Method and means for normalizing decreased male sexual activity caused by androgen deficiency

Abstract

FIELD: pharmacology.SUBSTANCE: use of Neuropren is proposed for the normalization of reduced male sexual activity caused by androgen deficiency, in combination with standard therapy.EFFECT: expansion of the range of methods for normalizing reduced male sexual activity caused by androgen deficiency.1 cl, 5 dwg, 1 ex

Description

[0001] The invention relates to the field of medicine, specifically to pharmacology, andrology, to methods and means for normalizing reduced male sexual activity caused by androgen deficiency.

[0002] Copulatory activity is one of the components of male sexual function [1]. Copulation is the process by which the male and female reproductive cells fuse. Copulatory dysfunction is a complex of symptoms that includes a number of disorders of copulatory behavior. Copulatory disorders are related to male sexual dysfunction and most often manifest as erectile dysfunction (ED) [2]. The treatment of this pathology is one of the most important modern medical and social problems [3, 4].

[0003] ED affects 1 in 5 men, with the incidence increasing with age and the prevalence of comorbidities [5]. It is characterized by the inability to achieve and maintain a satisfactory penile erection necessary for copulation. The causes of ED vary in nature (psychogenic, endocrine, neurological, vascular) [6]. A high incidence (up to 60%) of erectile dysfunction is observed in men over 50 years of age, which is associated with an age-related decrease in hormonal activity of the gonadal organs, namely, androgen deficiency [7].

[0004] Androgens play a crucial role in the physiology of erection by acting on the cavernous tissue. They perform central regulation of ED [3]. Androgen deficiency leads to ED by suppressing a number of signaling pathways (nitric oxide synthase / nitric oxide / cyclic guanosine monophosphate) and altering the expression of ion channel proteins, as well as causing oxidative stress, cell death and fibrosis in the cavernous bodies of the penis [8]. If ED is caused by low plasma testosterone levels, the main pathogenetic drug treatment is androgen hormone replacement therapy, and testosterone monotherapy is often sufficient [4, 8]. The use of testosterone drugs for erectile dysfunction is considered indicated only in patients with clinical and laboratory signs of hypogonadism [9]. Symptomatic treatment with well-known phosphodiesterase type 5 inhibitors (PDE-5, Viagra, etc.) does not affect the underlying pathogenetic mechanism of erectile dysfunction in patients with this condition. Moreover, PDE5 inhibitor therapy alone will leave such patients without any pathogenetic therapy and, in addition, expose them to a high risk of developing obesity, diabetes, dyslipidemia, and cardiovascular diseases [9]. It should be noted that testosterone therapy itself is not safe. Testosterone has many contraindications and side effects. The risk-benefit ratio of its use in relation to cardiovascular diseases, prostate cancer, lower urinary tract symptoms, obstructive sleep apnea, erythrocytosis, and other theoretical risks is still under careful study and has not been definitively determined [4, 9]. In this regard, there is a continuous search for new drugs for the treatment of ED in hypogonadism, which indicates the relevance of the problem.Herbal remedies have been shown to be effective in this regard [10, 11]. Such medications are considered the safest treatment option compared to synthetic pharmaceuticals, as they have significantly fewer unwanted side effects. Furthermore, their effectiveness is quite high

[11] . A number of herbal remedies have the potential to effectively treat erectile dysfunction and hypogonadism [11, 12].

[0005] Ginseng is one of them [12, 13]. The instructions for the drug note that it is recommended for use in the treatment of weakened sexual function caused by neurasthenia. There is evidence of its use in the treatment of erectile dysfunction, as it has a significant positive effect on the psychogenic etiology of sexual dysfunction. The reliability of the results has not been confirmed

[12] . It has been established that the use of ginseng can alleviate the symptoms of castrated male rats caused by androgen deficiency. However, only indirect methods of assessing androgen saturation (metabolomics methods and intestinal flora analysis) are used as evidence of a decrease in androgen levels

[13] .

