of androgens which leads to the appearance of clinical symptoms of ΓΙΑ.
    Indication of the source of genetic resources according to article 138 let. b LBI and article 49a LBI:
    The bumblebee broods used to produce the homogenates were obtained in the Kulyasovo and Mamadysh region of Kameshkirsky, Penza district in Russia, according to a method described in EP 2 756 848.
    Genetic resource Source of genetic resource Bumblebee brood Kulyasovo and Mamadysh region of Kameshkirsky, Penza district in Russia
    Literature
    1. Marchenko L.A., Ilyina L.M. Informational material on androgen insufficiency for distribution to members of Association of gynecologists-endocrinologists. 2005.
    2. Kalinchenko S. Yu., Apetov S. S. Role of androgens in women: what we know // Attending doctor 2010; 8: 78-83.
    3. Kalinchenko S. Yu., Apetov S. S. Use of androgens in women in the menopausal age // Attending doctor 2009; 3: 28-30.
    4. Riggs B.L., Hodgson I.F., O’Fallon W.M. et al. Fluoride treatment on the fracture rate in postmenopausal women with osteoporosis // New England Journal of Medicine, 1990; 322: 802-809.
    5. Kalinchenko S.Yu., Vishnevskiy E.L., Koval A.N., Mskhalaya G.J., Saad F. Benefitial effects of testosterone administration on symptoms of the lower urinary tract in men with late-onset hypogonadism: A pilot study // The Aging Male. 2008, vol. 11, lss. 2: 57-61.
    6. Mudali S., Dobs A.S., Ding J., Cauley J.A., Szklo Μ., Golden S.H. Endogenous postmenopausal hormones and serum lipids: the Atherosclerosis Risk in Communities Study // The Journal of Clinical Endocrinology and Metabolism, 2005, vol. 90, p. 1202-1209.
    7. Nathorst-Boos J., Floter A., Jarcander-Rollf Μ. Treatment with percutaneous testosterone gel in postmenopausal women with decreased libido-effects on sexuality and psychological well-being // Maturitas, 2006, vol.53, p. 11-18.
    8. Riverra-Woll L.M., Papalia Μ., Davis S.R., Burger H.G. Androgen insufficiency in women: diagnostic and therapeutic implications // Human Reproduction Update, 2004, vol. 10, Nr. 5, p. 421-432.
    权利要求:
    Claims (3)
    [1]
    Claims
    1. Composition for the treatment of androgen deficiency in women characterized in that it comprises a homogenate of brood of bumblebees.
    [2]
    2. Composition according to claim 1, wherein the composition is in the form of tablets, capsules or powder.
    [3]
    3. Composition for the treatment according to claim 1, characterized in that the dosage of brood bumblebee homogenate comprises from 10 mg to 600 mg per day.
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    UA140992U|2020-03-25|
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    引用文献:
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    US7026500B2|2000-08-24|2006-04-11|University Of Tennessee Research Foundation|Halogenated selective androgen receptor modulators and methods of use thereof|
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    RU2491078C2|2011-09-16|2013-08-27|Общество С Ограниченной Ответственностью "Парафарм"|Method for preparing adsorbed male bee brood and formulation therof|
    RU2497533C1|2012-04-19|2013-11-10|Общество С Ограниченной Ответственностью "Парафарм"|Method and preparation for preventing and treating atypical osteoporosis with normal or increased bone mineralisation with cavitary lesions in trabecular bones |RU2736997C1|2019-07-30|2020-11-23|Общество С Ограниченной Ответственностью "Парафарм"|Agent for treating hot flashes and recuperating menstrual cycle during perimenopause and method of using it|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    RU2015111086/10A|RU2577225C1|2015-03-27|2015-03-27|Preparation and method for the treatment of androgen deficiency in women, entomological containing proteins|
    PCT/RU2016/000130|WO2016159827A1|2015-03-27|2016-03-10|Insect protein-containing preparation and method for treating androgen deficiency in women|
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