Sildenafil Vertex, 100 mg, film-coated tablets, 1 pc.

Description and main characteristics

Sildenafil is a drug used by men to increase potency. Contains the active ingredient of the same name and is available in the form of granules with different dosages of the main component - from 35 to 140.5 mg per 1 piece. The most well-known brand of the drug, which also contains sildenafil, is Viagra.

The product is dispensed from pharmacies only with a prescription. The shelf life is 3 years from the date of production. It must be stored under standard conditions - a dark place, temperature up to 25 degrees.

Individual selection of the dose of sildenafil in the treatment of erectile dysfunction

Erectile dysfunction (ED) is the inability to achieve and maintain an erection sufficient for sexual intercourse. This condition is not life-threatening, but significantly affects the quality of life of the patient and those around him and affects the physical and mental components of health [2]. Among men of all ages, the prevalence of ED is 10%, and it is estimated that by 2025 the number of people suffering from ED will increase to 400 million. The greatest increase is expected in developed countries [3].

Risk factors for the development of ED may be vascular (≈20%), endocrine (≈10%), neurological diseases (≈20%), alcohol abuse (≈20%), side effects of medications (≈10%), psychological causes (≈ 20%), cardiovascular and systemic diseases (chronic renal failure, diabetes mellitus) and their combinations. ED of organic origin in 50–80% of men is caused by insufficiency of arterial blood supply to the penis of various origins [4–6]. The likelihood that a patient presenting with ED for the first time has coronary artery disease is estimated at 40%, and many such patients are treated with nitrates [7–9]. A multicenter, randomized, open-label study compared obese men with moderate ED who exercised for 2 years and lost weight with a control group in which patients were given the opportunity to change their diet or exercise [10]. Significant improvement in erectile function in the lifestyle group was accompanied by optimization of body mass index.

The development of diagnostic and treatment methods, fundamental research in physiology, pharmacology and other disciplines have made it possible to come closer to understanding the mechanism of erection and its disorders. At the moment of adequate sexual stimulation, relaxation of the smooth muscles of the cavernous bodies occurs. At the same time, nitric oxide is released from the presynaptic endings and the blood supply to the cavernous bodies increases. Due to their enlargement, the veins are pressed against the tunica albuginea, which leads to the cessation of venous outflow and the achievement of an erection sufficient for penetration [11–13].

It is currently believed that nitric oxide, released by non-cholinergic and non-adrenergic nerve endings, the synthesis of which occurs as a result of the action of neuronal NO synthase, plays a key role in “triggering” penile erection [14]. The physiological antagonist of NO is the vasoconstrictor, which produces anti-inflammatory, mitogenic and profibrotic effects, endothelin-1 [13]. Apparently, the interaction of these factors is a universal, general biological process [15].

Modern ideas about the physiology of erection have become the basis for various methods of treating ED [16–18]. Previously used reconstructive vascular surgical treatment methods did not provide effective results [19, 20].

In order to objectify the diverse symptoms of ED, questioning patients using questionnaires has become widespread. This method allows you to assess all components of sexual function and determine the effectiveness of the treatment methods used [21, 22].

It has been suggested that the basis of arteriogenic ED in some patients is not organic, but functional, potentially reversible damage to the arteries - endothelial dysfunction, which is currently considered as a functional stage in the development of atherosclerosis [11]. Currently, the term “endothelial dysfunction” is usually used to refer to a decrease in endothelium-dependent relaxation of smooth muscle cells [23]. A method for assessing post-occlusion changes in the diameter of cavernous arteries is proposed. The pattern revealed during the analysis of the results, which consists in the presence of signs of endothelial dysfunction in all patients with values ​​less than 50%, indicating arteriogenic ED, is confirmation of the presence of systemic vascular diseases, which emphasizes the importance of more active identification of ED by doctors of various specialties [24, 25].

The intracavernosal injection test with vasoactive drugs does not provide complete information about the condition of the vessels. A positive result is considered to be a rigid erection that occurs 10 minutes after intracavernosal injection and lasts for 30 minutes [26]. Such a response to intracavernosal administration of a vasoactive drug indicates a functional, but not necessarily physiological, erection, since the latter can occur against the background of venous insufficiency [27]. A positive test result indicates that the intracavernosal injection method is effective for the patient. This test is not sufficient to establish a diagnosis, and a duplex ultrasound of the penile arteries is necessary.

If the maximum blood flow velocity is more than 30 cm/s, and the resistance index is above 0.8, then such indicators are considered normal [28]. If the results of the duplex study are normal, further examination of the vascular system is not required.

The primary goal of treatment for ED is to determine the etiology of the disease and, if possible, treat it, rather than treat the symptoms. This may include recommendations regarding the patient’s lifestyle and the possibility of changing them. Significant progress in understanding the peripheral physiology of penile erection has led to great advances in the pharmacological treatment of ED through the use of phosphodiesterase type 5 (PDE5) inhibitor drugs. The enzyme PDE-5 hydrolyzes cyclic guanosine monophosphate in the cavernous tissue of the penis. Inhibition of PDE5 stimulates blood flow in the penis, resulting in smooth muscle relaxation, dilation of blood vessels, and erection [29].

In 1998, the “ideal” drug for the treatment of ED was described [30]. Such a drug must be effective, safe, quickly manifest its effect and have a long-lasting effect. The effect of the drug should not be affected by food, alcohol and other drugs, it should be suitable for periodic use on demand and provide spontaneous sexual activity [31].

