Twenty years of use of sildenafil in urology

Erectile dysfunction (ED) is a man’s inability to achieve and maintain an erection necessary for adequate intercourse. This problem is widespread throughout the world. Thus, a number of studies conducted in Europe and America have shown that in the United States, from 20 to 30 million men suffer from this disease. A 2005 study in the male population in the Netherlands showed that the annual detection rate of ED (per 1000 men) is 19.2 people. As a multifactorial disease, ED deeply affects not only the physical and material aspects of a man’s health, but is also a powerful source of psychological dissatisfaction, as well as an important factor in the development of depression and family problems. Many specialists in various fields and patients are used to believing that ED is just a psychological aspect that negatively affects the quality of life. However, this statement is unfair, given the fact that, according to the European Association of Urology (EAU), ED is often inextricably linked with metabolic, cardiovascular, neurogenic diseases and is often their most important companion.

An erection is determined by the ability of trabecular smooth muscle fibers to adequately relax, which increases the compliance of the cavernous sinusoids, contributes to their rapid blood filling and expansion. Due to the increase in the volume of sinusoids, the dorsal and emissary veins are compressed, as a result of which the outflow of blood from the organ temporarily stops. In this case, the intracavernous pressure increases up to 100 mm Hg. Art., which provides an erection adequate for the initiation and conduct of a full sexual intercourse. The functional capabilities of the cavernous tissue, like most tissues and cells of the body, depend on the work of the sympathetic and parasympathetic nervous systems, as well as on vasoactive substances secreted by the endothelium. Under the influence of visual, tactile and other types of sexual stimulation, nitric oxide is produced in the terminals of the sympathetic nerve fibers and the endothelium of the corpora cavernosa. Nitric oxide with the help of secondary mediators – cyclic adenosine monophosphate (c-AMP) and, mainly, cyclic guanosine monophosphate (c-GMP), responsible for smooth muscle relaxation, leads to the opening of potassium and closure of calcium membrane channels, as well as the utilization of calcium ions into the endoplasmic reticulum. This decrease in the concentration of calcium ions in the cytoplasm promotes relaxation of the smooth muscle cells of the sinusoids of the corpora cavernosa, which ensures an erection. Subsequently, c-GMP is catabolized by a specific substance – phosphodiesterase type 5 (PDE-5), this helps to restore the muscle tone of the walls of the cavernous sinusoids and regression of erection. Violation of this mechanism at one stage or another can lead to ED.

Depending on the type of such a disorder, three types of ED are distinguished: psychogenic, organic (neurogenic, hormonal, arterial, cavernous and drug-induced) and mixed, which is the most common.

Treatment

All forms of ED are based on damage to a single molecular mechanism of relaxation of the smooth muscle cell of the cavernous tissue of the penis, as described above. For this reason, the algorithm of therapeutic measures associated with this disease is more or less general for different groups of patients and is not specific. Considering that ED is usually associated with concomitant diseases (endocrine and metabolic disorders (diabetes mellitus), cardiovascular diseases, etc.), the first stage of treatment is the achievement of adequate control over intercurrent pathology.

In general, ED is successfully amenable to symptomatic correction, but it cannot be completely eliminated. The only exceptions can be psychogenic and post-traumatic forms in young patients, as well as ED caused by hormonal disorders (hypogonadism, hyperprolactinemia, etc.). This is only a limited list of diseases leading to erectile dysfunction with the expected favorable prognosis. Most patients are likely to receive lifelong non-specific treatment, regardless of the type of disease. The results of treatment tactics depend on the effectiveness, safety, cost of the chosen technique, as well as the preferences and interest of the patient. According to the EAU, treatment of ED should begin with lifestyle changes and addressing possible organic and psychogenic causes of the disease. In case of insufficient or complete ineffectiveness of these measures, you can start drug treatment. The drugs of choice in this case are type 5 phosphodiesterase inhibitors (IFDE-5) (grade of recommendation 1a, EAU recommendations 2017). The fact is that the substances of this group prevent the capture and subsequent splitting of c-GMP, the very substance that is responsible for the blood filling of the corpora cavernosa and erection as such. Thus, IFDE-5 provides erectile activity of the penis, which is possible in this case only after sexual stimulation, without which, with an insufficient concentration of nitric oxide in the synaptic terminals, the start of the cascade of reactions that ensure an erection would be impossible.

