WO2021048688A1

WO2021048688A1 - Product for the treatment of erectile dysfunction

Info

Publication number: WO2021048688A1
Application number: PCT/IB2020/058132
Authority: WO
Inventors: Angelina Igorevna PLATOVA; Nikolai Vasilevich KOROBOV
Original assignee: Pvp Labs Pte. Ltd.
Priority date: 2019-09-09
Filing date: 2020-09-01
Publication date: 2021-03-18
Also published as: RU2727506C1

Abstract

The invention is related to medicine, in particular urology, and can be used for creating a product for the treatment of erectile dysfunction. The product contains, as the active ingredient, 5-20 wt % of 9-phenyl-sym-octahydroselenoxanthene and excipients. The product can be produced in the form of capsules or tablets. The proposed product may be a good alternative to phosphodiesterase type 5 inhibitors, as it does not have pronounced side effects, and its effect is "cumulative" in nature. 2 dependent claims of the invention, 6 examples, 6 figures, 1 table.

Description

Product for the treatment of erectile dysfunction

Pertinent art

The invention is related to medicine, in particular urology, and can be used for creating a product for the treatment of erectile dysfunction (ED) that contains 9-phenyl-sym- octahydroselenoxanthene (selenoxanthene).

State of the art

Erectile dysfunction is becoming more and more important. Approximately 150 million men worldwide suffer form erectile dysfunction (ED), a number that may double in the next 25 years. High prevalence of ED is associated not only with age, but also with an increase in morbidity, administration of pharmaceutical products that cause sexual dysfunction, stress and bad habits (such as smoking and alcohol consumption). For this reason, the overall prevalence of ED reflects social aspects of public healthcare [1]. Epidemiological data concerning the prevalence of ED in Russia are limited to the results of a study indicating a prevalence of 26.9% in the Central Federal District among surveyed males at the age of 20 to 75. First line treatments are phosphodiesterase type 5 inhibitors (PDE5 inhibitors) [3]. Despite the high efficacy of PDE5 inhibitors, there remains a large proportion of patients who do not respond to such treatments treatments, or to whom they are contraindicated due to concomitant administration of nitrates [4]. Additionally, concomitant administration with hypotensive medications is fraught with episodes of orthostatic hypotension, and co-administration with a blockers is contraindicated. As ED often develops in patients with an underlying pathology, these circumstances make the search for and development of new ED treatments especially important.

Additionally, other approaches to the treatment of ED are known, such as administration of selenium-containing products as part of combination therapy. Specifically, claim US2002182585 (08/01/2002) describes the application of a composition that contains EDTA, cystine, vitamin C, vitamin E and zinc in vascular disorders, which, in turn, in some cases cause erectile dysfunction.

Patent CN 104799271 (26/01/2014) describes a composition for the improvement of erection, which includes 10-35 g of plant-based protein, 12-58.8 g of plant-based fat, 3.5-15 g of dietary fibre, 0.0018-0.0026 g of zinc and 0.000003-0.0000015 g of selenium.

However, these methods have a complex effect on the organism, and improvement of erection is one of several effects associated with their use. Additionally, the use of these methods does not imply an impact on erectile dysfunction, as the exhibited effect is a result of multiple factors and multiple compounds acting together, i.e. the course of the disease is determined by low-specificity factors.

At the same time, selenoxanthene, a selenium-containing substance, is known from the state of the art to be used for the treatment of a variety of diseases. Selenoxanthene is the selenium-containing biologically active compound 9-phenyl-sym- octahydroselenoxanthene (9-phenyl-symmetrical-octahydroselenoxanthene, C19H22Se, molecular weight 329.37 amu). This compound has an antioxidant, bactericidal, radioprotective, antitumour, sedative, spasmolytic, analgesic and hypnotic effect and is used for preventing selenium deficiency in humans and animals, normalizing of thyroid gland functions, increasing the activity of antioxidant enzymes and normalizing reproductive system functions. In particular, one example of the normalizing effect of selenoxanthene on reproductive system function is a method for the correction of spermatogenesis in animals under chronic intoxication with natural gas (patent RU 2480221 Cl, 28/02/2012), which discloses the ability of selenoxanthene to improve the reproductive potential of males due to positive effects on semen parameters. However, in this work, ED therapy in humans was not discussed (ICD-10 codes N48.4 and F52), and possible comorbidities (such as asthenozoospermia) are not taken into account.