Sildenafil citrate is the first drug that was used to treat ED. The effect of sildenafil appears 30–60 minutes after administration. Eating a heavy, fatty meal before taking the drug reduces its effectiveness by slowing down absorption. The effect of the drug can last up to 12 hours [32]. Adverse events (headache (12.8%), flushing (10.4%), dyspepsia (4.6%), nasal congestion (1.1%), dizziness (1.2%), blurred vision (1 .9%)), as a rule, are insignificant and self-limiting. The rate of drug discontinuation due to complications is comparable to that of placebo [33]. After 24 weeks, according to the study, which revealed the effectiveness of the dose used, erectile dysfunction was observed in 56, 77 and 84% of men taking 25, 50 and 100 mg of sildenafil, respectively, compared with 25% in the placebo group [16 ].

A common, effective, affordable and convenient form of sildenafil is the drug Tornetis®. Its use statistically significantly improves the International Index of Erectile Function (IIEF) scores, the profile of sexual contacts and satisfaction with treatment.

The uniqueness of Tornetis® is not limited to its ability to provide a pronounced functional effect in the form of restoration of erection. The anti-stress properties of the drug are of a certain importance - it seems to complement the mechanism of natural limitation of the adrenergic response in extreme situations, which is the essence of the second (protective) action [34]. Rehabilitation of sexual function is achieved by a unique mechanism for individual selection of the dose of the drug.

The effectiveness of sildenafil was found in almost every group with ED. Among patients with diabetes, 66% reported improved erection, 63% reported successful attempts at sexual intercourse (28.6 and 33%, respectively, in the placebo group) [35].

Patients choose the dose of sildenafil found in Tornetis® depending on their dynamic stereotype, since the needs of men and their partners have become much more than just achieving an erection [31]. The choice of dosage and frequency of taking the drug depend on the frequency of sexual intercourse and the patient’s personal perception of the drug. Patients need to plan for the duration of the effect. Objective examination data allows us to have good grounds for selecting the optimal dose of the drug.

A necessary condition for choosing the dosage of the drug Tornetis® is the possibility of individual selection of the dose. Despite the effectiveness of PDE5 inhibitors, most patients want to reduce their use of erection-improving medications. The prescriber should also be able to titrate the dose based on its effectiveness. Sildenafil is the drug with the most experience in clinical practice. The effectiveness of sildenafil has been proven in various categories of patients. Along with these properties, patients taking Tornetis® have a unique opportunity to independently select the dosage of the drug. With the touch of a finger, a 100 mg tablet can be divided into 4 pieces of exactly 25 mg. This allows you to accurately select the dose and avoid unjustifiably taking an increased dose.

Doppler examination of the cavernous arteries is based on anatomical data and modern ideas about the physiology of erection [36, 37]. At rest, the smooth muscles of the corpora cavernosa of the penis are in a state of full contraction, peripheral resistance is high, and as a result there is moderate arterial blood flow. At the beginning of an erection, the smooth muscles of the cavernous bodies relax due to the neurotransmitter response, the resistance of the cavernous bodies decreases, and the supplying arteries dilate. This leads to increased arterial blood flow and an increase in the volume of the penis (swelling phase). Since the dense tunica albuginea has little extensibility, due to an increase in blood volume, the venules between the filled sinusoids and the tunica are compressed. Venous outflow stops, the penis becomes hard.

In the urology clinic of the First Moscow State Medical University named after. THEM. Sechenov examined 398 patients with complaints of ED. The age of the subjects was 43 (23–61) years1. All patients answered questions on the IIEF-5 scale. Of all those who applied, 25 (6.3%) had no sexual activity for at least 4 weeks. before applying. 56 (14.1%) had significant ED, 123 (30.9%) had moderate ED, 152 (38.2%) had mild ED, and 42 (10.6%) had no abnormalities (Table 1 ).

The survey data confirm the well-known fact that the main factor influencing the decline in erectile function is age (p = 0.006)2. Already on the basis of a questionnaire, it is possible to objectify patient complaints, the degree of ED and choose a drug, its dosage and duration of use. Logic dictates that when ED symptoms are most severe, a larger amount of the drug is indicated.

During the history collection process, no risk factors for ED were identified in 281 (70.6%) patients. In 62 (15.6%) patients, vasculogenic risk factors (atherosclerosis) were identified, in 30 (7.5%) - neurogenic factors (diabetic, alcoholic polyneuropathy), in 25 (6.3%) - others (taking calcium channel blockers , angiotensin-converting enzyme inhibitors, drug use). The distribution of patients with or without sexual activity depending on the presence and type of risk factors was not significant (p=0.062)3. The severity of ED was statistically associated with vasculogenic and neurogenic risk factors (p=0.001)4. Thus, anamnestic data can also serve as a basis for choosing a drug and its dosage.

The method of differential diagnosis of forms of ED by pharmacodopplerography using oral administration of a PDE-5 inhibitor and assessing changes in Doppler ultrasound parameters does not allow determining the degree of venous “leakage” as the cause of ED [38]. Injection of a vasodilator into the corpus cavernosum is a useful, inexpensive, and minimally invasive diagnostic method in patients with suspected vasculogenic ED [39].

For the purpose of pharmacodopplerography of the cavernous arteries, we used alprostadil, a naturally occurring form of prostaglandin E1, which has a wide spectrum of pharmacological action. Among its most significant effects are vasodilation and suppression of platelet aggregation. When administered intracavernosally, alprostadil inhibits α1-adrenergic receptors in tissues, relaxes the muscles of the cavernous bodies, increases blood flow and improves microcirculation. Alprostadil causes erection by relaxing the trabecular smooth muscle of the corpus cavernosum and dilating the cavernous arteries, which leads to expansion of the lacunar spaces and occlusion of blood flow by pressing the venules against the tunica albuginea (penile vein occlusion).

To study blood flow, a linear sensor with a frequency of 7 MHz is used. It is used to assess the condition of the cavernous arteries before and after intracavernous administration of prostaglandin E1 using a 27–30 G needle. The dose of alprostadil was 5 mcg.

