EA013948B1 - Preparation stimulating sexual function - Google Patents

Abstract

The invention relates to heptapeptide Thr-Lys-Pro-Arg-Pro-Gly-Pro) in use as a preparation stimulating sexual potency. Experiments on male rats have shown, that single (100 mkg/rat) or triple (3 times by 100 mkg/rat) heptapeptide injection caused activation of central starting mechanisms of sexual function resulting substantial (more than 3 times) shortening of latency intervals and intromissions. General structural strengthening of sexual function is marked at 7-th day after last injection of heptapeptide (delayed effect). There also increased a number of ejaculations with shortening its time characteristics. Comparison preparation (an extract of knot grass) displayed a weaker stimulating sexual function activity and not manifested an effect of after-action marked for heptapeptide.

Description

The invention relates to the field of pharmacology and veterinary medicine, namely to a means of increasing sexual activity and reproductive ability in a mammal, including humans.

Sexual function is an essential component of the reproductive system of the body. The relevance of studying the mechanisms of functioning of normal and pathological sexual function is due to the tendency to increase the frequency of sexual disorders in men and women in developed countries. Most studies of the mechanisms of regulation of male sexual function are focused on its final phase (coitus), while the initial, motivational phase, regulated by central mechanisms, remains poorly understood. Since the sexual function of males is launched with sexual activation, the study of the central motivational mechanisms of adequate sexual behavior is an urgent modern task.

Correction of sexual dysfunction in men is a very difficult task. For the treatment of erectile dysfunction, tranquilizers are used mainly, which reduce psychogenic (neurotic) sexual dysfunction, and a ₂ -adrenoreceptor agonists (yohimbine and related compounds) that increase the venous filling of the cavernous bodies of the penis. Peptide preparations have not been previously used to treat sexual disorders. Nevertheless, they are of considerable interest, since many of these drugs improve the metabolism of the central nervous system (CNS) and the urogenital sphere, contributing to the elimination of sexual dysfunction.

An important role in the mechanisms of the formation of sexual function, and in particular its appetizing, or motivational aspects, is played by the interaction of the functional systems of the central nervous system, which is an integrator of the motor, autonomic, and endocrine components of sexual function. Acetylcholine is a mediator that mediates the transmission of non-specific information to the neocortex from subcortical structures (reticular formation, hypothalamus) and is involved in the functioning of the cortical activating system [Bayramov A. A. Author. dis. Dr. med. sciences. SPb .: VMedA, 2008]. Despite the important role of the cholinergic system in various aspects of the central nervous system, its significance in the formation of neurophysiological correlates of bioelectrical activity of the brain, changes in the excitability and mobility of nervous processes in the brain structures with an imbalance of gonadal hormones has been little studied.

Monoaminergic (dopamine, norepinephrine, serotonin) brain mechanisms regulate mainly the emotional component of sexual function [Shabanov PD Psychopharmacology. St. Petersburg: NL, 2008]. In experiments on animals (rats), it was shown that stimulation of the lateral hypothalamus, through which the dopaminergic and noradrenergic terminals pass, causes an erection in males and activation of sexual behavior. The same is observed in the study of self-stimulation of the lateral hypothalamus, when the rat is trained to press the pedal in the Skinner's chamber and receive an electric current discharge sufficient to activate sexual behavior (usually 1-1.5 μA for 0.4 s at a frequency of 50 Hz) . However, it is difficult to isolate the sexual component in the behavior of self-stimulation, since the animal causes the activation of the emotiogenic zones of the hypothalamus for quite a long time (up to 20 hours), later dying from exhaustion [Shabanov P.D. Psychopharmacology. St. Petersburg: NL, 2008]. The rat, as a rule, is in the chamber alone without a partner, and an erection of the penis is only the only indication of the activation of the reproductive system.

In the regulation of sexual behavior, the significance of peptide factors (natural peptides and peptide-based pharmacological preparations) has not been completely studied.

Of considerable interest is the heptapeptide structure (Tyg-Tu8-Progo-Agd-Progo-C1u-Progo). Its molecule consists of a tetrapeptide similar to the endogenous tuftsin peptide and a tripeptide containing 3 naturally occurring levorotatory amino acids (PTO-C1U-PTO).

