Certain aspects of the effectiveness and safety of using sildenafil citrate in urological practice
The history of the use of phosphodiesterase-5 inhibitors in the pharmacotherapy of erectile dysfunction (EG) began on March 27, 1998, after the FDA approved sildenafil citrate for clinical usе.
This drug made a real revolution in the treatment of erectile dysfunction, which previously consisted either in the appointment of ineffective aphrodisiacs, or in the use of unsafe intracavernous injections, or in the operation of phallo- endop rotosis.
Sildenafil was developed as a selective inhibitor of the activity of the enzyme phosphodiesterase-5 (PDE5), which inactivates cyclic guanosine monophosphate (cGMP).
Initially it was assumed that inhibitors of this enzyme isoform can have a positive effect in coronary heart disease, mediating relaxation of vascular smooth muscle, which was observed in the experiment. However, this drug was ineffective from these positions already in clinical trials of phase I.
However, some male patients receiving it noted an increase in the frequency of erections and an improvement in their quality. The drug was studied in this direction, the data were confirmed and sildenafil received medical use.
Sildenafil provides an increase in cGMP concentration in the smooth muscle cells of the cavernous body of the penis, which, in turn, leads to an increase in the level of nitric oxide II (NO) in these cells and, consequently, to the relaxation of these cells.
According to the results of a double-blind, placebo-controlled study of the duration of action of sildenafil , the frequency of a positive response 12 hours after taking the drug was 45%, despite the fact that the half-life (T 1/2) of sildenafil is 3-5 h, and its metabolite about 4 hours. This is because the half-life does not necessarily directly correlate with the duration of action.
EFFICIENCY OF SILDENAFIL IN SEPARATE GROUPS OF PATIENTS
The use of sildenafil in patients with chronic renal failure
Sildenafil has shown high efficacy in patients with erectile dysfunction on chronic hemodialysis. A randomized , double-blind , placebo-controlled study showed that in this group of patients, sildenafil significantly increased the number of points on the IIEF-5 scale .
Many practicing nephrologists consider sildenafil to be the drug of first choice in the treatment of ED in patients with chronic renal failure. Several studies have established the effectiveness and good tolerability of the drug in this group of patients.
Sildenafil (50 mg for 3 weeks) caused an increase in satisfaction with sexual function and its improvement by 60% in 9 men with ED treated with dialysis treatment.
A significant increase in the incidence of sexual intercourse and persistent erection was also observed in 14 men on dialysis, who received sildenafil for at least 4 weeks.
Although the clearance of sildenafil is reduced, and the maximum plasma concentration in patients with severe renal failure ( creatinine clearance less than 30 ml / min), the results of the study in men with end-stage renal failure treated with dialysis indicate that the drug is not removed with hemodialysis (less than 1% of the dose). The tolerability of sildenafil in this group of patients was generally good. Only mild to moderate adverse events were reported.
Sildenafil did not increase the risk of hypotension (a decrease in systolic blood pressure by more than 40 mmHg, systolic blood pressure <100 mmHg or diastolic blood pressure <40 mmHg) during dialysis. The number of such episodes did not change when taking sildenafil 2 hours before or after dialysis.
Application of sildenafil after radical prostatectomy
The most effective treatment for localized prostate cancer is radical prostatectomy . Along with urinary incontinence, the most common complication of this intervention is erectile dysfunction. The majority (82.3%) of patients after radical prostatectomy have erectile dysfunction of varying severity. The most significant predictors of recovery of erectile function after radical prostatectomy is the bilateral preservation of the neurovascular bundles and the absence of erectile disorders prior to surgical treatment .
It’s no secret that many urologists the only effective treatment for erectile dysfunction after radical prostatectomy is considered falloendoprotezirovanie. However, in our opinion, this approach is too aggressive.
A systematic analysis of studies on the treatment of postoperative erectile dysfunction using sildenafil citrate, showed the effectiveness of sildenafil in the range of 14% -53%.
In this case, the criterion of effectiveness was considered not just to improve erectile function, but to achieve the degree of erection that is sufficient for successful sexual intercourse.
The combined score for a positive response was 35% . In addition, there is strong evidence of a lower efficacy of sildenafil with the classical method of operation.
In the postoperative period for patients suffering from erectile dysfunction, the first-line drugs are modern type 5 phosphodiesterase inhibitors (including sildenafil citrate), and the most expedient period of their use is in the early stages from 1 to 12 months after surgery.
SELECTED SAFETY ISSUES OF CLEDICAL PRACTICE FOR SILDENAFIL
The effect of sildenafil on spermatogenesis
Estimated number of patients with erectile dysfunction has reached 400 million people. It is known that only 25.4% of patients with erectile dysfunction receive any treatment. Of these, in 75.2% of cases phosphodiesterase type 5 inhibitors are prescribed , 30.6% of patients receive androgen replacement therapy, and 2% use prostaglandin therapy .
Effect of iFDE-5 on sperm parameters as in vivo and in vitro has been of interest to scientists eschѐ in the early 90-ies of XX century. The stimulating effect of iFDE-5 on sperm motility was widely discussed, which could be due to the relationship between the intracellular level of cytosolicnucleotides and the ability of sperm cells to move.
Mostafa T C. et al . in their work demonstrated the stimulating effect of sildenafil on sperm motility, depending on the concentration of the drug.
Lefievre L C. et al . also investigated the effect of sildenafil on sperm function. The authors showed that this drug stimulates sperm motility.
Considering the proven high level of safety and considerable experience already available in using these drugs, a large number of studies have begun to be carried out in vivo on volunteers.