In Russia, the first experience of using prostaglandin E1 in the diagnosis and treatment of ED was reported in 1995 [40]. Then there was a proposal to use and even produce prostaglandin E1 in a dosage of 5 mcg for diagnostic purposes. Most sources describe prostaglandin dosages of 10 to 20 mcg [36, 41–44]. However, there are indications that the amount of the drug must be differentiated: in patients under 50 years of age, 5 mcg of the drug should be administered, and in patients over 50 years of age – 10 mcg [39]. The test result was assessed 15 minutes after intracavernous injection. The degree of erection was determined in accordance with the degree of swelling and rigidity of the penis (Table 1) [4, 43]. The clinical result of the test with alprostadil is presented in Table 2.

15 minutes after administration of 5 μg of alprostadil, various combinations of swelling and rigidity of the penis were obtained, while there was no sexual stimulation during the study.

We noted that the clinical result of intracavernosal administration of alprostadil significantly depended on age (p = 0.008)5. Younger patients had higher degrees of swelling and stiffness than older patients. Moreover, the presence or absence of identified risk factors did not have a statistically significant effect on the clinical result of the intracavernous test (p = 0.29)6. Also, the test result did not depend on the type of ED risk factors (p=0.064)7.

A statistically significant distribution of patients was revealed depending on the degree of swelling and rigidity of the penis after intracavernosal administration of alprostadil and the results of a questionnaire on the IIEF-5 scale (p = 0.011)8. In patients with preserved sexual activity, the clinical result of intracavernosal administration of the drug was significantly better (p = 0.002)9. Thus, a clinical assessment of the intracavernous test in combination with anamnesis data and the results of the questionnaire will make it possible to clarify the cause and type of ED with a sufficient degree of probability.

Along with assessing the effectiveness of alprostadil administration, the spectral characteristics of blood flow in the cavernous arteries were analyzed. The maximum systolic velocity was measured in the area of ​​the proximal third of the penis, since at this level the velocities have the greatest values. If blood flow velocity is measured in the distal region, the results are underestimated.

Spectral Dopplerography of the cavernous arteries began 5 minutes after injection and then repeated every 5 minutes until the 25th minute. After administration of drugs containing prostaglandins, the blood flow velocity should be at least 35–40 cm/s [36, 45].

Pathological venous outflow was suspected if there was adequate arterial inflow, an erection developed, but its duration was short, and constant antegrade diastolic blood flow was determined throughout the study. Constant diastolic blood flow is the preservation of the speed of diastolic blood flow throughout all stages of erection. The speed value is determined after correction for the angle. Another sign of venous outflow is the resistance index. This is a reliable method for diagnosing cavernous venous drainage. A resistance index of less than 0.75 is accompanied by venous outflow in 90% of patients. A resistance index of more than 0.9 is observed in 90% of healthy subjects.

When assessing the results, we were guided by the recommendations of the European Society of Urology (peak systolic blood flow - above 30 cm/s, resistance index - above 0.8) [46].

First of all, we clarified the symmetry of blood flow in the right and left cavernous arteries after the administration of prostaglandin E1. Blood flow velocity (p=0.662) and resistance index (p=0.297) did not have significant differences. Therefore, for further evaluation, indicators of one artery are presented10. The results of pharmacodopplerography of the cavernous arteries are presented in Table 3, from which it can be seen that the clinical result of this study of the cavernous arteries depends on the maximum blood flow velocity and blocking of venous outflow after intracavernous administration of 5 μg of prostaglandin E1.

The maximum blood flow velocity in the cavernous artery during control measurements was higher in young patients compared to older groups (p = 0.001). Also, the resistance index was higher in young patients (p=0.001)11. Thus, age affects not only the clinical signs and severity of ED, but also the objective parameters of blood flow in the cavernous arteries.

The presence or absence of intimate activity for at least 4 weeks. before the study did not have a significant effect on the maximum blood flow velocity (p = 0.291) and the resistance index (p = 0.187)12.

The maximum blood flow velocity was significantly lower (p=0.002) in patients with identified risk factors for ED (vasculogenic, neurogenic, etc.). Moreover, the resistance index did not depend on risk factors (p=0.255)13. The maximum blood flow velocity in the cavernous arteries did not depend on the degree of erectile dysfunction, as determined by questionnaire data on the IIEF-5 scale (p = 0.901)14. There was also no correlation between the resistance index (p=0.226)15.

The clinical result of intracavernosal administration of alprostadil (degree of filling and penile rigidity) is most pronounced in young patients. The presence and type of risk factors did not have a significant effect on the clinical result of the test. In patients with preserved sexual activity, the clinical result of intracavernosal administration of the drug was significantly better. This aspect of the study allows us to imagine the influence of psychological or organic causes of ED.

The maximum blood flow velocity and resistance index in the cavernous artery after the administration of alprostadil were higher in young patients. The presence or absence of intimate activity had no significant effect on the spectral characteristics of blood flow. The influence of established risk factors on the maximum velocity of blood flow in the cavernous arteries was noted.

Thus, the use of 5 mcg of alprostadil is an effective and safe method for examining patients with ED of various origins and severity. This made it possible to clarify the hemodynamic causes of complaints of ED (Table 4).

The absence of hemodynamic changes was detected in 244 (61.3%) patients, insufficient arterial inflow - in 67 (16.8%), venous leakage with sufficient arterial inflow - in 51 (12.8%), a combination of insufficient inflow and venous leakage - in 36(9.0%) patients.