Known heptapeptide called selank, which has anti-anxiety [Seredenin SB and coauthors. Study of the anti-anxiety effect of an analogue of the endogenous peptide of tafcin on inbred mice with different phenotypes of emotional-stress reactions, VND journal, 1998, v. 48, no. 1], or anxiolytic [patent VI 2155065], or anti-stress action in animals [Psychopharmacol. and biol. drug addict. 2005, v. 5, No. 2, p. 939-945; ibid., 2005, v. 5, No. 3, p. 989-996]. It is also known the use of hepatapeptide Selank as an agent with anticoagulant, antiplatelet, fibrinolytic activity [patent VI 2290195] and a means of prevention and correction of immunodeficiency [patent VI 2318533]. However, the properties of the indicated peptide that increase sexual activity and reproductive function in men are not described.

The information contained in the above publications does not contain any information suggesting the ability of this peptide to increase sexual activity and reproductive function in mammals, including humans.

It is known the use of herbal remedies as activators of sexual activity and reproductive function in men [patent VI 2173166]. According to this patent, the herb of the mountaineer of the bird acts as a herbal remedy (Poopudopus aulcata b.8.1.). However, it is difficult to standardize plant materials, since the content of active substances in it varies greatly depending on the place of collection, growing conditions, season of collection, time of day during which the grass was collected. This suggests the unstable nature of the action of herbal preparations on such a delicacy.

- 1 013948 sphere, as sexual function and reproductive behavior. Moreover, extracts from plant materials are easy to overdose or get an undesirable effect, which depends on the scheme and extraction conditions of the active ingredients contained in the plant material. Pharmacological preparations with a known chemical structure in this regard make it easy to reproduce the observed effect in a certain dose range.

The objective of the proposed technical solution was to search for new effective agents that increase sexual activity among peptide drugs.

The problem is solved by means of a heptapeptide of the formula (Tyg-Li8-Prgo-LGD-Prgo-Clu-Prgo), which has the ability to increase sexual activity and reproductive function in mammals, including humans.

The study of a new purpose, namely the new biological activity of the heptapeptide

The experimental model involved the study of induced receptivity in female rats to test sexual behavior. To this end, estrus was induced in ovariectomized female rats by the administration of an oily solution of estradiol (50 μg / animal) 48 hours before testing and progesterone (500 μg / animal) subcutaneously 4 hours before testing. The manifestation of receptivity in females was determined immediately before the test by the presence of lordosis reaction.

In the test of sexual behavior, young sexually mature male Wistar rats with acquired sexual experience were used. The animals were kept in a room with inverted light (12.00 / 12.00 day / night cycle, light from 22.00). Given the activity of rats during the day, experiments were carried out between 14.00 and 17.00 hours. The heptapeptide was administered at a dose of 100 μg / rat (0.5 mg / kg) 30 minutes before testing. As a comparison drug, an extract of grass of the mountaineerian bird at a dose of 1 ml / rat was used (extraction was carried out as described in patent K.I 2173166). The animals of the control group were injected with an isotonic (0.9%) sodium chloride solution. Each group of animals included 15 rats.

The parameters of sexual behavior were recorded before the main experiment in order to determine the control parameters of sexual activity of each rat and each experimental group. To determine the components of sexual behavior, the test male was placed in a 40x40x30 cm test chamber of transparent plexiglass 5 minutes before the presentation of a sexually susceptible female during the dark phase of the diurnal cycle and in dim red light. Components of sexual activity in males were recorded visually for 15 minutes. Latent periods (LP) and the number of cages, intromissions and ejaculations were measured, and two secondary parameters were calculated: recovery period — time from the first ejaculation to the next intromission; interejaculation interval - the time between the first and second ejaculatory sessions. The indices obtained in intact rats, or control values in the experimental groups before testing, for more demonstrative changes in sexual behavior in some cases were taken as 100%. For a comparative study of the sexual activity of the studied groups, we used data obtained both during the first session (before the first ejaculation) and throughout the experiment, with the exception of the components of ejaculatory activity.

A single (100 μg / rat) or triple (3 times 100 μg / rat) heptapeptide injection caused activation of the central triggers of sexual function (see table). At the same time, a significant (more than 3-fold) reduction in latency of cages and intromissions was noted. The reduction in the latency of ejaculation after a triple injection indicates activation of the spinal ejaculatory centers of regulation of sexual function, although the number of ejaculations did not increase after a 3-fold injection of heptapeptide. General structural enhancement of sexual function was noted on the 7th day after the last heptapeptide injection (delayed effect). The number of ejaculations also increased with a reduction in its temporal characteristics.