In 2000, Aversa A. et al . published a paper that brought the results of double-blind, placebo-controlled , cross-sectional studies. The work involved 20 men who received sildenafil or placebo. During the study, the authors did not find any significant differences between placebo and sildenafilon the effect on the average indicators of the number of spermatozoa, their mobility and the percentage of pathological spermatozoa between the two groups.
In the 2004 open pilot studies, Jannini EA. et al . studied the effect of sildenafil at a dosage of 50 mg. A group of sexually healthy men involved in the artificial insemination program took part in the work. The authors did not see the effect of sildenafil on sperm motility, their concentration or their total number in the ejaculate .
Scientists have shown no change in the nonlinear progressive movement of spermatozoa, however, the linear progressive movement of spermatozoids has significantly increased after taking sildenafil . The authors noticed a positive effect of sildenafil on sperm count and their mobility in cervical mucus. In this paper, recommendations were made to use sildenafil before the delivery of sperm. The authors suggested that the use of sildenafil plays a role in reducing the stress associated with the necessary ejaculation, to increase sexual satisfaction and thus further increase the number of sperm of good quality in ejaculate.
The effect of sildenafil on sperm quality and male genital glands was the aim of a study conducted by Kanakas N. et al.
Three sperm samples were collected from each infertile male with oligozoospermia before and after treatment with sildenafil . The authors estimated the total number of spermatozoa, the percentage ratio of motile spermatozoa, and the number of spermatozoa with normal morphology in all samples. Scientists have found that the average value of the total number of sperm and the percentage of motile sperm is increased in sperm samples obtained after taking sildenafil , compared with samples where sildenafil was not used.
The authors also concluded that after the administration of sildenafil, due to increased sexual stimulation, the secretory function of the prostate gland increases, which in turn leads to an increase in sperm motility.
This conclusion also echoes the research conducted by Sofikitis N. et al ., in which it was demonstrated that dysfunction of the prostate gland due to an infectious lesion is masculine potential for fertilization.
The research institute of urology of the Ministry of Health of the Russian Federation carried out a study of the effect of PDE-5 inhibitors on spermatogenesis. In the experimental part of the study in In vitro , a sharp increase in total motility of spermatozoa (A + B) was shown with exposure to sildenafil at a concentration of 25 ng / ml (p <0.001) and a tendency to suppression of total motility (A + B) at a concentration of 250 ng / ml (p = 0.09) . This may indicate the presence of a stimulating effect on spermatogenesis and the maturation of spermatozoa when using the forces sildenafil in a low dosage.
Analysis of histological data obtained in the rat, carried out in this work has shown that sildenafil has no adverse effect on the roll stands ki seminiferous epithelium.
The safety of using sildenafil in patients with concomitant cardiovascular diseases
The previous section dealt with patients of middle and young age. But most of the men taking sildenafil are men of mature and old age, and for them the safety issues of the cardiovascular system are extremely important.
Moreover, some studies show that sildenafil has beneficial pleiotropic effects in various diseases, including ischemic heart disease, arterial hypertension, heart failure, and diabetes mellitus.
Sildenafil relaxes the smooth muscles of the blood vessels, which leads to a slight decrease in blood pressure, which, however, is not enough to stimulate a reflex increase in heart rate.
This reduction in blood pressure is the same for healthy men and men with coronary heart disease (CHD), or taking antihypertensive drugs. Sildenafil does not affect the strength of the heartbeat, and the condition of the heart muscle remains unchanged. Sildenafil slightly dilates the coronary arteries without increasing the risk of developing ventricular arrhythmias.
During exercise and recovery, sildenafil does not cause clinically significant changes in hemodynamics in men with coronary heart disease, and does not adversely affect oxygen consumption by cardiomyocytes, the degree of ischemia, or exercise tolerance.
Clinical trial data from more than 13,000 patients, 7 years of international post-marketing data and observational studies involving more than 28,000 men in the UK and 3,813 men in the European Union show that there are no cardiovascular complications, in cases where Sildenafil is used in accordance with the instructions for use .
Sildenafil also does not increase the risk of serious cardiovascular events, such as myocardial infarction or sudden cardiac death. However, since the safety of sildenafil has not been established in patients with recent myocardial infarction, arterial hypotension or uncontrolled arterial hypertension, the urologist/andrologist should consult with a cardiologist before prescribing sildenafil to these patients.
Among men with erectile dysfunction without cardiovascular diseases who received sildenafil, the profile of adverse events is generally the same as that of men with concomitant cardiovascular diseases, and those who received antihypertensive therapy (regardless of dosage or class of the drug).
In a controlled study of the interaction of sildenafil and amlodipine , the average additional decrease in blood pressure at rest was 8 mmHg . for systolic blood pressure and 7 mm Hg . – for diastolic.
Sildenafil should be used with caution in patients taking α- blockers because their co-administration can lead to symptomatic and hypotension in some people. Furthermore, due to the lack of information about the interaction with the combined α / β -b locators such as labetalol and carvedilol , to the destination sildenafil such patients must also be treated with caution.
Sildenafil enhances the hypotensive effect of nitrates and its administration to patients who use organic nitrates in any form, constantly or intermittently, is contraindicated. When prescribing sildenafil, doctors should carefully consider the feasibility of sexual activity in patients with concomitant cardiovascular diseases.
Because in this case, sexual activity can adversely affect the state of the cardiovascular system. The management of this group of patients is described in detail in the recommendations of the Third Princeton Consensus.