Data from pharmacodopplerography of the penis also make it possible to select the dosage of sildenafil depending on the presence and combination of hemodynamic causes of ED. Tornetis® has the most acceptable form of application. The unique split technology of the Tornetis® tablet allows you to select the dose for the patient. With one click, the tablet is precisely divided into equal parts of 25 mg. For patients of older age groups with the presence of risk factors and a combination of hemodynamic reasons, the maximum dosage of Tornetis® is indicated (100 mg). For young patients with no hemodynamic changes according to pharmacodoppler ultrasound, the minimum dose of Tornetis® (25 mg) is indicated. This allows you to get maximum effectiveness and reduce the likelihood of side effects.

Thus, Tornetis® is a unique dosing system, the ability to individually select the dose according to the patient’s needs, and adequate effectiveness after each dose.

RU1407227686

[1] The median is indicated, as well as the 5th and 95th percentiles

[2–4] Chi-square test applied

[5–9] Chi-square test applied

[10] Wilcoxon test applied

[11–15] Kruskall–Wallis test applied

Contraindications

The use of Silenafil has a fairly wide range of contraindications:

• hypersensitivity to the active substance or auxiliary components of the drug;
• severe disturbances in liver function;
• low blood pressure (less than 90/50);
• recently suffered pathologies associated with cerebral circulatory disorders;
• recent myocardial infarction;
• phenylkenothuria;
• loss of vision in one eye;
• hereditary retinal dystrophy;
• simultaneous use with Amylnitrite, nitrates and other nitric oxide NO donors;
• simultaneous use with the drug "Ritonavir";
• children under 18 years of age.

There are other contraindications. For example, the drug is not recommended for use by men who should not be sexually active due to severe heart failure.

Hypertensive patients with blood pressure above 170/100 should take this medication with caution, as well as in the presence of:

• severe arrhythmia that threatens life;
• left ventricular obstruction;
• conditions that predispose to prialism;
• ischemic optic neuropathy;
• anatomical deviations of the penis (deformation, Peyronie's disease and others).

Modern view on the use of sildenafil citrate

Journal "Experimental and Clinical Urology" Issue No. 1 for 2015

Efremov E.A., Kasatonova E.V., Melnik Ya.I.

Erectile dysfunction (ED) is characterized by a persistent inability to achieve or maintain an erection sufficient for successful sexual intercourse. This erectile dysfunction is widespread and according to KK Chew et al. by 2025, it is estimated to affect 322 million men worldwide [1].

Data from the latest separate study on the prevalence of ED in 6 regions of the Russian Federation were obtained in 2012 based on an analysis of survey data from 1225 respondents. When analyzing the IIEF-5 questionnaire, it was revealed that only 10.1% of surveyed men had no signs of ED, while a mild degree of ED was noted in 71.3%, a moderate degree in 6.6% and a severe degree in 12 % of respondents. Thus, out of 1225 men surveyed, symptoms of ED were present in 1101 (89.9%) respondents [2].

For many decades, treatment of ED was carried out by specialists who did not have sufficient knowledge of the pathophysiology and mechanisms of erection. Thus, in 1668, intracavernosal injections of salt solutions were first performed, then numerous options for oral therapy with various tinctures (for example, from animal testicles) were used; in the 19th century, subcutaneous injections of ejaculate were proposed; in 1936, the first penile implantation was performed [3 ].

Currently, in the treatment of ED, the polyetiological nature of the disease is taken into account, but the first line of therapy, despite the variety of causes of ED, are phosphodiesterase type 5 inhibitors (PDE-5 inhibitors). The noninvasive nature of PDE5 inhibitor therapy has increased the availability of treatment compared to other treatment modalities, which include intracavernous injections of vasoactive drugs, vacuum devices, penile prostheses, and surgical vascular reconstructions [3].

The history of the use of PDE-5 inhibitors began in March 1998, when the drug sildenafil was approved for use by the Food and Drug Administration (FDA) in the United States of America. With the appearance on the market of this first effective tablet drug for the treatment of ED, sildenafil rightfully became the flagship and gold standard of first-line treatment for ED. Vardenafil and tadalafil, which were introduced somewhat later, are also known as selective PDE5 inhibitors. Thus, sildenafil is the most studied drug among PDE-5 inhibitors in terms of safety and effectiveness.

Sildenafil citrate provides an increase in the concentration of cyclic guasine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum of the penis, which, in turn, leads to an increase in the level of nitric oxide (NO) in these cells and, as a result, to the relaxation of these cells and increased blood flow in the penis. When the NO-cGMP chain is activated, which is observed during sexual arousal, inhibition of PDE5 leads to an increase in cGMP in the corpus cavernosum. The pharmacological effect is achieved only in the presence of sexual stimulation [4].

USE OF SILDENAFIL IN PATIENTS WITH CARDIOVASCULAR DISEASES

In the American Massachusetts Male Aging Study, the incidence of ED in men aged 40-70 years was 52%. In the German study Cologne Male Survey, when analyzing the population, the incidence of ED was 10% in men aged 40-49 years, 16% in men aged 50-59 years, 34% in men aged 60-69 years and more than 50% in men aged from 70 to 80 years [5-7]. Thus, the main group of patients with erectile dysfunction are men over 50 years old; at this age, the incidence of cardiovascular diseases, including myocardial infarction and stroke, increases. Sexual dysfunction in men with cardiovascular disease is common. Many patients stop sexual activity due to fear that physical efforts during sexual activity will be complicated by recurrent myocardial infarction. However, there are a number of studies proving the safety and effectiveness of sildenafil citrate in a group of patients with ED and cardiovascular diseases [8-9].