Sildenafil (Viagra®) was the very first and main IFDE-5 on the drug market. In 1998, it was approved for use by the FDA (Food and Drug Administration), and since then has been the drug of choice for a huge number of men with ED around the world. To date, scientific knowledge contains data from more than 67 clinical randomized placebo-controlled and post-marketing studies on the efficacy and safety of sildenafil (Viagra). In our review, we will focus on the most basic of them. Thus, one of the first and most important works are two studies conducted under the leadership of I. Goldstein in 1998 and formally combined into one. The first study (the first part of the research program) was a standard, randomized, placebo-controlled, double-blind study, which included 532 people who took sildenafil in different dosages – 25, 50, 100 mg or placebo for 24 weeks. The second part of the program included 329 men who also received sildenafil or placebo, but the sildenafil was started at 50 mg, which at the follow-up visit could be reduced or increased by 50%, until a maximum single dose of 100 mg was reached. After 12 weeks. the study design changed, became open and continued for another 32 weeks. Patients could withdraw from the study if the drug was poorly tolerated or ineffective. Treatment results were assessed based on the IIEF (International Index of Erectile Function) questionnaire. It turned out that in the group with a fixed dose, taking Sildenafil Cenforce contributed to a significant (p <0.001) improvement in sexual function compared to the baseline (a group of questions related to the possibility of achieving and maintaining an erection necessary for full intercourse). So, patients who took 25, 50 and 100 mg, noted an improvement in the category “the number of sexual intercourses” (question No. 3 of the IIEF scale) by 60, 84 and 100%, respectively, while patients from the placebo group noted an improvement in this indicator by only 5 %. With regard to the question of the ability to maintain an erection throughout the entire sexual intercourse (question No. 4 IIEF), the patients noted improvement by 121, 133 and 130% when taking 25, 50 and 100 mg, respectively. In a study with a stepwise increase / decrease in dose, patients noted an improvement in symptoms by 69%, while in the placebo group – only 22% (p <0.001). In the group with a gradual increase / decrease in the dose of sildenafil by the end of the study, patients noted an improvement in question No. 3 by 95%, and in question No. 4 – by 140%, in the placebo group – only by 10% and 13%, respectively (p <0.001) … As for the side effects, the main ones were headache, facial flushing and a feeling of heat, dyspepsia, rhinitis and visual disturbances (color vision disturbance). These effects were most pronounced at the stage of gradual increase / decrease in the dose of sildenafil and amounted to 30, 9, 8 and 4%, respectively. In the placebo group, these rates were much lower. However, 92% of patients participating in an open 32-week study expressed a desire to complete treatment, i.e., for the majority of patients, these adverse events were tolerable.

The results of another placebo-controlled study conducted by F. Montorsi et al are in agreement with the above data. The 12-week study included 514 men with ED of various etiologies – 32% had organic ED, 25% psychogenic ED and 43% mixed ED. The average age of the patients was 54 years. All patients were randomized and randomly divided into 4 groups, depending on the dose of sildenafil: 25, 50, 100 mg and placebo. The effectiveness of treatment was assessed, as in the previous work, in accordance with the data of the IIEF questionnaire. It turned out that sildenafil significantly contributed to the improvement of these functions, while they were significantly better in the groups taking higher doses of the drug. Significant improvements were noted in parameters such as erectile function, orgasmic function, satisfaction with intercourse, and overall sexual satisfaction (p <0.0001). Thus, the number of patients who noted that sildenafil improves erection and the quality of their sex life was 67–86% (depending on the dose of the drug), compared with 24% who took placebo (p <0.0001). The number of successful attempts at intercourse in the sildenafil group was also significantly higher than the number of those in the placebo group (p <0.0001). Interviewing sexual partners – study participants correlated with the responses received from patients. All participants noted that the drug was well tolerated.

These data indicate that sildenafil is not only effective against various forms of ED and is well tolerated, but also remains effective for several hours after administration. This is confirmed by a group of scientists led by I. Moncada, who published the results of a study involving 40 patients with ED. Patients who took 100 mg of sildenafil, according to the conditions of the study, were to have intercourse after 1 hour, and then 12 hours after taking the drug. As a result, it turned out that 97% of men were able to successfully achieve and maintain an erection throughout the entire sexual intercourse one hour after taking Viagra®, and after 12 hours this ability remained in 74% of people, which indicates the high efficiency of the drug for half a day. Due to the good tolerability of sildenafil, 38 out of 40 people were able to complete the study.