Therefore, the technical problem solved by the claimed invention is the production of a product for the treatment of erectile dysfunction, which comprises 9-phenyl-sym- octahydroselenoxanthene.

Disclosure of the technical character of the invention.

Studies performed by us on animal models demonstrated the effect of 9-phenyl-sym- octahydroselenoxanthene on erectile function, which allows to use it as a component of a treatment for ED, including ED associated with somatic causes.

Based on the above, we propose a product for the treatment of erectile dysfunction, which contains, as the active ingredient, 5-20 wt % of 9-phenyl-sym-octahydroselenoxanthene and excipients.

In a particular embodiment, the pharmaceutical composition is prepared in the form of capsules or tablets.

In a particular embodiment, the following components are used as excipients for tablets: MCC 65-77 wt %, calcium carbonate 4-5 wt %, calcium stearate 1.5-2.5 wt %, talc 2.5-3.5 wt %, silica 4.5-5 wt %. for capsules: MCC 60-75 wt %, calcium carbonate 3.5-4.5 wt %, calcium stearate 2-3 wt %, talc 3-3.5 wt %, silica 7.5-9 wt %.

The technical result of the claim invention is the production of a product that eliminates erectile dysfunction in men and does not produce side effects in patients with somatic comorbidities. The proposed product may be a good alternative to PDE5 inhibitors, as it does not have pronounced side effects, and its effect is “cumulative” in nature. Brief description of the drawings.

Table 1. Results of peak pressure measurement in the cavernous sinus after electrostimulation of the cavernous nerve in a model of bilateral internal iliac artery ligation in rats, where * is significance level p < 0.05 (compared to the control group).

Figure 1. Peak intracavemosal pressure (ICP) after electrostimulation of the cavernous nerve in a model of bilateral internal iliac artery ligation in rats, where = group 1, = group 2.

Figure 2. ICP/BP ratio (intracavemosal pressure / mean blood pressure ratio) at different dosages of 9-phenyl-sym-octahydroselenoxanthene in a 2-week cavernous nerve injury model in rats, where o Control (intact) o Control (trauma) o Selenoxanthene 0.1 mg/kg o Selenoxanthene 0.5 mg/kg o Selenoxanthene 1.0 mg/kg o Selenoxanthene 10 mg/kg

Figure 3. Total ICP exposure (AUC) at different dosages of 9-phenyl-sym- octahydroselenoxanthene in a 2-week cavernous nerve injury model in rats, where o Control (intact) o Control (trauma) o Selenoxanthene 0.1 mg/kg o Selenoxanthene 0.5 mg/kg o Selenoxanthene 1.0 mg/kg o Selenoxanthene 10 mg/kg

Figure 4. Severity of fibrosis over time (%) at different dosages of 9-phenyl-sym- octahydroselenoxanthene in a 2-week cavernous nerve injury model in rats, where o Control (intact) o Control (trauma) o Selenoxanthene 0.1 mg/kg o Selenoxanthene 0.5 mg/kg o Selenoxanthene 1.0 mg/kg o Selenoxanthene 10 mg/kg

Figure 5. A comparison of the activity of 9-phenyl-sym-octahydroselenoxanthene and Impaza with respect to peak ICD in a hyperlypidaemia model in rats, where o Control (intact) o Control (high-calorie diet) o Selenoxanthene 1.0 mg/kg o Impaza 0.3 mg/kg

Figure 6. NO synthase activity in penile tissue homogenate (L-arginine/citrulline conversion in pmol/min/mg) in a “passive smoking” model in rats (comparison of 9-phenyl-sym- octahydroselenoxanthene and Impaza), where o Control (intact) o Control (“passive smoking”) o Selenoxanthene 1.0 mg/kg o Impaza 0.3 mg/kg

Embodiment of the invention.

Examples of implementation of the invention in particular embodiments are presented below.