In a phase II/III, double-blind, open-label study conducted by the FDA, more than 3,700 patients received sildenafil for ED and nearly 2,000 received placebo. Approximately 25% of patients had hypertension and were taking antihypertensive drugs, and 17% had diabetes. In these studies, the incidence of major cardiovascular events was similar in the sildenafil and placebo groups. 28 patients who suffered myocardial infarction during the study were registered. The incidence of myocardial infarction was 1.7% in the sildenafil group and 1.4% in the placebo group. There were no differences in the incidence of cardiovascular disease between the two groups, and no deaths were related to treatment. Histomorphological studies did not find any traces of PDE-5 inhibitors in the area of ​​necrosis and tissue of the ventricles of the heart, but traces of PDE-5 inhibitors were found in the atria [10].

In studies by M. Guazzi et al. It was found that sildenafil improves the condition of the endothelium. The authors noted flow-dependent dilatation of the brachial artery in patients with heart failure and type 2 diabetes mellitus [11].

In patients with heart failure due to ischemic or non-ischemic heart disease without pulmonary disease, a single dose of 50 mg of sildenafil caused a significant increase in cardiac index and a decrease in pulmonary vascular resistance both at rest and during exercise. In patients with coronary artery diseases, a positive effect of sildenafil on skin microcirculation has been established [12].

The vasodilator effect of sildenafil affects both arteries and veins, so the most common side effects are headache and facial flushing. Sildenafil causes a slight decrease in systolic and diastolic blood pressure, but clinically significant hypotension is rare, while co-administration of sildenafil and nitrates causes a more significant drop in blood pressure. For this reason, sildenafil is contraindicated for use in patients within 24 hours after taking short-acting nitrates. Meanwhile, about 5.5 million men require constant intake of nitrates, which leaves the question of further research on the joint use of these substances open [9].

USE OF SILDENAFIL IN PATIENTS WITH DIABETES MELLITUS

In the practice of a therapist, a pressing issue is the use of sildenafil for diabetes mellitus, since in patients suffering from type 1 and type 2 diabetes mellitus, erectile dysfunction occurs three times more often than in the general patient population. Moreover, erectile dysfunction can be considered as an early marker of diabetes mellitus. Thus, 12% of men suffering from erectile dysfunction were diagnosed with diabetes mellitus for the first time during examination. An additional 50% are expected to develop ED within 5–10 years of diagnosis [13]. The mechanism of ED in men with diabetes mellitus is predominantly caused by organic factors: vasculogenic and neurological. Goldstein et al. A study of sildenafil citrate 50 mg in patients with diabetes reported a 52% improvement in erectile function compared with placebo [14]. Similar data were obtained by MS Rendell et al. They noted an improvement in erectile function in 56% of patients taking sildenafil at a dosage of 100 mg versus 10% in the placebo group. Thus, sildenafil is effective and well tolerated in the treatment of organic ED in men with diabetes mellitus [15].

USE OF SILDENAFIL IN PSYCHOTHERAPY PRACTICE

Erectile dysfunction is a polyetiological disease and in some cases can be caused by various psychogenic factors that require specialized therapy. ED can both cause depression and be its consequence.

It has been noted that with monotherapy with antidepressants, antidepressant-induced ED occurs in 37% of cases, manifested by decreased libido, difficult ejaculation and anorgasmia. In a 12-week randomized, double-blind, placebo-controlled study in 20 urology clinics, the effect of sildenafil on erectile dysfunction in men with mild to moderate depressive disorders was assessed. Not only has sildenafil been shown to be an effective drug for the treatment of erectile dysfunction, but it has also been associated with a marked reduction in depressive symptoms and an improvement in quality of life: 60 (90.9%) of 66 men taking sildenafil reported that the treatment improved their erections and 59 (89.4%) %) noted an improvement in the ability to perform sexual intercourse, compared with 8 (11.4%) and 9 (12.9%) of 70 men receiving placebo, respectively [16-17].

A meta-analysis of 9 randomized studies was conducted involving 398 men with ED of mixed etiology who received various treatments: 141 patients used psychotherapy only, 109 only sildenafil, 68 patients used psychotherapy in combination with sildenafil, 20 people used vacuum devices and 59 people included to the control group. The best rates of successful treatment were obtained for a group of patients in which psychotherapeutic treatment was combined with sildenafil [18].

Another study assessed the effect of sildenafil on couple mental health using the Self-Esteem And Relationship (SEAR) questionnaire. According to the results of the survey, after a year of taking the drug, indicators such as general well-being, self-control, and satisfaction in relationships increased significantly. The authors recommend taking the drug to improve the overall mental health of not only the man, but also the couple as a whole [19].

SELECTED ISSUES OF THE APPLICATION OF SILDENAFIL IN VARIOUS UROLOGICAL DISEASES

Currently, the world has extensive experience in the use of sildanafil for various urological diseases complicated by ED.

Lower urinary tract dysfunction and ED

There are several clinical studies demonstrating the effectiveness of PDE5 inhibitors in the treatment of lower urinary tract dysfunction (LUTS). JP Mulhall et al. studied the effect of sildenafil on LUTS in men referred for sexual dysfunction. After the administration of sildenafil, 60% improved their IPSS questionnaire scores. The mean decrease in IPSS scores per week was 2 ± 0.6. The authors concluded that sildenafil helps improve urination in men with mild to moderate forms of LUTS and ED [20].

Many studies have been devoted to studying the role of PDE-5 inhibitors in combination with α-blockers in improving sexual function. SAKaplan et al. reported the results of their experimental work demonstrating the safety and effectiveness of combination treatment with the blocker alfuzosin and sildenafil compared with monotherapy groups in the treatment of LUTS and ED. After 12 weeks of therapy, patients in all groups showed an improvement in IPSS, Qmax and IIEF scores, but the best results were obtained in the combination therapy group. The researchers concluded that treatment with sildenafil in combination with an adrenergic blocker was safe and effective in the treatment of both LUTS and ED [21]. In another randomized, double-blind, placebo-controlled study performed by K. McVary et al. similar results were noted. In this 12-week study, 366 men over 45 years of age with IIEF-5 scores less than 25 and IPSS scores greater than 12 received sildenafil 50 and 100 mg or placebo. The results showed a reduction in mean IPSS score of 6.32 points in the sildenafil group compared to 1.93 in the placebo group. On the IIEF-5 scale, an improvement in the mean score was found by 9.17 compared to 1.86 points when taking placebo (p < 0.0001) [22].