The topic of sildenafil safety occupies a separate place in the discussion of it as the drug of choice for ED. Sildenafil (Viagra®) is a drug with a 20-year history of presence on the global market, and, perhaps, given this circumstance, there are many prejudices and doubts about its safety. The work of A. Morales et al. demonstrates good tolerability of sildenafil, and most side effects are generally mild to moderate and transient. Among more than 3,700 men with ED and long-term use of sildenafil at a dose of 25 to 100 mg, 16% reported headache, 10% – facial flushing and fever, 7% – dyspepsia, 4% – nasal congestion and 3% – visual impairment (slight and transient change in color perception or increased sensitivity to light). These adverse events mainly occurred in patients who received the highest dose of the drug – 100 mg, and were less pronounced when using 25 or 50 mg. Minor visual impairments are probably associated with combined inhibition of the phosphodiesterase type 6 enzyme in the retina. However, no chronic or serious episodes of visual impairment have been reported. It is noteworthy that visual side effects are equally pronounced and common in patients with diabetes mellitus and patients without diabetes mellitus. However, it must be emphasized that men with retinal disorders are advised to consult an ophthalmologist before prescribing sildenafil and other IFDE-5.

Adverse events associated with the vascular system (nasal congestion, headache, skin redness, and fever) are also usually mild and temporary in most men. The proportion of cases of serious cardiovascular complications (acute coronary syndrome) is approximately 4.1 per 100 people per year among patients taking sildenafil, and 5.7 per 100 men per year taking placebo. The average number of acute myocardial infarctions averaged 1.7 and 1.4 per 100 people per year taking sildenafil and placebo, respectively. It should be noted, however, that patients taking nitrates (nitroglycerin) are excluded from most clinical trials.

Previously, it was believed that sexual activity itself makes a significant contribution to the development of acute myocardial infarction in patients with a history of cardiovascular disease. However, this statement was refuted because the risk of such a heart attack was only 0.9% of the 856 men included in the study by J.E. Muller. Thus, in the general population, the risk of serious cardiovascular complications due to sexual activity is even lower (one in a million healthy men). According to the Framingham National Statistics Center for Health and Clinical Cardiology, the number of deaths among ED patients who do not take IFDE-5 is 170 per million people per week. For this reason, it is clear that sildenafil is safe for most men, contrary to common misconceptions. However, before prescribing sildenafil, a thorough examination of the cardiovascular system and an assessment of the risk associated with cardiovascular disease is necessary. At the request of the medical community, the American Health Association has developed clinical guidelines for the use of sildenafil. This guideline instructs patients with cardiovascular disease to perform a treadmill test before prescribing sildenafil, as well as monitoring blood pressure during the first time the drug is taken.

Sildenafil is well absorbed in the intestine and reaches its maximum concentration in the period from 30 to 120 minutes (on average 60 minutes) after administration. The drug is eliminated mainly through the liver, the half-life from the body is on average 4 hours. The initial recommended dose of the drug is 50 mg, it must be taken about 1 hour before the expected sexual intercourse. To improve the desired effect or reduce the number of adverse events, the dose may be increased to 100 mg or decreased to 25 mg, respectively. Given this circumstance, the manufacturer of sildenafil (Viagra), Pfizer®, produces the drug in dosages of 25, 50 and 100 mg, and the number of tablets in a package varies from 1 to 8, which can be convenient from a practical and economic point of view. It should also be noted that sildenafil (Viagra®) can be combined with alcohol intake, however, the manufacturer recommends avoiding high doses of alcohol to achieve the maximum possible positive effect of the drug.

Currently, the issue of restoring erection in patients who underwent radical prostatectomy (RP) for prostate cancer is highly relevant. It is necessary to note the high value of drug therapy in this group of patients due to the fact that with the invention of drugs of the IFDE-5 group, they have a chance to maintain a sufficient postoperative quality of life. This statement is true despite the fact that patients with RP and those taking IDE-5 have equally modest results in the treatment of ED. The fact is that for many years before the introduction of sildenafil (Viagra), the only way out for such patients was surgical treatment, which, in addition to the high cost, is associated with a considerable number of complications, both medical and technical. This is why IFDE-5 drugs are considered the treatment of choice for ED in men after nerve-sparing RPE (NS-RPE), and it is only if they are not effective enough to resort to other treatments. Thanks to a number of clinical studies, it was possible to determine the main parameters influencing the success of therapeutic measures in patients with ED that developed as a result of NS-RPE – these are, first of all, the age and the quality of nerve-saving performed during the operation.