[0006] A drug is known to enhance copulatory activity in male rats with androgen deficiency

[14] . This pharmacological composition is based on a bisamide derivative of dicarboxylic acids (Treamide). Androgen deficiency was modeled during a study of its effectiveness by administering the female sex hormone sinestrol to male rats, which weakens the effects of male sex hormones. However, this compound is not plant-based; it is synthetic in origin. The closest natural derivative to the claimed drug is the plant-based drug tribestan, which was chosen as a prototype.

[0007] Tribestan (manufactured by Sofarma, Bulgaria), which stimulates testosterone production in men, is indicated for erectile dysfunction [15, 16]. This herbal remedy, obtained from the aerial parts of Tribulus terrestris L., contains a number of biologically active substances (flavonoids, saponins, etc.). However, the effectiveness of this drug is not always high. In addition, Tribestan has contraindications and side effects

[16] .

[0008] Hypogonadism syndrome in men is a clinical and biochemical syndrome associated with low testosterone levels, as well as receptor insensitivity to it and its metabolites, which can have a negative impact on numerous organs and systems, worsening quality of life and prognosis [1, 2]. There are large individual variations in testosterone concentrations. The most common clinical manifestations of androgen deficiency are decreased libido, erectile dysfunction, decreased muscle mass, low bone mineral density, weakness, metabolic syndrome, and depression.It is necessary to differentiate androgen deficiency from conditions associated with similar symptoms and assess overall health to rule out systemic diseases, eating disorders, excessive physical activity, sleep disturbances, and adverse reactions to medications that affect testosterone production and metabolism. The clinical presentation, signs, and symptoms of hypogonadism may be masked due to physiological phenotypic variability. Hypogonadism associated with impaired negative feedback mechanisms of the pituitary-gonadal axis develops in the context of metabolic disturbances, suggesting its potential reversibility with treatment, unlike hypergonadotropic, hypogonadotropic, or mixed hypogonadism.Moreover, according to literary data, the prevalence of androgen deficiency in the presence of concomitant chronic diseases, especially obesity and type 2 diabetes mellitus, is up to 30%, and isolated forms - only 5%.

[0009] Testosterone replacement therapy can alleviate symptoms associated with androgen deficiency. It is important to understand the potential risks and benefits of this treatment [2]. Functional hypogonadism occurs in the absence of reliable data on organic changes in the hypothalamic-pituitary-gonadal axis and should be treated with therapeutic interventions aimed at eliminating or improving comorbidities. This requires the search for new additional agents that improve androgen function with sufficient efficacy and safety.

[0010] The use of an effective dose of Verva fir extract, which increases sperm motility and reduces the number of abnormal sperm, is known. It is administered once daily for 5 days before and 5 days after cytostatic exposure as a means for the prevention and treatment of asthenozoospermia and teratozoospermia (Russian Patent No. 2739491, published December 21, 2020). The scope of application of this product is limited.

[0011] New technical result - expansion of the range of methods and available herbal remedies for normalizing reduced male sexual activity caused by androgen deficiency, methods with their use with the least number of complications.

[0012] To achieve a new technical result as a means of normalizing reduced male sexual activity caused by androgen deficiency, use "Neuropren" 1 capsule 1 time per day in combination with standard therapy for 3 months.

[0013] A new property of the drug "Neuropren" - the ability to normalize reduced male sexual activity caused by androgen deficiency - was discovered during clinical trials.

[0014] In accordance with the State Registration Certificate No. AM.01.11.01.003.R.000506.12.23 dated 04.12.2023, the dietary supplement "Neuropren", which contains polyprenols of Siberian fir needles, is recommended for neurodegenerative diseases such as Alzheimer's disease, senile dementia, etc.; chronic cerebral circulatory insufficiency (dyscirculatory encephalopathy); with decreased memory and mental performance, depression and anxiety; for the prevention of age-related changes in cognitive functions; for effective recovery after physical exertion; with traumatic brain injury, vegetative-vascular disorders; with intoxication (acute and chronic) and

[0015] Clinical testing of the drug "Neuropren" was carried out at the Federal State Budgetary Educational Institution of Higher Education Siberian State Medical University of the Ministry of Health of the Russian Federation in Tomsk in clinical and outpatient settings.