Example 1. Preparation of 9-phenyl- sym-octahydroselenoxanthene.

In order to obtain 9-phenyl-sym-octahydroselenoxanthene, 12.5 g of 9-(o-oxyphenyl)- octahydro- 10-oxoxanthene were placed in a three-necked flask with a magnetic stirrer and gas inlet. Then 30 mL of acetic acid : acetic anhydride mixture (4:1) were added. The reaction mixture was purged with nitrogen during mixing for 30 minutes, then the flow of nitrogen was stopped, and hydrogen selenide was passed through the reaction mixture. After 30 minutes of passing hydrogen selenide through the reaction mixture, 1.0 mL portions of concentrated hydrochloric acid were added to the reaction mixture twice at a one-hour interval. Hydrogen selenide was passed at a rate of 2-3 bubbles per second. The total time of passing hydrogen selenide was 6 hours. At the end of the procedure, the reaction mixture was purged with nitrogen for 40 minutes. The reaction mixture was then placed in a refrigerator, after one day the precipitate was filtered, washed with acetic acid and alcohol. The yield of the product was 11.5 g.

Example 2. Preparation of a product containing 9-phenyl-sym- octahydroselenoxanthene.

It was experimentally established that the most preferable (without limiting the scope of claims in connection with this invention) method of production of the dosage form (tablets or capsules) of 9-phenyl-sym-octahydroselenoxanthene includes:

Sifted powder of microcrystalline cellulose is mixed for 2 min., 9-phenyl-sym- octahydroselenoxanthene and calcium carbonate powders are added, the mixture is thoroughly mixed for 4 min., calcium stearate powder is added and mixed or 3 min., sifted talc and silica powders are added and mixed for 2-4 min., the resulting mixture is tableted by direct compression of the solid dosage form, or the mixture is placed in capsules.

Composition of the dosage form of 9-phenyl-sym-octahydroselenoxanthene as tablets

Composition of the dosage form of 9-phenyl-sym-octahydroselenoxanthene as capsules

Results of experiments confirming the efficacy of 9-phenyl-sym- octahydroselenoxanthene with respect to erectile dysfunction are presented below. The studies provided in these examples were designed and performed in accordance with the relevant publications concerning the development of animal models for ED studies.

Importantly, many patients take over-the-counter medications, the most popular of which is Impaza, without a physician-confirmed diagnosis or an appropriate examination. For this reason, additional investigations of the efficacy of 9-phenyl-sym-octahydroselenoxanthene and Impaza were carried out, and the results are described in examples 5 and 6.

Example 3. Evaluation of the pharmacological activity if 9-phenyl-sym- octahydroselenoxanthene in a model of bilateral internal iliac artery ligation in rats.

Materials and Methods. Arterial insufficiency of the corpora cavernosa is a major cause of erectile dysfunction. Atherosclerosis or traumatic artery occlusion affects the quality of erection by reducing blood flow and engorgement of the corpora cavernosa. Such vascular risk factors include hypertension, hyperlipidaemia, smoking, diabetes mellitus and irradiation of the pelvic organs [5, 6, 7, 8]. Vasculogenic erectile dysfunction is the most common type of erectile dysfunction in clinical practice. The experiment was based on the model described in publication

[8].

The study involved 40 male rats at the age of 3 months, with a body weight of 350-400 g. General anaesthesia was induced by an intraperitoneal injection of 35 mg/kg or pentobarbital after premedication by inhalation of methoxyflurane. After midline laparotomy, ligatures were bilaterally applied to the internal iliac arteries of 40 rats under a microscope. The remaining animals (control group, n = 10) underwent only an exploratory surgery. An additional incision in the crural region allowed to install a 23G catheter for monitoring the intracavemosal pressure (ICP) during electrostimulation of the cavernous nerve. Additional ligatures ere applied to achieve a flat ICP response (absence of ICP elevation) during electrostimulation. The would was sutured, and the condition of the animals was monitored at 1, 2 and 6 weeks.