- 2 013948

The effect of heptapeptide (100 μg per rat) and bird's mountain extract (1 ml per rat) on the sexual behavior of males

Rat group Number of cages LP cages, with The number of intro missions LP the first intro of Russia, with The number of ejaculations LP of the first ejaculation, s Mezheyaku-] Period interval, s recovery, with The control 22.6 ± 2.15 35.0 ± 14.7 15.6 ± 0.95 50.0 ± 21.9 1.86 ± 0.14 460.0 ± 109.7 654.9 ± 71.4 370.0 ± 25.8 Heptapeptide once 24.6 ± 4.14 11.3 ± 5.67 * 16.7 ± 3.47 16.6 ± 6.32 * 1.86 ± 0.14 414.0 ± 118.8 621.2 ± 36.9 267.5 ± 47.4 * Heptaleptide 3 times 24.7 ± 2.13 7.92 ± 2.03 * 16.3 ± 1.44 18.7 ± 6.38 * 1.86 ± 0.14 285.6 ± 64.8 * 545.3 ± 48.0 376.1 ± 32.9 7 days after heptapeptide administration 24.9 ± 2.46 21.7 ± 13.9 17.6 ± 1.95 29.9 ± 16.9 2.14 ± 0.26 343.3 ± 101.3 455.2 ± 34.9 * 309.3 ± 23.5 * Highlander's herb extract once 23.4 ± 4.0 26.5 ± 5.44 * 15.9 ± 2.66 38.4 ± 7.21 * 1.88 ± 0.14 439.0 ± 111.5 651.9 ± 27.8 306.8 ± 31.2 * Highlander Herb Extract 3x 23.7 ± 2.11 22.81 ± 2.14 * 16.0 ± 1.53 35.2 ± 7.12 * 1.84 ± 0.14 403.5 ± 51.2 609.2 ± 49.6 385.1 ± 42.8 7 days after the introduction of the extract of the herb Highlander 25.5 ± 3.22 29.7 ± 11.7 17.9 ± 2.04 39.8 ± 13.5 1.98 ± 0.21 398.4 ± 96.3 588.3 ± 43.7 314.2 ± 33.9

Note: LP - latent period; * p <0.05 with respect to the control group.

Comparison drug - extract of highlander grass - significantly weaker in comparison with heptapeptide increased sexual activity of animals. This increase was noted after 1- and 3-fold administration of the extract, but not 7 days after discontinuation of the drug.

Thus, as a result of the 3-fold introduction of the heptapeptide (Tyr-Luz-Rgo-Agd-Rgo-Szu-Rgo), downward prolonged activation of sexual function with an aftereffect is observed, at the beginning with an increase in central motivational, and then peripheral ejaculatory components of sexual function , i.e. all components of sexual behavior. The study showed that a single or subchronic (3-fold) intramuscular administration of a heptapeptide caused activation of the central triggers of sexual function, which was manifested by a significant reduction in latent periods of cages, intromission and ejaculation. The latter fact indicates the activation of the spinal cord ejaculatory centers of regulation of sexual function. This effect persisted for 7 days after discontinuation of the drug after its subchronic administration. A similar, but weaker activating effect with respect to sexual function was also noted in the preparation of comparison, an extract of the mountaineer bird. In addition, the effect of the aftereffect (after discontinuation of the drug) was not observed in the preparation.

Sexual behavior of males and females is a two-fold phenomenon: by studying the behavior of males, a priori they allow a fairly high level of sexual activity of females. Without this, sexual behavior does not end in cage, intromission and ejaculation in the male. That is, by the behavior of the male, to a large extent, one can judge the sexual activity of the female. A sexually inactive female will never let a male in. In this sense, studying the sexual behavior of males, the results obtained are, with a significant degree of probability, transferred to the assessment of the sexual activity of females.

If the studied drug increases sexual activity in males, then the sexual activity of females also increases in a mirror, while it is impossible to increase activity in males without changing the sexual activity of females.

These premises indicate the relationship between the sexual activity of men and women in terms of the similarity of the metabolic regulation of sexual function and the possibility of its modulation using a peptide preparation and allow extrapolating the data on the increase in sexual activity of males with the help of heptapeptide not only to men, but also to women. In addition, there are indirect (based on surveys of people taking the drug) unpublished data that the heptapeptide when used increases libido (sex drive) and sexual activity. This phenomenon is more evident in women suffering from frigidity.

Claims (1)

CLAIM A means of activating sexual function, which is a heptapeptide of the formula (TybLu8-Prgo-Agd-Prgo-O1y-Prgo). Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2