Thus, the use of sildenafil, either alone or in combination with alpha-blockers, has demonstrated efficacy and safety in the treatment of LUTS caused by benign prostatic hyperplasia (BPH) and erectile dysfunction.

Prostate Cancer and ED

Treatment of erectile dysfunction with sildenafil in patients undergoing radiation therapy for prostate cancer (PCa) was initially shown to be effective in uncontrolled studies and later confirmed in a controlled study. 50 patients with ED after radiation therapy for localized prostate cancer took 50 mg of sildenafil. At the same time, a significant improvement in erection was noted by 66-74% of patients [23, 24].

The most significant prognostic factors for the restoration of erectile function after radical prostatectomy are bilateral preservation of the neurovascular bundles and the absence of erectile disorders before surgical treatment. According to M. Tutolo et al. The effectiveness of sildenafil for the treatment of ED in 170 men after radical nerve-sparing prostatectomy was 80% [25]. In a randomized, double-blind, placebo-controlled study, H. Padma-Nathan et al. report that early administration of a PDE5 inhibitor increases the recovery of spontaneous erections, with the effectiveness of sildenafil increasing over time, with better results observed 12–24 months after surgery [26].

Pelvic trauma and ED

Injuries to the pelvis and perineum can cause erectile dysfunction. PJ Harwood et al. noted that as a result of pelvic fracture and urethral injury, 30% and 42% of patients, respectively, had erectile dysfunction [25]. OZ Shenfield et al. reported that after urethroplasty, the administration of sildenafil at a dosage of 100 mg significantly reduced the manifestation of ED in 47% of patients. It has been noted that the drug is most effective for injuries of the genitourinary organs with preserved innervation and blood supply [27-28].

Fertility and ED

Equally important is the assessment of the effect of sildenafil on male fertility. After sildenafil entered the pharmaceutical market, many scientific works were devoted to studying the effect of the drug on the characteristics of sperm in vitro. Research by A.O. Kulikova et al., conducted at the Federal State Budgetary Institution "Research Institute of Urology" of the Ministry of Health of Russia in 2013, showed that in vitro conditions revealed a sharp increase in total sperm motility (A + B) when exposed to sildenafil at a concentration of 25 ng/ml (p < 0.001 ) and a tendency towards inhibition of general mobility (A+B) at drug concentrations above 250 ng/ml (p=0.09). This may indicate the presence of a stimulating effect on spermatogenesis and sperm maturation at a low dose of the drug. According to the data obtained, the author recommends avoiding maximum therapeutic dosages of sildenafil in patients planning pregnancy [29].

Currently, in addition to the original drug sildenafil, a generic Erexezil, produced in Hungary, has appeared on the Russian market. The results of the studies show that the effectiveness and safety of the drug Erexesil is comparable to that of the original drug [30]. Studies have noted a significant positive effect of Erexesil on erectile function. There was an improvement in the quality of life of patients taking this drug [31]. Available release forms of 50 mg and 100 mg No. 1 and No. 4 allow effective dosing of the drug, which ensures an individual approach to the treatment of each patient.