Electrostimulation was carried out using bipolar platinum electrodes. The positive electrode was applied to the nerve fibre 2-3 mm proximally to the negative electrode, the voltage was 1.5 V, the frequency was 20 Hz, the pulse width was 0.2 ms, and the total duration of the procedure was 50 s.

Before the start of the experiment, animals were randomly assigned to two groups: (1) control: only exploration of the abdominal cavity; (2) 9-phenyl-sym-octahydroselenoxanthene 1 mg/kg*day. The animals received all the products orally (through a gastric tube) for 6 weeks, whereupon they were euthanised, and penile tissue was examined under a microscope after immunohistochemical staining.

It can be seen from the data presented in Table 1 that 9-phenyl-sym- octahydroselenoxanthene was superior to placebo with respect to ICP restoration.

Example 4. Investigation of the effect of 9-phenyl-sym- octahydroselenoxanthene on ED in a cavernous nerve (CN) injury model. Finding optimum dosages.

The following study was carried out in order to establish the dosages with the greatest efficacy. The rat model of cavernous nerve injury, whose benefits were demonstrated in [9], was selected.

The following dosages of 9-phenyl-sym-octahydroselenoxanthene were studied 0.1, 0.5, 1.0 and 10 mg/kg. Additional cohorts included the control group (intact) and the control group with with CN injury, which received placebo.

A total of 120 rats at the age of 8 to 10 weeks were assigned to 6 cohorts (n = 20 per cohort); 10 animals in each cohort were included in the ICP study and euthanised on day 14 of the experiment, and the other 10 animals were euthanised on day 30.

9-phenyl-sym-octahydroselenoxanthene was administered through a gastric tube (orally) in the form of pulverized pharmaceutical composition (Example 2).

The pharmacological activity of the compounds was evaluated based on the following criteria: (1) ICP to mean BP ratio; (2) ICP exposure and (3) percentage of fibrosis.

The animals were anaesthetised with ketamine (100+10 mg/kg) by intraperitoneal injection. The prostate was accessed by midline laparotomy. The cavernous nerve and the major pelvic ganglion are located posteriorly and laterally to the prostate. Bilateral nerve injury was induced by Dumont No. 5 forceps, which were used to clamp the cavernous nerve 2-3 mm distally to the major pelvic ganglion. The nerve was clamped by the forceps three times, for 15 seconds a time, which helped standardize injury severity. In the control group the cavernous nerve was not injured, and the wound was simply sutured. Erectile function parameters were measured and the animals were euthanised at 14 and 30 days after the operation, whereupon a histological examination was performed. Blood pressure was measured using a 25G catheter installed in the crural region and connected to a heparin (250 U/mL) polyethylene tube, which was introduced for ICP measurements. An electrostimulation device was installed on the cavernous nerve at the injured section. Electrical pulses were applied at a frequency of 20 Hz and pulse width of 0.5 ms, the total duration was 30 s at 8 volts.

For normalization to the mean blood pressure (BP), the ratio between peak ICP and mean BP measured at the peak of erectile dysfunction was calculated. The total ICP exposure was calculated as the area under the erectile curve (AUC; mm Hg x s) from the start of cavernous nerve stimulation to the point of ICP return to baseline. Erectile response was measured at 14 and 30 days after cavernous nerve injury. Body weight was also monitored. The animals were then euthanised, and penal tissues were collected for a histological evaluation.

It is noteworthy that an increase in 9-phenyl-sym-octahydroselenoxanthene dosage to 10 mg/kg did not improve efficacy parameters (ICP/BP and total ICP exposure), causing a statistically insignificant decline instead. The maximum efficacy was observed at a dosage of 1 mg/kg (Fig. 2 and 3).

Fibrosis induction was observed after bilateral cavernous nerve injury in all the groups. At the same time, the fibrotic process was less severe in the group receiving 9-phenyl-sym- octahydroselenoxanthene. The smooth muscle region was not altered after the injury. The proportion of collagenous and smooth muscle elements was determined visually in cross-sections after Masson's trichrome staining. The ratio of collagenous to smooth muscle elements was evaluated as percentage of fibrosis.