The analysis of works by F. Montorsi et al. between 1998 and 2004, demonstrated a higher efficacy of sildenafil in patients after NS-RP than in patients after RP without nerve sparing. The authors found with high statistical reliability that in the former, sildenafil was effective in 35–75% of cases, while in the latter, in 0–15% of cases (OR = 12.1; 95% CI 5.5–26.6). Moreover, in order to maintain an erection in the postoperative period, it does not matter whether the patient has performed a bilateral or unilateral nerve-saving technique. The authors noted that with the unilateral technique, the effectiveness of sildenafil (Viagra) was in different studies from 10 to 80%, while with the bilateral technique it was from 46 to 72% (OR = 2.21; 95% CI 0.75-6.54) … Researchers concluded that sildenafil promoted the achievement and maintenance of effective erections in about 1/3 of patients with RP. However, for this it is sufficient to have at least one preserved nerve bundle. The doctor needs to motivate the patient and explain to him the importance of being prepared for a possible long-term rehabilitation of erectile function by titrating the dose of sildenafil up to 100 mg.

Another important work, from our point of view, is a study conducted in the United States in 2004. Scientists confirm the concept of early use of sildenafil in the postoperative period. It is believed that this approach is valid for the prevention of cavernous fibrosis, which usually accompanies patients with RP, and, therefore, worsens the prognosis for the rehabilitation of erectile function. The study included 40 patients who received 50 mg (first group) or 100 mg (second group) sildenafil on the day of removal of the urethral catheter after RP. Before the operation, all patients underwent a biopsy of the corpora cavernosa, after 6 months. the procedure was repeated after the initiation of sildenafil. In the 100 mg group, a significant increase in the content of smooth muscle fibers of the cavernous tissue was noted. In patients who received 50 mg of the drug, the difference in the number of smooth muscle fibers before and after the operation was not found, i.e., the state of the cavernous tissue after the treatment remained unchanged and did not develop cavernous fibrosis, and even improved at a dose of 100 mg. Thus, the administration of sildenafil in the early postoperative period not only promotes clinical recovery of erection after RP, but also prevents cavernous fibrosis, in other words, ensures the invariability of the penile tissue responsible for erectile function.

A double-blind, randomized, placebo-controlled study conducted in 2008 included patients who underwent bilateral nerve-sparing RP and had normal erections before surgery. After 4 weeks. after NS-RPE, the patients were randomly divided into 3 groups, depending on the dose of sildenafil taken: 50 mg, 100 mg and placebo. The drug was suggested to be taken once a week for 36 weeks, followed by an 8-week “clean” period without therapy aimed at restoring an erection. As a result, it turned out that a total of 27% of patients from both groups noted the appearance of spontaneous erections, whereas in the placebo group, such erections occurred only in 4% of participants (p = 0.0156). Thus, the authors of the work conclude that long-term routine use of sildenafil in patients with bilateral NS-RPE promotes the restoration of spontaneous erections in the postoperative period.

Another study by D.J. In contrast, Kim et al., And published in 2016, found no benefit of routine long-term use of sildenafil versus on-demand drug use in patients with ED after NS-RP.

It should be noted that sildenafil is also effective in a difficult category of patients with neurogenic ED. This is supported by a number of studies. So, in the work of D. Ohl presented data from a large-scale placebo-controlled study involving 248 men with spinal trauma and ED. The study included patients with both incomplete and complete spinal cord injury, diagnosed at least 6 months in advance. prior to inclusion in the study. The starting dose of the drug was 50 mg and then could be changed to 25 or 100 mg. The duration of the drug was 6 weeks, followed by a 2-week “clean” period, after which the patients resumed the 6-week drug or placebo. At the end of the work, the authors noted a statistically significant improvement in all parameters of sexual life, according to the IIEF questionnaire, in patients taking sildenafil, in contrast to those taking placebo, including patients with complete spinal cord injury (p <0.01). The number of successful intercourses that occurred 1 hour after taking sildenafil was 53%, while after taking placebo – only 12% (p <0.001). 96% of patients preferred treatment with sildenafil, expressing a desire to continue treatment after the end of the study, and only 4% favored placebo (p <0.001).

