RU2829548C1 - Method of treating hypogonadotropic hypogonadism, nasal spray as method for administering peptide complex "mh-gndr-19-21" in treating hypogonadotropic hypogonadism - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to a method of treating hypogonadotropic hypogonadism, which consists in administering an intranasal spray in dosage of 1 to 20 mcg in a pulsed mode simulating physiological secretion, where the intranasal spray contains the peptide complex "MH-GNDR-19-21" and auxiliary additives, such as benzalkonium chloride, purified water, with the following content of components, wt %: peptide complex "MH-GNDR-19-21" 2.94, benzalkonium chloride 2.2, purified water—the rest, and wherein the peptide complex "MH-GNDR-19-21" contains, mcg: glycine 111.2, proline 82, arginine 133.5, leucine 95.5, tyrosine 137.7, serine 73.5, tryptophan 157.1, histidine 115.7, pyroglutamic acid 93.8, also relates to an intranasal spray in the treatment of hypogonadotropic hypogonadism, containing a peptide complex "MH-GNDR-19-21" and auxiliary additives such as benzalkonium chloride, purified water, with the following content of components, wt %: peptide complex "MH-GNDR-19-21" 2.94, benzalkonium chloride 2.2, purified water—the rest, wherein peptide complex "MH-GNDR-19-21" contains, mcg: glycine 111.2, proline 82, arginine 133.5, leucine 95.5, tyrosine 137.7, serine 73.5, tryptophan 157.1, histidine 115.7, pyroglutamic acid 93.8.

EFFECT: group of inventions provides treating hypogonadotropic hypogonadism.

3 cl

Description

The invention relates to medicine, namely to urology and endocrinology. A new method for treating hypogonadotropic hypogonadism with the peptide complex "MH-GNDR-19-21" is proposed. The method allows diagnosing and treating hypogonadotropic hypogonadism with a new method of introducing the peptide complex "MH-GNDR-19-21" into the body.

The active substance is a complex of short signal peptides (constituents of gonadotropin-releasing hormone), which stimulates the pituitary gland in a natural form to increase the release of LH (the hormone responsible for the production of testosterone) and FSH (the hormone responsible for the quality of sperm). Peptide complex MH + GNDR-19-21 (glycine, proline, arginine, leucine, tyrosine, serine, tryptophan, histidine, pyroglutamic acid). The complex of regulatory peptides was chemically isolated from the gonadotropin-releasing hormone polypeptide by a group of scientists from the M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences in collaboration with the Endocrinology Center.

The project is being implemented within the framework of the biomedical direction of the Priority 2030 program. Short peptides are active chains of amino acids that have a regulatory effect on organs and organ systems. Using artificial intelligence programs, statistical data was processed. By means of mathematical modeling, chains of amino acids included in short peptides with regulatory functions were determined. Chromatography-mass spectrometry, as a method, made it possible to isolate these active parts in the gonadotropin-releasing hormone molecule. Then, the biosynthesis of these regulatory peptides was performed and the peptide complex MH-GNDR-19-21 was named.

Regulatory peptides (RP) are biologically active substances consisting of a sequential chain of amino acid residues and performing multiple polyfunctional roles in the human body. RP have tropism for tissues and organs of the body, attaching to the same receptors as hormones, thereby giving the necessary signal to launch biochemical processes aimed at activating testosterone synthesis.

The transfer of biological additives to the brain from the bloodstream is usually hampered by the blood-brain barrier, which is virtually impermeable to the passive diffusion of all drugs except small, lipophilic substances. However, if drugs can be transported along the processes of the olfactory nerve cells, they can bypass the BBB and directly enter the brain. The nasal mucosa is also used to administer drugs that are subject to significant pre-systemic elimination when administered orally. Delivery of the biocomplex through the nose has a number of advantages, including rapid onset of pharmacological effect, the ability to bypass the blood-brain barrier, reduced likelihood of side effects, and a rapid and non-invasive route of administration.
Sublingual administration. Spray under the tongue, as a result of which the regulatory peptides get directly into the small blood vessels located on the underside of the tongue. This route of administration (sublingual) is especially good because the drug immediately enters the general bloodstream, bypassing the intestinal wall and liver. However, when using sublingually, you cannot swallow for 2 minutes, otherwise absorption will be incomplete.