[0016] The study was conducted in accordance with the ethical principles of the Declaration of Helsinki adopted by the XVII session of the World Health Assembly in 1964, the Rules of Clinical Practice in the Russian Federation, approved by the Order of the Ministry of Health of the Russian Federation dated April 1, 2016 No. 200n "On approval of the rules of good clinical practice", the Constitution of the Russian Federation, Federal Law of the Russian Federation No. 323-FZ dated November 21, 2011 "On the Fundamentals of Health Protection of Citizens in the Russian Federation", other relevant legislative acts and orders of the Ministry of Health of the Russian Federation.

[0017] The number of study participants taking the dietary supplement "Neuropren" containing polyprenols from Siberian fir needles (22 volunteers) and the number of study participants not taking the dietary supplement (comparison group) (22 volunteers) was selected taking into account the sample size, which is the minimum number of volunteers sufficient to achieve the objectives of this study. Distribution was carried out randomly using the simple randomization method. The safety of the product was assessed throughout the study, while the volunteers were closely monitored clinically, including a physical examination and monitoring of vital signs (measurement of height, weight, blood pressure, heart rate, respiratory rate, and body temperature) at all visits. All clinical examination data were recorded in the primary medical documentation - the individual registration card (IRC).

[0018] Adverse events were assessed through: clinical examination, laboratory tests, and instrumental examination methods; monitoring of vital signs (monitoring of blood pressure, heart rate, respiratory rate, and body temperature); and observation by a physician for the occurrence of AEs and SAEs through 24-hour telephone access.

[0019] Statistical processing of study participant data, vital signs, and laboratory and instrumental examination data was performed using variation statistics methods and Microsoft Excel software. Medians and quartiles (Me [Q1; Q3]) of the determined laboratory parameters were calculated. For laboratory and instrumental examination data, differences between groups were assessed, and the probability value (P) was calculated.

[0020] The difference between two compared values ​​was considered reliable if the probability of their identity was less than 5% (P<0.05).

[0021] The proposed technical solution is illustrated by the data in Figs. 1-5

[0022] Figure 1 shows the characteristics of the body mass index (BMI), blood pressure (BP), heart rate (HR), respiratory rate (RR), temperature.

[0023] Figure 2 shows the characteristics of body composition in the examined patients of both groups (Me [Q1; Q3])

[0024] Note: Me is the median, Q1; Q3 are the lower; upper quartiles.

[0025] *p - significance of differences between groups (Z - Mann-Whitney test, differences are significant at p<0.05).

[0026] Figure 3 in the table shows the characteristics of the hormonal status indicators and questionnaire data of the main group (Me [Q1; Q3])

[0027] Note: Me - median, Q1; Q3 - lower; upper quartiles; FSH - follicle-stimulating hormone, LH - luteinizing hormone, SHBG - sex hormone-binding globulin;

[0028] *p - significance of differences between groups (Z - Mann-Whitney test, differences are significant at p<0.05;

[0029] ** Interpretation of scores according to the AMS questionnaire: 17-26 points - signs of testosterone deficiency are not expressed, 27-36 points - signs of deficiency are weakly expressed, 37-49 points - signs of deficiency of moderate severity, more than 50 points - signs of deficiency are sharply expressed

[0030] **Yes to questions 1 or 7 or more than 3 questions indicates a possibility of low testosterone levels.

[0031] Figure 4. The table shows the characteristics of the hormonal status indicators and questionnaire data of the comparison group (Me [Q1; Q3])

[0032] Note: Me - median, Q1; Q3 - lower; upper quartiles. FSH - follicle-stimulating hormone, LH - luteinizing hormone, SHBG - sex hormone-binding globulin;

[0033] *p - significance of differences between groups (Z - Mann-Whitney criterion); ** Interpretation of scores according to the AMS questionnaire: 17-26 points - signs of testosterone deficiency are not expressed, 27-36 points - signs of deficiency are weakly expressed, 37-49 points - signs of deficiency of moderate severity, more than 50 points - signs of deficiency are sharply expressed

[0034] **Yes to questions 1 or 7 or more than 3 questions indicates a possibility of low testosterone levels.

[0035] In the comparison group, no significant changes were noted over time; however, a deterioration in subjective complaints according to the AMS questionnaire is noteworthy.