Another important point of application of sildenafil (Viagra) is premature ejaculation. The data available today indicate the wide involvement of biological and psychogenic factors (anxiety, increased excitability of the penis, dysfunction of 5-HT serotonin receptors) in the etiology of the disease. Premature ejaculation almost always negatively affects the quality of your sex life, lowers self-confidence and impairs the relationship with your partner, and can also cause mental disorders, anxiety, false shame and depression. One of the few effective treatments for premature ejaculation today are serotonin reuptake inhibitors. However, in order to achieve maximum satisfaction from sexual activity, an active search for other methods of treatment is currently underway. Thus, the EAU 2017 recommendations suggest using IFDE-5 both in combination with antidepressants and as monotherapy. It should be noted that, as with ED and with premature ejaculation, sildenafil is the drug with the greatest amount of clinical data in comparison with other drugs of the same group. For example, a study conducted by A. Salonia et al. Is devoted to comparing the combined use of sildenafil + paroxetine and monotherapy with paroxetine. The study included 80 people who were divided into 2 groups. The first group consisted of 40 people who took paroxetine 10 mg routinely for 21 days, and then 20 mg paroxetine on demand 3-4 hours before the expected sexual intercourse for 6 months. In the second group, 40 patients also received routinely 10 mg of paroxetine at the beginning of treatment, and then, on demand, 20 mg of paroxetine and 50 mg of sildenafil for six months. As a result, it turned out that the patients of the first group noted an increase in the intravaginal latent time of ejaculation from 0.33 ± 0.04 min to 4.2 ± 0.03 min (p <0.01), while the patients of the second group showed an increase in this indicator. from 0.35 ± 0.03 min to 5.3 ± 0.02 min (p <0.01). When comparing the final results in both groups, it turned out that the lengthening of the intravaginal latent time of ejaculation in patients taking paroxetine and sildenafil was statistically significantly higher than in those taking only monotherapy (p <0.05). According to the IIEF scale, the average satisfaction with intercourse in patients of the first group increased from 9 to 11 points, but not statistically significant. In patients of the second group, before and after treatment, it was 9 and 14 points, respectively, the difference is statistically significant (p <0.05). Patients of the second group also noted a greater number of intercourse per week compared to the participants in the first group. Both treatments have proven to be relatively safe. All side effects were mild to moderate and temporary. Thus, the combination therapy with paroxetine and sildenafil is able to improve the results of treatment of patients with premature ejaculation, without leading to a deterioration in the tolerability of such therapy, and is superior in effectiveness to monotherapy with a serotonin reuptake inhibitor.

In conclusion, it should be noted that sildenafil (Viagra®) is a cost-effective drug compared to other treatments. This is evidenced by data from a systematic review of the literature published in 2013 by A.L. Martin et al .. In their work, the researchers carried out a systematic assessment of studies published in the MEDLINE and EMBASE databases in English between 2001 and 2011. The authors assessed the following parameters: cost of a treatment, value for money, cost of treating a disease, the cost of treating complications associated with the disease and treatment loss of work, the patient’s willingness to pay for treatment and purchase of drugs, etc. It turned out that sildenafil (Viagra®) in total has the most favorable cost compared to other IFDE-5 (tadalafil, vardenafil, avanafil) and is preferred by patients. The authors of the study found that among the groups of patients with ED due to diabetes mellitus, arterial hypertension and spinal trauma, sildenafil is considered the most economically viable compared to other treatments.

Conclusion

Thus, evaluating the literature data, we can conclude that sildenafil (Viagra®) is a highly effective and safe drug for patients with various types of ED and various concomitant diseases (diabetes mellitus, cardiovascular diseases, multiple sclerosis, spinal trauma) and after RP.  20 years after the advent of sildenafil (Viagra®), it remains the method of choice in the treatment of erectile dysfunction, preserves and restores the quality of life for men.

Urostomy Association of Great Britain and Ireland

The Association was formed in 1971 as the Urinary Conduit Association to help people who are about to undergo or have undergone surgery resulting in diversion of the urinary stream. In 1984 the name was changed to the Urostomy Association of Great Britain & Ireland.

The Aims of the Urostomy Association:

• To assist those who are about to undergo or who have undergone surgery which results in a urinary diversion.
• To assist carers in the rehabilitation of the ostomate.
• To improve the quality of life of urostomates and those who care for them.
• To undertake such research as the membership feels is necessary to enhance the life of members.