Sublingual route of administration. Absorption from the oral cavity through the mucous membrane of the cheeks or from the sublingual area (sublingually) allows the biocomplex to enter directly into the blood, bypassing the effects in the gastrointestinal tract and liver associated with the transition to the portal vein system. This route is suitable when a rapid effect is required.

Hypogonadism in men is a clinical and biochemical syndrome associated with low testosterone levels. Low testosterone levels can cause disruption of male sexual development, resulting in decreased fertility, sexual dysfunction, decreased intensity of muscle mass formation and bone mineralization, impaired fat metabolism, and cognitive dysfunction. Most forms of hypogonadism diagnosed in adults are acquired and most often develop as a result of obesity, severe systemic diseases, and the use of steroids and drugs. Secondary hypogonadism can be caused by epidemiological factors (smoking, alcohol consumption), age-related changes in the hypothalamus and pituitary gland [1, 2].

With age, men experience a decrease in testosterone levels (an annual decrease in circulating testosterone levels by 0.4-2.0% has been recorded starting from the age of 30) [3, 4]. In middle-aged men without concomitant pathology, the prevalence of hypogonadism is 6% [5]. The prevalence of hypogonadism in obesity and uncompensated diabetes mellitus can exceed 50% [6].

All of the above indicates the need to expand treatment options for men with hypogonadism.

A method for treating hypogonadotropic hypogonadism is known, a nasal spray, as a method for administering gonadorelin acetate in the treatment of hypogonadotropic hypogonadism, see Russian patent No. 2733465, dated 01.10.2020 [7]. This method is based on the intranasal administration of gonadorelin acetate. The disadvantage of this method is the need for a doctor to monitor the administration of gonadorelin acetate. Due to the technical complexity, this treatment method is used only in specialized clinics.

During the research it was found that the use of the peptide complex "MH-GNDR-19-21" in low concentrations can also be used to restore the synthesis of sex hormones in patients with hypothalamic hypogonadism. The main purpose of the drug based on the peptide complex "MH-GNDR-19-21" is to stimulate the pituitary gland in a natural form to increase the release of LH and FSH, and therefore, testosterone production and improve the quality of the spermogram. Having restored the physiological rhythm of gonadotropin secretion, you can refuse to undergo a course of hormone replacement therapy.

During the patent search, the use of the peptide complex "MH-GNDR-19-21" in the form of a spray for the treatment of hypogonadotropic hypogonadism in men was not found.

The objective of the invention is to expand the possibilities of treating hypogonadotropic hypogonadism in men by using the peptide complex "MH-GNDR-19-21" in the form of a spray, which ensures the supply of the active substance within the framework of physiological secretion.

The stated objective is achieved by administering the peptide complex "MH-GNDR-19-21" intranasally, in a dosage of 1-20 mcg, in a pulsed manner, simulating physiological secretion, as a method of treating hypogonadotropic hypogonadism. In this case, the peptide complex "MH-GNDR-19-21" contains:

Glycine - 111.2 mcg

Proline - 82 mcg

Arginine - 133.5 mcg

Leucine - 95.5 mcg

Tyrosine - 137.7 mcg

Serine - 73.5 mcg

Tryptophan - 157.1 mcg

Histidine - 115.7 mcg

Pyroglutamic acid - 93.8 mcg

In this case, the introduction of the peptide complex “MH-GNDR-19-21” is carried out in a pulsed mode - once every 60-90 minutes.

A nasal spray is also proposed as a method of administering the peptide complex "MH-GNDR-19-21" in the treatment of hypogonadotropic hypogonadism. Where the peptide complex "MH-GNDR-19-21" contains:

Glycine - 111.2 mcg

Proline - 82 mcg

Arginine - 133.5 mcg

Leucine - 95.5 mcg

Tyrosine - 137.7 mcg

Serine - 73.5 mcg

Tryptophan - 157.1 mcg

Histidine - 115.7 mcg

Pyroglutamic acid - 93.8 mcg

The proposed solution is clinically proven.