LITERATURE

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2. Pushkar D.Yu., Kamalov A.A., Al-Shukri S.H., Erkovich A.A., Kogan M.I., Pavlov V.N., Zhuravlev V.N., Bernikov A.N. Analysis of the results of an epidemiological study of the prevalence of erectile dysfunction in the Russian Federation // Urology. 2012. N 6. P. 5–9.
3. Jonas U. The history of erectile dysfunction management. // Int J Impot Res. 2001. Vol. 3. P. 3-7.
4. Boswell-Smith V, Spina D, Page CP. Phosphodiesterase inhibitors. //Br J Pharmacol. 2006. Vol. 147. P. 252–257.
5. Stolk EA, Busschbach JJ. Are patients and the general public likeminded about the effect of erectile dysfunction on quality of life? // Urology. 2003. Vol. 61, N 4. P. 810-815.
6. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. // J Urol. 1994. Vol. 151, N 1. P. 54-61.
7. Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann U. Epidemiology of erectile dysfunction: results of the “Cologne Male Survey”. // Int J Impot Res. 2000. Vol. 12, N 6. P. 305-311.
8. Cakir O. The frequencies and characteristics of men receiving medical intervention for erectile dysfunction: Analysis of 6.2 million patients. // 28th Annual EAU congress, 15-19 March, 2013. Milan. Italy, abst. N 126.
9. American Heart Association. 1998 Heart and Stroke Statistical Update. Dallas, Tx: American Heart Association; 1997.
10. Zusman RM. Cardiovascular data on sildenafil citrate. // Am J Cardiol. 1999. Vol. 83(1). P. 44.
11. Guazzi M, Tumminello G, Di Marco F, Guazzi MD. Influences of Sildenafil on lung function and hemodynamics in patients with chronic heart failure. //Clin Pharmacol Ther. 2004. Vol. 76. P. 371–8.
12. Lewis GD, Lachmann J, Camuso J, Lepore JJ, Shin J, Martinovic ME, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. // Circulation. 2007. Vol. 115. P. 59-66.
13. Shabsigh R, Perelman M, Lue TF, Broderick GA, Lockhardt D. Men's health issues: prevalence and correlates of erectile dysfunction. //Jurol. 2005. Vol. 174. P. 662–667.
14. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. //N Engl J Med. 1998. Vol. 338. P.1397-1404.
15. Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. // JAMA. 1999. Vol. 281, N 5. P. 421-426.
16. Seidman SN, Roose SP, Menza MA, Shabsigh R, Rosen RC. Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate. //Am J Psychiatry. 2001. Vol. 158. P. 1623–1630.
17. Zajecka J, Mitchell S, Fawcett J. Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the Rush Sexual Inventory. //Psychopharmacol Bull. 1997.Vol. 33. P. 755-760.
18. Melnik T, Soares B, Nasello AG. Psychosocial interventions for erectile dysfunction. //Cochrane Database of Systematic Reviews. 2007. Vol 3.
19. O'Leary MP, Althof SE, Cappelleri JC, Crowley A, Sherman N, Duttagupta S. Selfesteem, confidence and relationship satisfaction of men with erectile dysfunction treated with sildenafil citrate: a multicentre, randomized, parallel group, double-blind, placebo controlled study in the United States. // J Urol. 2006. Vol. 175. P. 1058–1062.
20. Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. //J Sex Med. 2006. Vol. 3, N 4. P. 662-667.
21. Kaplan SA, Gonzalez RR, Ogiste J, et al. Combination of an alpha-blocker, alfuzosin SR, and a PDE-5 inhibitor, sildenafil citrate, is superior to monotherapy in treating lower urinary tract symptoms (LUTS) and sexual dysfunction. //Jurol. 2006. Vol.175, Suppl. 4 P. 528. Abstract 1638
22. McVary K, Camps J, Henry G, Camps JL, Jr, Young JM, Tseng LJ, van den Ende G. Sildenafil improves erectile function and urinary symptoms in men with erectile dysfunction and concomitant lower urinary tract symptoms. // J Urol. 2006. Vol. 175, Suppl. 4. P. 527–528. Abstract 1637
23. Zelefsky MJ, Mckee AB, Lee H, Leibel SA. Efficacy of oral sildenafil in patients with erectile dysfunction after radiotherapy for carcinoma of the prostate. //Urology. 1999. Vol. 53. P. 775–778.
24. Merrick GS, Butler WM, Lief JH, Stipetich RL, Abel LJ, Dorsey AT. Efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. //Urology. 1999. Vol. 53. P. 1112–1116.
25. Tutolo M, Briganti A, Suardi N, Gallina A, Abdollah F, Capitanio U, Bianchi M, Passoni N, Nini A, Fossati N, Rigatti P, Montorsi F. Optimizing postoperative sexual function after radical prostatectomy. // Ther Adv Urol. 2012. Vol. 4, N 6. P. 347-365.
26. Padma-Nathan H, McCullough AR, Levine LA, Lipshultz LI, Siegel R, Montorsi F, Giuliano F, Brock G; Study Group. Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve sparing radical prostatectomy. // Int J Impot Res. 2008. Vol. 20, N 5. P. 479-86.
27. Harwood PJ, Grotz M, Eardley I, Giannoudis PV. Erectile dysfunction after fracture of the pelvis. // J Bone Joint Surg Br. 2005. Vol. 87, N 3. P. 281-90.
28. Shenfield OZ, Gofrit OD, Gdor Y, Landau I, Katz R, Pode D. The role of sildenafil in the treatment of erectile dysfunction with pelvic fracture urethral disruption. // J Urol. 2004. Vol. 172. P. 2350–2352
29. Kulikov A.O. The influence of phosphodiesterase type 5 inhibitors on spermatogenesis: Diss. Ph.D. honey. Sci. Moscow. 2013. 178 p.
30. Randomized, open label, 2-way crossover, bioequivalence study of sildenafil 100 mg tablet and Viagra (reference) following a 100 mg dose in healthy subjects under fasting conditions. // Final integrated clinical and statistical report. Version Date: 2007-02-26.
31. Instructions for medical use of the drug Erexesil. // URL: https://www.egis.ru/images/science/bioequivalencestudy_2007.pdf

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Journal "Experimental and Clinical Urology" Issue No. 1 for 2015

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Side effects

In some cases (often due to an overdose), minor side effects are possible:

• dyspepsia;
• dizziness;
• headache;
• feeling of nasal congestion;
• flushes of blood;
• temporary vision problems;
• noise in ears;
• hypersensitivity reactions.

In rare cases, the following were observed:

• temporary deafness;
• cardiopalmus;
• nosebleeds;
• skin rash;
• nausea;
• myalgia;
• chest pain;
• fast fatiguability;
• an erection that lasts too long.

"Sildenafil": instructions for use

The drug is taken orally and washed down with a small volume of water. The standard single dosage is 50 mg one hour before sexual intercourse. If the effect is insufficient, increase the dosage by 2 times (subject to normal tolerance and absence of contraindications). The maximum amount per day is 100 mg, frequency of use is 1 time per day.

For older people, the same dosages are established. In this case, the daily intake rate can be adjusted in the presence of certain diseases:

1. Renal dysfunction – 25 mg.
2. Liver dysfunction – 25 mg.
3. Simultaneous use with other drugs such as Ketoconazole, Cimetidine (except Ritonavir), Erithoromycin - up to 25 mg.

These restrictions are not “hard” ones. If the effect is insufficient, the daily dosage can be gradually increased to 50 mg, then to 100 mg.

Description of the drug SILDENAFILUM

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages 40% (25-63%). After a single oral dose of 100 mg, Cmax is 18 ng/ml and is achieved when taken on an empty stomach for 30-120 minutes. When taking sildenafil in combination with fatty foods, the rate of absorption is reduced; Tmax increases by 60 minutes, and Cmax decreases by an average of 29%. The Vd of sildenafil at steady state is on average 105 liters. Sildenafil and its main circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding is independent of the total concentration of sildenafil. Less than 0.0002% of the dose (mean 188 ng) was detected in semen 90 minutes after sildenafil administration.