The percentage of fibrosis substantially increased after injury, within 14 and 30 days, relative to the control group (p value < 0.05). However, fibrotic changes were reversible; moreover, with 9-phenyl-sym-octahydroselenoxanthene treatment, the effect was significant at dosages of 0.5 mg/kg and 1.0 mg/kg (Fig. 4).

Example 5. A comparison of the efficacy of 9-phenyl-sym- octahydroselenoxanthene and Impaza in a model of hyperlypidaemia -associated ED.

Hyperlipidaemia is associated with endothelial dysfunction and is a rather common cause of ED. Additionally, the risk of ED development is directly proportional to the level of cholesterol and low density lipoproteins in blood [10, 11]. Hyperlipidaemia, whose manifestations at the cellular level include reduced nitric oxide production (NO), and which acts as a neurogenic and vasculogenic factor, can be successfully used for modelling ED [12].

A total of 40 three-months-old white male Wistar rats were used in the study. The animals were assigned to 4 groups: (1) controls receiving a normal diet; (2) controls receiving a diet with an increased fat content, but no therapy; (3) active controls receiving Impaza (at a dose of 0.3 mg/kg day); (4) the group receiving 9-phenyl-sym-octahydroselenoxanthene at a dose of 1 mg/kg -day. The animals received the evaluated drugs for 28 days (4 weeks) after 5 months of feeding.

9-phenyl-sym-octahydroselenoxanthene was administered once daily through a gastric tube, Impaza was administered with water: one 3 mg tablet was dissolved in 1000 mL of water; considering the consumed fluid volume of 20±3 mL/animal day, each animal received 0.3 mg/kg of the active pharmaceutical ingredient of Impaza per day, which corresponds to the human therapeutic dose (3 mg).«

Hyperlipidaemia was modelled using a diet with a high fat content, which the animals received for 5 months (the diet included 2% of cholesterol and 10% of pig fat). Then the animals received either 9-phenyl-sym-octahydroselenoxanthene (group 4), Impaza (group 3) or no therapy (group 2). The control group 1 received a normal diet throughout the experiment. All the rats were given general anaesthesia by an intraperitoneal injection of ketamine (100 mg/kg) and midazolam (5 mg/kg) 28 days after receiving the study drugs. Lower midline laparotomy was performed, and the cavernous nerve was isolated bilaterally.

ICP was measured while administering electrostimulation for 50 s. The penis was freed from the covering skin, and the cavernous sinus was catheterized with a 25G heparin catheter for ICP monitoring. The cavernous nerves were stimulated with a 20 Hz electric pulse at 1.5 mA for 50 s. The ICP response was recorded using Lab View 6.0.2 (USA). Maximum (peak) values were used for analysis. After the functional tests were completed, blood pressure was measured by aortic catheterisation. Mean blood pressure was calculated using the following formula: mean BP = (2/3 diastolic BP + 1/3 systolic BP). A blood sample was then collected for carrying out a biochemical blood test for testosterone. Additionally, neuronal NO synthase (nNOS) level was determined in the dorsal nerve by immunohistochemistry.

Hyperlipidaemia was shown to significantly reduce the number of nNOS-positive fibres; meanwhile, both 9-phenyl-sym-octahydroselenoxanthene and Impaza had a positive effect by increasing the number of these fibres. No differences between the products were detected. Mean blood pressure did not differ across groups. Testosterone level was also comparable across the evaluated treatment groups; additionally, it was not significantly different from the control groups. However, ICP monitoring demonstrated a clear and statistically significant superiority of 9- phenyl-sym-octahydroselenoxanthene to Impaza (Fig. 5).

Example 6. A comparison of the efficacy of 9-phenyl-sym- octahydroselenoxanthene and Impaza with respect to NO synthase activity in a model of passive exposure to cigarette smoke (passive smoking model).

The study was based on the model that proved suitable in [13]. Smoking is a known risk factor of ED. It is also an established fact that exposure to cigarette smoke damages the NO- dependent mechanism of erection by reducing nitric oxide synthase (NOS) levels in penile tissues, and these changes are associated with changes of systemic blood pressure. Additionally, cigarette smoke exposure was demonstrated in [13] to have a certain stimulating effect on ICP. For this reason, in our experiment it was decided to evaluate only NO synthase activity in penile tissues, as this is the parameter that reflects long-term effects of smoking on erectile function. The activity of NO synthase was determined by evaluating arginine-citrulline conversion using [³H]-labelled arginine and expressed in pmol/min per 1 mg of protein cytosol.