The drug. Intranasal spray containing:

- purified water,

peptide complex MH+GNDR-19-21 (glycine, proline, arginine, leucine, tyrosine, serine, tryptophan, histidine, pyroglutamic acid),

dosed into bottles of various sizes.

To prepare the spray, use the following composition per 100 ml:

peptide complex MH+GNDR-19-21 (glycine, proline, arginine, leucine, tyrosine, serine, tryptophan, histidine, pyroglutamic acid) - 3000 mcg,

benzalkonium chloride - 0.7 mg,

the rest is water.

Or in wt.%:

peptide complex MH+GNDR-19-21 (glycine, proline, arginine, leucine, tyrosine, serine, tryptophan, histidine, pyroglutamic acid) - 2.94,

benzalkonium chloride - 2.2,

the rest is water.

The specified composition is poured into vials. The nasal sprayer of the vial can be adjusted in such a way that 1 to 20 mcg of the peptide complex "MH-GNDR-19-21" is delivered intranasally in one injection.

The effectiveness of the use of the peptide complex "MH-GNDR-19-21" for the treatment of hypogonadotropic hypogonadism in men is shown in the following examples:

Patient S. (41 years old) was undergoing routine examination and treatment in the urology department of the Ruszdravproekt clinic from 11.06.19 to 25.06.19, outpatient treatment up to 8 weeks. He consulted a urologist with complaints of decreased sexual desire, erectile dysfunction, increased fatigue, shortness of breath during physical activity, excess weight, and ineffectiveness of physical activity and diets.

The above complaints have been bothering me for the past 5 years. I have not treated myself or been examined. I have been using anabolic steroids for the past 5 years.

Objectively upon examination:

height - 188 cm; weight - 121 kg; BMI - 37.5 kg/ ^m2 ; waist circumference (WC) - 127 cm;

hip circumference (HC) - 138 cm; WC/HR - 0.94; BP - 150/90 mmHg, HR - 84 beats per minute.

Hair growth in the armpits, on the chest, anterior abdominal wall, in the groin area is normal. The external genitalia are formed correctly, without any peculiarities.

When using the ADAM questionnaire, positive answers were given to 8 out of 10 questions, indicating the severity of androgen deficiency symptoms in this patient.

Laboratory indicators:

total cholesterol - 6.5 mmol/l (normal 3.1-5.2); LDL - 3.8 mmol/l (normal 0-3.3);

triglycerides - 2.6 mmol/l (normal - less than 2.3); total testosterone - 7.1 nmol/l (normal 12.0-41.0);

SSSG - 25.9 pmol/l (normal 12.9-61.7); LH - 1.2 IU/l (normal 2.5-11.0);

FSH - 1.2 IU/L (normal 1.5-12.4); TSH - 1.6 mIU/L (normal 0.25-4.0);

prolactin - 249 IU/l (normal 50-610); estradiol - 166 pmol/l (normal 20-240);

total PSA - 0.9 ng/ml (normal 0-4).

According to the ultrasound examination of the prostate gland, no echographic signs of pathology were detected.

The patient was diagnosed with hypogonadotropic hypogonadism. Metabolic syndrome: Abdominal obesity (grade 2). Arterial hypertension. Dyslipidemia.

Treatment goal:

Restoration of gonadotropin secretion. Normalization of testosterone levels. Therapy was prescribed: "Vivamen" in a dosage of 5 mcg per intranasal injection every hour for three days, followed by monitoring of LH, FSH, and testosterone in the blood. The patient showed an increase in LH and FSH levels by more than 30% of the initial level. After that, the patient was prescribed a course of therapy with "Vivamen" from 2.5 mcg per intranasal injection every hour for 2 months. LH, FSH, and testosterone levels were monitored monthly. It is recommended to adhere to the principles of rational nutrition with limited consumption of fats and easily digestible carbohydrates, table salt, as well as additional aerobic exercise (active walking for 1 hour per day).