Sildenafil is metabolized mainly by the liver microsomal isoenzymes CYP3A4 (the main route) and CYP2C9.

The main circulating metabolite, which is formed as a result of N-desmethylation of sildenafil, undergoes further metabolism. In terms of selectivity of action on PDE, the metabolite is comparable to sildenafil, and its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil itself. The concentration of the metabolite in plasma is approximately 40% of that of sildenafil. The N-desmethyl metabolite undergoes further metabolism; its terminal T1/2 is about 4 hours.

The total clearance of sildenafil from the body is 41 l/h, and T1/2 in the terminal phase is 3-5 hours. After oral administration, sildenafil is excreted in the form of metabolites mainly in feces (approximately 80% of the dose) and to a lesser extent in urine ( approximately 13% of the dose).

In elderly patients (65 years and older), the clearance of sildenafil is reduced, and the concentration of the free active substance in plasma is approximately 40% higher than its concentration in young (18-45 years) patients.

In case of mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal failure, the pharmacokinetic parameters of sildenafil after a single oral dose (50 mg) do not change. In severe renal failure (creatinine clearance ≤30 ml/min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared to those with normal renal function in patients of the same age group.

In patients with liver cirrhosis (Child-Pugh class A and B), the clearance of sildenafil is reduced, resulting in an increase in AUC (84%) and Cmax (47%) compared with those with normal liver function in patients of the same age group .

special instructions

One-time use is allowed without consulting a doctor, except in cases associated with severe pathologies of the cardiovascular system, kidneys or liver. For long-term use, preliminary consultation with a specialist is recommended.

In extremely rare cases, cardiac instability may occur. In case of overdose, myocardial infarction, including death, cannot be ruled out. Complications can develop during, after, or even without sexual intercourse.

Sildenafil leads to dilation of blood vessels, which leads to a slight, reversible decrease in blood pressure. Therefore, on the eve of the appointment, the doctor should assess the possible risks associated with a decrease in blood pressure.

Sildenafil Vertex, 100 mg, film-coated tablets, 1 pc.

The influence of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly in the liver under the influence of cytochrome isoenzymes CYP3A4 (the main pathway) and CYP2C9, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, accordingly, increase the clearance of sildenafil. A decrease in the clearance of sildenafil was noted with simultaneous use of inhibitors of the cytochrome CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a nonspecific inhibitor of the cytochrome CYP3A4 isoenzyme, when taken together with sildenafil (50 mg), causes an increase in plasma sildenafil concentrations by 56%.

A single dose of 100 mg of sildenafil together with erythromycin (500 mg/day 2 times a day for 5 days), a specific inhibitor of the cytochrome CYP3A4 isoenzyme, while achieving a constant concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%.

When co-administered with sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times a day), an inhibitor of HIV protease and the cytochrome CYP3A4 isoenzyme, while achieving a constant concentration of saquinavir in the blood, the Cmax of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir. Stronger inhibitors of the cytochrome CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may cause more severe changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg 2 times a day), an HIV protease inhibitor and a strong cytochrome P450 inhibitor, while achieving a constant concentration of ritonavir in the blood leads to an increase in sildenafil Cmax by 300% (4 times ), and AUC - by 1000% (11 times). After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng/ml (after a single use of sildenafil alone - 5 ng/ml).

Grapefruit juice, a weak inhibitor of CYP3A4, may moderately increase plasma concentrations of sildenafil.

If sildenafil is taken in recommended doses by patients simultaneously receiving strong inhibitors of the cytochrome CYP3A4 isoenzyme, then the Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated.

A single dose of an antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

Inhibitors of the cytochrome CYP2C9 isoenzyme (such as tolbutamide, warfarin), the cytochrome CYP2D6 isoenzyme (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors (angiotensin-converting enzyme) and calcium antagonists do not affect the pharmacokinetic parameters of sildenafil.

Azithromycin (500 mg/day for 3 days) has no effect on the AUC, Cmax, Tmax, elimination rate constant and T1/2 of sildenafil or its main circulating metabolite.

Nicorandil is a hybrid of a nitrate and a potassium channel activator. Due to the presence of a nitrate component, it may have serious interactions with sildenafil.

Effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50>150 µmol). When sildenafil is taken at recommended doses, its Cmax is approximately 1 µmol, so it is unlikely that sildenafil could affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates both with long-term use of the latter and when they are prescribed for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

When co-administering the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional reduction in systolic/diastolic blood pressure in the supine position was 7 /7 mmHg Art., 9/5 mm Hg. Art. and 8/4 mm Hg. Art. respectively, and in a standing position - 6/6 mm Hg. Art., 11/4 mm Hg. Art. and 4/5 mm Hg. Art. respectively. Rare cases of symptomatic postural hypotension, manifested in the form of dizziness (without fainting), have been reported in such patients. In selected sensitive patients receiving alpha-blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

There were no signs of significant interaction between sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome CYP2C9 isoenzyme.

Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome CYP3A4 isoenzyme, at constant blood levels.

Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).

Sildenafil (50 mg) does not enhance the hypotensive effect of ethanol in healthy volunteers with a maximum ethanol concentration in the blood of an average of 0.08% (80 mg/dL).

In patients with arterial hypertension, no signs of interaction between sildenafil (100 mg) and amlodipine were detected. The average additional decrease in blood pressure in the supine position is 8 mm Hg. Art. (systolic) and 7 mm Hg. Art. (diastolic).

The use of sildenafil in combination with antihypertensive drugs does not lead to additional side effects.