Four groups of male rats 6 animals to a group were included in the study. All the animals were 5 months old. Group 1 was the intact control group (without exposure to tobacco smoke), group 2 was the control group of the passive smoking model (the animals were exposed to smoke), group 3 additionally received 9-phenyl-sym-octahydroselenoxanthene at a dose of 1.0 mg/kg for 4 weeks, and group 4 received Impaza for 4 weeks at a dose of 0.3 mg/kg.

Selenoxanthene was administered once daily through a gastric tube, Impaza was administered with water: one 3 mg tablet was dissolved in 1000 mL of water; considering the consumed fluid volume of 20±3 mL/animal day, each animal received 0.3 mg/kg of the active pharmaceutical ingredient of Impaza per day.

In order to model passive smoking, the rats were kept in 25x60x20 cm plastic containers, to which cigarette smoke was continuously supplied. Exposure to cigarette smoke continued for 1 hour daily over a period of 8 weeks.

Penile tissues were homogenised and prepared in 0.32 M sucrose / 20 mM HEPES (4-(2- hydroxyethyl)-l-piperazineethanesulfonic acid) pH 7.2 / 0.5 mM EDTA / 1 mM DTT

(dithiothreitol) and protease inhibitors (3 mM leupeptin, 1 mM PMSF (phenylmethylsulfonylfluoride), 1 mM pepstatin A). The microsomal fraction was isolated by centrifugation at 12500 g for 60 min. The fraction was then passed through Dowex AG50WX-8 medium (Na+, Sigma Aldrich, USA) to remove endogenous arginine, and aliquots (3 pcs.) were then incubated for 45 min at 37°C in the presence of [³H] -labelled L-arginine (2 mCi/mL), 100 mM of L-arginine, 0.45 mM Ca²⁺ , 2 mM NADPH, with and without L-NAME (L-nitro-N-arginine methyl ester) (2 mM). After eliminating [³H] -labelled L-arginine, the quantity of [³H] -labelled citrulline was determined, which was used to determine NO synthase activity. All the values were adjusted for radiation levels during the incubation of blank samples.⁰

The results demonstrated that exposure to cigarette smoke significantly reduces the activity of NO synthase in penile tissues. Selenoxanthene increased its activity to a greater degree than Impaza, and the effect was statistically significant (p value < 0.05) (Fig. 6).

Summary and conclusions

In this invention, we present results of the investigation of the efficacy of 9-phenyl-sym- octahydroselenoxanthene for ED therapy, which were obtained on a model of injury (neurogenic model), vascular and metabolic models, and in a physical stress model — the passive smoking model. Therefore, the effect of 9-phenyl-sym-octahydroselenoxanthene was evaluated taking into account all the aetiological causes of ED and all the most common pathophysiological mechanisms of ED development.

Good efficacy of 9-phenyl-sym-octahydroselenoxanthene in ED therapy, which was demonstrated in these models, may be associated with the antioxidant properties of this substance. At the same time, considering the multifaceted activity of selenium derivatives in the body, the existence of other mechanisms, which are more specific to ED, cannot be ruled out.

PDE5 inhibitors are indicated as the drugs of choice of choice in ED. However these recommendations are restricted to the organic component of the aetiology of the disease. In other clinical cases, with less pronounced clinical symptoms; in particular, in the presence of a psychogenic component of ED (stress, smoking, etc.), patients commonly use other products, such as Impaza (a homoeopathic remedy, affinity purified antibodies to endothelial NO synthase), natural remedies or symptomatic relief medications. For this, most numerous, group of patients, 9- phenyl-sym-octahydroselenoxanthene is a more justified choice, as it implies the absence of pronounced side effects.

The mechanism by which 9-phenyl-sym-octahydroselenoxanthene exhibits its activity, which is different from that of PDE5 inhibitors, and its antioxidant properties may explain the superior ICP parameters.