[0036] All volunteers underwent prostate ultrasound (Table 5).

[0037] Based on the analysis results, no statistically significant differences were found between the groups. All parameters were within the reference ranges. There were no exclusion criteria.

[0038] Figure 5 in the table shows the ultrasound characteristics of the prostate gland in the main group and the comparison group at visits 1 and 3.

[0039] *Note: PZh - prostate gland

[0040] The general clinical condition of the volunteers was assessed (Figure 1). The main and comparison groups included patients with grades 1-2 obesity. No statistically significant differences in body mass index (BMI) were found between the groups. All other parameters were within reference ranges. There were no exclusion criteria.

[0041] Taking into account the presence of obesity, an assessment of the body composition was carried out based on the results of bioimpedance analysis for indicators grouped from the point of view of the study of the body's water balance, components of fat and lean body mass, indicators of mineral status and basal metabolism (Fig. 2).

[0042] The body composition of patients with obesity and androgen deficiency was characterized by an increase in absolute adipose tissue content, visceral fat area, and a decrease in skeletal muscle mass as a percentage of body weight. Furthermore, a tendency toward fluid retention was observed, as evidenced by an increase in both intracellular and extracellular fluid components.

[0043] In addition, all patients were tested and blood bio-samples were collected strictly according to clinical guidelines twice at visit 1 and 4 (Fig. 3, 4).

[0044] Treatment with the drug resulted in a significant increase in total plasma testosterone levels. Positive changes in subjective data were also observed, reflected in a significant decrease in ASM scores. In some patients, androgen deficiency shifted from moderate to mild, and three patients rated their erectile function as normal according to the ADAM questionnaire.

[0045] Fig. 4. The characteristics of the hormonal status indicators and questionnaire data of the comparison group are shown (Me [Q1; Q3])

[0046] In the comparison group, no significant changes were noted over time; however, a deterioration in subjective complaints according to the AMS questionnaire is noteworthy.

[0047] All volunteers underwent prostate ultrasound (Fig. 5).

[0048] Based on the analysis results, no statistically significant differences were found between the groups. All parameters were within the reference ranges. There were no exclusion criteria.

[0049] Figure 5 shows the ultrasound characteristics of the prostate gland in the main group and the comparison group at visits 1 and 3.

[0050] The study revealed a positive effect of Neuropren in normalizing decreased male sexual activity caused by androgen deficiency. A dynamic hormonal profile was assessed with the use of Neuropren, a polyprenolid-containing drug, at a dose of 1 capsule once daily in combination with standard therapy, including diet (Pevzner's Diet No. 8), increased physical activity to 60 minutes per day with heart rate monitoring, and hypogonadism therapy with transdermal testosterone preparations for 3 months, taking into account clinical recommendations. An increase in total serum testosterone levels was verified. Positive dynamics in subjective data were observed, expressed as a significant decrease in AMS scores. In some patients, androgen deficiency lessened in severity, and in isolated cases, compensation of clinical signs was achieved more quickly. No significant changes were noted in the ultrasound image of the prostate gland.

[0051] Clinical example 1. Patient R., 47 years old,

[0052] BMI=31.50 kg / m 2 ; SBP=22 mmHg; DBP=87 mmHg; HR=76 bpm; RR=17 bpm; body temperature=36.7 °C; Diagnosis: hypogonadism

[0053] Treatment prescribed according to the invention formula is standard therapy, including diet therapy (table No. 8 according to Pevzner), increased physical activity to 60 minutes per day with heart rate monitoring, hypogonadism therapy taking into account clinical recommendations with transdermal testosterone preparations, and additionally the drug "Neuropren" containing polyprenols of Siberian fir needles, 1 capsule 1 time per day for 3 months. After the course of treatment, an increase in the level of total testosterone in the blood serum was verified. Positive dynamics of subjective data, expressed in a significant decrease in scores on the AMS questionnaire, were revealed. No side effects were observed. Thus, the proposed method using "Neuropren" containing polyprenols of Siberian fir needles is effective in combination with standard therapy for restoring decreased male sexual activity caused by androgen deficiency.

[0054] Sources of information taken into account when compiling the description:

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