When assessing the results of therapy after 2 months, the patient noted significant positive dynamics of general well-being - improvement of erectile function (increased sexual desire, increased frequency of spontaneous erections), disappearance of complaints of rapid fatigue, depressed mood; stabilization of blood pressure to 128/80 mm Hg. Objectively, upon examination, a decrease in all anthropometric indicators: weight - 98 kg, BMI - 28.5 kg / m ² , WC - 87 cm, HR - 108 cm, WC / HR - 0.82. During the treatment, normalization of all hormonal and biochemical indicators also occurred.

Laboratory indicators:

total cholesterol - 3.3 mmol/l (normal 3.1-5.2); LDL - 3.2 mmol/l (normal 0-3.3);

triglycerides - 2.2 mmol/l (normal - less than 2.3); total testosterone - 23.2 nmol/l (normal 12.0-41.0);

SSSH - 27.9 pmol/l (normal 12.9-61.7); LH - 3.6 IU/l (normal 2.5-11.0);

FSH - 3.7 IU/L (normal 1.5-12.4); TSH - 1.6 mIU/L (normal 0.25-4.0);

prolactin - 274 IU/l (normal 50–610); estradiol - 254 pmol/l (normal 20–240).

Thereafter, the patient was kept under observation by a urologist with laboratory parameters being monitored once every six months.

Patient N., 35 years old. Was undergoing routine examination and treatment in the urology department of the Ruszdravproekt clinic from 11.08.19 to 28.08.19, outpatient treatment up to 8 weeks. He consulted a urologist with complaints of decreased libido, erectile dysfunction, general weakness, increased fatigue, and infertility in marriage for 5 years. History of drug use. Did not self-medicate or undergo examination.

Objectively upon examination:

height - 176 cm; weight - 83 kg; BMI - 23.3 kg/ ^m2 ; waist circumference (WC) - 79 cm;

hip circumference (HC) - 107 cm; blood pressure - 130/90 mmHg, heart rate - 82 beats per minute.

Hair growth in the armpits, chest, anterior abdominal wall, and inguinal region is reduced. The external genitalia are formed correctly, without any peculiarities, the testicles in the scrotum are reduced in size.

When using the ADAM questionnaire, positive answers were given to 7 out of 10 questions, indicating the severity of androgen deficiency symptoms in this patient.

Laboratory indicators:

total cholesterol - 6.2 mmol/l (normal 3.1-5.2); LDL - 3.3 mmol/l (normal 0-3.3);

triglycerides - 2.3 mmol/l (normal - less than 2.3); total testosterone - 3.6 nmol/l (normal 12.0-41.0); SHBG - 16.9 pmol/l (normal 12.9-61.7); LH - 0.7 IU/l (normal 2.5-11.0); FSH - 1.2 IU/l (normal 1.5-12.4); TSH - 1.5 mIU/l (normal 0.25-4.0);

prolactin - 158 IU/l (normal 50-610); estradiol - 59 pmol/l (normal 20-240);

total PSA - 1.8 ng/ml (normal 0-4).

According to the ultrasound examination of the prostate gland, no echographic signs of pathology were detected. The testicles are reduced in size (hypoplasia).

In the spermogram: oligoasthenoteratozoospermia.

The patient was diagnosed with hypogonadotropic hypogonadism. Oligoasthenoteratozoospermia.

Treatment goal:

Restoration of gonadotropin secretion, improvement of spermatogenesis. Normalization of testosterone levels. Therapy was prescribed: "Vivamen" in a dosage of 5 mcg per intranasal injection every hour for 2 months. LH, FSH and testosterone levels were monitored monthly. Against the background of the specified therapy, the patient noted a significant improvement in general well-being, an increase in testosterone concentration, an increase in the concentration of luteinizing and follicle-stimulating hormone and, as a consequence of the above changes, normalization of spermatogenesis parameters, in particular an increase in the concentration of actively motile spermatozoa involved in fertilization. When assessing the results of therapy after 4 months, the patient noted significant positive dynamics of general well-being - improvement of erectile function, disappearance of complaints of rapid fatigue, improvement of mood; Against the background of treatment, normalization of all hormonal and biochemical parameters also occurred.