As for effective dosages of 9-phenyl-sym-octahydroselenoxanthene in ED, good results were obtained in rats for the dose of 1.0 mg/kg, which corresponds to the daily dose of approximately 10 mg/day in humans. The daily amount can be split to be taken twice daily. For this reason, dosage forms of 9-phenyl-sym-octahydroselenoxanthene with dosage strengths of 5 and 10 mg should be taken into consideration for ED treatment.. At the same time, therapeutically effective doses in humans do not always correspond to equivalent doses obtained by conversion from animal models. Dosage strengths and dosing regimens for patients with erectile dysfunction will obviously be determined more precisely during clinical development, which may necessitate adjusting the quantity of 9-phenyl-sym-octahydroselenoxanthene in the composition.

References

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[2] D. Yu. Pushkar et al. Analysis of results of an epidemiological study of the prevalence of erectile dysfunction in the Russian Federation // Urologiya. - 2012. - N° 6. - p. 5-9.

[3] Wespes E. et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Translated by M.N. Klimova // European Association of Urology - 2011. 51 pp.

[4] R.I. Ovchinnikov. Effect of pharmacotherapy of erectile dysfunction on cavernous electrical activity and penile haemodynamics // Abstract of a dissertation for the degree of a Candidate of Medical Sciences. Moscow. 2008. - p. 26-27.

[5] Goldstein, I., Feldman, M. I., Deckers, P. J. et al: Radiationassociated impotence. A clinical study of its mechanism. JAM A, 251: 903, 1984.

[6] Rosen, M. P., Greenfield, A. J., Walker, T. G. et al: Arteriogenic impotence: findings in 195 impotent men examined with selective internal pudendal angiography. Radiology, 174: 1043, 1990.

[7] Levine, F. J., Greenfield, A. J. and Goldstein, I.: Arteriographically determined occlusive disease within the hypogastriccavemous bed in impotent patients following blunt perineal and pelvic trauma. J Urol, 144: 1147, 1990.

[8] Lee M. C. et al. The effect of vascular endothelial growth factor on a rat model of traumatic arteriogenic erectile dysfunction //The Journal of urology. - 2002. - Vol. 167. - N° 2. - p. 761-767.

[9] Hannan J. L. et al. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve- injured rats //The journal of sexual medicine. - 2014. - Vol. 11. - N°. 6. - p. 1442-1451.

[10] Huang Y. C. et al. The effect of intracavemous injection of adipose tissue-derived stem cells on hyperlipidemia-associated erectile dysfunction in a rat model //The journal of sexual medicine. - 2010. - Vol. 7. - N° 4. - p. 1391-1400.

[11] Virag R., Bouilly P., Frydman D. Is impotence an arterial disorder?: A study of arterial risk factors in 440 impotent men //The Lancet. - 1985. - Vol. 325. - N°. 8422. - p. 181- 184.

[12] Gholami S. S. et al. The effect of vascular endothelial growth factor and adeno- associated virus mediated brain derived neurotrophic factor on neurogenic and vasculogenic erectile dysfunction induced by hyperlipidemia//The J.-2003.-Vol.l69.- N°4.-pp.1577- 1581.

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[14] Li H. et al. The effect of cavernous nerve traction on erectile function in rats //PloS one. - 2017. - Vol. 12. - N°. 10. - p. e0186077.

Claims

1. A product for the treatment of erectile dysfunction, which contains, as the active ingredient, 5-20 wt % of 9-phenyl-sym-octahydroselenoxanthene and excipients.

2. The product according to claim 1, which is produced in the form of capsules or tablets.

3. The product according to claim 2, wherein the following components are used as excipients for tablets: MCC 65-77 wt %, calcium carbonate 4-5 wt %, calcium stearate 1.5-2.5 wt %, talc 2.5-3.5 wt %, silica 4.5-5 wt %. for capsules: MCC 60-75 wt %, calcium carbonate 3.5-4.5 wt %, calcium stearate 2-3 wt %, talc 3-3.5 wt %, silica 7.5-9 wt %.