The proposed method involves intranasal administration of the MH-GNDR-19-21 preparation in a pulsating, close to physiological mode, and has shown stable results in restoring the production of LH and FSH by the pituitary gland in 130 patients. In male infertility associated with decreased synthesis of gonadotropins as a result of steroid and drug use, the peptide complex "MH-GNDR-19-21" can achieve testicular growth, normal secretion of sex hormones and spermatogenesis. All of the above indicates the need to expand the treatment options for men with hypogonadism. The advantage of this method is the wide range of safety of the peptide complex compared to the introduction of gonadorelin acetate.

The proposed method of treating hypogonadotropic infertility in men (administration of the peptide complex "MH-GNDR-19-21" in a low dosage, intranasally in a pulsating mode) restores the synthesis of LH and FSH, stimulates the growth of the seminiferous tubules, increases the level of testosterone in the blood, thereby ensuring the process of sperm maturation, reduces the duration of treatment, does not require hospitalization, is convenient for home use and does not have harmful side effects on the body, has no significant contraindications for use.

Sources of information

1. “Andrology. Men’s health and dysfunction of the reproductive system”. Under the general editorship of Nishlag E., Bere G.M. M. 2005;554.

2. Rozhivanov R.V. “Hypogonadism syndrome in men”. // Obesity and metabolism. 2014;11:2:24-31. . doi: 10.14341/omet2014230-34.

3. Dedov I.I., Kalinchenko S.Yu. “Age-related androgen deficiency in men”. Moscow: Practical Medicine. 2006. .

4. Rozhivanov R.V. “Effective therapy and errors in the treatment of endocrine disorders in andrology”. In the book: Endocrinology. Pharmacotherapy without errors. Edited by Academician of the Russian Academy of Sciences and Russian Academy of Medical Sciences Dedov I.I., Academician of the Russian Academy of Medical Sciences Melnichenko G.A. Moscow 2013; 615-625. .

5. Rozhivanov R.V. “Endocrine disorders of sexual function in men”. In the book: Rational pharmacotherapy of diseases of the endocrine system and metabolic disorders. Edited by Academician of the Russian Academy of Sciences and Russian Academy of Medical Sciences Dedov I.I., Academician of the Russian Academy of Medical Sciences Melnichenko G.A. Second edition, corrected and supplemented. Moscow, 2013; 754-775. .

6. Trinick TR, feneley MR, Welford H, Carruthers M. International web survey shows high prevalence of symptomatic testosterone deficiency in men. The aging male. 2015;14(1):10-15. doi: 10.3109/13685538.2010.511325.

7. Patent of the Russian Federation No. 2733465, dated 01.10.2020.

Claims (9)

1. A method for treating hypogonadotropic hypogonadism, which consists of administering an intranasal spray in a dosage of 1 to 20 mcg in a pulsed mode simulating physiological secretion, where the intranasal spray contains the peptide complex "MH-GNDR-19-21" and auxiliary additives such as benzalkonium chloride, purified water, with the following component content, wt.%: peptide complex "MH-GNDR-19-21" 2.94 benzalkonium chloride 2.2 purified water the rest, and the peptide complex "MH-GNDR-19-21" contains, mcg: Glycine 111.2 Proline 82 Arginine 133.5 Leucine 95.5 Tyrosine 137.7 Serene 73.5 Tryptophan 157.1 Histidine 115.7 Pyroglutamic acid 93.8 2. A method for treating hypogonadotropic hypogonadism according to paragraph 1, characterized in that the intranasal spray is administered in a pulsed mode - once every 60-90 minutes. 3. Intranasal spray for the treatment of hypogonadotropic hypogonadism, containing the peptide complex "MH-GNDR-19-21" and auxiliary additives such as benzalkonium chloride, purified water, with the following component content, wt.%: peptide complex "MH-GNDR-19-21" 2.94 benzalkonium chloride 2.2 purified water the rest, the peptide complex "MH-GNDR-19-21" contains, mcg: Glycine 111.2 Proline 82 Arginine 133.5 Leucine 95.5 Tyrosine 137.7 Serene 73.5 Tryptophan 157.1 Histidine 115.7 Pyroglutamic acid 93.8